Method of producing optically active chromene oxide compound

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing an optically active chromene oxide compound of formula or formula where R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and A are as described in the claim, and the absolute configuration of carbon atoms, denoted by *, denotes (R) or (S), which includes asymmetric epoxidation of a chromene compound of formula or formula with an oxidant in a solvent using optically active titanium complexes of formula formula formula and formula where R¹, R², R³ and R⁴ are defined in the claim, as a catalyst for asymmetric oxidation of the optically active chromene compound with high enantioselectivity and high chemical output.

EFFECT: efficient method of producing an optically active chromene oxide compound, which is an important intermediate compound used to produce a benzopyran compound, which is effective in treating arrhythmia.

18 cl, 26 ex

The technical field to which the invention relates

The present invention relates to an efficient method for obtaining optically active compound oxide chromene, which is an important intermediate compound used to obtain the compounds of benzopyrene, which is effective in the treatment of arrhythmia.

The level of technology

Previously described compounds benzopyrene, which can be used as a drug against arrhythmia, as well as the way they are received. For example, the connection of benzopyran obtained by asymmetric epoxidation of compounds of chromene using optically active manganese complex, resulting in optically active compound oxide chromene, and then unlock the ring of the epoxy with amine compounds (see patent document 1).

Has been previously described method for obtaining optically active compound oxide chromene by asymmetric epoxidation of compounds of chromene using optically active manganese complex (see patent document 2, patent document 3, patent document 4, patent document 5 and patent document 6). In the above-mentioned patent documents described examples of obtaining optically active compounds of oxide of chromene using) the ski active manganese complexes as catalysts, as well as using iodosobenzene, sodium hypochlorite or 30% aqueous hydrogen peroxide solution as soogilauaga reagent.

For the asymmetric oxidation reactions conducted using optical active complex of manganese, in addition to soogilauaga reagent requires the presence of additives, namely axial ligand such as 4-phenylpyridine-N-oxide, and it is therefore desirable to develop another method for obtaining optically active oxide chromene without using axial donor ligand.

In contrast, it was reported that using even from 0.01 to 0.2 mol% of asymmetric optical active manganese complex can be obtained optically active compound oxide chromene with high chemical and optical yield (see patent document 7). However, in this patent document describes only one example of iodosobenzene used as soogilauaga reagent. Therefore, it is desirable to develop a more profitable and more efficient way to obtain such a connection.

It was also reported that with the use of a complex of optically active titanium di-µ-Exotica-sallen" can be carried out highly enantioselective asymmetric epoxidation reaction of various simple olefins do not contain heteroatom(s). However, in this rebotini given any examples of olefinic compounds containing heteroatom(s), and connections chromene (non-patent document 8).

[Patent document 1] Publication of the patent application of Japan No. of JP-A-2001-151767.

[Patent document 2] the Publication of the patent application of Japan No. of JP-A-05-301878.

[Patent document 3] the Publication of the patent application of Japan No. of JP-A-07-285983.

[Patent document 4] the Publication of the patent application of Japan No. of JP-A-08-245668.

[Patent document 5] WO 2005/A.

[Patent document 6] WO 2005/A.

[Patent document 7] the Publication of the patent application of Japan No. of JP-A-11-335384.

[Non-patent document 8] K. Matsumoto, Y. Sawada, B. Saito, K. Sakai and T. Katsuki, Angew. Chem. Int. Ed. (2005), 44, 4935-4939.

Description of the invention

[Problem which can be solved using the present invention]

The present invention relates to a method for obtaining optically active compound oxide chromene, which is an important intermediate compound used to obtain the compounds of benzopyrene, effective in the treatment of arrhythmia.

[Means for solving this problem]

As a result of intensive studies on the development of a method for obtaining optically active compound oxide chromene, which is an important intermediate compound used to obtain the compounds of benzopyrene, effective for the treatment of arrhythmia, the authors of this image is etenia was detected, that optically active compound oxide chromene can be obtained with high enantioselectivity and high chemical yield using optical active complex of titanium as a catalyst, and based on this we developed the present invention.

In accordance with the first aspect, the present invention relates to a method for obtaining optically active compound oxide chromene represented by the formula (14), formula (15), formula (16) or formula (17):

(where R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰And, W, X, Y, and Z are as described below, and the absolute configuration of the carbon atoms indicated by *, mean (R) or (S)), where the method includes:

asymmetric epoxidation of compounds of chromene represented by the formula (10), formula (11), formula (12) or formula (13)with an oxidant in a solvent;

(where each of R⁵, R⁶, R⁷and R⁸in the formula (10) independently represents a hydrogen atom, a cyano, a nitro-group, a halogen atom, a C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylsulphonyl what monography or _1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkoxygroup (alkoxygroup may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkylcarboxylic (alkylcarboxylic may be optionally substituted by a halogen atom, a C_6-10aryl group (C_6-10the aryl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkyl group or a C_1-4alkoxygroup))_1-4alkylsulphonyl(N-C_1-4alkyl)amino group (alkylsulphonyl(N-C_1-4alkyl)amino group may be optionally substituted by halogen atom), With_1-4alkoxycarbonyl group (alkoxycarbonyl group may be optionally substituted by halogen atom), With_6-10arylcarboxylic (arylcarboxylic may be substituted atom g is lagena, With_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group)_6-10arylcarbamoyl(N-C_1-4alkyl)amino group (arylcarbamoyl(N-alkyl)amino group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), benicarbenicar, formyl group, carbamoyl group_1-4alkylsulfonyl group_6-10arylsulfonyl group (alkylsulfonyl group and arylsulfonyl group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), sulfamoyl group_1-4alkylsulfonamides group_6-10arylsulfonamides group (alkylsulfonamides group and arylsulfonamides group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_6-10arylsulfonyl)kidney group (arylsulfonyl bis(arylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano what do nitrogroup) or (N,N'-(C _1-4alkylsulfonyl)(C_6-10arylsulfonyl))kidney group (alkylsulfonyl and arylsulfonyl (N,N'-(alkylsulfonyl)(arylsulfonyl))kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group);

each of R⁹and R¹⁰in the formula (10) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom));

each of R⁹and R¹⁰in the formula (11) and formula (12) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom is) or hydroxy-group) or (C _6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom));

incomplete cyclic structure And the formula (11) and formula (12) represents nepolnuju structure, 5-, 6 - or 7-membered ring, to form a ring condensed with a part of the benzene ring (each of 5-, 6 - or 7-membered ring may be optionally substituted hR¹¹(R¹¹represents a halogen atom, a hydroxy-group, With_1-6alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, an amino group, a nitrogroup,_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-6alkoxygroup (alkoxygroup may be the long is correctly substituted by halogen atom, hydroxy-group, a cyano, an amino group, a nitrogroup,_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)), a nitrogroup, cyano, formyl group, formamide group, carbamoyl group, alphagroup, Sultanoglu, sulfamoyl group, sulfonyloxy group, amino group, carboxyl group, With_1-6alkylamino, di-C_1-6alkylamino,_1-6alkylcarboxylic,_1-6alkylsulfonamides group_6-14arylsulfonamides group_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group_6-14arylsulfonyl group or_6-14arylcarbamoyl group (alkylamino, dialkylamino, alkylcarboxylic, alkylsulfonamides group, arylsulfonate group, alkylaminocarbonyl group, dialkylaminoalkyl group, alkylcarboxylic group, alkoxycarbonyl group, alkylsulfonyl group, arylsulfonyl group and alcabala group can be optionally substituted by a halogen atom); where h denotes an integer of 1-6, and if h is an integer of 2-6, R¹¹may be the same or different); 1-3 atoms of oxygen, nitrogen or sulfur may be present alone or in combination with other atoms on the ring; the number of unsaturated bonds in the ring containing the unsaturated(s) relationship(s) and condensed with a benzene ring, a is 1, 2 or 3, and the atom(s) of the carbon component(s) this ring may be carbonyl or thiocarbonyl);

X in the formula (13) represents NR²⁰(R²⁰represents a hydrogen atom or a C_1-4alkyl group);

Y in the formula (13) represents the relationship, SO or SO₂;

Z in the formula (13) represents a C_1-4alkyl group (the alkyl group may be optionally substituted by 1-5 halogen atoms, or phenyl group (the phenyl group may be optionally substituted C_1-4alkyl group)) or phenyl group (the phenyl group may be optionally substituted C_1-4alkyl group);

W in the formula (13) represents a hydrogen atom, a hydroxy-group, With_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), halogen atom, With_1-4alkyl group or a C_1-6alkylsulfonamides group (an alkyl group and alkylsulfonamides group can be optionally replaced is received by a halogen atom); and

each of R⁹and R¹⁰in the formula (13) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom)));

where the above epoxidation is performed with the use of any optically active titanium complexes represented by formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4'), as a catalyst,

where R¹in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-22aryl is the group (the aryl group may be optionally substituted, With_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-7alkoxygroup or benzyloxypropionic, and is optically active or optically inactive);

R²represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-18aryl group;

R³represents a C_1-4alkyl group, a C_6-18aryl group or a bivalent_3-5group, where two of R³taken together form a ring;

each of R⁴independently represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, the nitro-group or cyano;

M represents TiJ¹J²(TiJ¹J², Ti represents a titanium atom, and each of the J¹and J²independently represents a halogen atom or With_1-4the alkoxide, or J¹and J²taken together form an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5)

(where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the following formula (6), corresponding to the formula (1); group O-E-O is represented below what armoloy (6'), corresponding to the formula (1'); group O-E-O is represented by the following formula (7), corresponding to the formula (2); group O-E-O is represented by the following formula (7')corresponding to the formula (2'); group O-E-O is represented by the following formula (8), corresponding to the formula (3); group O-E-O is represented by the following formula (8')corresponding to the formula (3'); group O-E-O is represented by the following formula (9), corresponding to the formula (4); and group O-E-O is represented by the following formula (9')corresponding to the formula (4');

b is an integer of 1-10, and R¹, R², R³and R⁴are as defined above)).

In accordance with the second aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the first aspect of the invention, in which the connection chromene represented by the formula (10), is subjected to asymmetric epoxidation reaction in a solvent with an oxidizing agent with an optically active complex of titanium represented by the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) or formula (4'), as a catalyst,

where each of R⁵and R⁶in the formula (10) independently represents a hydrogen atom, a cyano, a nitro-group, and the Ohm halogen, With_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkoxygroup (alkoxygroup may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkylcarboxylic (alkylcarboxylic may be optionally substituted by halogen atom), With_1-4alkylsulphonyl(N-C_1-4alkyl)amino group (alkylsulphonyl(N-alkyl)amino group may be optionally substituted by halogen atom), With_6-10arylcarbamoyl(N-C_1-4alkyl)amino group (arylcarbamoyl(N-alkyl)amino group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, what ionography or nitrogroup), karbamoilnuyu group, bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_6-10arylsulfonyl)kidney group (arylsulfonyl bis(arylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group) or (N,N'-(C_1-4alkylsulfonyl)(C_6-10arylsulfonyl))kidney group (alkylsulfonyl and arylsulfonyl (N,N'-(alkylsulfonyl)(arylsulfonyl))kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group);

R⁷in the formula (10) represents a hydrogen atom, a cyano, a nitro-group, bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_6-10arylsulfonyl)kidney group (arylsulfonyl bis(arylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group) or (N,N'-(C_1-4alkylsulfonyl)(C_6-10arylsulfonyl))kidney group (alkylsulfonyl and alsultan (N,N'-(alkylsulfonyl)(arylsulfonyl))kidney group may be substituted by halogen atom, With_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group);

R⁸in the formula (10) represents a hydrogen atom, a nitro-group or_1-4alkyl group (the alkyl group may be optionally substituted by a halogen atom); and

R⁹and R¹⁰in the formula (10) represents a_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom).

In accordance with a third aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the second aspect of the invention, where each of R⁵and R⁶in the formula (10) independently represents a hydrogen atom, a nitro-group, a fluorine atom, a methoxy group, medicalbilling or methylcarbamyl(N-ethyl)amino group; R⁷in the formula (10) represents a hydrogen atom, a nitro-group or bis(C_1-4alkylsulfonyl)kidney group; R⁸in the formula (10) represents a hydrogen atom, a nitro-group or triptorelin group; and R⁹and R¹⁰in the formula (10) represents a methyl group.

In accordance with the fourth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the first aspect of the invention, where the connection chromene represented by the formula (11) is (12), which incomplete cyclic structure And represented by the formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), formula (s), formula (t), formula (u), formula (v), formula (w), formula (x), formula (y), formula (z), formula (AA), formula (AB), formula (AC), formula (ad), formula (AE), formula (AF), formula (hell) and formula (h), is subjected to the asymmetric epoxydecane in solvent and oxidant using any of the optically active titanium complexes represented by formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) or formula (4')as catalyst

(where each of R¹²and R¹³in the formula (a), formula (b), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), the formula (p), formula (q), formula (v), formula (w), formula (x), formula (AB), formula (AE), formula (AF) and the formula (ad) independently represents a hydrogen atom, a C_1-6alkyl group (alcalina group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optional C is mesena a halogen atom), amino group, a hydroxy-group, With_6-14aryl group or_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted qR¹⁸(R¹⁸has the same meanings as R¹¹; q is an integer of 1-3, and all R¹⁸may be the same or different when q is 2 or 3)),_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic,_1-6alkylcarboxylic group (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), With_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group (cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group can be optionally substituted by halogen atom), a carboxyl group, With_6-14arylcarbamoyl group (arylcarbamoyl group may be optionally substituted by a halogen atom) or (C_2-9heteroarylboronic group)_6-14aryl group_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted qR¹⁸(R¹⁸has the same meanings as R¹¹; q is an integer of 1-3, and all R¹⁸ may be the same or different, if q is 2 or 3)),_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_3-8cycloalkylcarbonyl group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group_6-14arylsulfonyl group_2-9heteroarylboronic group (each of arylsulfonyl and heteroarylboronic groups may be optionally substituted qR¹⁸(R¹⁸has the same meanings as R¹¹; q is an integer of 1-3, and all R¹⁸may be the same or different when q is 2 or 3)), carboxyl group, With_6-14arylcarbamoyl group or_2-9heteroarylboronic group (each of arylcarboxylic and heteroarylboronic groups may be optionally substituted qR¹⁸(R¹⁸has the same meanings as R¹¹; q is an integer of 1-3, and all R¹⁸may be the same or different when q is 2 or 3));

each of R^14,R¹⁵, R¹⁶and R¹⁷in the formula (a), formula (b), formula (C), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), the formula (s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and in the form of the OLE (af) independently represents a hydrogen atom, a halogen atom, a C_1-6alkyl group (alcalina group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_6-14aryl group, With_2-9heteroaryl group (each of the aryl and heteroaryl groups can be optionally substituted and rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)), C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic, C_1-6alkylcarboxylic (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), C_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group (cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group can be optionally substituted by halogen atom), a carboxyl group, a C_6-14arylcarbamoyl group (arylcarbamoyl group may be optionally substituted by a halogen atom) or (C_2-9heteroarylboronic group)_3-8cycloalkyl group (cycle the alkyl group may be optionally substituted by a halogen atom, With_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group)_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), a carboxyl group, an amino group, a hydroxy-group, With_6-14aryl group or_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q))),_1-6dialkoxy (Tolkacheva may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), a carboxyl group, a hydroxy-group, With_6-14aryl group or_2-9heteroarenes group (each of the aryl and heteroaryl groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q))), a hydroxy-group, With_6-14aryl group_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same mn of the treatment, as q)),_1-6alkylcarboxylic, a nitrogroup, cyano, formyl group, formamide group, amino group, alphagroup,_1-6alkylamino, di-C_1-6alkylamino,_6-14killingray,_2-9geteroarilsulfoksidu (each of arylamino and heteroelement may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)),_1-6alkylcarboxylic,_1-6alkylsulfonamides group, carbamoyl group_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_6-14arylcarbamoyl group_2-9heteroarylboronic group (each of arylcarboxylic and heteroarylboronic groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)),_1-6alkoxycarbonyl group, sulfamoyl group_1-6alkylsulfonyl group_6-14arylsulfonyl group_2-9heteroarylboronic group (each of arylsulfonyl and heteroarylboronic groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)), the carboxyl group is Li _2-9heterocyclyl group (heterocyclyl group may be optionally substituted by a halogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group)_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), With_6-14aryl group, With_2-9heteroaryl group (each of the aryl and heteroaryl may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)), hydroxy-group, a nitrogroup, cyano, formyl group, formamide group, amino group, With_1-6alkylaminocarbonyl, di-C_1-6alkylaminocarbonyl,_1-6alkylcarboxylic,_1-6alkylsulfonamides group, carbamoyl group_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_1-6alkoxycarbonyl group, sulfamoyl group_1-6alkylsulfonyl group, a carboxyl group or_6-14arylcarboxylic group); and

Q in the formula (C), formula (d), formula (p), formula (q), formula (v), formula (w), is ormula (ab), the formula (ac) and in the formula (ad) represents O (oxygen atom), S (sulfur atom), SO (sulfonyloxy group) or SO₂(sulfonyloxy group)).

In accordance with the fifth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to a fourth aspect of the invention, where R⁹and R¹⁰in the formula (11) or the formula (12) represent a methyl group.

In accordance with the sixth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the fourth or fifth aspects of the invention, where a in the formula (11) or the formula (12) is represented by the following formula, namely formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (AE), formula (hell) and formula (h):

(where R¹², R¹³, R¹⁴, R¹⁵and R¹⁶have the meaning as defined in the fourth aspect).

In accordance with the seventh aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the sixth aspect of the invention, where a in the formula (11) or the formula (12) has the formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (AE), fo is the mule (hell) and the formula (h); each of R¹²and R¹³in the formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (ae) and formula (ag) independently represent a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group; and each of R¹⁴, R¹⁵and R¹⁶in the formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y) and the formula (AE) independently represents a hydrogen atom, a halogen atom or With_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic,_1-6alkylcarboxylic (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), With_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group or_1-6alkoxycarbonyl group), and Q represents O (oxygen atom).

In accordance with the eighth aspect, the present and the finding relates to a method for obtaining optically active compound oxide chromene according to the seventh aspect of the invention, where As in the formula (11) or the formula (12) is represented by formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (AE), formula (hell) or formula (h); each of R¹²and R¹³in the formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (ae) and formula (ag) independently represent a hydrogen atom or methyl group, and each of R¹⁴, R¹⁵and R¹⁶in the formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y) and the formula (AE) independently represents a hydrogen atom, a halogen atom or With_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic,_1-6alkylcarboxylic (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), With_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group or_1-6alkoxycarbonyl group), and Q represents O (oxygen atom).

In accordance with the ninth aspect, the present image is eenie relates to a method for obtaining optically active compound oxide chromene according to the first aspect of the invention, in which connection chromene represented by the formula (13), is subjected to the asymmetric epoxydecane in solvent and oxidant using optically active complex of titanium represented by the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4'), as a catalyst, and R⁹and R¹⁰in the formula (13) represent a methyl group.

In accordance with the tenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the ninth aspect of the invention, in which W in the formula (13) represents a hydrogen atom, a hydroxy-group, methoxy group, chlorine atom, bromine atom, methyl group, ethyl group or methanesulfonamido group.

In accordance with the eleventh aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the ninth or tenth aspect of the invention, in which Y in the formula (13) represents the SO₂(sulfonyloxy group), and Z represents a C_1-4alkyl group.

In accordance with the twelfth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the tenth aspect of the invention, in which Y in the formula (13) represents the Wallpaper link, and Z represents a C_1-4alkyl group.

In accordance with the thirteenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the first aspect of the invention, in which R¹in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents a C_6-22aryl group (the aryl group may be optionally substituted C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-7alkoxygroup or benzyloxypropionic, and is optically active or optically inactive);

R²represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-18aryl group;

R³represents a C_1-4alkyl group, a C_6-18aryl group or a bivalent_3-5group, where two of R³taken together form a ring; and

each of R⁴independently represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, the nitro-group or cyano;

M represents TiJ¹J²where Ti represents a titanium atom, and each of the J¹and J²independently represent an atom is alogena or _1-4the alkoxide, or J¹and J²taken together form an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5)

(where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the following formula (6), corresponding to the formula (1); group O-E-O is represented by the following formula (6')corresponding to the formula (1'); group O-E-O is represented by the following formula (7), corresponding to the formula (2); group O-E-O is represented by the following formula (7')corresponding to the formula (2'); group O-E-O is represented by the following formula (8), corresponding to the formula (3); group O-E-O is represented by the following formula (8')corresponding to the formula (3'); group O-E-O is represented by the following formula (9), corresponding to the formula (4); and group O-E-O is represented by the following formula (9')corresponding to the formula (4');

b is an integer of 1-10, and R¹, R², R³and R⁴are as defined above)).

In accordance with the fourteenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the thirteenth aspect of the invention, in which R¹in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula is (4) and formula (4') represents a phenyl group (the phenyl group may be optionally substituted C _1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), benzyloxypropionic or_1-7alkoxygroup) or naftalina group (naftalina group can be optionally substituted C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-7alkoxygroup or phenyl group);

R²represents a hydrogen atom;

R³represents a bivalent_3-5group, where two of R³taken together form a ring;

R⁴represents a hydrogen atom, and

M represents TiJ¹J²where Ti represents a titanium atom, and each of the J¹and J²independently represent a halogen atom or With_1-4the alkoxide, or J¹and J²taken together form an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5)

(where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the following formula (6), corresponding to the formula (1); group O-E-O is represented by the following formula (6')corresponding to the formula (1'); group O-E-O is represented by the following formula (7), corresponding to the formula (2); group O-E-O is represented by the following formula (7')that meet the overall formula (2'); group O-E-O is represented by the following formula (8), corresponding to the formula (3); group O-E-O is represented by the following formula (8')corresponding to the formula (3'); group O-E-O is represented by the following formula (9), corresponding to the formula (4); and group O-E-O is represented by the following formula (9')corresponding to the formula (4'); b represents an integer of 1-10, and R¹, R², R³and R⁴are as defined above)).

In accordance with the fifteenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to any of 1-14 aspects of the invention, in which the amount of the optically active complex of titanium with respect to the number of connections chromene represented by the formula (10), formula (11), formula (12) or formula (13)is 0.001 to 100 mol%.

In accordance with the sixteenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to any of 1-14 aspects of the invention, in which the solvent used for the asymmetric epoxidation is a halogen solvent, an aromatic hydrocarbon solvent, ester solvent, ether solvent, nitrile solvent, an alcohol solvent, or a mixture thereof.

the accordance with the seventeenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to any of 1-14 aspects of the invention, in which the oxidizing agent used in the asymmetric epoxidation reaction is iodosobenzene, sodium hypochlorite, m-chloroperbenzoic acid, Oxon (registered trademark of E.I. du Pont de Nemours and Company), an aqueous solution of hydrogen peroxide, the product of the merger of urea-hydrogen peroxide (UHP), oxaziridine, N-methylmorpholine (NMO), tert-butylhydroperoxide (TBHP), cumene hydroperoxide (CHP), or a mixture thereof.

In accordance with the eighteenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the seventeenth aspect of the invention, in which the oxidizing agent used for the asymmetric epoxidation reaction is an aqueous solution of hydrogen peroxide, the product of the merger of urea-hydrogen peroxide (UHP), or a mixture thereof.

In accordance with the nineteenth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the eighteenth aspect of the invention, in which the oxidizing agent used for the asymmetric epoxidation reaction is an aqueous solution of hydrogen peroxide at a concentration of 1-100 wt.%

In accordance with the laws the AI with the twentieth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to any of 1-14 aspects of the invention, in which the amount of oxidant used for asymmetric epoxidation, in relation to the number of connections chromene represented by the formula (10), formula (11), formula (12) or formula (13)is 1-10 equivalents.

In accordance with a twenty-first aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the twentieth aspect of the invention, in which the method of adding the oxidizing agent used for the asymmetric epoxidation is a stepwise or continuous addition.

In accordance with a twenty-second aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the twenty-first aspect of the invention, in which the method of adding the oxidizing agent used for the asymmetric epoxidation, represents the continuous addition, the speed of which is from 0.01 to 40,000 equivalents per hour.

In accordance with the twenty-third aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to the twenty-first aspect of the image is the shadow, in which way of adding oxidizing agent used for the asymmetric epoxidation is a stepwise addition, where the number of stages is in the range of 2 to 100.

In accordance with a twenty-fourth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to any of 1-23 aspects of the invention, where the reaction temperature of the asymmetric epoxidation is from 0°C to temperature distillation of the solvent.

In accordance with its twenty-fifth aspect, the present invention relates to a method for obtaining optically active compound oxide chromene according to any of 1-24 aspects of the invention, where the pressure in the reaction system asymmetric epoxidation is from 10 kPa to 1100 kPa.

[Effects of the invention]

In accordance with the present invention can be effectively obtained optically active compound oxide chromene, which is an important intermediate compound for connection of benzopyrene, which can be used to treat arrhythmias.

The best ways of carrying out the invention

Used in this document the symbols mean: "n" ("n") is normal; ("and") - from, "Deut" secondary, "tert" - tertiary; "C" - ring; o - ortho; m - IU the and, and "p" - pair.

The present invention is described in detail below. In the present invention, the complex of titanium used for the asymmetric epoxidation reaction of compounds of chromene with oxidizer represented by the following formula, namely formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4'):

where R¹in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-22aryl group (the aryl group may be optionally substituted C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-7alkoxygroup or benzyloxypropionic) and is optically active or optically inactive;

R²represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-18aryl group;

R³represents a C_1-4alkyl group, a C_6-18aryl group or a bivalent_3-5group, where two of R³taken together form a ring;

each of R⁴independently represents an atom in which aroda, halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, the nitro-group or cyano;

M represents TiJ¹J²(TiJ¹J², Ti represents a titanium atom, and each of the J¹and J²independently represent a halogen atom or With_1-4alkoxide group, or J¹and J²taken together form an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5)

(where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the following formula (6), corresponding to the formula (1); group O-E-O is represented by the following formula (6')corresponding to the formula (1'); group O-E-O is represented by the following formula (7), corresponding to the formula (2); group O-E-O is represented by the following formula (7')corresponding to the formula (2'); group O-E-O is represented by the following formula (8), corresponding to the formula (3); group O-E-O is represented by the following formula (8')corresponding to the formula (3'); group O-E-O is represented by the following formula (9), corresponding to the formula (4); and group O-E-O is represented by the following formula (9')corresponding to the formula (4');

b is an integer of 1-10, and R^{1 , R2, R3and R4are as defined above).}

Each group is a substituent in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') described below.

R¹in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-22aryl group (the aryl group may be optionally substituted C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-7alkoxygroup or benzyloxypropionic and is optically active or optically inactive);

R¹specifically described in the above formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4').

Examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom;

examples_1-4alkyl groups are methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group;

examples_1-4alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, isopropoxide, cyclopropane, n ' bout xygraph, isobutoxide, second-butoxypropan, tert-butoxypropan and cyclobutene;

examples_6-12alloctype are fenoxaprop, 1-naphthyloxy, 2-naphthyloxy, 2-biphenyloxy, 3-biphenyloxy and 4-biphenyloxy; and

examples_6-22aryl group (the aryl group may be optionally substituted C_1-4alkyl group (alcalina group may be optionally substituted by halogen atom), With_1-7alkoxygroup or benzyloxypropionic and is optically active or optically inactive) are phenyl group, 2-methylphenylene group, 2-triftormetilfullerenov group, 4-methylphenylene group, 2-ethylenimine group, 2-pentabromodiphenyl group, 3,5-dimethylaniline group, 2-metoksifenilny group, 3-metoksifenilny group, 4-metoksifenilny group, 2-ethoxyphenyl group, 2-isopropoxyphenyl group, 2-benzyloxyphenyl group, 3,5-dimethoxyphenyl group, 1-naftalina group, 2-naftalina group, 2-biphenylene group, 3-biphenylene group, 4-biphenylene group, 2-methyl-1-naftalina group, 2-phenyl-1-naftalina group, 2-methoxy-1-naftalina group, 2-(3, 5dimethylphenyl)-1-naftalina group, 2-(4-were)-1-naftalina group, 2-(o-biphenylyl)-1-naftalina group, 2-(m-biphenylyl)-1-naftalina group and 2-(p-biphenylyl)-1-naftalin the group. The above With_6-22the aryl group may be optically active or optically inactive.

R¹in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) or the formula (4') preferably represents a hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, cyclopropane, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, cyclobutanes, fenoxaprop, 1-naphthyloxy, 2-naphthyloxy, phenyl group, 2-methylphenyl group, 2-triftormetilfullerenov group, 4-methylphenyl group, 2-ethylphenyl group, 3,5-dimethylphenyl group, 2-metoksifenilny group, 3-metoksifenilny group, 4-metoksifenilny group, 2-ethoxyphenyl group, 2-isopropoxyphenyl group, 2-benzyloxyphenyl group, 3,5-dimethoxyphenyl group, 1-naftalina group, 2-naftalina group, 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl group, 2-phenyl-1-naftalina group, 2-methoxy-1-naftalina group, 2-(m-biphenylyl)-1-naftalina group and 2-(p-biphenylyl)-1-naftalina group. Of these the volumes and groups more preferred for R¹are phenyl group, 2-methylphenylene group, 2-triftormetilfullerenov group, 2-ethylenimine group, 2-metoksifenilny group, 2-benzyloxyphenyl group, 1-naftalina group, 2-naftalina group, 2-biphenylene group, 2-phenyl-1-naftalina group, 2-methoxy-1-naftalina group, 2-(m-biphenylyl)-1-naftalina group or 2-(p-biphenylyl)-1-naftalina group (2-phenyl-1-naftalina group, 2-methoxy-1-naftalina group, 2-(m-biphenylyl)-1-naftalina group and 2-(p-biphenylyl)-1-naftalina group are optically active or optically inactive), and the most preferred for R¹are phenyl group, 2-methylphenylene group, 2-triftormetilfullerenov group, 2-metoksifenilny group, 2-benzyloxyaniline group and 2-phenyl-1-naftalina group.

R²in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-18aryl group.

R²specifically described in the above formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4').

Examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom;

examples_1-4Ala is through group are methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group;

examples_1-4alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, isopropoxide, cyclopropane, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan and cyclobutene;

examples_6-12alloctype are fenoxaprop, 1-naphthyloxy, 2-naphthyloxy, 2-biphenyloxy, 3-biphenyloxy and 4-biphenyloxy; and

examples_6-18aryl group are phenyl group, 3,5-dimethylaniline group, 4-methylphenylene group, 1-naftalina group, 2-naftalina group, 2-biphenylene group, 2-phenyl-1-naftalina group, 2-methyl-1-naftalina group, 2-(3, 5dimethylphenyl)-1-naftalina group, 2-(4-were)-1-naftalina group and 2-methoxy-1-naftalina group.

R²in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') preferably represents a hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, tert-boutelou group, a methoxy group, fenoxaprop, 1-naphthyloxy, 2-naphthyloxy, vinyloop, 3,5-dimethylphenyl group, 4-methylphenyl group, 3,5-dimethoxyphenyl group, 4-metoksifenilny group, 1-naftalina group, 2-naftalina group, 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl group and 2-methoxy-1-naftalina group. Of these atoms and groups, more preferred for R²are a hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, tert-bucilina group, methoxy group, fenoxaprop, phenyl group, 1-naftalina group, 2-naftalina group and 2-biphenylene group, and most preferred for R²is a hydrogen atom.

R³in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents a C_1-4alkyl group, a C_6-18aryl group or a bivalent_3-5group, if two R³taken together form a ring.

R³in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') is specifically described below.

Examples_1-4alkyl groups are methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group;</>

examples_6-18aryl group are phenyl group, 3,5-dimethylaniline group, 2,4,6-trimethylphenyl group, 4-methylphenylene group, 1-naftalina group, 2-biphenylene group, 2-phenyl-1-naftalina group, 2-methyl-1-naftalina group, 2-(3, 5dimethylphenyl)-1-naftalina group, 2-(4-were)-1-naftalina group and 2-methoxy-1-naftalina group; and

if two R³taken together form a ring, they represent a bivalent_3-5group, and examples of such divalent groups are trimethylene group and tetramethylene group.

R³in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') preferably represents a phenyl group, 3,5-dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-methylphenyl group and tetramethylene group formed by linking two R³and of these groups, preferred for R³is tetramethylene group formed by linking two R³each other.

R⁴in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, the nitro-group or cyano.

R⁴in the formula (1), f is rule (1'), the formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') is specifically described below.

Examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom;

examples_1-4alkyl groups are methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group; and

examples_1-4alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan and tert-butoxypropan.

R⁴in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') preferably represents a hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl and tert-butoxypropan. Of these atoms and groups, more preferred for R⁴is a hydrogen atom.

M in the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') represents TiJ¹J² (TiJ¹J², Ti represents a titanium atom, and each of the J¹and J²independently represent a halogen atom or With_1-4alkoxide group, or J¹and J²taken together form an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5)

where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the following formula (6), corresponding to the formula (1); group O-E-O is represented by the following formula (6')corresponding to the formula (1'); group O-E-O is represented by the following formula (7), corresponding to the formula (2); group O-E-O is represented by the following formula (7')corresponding to the formula (2'); a group Of-E-O is represented by the following formula (8), corresponding to the formula (3); group O-E-O is represented by the following formula (8')corresponding to the formula (3'); group O-E-O is represented by the following formula (9), corresponding to the formula (4); and group O-E-O is represented by the following formula (9')corresponding to the formula (4'); and

b is an integer of 1-10, and R¹, R², R³and R⁴are as defined above.

If J¹and J²taken together, represent the atoms is of ikorodu, the compounds of formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') are mononuclear complexes of oxititan in the form of whole molecular structures, and if J¹and J²taken together form a ring represented by the divalent group of formula (5), the compounds of formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') are multi-core complexes, namely (b+1)-nuclear complexes µ-oxathiane in the form of whole molecular structures.

In addition, if the compounds of formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4') are complexes of oxititan or (b+1)-nuclear complexes µ-oxathiane, the optically active complex of titanium can be a mixture of complexes of oxititan or (b+1)-nuclear complexes µ-oxathiane, where b is any number from 1 to 10.

Preferably, if J¹and J²taken together, represent an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5). In such cases, the optically active complex titanium is a mononuclear complex of oxititan or (b+1)-nuclear complex µ-oxathiane (where b is any integer from 1 to 10).

In addition, optically active complex is s titanium according to the invention are divided into optically active titanium complexes-sallina, represented by formula (1), formula (1'), formula (3) and formula (3'), and complexes of titanium-Solana represented by the above formula (2), formula (2'), formula (4) and formula (4'), and combinations of preferred group of substituents and structures of many molecules are described below.

Optically active titanium complexes-sallena represented by the above formula (1), formula (1'), formula (3) and formula (3'), include the J¹and J²where these J¹and J²connected together, form a ring represented by the divalent group of formula (5), preferably, b in the formula (5) was equal to 1. In this case, the compounds of formula (1), formula (1'), formula (3) and formula (3') are dual core complexes µ-oxathiane represented by the following formula (18) and formula (18'), in the form of whole molecular structures:

(where a group OF-NH-N-O is presented in the following formula (19), corresponding to the formula (1), the following formula (19')corresponding to the formula (1'), the following formula (20)corresponding to the formula (2), the following formula (20')corresponding to the formula (2'), and

(where R¹, R², R³and R⁴have the meanings given above), and this complex of formula (18') is an enantiomer of a complex of four the uly (18)).

The combination is particularly preferred group of substituents and structures of many molecules of the optically active titanium complexes-sallena described below. Particularly preferred optically active titanium complexes-sallena represented by the formula (18) and formula (18'), and the complete structure of the O-NH-N-ABOUT in the following formulas(21), (21'), (22) or (22')

are dual core complex (RSΔ,RSΔ)di-µ-oxathiane and binuclear complex (SRΔ,SRΔ)di-µ-oxathiane.

Combinations particularly preferred group of substituents for the optically active titanium complexes of Salina represented by the formula (2), formula (2'), formula (4) and formula (4')are mononuclear complexes of oxititan represented by the following formulas(23), (23'), (24) and (24'):

(where M represents TiJ¹J²where J¹and J²taken together, represent an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5), where b is an integer of 1-10, and the complete structure of the O-E-O is represented by the following formula(25), (25'), (26) or (26')

or oligomer µ-oxititan formed by binding (b+1)-parts mononuclear complexes of oxititan (b is an integer of 1-10.

In addition, the following describes a method of obtaining optically active titanium complexes represented by formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4').

Salanova ligands represented by the formula (29), equation (29'), formula (31) and formula (31'), which are ligands of complexes of titanium-Solana represented by the formula (2), formula (2'), formula (4) and formula (4'), respectively, can be obtained by restoring connections salena represented by the following formula (28), formula (28'), formula (30) and formula (30'), respectively.

Examples of reducing agents are sodium borohydride (N₄), cyanoborohydride sodium (N₃JV) and alumoweld lithium (LilH₄), and preferred is sodium borohydride (N₄).

Optically active titanium complexes of Salina represented by the formula (2), formula (2'), formula (4) and formula (4')can be obtained by reaction of the corresponding salinovich ligands with titanium alkoxide, titanium tetrachloride or tetrabromide titanium in an organic solvent, such as dichloromethane, followed by treatment of the resulting mixture with water or aqueous solvent (a mixed solvent obtained by mixing 0.1 to 100 wt.% water in organic is kOhm solvent, and examples of the organic solvent are THF, methanol and isopropanol). The amount of water used, preferably is in the range from 1 to 1000 mol, and more preferably in the range from 1 to 10 mol relative to the equivalent of the above salanova ligand.

In addition, the above-mentioned optically active complex titanium-Solana formedin situand asymmetric epoxidation connection chromene can also be carried out without isolating the complex used as a catalyst.

In this case, the reaction of the joining of water can also be carried out by adding an aqueous solution of hydrogen peroxide, used as oxidant.

The preferred titanium compounds are titanium alkoxides, and examples of titanium alkoxides are tetramethoxy titanium, tetraethoxy titanium, Tetra-n-propoxy titanium, tetraisopropoxide titanium, Tetra-n-piperonyl titanium Tetra-tert-piperonyl titanium. The preferred titanium alkoxide is tetraisopropoxide titanium (Ti(Oi-Pr)₄). The amount of titanium alkoxide, preferably, is from 1 to 2 mol per one mol of the above-mentioned salanova ligand.

Optically active titanium complexes-sallena represented by the formula (1), formula (1'), formula (3) and formula 3'), can be obtained by the method described in non-patent document 8 (Angew. Chem. Int. Ed. (2005), 44, 4935-4939). That is, Allenby complex get through interaction of the corresponding sleevage ligand with a titanium alkoxide with the formation of a complex of titanium and restore one of the two eminovic ties in salanova ligand in the reaction of Meerwein-Ponndorf-Verley (MPV), and after completion of the reaction the mixture is treated with water or aqueous solvent (a mixed solvent obtained by mixing 0.1 to 100 wt.% water in an organic solvent, and examples of the used organic solvent are THF, methanol and isopropanol).

In addition, the above-mentioned optically active complex titanium-sallena formedin situand asymmetric epoxidation connection chromene can also be carried out without isolating the complex used as a catalyst.

Examples of titanium alkoxides are tetramethoxy titanium, tetraethoxy titanium, Tetra-n-propoxy titanium, tetraisopropoxide titanium, Tetra-n-piperonyl titanium Tetra-tert-piperonyl titanium. The preferred titanium alkoxide is tetraisopropoxide titanium (Ti(Oi-Pr)₄). The amount of titanium alkoxide, preferably, is from 1 to 2 mol per one mol vysheupomjanutoj salanova ligand. The amount of water preferably ranges from 1 to 1000 mol, and more preferably from 1 to 10 mol relative to the equivalent of the above salanova ligand.

Examples of solvents for the reaction used to obtain the optically active complex of titanium, are aprotic organic solvent, proton organic solvent or mixtures thereof. Examples of the aprotic organic solvent is a halogen solvent, an aromatic hydrocarbon solvent, ester solvent, an ether solvent or a nitrile solvent, and in particular, such solvents are dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, toluene, ethyl acetate, tetrahydrofuran, diethyl ether, butyronitrile, propionitrile and acetonitrile. Examples of proton organic solvent is an alcohol solvent, and in particular, such solvents are ethanol, isopropanol and tert-butanol.

The preferred solvent for the reaction is aprotic organic solvent, such as dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene and ethyl acetate.

In the method of obtaining the compounds according to the invention, one of the enantiomers of the compound oxide chromene can be obtained with high selectivity by asymmetric Epoque is hydrovane connection chromene, which is a starting material, an optically active complex of titanium of formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4'). In particular, one of the two enantiomers of the optically active compound oxide chromene can be selectively obtained using any of the complexes of formula (1) and formula (1'); one of the two enantiomers of the optically active compound oxide chromene can be selectively obtained using any of the complexes of the formula (2) and formula (2'); one of the two enantiomers of the optically active compound oxide chromene can be selectively obtained using any of the complexes of the formula (3) and formula (3'); and one of the two enantiomers of the optically active compound oxide chromene can be selectively obtained using any of the complexes of the formula (4) and formula (4').

Below is described a method of obtaining optically active compound oxide chromene according to the invention.

This method is a method of obtaining optically active compound oxide chromene represented by the formula (14), formula (15), formula (16) or formula (17):

where R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰And, W, X, Y, and Z are the same as described below, and the absolute configuration is oracea carbon atoms, marked with *means (R) or (S); where the method includes dissolving the connection chromene represented by the formula (10), formula (11), formula (12) or formula (13), and optically active complex of titanium represented by the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4'), in an organic solvent in a nitrogen atmosphere or in environmental conditions; asymmetric epoxidation carried out by adding an oxidizing agent in the reaction solution, and stirring

where each of R⁵, R⁶, R⁷and R⁸in the formula (10) independently represents a hydrogen atom, a cyano, a nitro-group, a halogen atom, a C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkoxygroup (alkoxygroup may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup is, With_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkylcarboxylic (alkylcarboxylic may be optionally substituted by a halogen atom, phenyl group (the phenyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkyl group or a C_1-4alkoxygroup))_1-4alkylsulphonyl(N-C_1-4alkyl)amino group (alkylsulphonyl(N-alkyl)amino group may be optionally substituted by halogen atom), With_1-4alkoxycarbonyl group (alkoxycarbonyl group may be optionally substituted by halogen atom), With_6-10arylcarboxylic (arylcarboxylic may be optionally substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group)_6-10arylcarbamoyl(N-C_1-4alkyl)amino group (arylcarbamoyl(N-alkyl)amino group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), benicarbenicar, formyl group, carbamoyl is inuu group, With_1-4alkylsulfonyl group_6-10arylsulfonyl group (alkylsulfonyl group and arylsulfonyl group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), sulfamoyl group_1-4alkylsulfonamides group_6-10arylsulfonamides group (alkylsulfonamides group and arylsulfonamides group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be substituted by halogen atom), With_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_6-10arylsulfonyl)kidney group (arylsulfonyl bis(arylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group) or (N,N'-(C_1-4alkylsulfonyl)(C_6-10arylsulfonyl))kidney group (alkylsulfonyl and arylsulfonyl (N,N'-(alkylsulfonyl)(arylsulfonyl))kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group);

each of R⁹and R¹⁰in the formula (10) independently represents the atoms is hydrogen, With_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom or hydroxy-group) or (C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom));

each of R⁹and R¹⁰in the formula (11) and formula (12) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), or g is proxygroup) or (C _1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom));

incomplete cyclic structure And the formula (11) and formula (12) represents a partial structure represented by the 5-, 6 - or 7-membered ring, to form a ring condensed with a part of the benzene ring (each of 5-, 6 - or 7-membered ring may be optionally substituted hR¹¹(R¹¹may be optionally substituted by halogen atom, hydroxy-group, With_1-6alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, an amino group, a nitrogroup,_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom, hydroxy-group, a cyano, an amino group, a nitrogroup,_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can in order to be optionally substituted by a halogen atom)), the nitrogroup, cyano, formyl group, formamide group, carbamoyl group, alphagroup, Sultanoglu, sulfamoyl group, sulfonyloxy group, amino group, carboxyl group, With_1-6alkylamino, di-C_1-6alkylamino,_1-6alkylcarboxylic,_1-6alkylsulfonamides group_6-14arylsulfonamides group_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group_6-14arylsulfonyl group or_6-14arylcarbamoyl group (alkylamino, dialkylamino, alkylcarboxylic, alkylsulfonamides group, arylsulfonate group, alkylaminocarbonyl group, dialkylaminoalkyl group, alkylcarboxylic group, alkoxycarbonyl group, alkylsulfonyl group, arylsulfonyl group or arylcarbamoyl group can be optionally substituted by a halogen atom); where h denotes an integer of 1-6, and if h is an integer of 2-6, R¹¹may be the same or different); 1-3 atoms of oxygen, nitrogen or sulfur may be present alone or in combination with other atoms on the ring; the number of unsaturated bonds in the ring containing nanosys is NNOU(s) relationship(s) and condensed with a benzene ring, is 1, 2 or 3, and the atom(s) of the carbon component(s) this ring can represent a carbonyl group or tonilou group); X in the formula (13) represents NR²⁰(R²⁰represents a hydrogen atom or a C_1-4alkyl group); Y in the formula (13) represents a chemical bond, SO or SO₂; Z in the formula (13) represents a C_1-4alkyl group (the alkyl group may be optionally substituted by 1-5 halogen atoms, or phenyl group (the phenyl group may be optionally substituted C_1-4alkyl group)) or phenyl group (the phenyl group may be optionally substituted C_1-4alkyl group); W in the formula (13) represents a hydrogen atom, a hydroxy-group, With_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), halogen atom, With_1-4alkyl group or a C_1-6alkylsulfonamides group (an alkyl group and alkylsulfonamides group can be optionally substituted by a halogen atom); and

each of R⁹and R¹⁰in the formula (13) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxyprop is Oh) or (C _6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom or With_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom)). Such optically active compound oxide chromene can be obtained by the method illustrated in reaction scheme 1.

Reaction scheme 1

In reaction scheme 1, where R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰And, W, X, Y, and Z are as described above and the absolute configuration of the carbon atoms indicated by *, mean (R) or (S), illustrated is a method of obtaining optically active compound oxide chromene represented by the formula (14), formula (15), formula (16) and formula (17), carried out by treating compounds of chromene represented by the formula (10), formula (11), formula (12) and formula (13), respectively, oxidant and optically active complex titanium.

Connection chromene represented by the formula (10), formula (11), formula (12) and formula (13), which is the source of the m compound according to the invention, can be synthesized by the General methods of synthesis benzopyrano rings. Synthesis of condensed rings of the formulas (11) and formula (12) can be carried out by various methods of synthesis of heterocycles, in combination with optional methods of synthesis benzopyrano rings.

about General methods of synthesis benzopyrano rings

Benzopyrrole ring can be synthesized by known methods (the methods described in the publications J. M. Evans et al., J. Med. Chem. 1984, 27, 1127., J. Med. Chem. 1986, 29, 2194., J. T. North et al., J. Org. Chem. 1995, 60, 3397., in publications of patent applications in Japan nos JP-A-56-57785, JP-A-56-57786, JP-A-58-188880, JP-A-2-141, JP-A-10-87650 and JP-A-11-209366, and in other works).

on Indole and oxindole

Indole and oxindole can be synthesized by known methods (the methods described in the publications of T. Sakamoto et al., Heterocycles, 1986, 24, 31., M. Belley et al., Synthesis, 2001, 222., A. D. Cross et al., J. Chem. Soc., 1961, 2714 and in other works).

about Imidazoline

Imidazoline can be synthesized by a known method (the method described in the publication J. Kitteringham et al., Synthetic Commun., 2000, 30, 1937).

on the Quinoline

The quinoline can be synthesized by known methods (the methods described in the publications S. Imor et al., Synthetic Commun., 1996, 26, 2197., Y. Kitahara et al., Tetrahedron, 1997, 53, 6001., A. G. Osborne et al., J. Chem. Soc. Perkin Trans. 1993, 1, 181, R. T. Shuman et al., J. Org. Chem., 1990, 55, 738., T. Sakamoto et al., Chem. Pharm. Bull., 1981, 29, 2485, Y. Tsuji et al., J. Org. Chem., 1987, 52, 1673, Z. Song et al., J. Heterocyclic Chem., 1993, 30, 17, and in the other the servant of the tah).

about Chinoline

Chinoline can be synthesized by known methods (the methods described in the publications of M. R. Sabol et al., Synthetic Commun., 2000, 30, 427, Z-Y. Yang et al., Tetrahedron Lett., 1999, 40, 4505., H-B Sun et al., Synthesis, 1997, 1249., A. Guiotto et al., J. Heterocyclic Chem., 1989, 26, 917., K. Konno et al., Heterocycles, 1986, 24, 2169, E. Fernandez et al., Synthesis, 1995, 1362, and in other works).

about Benzothiazole and triazole

Benzothiazole and triazole can be synthesized by known methods (the methods described in the publications N.B. Ambati et al., Synthetic Commun., 1997, 27, 1487., D.E. Burton et al., J. Chem. Soc (C), 1968, 1268, and in other works).

about Cinoxacin, chynoxaline

Cinoxacin, chynoxaline can be synthesized by known methods (the methods described in the publications J.H. Liu et al., J. Org. Chem., 2000, 65, 3395., J. J. Li et al., Tetrahedron Lett., 1999, 40, 4507., Y. Ahmed et al., Bull. Chem. Soc. Jpn., 1987, 60, 1145, and in other works).

about Benzoxazine

Benzoxazine can be synthesized by known methods (the methods described in the publications by G. H. Jones et al., J. Med. Chem., 1987, 30, 295., J. L. Wright et al., J. Med. Chem. 2000, 43, 3408., M. Kluge et al., J. Heterocyclic Chem., 1995, 32, 395, and in other works).

Compounds represented by formula (35) and (36)can be obtained by reaction of compound (33) with compound (34) (Publication: Y. Tsuji et al., J. Org. Chem. 1987, 52, 1673).

Compounds represented by formula (35) and (36)can also be obtained by reaction of compound (33) with soy is inanam (37) in the presence of acid catalyst (Publications: Y. Kitahara et al., Tetrahedron, 1997, 53, 6001, Z. Song et al., J. Heterocyclic Chem., 1993, 30, 17).

Connection chromene represented by the following formula (40) can be synthesized from compound (38) by nitrogroup reduction of the compound (38) in the presence of platinum on coal as a catalyst to obtain amine compound (39) with subsequent metilirovaniem amino group of the compound (39).

Each group Deputy connections chromene represented by the formula (10), formula (11), formula (12) and formula (13), specifically described below.

The following describes each group Deputy for the compounds of formula (10). Each of R⁵, R⁶, R⁷and R⁸in the formula (10) independently represents a hydrogen atom, a cyano, a nitro-group, a halogen atom, a C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkoxygroup (alkoxygroup may be optionally substituted atom g is lagena, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkylcarboxylic (alkylcarboxylic may be optionally substituted by a halogen atom, a C_6-10aryl group (C_6-10the aryl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkyl group or a C_1-4alkoxygroup))_1-4alkylsulphonyl(N-C_1-4alkyl)amino group (alkylsulphonyl(N-alkyl)amino group may be optionally substituted by halogen atom), With_1-4alkoxycarbonyl group (alkoxycarbonyl group may be optionally substituted by halogen atom), With_6-10arylcarboxylic (arylcarboxylic may be optionally substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group)_6-10arylcarbamoyl(N-C_1-4alkyl)amino group (arylcarbamoyl(N-alkyl)amino group may be optionally substituted by a halogen atom, a C_1-4alkyl group, a C_1-4what alkoxygroup, the cyano or nitro-group), benicarbenicar, formyl group, carbamoyl group_1-4alkylsulfonyl group (alkylsulfonyl group can be can be optionally substituted by halogen atom), With_6-10arylsulfonyl group (arylsulfonyl group may be optionally substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), sulfamoyl group_1-4alkylsulfonamides group_6-10arylsulfonamides group (alkylsulfonamides group and arylsulfonamides group can be optionally substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be optionally substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), bis(C_6-10arylsulfonyl)kidney group (arylsulfonyl bis(arylsulfonyl)kidney group may be optionally substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group) or (N,N'-(C_1-4alkylsulfonyl)(C_6-10arylsulfonyl))kidney group (alkylsulfonyl and arylsulfonyl (N,N'-(alkylsulfonyl)(arylsulfonyl))kidney g is uppy may be optionally substituted by a halogen atom, With_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group).

Each group is a substituent R⁵, R⁶, R⁷and R⁸in the formula (10) is specifically described below.

Examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom; examples_1-4alkyl groups are methyl group, triptorelin group, trichlorethylene group, ethyl group, n-sawn group, isopropyl group, cyclopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group and cyclobutyl group; examples_1-4alkoxygroup are a methoxy group, tripterocarpa, trichlormethiazide, ethoxypropan, n-propoxylate, isopropoxide, cyclopropane, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan and cyclobutene; examples_1-4alkylcarboxylic are methylcobalamine, triftormetilfullerenov, trichlorocarbanilide, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, cyclopropanecarboxaldehyde, n-BUTYLCARBAMATE, isobutyleneisoprene, second-BUTYLCARBAMATE, tert-BUTYLCARBAMATE, cyclobutanecarbonitrile, p-methoxyp ylmethylamino, p-nitrophenyldiazonium and p-methoxyphenylethylamine; examples_1-6alkylsulphonyl(N-C_1-4alkyl)amino group are methylcarbamyl(N-methyl)amino group, triptoreline(N-methyl)amino group, methylcarbamyl(N-ethyl)amino group, triptoreline(N-ethyl)amino group, ethylcarboxyl(N-ethyl)amino group, n-propylboronic(N-ethyl)amino group, isopropylcarbonate(N-ethyl)amino group, cyclopropanecarbonyl(N-ethyl)amino group, n-butylcarbamoyl(N-ethyl)amino group, isobutylketone(N-ethyl)amino group, sec-butylcarbamoyl(N-ethyl)amino group, tert-butylcarbamoyl(N-ethyl)amino group and cyclobutanecarbonyl(N-ethyl)amino group; examples_1-4alkoxycarbonyl groups are methoxycarbonyl group, triphtalocyaninine group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, cyclopropanecarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl group, tert-butoxycarbonyl group and cyclobutanecarbonyl group; examples_6-10arylcarboxylic are phenylcarbonylamino, 1-afterburning and 2-afterburning; examples_6-10arylcarbamoyl(N-C_1-4alkyl)amino group are phenylcarbinol(N-methyl)aminor the PAP, phenylcarbinol(N-ethyl)amino group, 1-afterburner(N-ethyl)amino group and 2-afterburner(N-ethyl)amino group; examples_1-4alkylsulfonyl groups are methanesulfonyl group, trifloromethyl group, acanaloniidae group, n-propanesulfonyl group, isopropylaniline group, cyclopropanesulfonyl group, n-butanesulfonyl group, isobutylphenyl group, sec-butanesulfonyl group, tert-butanesulfonyl group and cyclobutanemethanamine group; examples_6-10arylsulfonyl groups are benzolsulfonat group, p-permentantly group, p-toluensulfonyl group, 1-naphthalenesulfonyl group and 2-naphthalenesulfonyl group; examples_1-4alkylsulfonamides groups are methanesulfonamido group, triftoratsetofenona group, acanaloniidae group, n-propanesulfinamide group, isopropanolamine group, cyclopropanesulfonyl group, n-butanesulfinamide group, isobutylphenyl group, sec-butanesulfinamide group, tert-butanesulfinamide group and cyclobutanemethanamine group; examples_6-10arylsulfonamides groups are benzosulfimide group, p-forbindelsesfaneblad group, p-toluensulfonate group, 1-naphthalene is sulfonamide group and 2-naphthalenemethanamine group; examples of bis(C_1-4alkylsulfonyl)amide group are bis(metasolv)midna group, bis(triftorbyenzola)midna group, bis(atenshon)midna group, bis(n-propanesulfonyl)midna group, bis(isopropanole)midna group, bis(cyclopropanesulfonyl)midna group, bis(n-butanesulfonyl)midna group, bis(Isobutanol)midna group, bis(sec-butanesulfonyl)midna group, bis(tert-butanesulfonyl)midna group and bis(cyclobutanone)midna group; examples of the bis(C_6-10arylsulfonyl)kidney group are bis(benzolamide)midna group, bis(p-forbindelsen)midna group, bis(p-toluensulfonyl)midna group, bis(1-naphthalenesulfonyl)midna group and bis(2-naphthalenesulfonyl)midna group; and examples of (N,N'-(C_1-4alkylsulfonyl)(C_6-10arylsulfonyl))kidney groups are (N,N'-(methane)(benzene))midna group, (N,N'-(triptorelin)(benzene))midna group, (N,N'-(tryptomer)(p-torbenson))midna group, (N,N'-(ethane)(benzene))midna group, (N,N'-(methane)(p-toluene))midna group, (N,N'-(triptorelin)(p-toluene))midna group, (N,N'-(ethane)(p-toluene))midna group, (N,N'-(methane)(1-naphthalene))midna group, (N,N'-(triptorelin)(1-naphthalene))midna group, (N,N'-(ethane)(1-naphthalene))midna group, (N,N'-(methane)(2-naphthalene))midna group (N,N'-(triptorelin)(2-naphthalene))midna group and (N,N'-(ethane)(2-naphthalene))midna groups is.

R⁵and R⁶in the formula (10) and independently preferably represent a hydrogen atom, a cyano, a nitro-group, a fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, cyclopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, cyclobutyl group, a methoxy group, cryptometer, ethoxypropan, n-propoxylate, isopropoxy, cyclopropane, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, cyclobutanes, medicalbilling, triftormetilfullerenov, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, cyclopropanecarboxaldehyde, n-BUTYLCARBAMATE, isobutylamino, sec-BUTYLCARBAMATE, tert-BUTYLCARBAMATE, cyclobutanecarbonyl, methylcarbamyl(N-methyl)amino group, triptoreline(N-methyl)amino group, methylcarbamyl(N-ethyl)amino group, triptoreline(N-ethyl)amino group, ethylcarboxyl(N-ethyl)amino group, n-propylboronic(N-ethyl)amino group, isopropylcarbonate(N-ethyl)amino group, cyclopropanecarbonyl(N-ethyl)amino group, n-butylcarbamoyl(N-ethyl)amino group, isobutylketone the(N-ethyl)amino group, second-butylcarbamoyl(N-ethyl)amino group, tert-butylcarbamoyl(N-ethyl)amino group, cyclobutanecarbonyl(N-ethyl)amino group, methoxycarbonyl group, triphtalocyaninine group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, phenylcarbonylamino, 1-afterburning, 2-afterburning, phenylcarbinol(N-methyl)amino group, phenylcarbamoyl(N-ethyl)amino group, 1-afterburner(N-ethyl)amino group, 2-afterburner(N-ethyl)amino group, benicarbenicar, formyl group, karbamoilnuyu group, methanesulfonamido group, triftormetilfullerenov group, acanaloniidae group, n-propanesulfinamide group, isopropylamino group, cyclopropanesulfonyl group, n-butanesulfinamide group, isobutylene group, sec-butanesulfinamide group, tert-butanesulfinamide group, cyclobutanemethanamine group, bis(metasolv)kidney group, bis(triftorbyenzola)kidney group, bis(atenshon)kidney group, bis(n-propanesulfonyl)kidney group, bis(isopropanole)kidney group, bis(cyclopropanesulfonyl)kidney group, bis(n-butanesulfonyl)kidney group, bis(Isobutanol)kidney group, bis(second-butanesultone)kidney group, bis(tert-butanesulfonyl)kidney group, bis(cyclobe ansulite)kidney group, bis(benzolamide)kidney group, bis(p-toluensulfonyl)kidney group, bis(1-naphthalenesulfonyl)kidney group, bis(2-naphthalenesulfonyl)kidney group, (N,N'-(methane)(benzene))kidney group, (N,N'-(triptorelin)(benzene))kidney group, (N,N'-(ethane)(benzene))kidney group, (N,N'-(methane)(p-toluene))kidney group, (N,N'-(triptorelin)(p-toluene))kidney group, (N,N'-(ethane)(p-toluene))kidney group, (N,N'-(methane)(1-naphthalene))kidney group, (N,N'-(triptorelin)(1-naphthalene))kidney group, (N,N'-(ethane)(1-naphthalene))kidney group, (N,N'-(methane)(2-naphthalene))kidney group, (N,N'-(triptorelin)(2-naphthalene))kidney group and (N,N'-(ethane)(2-naphthalene))kidney group, and more preferably, a hydrogen atom, a nitro-group, a fluorine atom, a chlorine atom, a methoxy group, medicalbilling, methylcarbamyl(N-ethyl)amino group, bis(triftorbyenzola)kidney group, (N,N'-(triptorelin)(benzene))kidney group and (N,N'-(triptorelin)(p-toluene))kidney group.

R⁷in the formula (10) preferably represents a hydrogen atom, a cyano, a nitro-group, methanesulfonamido group, triftormetilfullerenov group, acanaloniidae group, n-propanesulfinamide group, isopropylamino group, cyclopropanesulfonyl group, n-butanesulfinamide group, isobutylene group, sec-butanesulfinamide group, tert-butanesulfinamide group, iglobalinterfacetable group, bis(metasolv)kidney group, bis(triftorbyenzola)kidney group, bis(atenshon)kidney group, bis(n-propanesulfonyl)kidney group, bis(isopropanole)kidney group, bis(cyclopropanesulfonyl)kidney group, bis(n-butanesulfonyl)kidney group, bis(Isobutanol)kidney group, bis(sec-butanesulfonyl)kidney group, bis(tert-butanesulfonyl)kidney group, bis(cyclobutanone)kidney group, bis(benzolamide)kidney group, bis(p-toluensulfonyl)kidney group, bis(1-naphthalenesulfonyl)kidney group, bis(2-naphthalenesulfonyl)kidney group, (N,N'-(methane)(benzene))kidney group, (N,N'-(triptorelin)(benzene))kidney group, (N,N'-(triptorelin)(p-torbenson))kidney group, (N,N'-(ethane)(benzene))kidney group, (N,N'-(methane)(p-toluene))kidney group, (N,N'-(triptorelin)(p-toluene))kidney group, (N,N'-(ethane)(p-toluene))kidney group, (N,N'-(methane)(1-naphthalene))kidney group, (N,N'-(triptorelin)(1-naphthalene))kidney group, (N,N'-(ethane)(1-naphthalene))kidney group, (N,N'-(methane)(2-naphthalene))kidney group, (N,N'-(triptorelin)(2-naphthalene))kidney group and (N,N'-(ethane)(2-naphthalene))kidney group, and more preferably, a hydrogen atom, a nitro-group, bis(metasolv)kidney group, bis(triftorbyenzola)kidney group, (N,N'-(triptorelin)(benzene))kidney group and (N,N'-(triptorelin)(p-toluene))kidney group.

R⁸in the formula (10) predpochtitel is but represents a hydrogen atom, a fluorine atom, a chlorine atom, a cyano, a nitro-group, methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, cyclopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group and cyclobutyl group, and more preferably, a hydrogen atom, a fluorine atom, a nitro-group, methyl group and triptorelin group.

each of R⁹and R¹⁰in the formula (10) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom)).

Each group Deputy for R⁹and R¹⁰in the formula (10) is specifically described below. Examples_1-6alkyl groups are methyl groups is, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, 1-pencilina group, 2-pencilina group, 3-pencilina group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, 1-exilda group, 2-exilda group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group and 3,3-dimethyl-n-bucilina group, and examples With_6-14aryl group are phenyl group, o-biphenylene group, m-biphenylene group, p-biphenylene group, 1-naftalina group, 2-naftalina group, 1-antenna group, 2-antenna group, 9-antenna group, 1-phenanthroline group, 2-phenanthroline group, 3-phenanthroline group, 4-phenanthroline group and 9-phenanthroline group.

R⁹and R¹⁰in the formula (10) preferably represent a hydrogen atom, methyl group, triptorelin group, ethyl group and phenyl group, and more preferably methyl group.

Each group is a substituent in the formula (11) and formula (12) described below.

Each of R⁹and R¹⁰in the formula (11) and formula (12) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally is Emesene a halogen atom, With_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group), or With_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom)).

Each group Deputy for R⁹and R¹⁰in the formula (11) and formula (12) is specifically described below.

Examples_1-6alkyl groups are methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, 1-pencilina group, 2-pencilina group, 3-pencilina group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, 1-exilda group, 2-exilda group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group and 3,3-dimethyl-n-bucilina group, and examples With_6-14aryl group are phenyl group, o-bifen lilina group, m-biphenylene group, p-biphenylene group, 1-naftalina group, 2-naftalina group, 1-antenna group, 2-antenna group, 9-antenna group, 1-phenanthroline group, 2-phenanthroline group, 3-phenanthroline group, 4-phenanthroline group and 9-phenanthroline group.

R⁹and R¹⁰in the formula (11) and formula (12), preferably represent a hydrogen atom, methyl group, triptorelin group, ethyl group and phenyl group, and more preferably methyl group.

Incomplete cyclic structure And the formula (11) and formula (12) described below. Incomplete cyclic structure And means partial structure represented by the 5-, 6 - or 7-membered ring, to form a ring condensed with a part of the benzene ring (each of 5-, 6 - or 7-membered ring may be optionally substituted hR¹¹(R¹¹can be optional by halogen atom, hydroxy-group, With_1-6alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, an amino group, a nitrogroup,_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optional is entrusted substituted by halogen atom)), With_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom, hydroxy-group, a cyano, an amino group, a nitrogroup,_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)), a nitrogroup, cyano, formyl group, formamide group, carbamoyl group, sulfopropyl, Sultanoglu, sulfamoyl group, sulfonyloxy group, amino group, carboxyl group, With_1-6alkylaminocarbonyl, di-C_1-6alkylaminocarbonyl,_1-6alkylcarboxylic,_1-6alkylsulfonamides group_6-14arylsulfonamides group_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group_6-14arylsulfonyl group or_6-14arylcarboxylic (alkylamino, dialkylamino, alkylcarboxylic, alkylsulfonamides group, arylsulfonate group, alkylaminocarbonyl group, dialkylaminoalkyl g is the SCP, acylcarnitine group, alkoxycarbonyl group, alkylsulfonyl group, arylsulfonyl group or arylcarbamoyl group can be optionally substituted by a halogen atom); where h denotes an integer of 1-6, and if h is an integer of 2-6, R¹¹may be the same or different); 1-3 atoms of oxygen, nitrogen or sulfur may be present alone or in combination with other atoms on the ring; the number of unsaturated bonds in the ring containing the unsaturated(s) relationship(s) and condensed with a benzene ring, a is 1, 2 or 3, and the carbon atoms constituting the ring may be carbonyl or thiocarbonyl).

R¹¹specifically described below.

Examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom;

examples_1-6alkyl groups are methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, 1-pencilina group, 2-pencilina group, 3-pencilina group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, 1-exilda group, 2-exilda group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group, 3,3-dimethyl-n-the waste group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, triftormetilfullerenov group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group, triftormetilfullerenov group, ethoxycarbonylmethyl group, methoxycarbonylethyl group and ethoxycarbonylethyl group;

examples_1-6alkoxygroup are a methoxy group, tripterocarpa, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentylamine, neopentadactyla, 2,2-DIMETHYLPROPANE, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxylate, 1,2,2-trimethyl-n-propoxylate, 3,3-dimethyl-n-butoxypropyl, methylcarbaniloyloxy, ethylcarboxylate, methylcarbamoylmethyl, ethylcarboxylate, methylcarbamoylmethyl, triftormetilfullerenov, ethylcarbodiimide, methylcarbamoylmethyl, eTalk beniaminovna, ethoxycarbonylmethoxy, triftormetilfullerenov, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy and ethoxycarbonylmethoxy;

examples_1-6alkylamino are methylaminopropyl, triptoreline, atramentaria, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, isobutylamino, second-butylamino, tert-butylamino, cyclobutylamine, 1-pentylamine, 2-pentylamine, 3-pentylamine, isopentylamine, neopentylene, tert-pentylamine, cyclopentylamine, 1-hexylamine, 2-hexylamine, 3-hexylamino, cyclohexylamino, 1-methyl-n-pentylamine, 1,1,2-trimethyl-n-propylamino, 1,2,2-trimethyl-n-propylamino and 3,3-dimethyl-n-butylamine;

examples of di-C_1-6alkylamino are dimethylaminopropan, di-(trifluoromethyl)amino group, diethylaminopropyl, di-n-propylamino, di-isopropylamino, Dicyclopentadiene, di-n-butylamino, diisobutylamine, di-sec-butylamino, di-tert-butylamino, bicyclobutane, di-1-pentylamine, di-2-pentylamine, di-3-pentylamine, diisobutylamine, dineopentyl, di-tert-pentylamine, di is kilometrekilograms, di-1-hexylamine, di-2-hexylamine, di-3-hexylamino, dicyclohexylamine, di-(1-methyl-n-pentyl)amino group, di-(1,1,2-trimethyl-n-propyl)amino group, di-(1,2,2-trimethyl-n-propyl)amino group, di-(3,3-dimethyl-n-butyl)amino group, methyl(ethyl)amino group, methyl(n-propyl)amino group, methyl(isopropyl)amino group, methyl(cyclopropyl)amino group, methyl(n-butyl)amino group, methyl(isobutyl)amino group, methyl(sec-butyl)amino group, methyl(tert-butyl)amino group, methyl(cyclobutyl)amino group, ethyl(n-propyl)amino group, ethyl(isopropyl)amino group, ethyl(cyclopropyl)amino group, ethyl(n-butyl)amino group, ethyl(isobutyl)amino group, ethyl(sec-butyl)amino group, ethyl(tert-butyl)amino group, ethyl(cyclobutyl)amino group, n-propyl(isopropyl)amino group, n-propyl(cyclopropyl)amino group, n-propyl(n-butyl)amino group, n-propyl(isobutyl)amino group, n-propyl(sec-butyl)amino group, n-propyl(tert-butyl)amino group, n-propyl(cyclobutyl)amino group, isopropyl(cyclopropyl)amino group, isopropyl(n-butyl)amino group, isopropyl(isobutyl)amino group, isopropyl(sec-butyl)amino group, isopropyl(tert-butyl)amino group, isopropyl(cyclobutyl)amino group, cyclopropyl(n-butyl)amino group, cyclopropyl(isobutyl)amino group, cyclopropyl(sec-butyl)amino group, cyclopropyl(tert-butyl)amino group, cyclopropyl(qi is lomotil)amino group, n-butyl(isobutyl)amino group, n-butyl(sec-butyl)amino group, n-butyl(tert-butyl)amino group, n-butyl(cyclobutyl)amino group, isobutyl(sec-butyl)amino group, isobutyl(tert-butyl)amino group, isobutyl(cyclobutyl)amino group, sec-butyl(tert-butyl)amino group, sec-butyl(cyclobutyl)amino group and tert-butyl(cyclobutyl)amino group;

examples_1-6alkylcarboxylic are methylcobalamine, triftormetilfullerenov, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-BUTYLCARBAMATE, isobutyleneisoprene, second-BUTYLCARBAMATE, tert-BUTYLCARBAMATE, 1-intelcorporation, 2-intelcorporation, 3-intelcorporation, isopentenyladenine, neopentylmagnesium, tert-intelcorporation, 1-hexylcinnamaldehyde, 2-hexylcinnamaldehyde and 3-hexylcinnamaldehyde;

examples_1-6alkylsulfonamides groups are methanesulfonamido group, triftoratsetofenona group, acanaloniidae group, n-propanesulfinamide group, isopropanolamine group, n-butanesulfinamide group, isobutylphenyl group, sec-butanesulfinamide group, tert-butanesulfinamide group, 1-pentanesulfonic Edna group, 2-pentanesulfonate group, 3-pentanesulfonate group, isopentenyladenine group, neopentylene group, tert-pentanesulfonate group, 1-hexanesulfonate group, 2-hexanesulfonate group and 3-hexanesulfonate group;

examples_6-14arylsulfonamides groups are benzosulfimide group, p-toluensulfonate group, biphenylamine group, m-biphenylamine group, p-biphenylamine group, 1-naphthalenemethanamine group, 2-naphthalenemethanamine group, 1-anthracenesulfonic group, 2-anthracenesulfonic group, 9-anthracenesulfonic group, 1-finantsinstrument group, 2-finantsinstrument group, 3-finantsinstrument group, 4-finantsinstrument group and 9-finantsinstrument group;

examples_1-6alkylaminocarbonyl groups are methylaminomethyl group, triftormetilfullerenov group, ethylaminomethyl group, n-propylaminosulfonyl group, isopropylaminocarbonyl group, n-butylaminoethyl group, isobutyleneisoprene group, sec-butylaminoethyl group, tert-butylaminoethyl group, 1-intramyocardially group, 2-intramyocardially group, 3-intramyocardially group, from intramyocardially group, neopentadactyla group, tert-intramyocardially group, 1-hexylaniline group, 2-hexylaniline group and 3-hexylaniline group;

examples of di-C_1-6alkylaminocarbonyl groups are dimethylaminocarbonylmethyl group, di-(trifluoromethyl)aminocarbonyl group, diethylaminocarbonylmethyl group, di-n-propylaminoethyl group, diisopropylaminoethyl group, dicyclopentadienyl group, di-n-butylaminoethyl group, diisobutyldimethoxysilane group, di-sec-butylaminoethyl group, di-tert-butylaminoethyl group, Dicyclopentadiene group, di-1-intramyocardially group, di-2-intramyocardially group, di-3-intramyocardially group, di-isopentenyladenine group, lineapellebologna group, di-tert-intramyocardially group, dicyclopentadienyl group, di-1-hexylaniline group, di-2-hexylaniline group, di-3-hexylaniline group, dicyclohexylcarbodimide group, di-(1-methyl-n-pentyl)aminocarbonyl group, di-(1,1,2-trimethyl-n-propyl)aminocarbonyl group, di-(1,2,2-trimethyl-n-propyl)aminocarbonyl group, di-(3,3-dimethyl-n-butyl)aminocarbonyl group, methyl(ethyl)aminomar Vilna group, trifluoromethyl(ethyl)aminocarbonyl group, methyl(n-propyl)aminocarbonyl group, methyl(isopropyl)aminocarbonyl group, methyl(cyclopropyl)aminocarbonyl group, methyl(n-butyl)aminocarbonyl group, methyl(isobutyl)aminocarbonyl group, methyl(sec-butyl)aminocarbonyl group, methyl(tert-butyl)aminocarbonyl group, methyl(cyclobutyl)aminocarbonyl group, ethyl(n-propyl)aminocarbonyl group, ethyl(isopropyl)aminocarbonyl group, ethyl(cyclopropyl)aminocarbonyl group, ethyl(n-butyl)aminocarbonyl group, ethyl(isobutyl)aminocarbonyl group, ethyl(sec-butyl)aminocarbonyl group, ethyl(tert-butyl)aminocarbonyl group, ethyl(cyclobutyl)aminocarbonyl group, n-propyl(isopropyl)aminocarbonyl group, n-propyl(cyclopropyl)aminocarbonyl group, n-propyl(n-butyl)aminocarbonyl group, n-propyl(isobutyl)aminocarbonyl group, n-propyl(sec-butyl)aminocarbonyl group, n-propyl(tert-butyl)aminocarbonyl group, n-propyl(cyclobutyl)aminocarbonyl group, isopropyl(cyclopropyl)aminocarbonyl group, isopropyl(n-butyl)aminocarbonyl group, isopropyl(isobutyl)aminocarbonyl group, isopropyl(sec-butyl)aminocarbonyl group, isopropyl(tert-butyl)aminocarbonyl group, isopropyl(cyclobutyl)amino is arborina group, cyclopropyl(n-butyl)aminocarbonyl group, cyclopropyl(isobutyl)aminocarbonyl group, cyclopropyl(sec-butyl)aminocarbonyl group, cyclopropyl(tert-butyl)aminocarbonyl group, cyclopropyl(cyclobutyl)aminocarbonyl group, n-butyl(isobutyl)aminocarbonyl group, n-butyl(sec-butyl)aminocarbonyl group, n-butyl(tert-butyl)aminocarbonyl group, n-butyl(cyclobutyl)aminocarbonyl group, isobutyl(sec-butyl)aminocarbonyl group, isobutyl(tert-butyl)aminocarbonyl group, isobutyl(cyclobutyl)aminocarbonyl group, sec-butyl(tert-butyl)aminocarbonyl group, sec-butyl(cyclobutyl)aminocarbonyl group and tert-butyl(cyclobutyl)aminocarbonyl group;

examples_1-6alkylcarboxylic groups are methylcarbamyl group, triftormetilfullerenov group, acylcarnitine group, n-propellerblade group, isopropylcarbodiimide group, n-butylcellosolve group, isobutylamine group, sec-butylcellosolve group, tert-butylcellosolve group, 1-intercurrently group, 2-intercurrently group, 3-intercurrently group, isopentenyladenine group, neopentadactyla group, tert-intercurrently group, 1-paxilonline group, 2-paxilonline group and 3-paxilonline gr is the PAP;

examples_1-6alkoxycarbonyl groups are methoxycarbonyl group, triphtalocyaninine group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, 1-ventilatsiooniga group, 2-ventilatsiooniga group, 3-ventilatsiooniga group, isobutylacetophenone group, neopentadactyla group, tert-ventilatsiooniga group, 1-hexyloxymethyl group, 2-hexyloxymethyl group and 3-hexyloxymethyl group;

examples_1-6alkylsulfonyl groups are methanesulfonyl group, trifloromethyl group, acanaloniidae group, n-propanesulfonyl group and n-butanesulfonyl group;

examples_6-14arylsulfonyl groups are benzolsulfonat group, p-permentantly group, p-toluensulfonyl group, biphenylmethanol group, m-biphenylmethanol group, p-biphenylmethanol group, 1-naphthalenesulfonyl group, 2-naphthalenesulfonyl group, 1-anthracenesulfonic group, 2-anthracenesulfonic group, 9-anthracenemethanol group, 1-fantranslation the group, 2-fantranslation group, 3-fantranslation group, 4-fantranslation group and 9-fantranslation group; and

examples_6-14arylcarboxylic groups are phenylcarbonylamino group, p-tortenelmebol group, biphenylcarboxylic group, m-biphenylcarboxylic group, p-fenilalanina group, 1-nattermannallee group, 2-nattermannallee group, 1-atilcarnitina group, 2-atilcarnitina group, 9-atilcarnitina group, 1-financialstability group, 2-financialstability group, 3-financialstability group, 4-financialstability group and 9-financialstability group.

Preferred atoms and groups for the above R¹¹specifically described below.

R¹¹preferably represents fluorine atom, chlorine atom, bromine atom, methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, n-pentelow group, isopentyl group, 3,3-dimethyl-n-boutelou group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, triftormetilfullerenov group, ethylcarbodiimide group, methylcarbonate outilne group, ethylcarbodiimide group, methoxycarbonylmethyl group, triftormetilfullerenov group, ethoxycarbonylmethyl group, methoxycarbonylamino group, ethoxycarbonylethyl group, a methoxy group, cryptometer, ethoxypropan, n-propoxylate, isopropoxy, 3,3-dimethyl-n-butoxypropyl, methylcarbaniloyloxy, ethylcarboxylate, methylcarbamoylmethyl, ethylcarboxylate, methylcarbamoylmethyl, triftormetilfullerenov, ethylcarbodiimide, methylcarbamoylmethyl, ethylcarbodiimide, ethoxycarbonylmethoxy, triftormetilfullerenov, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, methylaminopropyl, triptorelin, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylaminopropyl, di-(trifluoromethyl)amino group, diethylaminopropyl, di-n-propylamino, diisopropylamino di-n-butylamino, medicalbilling, triftormetilfullerenov, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-BUTYLCARBAMATE, methanesulfonamido group, triftormetilfullerenov g is the SCP, acanaloniidae group, n-propanesulfinamide group, isopropylamino group, n-butanesulfinamide group, benzosulfimide group, p-toluensulfonate group, methylaminomethyl group, triftormetilfullerenov group, ethylaminomethyl group, n-propylaminosulfonyl group, isopropylaminocarbonyl group, n-butylaminoethyl group, dimethylaminocarbonylmethyl group, di(trifluoromethyl)aminocarbonyl group, diethylaminocarbonylmethyl group, di-n-propylaminoethyl group, diisopropylaminoethyl group, dicyclopentadienyl group, di-n-butylaminoethyl group, methyl(ethyl)aminocarbonyl group, trifluoromethyl(ethyl)aminocarbonyl group, methylcarbamyl group, triftormetilfullerenov group, ethylcarbitol group, n-propelleronline group, isopropylcarbodiimide group, n-butylcarbamoyl group, methoxycarbonyl group, triphtalocyaninine group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxyethanol group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, methanesulfonyl group, trifloromethyl group, ethanolgasoline group, benzolamide the optimum group, on-biphenylmethanol group, m-biphenylmethanol group, p-biphenylmethanol group, 1-naphthalenesulfonyl group, 2-naphthalenesulfonyl group, phenylcarbonylamino group, biphenylcarboxylic group, m-biphenylcarboxylic group, p-biphenylcarboxylic group, 1-afterburning group, 2-afterburning group, a hydroxy-group, a nitrogroup, cyano, formyl group, formamide group, carbamoyl group, Sultanoglu, sulfamoyl group, amino group and carboxyl group.

Each group of substituents R¹², R¹³, R¹⁴, R¹⁵, R¹⁶and R¹⁷in the formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), the formula (s), formula (t), formula (u), formula (v), formula (w), formula (x), formula (y), formula (z), formula (AA), formula (AB), formula (AC), formula (ad), formula (AE), formula (AF), the formula (hell) and the formula (h) described below.

where incomplete cyclic structure And the formula (11) or the formula (12)represented by the formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), the formula is y (o), formula (p), formula (q), formula (r), formula (s), formula (t), formula (u), formula (v), formula (w), formula (x), formula (y), formula (z), formula (AA), formula (AB), formula (AC), formula (ad), formula (AE), formula (AF), formula (hell) and formula (ah).

Below first describes the R¹²and R¹³in the formula (a), formula (b), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), the formula (p), formula (q), formula (v), formula (w), formula (x), formula (ab), formula (AE), formula (af) and formula (ag).

Each of R¹²and R¹³in the formula (a), formula (b), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), the formula (p), formula (q), formula (v), formula (w), formula (x), formula (ab), formula (AE), formula (af) and formula (ag) independently represents a hydrogen atom, a C_1-6alkyl group (alcalina group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_6-14aryl group or_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted qR¹⁸(R¹⁸has the same meanings as R¹¹; q is an integer of 1-3, and all R^{18/sup> may be the same or different when q is 2 or 3)), C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group, C_1-6alkylcarboxylic,_1-6alkylcarboxylic (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), C_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group (cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group can be optionally substituted by halogen atom), a carboxyl group, With_6-14arylcarbamoyl group (arylcarbamoyl group may be optionally substituted by a halogen atom or optionally substituted C_2-9heteroarylboronic group)_6-14aryl group_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted qR18(R18has the same meanings as R11; q is an integer of 1-3, and all R18may be the same or different when q is 2 or 3)),_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_3-8cycloalkylcarbonyl group_1-6ALCO is dicarbonyl group, With_1-6alkylsulfonyl group_6-14arylsulfonyl group_2-9heteroarylboronic group (arylsulfonyl and heteroarylboronic group may be optionally substituted qR18(R18has the same meanings as R11; q is an integer of 1-3, and all R18may be the same or different when q is 2 or 3)), carboxyl group, With_6-14arylcarbamoyl group or_2-9heteroarylboronic group (kilcarbery and heteroarylboronic groups can be optionally substituted qR18(R18has the same meanings as R11; q is an integer of 1-3, and all R18may be the same or different when q is 2 or 3)).}

Below specifically described, each of the groups of substituents for R¹²and R¹³in the formula (a), formula (b), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), the formula (p), formula (q), formula (v), formula (w), formula (x), formula (AB), formula (AE), formula (AF) and the formula (hell).

Examples_1-6alkyl groups are methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 2-pencilina group, pencilina group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, n-exilda group, 2-exilda group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group, 3,3-dimethyl-n-bucilina group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, triftormetilfullerenov group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, methoxycarbonylethyl group and group ethoxycarbonylmethylene; and examples With_6-14aryl group are phenyl group, o-biphenylene group, m-biphenylene group, p-biphenylene group, 1-naftalina group, 2-naftalina group, 1-antenna group, 2-antenna group, 9-antenna group, 1-phenanthroline group, 2-phenanthroline group, 3-phenanthroline group, 4-phenanthroline group and 9-phenanthroline group.

Examples_2-9heteroaryl groups are_2-6-monocyclic heterocyclic group having 5 to 7-membered ring which may contain 1-3 oxygen atoms, nitrogen atoms, sulfur atoms, and combinations thereof, and the _5-9-condensed bicyclic heterocyclic group having 8 to 10 atoms in the ring.

Examples_2-6monocyclic heterocyclic group having 5 to 7-membered ring are the 2-thienyl group, 3-thienyl group, 2-furilla group, 3-furilla group, 2-Pernilla group, 3-Pernilla group, 4-Pernilla group, 1-pyrrolidine group, 2-pyrrolidine group, 3-pyrrolidine group, 1-imidazolidinyl group, 2-imidazolidinyl group, 4-imidazolidinyl group, 1-pyrazolidine group, 3-pyrazolidine group, 4-pyrazolidine group, 2-thiazolidine group, 4-thiazolidine group A 5-thiazolidine group, 3-isothiazolinone group, 4-isothiazoline group, 5-isothiazolinone group, 2-oxazolidinyl group, 4-oxazolidinyl group, 5-oxazolidinyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-Peregrina group, 3-Peregrina group, 4-Peregrina group, 2-pyridinoline group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolidine group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolyl group, 5-1,2,4-thiadiazolyl group, a 3-1,2,5-oxadiazolyl group and 3-1,2,5-thiadiazolyl group; aprimary -condensed bicyclic heterocyclic group having 8 to 10 atoms in the ring are 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiazoline group, 3-benzothiazoline group, 4-benzothiazoline group, 5-bentenjima group, 6-benzothiazoline group, 7-benzothiazoline group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromadorina group, 3-chromadorina group, 4-chromadorina group, 5-chromadorina group, 6-chromadorina group, 7-chromadorina group, 8-chromadorina group, 1-indolizinyl group, 2-indolizinyl group, 3-indolizinyl group, 5-indolizinyl group, 6-indolizinyl group, 7-indolizinyl group, 8-indolizinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indlela group, 2-indlela group, 3-indlela group, 4-indlela group, 5-indlela group, 6-indlela group, 7-indlela group, 1-indazolinone group, 2-indazolinone group, 3-indazolinone group, 4-indazolinone group, 5-indazolinone group, 6-indazolinone groups who, 7-indazolinone group, 1-polylina group, 2-polylina group, 3-polylina group, 6-polylina group, 7-polylina group, 8-polylina group, 2-kinolinna group, 3-kinolinna group, 4-kinolinna group, 5-kinolinna group, 6-kinolinna group, 7-kinolinna group, 8-kinolinna group, 1-izochinolina group, 3-izochinolina group, 4-izochinolina group, 5-izochinolina group, 6-izochinolina group, 7-izochinolina group, 8-izochinolina group, 1-vladimirka group, 5-vladimirka group, 6-vladimirka group, 1-2,7-naphthyridinone group, 3-2,7-naphthyridinone group, 4-2,7-naphthyridinone group, 1-2,6-naphthyridinone group, 3-2,6-naphthyridinone group, 4-2,6-naphthyridinone group, 2-1,8-naphthyridinone group, 3-1,8-naphthyridinone group, 4-1,8-naphthyridinone group, 2-1,7-naphthyridinone group, 3-1,7-naphthyridinone group, 4-1,7-naphthyridinone group, 5-1,7-naphthyridinone group, 6-1,7-naphthyridinone group, 8-1,7-naphthyridinone group, 2-1,6-naphthyridinone group, 3-1,6-naphthyridinone group, 4-1,6-naphthyridinone group, 5-1,6-naphthyridinone group, 7-1,6-naphthyridinone group, 8-1,6-naphthyridinone group, 2-1,5-naphthyridinone group, 3-1,5-naphthyridinone group, 4-1,5-naphthyridinone group, 6-1,5-naphthyridinone group, 7-1,5-naphthyridinone group, 8-1,5-nattered nilina group, 2-khinoksalinona group, 5-khinoksalinona group, 6-khinoksalinona group, 2-chinadaily group, 4-chinadaily group, 5-chinadaily group, 6-chinadaily group, 7-chinadaily group, 8-chinadaily group, 3-indolenine group, 4-indolenine group, 5-indolenine group, 6-indolenine group, 7-indolenine group, 8-indolenine group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group and 7 peridiniella group.

Examples_1-6alkylaminocarbonyl groups are methylaminomethyl group, ethylaminomethyl group, n-propylaminosulfonyl group, isopropylaminocarbonyl group, n-butylaminoethyl group, isobutyleneisoprene group, sec-butylaminoethyl group, tert-butylaminoethyl group, 1-intramyocardially group, 2-intramyocardially group, 3-intramyocardially group, isopentenyladenine group, neopentadactyla group, tert-intramyocardially group, 1-hexylaniline group, 2-hexylaniline group and 3-hexylaniline groups;

examples of di-C_1-6alkylaminocarbonyl groups are dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, di-n-propylaminoethyl g is the SCP, diisopropylaminoethyl group, dicyclopentadienyl group, di-n-butylaminoethyl group, diisobutyldimethoxysilane group, di-sec-butylisoxazole group, di-tert-butylaminoethyl group, Dicyclopentadiene group, di-1-intramyocardially group, di-2-intramyocardially group, di-3-intramyocardially group, di-isopentenyladenine group, lineapellebologna group, di-tert-intramyocardially group, dicyclopentadienyl group, di-1-hexylaniline group, di-2-hexylaniline group, di-3-hexylaniline group, dicyclohexylcarbodimide group, di-(1-methyl-n-pentyl)aminocarbonyl group, di-(1,1,2-trimethyl-n-propyl)aminocarbonyl group, di-(1,2,2-trimethyl-n-propyl)aminocarbonyl group, di-(3,3-dimethyl-n-butyl)aminocarbonyl group, methyl(ethyl)aminocarbonyl group, methyl(n-propyl)aminocarbonyl group, methyl(isopropyl)aminocarbonyl group, methyl(cyclopropyl)aminocarbonyl group, methyl(n-butyl)aminocarbonyl group, methyl(isobutyl)aminocarbonyl group, methyl(second-butyl)aminocarbonyl group, methyl(tert-butyl)aminocarbonyl group, methyl(cyclobutyl)aminocarbonyl group, ethyl(n-propyl)aminocarbonyl GRU is PA, ethyl(isopropyl)aminocarbonyl group, ethyl(cyclopropyl)aminocarbonyl group, ethyl(n-butyl)aminocarbonyl group, ethyl(isobutyl)aminocarbonyl group, ethyl(sec-butyl)aminocarbonyl group, ethyl(tert-butyl)aminocarbonyl group, ethyl(cyclobutyl)aminocarbonyl group, n-propyl(isopropyl)aminocarbonyl group, n-propyl(cyclopropyl)aminocarbonyl group, n-propyl(n-butyl)aminocarbonyl group, n-propyl(isobutyl)aminocarbonyl group, n-propyl(sec-butyl)aminocarbonyl group, n-propyl(tert-butyl)aminocarbonyl group, n-propyl(cyclobutyl)aminocarbonyl group, isopropyl(cyclopropyl)aminocarbonyl group, isopropyl(n-butyl)aminocarbonyl group, isopropyl(isobutyl)aminocarbonyl group, isopropyl(sec-butyl)aminocarbonyl group, isopropyl(tert-butyl)aminocarbonyl group, isopropyl(cyclobutyl)aminocarbonyl group, cyclopropyl(n-butyl)aminocarbonyl group, cyclopropyl(isobutyl)aminocarbonyl group, cyclopropyl(sec-butyl)aminocarbonyl group, cyclopropyl(tert-butyl)aminocarbonyl group, cyclopropyl(cyclobutyl)aminocarbonyl group, n-butyl(isobutyl)aminocarbonyl group, n-butyl(sec-butyl)aminocarbonyl group, n-butyl(tert-butyl)aminocarbonyl group, n-butyl(cyclobutyl)aminaka Bonilla group, isobutyl(sec-butyl)aminocarbonyl group, isobutyl(tert-butyl)aminocarbonyl group, isobutyl(cyclobutyl)aminocarbonyl group, sec-butyl(tert-butyl)aminocarbonyl group, sec-butyl(cyclobutyl)aminocarbonyl group and tert-butyl(cyclobutyl)aminocarbonyl group;

examples_1-6alkylcarboxylic groups are methylcarbamyl group, acylcarnitine group, n-propellerblade group, isopropylcarbodiimide group, n-butylcellosolve group, isobutylamine group, sec-butylcellosolve group, tert-butylcellosolve group, 1-intercurrently group, 2-intercurrently group, 3-intercurrently group, isopentenyladenine group, neopentadactyla group, tert-intercurrently group, 1-paxilonline group, 2-paxilonline group and 3-paxilonline group;

examples_3-8cycloalkylcarbonyl groups are cyclopropanecarbonyl group, cyclobutanecarbonyl group, 1-methyl-cyclopropanecarbonyl group, 2-methylcyclopropyl group, cyclopentanecarbonyl group, 1-methylcyclopentadienyl group, 2-methylcyclopentadienyl group, 3-methylcyclopentadienyl group, 1,2-dimethylcyclopropanecarboxylate group, 2,3-dimethylcyclopropanecarboxylate group, 1-atheltic propellerblade group, 2-ethylcyclopentadienyl group, cyclohexylcarbonyl group, cyclohexylcarbonyl group, cyclooctylmethyl group, 1-methyl-cyclohexylcarbonyl group, 2-methylcyclohexylamine group, 3-methylcyclohexylamine group, 1,2-dimethylcyclohexylamine group, 2,3-dimethylcyclopropanecarboxylate group, 1-ethylcyclopentadienyl group, 1-methylcyclopentadienyl group, 2-methylcyclopentadienyl group, 3-methylcyclopentadienyl group, 1-ethylcyclopentadienyl group, 2-ethylcyclopentadienyl group, 3-ethylcyclopentadienyl group, 1,2-dimethylcyclobutyl group, 1,3-dimethylcyclobutyl group, 2,2-dimethylcyclobutyl group, 2,3-dimethylcyclobutyl group, 2,4-dimethylcyclobutane group, 3,3-dimethylcyclobutyl group, 1-n-propylcyclohexanone group, 2-n-propylcyclohexanone group, 1-isopropylcyclopentadienyl group, 2-isopropylcyclopentadienyl group, 1,2,2-trimethylcyclopentanone group, 1,2,3-trimethylcyclopentanone group, 2,2,3-trimethylcyclopentanone group, 1-ethyl-2-methylcyclopentadienyl group, 2-ethyl-1-methylcyclopropyl group, 2-ethyl-2-methylcyclopentadiene GRU is PA and 2-ethyl-3-methylcyclopentadienyl group;

examples_1-6alkoxycarbonyl groups are methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, 1-ventilatsiooniga group, 2-ventilatsiooniga group, 3-ventilatsiooniga group, isobutylacetophenone group, neopentadactyla group, tert-ventilatsiooniga group, 1-hexyloxymethyl group, 2-hexyloxymethyl group and 3-hexyloxymethyl group;

examples_1-6alkylsulfonyl groups are methanesulfonyl group, trifloromethyl group and acanaloniidae group; and

examples_6-14arylsulfonyl groups are benzolsulfonat group, biphenylmethanol group, m-biphenylmethanol group, p-biphenylmethanol group, 1-naphthalenesulfonyl group, 2-naphthalenesulfonyl group, 1-anthracenesulfonic group, 2-anthracenesulfonic group, 9-anthracenemethanol group, 1-fantranslation group, 2-fantranslation group, 3-fantranslation group, 4-fantranslation group and 9-fantranslation group.

Examples_-9 heteroarylboronic groups are_2-6-monocyclic heterocyclic sulfonylurea group having 5-7-membered ring which may contain 1-3 oxygen atoms, nitrogen atoms, sulfur atoms, and combinations thereof, and C_5-9-condensed bicyclic heterocyclic sulfonylurea group having 8 to 10 atoms in the ring.

Examples_2-6monocyclic heterocyclic sulfonyloxy group having 5-7-membered ring are 2-tierralinda group, 3-tierralinda group, 2-fenilalanina group, 3-fenilalanina group, 2-piranishvili group, 3-piranishvili group, 4-piranishvili group, 1-pyrrolylacetylenes group, 2-pyrrolylacetylenes group, 3-pyrrolylacetylenes group, 1-imidazolylalkyl group, 2-imidazolylalkyl group, 4-imidazolylalkyl group, 1-pyrazolecarboxylate group, 3-pyrazolecarboxylate group, 4-pyrazolecarboxylate group, 2-triazolylmethyl group, 4-triazolylmethyl group, 5-triazolylmethyl group, 3-isothiazolinone group, 4-isothiazolinone group, 5-isothiazolinone group, 2-occasionally group, 4-occasionally group, 5-occasionally group, 3-isoxazolecarboxylic group, 4-from casalincontrada group, 5-isoxazolecarboxylic group, 2-pyridylsulfonyl group, 3-pyridylsulfonyl group, 4-pyridylsulfonyl group, 2-pyridinesulfonamide group, 2-pyrimidinemethanol group, 4-pyrimidinemethanol group, 5-pyrimidinemethanol group, 3-pyridinylmethyl group, 4-pyridinylmethyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolidine group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolidine group, 5-1,2,4-thiadiazolidine group, a 3-1,2,5-oxadiazolyl group and 3-1,2,5-thiadiazolidine group.

Examples_5-9-condensed bicyclic heterocyclic sulfonyloxy group having 8 to 10 atoms in the ring are 2-benzofurazanyl group, 3-benzofurazanyl group, 4-benzofurazanyl group, 5-benzofurazanyl group, 6-benzofurazanyl group, 7-benzofurazanyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiazolesulfonamide group, 3-benzothiazolesulfonamide group, 4-benzothiazolesulfonamide group, 5-benzothiazolesulfonamide group, 6-benzothiazolesulfonamide group, 7-inttionalsexguideerna group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromelalumel group, 3-chromelalumel group, 4-chromelalumel group, 5-chromelalumel group, 6-chromelalumel group, 7-chromelalumel group, 8-chromelalumel group, 1-indolylalanine group, 2-indolylalanine group, 3-indolylalanine group, 5-indolylalanine group, 6-indolylalanine group, 7-indolylalanine group, 8-indolylalanine group, 1-isoindoloannulated group, 2-isoindoloannulated group, 4-isoindoloannulated group, 5-isoindoloannulated group, 1-indolylmaleimide group, 2-indolylmaleimide group, 3-indolylmaleimide group, 4-indolylmaleimide group, 5-indolylmaleimide group, 6-indolylmaleimide group, 7-indolylmaleimide group, 1-indotricarbocyanine group, 2-indotricarbocyanine group, 3-indotricarbocyanine group, 4-indotricarbocyanine group, 5-indotricarbocyanine group, 6-indotricarbocyanine group, 7-indotricarbocyanine group, 1-puenylalanine group, 2-puenylalanine group, 3-puenylalanine group, 6-puenylalanine group, 7-purine is sulfonylurea group, 8-puenylalanine group, 2-hinolincarbonova group, 3-hinolincarbonova group, 4-hinolincarbonova group, 5-hinolincarbonova group, 6-hinolincarbonova group, 7-hinolincarbonova group, 8-hinolincarbonova group, 1-ethynodiolthinyl group, 3-ethynodiolthinyl group, 4-ethynodiolthinyl group, 5-ethynodiolthinyl group, 6-ethynodiolthinyl group, 7-ethynodiolthinyl group, 8-ethynodiolthinyl group, 1-phthalodinitrile group, 5-phthalodinitrile group, 6-phthalodinitrile group, 1-2,7-naturalistically group, 3-2,7-naturalistically group, 4-2,7-naturalistically group, 1-2,6-naturalistically group, 3-2,6-naturalistically group, 4-2,6-naturalistically group, 2-1,8-naturalistically group, 3-1,8-naturalistically group, 4-1,8-naturalistically group, 2-1,7-naturalistically group, 3-1,7-naturalistically group, 4-1,7-naturalistically group, 5-1,7-naturalistically group, 6-1,7-naturalistically group, 8-1,7-naturalistically group, 2-1,6-naturalistically group, 3-1,6-naturalistically group, 4-1,6-naturalistically group, 5-1,6-naphthyridines ponilina group, 7-1,6-naturalistically group, 8-1,6-naturalistically group, 2-1,5-naturalistically group, 3-1,5-naturalistically group, 4-1,5-naturalistically group, 6-1,5-naturalistically group, 7-1,5-naturalistically group, 8-1,5-naturalistically group, 2-chynoxalinilmethylen group, 5-chynoxalinilmethylen group, 6-chynoxalinilmethylen group, 2-chineselearnonline group, 4-chineselearnonline group, 5-chineselearnonline group, 6-chineselearnonline group, 7-chineselearnonline group, 8-chineselearnonline group, 3-indolinecarboxylic group, 4-indolinecarboxylic group, 5-indolinecarboxylic group, 6-indolinecarboxylic group, 7-indolinecarboxylic group, 8-indolinecarboxylic group, 2-peridiniella group, 4-peridiniella group, 6-peridiniella group and 7 peridiniella group.

Examples_6-14arylcarboxylic groups are phenylcarbonylamino group, biphenylcarboxylic group, m-biphenylcarboxylic group, p-fenilalanina group, 1-nattermannallee group, 2-nattermannallee group, 1-atilcarnitina group, 2-atilcarnitina group, 9-atilcarnitina group, 1-dryer is tricarbonyl group, 2-financialstability group, 3-financialstability group, 4-financialstability group and 9-financialstability group.

Examples_2-9heteroarylboronic groups are_2-6-monocyclic heterocyclic carbonyl group having 5-7-membered ring which may contain 1-3 oxygen atoms, nitrogen atoms, sulfur atoms, and combinations thereof, and C_5-9-condensed bicyclic heterocyclic carbonyl group having 8 to 10 atoms in the ring.

Examples_2-6monocyclic heterocyclic carbonyl group having 5-7-membered ring are 2-taylorsville group, 3-taylorsville group, 2-forelornly group, 3-forelornly group, 2-pernikarly group, 3-pernikarly group, 4-pernikarly group, 1-pyrrolidinedione group, 2-pyrrolidinone group, 3-pyrrolidinone group, 1-imidazoledicarbonitrile group, 2-imidazoledicarbonitrile group, 4-imidazolecarboxamide group, 1-pyrazolecarboxylate group, 3-pyrazolecarboxylate group, 4-pyrazolecarboxylate group, 2-thiazolecarboxamide group, 4-thiazolecarboxamide group, 5-thiazolecarboxamide group, 3-isothiazolinone group, 4-isothiazolinone group, 5-isothiazolinone group, 2-oxazoline Bonilla group, 4-oxazolidinyl group, 5-oxazolidinyl group, 3-isoxazolecarboxylic group, 4-isoxazolecarboxylic group, 5-isoxazolecarboxylic group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group, 4-pyridylcarbonyl group, 2-pyridinecarboxylic group, 2-pyrimidinecarbonitrile group, 4-pyrimidinecarbonitrile group, 5-pyrimidinecarbonitrile group, 3-pyridinecarboxylic group, 4-pyridinecarboxylic group, 2-1,3,4-oxadiazoline group, 2-1,3,4-thiadiazolidine group, 3-1,2,4-oxadiazolidine group, 5-1,2,4-oxadiazolidine group, 3-1,2,4-thiadiazolidine group, 5-1,2,4-thiadiazolidine group, a 3-1,2,5-oxadiazolidine group and 3-1,2,5-thiadiazolidine group.

Examples_5-9-condensed bicyclic heterocyclic carbonyl group having 8 to 10 atoms in the ring are 2-benzofurazanyl group, 3-benzofurazanyl group, 4-benzofurazanyl group, 5-benzofurazanyl group, 6-benzofurazanyl group, 7-benzofurazanyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiadiazole group, 3-benzothiadiazole group, 4-benzac talkability group, 5-benzothiadiazole group, 6-benzothiadiazole group, 7-benzothiadiazole group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromenickel group, 3-chromenickel group, 4-chromenickel group, 5-chromenickel group, 6-chromenickel group, 7-chromenickel group, 8-chromenickel group, 1-indolizinecarboxamides group, 2-indolizinecarboxamides group, 3-indolizinecarboxamides group, 5-indolizinecarboxamides group, 6-indolizinecarboxamides group, 7-indolizinecarboxamides group, 8-indolizinecarboxamides group, 1-soundararaja group, 2-soundararaja group, 4-soundararaja group, 5-soundararaja group, 1-indolocarbazole group, 2-indolinecarboxylic group, 3-indolocarbazole group, 4-indolocarbazole group, 5-indolocarbazole group, 6-indolocarbazole group, 7-indolocarbazole group, 1-indotricarbocyanine group, 2-indotricarbocyanine group, 3-indotricarbocyanine group, 4-indotricarbocyanine group, 5-indotricarbocyanine group, 6-indotricarbocyanine group, 7-indotricarbocyanine group, 1-painikkeella group, 2-painikkeella group, 3-purine is carbonilla group, 6-painikkeella group, 7-painikkeella group, 8-painikkeella group, 2-hinolincarbonova group, 3-hinolincarbonova group, 4-hinolincarbonova group, 5-hinolincarbonova group, 6-hinolincarbonova group, 7-hinolincarbonova group, 8-hinolincarbonova group, 1-isopinolcamphone group, 3-isopinolcamphone group, 4-isopinolcamphone group, 5-isopinolcamphone group, 6-isopinolcamphone group, 7-isopinolcamphone group, 8-isopinolcamphone group, 1-phthalodinitrile group, 5-phthalodinitrile group, 6-phthalodinitrile group, 1-2,7-naturalenvironment group, 3-2,7-naturalenvironment group, 4-2,7-naturalenvironment group, 1-2,6-naturalenvironment group, 3-2,6-naturalenvironment group, 4-2,6-naturalenvironment group, 2-1,8-naturalenvironment group, 3-1,8-naturalenvironment group, 4-1,8-naturalenvironment group, 2-1,7-naturalenvironment group, 3-1,7-naturalenvironment group, 4-1,7-naturalenvironment group, 5-1,7-naturalenvironment group, 6-1,7-naturalenvironment group, 8-1,7-naturalenvironment group, 2-1,6-naturalenvironment group, 3-1,6-naturalenvironment group, 4-1,6-naturalenvironment group 5-1,6-naturalenvironment group, 7-1,6-naturalenvironment group, 8-1,6-naturalenvironment group, 2-1,5-naturalenvironment group, 3-1,5-naturalenvironment group, 4-1,5-naturalenvironment group, 6-1,5-naturalenvironment group, 7-1,5-naturalenvironment group, 8-1,5-naturalenvironment group, 2-inoxidizability group, 5-inoxidizability group, 6-inoxidizability group, 2-girasolereale group, 4-girasolereale group, 5-girasolereale group, 6-girasolereale group, 7-girasolereale group, 8-girasolereale group, 3-indolinecarboxylic group, 4-indolinecarboxylic group, 5-indolinecarboxylic group, 6-indolinecarboxylic group, 7-indolinecarboxylic group, 8-indolinecarboxylic group, 2-peridiniella group, 4-peridiniella group, 6-peridiniella group and 7 peridiniella group.

R¹²and R¹³in the formula (a), formula (b), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), the formula (p), formula (q), formula (v), formula (w), formula (x), formula (AB), formula (AE), formula (AF) and the formula (ad), preferably represent a hydrogen atom, methyl group, ethyl group, n-through is the Rupp, ISO-propyl group, n-boutelou group, n-pentelow group, isopentyl group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, methoxycarbonylamino group, ethoxycarbonylethyl group, phenyl group, o-biphenylyl group, m-biphenylyl group, p-biphenylyl group, 1-naftalina group, 2-naftalina group, 2-pyridyloxy group, 3-pyridyloxy group, 4-pyridyloxy group, methylaminomethyl group, ethylaminomethyl group, n-propylaminosulfonyl group, isopropylaminocarbonyl group, n-butylaminoethyl group, dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, di-n-propylaminoethyl group, diisopropylaminoethyl group, dicyclopentadienyl group, di-n-butylaminoethyl group, methylcarbamyl group, ethylcarbitol group, n-propelleronline group, isopropylcarbodiimide group, n-butylcarbamoyl group, Cyclops is nicarbazine group, cyclohexylcarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxyethanol group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, methanesulfonyl group, trifloromethyl group, benzosulfimide group, biphenylmethanol group, m-biphenylmethanol group, p-biphenylmethanol group, 1-naphthalenesulfonyl group, 2-naphthalenesulfonyl group, 2-pyridylsulfonyl group, 3-pyridylsulfonyl group, 4-pyridylsulfonyl group, phenylcarbonylamino group, biphenylcarboxylic group, m-biphenylcarboxylic group, p-biphenylcarboxylic group, 1-afterburning group, 2-afterburning group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group and 4-pyridylcarbonyl group, and more preferably, hydrogen atom and methyl group.

R^14,R¹⁵, R¹⁶and R¹⁷in the formula (a), formula (b), formula (C), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), the formula (s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and is ormula (af) described below. Each of R^14,R¹⁵, R¹⁶and R¹⁷in the formula (a), formula (b), formula (C), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), the formula (s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and formula (af) independently represents a hydrogen atom, a halogen atom, a C_1-6alkyl group (alcalina group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_6-14aryl group, With_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)),_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic,_1-6alkylcarboxylic group (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), With_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group_1-6alkoxycarbonyl group_1-6alkylsulfonyl group (recloak carbonilla group, alkoxycarbonyl group and alkylsulfonyl group can be optionally substituted by halogen atom), a carboxyl group, With_6-14arylcarbamoyl group (arylcarbamoyl group may be optionally substituted by a halogen atom) or (C_2-9heteroarylboronic group)_3-8cycloalkyl group (cycloalkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group)_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom, or With_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom)), a carboxyl group, an amino group, a hydroxy-group, With_6-14aryl group or_2-9heteroaryl group (each of the aryl and heteroaryl groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q))),_1-6dialkoxy (Tolkacheva may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), a carboxyl group, a hydroxy-group, With_6-14aryl group or_2-9heteroarenes group (which each of the aryl and heteroaryl groups may be optionally substituted rR ¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q))), a hydroxy-group, With_6-14aryl group or_2-9heteroaryl group, each of the aryl and heteroaryl groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)),_1-6alkylcarboxylic, a nitrogroup, cyano, formyl group, formamide group, amino group, alphagroup,_1-6alkylamino, di-C_1-6alkylamino,_6-14killingray,_2-9geteroarilsulfoksidu (each of arylamino and heteroelement may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)),_1-6alkylcarboxylic,_1-6alkylsulfonamides group, carbamoyl group_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_6-14arylcarbamoyl group_2-9heteroarylboronic group (any arylcarboxylic and heteroarylboronic groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)),_1-6alkoxycarbonyl group, sulfamoyl group _1-6alkylsulfonyl group_6-14arylsulfonyl group_2-9heteroarylboronic group (any arylsulfonyl and heteroarylboronic groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)), carboxyl group or_2-9heterocyclyl group (heterocyclyl group may be optionally substituted by a halogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, carboxyl group or hydroxy-group)_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), With_6-14aryl group, With_2-9heteroaryl group each of the aryl and heteroaryl groups may be optionally substituted rR¹⁹(R¹⁹has the same meanings as R¹¹; r has the same value as q)), hydroxy-group, a nitrogroup, cyano, formyl group, formamide group, amino group, With_1-6alkylaminocarbonyl, di - C_1-6alkylaminocarbonyl,_1-6alkylaminocarbonyl group_1-6alkylsulfonamides group, carbamoyl group_1-6alkylamino bonalnoy group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_1-6alkoxycarbonyl group, sulfamoyl group_1-6alkylsulfonyl group, a carboxyl group or_6-14arylcarboxylic group).

Each atom and each group Deputy for R¹⁴, R¹⁵, R¹⁶and R¹⁷in the formula (a), formula (b), formula (C), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), the formula (s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (AB), formula (AC), formula (ad), formula (AE) and formula (AF) is specifically described below. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom. Examples_1-6alkyl groups are methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 2-pencilina group, 3-pencilina group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, n-exilda group, 2-exilda group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group, 3,3-dimethyl-n-bucilina group, methylcarbonate is a methyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, methoxycarbonylethyl group and ethoxycarbonylethyl group;

examples_3-8cycloalkyl groups are cyclopropyl, cyclobutyl, 1-methyl-cyclopropyl, 2-methyl-cyclopropyl, cyclopentyl, 1-methyl-cyclobutyl, 2-methyl-cyclobutyl, 3-methyl-cyclobutyl, 1,2-dimethylcyclopropane, 2,3-dimethylcyclopropane, 1-ethylcyclopropane, 2-ethylcyclopropane, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 1,2-dimethylcyclohexyl, 2,3-dimethylcyclopropane, 1-ethylcyclopropane, 1-methylcyclopentanol, 2-methylcyclopentene, 3-methyl-cyclopentyl, 1-ethylcyclohexyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 1,2-dimethylcyclobutyl, 1,3-dimethylcyclobutyl, 2,2-dimethylcyclobutyl, 2,3-dimethylcyclobutyl, 2,4-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, 1-n-propylcyclohexyl, 2-n-propylcyclohexyl, 1-isopropylcyclohexane, 2-isopropylcyclohexane, 1,2,2-trimethylpropyl, 1,2,3-trimethylpropyl, 2,2,3-trimethylpropyl, 1-ethyl-2-methylcyclopropyl, 2-ethyl-1-methylcyclopropyl, 2-ethyl-2-methylcyclopropyl 2-ethyl-3-methylcyclopropyl;

examples_1-6alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentylamine, neopentadactyla, 2,2-DIMETHYLPROPANE, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxylate, 1,2,2-trimethyl-n-propoxylate and 3,3-dimethyl-n-butoxypropan;

examples_1-6toolcategory are methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropyl, n-butylthio, isobutyric, sec-butylthio, tert-butylthio, n-pentylthio, isopentyl, neopentyl, tert-pentylthio, n-hexylthio, cyclohexylthio; and

examples_6-14aryl group are phenyl group, o-biphenylene group, m-biphenylene group, p-biphenylene group, 1-naftalina group, 2-naftalina group, 1-antenna group, 2-antenna group, 9-antenna group, 1-phenanthroline group, 2-phenanthroline group, 3-phenanthroline group, 4-phenanthroline group and 9-phenanthroline group.

Examples_2-9heteroaryl groups are_2-6-monocyclic heterocyclic group having 5 to 7-membered ring which may contain 1-3 oxygen atoms, nitrogen atoms, and the Ohm sulfur and combinations thereof, and C_5-9-condensed bicyclic heterocyclic group having 8 to 10 atoms in the ring.

Examples_2-6monocyclic heterocyclic group having 5 to 7-membered ring are the 2-thienyl group, 3-thienyl group, 2-furilla group, 3-furilla group, 2-Pernilla group, 3-Pernilla group, 4-Pernilla group, 1-pyrrolidine group, 2-pyrrolidine group, 3-pyrrolidine group, 1-imidazolidinyl group, 2-imidazolidinyl group, 4-imidazolidinyl group, 1-pyrazolidine group, 3-pyrazolidine group, 4-pyrazolidine group, 2-thiazolidine group, 4-thiazolidine group A 5-thiazolidine group, 3-isothiazolinone group, 4-isothiazoline group, 5-isothiazolinone group, 2-oxazolidinyl group, 4-oxazolidinyl group, 5-oxazolidinyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-Peregrina group, 3-Peregrina group, 4-Peregrina group, 2-pyridinoline group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolidine group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolyl group, 5-1,2,4-thiadiazolyl group, a 3-1,2,5-oxadiazolyl group and 3-1,2,5-thiadiazolyl group.

Note the Rami _5-9-condensed bicyclic heterocyclic group having 8 to 10 atoms in the ring are 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiazoline group, 3-benzothiazoline group, 4-benzothiazoline group, 5-benzothiazoline group, 6-benzothiazoline group, 7-benzothiazoline group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromadorina group, 3-chromadorina group, 4-chromadorina group, 5-chromadorina group, 6-chromadorina group, 7-chromadorina group, 8-chromadorina group, 1-indolizinyl group, 2-indolizinyl group, 3-indolizinyl group, 5-indolizinyl group, 6-indolizinyl group, 7-indolizinyl group, 8-indolizinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indlela group, 2-indlela group, 3-indlela group, 4-indlela group, 5-indlela group, 6-indlela group, 7-indlela group, 1-indazolinone group, 2-indazolinone group, 3-indazolinone group, 4-indazolinone group, 5-indazolinone group, 6-indazolinone the group, 7-indazolinone group, 1-polylina group, 2-polylina group, 3-polylina group, 6-polylina group, 7-polylina group, 8-polylina group, 2-kinolinna group, 3-kinolinna group, 4-kinolinna group, 5-kinolinna group, 6-kinolinna group, 7-kinolinna group, 8-kinolinna group, 1-izochinolina group, 3-izochinolina group, 4-izochinolina group, 5-izochinolina group, 6-izochinolina group, 7-izochinolina group, 8-izochinolina group, 1-vladimirka group, 5-vladimirka group, 6-vladimirka group, 1-2,7-naphthyridinone group, 3-2,7-naphthyridinone group, 4-2,7-naphthyridinone group, 1-2,6-naphthyridinone group, 3-2,6-naphthyridinone group, 4-2,6-naphthyridinone group, 2-1,8-naphthyridinone group, 3-1,8-naphthyridinone group, 4-1,8-naphthyridinone group, 2-1,7-naphthyridinone group, 3-1,7-naphthyridinone group, 4-1,7-naphthyridinone group, 5-1,7-naphthyridinone group, 6-1,7-naphthyridinone group, 8-1,7-naphthyridinone group, 2-1,6-naphthyridinone group, 3-1,6-naphthyridinone group, 4-1,6-naphthyridinone group, 5-1,6-naphthyridinone group, 7-1,6-naphthyridinone group, 8-1,6-naphthyridinone group, 2-1,5-naphthyridinone group, 3-1,5-naphthyridinone group, 4-1,5-naphthyridinone group, 6-1,5-naphthyridinone group, 7-1,5-naphthyridinone group, 8-1,5-nattered nilina group, 2-khinoksalinona group, 5-khinoksalinona group, 6-khinoksalinona group, 2-chinadaily group, 4-chinadaily group, 5-chinadaily group, 6-chinadaily group, 7-chinadaily group, 8-chinadaily group, 3-indolenine group, 4-indolenine group, 5-indolenine group, 6-indolenine group, 7-indolenine group, 8-indolenine group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group and 7 peridiniella group.

Examples_1-6alkylcarboxylic are methylcarbonate, ethylcarboxylate, n-propylmalonate, isopropylcarbonate, n-butylcarbamoyl, isobutyryloxy, second-butylcarbamoyl, tert-butylcarbamoyl, 1-intercambiablesup, 2-intercambiablesup, 3-intercambiablesup, isopentenyladenosine, neopentadactyla, tert-intercambiablesup, 1-hexylcinnamaldehyde, 2-hexylcinnamaldehyde, 3-hexylcinnamaldehyde, 1-methyl-n-intercambiablesup, 1,1,2-trimethyl-n-propylmalonate, 1,2,2-trimethyl-n-propylmalonate and 3,3-dimethyl-n-BUTYLCARBAMATE;

examples_1-6alkylamino are methylaminopropyl, atramentaria, n-propylamino, isoprop luminograph, cyclopropylamino, n-butylamino, isobutylamino, second-butylamino, tert-butylamino, cyclobutylamine, 1-pentylamine, 2-pentylamine, 3-pentylamine, isopentylamine, neopentylene, tert-pentylamine, cyclopentylamine, 1-hexylamine, 2-hexylamine, 3-hexylamino, cyclohexylamino, 1-methyl-n-pentylamine, 1,1,2-trimethyl-n-propylamino, 1,2,2-trimethyl-n-propylamino and 3,3-dimethyl-n-butylamine;

examples of di-C_1-6alkylamino are dimethylaminopropan, diethylaminopropyl, di-n-propylamino, di-isopropylamino, Dicyclopentadiene, di-n-butylamino, diisobutylamine, di-sec-butylamino, di-tert-butylamino, bicyclobutane, di-1-pentylamine, di-2-pentylamine, di-3-pentylamine, diisobutylamine, dineopentyl, di-tert-pentylamine, di-cyclopentylamine, di-1-hexylamine, di-2-hexylamine, di-3-hexylamino, dicyclohexylamine, di-(1-methyl-n pentyl)amino group, di-(1,1,2-trimethyl-n-propyl)amino group, di-(1,2,2-trimethyl-n-propyl)amino group, di-(3,3-dimethyl-n-butyl)amino group, methyl(ethyl)amino group, methyl(n-propyl)amino group, methyl(isopropyl)amino group, METI the(cyclopropyl)amino group, methyl(n-butyl)amino group, methyl(isobutyl)amino group, methyl(sec-butyl)amino group, methyl(tert-butyl)amino group, methyl(cyclobutyl)amino group, ethyl(n-propyl)amino group, ethyl(isopropyl)amino group, ethyl(cyclopropyl)amino group, ethyl(n-butyl)amino group, ethyl(isobutyl)amino group, ethyl(sec-butyl)amino group, ethyl(tert-butyl)amino group, ethyl(cyclobutyl)amino group, n-propyl(isopropyl)amino group, n-propyl(cyclopropyl)amino group, n-propyl(n-butyl)amino group, n-propyl(isobutyl)amino group, n-propyl(sec-butyl)amino group, n-propyl(tert-butyl)amino group, n-propyl(cyclobutyl)amino group, isopropyl(cyclopropyl)amino group, isopropyl(n-butyl)amino group, isopropyl(isobutyl)amino group, isopropyl(sec-butyl)amino group, isopropyl(tert-butyl)amino group, isopropyl(cyclobutyl)amino group, cyclopropyl(n-butyl)amino group, cyclopropyl(isobutyl)amino group, cyclopropyl(sec-butyl)amino group, cyclopropyl(tert-butyl)amino group, cyclopropyl(cyclobutyl)amino group, n-butyl(isobutyl)amino group, n-butyl(sec-butyl)amino group, n-butyl(tert-butyl)amino group, n-butyl(cyclobutyl)amino group, isobutyl(sec-butyl)amino group, isobutyl(tert-butyl)amino group, isobutyl(cyclobutyl)amino group, sec-butyl(tert-butyl)amino group, second-butyl(cyclobutyl)amino group and tert-butyl(cyclobutyl)aminogroup is a;

examples_6-14killingray are phenylaminopropyl, biphenylamine, m-biphenylamine, p-biphenylamine, 1-naphthylamine, 2-naphthylamine, 1-intellimorph, 2-intellimorph, 9-intellimorph, 1-financiamiento, 2-financiamiento, 3-financiamiento, 4-financiamiento and 9-financiamiento; and

examples_2-9heteroarylboronic are_2-6-monocyclic heterocyclic amino group having 5-7-membered ring which may contain 1-3 oxygen atoms, nitrogen atoms, sulfur atoms, and combinations thereof, and C_5-9-condensed bicyclic heterocyclic amino group having 8 to 10 atoms in the ring.

Examples_2-6monocyclic heterocyclic amino group having 5-7-membered ring are 2-trilaminar, 3-trilaminar, 2-filmikauppa, 3-filmikauppa, 2-pernilleborup, 3-pernilleborup, 4-pernilleborup, 1-pyrrolidinone, 2-pyrrolidinone, 3-pyrrolidinone, 1-imidazolidinone, 2-imidazolidinone, 4-imidazolidinone, 1-pyrazolidinone, 3-pyrazolidinone, 4-pyrazolidinone, 2-thiazolidinone, 4-thiazolidinone, 5-thiazolidinone, 3-isothiazolinone, 4-isothiazolinone, 5-isothiazol luminograph, 2-oxazolidinone, 4-oxazolidinone, 5-oxazolidinone, 3-isoxazolidinone, 4-isoxazolidinone, 5-isoxazolidinone, 2-pyridylamino, 3-pyridylamino, 4-pyridylamino, 2-pyridinylamino, 2-pyrimidinamine, 4-pyrimidinamine, 5-pyrimidinediamine, 3-pyridinylamino, 4-pyridinylamino, 2-1,3,4-oxadiazoline, 2-1,3,4-thiadiazolidine, 3-1,2,4-oxadiazolidine, 5-1,2,4-oxadiazolidine, 3-1,2,4-thiadiazolidine, 5-1,2,4-thiadiazolidine, 3-1,2,5-oxadiazolidine and 3-1,2,5-thiadiazolidine.

Examples_5-9-condensed bicyclic heterocyclic amino group having 8 to 10 atoms in the ring are 2-benzoguanamine, 3-benzoguanamine, 4-benzoguanamine, 5-benzoguanamine, 6-benzoguanamine, 7-benzoguanamine, 1-isobenzofurandione, 4-isobenzofurandione, 5-isobenzofurandione, 2-benzothiazolinone, 3-benzothiazolinone, 4-benzothiazolinone, 5-benzothiazolinone, 6-benzothiazolinone, 7-benzothiazolinone, 1-isobenzofuranone, 4-isobenzofurandione, 5-isobenzofurandione, 2-hermanellonota, 3-hermanellonota, 4-hermanellonota-hermanellonota, 6-hermanellonota, 7-hermanellonota, 8-hermanellonota, 1-ingredientallegra, 2-ingredientallegra, 3-ingredientallegra, 5-ingredientallegra, 6-ingredientallegra, 7-ingredientallegra, 8-ingredientallegra, 1-isoindoline, 2-isoindoline, 4-isoindoline, 5-isoindoline, 1-indoleamines, 2-indoleamines, 3-indoleamines, 4-indoleamines, 5-indoleamines, 6-indoleamines, 7-indoleamines, 1-indazolinone, 2-indazolinone, 3-indazolinone, 4-indazolinone, 5-indazolinone, 6-indazolinone, 7-indazolinone, 1-polylaminate, 2-polylaminate, 3-polylaminate, 6-polylaminate, 7-polylaminate, 8-polylaminate, 2-chinarating, 3-chinarating, 4-chinarating, 5-chinarating, 6-chinarating, 7-chinarating, 8-chinarating, 1-ethanolamine, 3-ethanolamine, 4-ethanolamine, 5-ethanolamine, 6-ethanolamine, 7-ethanolamine, 8-ethanolamine, 1-palatinolinotype, 5-palatinolinotype, 6-palatinolinotype, 1-2,7-naphthyridinone, 3-2,7-naphthyridinone, 4-2,7-naphthyridinone, 1-2,6-naphthyridin luminograph, 3-2,6-naphthyridinone, 4-2,6-naphthyridinone, 2-1,8-naphthyridinone, 3-1,8-naphthyridinone, 4-1,8-naphthyridinone, 2-1,7-naphthyridinone, 3-1,7-naphthyridinone, 4-1,7-naphthyridinone, 5-1,7-naphthyridinone, 6-1,7-naphthyridinone, 8-1,7-naphthyridinone, 2-1,6-naphthyridinone, 3-1,6-naphthyridinone, 4-1,6-naphthyridinone, 5-1,6-naphthyridinone, 7-1,6-naphthyridinone, 8-1,6-naphthyridinone, 2-1,5-naphthyridinone, 3-1,5-naphthyridinone, 4-1,5-naphthyridinone, 6-1,5-naphthyridinone, 7-1,5-naphthyridinone, 8-1,5-naphthyridinone, 2-hinoklidilkarbinola, 5-hinoklidilkarbinola, 6-hinoklidilkarbinola, 2-hiazolidinedione, 4-hiazolidinedione, 5-hiazolidinedione, 6-hiazolidinedione, 7-hiazolidinedione, 8-hiazolidinedione, 3-sinolingua, 4-sinolingua, 5-sinolingua, 6-sinolingua, 7-sinolingua, 8-sinolingua, 2-peridiniella, 4-peridiniella, 6-peridiniella and 7-peridiniella.

Examples_1-6alkylcarboxylic are methylcobalamine, ethylcarbodiimide, n-propylnitrosamine is a, isopropylcarbodiimide, n-BUTYLCARBAMATE, isobutyleneisoprene, second-BUTYLCARBAMATE, tert-BUTYLCARBAMATE, 1-intelcorporation, 2-intelcorporation, 3-intelcorporation, isopentenyladenine, neopentylmagnesium, tert-intelcorporation, 1-hexylcinnamaldehyde, 2-hexylcinnamaldehyde and 3-hexylcinnamaldehyde;

examples_1-6alkylsulfonamides groups are methanesulfonamido group, acanaloniidae group, n-propanesulfinamide group, isopropanolamine group, n-butanesulfinamide group, isobutylphenyl group, sec-butanesulfinamide group, tert-butanesulfinamide group, 1-pentanesulfonate group, 2-pentanesulfonate group, 3-pentanesulfonate group, isopentenyladenine group, neopentylene group, tert-pentanesulfonate group, 1-hexanesulfonate group, 2-hexanesulfonate group and 3-hexanesulfonate group;

examples_1-6alkylaminocarbonyl groups are methylaminomethyl group, ethylaminomethyl group, n-propylaminosulfonyl group, isopropylaminocarbonyl group, n-butylaminoethyl group, isobutyleneisoprene group, sec-b is tramadolonline group, tert-butylaminoethyl group, 1-intramyocardially group, 2-intramyocardially group, 3-intramyocardially group, isopentenyladenine group, neopentadactyla group, tert-intramyocardially group, 1-hexylaniline group, 2-hexylaniline group and 3-hexylaniline group;

examples of di-C_1-6alkylaminocarbonyl groups are dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, di-n-propylaminoethyl group, diisopropylaminoethyl group, dicyclopentadienyl group, di-n-butylaminoethyl group, diisobutyldimethoxysilane group, di-sec-butylisoxazole group, di-tert-butylaminoethyl group, Dicyclopentadiene group, di-1-intramyocardially group, di-2-intramyocardially group, di-3-intramyocardially group, di-isopentenyladenine group, lineapellebologna group, di-tert-intramyocardially group, dicyclopentadienyl group, di-1-hexylaniline group, di-2-hexylaniline group, di-3-hexylaniline group, dicyclohexylcarbodimide group, di-(1-methyl-n-pentyl)aminocarbonyl group, di-(1,1,2-trimethyl-n-propyl)aminocarbonyl the Naya group, di-(1,2,2-trimethyl-n-propyl)aminocarbonyl group, di-(3,3-dimethyl-n-butyl)aminocarbonyl group, methyl(ethyl)aminocarbonyl group, methyl(n-propyl)aminocarbonyl group, methyl(isopropyl)aminocarbonyl group, methyl(cyclopropyl)aminocarbonyl group, methyl(n-butyl)aminocarbonyl group, methyl(isobutyl)aminocarbonyl group, methyl(sec-butyl)aminocarbonyl group, methyl(tert-butyl)aminocarbonyl group, methyl(cyclobutyl)aminocarbonyl group, ethyl(n-propyl)aminocarbonyl group, ethyl(isopropyl)aminocarbonyl group, ethyl(cyclopropyl)aminocarbonyl group, ethyl(n-butyl)aminocarbonyl group, ethyl(isobutyl)aminocarbonyl group, ethyl(sec-butyl)aminocarbonyl group, ethyl(tert-butyl)aminocarbonyl group, ethyl(cyclobutyl)aminocarbonyl group, n-propyl(isopropyl)aminocarbonyl group, n-propyl(cyclopropyl)aminocarbonyl group, n-propyl(n-butyl)aminocarbonyl group, n-propyl(isobutyl)aminocarbonyl group, n-propyl(sec-butyl)aminocarbonyl group, n-propyl(tert-butyl)aminocarbonyl group, n-propyl(cyclobutyl)aminocarbonyl group, isopropyl(cyclopropyl)aminocarbonyl group, isopropyl(n-butyl)aminocarbonyl group, isopropyl(isobutyl)aminocarbonyl group, isopropyl(sec-butyl)aminocarb nilina group, isopropyl(tert-butyl)aminocarbonyl group, isopropyl(cyclobutyl)aminocarbonyl group, cyclopropyl(n-butyl)aminocarbonyl group, cyclopropyl(isobutyl)aminocarbonyl group, cyclopropyl(sec-butyl)aminocarbonyl group, cyclopropyl(tert-butyl)aminocarbonyl group, cyclopropyl(cyclobutyl)aminocarbonyl group, n-butyl(isobutyl)aminocarbonyl group, n-butyl(sec-butyl)aminocarbonyl group, n-butyl(tert-butyl)aminocarbonyl group, n-butyl(cyclobutyl)aminocarbonyl group, isobutyl(Deut-butyl)aminocarbonyl group, isobutyl(tert-butyl)aminocarbonyl group, isobutyl(cyclobutyl)aminocarbonyl group, sec-butyl(tert-butyl)aminocarbonyl group, sec-butyl(cyclobutyl)aminocarbonyl group and tert-butyl(cyclobutyl)aminocarbonyl group;

examples_1-6alkylcarboxylic groups are methylcarbamyl group, acylcarnitine group, n-propellerblade group, isopropylcarbodiimide group, n-butylcellosolve group, isobutylamine group, sec-butylcellosolve group, tert-butylaminoethyl group, 1-intercurrently group, 2-intercurrently group, 3-intercurrently group, isopentenyladenine group, neopentadactyla group, tert-intercurrently group, 1-hexylcaine the other group, 2-paxilonline group and 3-paxilonline group; and

examples_6-14arylcarboxylic groups are phenylcarbonylamino group, biphenylcarboxylic group, m-biphenylcarboxylic group, p-fenilalanina group, 1-nattermannallee group, 2-nattermannallee group, 1-atilcarnitina group, 2-atilcarnitina group, 9-atilcarnitina group, 1-financialstability group, 2-financialstability group, 3-financialstability group, 4-financialstability group and 9-financialstability group.

Examples_2-9heteroarylboronic groups are_2-6-monocyclic heterocyclic carbonyl group having 5-7-membered ring which may contain 1-3 oxygen atoms, nitrogen atoms, sulfur atoms, and combinations thereof, and C_5-9-condensed bicyclic heterocyclic carbonyl group having 8 to 10 atoms in the ring.

Examples_2-6monocyclic heterocyclic carbonyl group having 5-7-membered ring are 2-taylorsville group, 3-taylorsville group, 2-forelornly group, 3-forelornly group, 2-pernikarly group, 3-pernikarly group, 4-pernikarly group, 1-pyrrolidinedione group, 2-pyrrolidinone group, 3-pyrrolidinone the other group, 1-imidazoledicarbonitrile group, 2-imidazoledicarbonitrile group, 4-imidazolecarboxamide group, 1-pyrazolecarboxylate group, 3-pyrazolecarboxylate group, 4-pyrazolecarboxylate group, 2-thiazolecarboxamide group, 4-thiazolecarboxamide group, 5-thiazolecarboxamide group, 3-isothiazolinone group, 4-isothiazolinone group, 5-isothiazolinone group, 2-oxazolidinyl group, 4-oxazolidinyl group, 5-oxazolidinyl group, 3-isoxazolecarboxylic group, 4-isoxazolecarboxylic group, 5-isoxazolecarboxylic group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group, 4-pyridylcarbonyl group, 2-pyridinecarboxylic group, 2-pyrimidinecarbonitrile group, 4-pyrimidinecarbonitrile group, 5-pyrimidinecarbonitrile group, 3-pyridinecarboxylic group, 4-pyridinecarboxylic group, 2-1,3,4-oxadiazoline group, 2-1,3,4-thiadiazolidine group, 3-1,2,4-oxadiazolidine group, 5-1,2,4-oxadiazolidine group, 3-1,2,4-thiadiazolidine group, 5-1,2,4-thiadiazolidine group, a 3-1,2,5-oxadiazolidine group and 3-1,2,5-thiadiazolidine group.

Examples_5-9-condensed bicyclic heterocyclic carbonyl group having 8 to 10 atoms is a ring, are 2-benzofurazanyl group, 3-benzofurazanyl group, 4-benzofurazanyl group, 5-benzofurazanyl group, 6-benzofurazanyl group, 7-benzofurazanyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiadiazole group, 3-benzothiadiazole group, 4-benzothiadiazole group, 5-benzothiadiazole group, 6-benzothiadiazole group, 7-benzothiadiazole group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromenickel group, 3-chromenickel group, 4-chromenickel group, 5-chromenickel group, 6-chromenickel group, 7-chromenickel group, 8-chromenickel group, 1-indolizinecarboxamides group, 2-indolizinecarboxamides group, 3-indolizinecarboxamides group, 5-indolizinecarboxamides group, 6-indolizinecarboxamides group, 7-indolizinecarboxamides group, 8-indolizinecarboxamides group, 1-soundararaja group, 2-soundararaja group, 4-soundararaja group, 5-soundararaja group, 1-indolocarbazole group, 2-indolinecarboxylic group, indolocarbazole group, 4-indolocarbazole group, 5-indolocarbazole group, 6-indolocarbazole group, 7-indolocarbazole group, 1-indotricarbocyanine group, 2-indotricarbocyanine group, 3-indotricarbocyanine group, 4-indotricarbocyanine group, 5-indotricarbocyanine group, 6-indotricarbocyanine group, 7-indotricarbocyanine group, 1-painikkeella group, 2-painikkeella group, 3-painikkeella group, 6-painikkeella group, 7-painikkeella group, 8-painikkeella group, 2-hinolincarbonova group, 3-hinolincarbonova group, 4-hinolincarbonova group, 5-hinolincarbonova group, 6-hinolincarbonova group, 7-hinolincarbonova group, 8-hinolincarbonova group, 1-isopinolcamphone group, 3-isopinolcamphone group, 4-isopinolcamphone group, 5-isopinolcamphone group, 6-isopinolcamphone group, 7-isopinolcamphone group, 8-isopinolcamphone group, 1-phthalodinitrile group, 5-phthalodinitrile group, 6-phthalodinitrile group, 1-2,7-naturalenvironment group, 3-2,7-naturalenvironment group, 4-2,7-naturalenvironment group, 1-2,6-naturalenvironment group, 3-2,6-naturalenvironment group, 4-2,6-naturalenvironment group, 2-1,8-naphthyridine the carbonyl group, 3-1,8-naturalenvironment group, 4-1,8-naturalenvironment group, 2-1,7-naturalenvironment group, 3-1,7-naturalenvironment group, 4-1,7-naturalenvironment group, 5-1,7-naturalenvironment group, 6-1,7-naturalenvironment group, 8-1,7-naturalenvironment group, 2-1,6-naturalenvironment group, 3-1,6-naturalenvironment group, 4-1,6-naturalenvironment group, 5-1,6-naturalenvironment group, 7-1,6-naturalenvironment group, 8-1,6-naturalenvironment group, 2-1,5-naturalenvironment group, 3-1,5-naturalenvironment group, 4-1,5-naturalenvironment group, 6-1,5-naturalenvironment group, 7-1,5-naturalenvironment group, 8-1,5-naturalenvironment group, 2-inoxidizability group, 5-inoxidizability group, 6-inoxidizability group, 2-girasolereale group, 4-girasolereale group, 5-girasolereale group, 6-girasolereale group, 7-girasolereale group, 8-girasolereale group, 3-indolinecarboxylic group, 4-indolinecarboxylic group, 5-indolinecarboxylic group, 6-indolinecarboxylic group, 7-indolinecarboxylic group, 8-indolinecarboxylic group, 2-peridiniella group, 4-pteridine the carbonyl group, 6-peridiniella group and 7 peridiniella group.

Examples_1-6alkoxycarbonyl groups are methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, 1-ventilatsiooniga group, 2-ventilatsiooniga group, 3-ventilatsiooniga group, isobutylacetophenone group, neopentadactyla group, tert-ventilatsiooniga group, 1-hexyloxymethyl group, 2-hexyloxymethyl group and 3-hexyloxymethyl group; and

examples_1-6alkylsulfonyl groups are methanesulfonyl group, trifloromethyl group and acanaloniidae group. Examples_6-14arylsulfonyl groups are benzolsulfonat group, biphenylmethanol group, m-biphenylmethanol group, p-biphenylmethanol group, 1-naphthalenesulfonyl group, 2-naphthalenesulfonyl group, 1-anthracenesulfonic group, 2-anthracenesulfonic group, 9-anthracenemethanol group, 1-fantranslation group, 2-fantranslation group, 3-fantranslation group, 4-fantranslation the group, and 9-fantranslation group.

Examples_2-9heteroarylboronic groups are_2-6-monocyclic heterocyclic sulfonylurea group having 5-7-membered ring which may contain 1-3 oxygen atoms, nitrogen atoms, sulfur atoms, and combinations thereof, and C_5-9-condensed bicyclic heterocyclic sulfonylurea group having 8 to 10 atoms in the ring. Examples_2-6monocyclic heterocyclic sulfonyloxy group having 5-7-membered ring are 2-tierralinda group, 3-tierralinda group, 2-fenilalanina group, 3-fenilalanina group, 2-piranishvili group, 3-piranishvili group, 4-piranishvili group, 1-pyrrolylacetylenes group, 2-pyrrolylacetylenes group, 3-pyrrolylacetylenes group, 1-imidazolylalkyl group, 2-imidazolylalkyl group, 4-imidazolylalkyl group, 1-pyrazolecarboxylate group, 3-pyrazolecarboxylate group, 4-pyrazolecarboxylate group, 2-triazolylmethyl group, 4-triazolylmethyl group, 5-triazolylmethyl group, 3-isothiazolinone group, 4-isothiazolinone group, 5-isothiazolinone group, 2-occasionally group, 4-occasionally group, 5-occasionally group, 3-isoxazolidinone the other group, 4-isoxazolecarboxylic group, 5-isoxazolecarboxylic group, 2-pyridylsulfonyl group, 3-pyridylsulfonyl group, 4-pyridylsulfonyl group, 2-pyridinesulfonamide group, 2-pyrimidinemethanol group, 4-pyrimidinemethanol group, 5-pyrimidinemethanol group, 3-pyridinylmethyl group, 4-pyridinylmethyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolidine group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolidine group, 5-1,2,4-thiadiazolidine group, a 3-1,2,5-oxadiazolyl group and 3-1,2,5-thiadiazolidine group.

Examples_5-9-condensed bicyclic heterocyclic sulfonyloxy group having 8 to 10 atoms in the ring are 2-benzofurazanyl group, 3-benzofurazanyl group, 4-benzofurazanyl group, 5-benzofurazanyl group, 6-benzofurazanyl group, 7-benzofurazanyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiazolesulfonamide group, 3-benzothiazolesulfonamide group, 4-benzothiazolesulfonamide group, 5-benzothiazolesulfonamide group, 6-inttionalsexguideerna group, 7-benzothiazolesulfonamide group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-chromelalumel group, 3-chromelalumel group, 4-chromelalumel group, 5-chromelalumel group, 6-chromelalumel group, 7-chromelalumel group, 8-chromelalumel group, 1-indolylalanine group, 2-indolylalanine group, 3-indolylalanine group, 5-indolylalanine group, 6-indolylalanine group, 7-indolylalanine group, 8-indolylalanine group, 1-isoindoloannulated group, 2-isoindoloannulated group, 4-isoindoloannulated group, 5-isoindoloannulated group, 1-indolylmaleimide group, 2-indolylmaleimide group, 3-indolylmaleimide group, 4-indolylmaleimide group, 5-indolylmaleimide group, 6-indolylmaleimide group, 7-indolylmaleimide group, 1-indotricarbocyanine group, 2-indotricarbocyanine group, 3-indotricarbocyanine group, 4-indotricarbocyanine group, 5-indotricarbocyanine group, 6-indotricarbocyanine group, 7-indotricarbocyanine group, 1-puenylalanine group, 2-puenylalanine group, 3-puenylalanine group, 6-p is rhinelandpalatinate group, 7-puenylalanine group, 8-puenylalanine group, 2-hinolincarbonova group, 3-hinolincarbonova group, 4-hinolincarbonova group, 5-hinolincarbonova group, 6-hinolincarbonova group, 7-hinolincarbonova group, 8-hinolincarbonova group, 1-ethynodiolthinyl group, 3-ethynodiolthinyl group, 4-ethynodiolthinyl group, 5-ethynodiolthinyl group, 6-ethynodiolthinyl group, 7-ethynodiolthinyl group, 8-ethynodiolthinyl group, 1-phthalodinitrile group, 5-phthalodinitrile group, 6-phthalodinitrile group, 1-2,7-naturalistically group, 3-2,7-naturalistically group, 4-2,7-naturalistically group, 1-2,6-naturalistically group, 3-2,6-naturalistically group, 4-2,6-naturalistically group, 2-1,8-naturalistically group, 3-1,8-naturalistically group, 4-1,8-naturalistically group, 2-1,7-naturalistically group, 3-1,7-naturalistically group, 4-1,7-naturalistically group, 5-1,7-naturalistically group, 6-1,7-naturalistically group, 8-1,7-naturalistically group, 2-1,6-naturalistically group, 3-1,6-naturalistically group, 4-1,6-naftiridinelor the th group, 5-1,6-naturalistically group, 7-1,6-naturalistically group, 8-1,6-naturalistically group, 2-1,5-naturalistically group, 3-1,5-naturalistically group, 4-1,5-naturalistically group, 6-1,5-naturalistically group, 7-1,5-naturalistically group, 8-1,5-naturalistically group, 2-chynoxalinilmethylen group, 5-chynoxalinilmethylen group, 6-chynoxalinilmethylen group, 2-chineselearnonline group, 4-chineselearnonline group, 5-chineselearnonline group, 6-chineselearnonline group, 7-chineselearnonline group, 8-chineselearnonline group, 3-indolinecarboxylic group, 4-indolinecarboxylic group, 5-indolinecarboxylic group, 6-indolinecarboxylic group, 7-indolinecarboxylic group, 8-indolinecarboxylic group, 2-peridiniella group, 4-peridiniella group, 6-peridiniella group and 7 peridiniella group.

Examples_2-9heterocyclyl groups are monocyclic and bicyclic heterocyclic group condensed rings containing one or more atoms independently selected from nitrogen atom, oxygen atom and sulfur atom, and 2 to 9 carbon atoms, and in particular, tako the group are the following groups:

In the above formulas, the symbol "-" (which indicates a chemical bond)present in each cyclic structure, means that the group-Deputy may be present in any position, which may be substituted in a given chemical structure, and does not mean any particular position of substitution.

R^14,R¹⁵, R¹⁶and R¹⁷in the formula (a), formula (b), formula (C), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), the formula (s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and formula (af) and independently preferably represent a hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, n-pentelow group, isopentyl group, 3,3-dimethyl-n-boutelou group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group, ethoxycarbonyl the methyl group, methoxycarbonylamino group, ethoxycarbonylethyl group, cyclopropyl group, cyclopentyl group, tsiklogeksilnogo group, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, methylthiourea, ethylthiourea, phenyl group, o-biphenylyl group, m-biphenylyl group, p-biphenylyl group, 1-naftalina group, 2-naftalina group, 2-pyridyloxy group, 3-pyridyloxy group, 4-pyridyloxy group, methylcarbonate, ethylcarboxylate, n-propylmalonate, isopropylcarbonate, n-butylcarbamoyl, tert-butylcarbamoyl, methylaminopropyl, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylaminopropyl, diethylaminopropyl, di-n-propylamino, diisopropylamino, di-n-butylamino, phenylaminopropyl, biphenylamine, m-biphenylamine, p-biphenylamine, 1-naphtylamine, 2-naphtylamine, 2-pyridylamino, 3-pyridylamino, 4-pyridylamino, medicalbilling, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-BUTYLCARBAMATE, methanesulfonamido group, acanaloniidae group, n-propanesulfinamide group, isopropylamino group, n-butanesulfinamide group,methylaminomethyl group, ethylaminomethyl group, n-propylaminosulfonyl group, isopropylaminocarbonyl group, n-butylaminoethyl group, dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, di-n-propylaminoethyl group, diisopropylaminoethyl group, dicyclopentadienyl group, di-n-butylaminoethyl group, methylcarbamyl group, ethylcarbitol group, n-propelleronline group, isopropylcarbodiimide group, n-butylcarbamoyl group, phenylcarbonylamino group, biphenylcarboxylic group, m-biphenylcarboxylic group, p-biphenylcarboxylic group, 1-afterburning group, 2-afterburning group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group 4-pyridylcarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxyethanol group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, methanesulfonyl group, trifloromethyl group, benzosulfimide group, biphenylmethanol group, m-biphenylmethanol group, p-biphenylmethanol group, 1-naphthalenesulfonyl group, 2-naphthalenesulfonyl group, 2-pyridylsulfonyl group, 3-p is redissolving group, 4-pyridylsulfonyl group, amino group, cyano, karbamoilnuyu group, carboxyl group and the following groups:

In the above formulas, the symbol "-" (which indicates a chemical bond)present in each cyclic structure, means that the group-Deputy may be present in any position, which may be substituted in a given chemical structure, and does not mean any particular position of substitution.

Q in the formula (C), formula (d), formula (p), formula (q), formula (v), formula (w), formula (ab), formula (ac) and in the formula (ad) represents O (oxygen atom), S (sulfur atom), SO (sulfonyloxy group) or SO₂(sulfonyloxy group). Q in the formula (C), formula (d), formula (p), formula (q), formula (v), formula (w), formula (ab), formula (ac) and in the formula (ad), preferably represents O (oxygen atom).

If incomplete cyclic structure And the formula (11) or the formula (12) is represented by formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (AE), formula (hell) or formula (h), below is a description of R¹², R¹³, R¹⁴, R¹⁵and R¹⁶in the formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (AE), formula (ad), or f is rule (h).

If incomplete cyclic structure And the formula (11) or the formula (12) is represented by formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (AE), formula (hell) or formula (h), below is a description of R¹²and R¹³in the formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (AE) or the formula (hell).

Each of R¹²and R¹³in the formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (AE) and formula (ad) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom, amino group or hydroxy-group).

Each group Deputy for R¹²and R¹³in the formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (AE) and formula (hell) specifically described below.

Examples_1-6alkyl groups are methyl group, triptorelin group, methoxymethyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 2-pencilina group, 3-pentalen the group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, n-exilda group, 2-exilda group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group and 3,3-dimethyl-n-bucilina group.

R¹²and R¹³in the formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (AE) and formula (ad) independently represents a hydrogen atom, methyl group, triptorelin group, methoxymethyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, n-pentelow group, isopentyl group, amino group and hydroxy-group, and more preferably, hydrogen atom and methyl group.

If incomplete cyclic structure And the formula (11) or the formula (12) is represented by formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (AE), formula (hell) or formula (h), below is a description of R¹⁴, R¹⁵and R¹⁶in the formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y) and the formula (AE). Each of R¹⁴, R¹⁵and R¹⁶in the formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y) and the formula (AE) independently represents a hydrogen atom, the atom halog is on or _1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic,_1-6alkylcarboxylic (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), With_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group or_1-6alkoxycarbonyl group).

Each atom and each group Deputy for R¹⁴, R¹⁵and R¹⁶in the formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y) and the formula (AE) specifically described below.

Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom;

examples_1-6alkyl groups are methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 2-pencilina group, 3-pencilina group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, n-exilda group, 2-hexylen the group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group, 3,3-dimethyl-n-bucilina group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, methoxycarbonylethyl group, triftormetilfullerenov group and ethoxycarbonylethyl group. Examples_1-6alkylcarboxylic are methylcobalamine, triftormetilfullerenov, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-BUTYLCARBAMATE, isobutyleneisoprene, second-BUTYLCARBAMATE, tert-BUTYLCARBAMATE, 1-intelcorporation, 2-intelcorporation, 3-intelcorporation, isopentenyladenine, neopentylmagnesium, tert-intelcorporation, 1-hexylcinnamaldehyde, 2-hexylcinnamaldehyde and 3-hexylcinnamaldehyde;

examples_3-8cycloalkylcarbonyl groups are cyclopropanecarbonyl group is a, cyclobutanecarbonyl group, 1-methyl-cyclopropanecarbonyl group, 2-methylcyclopropyl group, cyclopentanecarbonyl group, 1-methylcyclopentadienyl group, 2-methylcyclopentadienyl group, 3-methylcyclopentadienyl group, 1,2-dimethylcyclopropanecarboxylate group, 2,3-dimethylcyclopropanecarboxylate group, 1-ethylcyclopentadienyl group, 2-ethylcyclopentadienyl group, cyclohexylcarbonyl group, cyclohexylcarbonyl group, cyclooctylmethyl group, 1-methyl-cyclohexylcarbonyl group, 2-methylcyclohexylamine group, 3-methylcyclohexylamine group, 1,2-dimethylcyclohexylamine group, 2,3-dimethylcyclopropanecarboxylate group, 1-ethylcyclopentadienyl group, 1-methylcyclopentadienyl group 2-methylcyclopentadienyl group, 3-methylcyclopentadienyl group, 1-ethylcyclopentadienyl group, 2-ethylcyclopentadienyl group, 3-ethylcyclopentadienyl group, 1,2-dimethylcyclobutyl group, 1,3-dimethylcyclobutyl group, 2,2-dimethylcyclobutyl group, 2,3-dimethylcyclobutyl group, 2,4-dimethylcyclobutyl group, 3,3-dimethylcyclobutyl group, 1-n-propylcyclohexanone group, 2-n-propyltin propellerblade group, 1-isopropylcyclopentadienyl group, 2-isopropylcyclopentadienyl group, 1,2,2-trimethylcyclopentanone group, 1,2,3-trimethylcyclopentanone group, 2,2,3-trimethylcyclopentanone group, 1-ethyl-2-methylcyclopentadienyl group, 2-ethyl-1-methylcyclopropyl group, 2-ethyl-2-methylcyclopentadienyl group and 2-ethyl-3-methylcyclopentadienyl group; and

examples_1-6alkoxycarbonyl groups are methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, 1-ventilatsiooniga group, 2-ventilatsiooniga group, 3-ventilatsiooniga group, isobutylacetophenone group, neopentadactyla group, tert-ventilatsiooniga group, 1-hexyloxymethyl group, 2-hexyloxymethyl group and 3-hexyloxymethyl group.

R¹⁴, R¹⁵and R¹⁶in the formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y) and the formula (AE) independently represent a hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl group, triptorelin group, ethyl group who, n-sawn group, isopropyl group, n-boutelou group, n-pentelow group, isopentyl group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, methoxycarbonylamino group, triftormetilfullerenov group and ethoxycarbonylethyl group, and more preferably, a hydrogen atom, fluorine atom, chlorine atom, methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, methylcarbamoylmethyl group, ethylcarboxylate group, methylcarbamoylmethyl group, ethylcarbodiimide group, methoxycarbonylmethyl group and triftormetilfullerenov group.

Incomplete cyclic structure And the formula (11) or the formula (12) is represented by formula (p) and formula (v), and Q in formula (p) or formula (v) means O (oxygen atom), S (sulfur atom), SO (sulfonyloxy group) or SO₂(sulfonyloxy group). Q in the formula (p) or formula (v)preferably represents O (oxygen atom).

R⁹, R^{10 , W, X, Y, and Z in the formula (13) described below.}

^{Each of R9and R10in the formula (13) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group)_6-14aryl group (the aryl group may be optionally substituted by halogen atom, hydroxy-group, a nitrogroup, cyano, C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group) or (C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom)).}

Each group Deputy for R⁹and R¹⁰in the formula (13) is specifically described below.

Examples_1-6alkyl groups are methyl group, triptorelin group, methoxymethyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 2-pencilina group, 3-pencilina group, isopentyl group, neopentylene group, 2,2-dimethylpropylene group, 1-exilda group, 2-hexyl is owned by the group, 3-exilda group, 1-methyl-n-pencilina group, 1,1,2-trimethyl-n-through the group, 1,2,2-trimethyl-n-through the group, 3,3-dimethyl-n-bucilina group, and examples With_6-14aryl group are phenyl group, o-biphenylene group, m-biphenylene group, p-biphenylene group, 1-naftalina group, 2-naftalina group, 1-antenna group, 2-antenna group, 9-antenna group, 1-phenanthroline group, 2-phenanthroline group, 3-phenanthroline group, 4-phenanthroline group and 9-phenanthroline group.

R⁹and R¹⁰in the formula (13), preferably represent a methyl group, triptorelin group and ethyl group, and more preferably methyl group.

W in the formula (13), preferably represents a hydrogen atom, a hydroxy-group, With_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), halogen atom, With_1-4alkyl group or a C_1-6alkylsulfonamides group (an alkyl group and alkylsulfonamides group can be optionally substituted by a halogen atom).

Each atom and each group-zamestitel for W in the formula (13) is specifically described below.

Examples_1-6alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-bout xygraph, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentylamine, neopentadactyla, 2,2-DIMETHYLPROPANE, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxylate, 1,2,2-trimethyl-n-propoxylate and 3,3-dimethyl-n-butoxypropan;

examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom;

examples_1-4alkyl groups are methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group; and

examples_1-6alkylsulfonamides groups are methanesulfonamido group, triftoratsetofenona group, acanaloniidae group, n-propanesulfinamide group, isopropanolamine group, n-butanesulfinamide group, isobutylphenyl group, sec-butanesulfinamide group, tert-butanesulfinamide group, 1-pentanesulfonate group, 2-pentanesulfonate group, 3-pentanesulfonate group, isopentenyladenine group, neopentylene group, tert-pentanesulfonate group, 1-hexanesulfonate group, 2-hexanesulfonate group and 3-hexanesulfonate group.

W in the formula (13), preferably represents a hydrogen atom, the hydroxy-group, fluorine atom, chlorine atom, bromine atom, methyl group, triptorelin group, ethyl group, methoxy group, ethoxypropan, n-propoxylate, isopropoxy, methanesulfonamido group, triftormetilfullerenov group, acanaloniidae group, n-propanesulfinamide group, isopropylamino group and n-butanesulfinamide group, and more preferably, a hydrogen atom, a hydroxy-group, fluorine atom, methyl group, triptorelin group, ethyl group, methoxy group, methanesulfonamido group and triftormetilfullerenov group.

X in the formula (13) represents NR²⁰; N represents a nitrogen atom, and R²⁰represents a hydrogen atom or a C_1-4alkyl group.

Each group is a substituent R²⁰for X in the formula (13) described below.

Examples_1-4alkyl groups are methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group.

R²⁰for X in the formula (13), preferably represents a hydrogen atom, methyl group and ethyl group.

Y in the formula (13) represents a chemical bond, SO (sulfonyloxy group) or SO₂(sulfonyloxy group), and preferably, the chemical bond and SO₂.

Z in the formula (13) represents a C_1-4alkyl group, (C_1-4the alkyl group may be optionally substituted by 1-5 halogen atoms, or phenyl group (the phenyl group may be optionally substituted C_1-4alkyl group)) or phenyl group (the phenyl group may be optionally substituted C_1-4alkyl group).

Each group Deputy for Z in the formula (13) is specifically described below.

Examples_1-4alkyl groups are methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group.

Z in the formula (13), preferably, is a methyl group, triptorelin group, ethyl group, n-sawn group, isopropyl group and a phenyl group.

If optically active complex of titanium represented by any of these formulas, the formula (1), formula (1'), formula (2), formula (2'), formula (3), formula (3'), formula (4) and formula (4'), is used as catalyst, the amount used of the optically active complex of titanium with respect to the number of connections chromene represented by the formula (10), formula (11), formula (12) or formula (13)is from 0.001 to 100 mol%, preferably from 0.01 to 20 mol, and more preferably, from 0.3 to 5 mol%.

If the reaction asymmetric epoxidation, optically active complex of titanium represented by any of formulas(1), (1'), (2), (2'), (3), (3'), (4) and (4'), is used as a catalyst and if this reaction is used aprotic organic solvent, such aprotic organic solvent is a halogen solvent, an aromatic hydrocarbon solvent, ester solvent, an ether solvent or a nitrile solvent, if used proton organic solvent such proton organic solvent is alcohol solvent. Examples of halogen solvent are dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene; examples of the aromatic hydrocarbon solvent are benzene and toluene; ester solvent is ethyl acetate; examples of the ether solvent is tetrahydrofuran and diethyl ether; and examples of the nitrile solvent is butyronitrile, propionitrile and acetonitrile. Examples of the alcohol solvents are methanol, ethanol and isopropanol. Moreover, there may be included a mixture of the above solvents. In addition, if this reaction is used an aqueous solution of hydrogen peroxide, the organic layer and aq is th layer can be separated by mixing an aqueous solution of hydrogen peroxide with organic solvent, which is not soluble in water. However, such a two-phase solvent can also be used as solvent for the reaction according to the invention. The preferred solvent is an aprotic organic solvent, such as dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene, ethyl acetate and mixtures thereof.

To obtain a desired compound, an organic solvent type connection chromene, optically active complex of titanium and an oxidizer. Adding, preferably, carried out in the following order: first to the solution of organic solvent-type oxidizer, and then the connection chromene and optically active complex of titanium.

Specific examples of the oxidizing agent used in this reaction are iodosobenzene, sodium hypochlorite, m-chloroperbenzoic acid, Oxon (registered trademark of DuPont), an aqueous solution of hydrogen peroxide, the product of the merger of urea-hydrogen peroxide (UHP), oxaziridine, N-methylmorpholine (NMO), tert-butylhydroperoxide (TBHP), cumene hydroperoxide (CHP), or combinations thereof. Of these oxidizing agents, preferred are an aqueous solution of hydrogen peroxide, the product of the merger of urea-hydrogen peroxide (UHP), and mixtures thereof. If the oxidizing agent is aqueous hydrogen peroxide solution, its concentration can comp the manage from 1 to 100 wt.%, and preferably, from 5 to 60 wt.%.

The amount of oxidizing agent used in this reaction, in relation to the number of connections chromene represented by the formula (10), formula (11), formula (12) or formula (13)can be from 1 to 10 equivalents, and preferably 1 to 3 equivalents.

Examples of the method of adding an oxidant, in addition to a single add, are stepwise addition and continuous addition.

If adding exercise continuously, it is preferable that the rate of addition was such that not will be a sharp increase in the temperature of the reaction solvent system, and in particular, the rate of addition should be from 0.01 to 40,000 equivalents per hour, and more preferably in the range from 0.05 to 0.3 equivalents per hour. The term "stepwise addition" means a separate method add the used oxidizing agent, executed by the "p" (p may be any integer). Part of the added oxidant can be equal or unequal, and "R" preferably is 2-100.

The reaction temperature may be in the range from -78°C. to a temperature of distillation of the solvent or in the range from the melting temperature of the solvent to a temperature of distillation of the solvent, preferably in the range from -20 to 50°C, and more preferably, from 0°C to 35°C

The pressure in the reaction system epoxidation may range from 10 kPa to 1100 kPa, preferably from 15 kPa to 200 kPa. When applying pressure, the reaction may proceed at a temperature above the distillation temperature of the solvent at normal pressure.

The reaction time can be reduced by adding a catalyst, namely, optically active complex of titanium during the reaction. In addition, the reaction time can be reduced due to the additional oxidant.

After completion of the reaction, the desired optically active compound oxide chromene can be obtained by separation and purification of the reaction mixture through distillation, column chromatography on silica gel, procedures, separation and extraction, recrystallization or the mixed procedure.

The optical purity of the obtained optically active compound oxide chromene can be analyzed using analysis conducted with the use of optically active high-performance liquid chromatography analysis conducted with the use of optically active gas chromatography, or level measurement of the optical rotation.

The present invention is described in more detail by the following examples. However, the present invention is not limited to these example is mi.

Of the optically active compounds of chromene described in these examples, some compounds have an absolute configuration of asymmetric carbon atoms, which is still not exactly known. With regard to these soedinenii, in the description of chemical formulas and names of compounds is estimated absolute configuration marked with an asterisk (*)standing after the name of each connection and each asymmetric carbon atom in the chemical formula.

Synthesis of optically active titanium complexes-sallena (A), (b) and (C)

Optically active titanium complexes-sallena (A), (b) and (C)used in the examples were synthesized by the method described in non-patent document 8 (Angew. Chem. Int. Ed., 44, 4935-4939 (2005)).

Optically active complex titanium-Salina (D)represented by the following formula, was obtained by the method described below.

Casanovy ligand (42')

To a dichloromethane solvent for the reaction salanova ligand (42') was added to 1.1 mol per one mol salanova ligand (42') tetraisopropoxide titanium (Ti(Oi-Pr)₄in nitrogen atmosphere at 25-28°C. Then the mixture was stirred for 5 hours and was added to water at 25-28°C, and the resulting reaction solution was stirred for 12 hours. The solution of the tel for the reaction were removed by distillation to obtain crude product, and this product was recrystallized from dichloromethane to obtain optically active complex of titanium (D).

Slightly yellowish-white solid

MC(CSI)=1082, 2163.

Optically active titanium complexes of Salona (E) and (F) were also obtained by the method described above.

Example 1

Synthesis of (3S,4S)-6-ndimethylacetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (Compound (I))

6-ndimethylacetamide-2,2-dimethyl-7-nitro-2H-1-benzopyran (0.54 g, 2.1 mmol) was added to a dichloromethane solution (3 ml) of the optically active complex titanium-sallena (C) (38 mg, 0,021 mmol) (1.0 mol% with respect to the substrate) at 28°C. To the reaction solution, with stirring, for 10 hours was added to 7.5% aqueous solution of hydrogen peroxide (1.4 g, 3.1 mmol) at 28°C. the Initial time you add a 7.5% aqueous solution of hydrogen peroxide was determined as the start of the reaction. 14 hours after the start of the reaction was again added a 7.5% aqueous solution of hydrogen peroxide (0.1 g, 0.2 mmol)and the resulting solution was again stirred at 28°C for 19 hours after the start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (6 ml) and distilled water (6 ml)and the organic layer was separated. The organic layer is extracted from the aqueous layer with dichloromethane (6 ml), and separated the body of the ical layer was combined, and this merged layer are condensed to obtain the crude product. The obtained product was purified column chromatography to obtain compound (I) in the form of a yellowish powder (0,49 g, yield: 86%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALPAK OJ-RH, eluent: acetonitrile/methanol/0,01M aqueous solution of sodium chloride=1/3/5 (about./about./vol.), flow rate: 1.5 ml/min, column temperature: 40°C, retention time: the reaction product of (3S,4S) - 15.9 minutes enantiomer (3R,4R) - 11.7 minutes, the measured wavelength (absorption band): 242 nm.

¹H-NMR (CDCl₃) δ: 1,27 (s,3H), of 1.59 (s,3H), of 2.28 (s,3H), 3,55 (d, J=4,1 Hz, 1H), 3,97 (d, J=4,1 Hz, 1H), to 7.64 (s, 1H), 8,79 (s, 1H), 10,10 (width, 1H).

Example 2

Synthesis of (3R,4R)-6-ndimethylacetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (Compound (II))

6-Ndimethylacetamide-2,2-dimethyl-7-nitro-2H-1-benzopyran (537,4 mg, 2.1 mmol) was added to a dichloromethane solution (3 ml) of the optically active complex titanium-sallena (E) (25.6 mg, 0,021 mmol) (1.0 mol% with respect to the substrate) at 30°C. To the reaction solution, with stirring, for 1 second was added 30% aqueous hydrogen peroxide solution (302,7 mg, 2.7 mmol) at 30°C. Then, the resulting solution was again stirred for 7 hours at 30°C. After completion of the reaction, the reaction solution was added dichloromethane and dis is illirian water, and the organic layer was separated. The organic layer is extracted from the aqueous layer with dichloromethane, and the separated organic layer was combined, and the combined layer are condensed to obtain the crude product. The obtained product was purified column chromatography to obtain compound (II) in the form of a yellowish powder (0,53 g, yield: 93%, optical purity: 99.9% of AI (enantiomeric surplus) or more).

Analytical conditions: column name: CHIRALPAK OJ-RH, eluent: acetonitrile/methanol/0,01M aqueous solution of sodium chloride=1/3/5 (about./about./vol.), flow rate: 1.5 ml/min, column temperature: 40°C, retention time: the reaction product of (3R,4R) - 13.4 minutes, enantiomer (3S,4S) - 17.5 minutes, measured wavelength: 242 nm.

¹H-NMR (CDCl₃) δ: 1,27 (s,3H), of 1.59 (s,3H), of 2.28 (s,3H), 3,55 (d, J=4,2 Hz, 1H), 3,97 (d, J=4.5 Hz, 1H), 7,63 (s, 1H), 8,79 (s, 1H), to 10.09 (width, 1H).

Example 3

Synthesis of (3S,4S)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran (Compound (III))

2,2-Dimethyl-6-nitro-2H-1-benzopyran (0,41 g, 2.0 mmol) was added to a dichloromethane solution (8 ml) of the optically active complex titanium-sallena (B) (73 mg, 0,041 mmol) (2.0 mol% to a substrate) at 25°C. To the reaction solution, with stirring, for 2 seconds at 25°C. was added 30% aqueous solution of hydrogen peroxide (0.24 g, 2.1 mmol). Start time adding 30% water is th solution of hydrogen peroxide was determined as the start of the reaction. The resulting solution was stirred for 27 hours after start of the reaction at 25°C. After completion of the reaction, the reaction solution was added dichloromethane (6 ml) and distilled water (6 ml)and the organic layer was separated. The organic layer is extracted from the aqueous layer with dichloromethane, and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (III) in the form of a whitish-yellow powder (of 0.43 g, yield: 97%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALCEL OD-H, eluent: n-hexane/isopropanol=9/1 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: the reaction product of (3S,4S) - 9.6 minutes, enantiomer (3R,4R) - 8.4 minutes, measured wavelength: 300 nm.

¹H-NMR (CDCl₃) δ: 1,33 (s,3H), and 1.63 (s,3H), 3,57 (d, J=4.4 Hz, 1H), 4.00 points (d, J=4.4 Hz, 1H), 6.89 in (d, J=9.1 Hz, 1H), 8,15 (DD, J=9,1, 2.8 Hz, 1H), 8,31 (d, J=2,8 Hz, 1H).

Example 4

Synthesis of (3S,4S)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran (Compound (III))

Tetraisopropoxide titanium (Ti(Oi-Pr)₄) (2,3 mg, 0,0080 mmol) was added to a dichloromethane solution (0.3 ml) salanova ligand (4,9 mg, 0,0080 mmol) (4.0 mol% relative to the substrate)represented by the formula (43')at 20°C. After premesis is made for 1 hour at 20°C, to the solution was added 2,2-dimethyl-6-nitro-2H-1-benzopyran (41 mg, 0.20 mmol). 30% aqueous hydrogen peroxide solution (0,034 g, 0.30 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. The resulting solution was stirred at 20°C for 24 hours after start of the reaction and took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (III) was 99% or more, and the optical purity was 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: the reaction product of (3S,4S) - 15.8 minutes enantiomer (3R,4R) - 12.6 minutes, measured wavelength: 330 nm.

Example 5

Synthesis of (3R,4R)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran (Compound (IV))

2,2-Dimethyl-6-nitro-2H-1-benzopyran (0,41 g, 2.0 mmol) was added to a dichloromethane solution (6 ml) of the optically active complex titanium-fat is a (S) (48 mg, 0.040 mmol) (2.0 mol% to a substrate) at 20°C. of 30% aqueous solution of hydrogen peroxide (0.24 g, 2.1 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. Then, the resulting solution was stirred at 20°C for 24 hours after start of the reaction, and the reaction solution was added dichloromethane (5 ml) and distilled water (5 ml), after which the organic layer was separated. The organic layers twice extracted from the aqueous layer with dichloromethane (5 ml and 3 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (IV) in the form of a whitish-yellow powder (0,41 g, yield: 94%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: the reaction product of (3R,4R)- 12.6 minutes enantiomer (3S,4S) - 15.8 minutes, measured wavelength: 330 nm.

^{1 H-NMR (CDCl₃) δ: 1,33 (s,3H), of 1.62 (s,3H), to 3.58 (d, J=4.4 Hz, 1H), 4.00 points (d, J=4.4 Hz, 1H), 6.89 in (d, J=8.6 Hz, 1H), 8,14 (DD, J=8,6, 3.0 Hz, 1H), 8,30 (d, J=3.0 Hz, 1H).}

^{Example 6}

^{Synthesis of (3R,4R)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran (Compound (IV))}

^{2,2-Dimethyl-6-nitro-2H-1-benzopyran (0,41 g, 2.0 mmol) was added to a dichloromethane solution (8 ml) of the optically active complex titanium-sallena (A) (73 mg, 0,041 mmol) (2.0 mol% to a substrate) at 25°C. While stirring the reaction solution for 2 seconds was added 30% aqueous solution of hydrogen peroxide (0.24 g, 2.1 mmol) at 25°C. After addition, the solution was left for continuous stirring at 25°C. the Beginning of the first add 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. 8 hours after start of the reaction took a sample of the reaction solution, and the Degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (IV) was 99% or more, and the optical purity was 96% EE}

^{Analytical conditions: column name: CHIRALPAK AD-RH, eluent: acetonitrile/20 mm (m) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: the reaction product of (3R,4R) - 5.2 minutes, enantiomer (3S,4S) - 6,1 minute, measured wavelength: 330 nm.}

^{Example 7}

^{Synthesis of (3S*,4S*)-3,4-epoxy-3,4-dihydro-2,2-d is methyl-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V), * indicates the relative configuration)}

^{2,2-Dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (of 0.47 g, 2.0 mmol) was added to a dichloromethane solution (8 ml) of the optically active complex titanium-sallena (C) (71 mg, 0.040 mmol) (2.0 mol% to a substrate) at 25°C. While stirring the reaction solution for 2 seconds was added 30% aqueous solution of hydrogen peroxide (0.24 g, 2.1 mmol) at 25°C. the Beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. Then, the resulting solution was stirred at 25°C for 19 hours after the start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (3 ml) and distilled water (3 ml), after which the organic layer was separated. The organic layer is extracted from the aqueous layer with dichloromethane (3 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (V) in the form of a yellowish oil (0.50 g, yield: 99%, optical purity: 99.9% of ei or more).}

^{Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (m) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.8 ml/min, temperature Colo is Ki: 40°C, retention time: the reaction product is 12.1 min, enantiomer - 11.3 minutes, measured wavelength: 225 nm.}

^{1H-NMR (CDCl₃) δ: 1.26 in (s,3H), of 1.59 (s,3H), 3,53 (d, J=4.4 Hz, 1H), 3,90 (d, J=4.4 Hz, 1H), 3,95 (s, 3H), was 7.08 (s, 1H), 7,33 (s, 1H).}

Example 8

Synthesis of (3S*,4S*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V), * indicates the relative configuration)

Tetraisopropoxide titanium (Ti(Oi-Pr)₄) (5.7 mg, at 0.020 mmol) was added to a dichloromethane solution (0.9 ml) salanova ligand (14 mg, at 0.020 mmol)represented by the formula (41')at 20°C. After stirring for 1 hour at 20°C. to the solution was added 2,2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (amount of 0.118 g, 0.50 mmol). 30% aqueous hydrogen peroxide solution (of 0.085 g, 0.75 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. The resulting solution was stirred at 20°C for 24 hours after start of the reaction and took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (V) was 99% or more, and the optical purity SOS is alala 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.5 ml/min, column temperature: 40°C, retention time: reaction product - 18.3 minutes, enantiomer is 17.5 minutes, measured wavelength: 225 nm.

Example 9

Synthesis of (3R*,4R*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V'), * indicates the relative configuration)

2,2-Dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (of 0.47 g, 2.0 mmol) was added to a dichloromethane solution (7 ml) of the optically active complex titanium-Salina (S) (48 mg, 0.040 mmol) (2.0 mol% to a substrate) at 25°C. 30% aqueous solution of hydrogen peroxide (0.24 g, 2.1 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. Then, the resulting solution was stirred at 20°C for 24 hours after start of the reaction, and the reaction solution was added dichloromethane (5 ml) and distilled water (5 ml), after which the organic layer was separated. The organic layers twice extracted from the aqueous layer dihormati is ω (5 ml and 3 ml), and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (V') in the form of a yellowish oil (0,48 g, yield: 96%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.5 ml/min, column temperature: 40°C, retention time: the reaction product of 17.5 minutes, enantiomer - 18.3 per minute, measured wavelength: 225 nm.

¹H-NMR (CDCl₃) δ: 1.26 in (s,3H), 1,58 (s,3H), of 3.54 (d, J=4.5 Hz, 1H), 3,91 (d, J=4.5 Hz, 1H), 3,95 (s,3H), to 7.09 (s,1H), 7,32 (s,1H).

Example 10

Synthesis of (3R*,4R*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V'), * indicates the relative configuration)

2,2-Dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (0,47 mg, 2.0 mmol) was added to a dichloromethane solution (8 ml) of the optically active complex titanium-sallena (A) (71 mg, 0.040 mmol) (2.0 mol% to a substrate) at 25°C. While stirring the reaction solution at 25°C was added within 2 seconds of a 30% aqueous solution of hydrogen peroxide (0.24 g, 2.1 mmol). The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. After 18 hours the village is e start of the reaction took a sample of the reaction solution, and the degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (V') was 99% or more, optical purity was 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.8 ml/min, column temperature: 40°C, retention time: reaction product - 11.3 minutes, enantiomer - 12.1 minutes, measured wavelength: 225 nm.

Example 11

Synthesis of (3S*,4S*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (Compound (VI), * indicates the relative configuration)

2,2-Dimethyl-7-nitro-2H-1-benzopyran (0.21 mg, 1.0 mmol) was added to a dichloromethane solution (4 ml) of the optically active complex titanium-sallena (In) (36 mg, at 0.020 mmol) (2.0 mol% to a substrate) at 25°C. While stirring the reaction solution for 2 seconds was added 30% aqueous hydrogen peroxide solution (0.12 g, 1.1 mmol). The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. Then, the resulting solution was stirred at 25°C for 27 hours after start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (2 ml) and distilled water (2 ml), after which the organization the organic layer was separated. The organic layer is extracted from the aqueous layer with dichloromethane (2 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (VI) in the form of a yellowish powder (of 0.43 g, yield: 99%, optical purity: 99.9% of ei).

Analytical conditions: column name: CHIRALPAK AD-RH, eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 9.2 minutes, the enantiomer of 4.9 minutes, measured wavelength: 220 nm.

¹H-NMR (CDCl₃) δ: 1,29 (s,3H), of 1.62 (s,3H), to 3.58 (d, J=4.4 Hz, 1H), 3,97 (d, J=4.4 Hz, 1H), 7,50 (d, J=8,3 Hz, 1H), to 7.67 (DD, J=8,3, 2.2 Hz, 1H), 7,80 (d, J=2.2 Hz, 1H).

Example 12

Synthesis of (3S*,4S*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (Compound (VI), * indicates the relative configuration)

2,2-Dimethyl-7-nitro-2H-1-benzopyran (0,41 g, 2.0 mmol) was added to a dichloromethane solution (6 ml) of the optically active complex titanium-Salina (F) (48 mg, 0.040 mmol) (2.0 mol% to a substrate) at 25°C. of 30% aqueous hydrogen peroxide solution (0.25 g, 2.2 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to retu part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. Then, the resulting solution was stirred at 20°C for 24 hours after start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (5 ml) and distilled water (5 ml), after which the organic layer was separated. The organic layers twice extracted from the aqueous layer with dichloromethane (5 ml and 3 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (VI) in the form of yellowish crystals (0,44 g, yield: 98%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 25.2 minutes, enantiomer - 13.9 minutes, measured wavelength: 220 nm.

¹H-NMR (CDCl₃) δ: 1,29 (s,3H), of 1.61 (s,3H), 3,60 (d, J=4.5 Hz, 1H), 3,99 (d, J=4.5 Hz, 1H), 7,52 (d, J=8,3 Hz, 1H), 7.62mm (d, J=2.1 Hz, 1H), of 7.70 (DD, J=8,3, 2.1 Hz, 1H).

Example 13

Synthesis of (3R*,4R*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (Compound (VI), * indicates the relative configuration)

2,2-Dimethyl-7-neath the on-2H-1-benzopyran (0.21 g, 1.0 mmol) was added to a dichloromethane solution (4 ml) of the optically active complex titanium-sallena (A) (36 mg, at 0.020 mmol) (2.0 mol% to a substrate) at 25°C. While stirring the reaction solution for 2 seconds was added 30% aqueous hydrogen peroxide solution (0.12 g, 1.1 mmol) at 25°C. Then the reaction solution was left to continuous stirring at 25°C. the Beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. After 24 hours after start of the reaction took a sample of the reaction solution, and the degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (VI') was 99% or more, and the optical purity was 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH, eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: the reaction product of 4.9 minutes, enantiomer - 9.2 minutes, measured wavelength: 220 nm.

Example 14

Synthesis of (3R*,4R*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (Compound (VI'), * indicates the relative configuration)

2,2-Dimethyl-7-nitro-2H-1-benzopyran (0,205 g, 1.0 mmol) was added to a dichloromethane solution (3 ml) of the optically active complex titanium-Salina (E) (24 mg, at 0.020 mmol) (2.0 mol% with respect the substrate) at 20°C. 30% aqueous hydrogen peroxide solution (0.12 g, 1.1 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. After stirring the solution for 24 hours after start of the reaction at 20°C took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (VI') was 99% or more, and the optical purity was 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 13.9 minutes, enantiomer - 25.2 minutes, measured wavelength: 220 nm.

Example 15

Synthesis of (3S*,4S*)-3,4-epoxy-6-fluoro-3,4-dihydro-2,2-dimethyl-8-nitro-2H-1-benzopyran (Compound (VII), * indicates the relative configuration)

6-Fluoro-2,2-dimethyl-8-nitro-2H-1-benzopyran (0,23 g, 1.0 mmol) was added to a dichloromethane solution (4 ml) of the optically active complex titanium-sallena (In) (37 mg, 0,021 mmol) (2,0 the ol% relative to the substrate) at 25°C. With stirring the reaction solution for 2 seconds was added 30% aqueous hydrogen peroxide solution (0.12 g, 1.1 mmol). The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. Then, the resulting solution was stirred at 25°C for 29 hours after start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (2 ml) and distilled water (2 ml), after which the organic layer was separated. The organic layer is extracted from the aqueous layer with dichloromethane (2 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (VII) in the form of a yellowish powder (0,23 g, yield: 94%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.5 ml/min, column temperature: 40°C, retention time: the reaction product of 17.4 minutes, enantiomer - 18.1 minutes, measured wavelength: 220 nm.

¹H-NMR (CDCl₃) δ: 1,33 (s,3H), of 1.64 (s,3H), 3,57 (d, J=4.4 Hz, 1H), 3,94 (d, J=4.4 Hz, 1H), 7,35 (DD, J=4,4, 7,1 Hz, 1H), 7,56 (DD, J=4,4, 7.9 Hz, 1H).

Example 16

Synthesis of (3S*,4S*)-3,4-epoxy-6-fluoro-3,4-dihydro-2,2-di is ethyl-8-nitro-2H-1-benzopyran (Compound (VII), * indicates the relative configuration)

Tetraisopropoxide titanium (Ti(Oi-Pr)₄) (11 mg, 0.040 mmol) was added to a dichloromethane solution (1.7 ml) salanova ligand (43 mg, 0,080 mmol)(4.0 mol% relative to the substrate)represented by the formula (44'), at 25°C. After stirring for 1 hour at 20°C. to the solution was added 6-fluoro-2,2-dimethyl-8-nitro-2H-1-benzopyran (0,446 g, 2.0 mmol). 30% aqueous hydrogen peroxide solution (0.25 g, 2.2 mmol) was divided into three equal parts, and with stirring, the reaction solution was added to the first part at 20°C, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. The resulting solution was stirred at 20°C for 40 hours after start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (5 ml) and distilled water (5 ml), after which the organic layer was separated. The organic layers twice extracted from the aqueous layer with dichloromethane (5 ml and 3 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (VII) in the form of a yellowish oil (of 0.43 g, yield: 90%, optical purity: 99.9% of Eiji more).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.5 ml/min, column temperature: 40°C, retention time: reaction product - 16.8 minutes, enantiomer - 17.3 minutes, measured wavelength: 220 nm.

¹H-NMR (CDCl₃) δ: 1,33 (s,3H), and 1.63 (s,3H), 3,60 (d, J=4.5 Hz, 1H), 3,98 (d, J=4.5 Hz, 1H), 7,38 (DD, J=3.0 a, 7,4 Hz, 1H), 7,54 (DD, J=3.0 a, 7,4 Hz, 1H).

Example 17

Synthesis of (3R*,4R*)-3,4-epoxy-6-fluoro-3,4-dihydro-2,2-dimethyl-8-nitro-2H-1-benzopyran (Compound (VII'), * indicates the relative configuration)

6-Fluoro-2,2-dimethyl-8-nitro-2H-1-benzopyran (0,23 g, 1.0 mmol) was added to a dichloromethane solution (4 ml) of the optically active complex titanium-sallena (A) (37 mg, 0,021 mmol) (2.0 mol% to a substrate) at 25°C. While stirring the reaction solution for 2 seconds was added 30% aqueous hydrogen peroxide solution (0.12 g, 1.1 mmol) at 25°C. the Beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the beginning the reactions. After 3 hours after start of the reaction took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (VII') was 76%and the optical purity was 99% EE

Analytical conditions: column name: HIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.5 ml/min, column temperature: 40°C, retention time: the reaction product at 18.1 min, enantiomer of 17.4 minutes, measured wavelength: 220 nm.

Example 18

Synthesis of (3R*,4R*)-3,4-epoxy-6-fluoro-3,4-dihydro-2,2-dimethyl-8-nitro-2H-1-benzopyran (Compound (VII'), * indicates the relative configuration)

6-Fluoro-2,2-dimethyl-8-nitro-2H-1-benzopyran (0,23 g, 1.0 mmol) was added to a dichloromethane solution (3 ml) of the optically active complex titanium-Salina (E) (24 mg, at 0.020 mmol) (2.0 mol% to a substrate) at 20°C. of 30% aqueous hydrogen peroxide solution (0.12 g, 1.1 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. After stirring the solution for 24 hours after start of the reaction at 20°C took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (VII') was 96%and the optical purity was 99% EE or more.

Analytical conditions: column name: CHIRALPAK AD-RH (three to the lanky, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 0.5 ml/min, column temperature: 40°C, retention time: reaction product - 17.3 minutes, enantiomer - 16.8 minutes, measured wavelength: 220 nm.

Example 19

Synthesis of (3R*,4R*)-(3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano(2,3-g)quinoline-7-yl)acetate (Compound (VIII'), * indicates the relative configuration)

(2,2,9-Trimethyl-2H-pyrano(2,3-g)quinoline-7-yl)acetate (0,61 g, 2.1 mmol) was added to a dichloromethane solution (3 ml) of the optically active complex titanium-sallena (A) (71 mg, 0.040 mmol) (1.9 mol% relative to the substrate) at 28°C. While stirring the reaction solution for 10 hours was added to 7.5% aqueous solution of hydrogen peroxide (1.4 g, 3.1 mmol). The beginning of the first addition of a 7.5% aqueous solution of hydrogen peroxide was determined as the start of the reaction. 12 hours after start of the reaction was again added a 7.5% aqueous solution of hydrogen peroxide (0.1 g, 0.2 mmol) at 28°C, and then the resulting solution was stirred at 28°C for 14 hours after start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (6 ml) and distilled water (6 ml), after which the organic layer was separated. The organic layer is extracted from the aqueous layer with dichloromethane (6) - Rev. l), and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (VIII') in the form of a yellowish oil (0.65 g, yield: 99%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALPAK AD-RH, eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 3.9 minutes, enantiomer - 9.3 per minute, measured wavelength: 254 nm.

¹H-NMR (CDCl₃) δ: 1.30 on (s,3H), of 1.65 (s,3H), 2,19 (s,3H), 2,62 (d, J=0.8 Hz, 3H), 3,61 (d, J=4.4 Hz, 1H), 4,15 (d, J=4.4 Hz, 1H), and 5.30 (s,2H), 7,26 (s,1H), 7,32 (s,1H), 8,10 (s,1H).

Example 20

Synthesis of (3S*,4S*)-(3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano(2,3-g)quinoline-7-yl)acetate (Compound (VIII), * indicates the relative configuration)

(2,2,9-Trimethyl-2H-pyrano(2,3-g)quinoline-7-yl)acetate (34,2 mg, 0.12 mmol) was added to a dichloromethane solution (1.2 ml) of the optically active complex titanium-Salina (D) (6.2 mg, 0,006 mmol) (5.0 mol% with respect to the substrate) at 28°C. While stirring the reaction solution for 1 second was added 30% aqueous hydrogen peroxide solution (8.5 mg, of 0.075 mmol) at 28°C. the Beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. 20 minutes after h the beginning of the reaction for 1 second at 28°C was again added 30% aqueous hydrogen peroxide solution (8.5 mg, of 0.075 mmol). The resulting solution was continuously stirred at 28°C, and after 3 hours, took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (VIII) was 80%and the optical purity was 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH, eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 10.2 minutes, the enantiomer of 4.1 minutes, measured wavelength: 254 nm.

Example 21

Synthesis of (3R*,4R*)-(3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano(2,3-g)quinoline-7-yl)acetate (Compound (VIII'), * indicates the relative configuration)

(2,2,9-Trimethyl-2H-pyrano(2,3-g)quinoline-7-yl)acetate (0,595 g, 2.0 mmol) was added to a dichloromethane solution (4 ml) of the optically active complex titanium-Salina (S) (48 mg, 0.040 mmol)(2.0 mol% to a substrate) at 20°C. of 30% aqueous hydrogen peroxide solution (0.34 g, 3.0 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. The resulting solution was stirred n and 20°C for 24 hours after start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (5 ml) and distilled water (5 ml), after which the organic layer was separated. The organic layers twice extracted from the aqueous layer with dichloromethane (5 ml and 3 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (VIII') in the form of a yellowish powder (0,61 g, yield: 97%, optical purity: 99.3% of ei).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: the reaction product of 11.2 minutes, enantiomer - 26.6 minutes, measured wavelength: 320 nm.

¹H-NMR (CDCl₃) δ: 1.30 on (s, 3H), of 1.65 (s, 3H), 2,19 (C, d, J=1.9 Hz, 3H), 2,60 (s, 3H), of 3.60 (DD, J=4.5 Hz, 1.9 Hz, 1H), 4,14 (d, J=4.5 Hz, 1H), and 5.30 (s, 2H), 7,25 (s, 1H), 7,31 (s, 1H), 8,10 (s, 1H).

Example 22

Synthesis of (3S*,4S*)-7-chloro-3,4-epoxy-(2,2,9-trimethyl-3,4-dihydro-2H-pyrano(2,3-g)quinoline (Compound (IX), * indicates the relative configuration)

7-Chloro-2,2,9-trimethyl-2H-pyrano(2,3-g)quinoline (0.26 g, 1.0 mmol) was added to a dichloromethane solution (2 ml) of the optically active complex titanium-Salina (F) (120 m is, 0.10 mmol)(10 mol% with respect to the substrate) at 20°C. of 30% aqueous hydrogen peroxide solution (0.17 g, 1.5 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. The resulting solution was stirred at 20°C for 26 hours after start of the reaction. After completion of the reaction, the reaction solution was added dichloromethane (5 ml) and distilled water (5 ml), after which the organic layer was separated. The organic layers twice extracted from the aqueous layer with dichloromethane (5 ml and 3 ml)and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (IX) in the form of a slightly yellowish powder (0.21 g, yield: 77%, optical purity: 99.9% of ei or more).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 42.1 minutes, enantiomer - 21.7 minutes, measured wavelength: nm.

¹H-NMR (CDCl₃) δ: 1.30 on (s, 3H), of 1.64 (s, 3H), of 2.56 (s, 3H), 3,61 (d, J=4,2 Hz, 1H), 4,13 (d, J=4,2 Hz, 1H), 7,15 (s, 1H), 7,27 (s, 1H), 8,00 (s, 1H).

Example 23

Synthesis of (3R*,4R*)-7-chloro-3,4-epoxy-(2,2,9-trimethyl-3,4-dihydro-2H-pyrano(2,3-g)quinoline (Compound (IX'), * indicates the relative configuration)

Tetraisopropoxide titanium (Ti(Oi-Pr)₄) (2.8 mg, 0,010 mmol) was added to a dichloromethane solution (0.5 ml) salanova ligand (27 mg, 0,050 mmol)(10 mol% with respect to the substrate)represented by the formula (44), at 20°C. After stirring for 1 hour at 20°C. to the solution was added 7-chloro-2,2,9-trimethyl-2H-pyrano(2,3-g)quinoline (0,130 g, 0.50 mmol) and dichloromethane (1 ml). 30% aqueous hydrogen peroxide solution (of 0.085 g, 0.75 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes, added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. After stirring the solution at 20°C for 45 hours after the start of the reaction took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (IX') was 99% or more, and the optical purity was 99% EE

Analytical conditions: on the justification column: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=6/4 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 21.7 minutes, enantiomer - 42.1 minutes, measured wavelength: 220 nm.

Example 24

Synthesis of (3S*,4S*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-dimethanesulfonate-6-methoxy-2H-1-benzopyran (Compounds (X), * indicates the relative configuration)

2,2-Dimethyl-7-dimethanesulfonate-6-methoxy-2H-1-benzopyran (0.18 g, 0.50 mmol) was added to a dichloromethane solution (1 ml) of the optically active complex titanium-Salina (F) (12 mg, 0,010 mmol) (2.0 mol% to a substrate) at 20°C. of 30% aqueous hydrogen peroxide solution (of 0.085 g, 0.75 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes added the second part, and after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. Then, the resulting solution was stirred at 20°C for 30 hours after the beginning of the reaction and then the reaction solution was added dichloromethane (2 ml) and distilled water (2 ml), after which the organic layer was separated. The organic layers twice extracted from the aqueous layer, di is loretana (2 ml and 1 ml), and the separated organic layer was combined and then the combined layer are condensed to obtain the crude product. The product was purified column chromatography to obtain compound (X) in the form of a white powder (0.18 g, yield: 97,5%, optical purity: 99% EE).

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=3/7 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 19.8 minutes, enantiomer 18.6 minutes, measured wavelength: 320 nm.

¹H-NMR (CDCl₃) δ: 1.26 in (s,3H), of 1.55 (s,3H), at 3.35 (s,3H), 3,42 (s,3H), 3,49 (d, J=4.5 Hz, 1H), 3,88 (s,3H), 3,88 (d, J=4.5 Hz, 1H), 6,77 (s,1H), 7,00 (s,1H).

Example 25

Synthesis of (3R*,4R*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-dimethanesulfonate-6-methoxy-2H-1-benzopyran (Compounds (X'), * indicates the relative configuration)

2,2-Dimethyl-7-dimethanesulfonate-6-methoxy-2H-1-benzopyran (72 mg, 0.20 mmol) was added to a dichloromethane solution (1 ml) of the optically active complex titanium-Salina (E) (12 mg, 0,010 mmol) (2.0 mol% to a substrate) at 20°C. of 30% aqueous hydrogen peroxide solution (0,034 g, 0.30 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes added the second part, and e is e after 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. The solution was stirred at 20°C for 48 hours after start of the reaction and took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (X') was 99%and the optical purity was 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=3/7 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 18.5 minutes, enantiomer 20.0 minutes, measured wavelength: 320 nm.

Example 26

Synthesis of (3S*,4S*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-dimethanesulfonate-6-methoxy-2H-1-benzopyran (Compounds (X), * indicates the relative configuration)

2,2-Dimethyl-7-dimethanesulfonate-6-methoxy-2H-1-benzopyran (72 mg, 0.20 mmol) was added to a dichloromethane solution (0.5 ml) of the optically active complex titanium-sallena (C) (16 mg, 0,010 mmol)(2.0 mol% to a substrate) at 20°C. of 30% aqueous hydrogen peroxide solution (0,034 g, 0.30 mmol) was divided into three equal parts, and with stirring the reaction solution, initially at 20°C, was added the first part, after 30 minutes added the second part, and even che is ez 1 hour was added to the third part. The beginning of the first adding 30% aqueous solution of hydrogen peroxide was determined as the start of the reaction. The solution was stirred at 20°C for 24 hours after start of the reaction and took a sample of the reaction solution. The degree of conversion of the reaction is taken of the sample was analyzed using HPLC. The degree of conversion in the compound (X) was 83%and the optical purity was 99% EE

Analytical conditions: column name: CHIRALPAK AD-RH (three columns, connected in series with each other), eluent: acetonitrile/20 mm (pH 8) phosphate buffer solution=3/7 (about./vol.), flow rate: 1.0 ml/min, column temperature: 40°C, retention time: reaction product - 19.8 minutes, enantiomer 18.6 minutes, measured wavelength: 320 nm.

INDUSTRIAL APPLICATION

In accordance with the present invention, optically active compound oxide chromene having high optical purity, which is 99% EE or more can be obtained with a high yield, that is 90% or more, without the implementation procedure of the optical separation of the desired connection, and this connection can be successfully used as an important intermediate compounds for connection of benzopyrene, which is effective for the treatment of arrhythmia. Therefore, the present invention has industrial application.

1. A method of obtaining optically the active compound oxide chromene, represented by the formula (14) or formula (15):

(where R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰and a are as described below, and the absolute configuration of the carbon atoms indicated by *, mean (R) or (S)), where the method includes:
asymmetric epoxidation of compounds of chromene represented by the formula (10) or formula (11)with an oxidant in a solvent;

(where each of R⁵, R⁶, R⁷and R⁸in the formula (10) independently represents a hydrogen atom, a cyano, a nitro-group, a halogen atom, a C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic, C_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkoxygroup (alkoxygroup may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic, C_1-4alkyl what urbanrenewal or _1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkylcarboxylic (alkylcarboxylic may be optionally substituted by halogen atom), With_1-4alkylsulphonyl(N-C_1-4alkyl)amino group (alkylsulphonyl(N-alkyl) amino group may be optionally substituted by halogen atom), With_1-4alkoxycarbonyl group (alkoxycarbonyl group may be optionally substituted by halogen atom), a formyl group, carbamoyl group_1-4alkylsulfonyl group (alkylsulfonyl group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group), sulfamoyl group_1-4alkylsulfonamides group (alkylsulfonamides group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group) or bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group);
each of R⁹and R¹⁰in the formula (10) independently represents an atom in Dorada or _1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group);
each of R⁹and R¹⁰in the formula (11) independently represents a hydrogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom or With_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom) or hydroxy-group));
connection chromene represented by the formula (11), in which incomplete cyclic structure And represented by the formula (s):

(where each of R^14,R¹⁵and R¹⁶in the formula (s) independently represents a hydrogen atom, a halogen atom, a C_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic,_1-6alkylcarboxylic (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), With_1-6alkylcarboxylic is Oh, With_3-8cycloalkylcarbonyl group_1-6alkoxycarbonyl group, C_1-6alkylsulfonyl group (cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group can be optionally substituted by a halogen atom or a carboxyl group), With_3-8cycloalkyl group (cycloalkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group or hydroxy-group)_1-6alkoxygroup (alkoxygroup may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), carboxyl group, amino group or hydroxy-group)_1-6dialkoxy (Tolkacheva may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), a carboxyl group or a hydroxy-group), a hydroxy-group, With_6-14aryl group_1-6alkylcarboxylic, a nitrogroup, cyano, formyl group, formamide group, amino group, alphagroup,_1-6alkylamino, di-C_1-6alkylamino,_1-6alkylcarboxylic, C_1-6alkylsulfonamides gr the PPU, karbamoilnuyu group, C_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic group_1-6alkoxycarbonyl group, sulfamoyl group_1-6alkylsulfonyl group or carboxyl group);
where the above epoxidation is performed with the use of any optically active titanium complexes represented by formula (2), formula (2'), formula (4) and formula (4'), as a catalyst,


where R¹in the formula (2), formula (2'), formula (4) and formula (4') represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup,_6-12alloctype or_6-22aryl group (the aryl group may be optionally substituted With_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-7alkoxygroup or benzyloxypropionic, and is optically active or optically inactive);
R²represents a hydrogen atom, a halogen atom, a C_1-4alkyl group or a C_1-4alkoxygroup;
R³represents a C_1-4alkyl group or a bivalent_3-5group, where two of R³taken the together, form a ring;
each of R⁴independently represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, the nitro-group or cyano;
M represents TiJ¹J²(TiJ¹J², Ti represents a titanium atom, and each of the J¹and J²independently represents a halogen atom or With_1-4the alkoxide, or J¹and J²taken together, represent an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5)

(where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the following formula (7), corresponding to the formula (2); group O-E-O is represented by the following formula (7')corresponding to the formula (2'); group O-E-O is represented by the following formula (9), corresponding to the formula (4); and group O-E-O is represented by the following formula (9')corresponding to the formula (4'); and


b represents an integer of 1 a R¹, R², R³and R⁴are the same as defined above)).

2. A method of obtaining optically active compound oxide chromene according to claim 1, where the unity of chromene, represented by the formula (10), is subjected to asymmetric epoxidation reaction in a solvent with an oxidizing agent with an optically active complex of titanium represented by the formula (2), formula (2'), formula (4) or formula (4'), as a catalyst,
where each of R⁵and R⁶in the formula (10) independently represents a hydrogen atom, a cyano, a nitro-group, a halogen atom, a C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkoxygroup (alkoxygroup may be optionally substituted by halogen atom, hydroxy-group, a cyano, a nitro-group, With_1-4alkoxygroup,_1-4alkylcarboxylic,_1-4alkylcarboxylic or_1-4alkoxycarbonyl (alkoxygroup, alkylcarboxylic, alkylcarboxylic and alkoxycarbonyl group can be optionally substituted by a halogen atom)),_1-4alkylcarboxylic (and who killermanjango may be optionally substituted by halogen atom), With_1-4alkylsulphonyl(N-C_1-4alkyl)amino group (alkylsulphonyl(N-alkyl)amino group may be optionally substituted by halogen atom), karbamoilnuyu group, bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group);
R⁷in the formula (10) represents a hydrogen atom, a cyano, a nitro-group, bis(C_1-4alkylsulfonyl)kidney group (alkylsulfonyl bis(alkylsulfonyl)kidney group may be substituted by a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, cyano or nitro-group);
R⁸in the formula (10) represents a hydrogen atom, a nitro-group or C_1-4alkyl group (the alkyl group may be optionally substituted by a halogen atom); and
R⁹and R¹⁰in the formula (10) represents a_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom).

3. A method of obtaining optically active compound oxide chromene according to claim 2, where each of R⁵and R⁶in the formula (10) independently represents a hydrogen atom, a nitro-group, a fluorine atom, a methoxy group, medicalbilling or methylcarbamyl(N-ethyl)amino group; R⁷in the formula (10) represents the Oh hydrogen atom, the nitro-group or bis(C_1-4alkylsulfonyl)kidney group; R⁸in the formula (10) represents a hydrogen atom, a nitro-group or triptorelin group; R⁹and R¹⁰in the formula (10) represents a methyl group.

4. A method of obtaining optically active compound oxide chromene according to claim 1, where R⁹and R¹⁰in the formula (11) represent a methyl group.

5. A method of obtaining optically active compound oxide chromene according to claim 1, where each of R¹⁴, R¹⁵and R¹⁶in the formula (s) independently represents a hydrogen atom, a halogen atom or With_1-6alkyl group (the alkyl group may be optionally substituted by a halogen atom, a C_1-6alkoxygroup (alkoxygroup may be optionally substituted by halogen atom), amino group, hydroxy-group, With_1-6alkylaminocarbonyl group, di-C_1-6alkylaminocarbonyl group_1-6alkylcarboxylic,_1-6alkylcarboxylic (alkylcarboxylic and acylcarnitine group can be optionally substituted by halogen atom), With_1-6alkylcarboxylic,_3-8cycloalkylcarbonyl group or_1-6alkoxycarbonyl group).

6. A method of obtaining optically active compound oxide chromene according to claim 1, where R¹in the formula (2), formula (2'), Faure, the ule (4) and formula (4') represents a C _6-22aryl group (the aryl group may be optionally substituted C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), With_1-7alkoxygroup or benzyloxypropionic, and is optically active or optically inactive);
R²represents a hydrogen atom, a halogen atom, a C_1-4alkyl group or a C_1-4alkoxygroup;
R³represents a C_1-4alkyl group or a bivalent_3-5group, where two of R³taken together form a ring;
each of R⁴independently represents a hydrogen atom, a halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, the nitro-group, or cyano; and
M represents TiJ¹J²where Ti represents a titanium atom, and each of the J¹and J²independently represents a halogen atom or With_1-4the alkoxide, or J¹and J²taken together, represent an oxygen atom or J¹and J²taken together form a ring represented by the divalent group of formula (5)
(where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the above formula (7), corresponding to the formula (2); group O-E-O is represented by the above formula (7')corresponding to the formula (2'); groups of the O-E-O is represented by the above formula (9), corresponding to the formula (4); and group O-E-O is represented by the above formula (9')corresponding to the formula (4');
b represents an integer of 1 a R¹, R², R³and R⁴are the same as defined above)).

7. A method of obtaining optically active compound oxide chromene according to claim 6, where R¹in the formula (2), formula (2'), formula (4) and formula (4') represents a phenyl group (the phenyl group may be optionally substituted C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), benzyloxypropionic or_1-4alkoxygroup) or naftalina group (naftalina group can be optionally substituted C_1-4alkyl group (the alkyl group may be optionally substituted by halogen atom), or C_1-7alkoxygroup);
R²represents a hydrogen atom;
R³represents a bivalent_3-5group, where two of R³taken together form a ring;
R⁴represents a hydrogen atom, and
M represents TiJ¹J²where Ti represents a titanium atom, and each of the J¹and J²independently represents a halogen atom or With_1-4the alkoxide, or J¹and J²taken together, represent an oxygen atom or J¹and J²taken the place form a ring represented by the divalent group of formula (5)
(where, in the incomplete structure of the O-E-o, O represents an oxygen atom, and a group O-E-O is represented by the above formula (7), corresponding to the formula (2); group O-E-O is represented by the above formula (7')corresponding to the formula (2'); group O-E-O is represented by the above formula (9), corresponding to the formula (4); and group O-E-O is represented by the above formula (9')corresponding to the formula 4'); b represents an integer of 1 a R¹, R², R³and R⁴are the same as defined above)).

8. A method of obtaining optically active compound oxide chromene according to any one of claims 1 to 7, where the number of optically active complex of titanium with respect to the number of connections chromene represented by the formula (10) or formula (11)is 0.001 to 100 mol.%.

9. A method of obtaining optically active compound oxide chromene according to any one of claims 1 to 7, where the solvent used for the asymmetric epoxidation is a halogen solvent, an aromatic hydrocarbon solvent, ester solvent, ether solvent, nitrile solvent, an alcohol solvent, or a mixture thereof.

10. A method of obtaining optically active compounds of chromium oxide is as in any one of claims 1 to 7, where the oxidant used in the asymmetric epoxidation reaction is iodosobenzene, sodium hypochlorite, m-chloroperbenzoic acid, a mixture of peroxymonosulfate potassium, disulfate potassium and potassium sulfate, an aqueous solution of hydrogen peroxide, the product of the merger of urea-hydrogen peroxide (UHP), oxaziridine, N-methylmorpholine (NMO), tert-butylhydroperoxide (TNR), cumene hydroperoxide (CHP), or a mixture thereof.

11. A method of obtaining optically active compound oxide chromene of claim 10, where the oxidant used for the asymmetric epoxidation reaction is an aqueous solution of hydrogen peroxide, the product of the merger of urea-hydrogen peroxide (UHP), or a mixture thereof.

12. A method of obtaining optically active compound oxide chromene according to claim 11, where the oxidant used for the asymmetric epoxidation reaction is an aqueous solution of hydrogen peroxide at a concentration of 1-100 wt.%.

13. A method of obtaining optically active compound oxide chromene according to any one of claims 1 to 7, where the amount of oxidant used for asymmetric epoxidation, in relation to the number of connections chromene represented by the formula (10) and formula (11)is 1-10 equivalents.

14. A method of obtaining optically active compound oxide chromene indicated in paragraph 13, where the method add okoli the El, used for asymmetric epoxidation, is a stepwise or continuous addition.

15. A method of obtaining optically active compound oxide chromene on 14, where the method of adding the oxidizing agent used for the asymmetric epoxidation, represents the continuous addition, the speed of which is from 0.01 to 40,000 equivalents per hour.

16. A method of obtaining optically active compound oxide chromene on 14, where the method of adding the oxidizing agent used for the asymmetric epoxidation is a stepwise addition, where the number of stages is in the range of 2 to 100.

17. A method of obtaining optically active compound oxide chromene according to any one of claims 1 to 7, where the reaction temperature of the asymmetric epoxidation is from 0°C to temperature distillation of the solvent used.

18. A method of obtaining optically active compound oxide chromene according to any one of claims 1 to 7, where the pressure in the reaction system asymmetric epoxidation is from 10 kPa to 1100 kPa.