Method of producing pyripyropene derivatives and intermediate products for production thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound C of formula: [1] where R' is a linear, branched or cyclic C_2-6 alkyl carbonyl group. In this method, the protective group for the hydroxy group in position 7 used is R_1b; where R_1b is a formyl group, optionally substituted with a linear C_1-4 alkyl carbonyl group, optionally substituted benzyl group, a -SiR₃R₄R₅ group, where R₃, R₄ and R₅ are independently a linear or branched C_1-4 alkyl group or a phenyl group, which can be substituted with a halogen atom, a C_1-6alkyloxy-C_1-6alkyl group, which can be substituted with a halogen atom, C_1-6alkylthio-C_1-6alkyl group, which can be substituted with a halogen atom, a linear, branched or cyclic C_1-6alkyl group, which can be substituted with a halogen atom (in case of branched or cyclic, denotes a C_3-4alkyl group), C_2-6alkenyl group, which can be substituted with a halogen atom, C_2-6alkynyl group, which can be substituted with a halogen atom, or an optionally substituted saturated or unsaturated 5-member or 6-member heterocyclic group. The invention also includes methods of producing intermediate compounds B2a and B2b and the compound of formula 2Bb itself.

EFFECT: method enables to obtain a pyripyropene derivative with high output, which contains an acyloxy group in position 1 and in position 11 and a hydroxy group in position 7; such a pyripyropene derivative can be used as a pest control agent.

15 cl, 26 ex

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from previously filed application for the grant of the Japan patent No. 210804/2007 (filing date August 13, 2007). Full details of the application for the grant of a patent Japan 210804/2007 included in this document by reference.

BACKGROUND of INVENTION

The technical field to which the invention relates.

The present invention relates to a method for perioperative derivatives applicable as a means for pest control, and more specifically relates to a method for perioperative derivatives that contain alloctype in 1 - and 11-positions and a hydroxyl group at the 7-position.

The level of technology

Perioperative derivatives containing acyloxy in 1 - and 11-positions and a hydroxyl at the 7-position, are compounds that can be used for pest control, as described in WO 2006/129714.

In WO 2006/129714 and in published application for a patent of Japan No. 259569/1996 disclosed is a method of obtaining perioperative derivatives containing acyloxy in 1 - and 11-positions and a hydroxyl at the 7-position. In accordance with the method of obtaining perioperative derived purified or isolated from a variety of products obtained by selective hydrolysis of acyloxy using 1,7,11-triac is loxioides as the source connection. However, this method of obtaining suffers from disadvantages such as low yield and impractical for large-scale synthesis.

In addition, in published application for a patent of Japan No. 259569/1996 described the combination of a protective group for synthesis of perioperative derivatives; and in the Journal of Antibiotics Vol. 49, No. 11, p. 1149, 1996, Bioorganic Medicinal Chemistry Letter, Vol. 5, No. 22, p. 2683, 1995, published the application for the grant of the Japan patent No. 269065/1996 and WO 2008/013336 described an example of a synthesis, in which acyl is introduced into the 7-position with the use of protective groups. However, these documents do not describe a specific way in which the protective group is used to obtain perioperative derivatives containing acyloxy in 1 - and 11-positions and a hydroxyl at the 7-position.

The INVENTION

The authors of the present invention found that perioperative derivatives containing acyloxy in 1 - and 11-positions and a hydroxyl group at the 7-position can be obtained with high yield from peripherin A (published application for the grant of the Japan patent No. 259569/1996; Bioorganic Medicinal Chemistry Letter, Vol. 5, No. 22, p. 2683, 1995; and WO 2004/060065), obtained in the form of naturally occurring substances, using a suitable protective group. The present invention was made on the basis of this discovery.

Accordingly, the present invention is to provide the providing method of obtaining perioperative derivatives, applicable as a means for pest control, and compounds as intermediates for obtaining perioperative derivatives.

In accordance with the first aspect of the present invention relates to a method for producing compound C represented by the formula C:

[Chemical formula 1]

,

in which R' represents a linear, branched or cyclic C_2-6alkylaryl, provided that when the alkyl fragment in alkylcarboxylic group is branched or cyclic, R' represents a C_3-6alkylsulphonyl, and the method comprises the stages:

(a₁) hydrolysis of acetyl 7-position of compound A1 represented by formula A1:

[Chemical formula 2]

,

in which Ac represents acetyl,

the basis for selective disallowance connections A1, then protecting hydroxyl at the 7-position obtaining compounds B1 represented by the formula B1:

[Chemical formula 3]

,

in which

the value of Ac is defined above,

R_1arepresents an optionally substituted linear C_2-4alkylsulphonyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅regardless of performance, which defaults to a linear or branched C _1-6alkyl or phenyl; optionally substituted by a halogen atom C_1-6alkyloxy-C_1-6alkyl; optionally substituted by a halogen atom C_1-6alkylthio-C_1-6alkyl; optionally substituted by a halogen atom, a linear, branched or cyclic C_1-4alkyl, provided that when the alkyl C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_3-4alkyl; optionally substituted by a halogen atom C_2-6alkenyl; optionally substituted by a halogen atom C_2-6quinil; optionally substituted benzyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,

where R_1anot necessarily present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy, C_1-4halogenations, C_1-4alkylsulphonyl, C_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, but not necessarily present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy, C_1-4halogenations, C_1-4alkylthio, C_1-4halogenoalkane, C_1-4alkylsulphonyl, C_1-4halogenoalkane, C_1-4alkylboron is lexi, C_1-4halogenlithiumcarbeniods, nitro and cyano,

then hydrolysis of the acetyl 1 - and 11-positions of compound B1 grounds for disallowance compound B1 with obtaining thereby the connection Fa represented by the formula Fa:

[Chemical formula 4]

,

in which the value of R_1adefined above, or

(a₂) hydrolysis of acyl 1-, 7 - and 11-positions of compound A1 or connection A4', represented by formula A4':

[Chemical formula 5]

,

where A₁', A₇' and A₁₁'which may be identical or different, represent an acetyl or propionyl, provided that A₁', A₇' and A₁₁' not simultaneously represent acetyl,

the basis for disallowance connections A1 or A4', and then protecting hydroxyl at the 1 - and 11-positions of obtaining compound D represented by the formula D:

[Chemical formula 6]

,

where two R₂form together a group selected from groups represented by the formulae D-1, D-2, D-3 and D-4:

[Chemical formula 7]

,

in which Y₁represents a hydrogen atom or a C_1-4alkyl; the substituents X, which may be identical or different, represent a hydrogen atom, a C_1-4alkoxy or nitro; and n is equal is 0-5,

then protecting hydroxyl at the 7-position of compound D with obtaining compound E represented by the formula E:

[Chemical formula 8]

,

in which

R_1brepresents formyl; optionally substituted linear C_1-4alkylsulphonyl; optionally substituted benzyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; optionally substituted by a halogen atom C_1-6alkyloxy-C_1-6alkyl; optionally substituted by a halogen atom C_1-6alkylthio-C_1-6alkyl; optionally substituted by a halogen atom, a linear, branched or cyclic C_1-4alkyl, provided that when the alkyl C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_3-4alkyl; optionally substituted by a halogen atom C_2-6alkenyl; optionally substituted by a halogen atom C_2-6quinil; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,

where R_1bnot necessarily present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy, C_1-4halog is alkyloxy, C_1-4alkylsulphonyl, C_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, but not necessarily present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy, C_1-4halogenations, C_1-4alkylthio, C_1-4halogenoalkane, C_1-4alkylsulphonyl, C_1-4halogenoalkane, C_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano, and

the value of R₂defined above,

with the subsequent removal of the protective groups in the 1 - and 11-positions of compound E with connection Fb represented by the formula Fb:

[Chemical formula 9]

,

in which the value of R_1bdefined above, and

(b) acylation of the hydroxyl at the 1 - and 11-positions of compound Fa or Fb allermuir agent corresponding to the assumed R', to obtain the compound B2a or B2b represented by the formula B2a or B2b:

[Chemical formula 10]

,

in which the values of R_1a, R_1band R' are defined above,

and then removing the protective group in the 7-position of compound B2a or B2b connections.

In accordance with the second aspect of the present invention relates to a method for obtaining compounds of B2a, presents f is rmulas B2a:

[Chemical formula 11]

,

in which the value of R_1adefined above, and R' is a cyclic C_3-6alkylsulphonyl, and the method includes:

the hydrolysis of acetyl 7-position of compound A1 described above, the basis for selective disallowance connections A1, then protecting hydroxyl at the 7-position obtaining compounds B1 represented by the formula B1:

[Chemical formula 12]

,

in which the values of Ac and R_1adefined above,

then the hydrolysis of acetyl 1 - and 11-positions of compound B1 grounds for disallowance connections B1, obtaining thereby the connection Fa represented by the formula Fa:

[Chemical formula 13]

,

in which the value of R_1adefined above,

and then acylation of the hydroxyl at the 1 - and 11-positions of compound Fa allermuir agent corresponding to the assumed R'.

In accordance with a third aspect of the present invention relates to a method for obtaining compounds of B2b represented by the above formula B2b, in which R' is a cyclic C_3-6alkylsulphonyl, and the method includes:

hydrolysis of the acyl 1-, 7 - and 11-positions of compound A4 represented by formula A4:

[Chemical formula 14]

,</>

where A₁, A₇and A₁₁that may be the same or different, represent an acetyl or propionyl,

the basis for disallowance connection A4, then protecting hydroxyl at the 1 - and 11-positions with connection D, then protecting hydroxyl at the 7-position of compound D with obtaining the above-described compounds E, followed by removal of the protective group at the 1 - and 11-positions of compound E with obtaining the above-described compounds Fb, and then the acylation of the hydroxyl at the 1 - and 11-positions of compound Fb allermuir agent corresponding to R'.

In accordance with the fourth aspect of the present invention relates to a method for producing compound C represented by formula C in which R' is a cyclic C_3-6alkylsulphonyl. The method comprises the acylation of the hydroxyl at the 1 - and 11-positions of the above described compounds Fb allermuir agent corresponding to R', getting B2b connections, and then removing the protective group in the 7-position of compound B2b.

In accordance with the fifth aspect of the present invention relates to a method for producing the above compound C. the Method involves hydrolysis of acyl 1-, 7 - and 11-positions of compound A4 grounds for disallowance connection A4, then protecting hydroxyl at the 1 - and 11-positions with connection D, then protecting hydroxyl at the 7-floor the position of the connection D connection E, with the subsequent removal of the protective groups in the 1 - and 11-positions of compound E with connection Fb, and then the acylation of the hydroxyl at the 1 - and 11-positions of compound Fb allermuir agent corresponding to R', getting B2b connections, and then removing the protective group in the 7-position of compound B2b.

In accordance with the sixth aspect of the present invention relates to a connection that contains acyloxy in 1 - and 11-positions and a hydroxyl at the 7-position and is applicable as an intermediate product to obtain perioperative derivatives. The compound represented by formula B2b:

[Chemical formula 15]

,

in which the value of R_1bdefined above; and R' is a cyclic C_3-6alkylsulphonyl.

The present invention allows to obtain a high yield perioperative derivatives that contain alloctype in 1 - and 11-positions and a hydroxyl group at the 7-position and which are applied as tools for pest control.

DETAILED description of the INVENTION

Used in this document, the term "halogen" means fluorine, chlorine, bromine or iodine.

The terms "alkyl", "alkenyl" or "quinil"used in this text as a substituent or part of a substituent, means alkyl, alkenyl or quinil linear, branched or cyclizes the type, or combined type, unless otherwise specified particularly.

The designation "C_a-b"used in this document, in relation to the Deputy means that the number of carbon atoms contained in the Deputy is from a to b. In addition, "C_a-b" in the term "C_a-balkylaryl" means that the number of carbon atoms in the alkyl fragment, excluding carbon atoms in the carbonyl fragment is from a to b.

Used in this document the term "halogenated" means alkyl, substituted by at least one halogen atom. Similarly, the terms "halogenations", "halogenoalkanes and halogenlithiumcarbeniods", respectively, mean alkyloxy, substituted by at least one halogen atom, alkylaryl, substituted by at least one halogen atom, and alkylcarboxylic, substituted by at least one halogen atom.

Specific examples of the linear, branched or cyclic C_2-6alkylcarboxylic group represented by R', in which the alkyl fragment in C_2-6alkylcarboxylic group is branched or cyclic, alkyl fragment is a C_3-6alkylsulphonyl include cyclopropanecarbonyl and propionyl. Acylcarnitine group preferably is a cyclic C_3-6alkylboron is l, more preferably cyclopropanecarbonyl.

Specific examples of the group-SiR₃R₄R₅in which each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl, presents R_1aand R_1binclude trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl. Group-SiR₃R₄R₅is optionally substituted, and such substituents include halogen atoms. In the group-SiR₃R₄R₅all R₃, R₄and R₅preferably represent a linear or branched C_1-6alkyl, i.e. group-SiR₃R₄R₅preferably represents alkylsilane, more preferably tert-butyldimethylsilyl.

Specific examples of the linear, branched or cyclic C_1-4alkyl groups represented by R_1aand R_1b, in which the alkyl C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_3-4the alkyl include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl and tert-butyl. Alkyl group is optionally substituted, and such substituents include halogen atoms.

Concrete examples of C_2-6alkenylphenol group represented by R_{1a/sub> and R1binclude vinyl, (1 - or 2-)propenyl, (1-, 2 - or 3-)butenyl, (1-, 2-, 3 - or 4-)pentenyl and (1-, 2-, 3-, 4 - or 5-)hexenyl. Alchemilla group is optionally substituted, and such substituents include halogen atoms.}

Concrete examples of C_2-6alkenylphenol group represented by R_1aand R_1binclude ethinyl, (1 - or 2-PROPYNYL, (1-, 2 - or 3-)butenyl, (1-, 2-, 3 - or 4-)pentenyl and (1-, 2-, 3-, 4 - or 5-)hexenyl. Alchemilla group is optionally substituted, and such substituents include halogen atoms.

Specific examples of the saturated or unsaturated 5 - or 6-membered heterocyclic group represented by R_1aand R_1binclude tetrahydropyranyl, tetrahydropyranyl, tetrahydrofuranyl and tetrahydrofuranyl. Heterocyclic group is optionally substituted, and such substituents include halogen atoms, C_1-4alkyl, C_1-4alkyloxy, C_1-4halogenations, C_1-4alkylthio, C_1-4halogenated, C_1-4alkylsulphonyl, C_1-4halogenoalkanes, C_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano. The heterocyclic group preferably is tetrahydropyranyl.

Specific examples of the linear C_2-4alkylcarboxylic group represented by R_1ainclude propionyl, propylmalonic and n-butylboron is. Acylcarnitine group is optionally substituted, and such substituents include halogen atoms, C_1-4alkyloxy, C_1-4halogenations, C_1-4alkylsulphonyl, C_1-4halogenoalkanes, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods.

Specific examples of the linear C_1-4alkylcarboxylic group represented by R_1binclude acetyl, propionyl, propylmalonic and n-butylcarbamoyl. Acylcarnitine group is optionally substituted, and such substituents include halogen atoms, C_1-4alkyloxy, C_1-4halogenations, C_1-4alkylsulphonyl, C_1-4halogenoalkanes, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods.

C_1-6alkyloxy-C_1-6the alkyl group represented by R_1aand R_1bis optionally substituted, and such substituents include halogen atoms.

C_1-6alkylthio-C_1-6the alkyl group represented by R_1aand R_1bis optionally substituted, and such substituents include halogen atoms.

Benzyl group represented by R_1aand R_1bis optionally substituted, and such substituents include halogen atoms, C_1-4alkyl, C_1-4alkyloxy, C_1-4halogenations, C_1-4alkylthio, C_1-4halogenated, C_1-4kilcarbery, C_1-4halogenoalkanes, C_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano.

Preferably R_1arepresents optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group, more preferably a group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or a saturated or unsaturated 5 - or 6-membered heterocyclic group, more preferably a group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or tetrahydropyranyl, most preferably tert-butyldimethylsilyl or tetrahydropyranyl.

Preferably R_1brepresents acetyl, chloroacetyl, optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group, or optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents the t of a linear or branched C _1-6alkyl or phenyl, more preferably acetyl, chloroacetyl or optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl, more preferably acetyl, chloroacetyl or tert-butyldimethylsilyl, most preferably acetyl or chloroacetyl.

Deputy formed by combining together two of the substituents R₂preferably represents a group represented by formula D-1 or D-2:

[Chemical formula 16]

,

in which Y₁represents a hydrogen atom or a C_1-4alkyl; the substituents X, which may be identical or different, represent a hydrogen atom, a C_1-4alkoxy or nitro; and n is 0-5, more preferably isopropylidene, benzylidene or a pair of methoxybenzylidene. In accordance with another embodiment Deputy, formed by combining together two of the substituents R₂preferably represents-D-1, more preferably isopropylidene.

Preferably each A₁, A₇and A₁₁are acetyl.

In accordance with a preferred embodiment of the present invention, in the method in accordance with PE is the first aspect of the present invention or in the method in accordance with the fifth aspect of the present invention, R' is a cyclic C _3-6alkylsulphonyl.

In accordance with another preferred embodiment of the present invention, in the method in accordance with the first aspect of the present invention R_1arepresents optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group.

In accordance with another preferred embodiment of the present invention, in the method in accordance with the first aspect of the present invention or in the method in accordance with the third aspect of the present invention R_1brepresents acetyl, chloroacetyl or optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl.

In accordance with an additional preferred embodiment of the present invention, in the method in accordance with the first aspect of the present invention or in the method in accordance with the third aspect of the present invention, two Deputy R₂form together a group represented by the second formula D-1 or D-2:

[Chemical formula 17]

,

in which Y₁represents a hydrogen atom or a C_1-4alkyl; the substituents X, which may be identical or different, represent a hydrogen atom, a C_1-4alkoxy or nitro; and n is 0-5.

In accordance with another preferred embodiment of the present invention, in the method in accordance with the second aspect of the present invention R_1arepresents an optionally substituted linear C_2-4alkylsulphonyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group.

In accordance with another preferred embodiment of the present invention, in the method in accordance with the sixth aspect of the present invention R_1brepresents acetyl, chloroacetyl, optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl, or optionally substituted saturated or ninasimone the 5 - or 6-membered heterocyclic group; and R' is a cyclic C_3-6alkylsulphonyl.

In accordance with another another preferred embodiment of the present invention, R' in formula B2a, B2b and C represents propionyl or cyclopropanecarbonyl.

In accordance with an additional preferred embodiment of the present invention, in the method of the expected compound obtained in connection Fa, where R_1ain the formula B1, Fa or B2a represents an optionally substituted linear or branched alkylsilane or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group.

In accordance with another preferred embodiment of the present invention, in the method of the expected compound obtained in connection F_bwhere R_1bin the formula E, Fb or B2b represents acetyl, chloroacetyl or optionally substituted linear or branched alkylsilane.

In accordance with another preferred embodiment of the present invention, in the method of the expected compound obtained in connection Fb, where R₂in formula D or E is a group represented by formula D-3.

In accordance with the preferred embodiment of the present invention,the estimated connection receives through the connection D, E, Fb and B2b, where R₂in formula D or E is a group represented by formula D-3; R_1bin the formula E, Fb or B2b represents acetyl, chloroacetyl or optionally substituted linear or branched alkylsilane; and R' in formulas B2b and C represents cyclopropanecarbonyl.

In accordance with another aspect of the present invention relates to a method for producing compound C represented by the formula C:

[Chemical formula 18]

,

in which R' is a cyclic C_3-6alkylsulphonyl, and the method includes:

hydrolysis of the acyl 1-, 7 - and 11-positions of compound A4 represented by formula A4:

[Chemical formula 19]

,

where A₁, A₇and A₁₁that may be the same or different, represent an acetyl or propionyl,

the basis for disallowance connection A4, and then protecting hydroxyl at the 1 - and 11-positions of obtaining compound D represented by the formula D:

[Chemical formula 20]

,

where two R₂form together a group represented by formula D-1:

[Chemical formula 21]

,

in which Y₁represents a hydrogen atom or a C_1-4alkyl,

then protecting hydroxyl at the 7-put and connection D connection E, represented by the formula E:

[Chemical formula 22]

,

in which R_1brepresents acetyl or chloroacetyl, and the value of R₂defined above,

then removing the protective group at the 1 - and 11-positions of compound E with connection Fb represented by the formula Fb:

[Chemical formula 23]

,

then acylation of the hydroxyl at the 1 - and 11-positions of compound Fb allermuir agent corresponding to R', getting B2b connections represented by the formula B2b:

[Chemical formula 24]

,

in which the values of R_1band R' are defined above,

and then removing the protective group in the 7-position of compound B2b.

The present invention may be described in accordance with the following schema.

[Chemical formula 25]

In this scheme, the values of Ac, R_1a, R_1b, A₁, A₇, A₁₁and R₂defined above; R' represents a linear, branched or cyclic C_2-6alkylsulphonyl, where if the alkyl fragment in C_2-6alkylcarboxylic group is branched or cyclic, alkyl fragment is a C_3-6alkylsulphonyl.

The product of each stage can be used at a later stage without complement Inoi processing.

1-1: Getting connection A3 from compound A1

Compound A1 can be obtained by methods described, for example, in published application for a patent of Japan No. 184158/1994, WO 2004/060065 published the application for the grant of the Japan patent No. 259569/1996 or Bioorganic Medicinal Chemistry Letter, Vol. 5, No. 22, p. 2683.

The solvents used at the stage of obtaining compounds A3 from compound A1 include alcohol solvents containing 1-4 carbon atoms, such as methanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile, golozhabernyi solvents such as dichloromethane and chloroform, and water, and mixed solvents composed of two or more of these solvents.

The base used in this document, include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide and barium hydroxide, alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium alkoxides of alkaline earth metals, or organic base is, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine and guanidine. Preferred are 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide and tert-piperonyl potassium. Especially preferred are 1,8-diazabicyclo[5.4.0]undec-7-ene and tert-piperonyl potassium.

The amount of base is preferably from 0.01 to 1.2 equivalents relative to the amount of compound A1. The reaction temperature preferably ranges from -20°C to 50°C. the Duration of the reaction is preferably from 0.5 h to 7 days.

1-2: connection B1 of compounds A3

At the stage of obtaining compounds B1 of compounds A3 hydroxyl at the 7-position can be protected with the use of halide R_1apresented R_1a-Hal, where Hal represents a halogen atom, acid anhydride R_1aor mixed anhydride of the acid R_1acorresponding to the assumed R_1aor 3,4-dihydropyran in the presence of a base, in the presence of acid or in the absence of bases and acids, or by using a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)CT is diimide hydrochloride, carbonyldiimidazole, dipyridyl disulfide, diimidazole disulfide, 1,3,5-trichlorobenzoyl chloride, 1,3,5-trichlorobenzoyl anhydride, PyBop or PyBrop.

This stage can be carried out in the absence or in the presence of a solvent. Used in this document solvents include ketone solvents such as acetone and diethylketone, ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, aprotic polar organic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and acetonitrile, polar organic solvents, such as pyridine, golozhabernyi hydrocarbon solvents such as dichloromethane and chloroform, or an aromatic hydrocarbon solvents such as toluene, and mixed solvents composed of two or more of these solvents.

Used in this document includes, for example, sodium carbonate, potassium carbonate, sodium hydride, tert-piperonyl potassium, sodium methoxide, ethoxide sodium, pyridine, dimethylaminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine or diisopropylethylamine.

Used in this document acids include, for example, para-toluensulfonate acid, para-that is ursulinas acid monohydrate, pyridinium para-toluensulfonate, 10-camphorsulfonic acid, hydrochloric acid or sulphuric acid.

The reaction temperature preferably ranges from -20°C to 50°C. the Duration of the reaction is preferably from 0.5 h to 4 days.

1-3: Getting connection Fa from compound B1

The solvents used at the stage of obtaining compounds of Fa from compound B1 include alcohol solvents containing 1-4 carbon atoms, such as methanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile, golozhabernyi solvents such as dichloromethane and chloroform, or water, and mixed solvents composed of two or more of these solvents.

Used in this document the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide and barium hydroxide, alkaline earth metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, alkaline earth metal alkoxides, or the authority of the economic base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine and guanidine. Preferred are 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide. Particularly preferred is potassium carbonate.

The amount of base is preferably from 0.01 to 10 equivalents relative to the amount of compound B1. The reaction temperature preferably ranges from -20°C to 50°C. the Duration of the reaction is preferably from 0.5 to 48 hours

2-1: connection A2 of the connection A4

Compound A4 and connection A4' can be naturally occurring substances obtained by methods described, for example, in published application for a patent of Japan No. 184158/1994, WO 94/09147 and published the application for the grant of the Japan patent No. 239385/1996. Alternatively, for example, derivatives are described, for example, in published application for a patent of Japan No. 259569/1996.

The solvents used at the stage of obtaining connection A2 of the connection A4, include alcohol solvents containing 1-4 carbon atoms, such as methanol, ether solvents such as diethyl ether, visapro the silt ether, tetrahydrofuran and dioxane, aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile, golozhabernyi solvents such as dichloromethane and chloroform, or water, and mixed solvents composed of two or more of these solvents.

Used in this document the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide and barium hydroxide, alkaline earth metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, alkaline earth metal alkoxides or organic bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine and guanidine. Preferred are 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide. Particularly preferred is potassium carbonate.

The amount of base is preferably from 0.01 to 10 equivalents relative to the number with the unity A4. The reaction temperature preferably ranges from -20°C to 50°C. the Duration of the reaction is preferably from 0.5 to 48 hours

In accordance with this phase connection A2 can be similarly obtained from compound A1 or connection A4' (connection similar to the connection A4, except that A₁, A₇and A₁₁in connection A4 represent A₁', A₇' and A₁₁', respectively).

2-2: connection is obtained through E compound D from compound A2

The solvents used at the stage of obtaining compounds of D from compound A2, include ketone solvents such as acetone and diethylketone, ether solvents such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, aprotic polar organic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and acetonitrile, golozhabernyi hydrocarbon solvents such as dichloromethane and chloroform, or an aromatic hydrocarbon solvents such as toluene, and mixed solvents composed of two or more of these solvents.

Hydroxyl-1 - and 11-positions may be substituted with, for example, dimethoxypropane, acetone, optionally substituted benzaldehyde or e is about dimethylacetamide form, 2-methoxypropene, 2-ethoxypropane, phosgene, triphosgene, trichloroacetamide, para-nitrobenzotrifluoride or carbonyldiimidazole corresponding to the assumed R₂. In addition, it is preferable to use an acid catalyst such as para-toluensulfonate acid, para-toluensulfonate acid monohydrate, pyridinium para-toluensulfonate, 10-camphorsulfonic acid, hydrogen fluoride, hydrochloric acid, bromovalerate, sulfuric acid, iodine, iron chloride, tin chloride, zinc chloride, aluminium chloride, trimethylchlorosilane, trimethylsilyltriflate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (preferably pyridinium para-toluensulfonate and para-toluensulfonate acid), in an amount of from 0.001 to 20 equivalents, more preferably from 0.01 to 5 equivalents, more more preferably from 0.01 to 0.04 equivalent relative to the compound A2.

The reaction temperature preferably ranges from -20°C to 50°C, more preferably from room temperature to 50°C. the Duration of the reaction is preferably from 0.5 to 48 hours

More specifically, for example, compounds D and E, which are compounds in which R₂represents the D-1, can be obtained by conducting a reaction using a reagent for the introduction of protective groups, such as dimethoxypropane, 2-methoxypropene and the 2-ethoxypropan, in the presence of an acid catalyst such as para-toluensulfonate acid, para-toluensulfonate acid monohydrate, pyridinium para-toluensulfonate or 10-camphorsulfonic acid, in an amount of from 0.001 to 20 equivalents, preferably from 0.01 to 5 equivalents, more preferably from 0.01 to 0.04 equivalent relative to the compound A2, or by conducting the reaction in acetone using pair-toluensulfonate acid, pyridinium para-toluensulfonate, sulfuric acid or copper sulfate in an amount of from 0.001 to 20 equivalents relative to compound A2.

Compounds D and E, which are compounds in which R₂represents the D-2 can be obtained by conducting a reaction using the optional substituted benzaldehyde or its dimethylacetamide form in the presence of an acid catalyst such as para-toluensulfonate acid, para-toluensulfonate acid monohydrate, pyridinium para-toluensulfonate or zinc chloride, in an amount of from 0.001 to 20 equivalents relative to compound A2.

Next, the stage of obtaining compound E from compound D can be carried out in the absence or in the presence of a solvent. Used in this document solvents include ketone solvents such as acetone, diethylketone, ethereal solvents, such as the diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile, polar organic solvents, such as pyridine, golozhabernyi hydrocarbon solvents such as dichloromethane and chloroform, or an aromatic hydrocarbon solvents such as toluene, and mixed solvents composed of two or more of these solvents.

Protective group corresponding to R_1bmay be entered hydroxyl at the 7-position with the use of halide R_1bpresented R_1b-Hal, R_1bOH, R_1bCl, (R_1b)₂O, mixed acid anhydride R_1bor 3,4-dihydropyran in the presence of a base, in the presence of acid, or in the absence of a base or acid, or by using a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, carbonyldiimidazole, dipyridyl disulfide, diimidazole disulfide, 1,3,5-trichlorobenzoyl chloride, 1,3,5-trichlorobenzoyl anhydride, PyBop or PyBrop.

Used in this document includes, for example, sodium carbonate, potassium carbonate, sodium hydride, tert-piperonyl potassium methoxide NAT the Oia, ethoxide sodium, pyridine, dimethylaminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine or diisopropylethylamine.

Used in this document acids include, for example, para-toluensulfonate acid, para-toluensulfonate acid monohydrate, pyridinium para-toluensulfonate, 10-camphorsulfonic acid, hydrochloric acid or sulphuric acid.

The reaction temperature preferably ranges from -20°C to 50°C. the Duration of the reaction is preferably from 0.5 h to 7 days.

More specifically, for example, the compound in which R_1bis a linear C_1-4alkylsulphonyl, optionally substituted by a halogen atom, for example, acetyl or chloroacetyl, can be obtained by carrying out at temperatures from -20°C to 50°C reaction using R_1bCl or (R_1b)₂O in an amount of from 1 to 20 equivalents relative to compound D and pyridine, dimethylaminopyridine or triethylamine as a base in an amount of from 0.1 to 20 equivalents relative to compound D, in the absence of solvent or tetrahydrofuran, dichloromethane, N,N-dimethylformamide or pyridine or a mixed solvent composed of two or more of these solvents.

The compound in which R_1brepresents the optional samostoyatelna halogen group-SiR ₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl, can be obtained by carrying out at temperatures from -20°C to 50°C reaction using halide R_1bin an amount of from 1 to 10 equivalents relative to compound D and imidazole as the base number from 1 to 10 equivalents relative to compound D in dichloromethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or a mixed solvent composed of two or more of these solvents.

2-3: obtaining a connection from Fb connection E

The solvents used in the process of getting the Fb connection from the connection E, include alcohol solvents containing 1-4 carbon atoms, such as methanol, ketone solvents such as acetone and diethylketone, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile, golozhabernyi solvents such as dichloromethane and chloroform, or water, and mixed solvents composed of two or more of these solvents.

When removing the protective group from the fragment of R₂can be used bodies is practical acid, such as acetic acid, triperoxonane acid, triperoxonane anhydride, hydrogen fluoride, hydrochloric acid, bromovalerate, sulfuric acid, para-toluensulfonate acid, para-toluensulfonate acid monohydrate, pyridinium para-toluensulfonate or 10-camphorsulfonic acid, or a hydrogenation catalyst, such as boron chloride, bromide, magnesium, denitrating, bismuth chloride, cerium chloride, iron chloride, tin chloride, zinc chloride, aluminium chloride, palladium on coal or palladium hydroxide, in an amount of from 0.01 to 20 equivalents relative to compound E, depending on the type of the protective group.

The reaction temperature preferably ranges from -20°C to 50°C. the Duration of the reaction is preferably from 0.5 to 48 hours

More specifically, for example, if R₂in the compound E is a D-1, the connection Fb can be obtained by conducting a reaction using 0.01 to 20 equivalents (relative to the compound (E) hydrochloric acid, acetic acid, para-toluensulfonate acid, para-toluensulfonate acid monohydrate, pyridinium para-toluensulfonate, dimitrienko or chloride of bismuth (preferably hydrochloric acid, acetic acid or pyridinium para-toluensulfonate) in water, methanol, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, acetonitrile or the UKS the Noah acid or a mixed solvent composed of two or more of these solvents, at temperatures from -20°C to 50°C, preferably at a temperature from room temperature to 40°C.

If R₂represents the D-2, the connection Fb can be obtained by conducting a reaction using 0.01 to 20 equivalents (relative to the compound (E) 10-camphorsulfonic acid in water, methanol, tetrahydrofuran or chloroform or a mixed solvent composed of two or more of these solvents, at temperatures from -20°C to 50°C, preferably at a temperature from room temperature to 40°C.

3: Getting connection B2a from the connection Fa and the connection of B2b connections Fb

Stage receiving the connection B2a from the connection Fa and the stage of obtaining compounds of B2b connections Fb can be carried out in the absence or in the presence of a solvent. Used in this document solvents include ketone solvents such as acetone and diethylketone, ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, aprotic polar organic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and acetonitrile, golozhabernyi hydrocarbon solvents such as dichloromethane and chloroform, or aromatizes the e hydrocarbon solvents, such as toluene, and mixed solvents composed of two or more of these solvents.

The group R' may be introduced in the 1 - and 11-position using R OH, R Cl, R')₂O or mixed anhydride of the acid corresponding to the assumed R', in the presence or in the absence of a base or using a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, carbonyldiimidazole, dipyridyl disulfide, diimidazole disulfide, 1,3,5-trichlorobenzoyl chloride, 1,3,5-trichlorobenzoyl anhydride, PyBop or PyBrop.

Used in this document includes, for example, sodium carbonate, potassium carbonate, sodium hydride, tert-piperonyl potassium, sodium methoxide, ethoxide sodium, pyridine, 4-dimethylaminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine and diisopropylethylamine (preferably pyridine).

The reaction temperature preferably ranges from -20°C to 50°C, more preferably from 0°C to 30°C. the Duration of the reaction is preferably from 0.5 to 48 hours

4: get connection from connection B2a or B2b connections

The solvents used at the stage of obtaining connection C connection B2a or B2b, include alcohol solvents containing 1-4 carbon atoms, such as methanol, ether is the solvent, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, aprotic polar organic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and acetonitrile, golozhabernyi hydrocarbon solvents such as dichloromethane and chloroform, an aromatic hydrocarbon solvents such as toluene, or water, and mixed solvents composed of two or more of these solvents.

Removing the protective group R_1bin the B2b connection can be made depending on the type of the protective group. For example, if R_1brepresents a formyl, acetyl or chloroacetyl, the base can be used, for example, inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide or barium hydroxide, alkali metal such as sodium methoxide, ethoxide or sodium tert-piperonyl potassium alkoxide of the alkali earth metal, an organic base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine, or guanidine, preferably sodium methoxide, sodium hydroxide, carb is NAT sodium or sodium bicarbonate, in an amount of from 0.01 to 10 equivalents, preferably in an amount of from 0.1 to 2 equivalents relative to the compound B2b.

If R_1brepresents optionally substituted by a halogen atom C_1-6alkyloxy-C_1-6alkyl, optionally substituted by halogen atom C_1-6alkylthio-C_1-6alkyl, optionally substituted by a halogen atom, a linear, branched or cyclic C_1-4alkyl, optionally substituted by halogen atom C_2-6alkenyl, optionally substituted by halogen atom C_2-6quinil, optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic ring, optionally substituted benzyl or optionally substituted by halogen atom group-SiR₃R₄R₅it may be used, for example, an organic acid, such as para-toluensulfonate acid, para-toluensulfonate acid monohydrate, pyridinium para-toluensulfonate, hydrogen fluoride/pyridine, trihydrated/triethylamine, acetic acid, chloride of acetic acid, triperoxonane acid, triperoxonane anhydride, hydrogen fluoride, hydrochloric acid, bromovalerate, sulfuric acid, thiophenol or 10-camphorsulfonic acid, a hydrogenation catalyst, such as boron chloride, boron bromide, magnesium bromide, cerium chloride, copper chloride, copper sulfate, lithium chloride, chloride VC is for, the tin chloride, zinc chloride, zinc bromide, aluminum chloride, titanium chloride, palladium on charcoal, palladium hydroxide or palladium chloride, trimethylchlorosilane, trimethylsilane, trimethylsilyltriflate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in the amount of from 0.1 to 10 equivalents relative to compound B2b.

The reaction temperature preferably ranges from -20°C to 50°C, more preferably from 0°C to room temperature. The duration of the reaction is preferably from 0.5 h to 7 days.

In accordance with this phase connection C can be similarly obtained from compound B2a.

EXAMPLES

The present invention is additionally illustrated by the subsequent examples, which are not intended to limit the present invention.

Example 1

Synthesis of 7-desacetylrifabutin A

Peripherin A (30 mg) was dissolved in 80% aqueous solution of methanol (2 ml). To the solution was added 1,8-diazabicyclo[5.4.0]-undec-7-ene (9 mg), and the mixture was stirred at room temperature for 1.5 hours To the reaction solution was added acetic acid to stop the reaction. Then the solvent was removed by evaporation under reduced pressure, to the residue was added water and was extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Sistemasmemorial was removed by evaporation under reduced pressure to obtain crude 7-desacetylrifabutin A. The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, acetone/hexane=1/1) to obtain 7-desacetylrifabutin A (17 mg, yield 61%). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-7, as described in published application for a patent of Japan No. 259569/1996.

Example 2

Synthesis of 7-O-tert-butyldimethylsilyl-7-desacetylrifabutin A

7-Desacetylrifabutin A (30 mg)synthesized by the method described in example 1 was dissolved in N,N-dimethylformamide (5 ml)and added to a solution of imidazole (113 mg) and tert-butyldimethylchlorosilane (250 mg). The mixture was stirred at room temperature for 24 h Then the reaction solution was poured into water and was extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-tert-butyldimethylsilyl-7-desacetylrifabutin A (470 mg).

MS(IER): m/z 656 (M+H)⁺;

¹H-NMR (CDCl₃): δ 0,11 (3H, s), 0,16 (3H, s)of 0.90 (3H, s)to 0.96 (9H, s), 1.30 and to 1.38 (1H, m), of 1.32 to 1.37 (1H, m)of 1.41 (3H, s)to 1.60 (3H, s), 1,61 was 1.69 (2H, m), 1.77 in-1,92 (1H, m), is 2.05 (6H, s)to 2.15 (1H, m), 2,89 (1H, d, J=2.4 Hz), 3,64-3,70 (2H, m), of 3.73 (1H, d, J=11,6 Hz), 3,83 (1H, d, J=11,6 Hz), 4,78 (1H, DD, J=4,8, 11.2 Hz), 4,99 (1H, m), 6,36 (1H, s), 7,42 (H, DD, J=4,8, 8.0 Hz), 8,11 (1H, d, J=8.0 Hz), to 8.70 (1H, d, J=4.4 Hz), of 9.00 (1H, d, J=2.0 Hz).

Example 3

Synthesis of 7-O-tert-butyldimethylsilyl-1,7,11-triazacyclononane A

7-O-tert-butyldimethylsilyl-7-desacetylrifabutin A (470 mg)obtained in example 2 was dissolved in 88% aqueous solution of methanol (40 ml). To the solution was added potassium carbonate (307 mg)and the mixture was stirred at room temperature for a period of 19.5 hours the Solvent was removed by evaporation under reduced pressure. To the residue were added water and ethyl acetate. The remaining undissolved solid was collected by filtration to obtain 7-O-tert-butyldimethylsilyl-1,7,11-triazacyclononane A (65 mg). The mother liquor was extracted with ethyl acetate. Then an ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 7-O-tert-butyldimethylsilyl-1,7,11-triazacyclononane A (235 mg). Thus, he received a total of 300 mg (yield in two steps from compound of example 2: 95%) of 7-O-tert-butyldimethylsilyl-1,7,11-triazacyclononane A.

MS(IER): m/z 572 (M+H)⁺;

¹H-NMR (CD₃OD): δ 0,08 (3H, s)of 0.13 (3H, s)of 0.64 (3H, s)of 0.90 (9H, s), 1,19 (1H, dt, J=3,6, to 12.8 Hz), 1,31 (3H, s), 1,33-of 1.36 (2H, m)to 1.48 (1H, t, J=12.0 Hz), 1,53 (3H, s), 1,62 and 1.80 (3H, m), 1,99-2,03 (1H, m), 3,16 (1H, d, J=10,8 Hz), 3,44 (1H, d, J=10,8 Hz), of 3.56 (1H, DD, J=4,8, and 11.6 Hz), 3,76 (1, DD, J=5,2, 11.2 Hz), a 4.86 (1H, d, J=3.2 Hz), 6,47 (1H, s), 7,47 (1H, DDD, J=0,8, to 4.8, 8.0 Hz), 8,17 (1H, dt, J=2.0 a, and 8.4 Hz), 8,55 (1H, DD, J=2.0 a, 4,8 Hz), 8,91 (1H, DD, J=0.8, the 2,4 Hz).

Example 4

Synthesis of 7-O-tert-butyldimethylsilyl-1,11-O-dicyclopropyl-1,7,11-triazacyclononane A

7-O-tert-butyldimethylsilyl-1,7,11-treasurerelect A (57 mg)synthesized by the method described in example 3, was dissolved in N,N-dimethylformamide (2 ml). To the solution at 0°C was added pyridine (0.5 ml), the mixture was stirred at this temperature for 30 min, and added to it cyclopropanecarbonitrile (62 mg). The mixture was stirred at this temperature for 3 h, then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-tert-butyldimethylsilyl-1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (87 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=30/1) to obtain 7-O-tert-butyldimethylsilyl-1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (67 mg, yield 95%).

MS(IER): m/z 708 (M+H)⁺;

¹H-NMR (CDCl₃): δ 0,11 (3H, s), and 0.15 (3H, s), 0,85-0,88 (4H, m)of 0.91 (3H, s)to 0.96 (9H, s), 0,921,01 (4H, m), 1,25-of 1.36 (1H, m)of 1.42 (3H, s)of 1.45 to 1.47 (1H, m), 1,53-of 1.65 (5H, m), 1,58 (3H, s), 1,80-of 1.93 (2H, m), 2,12-of 2.16 (1H, m), of 2.81 (1H, d, J=2.0 Hz), the 3.65 (1H, d, J=12.0 Hz), 3,70 (1H, m), 3,91 (1H, d, J=to 11.6 Hz), to 4.81 (1H, DD, J=4,8, and 11.6 Hz), to 4.98 (1H, m), 6,36 (1H, s), 7,41 (1H, DD, J=4,8, 8.0 Hz), 8,10 (1H, dt, J=2.0 a, and 8.4 Hz), 8,69 (1H, DD, J=1,6, 4,8 Hz), of 9.00 (1H, d, J=2.0 Hz).

Example 5

Synthesis of 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A

7-O-tert-butyldimethylsilyl-1,11-O-dicyclopropyl-1,7,11-treasurerelect A (100 mg)synthesized by the method described in example 4, was dissolved in tetrahydrofuran (1.5 ml). To the solution at 0°C was added pyridine (0.6 ml) and hydrogen fluoride/pyridine (0.9 ml). The mixture was stirred at this temperature for 4 hours, then added to it an aqueous solution of sodium bicarbonate, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (92 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=20/1) to give 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (79 mg, yield 95%).

MS(IER): m/z 594 (M+H)⁺;

¹H-NMR (CDCl₃): δ 0,85-0,88 (4H, m)to 0.92 (3H, s), 0,96-1,01(4H, m)of 1.35 (1H, dt, J=4,0, of 12.6 Hz), of 1.42 (3H, s), 1,45-1,50 (2H, m), 1.56 to and 1.63 (3H, m)of 1.66 (3H, s), 1,79-of 1.93 (3H, m), and 2.14 (1H, m), 2,17 (1H, d, J=3.6 Hz), 2,85 (1H, d, J=2.0 Hz), 3,74 (1H, d, J=12.0 Hz), 3,78-3,82 (1H, m), 3,86 (1H, d, J=11,6 Hz), 4,82 (1H, DD, J=5,2, to 11.6 Hz), 4,99 (1H, m), of 6.52 (1H, s), 7,42 (1H, DD, J=4,8, 8.0 Hz), 8,11 (1H, dt, J=1,9, 8.1 Hz), to 8.70 (1H, DD, J=1,6, 4,8 Hz), of 9.00 (1H, d, J=2,0 Hz).

Example 6

Synthesis of 7-desacetyl-7-O-tetrahydroprotoberberine A

7-Desacetylrifabutin A (500 mg)obtained by the method described in example 1 was dissolved in dichloromethane (10 ml)and added to a solution of 3,4-dihydropyran (372 mg) and pyridinium para-toluensulfonate (348 mg). The mixture was stirred at room temperature for 73,5 hours Then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-desacetyl-7-O-tetrahydroprotoberberine A (742 mg). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-44, described in published application for a patent of Japan No. 259569/1996.

Example 7

Synthesis 1,7,11-treasareel-7-O-tetrahydroprotoberberine A

7-Desacetyl-7-O-tetrahydropyrimidine A (742 mg)obtained in example 6, was dissolved in 66% aqueous solution of methanol (9 ml). To restoratively potassium carbonate (511 mg), and the mixture was stirred at room temperature for 4 hours To the mixture was added water, and collected the remaining undissolved solid matter by filtration to obtain 1,7,11-treasareel-7-O-tetrahydroprotoberberine A (453 mg, yield in two steps from compound of example 6: 90%).

MS(IER): m/z 542 (M+H)⁺.

Example 8

Synthesis of 1,11-O-dicyclopropyl-1,7,11-treasareel-7-O-tetrahydroprotoberberine A

1,7,11-Treasareel-7-O-tetrahydropyrimidine A (450 mg)synthesized by the method described in example 7, was dissolved in N,N-dimethylformamide (6 ml). To the solution at 0°C was added pyridine (3 ml)and the mixture was stirred at this temperature for 10 minutes To the mixture was added cyclopropanecarbonyl (525 mg). The mixture was stirred at this temperature for 1 h Then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-O-dicyclopropyl-1,7,11-treasareel-7-O-tetrahydroprotoberberine A (800 mg).

MS(IER): m/z 678 (M+H)⁺.

Example 9

Synthesis of 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A

1,11-O-dicyclopropyl-1,7,11-treasareel-7-O-tetrahydropyranyl eropen A (800 mg), obtained in example 8, was dissolved in methanol (8 ml)at 0°C. to the solution was added para-toluensulfonate acid monohydrate (142 mg). The mixture was stirred at this temperature for a period of 21.5 hours Then thereto was added an aqueous solution of sodium bicarbonate. The methanol was removed by evaporation under reduced pressure, and the residue was extracted with with ethyl acetate. An ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (570 mg). The crude product was purified by chromatography on silica gel (Mega Bond Elut (Varian), acetone/hexane=3/5) with the receipt of 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (346 mg, yield in two steps from compound of example 8: 70%). Data MS(IER) and¹H-NMR of the compounds correspond to those of the compounds of example 5.

Example 10

Synthesis 1,7,11-triazacyclononane A

Peripherin A (1 g) was dissolved in 66% aqueous solution of methanol (15 ml). To the solution was added potassium carbonate (355 mg)and the mixture was stirred at room temperature for 20 hours the Solvent was removed by evaporation under reduced pressure. To the mixture was added ethyl acetate and water, and collected the remaining nerastvorim the suspended crystals by filtration to obtain 1,7,11-triazacyclononane A (737 mg, yield 94%). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-3, described in published application for a patent of Japan No. 259569/1996.

Example 11

Synthesis 1,7,11-treasareel-1,11-O-isopropylideneuridine A

1,7,11-Treasurerelect A (200 mg)synthesized by the method described in example 10, was dissolved in N,N-dimethylformamide (2 ml). To the solution was added acetonylacetone (456 mg) and pyridinium para-toluensulfonate (550 mg). The mixture was stirred at room temperature for 25,5 hours Then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain the crude 1,7,11-treasareel-1,11-O-isopropylideneuridine A. the Crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=10/1) to obtain the 1,7,11-treasareel-1,11-O-isopropylideneuridine A (171 mg, yield 79%). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-16, described in published application for the grant PA is enta Japan No. 269065/1996.

Example 12

Synthesis of 7-O-tert-butyldimethylsilyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A

1,11-Treasareel-1,11-O-isopropylideneuridine A (168 mg)synthesized by the method described in example 11, was dissolved in N,N-dimethylformamide (2 ml). To the solution was added imidazole (92 mg) and tert-butyldimethylchlorosilane (204 mg). The mixture was stirred at room temperature for 22 h, then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-tert-butyldimethylsilyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A (193 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=20/1) to obtain 7-O-tert-butyldimethylsilyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A (187 mg, yield 90%).

MS(IER): m/z 612 (M+H)⁺;

¹H-NMR (CDCl₃): δ 0,11 (3H, s), 0,16 (3H, s)to 0.96 (9H, s)of 1.03 (1H, m), 1,10 (3H, s)of 1.33 (1H, dt, J=3,6, to 12.8 Hz), of 1.40 (3H, s)of 1.43 (3H, s)of 1.44 (3H, s), 1,39-of 1.44 (1H, m), 1.55V is 1.58 (2H, m), 1,58 (3H, s), 1,64 (1H, q, J=12.0 Hz), is 1.81 (1H, DQC, J=3,6, to 12.8 Hz), measuring 2.20 (1H, dt, J=3.2, and to 12.8 Hz), of 2.81 (1H, d, J=1.6 Hz), 3,42 (1H, d, J=10,8 Hz), 3,51 (1H, d, J=10.4 Hz), 3,50-of 3.53 (1H, m), and 3.72 (1H, DD, J=4,8, 11.2 Hz), equal to 4.97 (1H, m), 6.35mm (1H, s), 41 (1H, DD, J=4,8, 8.0 Hz), 8,10 (1H, dt, J=1,6, 8.0 Hz), 8,69 (1H, DD, J=1,6, 4,8 Hz), of 9.00 (1H, d, J=2.0 Hz).

Example 13

Synthesis of 7-O-tert-butyldimethylsilyl-1,7,11-triazacyclononane A

7-O-tert-butyldimethylsilyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A (116 mg)synthesized by the method described in example 12, was dissolved in tetrahydrofuran (1 ml)at 0°C. to the solution was added 63% acetic acid (4 ml). The mixture was stirred at room temperature for 24 hours To the mixture was added an aqueous solution of sodium bicarbonate and was extracted with her chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-tert-butyldimethylsilyl-1,7,11-triazacyclononane A (101 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=10/1) to obtain 7-O-tert-butyldimethylsilyl-1,7,11-triazacyclononane A (91 mg, yield 84%).

MS(IER): m/z 572 (M+H)⁺;

¹H-NMR (CD₃OD): δ 0,08 (3H, s)of 0.13 (3H, s)of 0.64 (3H, s)of 0.90 (9H, s), 1,19 (1H, dt, J=3,6, to 12.8 Hz), 1,31 (3H, s), 1,33-of 1.36 (2H, m)to 1.48 (1H, t, J=12.0 Hz), 1,53 (3H, s), 1,62 and 1.80 (3H, m), 1,99-2,03 (1H, m), 3,16 (1H, d, J=10,8 Hz), 3,44 (1H, d, J=10,8 Hz), of 3.56 (1H, DD, J=4,8, and 11.6 Hz), 3,76 (1H, d is, J=5,2, 11.2 Hz), a 4.86 (1H, d, J=3.2 Hz), 6,47 (1H, s), 7,47 (1H, DDD, J=0,8, to 4.8, 8.0 Hz), 8,17 (1H, dt, J=2.0 a, and 8.4 Hz), 8,55 (1H, DD, J=2.0 a, 4,8 Hz), 8,91 (1H, DD, J=0.8, the 2,4 Hz).

Example 14

Synthesis of 1,11-dictater-1,11-O-isopropylideneuridine A

1,7,11-Treasareel-1,11-O-isopropylideneuridine A (100 mg)synthesized by the method described in example 11, was dissolved in dichloromethane (2 ml). To the solution was added triethylamine (61 mg), 4-dimethylaminopyridine (7 mg) and acetic anhydride (26 mg). The mixture was stirred at room temperature for 4 h Then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-dictater-1,11-O-isopropylideneuridine A (120 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=20/1) to give 1,11-dictater-1,11-O-isopropylideneuridine A (103 mg, yield 95%). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-43, described in published application for a patent of Japan No. 269065/1996.

Example 15

Synthesis of 1,11-deathcertificate A

1,11-Dictater-1,11-O-isopropylideneuridine is n A (99 mg), synthesized by the method described in example 14, was dissolved in tetrahydrofuran (1.2 ml) and methanol (2.4 ml)and added to a solution of pyridinium para-toluensulfonate (185 mg). The mixture was stirred at room temperature for 30 h, then added to it triethylamine, and the solvent was removed by evaporation under reduced pressure. To the residue were added chloroform and water, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-deathcertificate A (85 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=60/1) to give 1,11-deathcertificate A (64 mg, yield 72%). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-5, described in published application for a patent of Japan No. 259569/1996.

Example 15a

Synthesis of 1,11-deathcertificate A

1,7,11-Treasurerelect A (9,67 g) suspended in N,N-dimethylformamide (48 ml). To the suspension was added acetonylacetone (6,61 g) and para-toluensulfonate acid monohydrate (0.08 g), and stirred the mixture at 38-41°C for 4h. To the mixture was added 4-dimethylaminopyridine (0.08 g) and the solvent was removed by evaporation under reduced pressure for 1.5 hours, the Residue was cooled to 0°C. To the cooled solution was added triethylamine (2.57 m g) and acetic anhydride (2.37 g)and the mixture was stirred at this temperature for 16 hours Then the reaction mixture was added water (96 g), and adjusting the pH of the mixture to the 7,17 by adding 5% hydrochloric acid. Precipitated precipitated light yellow powder was collected by filtration and washed twice with water (20 g). Obtained thereby the crude product is suspended in methanol (48 ml)was added to a suspension of 15% hydrochloric acid (4.7 g), and stirred the mixture at 25-27°C for 2 hours To the mixture was added water (33 ml), and filtered insoluble materials, and then adjust the pH up to 4.41 by adding 5% aqueous sodium hydroxide solution. Then to the mixture was added water (31 ml). Precipitated precipitated light yellow powder was collected by filtration and washed twice 30% aqueous solution of methanol (20 ml). The washed powder was dried at 40°C for 23 h with getting to 8.62 g of 1,11-deathcertificate A. the results of the measurement method¹H-NMR showed that the data¹H-NMR were consistent with those of the compound obtained in example 15.

Example 16

Synthesis of 1,11-O-dicyclopropyl-1,11-deathcertificate the and A

1,11-Digitallyimported A (61 mg)synthesized by the method described in example 15, was dissolved in N,N-dimethylformamide (1.2 ml). To the solution at 0°C was added pyridine (0.3 ml), the mixture was stirred at this temperature for 10 min, was added to the mixture cyclopropanecarbonitrile (77 mg) and stirred it at this temperature for 1.5 hours and Then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-O-dicyclopropyl-1,11-deathcertificate A (97 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=20/1) to give 1,11-O-dicyclopropyl-1,11-deathcertificate A (73 mg, yield 93%).

MS(IER): m/z 636 (M+H)⁺;

¹H-NMR (CDCl₃): δ 0,84-0,89 (4H, m)to 0.89 (3H, s), 0,90 was 1.06 (4H, m)to 1.37 (1H, dt, J=3,8, 13,2 Hz)of 1.45 (3H, s), 1,53 (1H, d, J=4.0 Hz), 1,55-to 1.67 (4H, m)1,70 (3H, s), 1,79-to 1.87 (2H, m), 1,89-of 1.94 (2H, m), 2,14-to 2.18 (1H, m)of 2.16 (3H, s), 2,97 (1H, d, J=2.0 Hz), of 3.77 (2H, s), to 4.81 (1H, DD, J=4,8, 11.7 Hz), 5,00 (1H, m), 5,02 (1H, DD, J=5,0, to 11.4 Hz), 6,46 (1H, s), 7,40 (1H, DD, J=4,9, 8.0 Hz), of 8.09 (1H, dt, J=1,9, 8.1 Hz), 8,68 (1H, DD, J=1,6, 4,8 Hz), of 9.00 (1H, d, J=2.0 Hz).

Example 16a

Synthesis of 1,11-O-dicyclopropyl-1,11-digitately Pyropen A

1,11-Digitallyimported A (25,76 g) suspended in ethyl acetate (130 ml), was added to a suspension of pyridine (15,84 g). The mixture was cooled to 10-15°C. dropwise to the mixture was added cyclopropanecarbonyl (15,70 g), and stirred the mixture at 25-30°C for 3 hours the Reaction solution was again cooled to 10-15°C and was added dropwise thereto water (50 ml). The pH of the mixture was adjusted to 2.59 by adding 5N hydrochloric acid, and then spent the division. The organic layer is washed with 5% aqueous sodium bicarbonate (50 ml) and 10% brine (50 ml) in that order. Obtained thereby an ethyl acetate solution was removed by evaporation under reduced pressure, and then was replaced with methanol to adjust the liquid volume to 130 ml dropwise to the solution was added water (130 ml). Precipitated precipitated light yellow powder was collected by filtration, washed twice with 50% aqueous solution of methanol (40 ml) and dried at 40°C for 23 h to obtain 30,80 g of 1,11-O-dicyclopropyl-1,11-deathcertificate A. the results of the measurement method¹H-NMR showed that the data¹H-NMR were consistent with those of the compound obtained in example 16.

Example 17

Synthesis of 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A

1,11-O-dicyclopropyl-1,11-digitallyimported A (67 mg)synthesized by a method described is output in example 16, was dissolved in 95% aqueous solution of methanol (0,07 ml). To the solution at 0°C was added sodium carbonate (22 mg). The mixture was stirred at this temperature for 4 days. Then to the mixture was added acetic acid. The methanol was removed by evaporation under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (74 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=10/1) to give 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (47 mg, yield 76%). Data MS(IER) and¹H-NMR for compounds are consistent with those of the compound obtained in example 5.

Example 17a

Synthesis of 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A

1,11-O-dicyclopropyl-1,11-digitallyimported A (30,00 g) suspended in a mixed liquid consisting of water (20 ml) and methanol (190 ml)and cooled the mixture to 0-5°C. To the mixture was added a 1M solution of sodium methoxide in methanol (4,49 ml)and the mixture was stirred at this temperature for 23 hours To the reaction process is the added 1.2 percent hydrochloric acid (20 ml), and the mixture was filtered through a 0.5-μm filter, and then adjust the volume of liquid to approximately 90 ml by evaporation under reduced pressure. To the residue was added a mixed liquid (methanol/water=2/1, 120 ml) to adjust the volume of the liquid to approximately 150 ml and Then to the residue was added a mixed liquid (methanol/water=2/1, 120 ml) to adjust the volume of the liquid to approximately 180 ml and the Mixture was stirred at room temperature for 1 h, then was cooled to 5°C and was stirred for 17 hours Dropped to precipitate a light yellow powder was collected by filtration, washed twice 30% aqueous solution of methanol (50 ml) and dried at 40°C for 22 h with getting 23,82 g of 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A. the results of the measurement method¹H-NMR showed that the data¹H-NMR were consistent with those of the compound obtained in example 17.

Example 18

Synthesis of 7-O-chloroacetyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A

1,7,11-Treasareel-1,11-O-isopropylideneuridine A (100 mg)synthesized by the method described in example 11, was dissolved in tetrahydrofuran (2 ml) and triethylamine (61 mg)was added to a solution of Chloroacetic anhydride (103 mg). The mixture was stirred at room temperature for 3.5 h, then the reaction solution was poured into water and was extracted with chlorofo the IOM. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-chloroacetyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A (118 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=20/1) to obtain 7-O-chloroacetyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A (80 mg, yield 70%).

MS(IER): m/z 574 (M+H)⁺;

¹H-NMR (CDCl₃): δ 1,11 (3H, s)of 1.16 (1H, DD, J=2,4, and 12.6 Hz), 1,33-of 1.41 (1H, m)of 1.44 (3H, s)of 1.45 (3H, s), of 1.52 (1H, d, J=4.0 Hz), 1,58-of 1.65 (1H, m)of 1.62 (3H, s)to 1.70 (3H, s), of 1.66 and 1.75 (2H, m), 1.77 in is 1.86 (1H, m), 2,22 (1H, m), 2,90 (1H, d, J=2.0 Hz), of 3.48 (2H, s), of 3.54 (1H, DD, J=3,6, 12.0 Hz), 4,19 (2H, d, J=4.0 Hz), 5,00 (1H, m), 5,09 (1H, DD, J=5,6, and 11.6 Hz), of 6.45 (1H, s), 7,41 (1H, DD, J=4,8, 8.0 Hz), 8,10 (1H, dt, J=1,6, 8.0 Hz), to 8.70 (1H, DD, J=1,6, 4,8 Hz), of 9.02 (1H, d, J=1.6 Hz).

Example 19

Synthesis of 7-O-chloroacetyl-1,7,11-triazacyclononane A

7-O-chloroacetyl-1,7,11-treasareel-1,11-O-isopropylideneuridine A (35 mg)synthesized by the method described in example 18, was dissolved in tetrahydrofuran (0.6 ml) and methanol (1.2 ml), was added to a solution of pyridinium para-toluensulfonate (61 mg). The mixture was stirred at room temperature for 31 hours, then the reaction solution was poured into water and was extracted with chloroform. Chlorofor the hydrated layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-chloroacetyl-1,7,11-triazacyclononane A (30 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=10/1) to obtain 7-O-chloroacetyl-1,7,11-triazacyclononane A (24 mg, yield 74%).

MS(IER): m/z 534 (M+H)⁺;

¹H-NMR (CD₃OD): δ 0,74 (3H, s), 1,32 (1H, m)of 1.44 (3H, s), and 1.54 (2H, m), 1,69 is 1.75 (2H, m)of 1.75 (3H, s), 1,79 is 1.86 (1H, m), 1,91-of 1.94 (1H, m), 2,12 (1H, m), 3,26 (1H, d, J=11,6 Hz), 3,52 (1H, d, J=10,8 Hz)to 3.67 (1H, DD, J=5,2, to 11.6 Hz), 4,33 (2H, d, J=2.4 Hz), to 4.98 (1H, m), 5,15 (1H, DD, J=5,2, to 11.6 Hz), 6,79 (1H, s), 7,55 (1H, DD, J=4,8, 8.0 Hz), of 8.28 (1H, dt, J=2,4, 8.0 Hz), to 8.62 (1H, DD, J=1,6, 4,8 Hz), of 9.02 (1H, d, J=2,4 Hz).

Example 20

Synthesis of 7-O-chloroacetyl-1,11-O-dicyclopropyl-1,7,11-triazacyclononane A

7-O-chloroacetyl-1,7,11-treasurerelect A (21 mg)synthesized by the method described in example 19 was dissolved in N,N-dimethylformamide (1.2 ml) and pyridine (0.3 ml)and at 0°C was added to solution cyclopropanecarbonitrile (25 mg). The mixture was stirred at this temperature for 2.5 hours and Then the reaction solution was poured into water, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then the solvent was removed by evaporation under the conditions of pengendali to obtain crude 7-O-chloroacetyl-1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (37 mg). The crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=30/1) to obtain 7-O-chloroacetyl-1,11-O-dicyclopropyl-1,7,11-triazacyclononane A (16 mg, yield 58%).

MS(IER): m/z 670 (M+H)⁺;

¹H-NMR (CDCl₃): δ of 0.85-0.90 (4H, m)of 0.91 (3H, s), 0,96-1,08 (4H, m)to 1.38 (1H, dt, J=4,0, of 12.6 Hz), a 1.45 (3H, s), 1,54-to 1.67 (5H, m), 1,72 (3H, s), 1,81-of 1.95 (3H, m), 2,17 (1H, m), 2,89 (1H, d, J=1.6 Hz), of 3.78 (2H, s), to 4.17 (2H, d, J=2,8 Hz), 4,82 (1H, DD, J=4,8, and 11.6 Hz), free 5.01 (1H, m), 5,09 (1H, DD, J=5,2, to 11.6 Hz), of 6.45 (1H, s), 7,41 (1H, DD, J=4,8, 8.0 Hz), 8,10 (1H, dt, J=1,6, 8.0 Hz), 8,69 (1H, DD, J=1,6, 4,8 Hz), of 9.02 (1H, d, J=1.6 Hz).

Example 21

Synthesis of 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A

7-O-chloroacetyl-1,11-O-dicyclopropyl-1,7,11-treasurerelect A (14 mg)synthesized by the method described in example 20 was dissolved in 95% aqueous solution of methanol (1.4 ml). Then to the solution was added sodium bicarbonate (1.9 mg). The mixture was stirred at room temperature for 3 hours To the mixture was added acetic acid, and then methanol was removed by evaporation under reduced pressure to obtain the crude 1,11-O-dicyclopropyl-1,7,11-triazacyclononane A. the Crude product was purified by the method of preparative thin-layer column chromatography (Merck silica gel 60F₂₅₄0.5 mm, chloroform/methanol=10/1) to give 1,11-O-delloro acarboni-1,7,11-triazacyclononane A (12 mg, yield 94%). Data MS(IER) and¹H-NMR for compounds are consistent with those of the compound obtained in example 5.

Example 22

Synthesis of 1,11-O-benzylidene-1,7,11-triazacyclononane A

1,7,11-Treasurerelect A (1.0 g)synthesized by the method described in example 10, was dissolved in N,N-dimethylformamide (10 ml). To the solution was added pyridinium para-toluensulfonate (2,75 g) and benzaldehyde, dimethylacetal (3.3 grams). The mixture was stirred at room temperature for 5 hours and Then the reaction solution was poured into water and was extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-O-benzylidene-1,7,11-triazacyclononane A. the Crude product was purified by chromatography on silica gel (Mega Bond Elut (Varian), acetone/chloroform=1/10) to give 1,11-O-benzylidene-1,7,11-triazacyclononane A (887 mg, yield 74%). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-93, described in published application for a patent of Japan No. 269065/1996.

Example 23

Synthesis of 1,11-O-benzylidene-7-O-chloroacetyl-1,7,11-triazacyclononane A

1,11-O-benzylidene-1,7,11-treasurerelect A (1.0 g), sintesio the p way described in example 22 was dissolved in pyridine (2.5 ml). To the solution at 0°C was added Chloroacetic anhydride (206 mg). The mixture was stirred at this temperature for 1.5 h and then the reaction solution was poured into water. The mixture was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain the crude 1,11-O-benzylidene-7-O-chloroacetyl-1,7,11-triazacyclononane A. the Crude product was purified by chromatography on silica gel (Mega Bond Elut (Varian), acetone/hexane=1/100) to give 1,11-O-benzylidene-7-O-chloroacetyl-1,7,11-triazacyclononane A (359 mg, yield 72%).

MS(IER): m/z 622 (M+H)⁺;

¹H-NMR (CDCl₃): δ 1,19-1,22 (1H, m), 1,25 (3H, s)of 1.41 (1H, m)to 1.48 (3H, s), 1,53-of 1.56 (1H, m)1,70 (3H, s), 1.70 to of 1.84 (3H, m), of 1.95 (1H, m), and 2.27 (1H, m), is 2.88 (1H, d, J=1.6 Hz), 3,49 (1H, d, J=10.4 Hz), 3,50-3,53 (1H, m)to 3.89 (1H, d, J=10.4 Hz), 4,20 (2H, d, J=3.2 Hz), 5,02 (1H, m), 5,12 (1H, DD, J=5,2, to 11.6 Hz), 5,54 (1H, s), 6,46 (1H, s), 7,33-the 7.43 (4H, m), 7,51 (2H, DD, J=1,6, 8.0 Hz), 8,11 (1H, dt, J=2,0, 8.0 Hz), to 8.70 (1H, DD, J=1,6, 4,8 Hz), of 9.02 (1H, d, J=2.0 Hz).

Example 24

Synthesis of 7-O-chloroacetyl-1,7,11-triazacyclononane A

1,11-O-benzylidene-7-O-chloroacetyl-1,7,11-treasurerelect A (10 mg)synthesized by the method described in example 23 was dissolved in chloroform (1 ml) and methanol (9 ml)was added to a solution of 10-camphorsulfonic the th acid (3 mg). The mixture was stirred at room temperature for 5 days. Then the reaction solution was poured into water, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-chloroacetyl-1,7,11-triazacyclononane A. the Crude product was purified by chromatography on silica gel (Mega Bond Elut (Varian), acetone/chloroform=1/10) to obtain 7-O-chloroacetyl-1,7,11-triazacyclononane A (8 mg, yield 100%). Data MS(IER) and¹H-NMR for compounds are consistent with those of the compound obtained in example 19.

Example 25

Synthesis 1,7,11-treasareel-1,11-O-para-methoxybenzylideneamino A

1,7,11-Treasurerelect A (1.0 g)synthesized by the method described in example 10, was dissolved in N,N-dimethylformamide (22 ml). To the solution was added pyridinium para-toluensulfonate (2.76 g) and para-methoxybenzaldehyde dimethylacetal (0.4 g). The mixture was stirred at room temperature for 4 h Then the reaction solution was poured into water and was extracted with a mixture of ethyl acetate. An ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced davleniya receiving untreated 1,7,11-treasareel-1,11-O-p-methoxybenzylideneamino A. The crude product was purified by chromatography on silica gel (Mega Bond Elut (Varian), acetone/chloroform=1/10) to obtain the 1,7,11-treasareel-1,11-O-para-methoxybenzylideneamino A (520 mg, yield 41%). The results of measurement methods MS(IER) and¹H-NMR showed that the compound is a compound PR-124, described in published application for a patent of Japan No. 269065/1996.

Example 26

Synthesis of 7-O-chloroacetyl-1,7,11-treasareel-1,11-O-para-methoxybenzylideneamino A

1,7,11-Treasareel-1,11-O-para-methoxybenzylideneamino A (100 mg)synthesized by the method described in example 25 was dissolved in tetrahydrofuran (2 ml). To the solution was added triethylamine (50 mg) and Chloroacetic anhydride (60 mg). The mixture was stirred at room temperature for 2.5 h, then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-chloroacetyl-1,7,11-treasareel-1,11-O-para-methoxybenzylideneamino A. the Crude product was recrystallized from methanol and ethyl acetate, and then the recrystallized product is purified by chromatography on silica gel (Mega Bond Elut (Varian), acetone/chloroform=1/30) to obtain 7-Chloracetic-1,7,11-treasareel-1,11-O-para-methoxybenzylideneamino A (83 mg, yield 75%).

MS(IER): m/z 652 (M+H)⁺;

¹H-NMR (CDCl₃): δ 1,20 (1H, m), 1,24 (3H, s)of 1.40 (1H, m)of 1.47 (3H, s), and 1.54 (1H, d, J=3.6 Hz), 1,72 (3H, s), 1,66 and 1.80 (3H, m)of 1.93 (1H, m), and 2.26 (1H, m), 2,87 (1H, d, J=2.0 Hz), 3,47 (1H, d, J=10.0 Hz), 3,47-3,51 (1H, m), of 3.80 (3H, s), a 3.87 (1H, d, J=10.4 Hz), 4,20 (2H, d, J=3.2 Hz), free 5.01 (1H, m), 5,12 (1H, DD, J=5,6, and 11.6 Hz), of 5.50 (1H, s), 6,46 (1H, s), make 6.90 (2H, d, J=8,8 Hz), 7,41 (1H, DD, J=4,8, 12.0 Hz), 7,43 (2H, d, J=8,8 Hz), 8,10 (1H, dt, J=2.0 a, and 8.4 Hz), to 8.70 (1H, DD, J=2,4, 4,8 Hz), of 9.02 (1H, d, J=2.0 Hz).

Example 27

Synthesis of 7-O-chloroacetyl-1,7,11-triazacyclononane A

7-O-chloroacetyl-1,7,11-treasareel-1,11-O-para-methoxybenzylideneamino A (30 mg)synthesized by the method described in example 26 was dissolved in chloroform (5 ml) and methanol (1 ml)was added to a solution of 10-camphorsulfonic acid (3 mg). The mixture was stirred at room temperature for 5 hours, then the reaction solution was poured into water and was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was removed by evaporation under reduced pressure to obtain crude 7-O-chloroacetyl-1,7,11-triazacyclononane A. the Crude product was purified by chromatography on silica gel (Mega Bond Elut (Varian), acetone/chloroform=1:5) to obtain 7-O-chloroacetyl-1,7,11-triazacyclononane A (14 mg, yield 69%). Data MS(IER) and¹H-NMR for compound were consistent with those for whom soedineniya, obtained in example 19.

1. A method of obtaining a connection represented by the formula:
[Chemical formula 1]

in which R' represents a linear, branched or cyclic With_2-6alkylaryl, provided that when the alkyl fragment in alkylcarboxylic group is branched or cyclic, R' represents a C_3-6alkylsulphonyl, which includes stages:
(a₁) hydrolysis of acetyl 7-position of compound A1 represented by formula A1:
[Chemical formula 2]

in which AC represents acetyl,
the basis for selective disallowance connections A1, then protecting hydroxyl at the 7-position obtaining compounds B1 represented by the formula B1:
[Chemical formula 3]

where is the AC defined above,
R_1arepresents an optionally substituted linear C_2-4alkylsulphonyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; optionally substituted by a halogen atom_1-6alkyloxy-C_1-6alkyl; optionally substituted by a halogen atom_1-6alkylthio-C_1-6Alki is; optionally substituted by a halogen atom, a linear, branched or cyclic With_1-4alkyl, provided that when the alkyl in C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_3-4alkyl; optionally substituted by a halogen atom_2-6alkenyl; optionally substituted by a halogen atom_2-6quinil; optionally substituted, benzyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,
where R_1anot necessarily present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy, C_1-4halogenations,_1-4alkylcarboxylic,_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, but not necessarily present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy,_1-4halogenations,_1-4alkylthio,_1-4halogenoalkane, C_1-4alkylcarboxylic,_1-4halogenoalkane,_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano,
then hydrolysis of the acetyl 1 - and 11-positions of compound B1 is a basis for disallowance compound B1 with the floor is the group thereby join Fa, represented by formula Fa:
[Chemical formula 4]

in which the value of R_1adefined above, or
(a₂) hydrolysis of acyl 1-, 7-and 11-positions of compound A1 or connection A4', represented by formula A4':
[Chemical formula 5]

where$$A_1^{\text{'}}$$,$$A_7^{\text{'}}$$and$$A_{11}^{\text{'}}$$that may be the same or different, represent an acetyl or propionyl, provided that$$A_1^{\text{'}}$$,$$A_7^{\text{'}}$$and$$A_{11}^{\text{'}}$$at the same time do not represent acetyl, disallowance connections A1 or A4', and then protecting hydroxyl at the 1 - and 11-positions of obtaining compound D represented by formula D:
[Chemical formula 6]

where two R₂form groups together is, selected from the groups represented by formulas (D-1, D-2, D-3 and D-4:
[Chemical formula 7]

in which Y₁represents a hydrogen atom or a C_1-4alkyl;
the substituents X, which may be identical or different, represent a hydrogen atom, a C_1-4alkoxy or nitro; and n is 0-5, then protecting hydroxyl at the 7-position of compound D with obtaining compound E represented by the formula E;
[Chemical formula 8]

in which R_1brepresents formyl; optionally substituted linear C_1-4alkylsulphonyl; optionally substituted benzyl;
optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; optionally substituted by a halogen atom C_1-6alkyloxy-C_1-6alkyl; optionally substituted by a halogen atom C_1-6alkylthio-C_1-6alkyl; optionally substituted by a halogen atom, a linear, branched or cyclic With_1-4alkyl, provided that when the alkyl in C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_-4 alkyl; optionally substituted by a halogen atom_2-6alkenyl; optionally substituted by a halogen atom_2-6quinil; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,
where R_1bnot necessarily present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy, C_1-4halogenations,_1-4alkylcarboxylic,_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, but not necessarily present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy,_1-4halogenations,_1-4alkylthio,_1-4halogenoalkane, C_1-4alkylcarboxylic,_1-4halogenoalkane,_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano, and
the value of R₂defined above,
then removing the protective group at the 1 - and 11-positions of compound E with connection Fb represented by the formula Fb:
[Chemical formula 9]

in which the value of R_1bdefined above, and
(b) acylation of the hydroxyl at the 1 - and 11-positions of compound Fa or Fb allermuir agent corresponding to the assumed R', with the floor is the group of compounds VA or B2b, represented by the formula VA or B2b:
[Chemical formula 10]

in which the values of R_1a, R_1band R' are defined above, and then removing the protective group in the 7-position of compound VA or B2b connections.

2. The method according to claim 1 where R' is a cyclic_3-6alkylsulphonyl.

3. The method according to claim 1, where R_1arepresents optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group.

4. The method according to claim 1, where R_1brepresents acetyl; chloroacetyl; or optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl.

5. The method according to claim 1, where the two R₂form together a group represented by formula D-1 or D-2:
[Chemical formula 11]

in which Y₁represents a hydrogen atom or a C_1-4alkyl; the substituents X, which may be identical or different, represent an atom of water is an ode, With_1-4alkoxy or nitro; and n is 0-5.

6. The method of obtaining compounds of VA represented by the formula VA:
[Chemical formula 12]

in which R_1arepresents an optionally substituted linear C_2-4alkylsulphonyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; optionally substituted by a halogen atom_1-6alkyloxy-C_1-6alkyl; optionally substituted by a halogen atom_1-6alkylthio-C_1-6alkyl; optionally substituted by a halogen atom, a linear, branched or cyclic With_1-4alkyl, provided that when the alkyl in C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_3-4alkyl; optionally substituted by a halogen atom_2-6alkenyl; optionally substituted by a halogen atom_3-6quinil; optionally substituted benzyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,
where R_1anot necessarily present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy, C_1-4halogenations is, With_1-4alkylcarboxylic,_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, and need not be present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy,_1-4halogenations,_1-4alkylthio,_1-4halogenoalkane,_1-4alkylcarboxylic,_1-4halogenoalkane,_1-4alkylcarboxylic,_1-4halogenlithiumcarbeniods, nitro and cyano, and
R' is a cyclic_3-6alkylsulphonyl, including:
the hydrolysis of acetyl 7-position of compound A1 represented by formula A1:
[Chemical formula 13]

in which AC represents acetyl,
the basis for selective disallowance connections A1, and then protecting hydroxyl at the 7-position obtaining compounds B1 represented by the formula B1;
[Chemical formula 14]

where is the AC and R_1adefined above,
then the hydrolysis of 1 - and 11-positions of compound B1 is a basis for disallowance compound B1 with obtaining thereby the connection Fa represented by the formula Fa:
[Chemical formula 15]

where a value of R_1adefined above,
and then acylation hydro is power in the 1 - and 11-positions of compound Fa allermuir agent, the corresponding expected R'.

7. The method according to claim 6, where R_1arepresents an optionally substituted linear C_2-4alkylsulphonyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group.

8. The method of obtaining compounds of B2b represented by the formula B2b:
[Chemical formula 16]

in which R_1brepresents formyl; optionally substituted linear C_1-4alkylsulphonyl; optionally substituted benzyl;
optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-4alkyl or phenyl; optionally substituted by a halogen atom C_1-6alkyloxy-C_1-6alkyl; optionally substituted by a halogen atom C_1-6alkylthio-C_1-6alkyl; optionally substituted by a halogen atom, a linear, branched or cyclic With_1-4alkyl, provided that when the alkyl in C_1-4the alkyl group is branched or cyclic, the alkyl group is particularly the _3-4alkyl; optionally substituted by a halogen atom_2-6alkenyl; optionally substituted by a halogen atom_3-6quinil; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,
where R_1bnot necessarily present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy, C_1-4halogenations,_1-4alkylcarboxylic,_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, and need not be present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy,_1-4halogenations,_1-4alkylthio,_1-4halogenoalkane, C_1-4alkylcarboxylic,_1-4halogenoalkane,_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano, and
R' is a cyclic_3-6alkylsulphonyl, including:
hydrolysis of the acyl 1-, 7 - and 11-positions of compound A4 represented by formula A4:
[Chemical formula 17]

where A₁, A₇and a₁₁that may be the same or different, represent an acetyl or propionyl,
the basis for disallowance connection is 4, and then protecting hydroxyl at the 1-and 11-positions of obtaining compound D represented by formula D:
[Chemical formula 18]

where two R₂form together a group selected from groups represented by the formulae D-1, D-2, D-3 and D-4:
[Chemical formula 19]

in which Y₁represents a hydrogen atom or a C_1-4alkyl;
the substituents X, which may be identical or different, represent a hydrogen atom, a C_1-4alkoxy or nitro; and n is 0-5, then protecting hydroxyl at the 7-position of compound D with obtaining compound E represented by the formula E;
[Chemical formula 20]

in which the values of R_1band R₂defined above,
then removing the protective group at the 1 - and 11-positions of compound E with connection Fb represented by the formula Fb:
[Chemical formula 21]

in which the value of R_1bdefined above,
and then acylation of the hydroxyl at the 1 - and 11-positions of compound Fb allermuir agent corresponding to R'.

9. The method of claim 8, where R_1brepresents acetyl;
chloroacetyl; or optionally substituted by halogen atom group-SiR₃R₄R_{5 where each R3, R4and R5independently represents a linear or branched C1-6alkyl or phenyl.}

10. The method of claim 8, where the two R₂form together a group represented by formula D-1 or D-2:
[Chemical formula 22]

in which Y₁represents a hydrogen atom or a C_1-4alkyl; the substituents X, which may be identical or different, represent a hydrogen atom, a C_1-4alkoxy or nitro; and n is 0-5.

11. A method of obtaining a connection represented by the formula:
[Chemical formula 23]

in which R' represents a cyclic_3-6alkylsulphonyl, including:
the acylation of the hydroxyl at the 1 - and 11-positions of compound Fb represented by the formula Fb:
[Chemical formula 24]

in which R_1brepresents formyl; optionally substituted linear C_1-4alkylsulphonyl; optionally substituted benzyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; optionally substituted by a halogen atom_1-6alkyloxy-C_1-6alkyl; optionally substituted and the Ohm halogen, C _1-6alkylthio-C_1-6alkyl; optionally substituted by a halogen atom, a linear, branched or cyclic With_1-4alkyl, provided that when the alkyl in C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_3-4alkyl; optionally substituted by a halogen atom_2-6alkenyl; optionally substituted by a halogen atom_2-6quinil; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,
where R_1bnot necessarily present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy, C_1-4halogenations,_1-4alkylcarboxylic,_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, and need not be present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy,_1-4halogenations,_1-4alkylthio,_1-4halogenoalkane, C_1-4alkylcarboxylic,_1-4halogenoalkane,_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano,
allermuir agent corresponding to R', getting B2b connections represented by the formula B2b:
[Chemical is ormula 25]

in which the values of R_1band R' are defined above,
and then removing the protective group in the 7-position of compound B2b.

12. A method of obtaining a connection represented by the formula:
[Chemical formula 26]

in which R' represents a linear, branched or cyclic With_2-6alkylaryl, provided that when the alkyl fragment in C_2-6alkylcarboxylic group is branched or cyclic, alkyl fragment is a C_3-6alkylsulphonyl, including:
hydrolysis of the acyl 1-, 7 - and 11-positions of compound A4 represented by formula A4:
[Chemical formula 27]

where A₁And₇and a₁₁that may be the same or different, represent an acetyl or propionyl,
the basis for disallowance connection A4, then protecting hydroxyl at the 1 - and 11-positions of obtaining compound D represented by formula D:
[Chemical formula 28]

where two R₂form together a group selected from groups represented by the formulae D-1, D-2, D-3 and D-4:
[Chemical formula 29]

in which Y₁is the Wallpaper a hydrogen atom or a C _1-4alkyl;
the substituents X, which may be identical or different, represent a hydrogen atom, a C_1-4alkoxy or nitro; and n is 0-5, then protecting hydroxyl at the 7-position of compound D with obtaining compound E represented by the formula:
[Chemical formula 30]

in which R_1brepresents formyl; optionally substituted linear C_1-4alkylsulphonyl; optionally substituted benzyl; optionally substituted by halogen atom group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; optionally substituted by a halogen atom_1-6alkyloxy-C_1-6alkyl; optionally substituted by a halogen atom_1-6alkylthio-C_1-6alkyl; optionally substituted by a halogen atom, a linear, branched or cyclic With_1-4alkyl, provided that when the alkyl in C_1-4the alkyl group is branched or cyclic, the alkyl group is a C_3-4alkyl; optionally substituted by a halogen atom_2-6alkenyl; optionally substituted by a halogen atom_2-6quinil; or optionally substituted saturated or unsaturated 5 - or 6-membered heterocyclic group,
where R_1bthe optional is positive present at alkylcarboxylic Deputy is chosen from the group consisting of halogen atoms, C_1-4alkyloxy,_1-4halogenations,_1-4alkylcarboxylic,_1-4halogenoalkane, C_1-4alkylcarboxylic and C_1-4halogenlithiumcarbeniods, and need not be present on the heterocyclic group and the benzyl Deputy is chosen from the group consisting of halogen atoms, C_1-4of alkyl, C_1-4alkyloxy,_1-4halogenations,_1-4alkylthio,_1-4halogenoalkane, C_1-4alkylcarboxylic,_1-4halogenoalkane,_1-4alkylcarboxylic, C_1-4halogenlithiumcarbeniods, nitro and cyano, and
the value of R₂defined above,
then removing the protective group at the 1 - and 11-positions of compound E with connection Fb represented by the formula Fb:
[Chemical formula 31]

in which the value of R_1bdefined above,
then acylation of the hydroxyl at the 1 - and 11-positions of compound Fb allermuir agent corresponding to R', getting B2b connections represented by the formula B2b:
[Chemical formula 32]

in which the values of R_1band R' are defined above,
and then removing the protective group in the 7-position of compound B2b.

13. The method according to item 12, where R' is a cyclic_3-6alkylsulphonyl.

14. The connection represented by formula is B2b:
[Chemical formula 33]

in which R_1bis a linear C_1-4alkylsulphonyl, optionally substituted by a halogen atom; a group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; tetrahydropyranyloxy group, and R' is a cyclic_3-6alkylsulphonyl.

15. The connection 14, where R_1brepresents acetyl; chloroacetyl; group-SiR₃R₄R₅where each R₃, R₄and R₅independently represents a linear or branched C_1-6alkyl or phenyl; or tetrahydropyranyloxy group, and R' is a cyclic C_2-6alkylsulphonyl.