The way to obtain 2-substituted benzo[b]thiophene (options), the method of obtaining derivatives of 2-phenyl-3-arovent[b]thiophene (options), and derivatives of benzo[b]thiophene

 

(57) Abstract:

The invention relates to the field of pharmaceutical and organic chemistry. Describes how to obtain a new 2-substituted benzo(b)thiophene of the General formula (I), where the values of R1and R2specified in paragraph (1 formulas, some of which can be used as intermediates in obtaining pharmaceutically active compounds, and other useful for treatment of osteoporosis in women in the postmenopausal period. The method consists in the fact that receive a corresponding derived Bronevoy acid and combine it with the compound of the formula X-C6H4-R2, where X is bromine or iodine, and R2Is H, OH or or4where R4- hidroxizina group. The technical result is to simplify and cheapen the process. 5 C. and 27 C.p. f-crystals.

The present invention relates to the field of pharmaceutical and organic chemistry and the methods of obtaining 2-substituted benzo[b]thiophene, some of which can be used as intermediates in obtaining pharmaceutically active compounds, and other useful, among other things, for the treatment of osteoporosis in women in the postmenopausal period.

The compounds of formula V is;

R2represents-H, -OH or-OR4where R4is hydroxyamino group;

R5is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino;

n is 2 or 3, or their pharmaceutically acceptable salts are known as contraceptive agents (see , for example, U.S. patent N 4133814). Some compounds of formula VII, especially those in which R1, R2and n have the above significance, and R5is 1-piperidinyl, 1-pyrrolidinyl or 1 hexamethyleneimino, or their pharmaceutically acceptable salts, are known to be useful for inhibiting bone loss in humans (see, for example, U.S. patent N 5393763). A compound known in engineering as raloxifene, a compound of the formula VII, in which R1and R2each represent-OH, n = 2, and R5is 1-piperidinyl, or its pharmaceutically acceptable salt, especially the hydrochloride, is the preferred product described here:

Jones and Suarez (see U.S. patent N 4133814) first described the method of obtaining compounds of formula VII. In General terms, Jones et al. got benzothiophene f is the Rupp; and

R2represents-H, -OH or or4where R4is hydroxyamino group, receiving the first 2,3-dioxo-2,3-dihydrobenzofuran formula X

< / BR>
where R1has the previously indicated meaning, and subjecting the interaction of a compound of the formula X-chlorophenylalanine acid or its correspondingly substituted derivatives to obtain a dibasic acid, which cyclist mixture of sodium acetate and acetic anhydride to obtain the compounds of formula XI

< / BR>
where R1and R2have the previously indicated meanings. Then the compound of formula XI hydrolyzing in the presence of sodium hydroxide to obtain the compounds of formula XII

< / BR>
where R1and R2have these values, which can then be decarboxylate or used as it is.

So as a way of Jones obtaining compounds of formula I of the present invention lengthy and roads, it would be desirable to develop a new cheaper and shorter method of obtaining compounds of formula I and, ultimately, compounds of formula VII, which would correspond to a significant progress in this area. Accordingly, the present invention proposed new ways of producing compounds of the formulae I and VII of the b obtain the compounds of formula I:

< / BR>
including:

a) derivatization Bronevoy acid in position 2 of the compound of formula II:

< / BR>
b) combining the reaction product from stage a), the compounds of formula III:

< / BR>
with the compound of the formula IV:

< / BR>
where R1represents-H, -OH or or3where R3is hydroxyamino group;

R2represents-H, -OH or or4where R4is hydroxyamino group; and

X represents bromine, iodine or triflate.

Further, the present invention provides a method for obtaining compounds of formula I:

< / BR>
including:

a) selective bromination or iodination, or education triflates tsepliaeva group in 2-position of compounds of formula II:

< / BR>
obtaining the compounds of formula V:

< / BR>
b) the combination of the compounds of the formula V with the compound of the formula VI:

< / BR>
where R1represents-H, -OH or or3where R3is hydroxyamino group;

R2represents-H, -OH or or4where R4is hydroxyamino group; and

X represents bromine, iodine or triflate.

In addition, in the present invention are provided methods for obtaining the compounds of formula I is licensing the compounds of formula I a compound of formula VIII:

< / BR>
where R1represents-H, -OH or or3where R3is hydroxyamino group;

R2represents-H, -OH or or4where R4is hydroxyamino group;

R5is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino;

R6is bromine, chlorine, iodine or an activating ester group and

n = 2 or 3;

d) optionally removing R3and/or R4hydroxyamine groups and

e) optionally obtaining pharmaceutically acceptable salts of the compounds of the indicated formula VII.

In the present invention are provided compounds of the formula IX:

< / BR>
where R1'represents-OH or-OR3where R3is hydroxyamino group; and

Z represents bromine, iodine, triflate or-B(OH)2that are useful intermediate compounds in the formation of compounds of formulae I and VII of the present invention.

In one aspect of the present invention provided a convenient means of obtaining benzothiophene compounds of formula I.

The source material for nastee value which is commercially available or it is produced by known methods using known or commercially available materials [see , for example, Graham, S. L., et al., J. Med. Chem., 32(12):2548-2554 (1989)].

In this convenient way to get the derived arylboronic acid compounds of formula II, providing a compound of the formula III, which is then combined with arena formula IV, providing a compound of formula I. Alternatively, the compound of formula II selectively halodrol or triflate tsepliaeva group is introduced into position 2-receiving compound of formula V, which is then combined with the compound of arylboronic acid of formula VI, receiving compound of the formula I. These reactions are represented as method A and method B next on the scheme (see the end of the description).

When R1and/or R2represent OR3and OR4accordingly, R3and R4are hydroxyamine groups, which are fragments that are not commonly found in the end, therapeutically active compounds of formula VII, but intentionally introduced during a portion of the synthesis process to protect a group which otherwise might react in the course of chemical manipulations, and which is then removed in a later article is such intermediate compounds (although some derivatives also exhibit biological activity), their exact structure is not critical. Numerous reactions for the formation, removal, and possibly conversion of such protective groups are described in a number of standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Green, T. W., Protective Groups in Organic Synthesis, Wiley, New York, 1981; and The Pertides. Vol. I Schrooder and Lubke, Academic Press (London and New York, 1965).

Representative hydroxyamine groups include, for example, -C1-C4alkyl, -CO-(C1-C6alkyl), -SO2(C4-C6alkyl), and-CO-Ar, where Ar represents optionally substituted phenyl. The term "substituted phenyl" refers to phenyl group containing one or more substituents selected from the group consisting of C1-C4of alkyl, C1-C4alkoxy, hydroxy, nitro, halo, and three(chloro or fluoro)methyl. Most preferred is methyl.

General chemical terms used above, and throughout the description, have their ordinary meaning. For example, "C1-C4alkyl" refers to branched or unbranched aliphatic chains containing from 1 to 4 carbon atoms, including groups such as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, etc., the Term "halo" means bromine, chlorine, fluorine and iodine.

Appropriate solvents include inert solvent or mixture of solvents, such as, for example, diethyl ether, dioxane and tetrahydrofuran (THF). Of these the most preferred is anhydrous THF.

The preferred trialkylborane used in this reaction is triisopropylsilyl.

The product of this reaction, the compound of formula III, then subjected to the interaction with the coupling of the aryl of the formula IV by means of standard reactions combination Suzuki obtaining compounds of formula I. the compounds of formula IV in which R2is-H or or3and R3is hydroxyamino group, derived from commercially available compounds by methods well known to the specialist in the art [see, for example, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Edition, J. March, ed., John Wiley and Sons, Inc., 1992); and Suzuki, A., Pure and Appl. Chem., 6(2): 213-222 (1994)].

In this reaction, the combination of a slight excess of the compound of formula Tora and the appropriate base in an inert solvent, such as toluene.

Although this reaction mix are various palladium catalysts, the selected catalyst is usually specific reaction. Thus, it is most preferable in this reaction to use tetranitropentaerithrite.

Similarly, in the present reaction combinations you can use various grounds. However, it is preferable to use a carbonate of an alkali metal, especially 2N sodium carbonate.

Used at this stage, the temperature should be sufficient to complete the reaction combinations. Typically, the heating of the reaction mixture up to the boiling temperature under reflux for from about 2 to about 4 hours is sufficient and preferred.

In method B, represented in the diagram, the first stage involves bromination of 2-position, iodination or education triflates tsepliaeva group of compounds of formula II using standard methods. Usually, if you use bromination or iodination, the compound of formula II is subjected to interaction with a slight excess of n-utility in hexane, in an appropriate solvent, and, often in an inert atmosphere such as nitrogen atmosphere, with pesthouse solvent. Preferred Jodorowsky agent is iodine, and the preferred brainwashee agents include N-bromosuccinimide and bromine.

Appropriate solvents include inert solvent or mixture of solvents, such as, for example, diethyl ether, dioxane or THF. THF is preferred, and particularly preferred is anhydrous THF. This reaction is optionally carried out in the temperature range from about -75oC to about -85oC.

Then the product of the above reaction, galaran formula V, combined with the connection arylboronic acid of formula VI to obtain compounds of formula I. the Preferred reaction conditions for the reaction combinations are the same as the conditions described for the reaction of the combination, including the compounds of formula III and formula IV in the way A schema.

The processes represented in the diagram and described herein can be implemented in different phases, in which the reaction product from each stage purify and characterize, or the methods A and B, represented in the diagram, carry out in situ. Thus, the present process preferably each is carried out in a single reactor.

Compounds of formulas III and V, as shown in the present method, are Novia pharmaceutically active compounds of the formula VII, and further description of them together referred to as the compounds of formula IX:

< / BR>
where R1'represents-OH or-OR3where R3is hydroxyamino group; and

Z represents bromine, iodine, triflate or-B(OH)2.

In another aspect of the present invention the compounds of formula VII is obtained by the method, which includes stages that are represented in the diagram in methods A and B, and additionally including:

(c) acylation of the compounds of formula I a compound of formula VIII:

< / BR>
where R1represents-H, -OH or or3where R3is hydroxyamino group;

R2represents-H, -OH or or4where R4is hydroxyamino group;

R5is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino;

R6is bromine, chlorine, iodine or an activating ester group and

n = 2 or 3;

d) optionally removing R3and/or R4hydroxyamine groups and

e) optionally obtaining pharmaceutically acceptable salts of the compounds of formula VII.

Stage, method c), (d) and (e) good what s in the description by reference.

Although the form of the free base of the compounds of formula VII can be used for the above medical conditions, it is preferable to obtain and use the form pharmaceutically acceptable salts. Thus, the compounds of formula VII mainly form pharmaceutically acceptable acid additive salts with a wide range of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of the invention. Typical inorganic acids, which are used for such salts include hydrochloric, Hydrobromic, idiscovered, nitric, sulfuric, phosphoric, hypophosphorous, etc. Can also be used salts derived from organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate and hydroxyalkanoate acids, aromatic acids, aliphatic and aromatic sulfonic acids. Thus, such pharmaceutically acceptable salts include the acetate, phenyl acetate, triptorelin, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxy the, aprat, kaprilat, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymet, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, hydrogen phosphate, dihydrophosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, bansilalpet, p-bromophenylacetate, chlorobenzenesulfonate, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, ecological, tartrate, etc., the Preferred salt is the hydrochloride.

The following examples are presented to further illustrate obtain the compounds of the present invention. They in no way limit the scope of the invention.

Data of NMR in the following examples were obtained on a GE appliance 300 MHz NMR, and as a solvent used anhydrous DMSO-d6if there are no other indications.

Example 1

6 methoxybenzo[b]thiophene-2-baronova acid

< / BR>
To a solution of 6-methoxybenzo[b]thiophene (18,13 g, 0,111 mol) in 150 ml of anhydrous tetrahydrofuran (THF) is Les stirring for 30 minutes via a syringe injected triisopropylsilyl (28,2 ml, 0,122 mol). The obtained mixture was allowed to gradually warm to 0oC and then partitioned between 1 N. hydrochloric acid and ethyl acetate (300 ml each). The layers are separated and the organic layer dried over sodium sulfate. In the result, concentration in vacuo get a solid white color, which is pounded into powder and extracted from a mixture of ethyl ether and hexanol. Filtered off and get to 16.4 g (71%) 6 methoxybenzo[b]thiophene-2-Bronevoy acid in a solid white color.

So melting 200oC (decomp.).

1H-NMR (DMSO-d6) : 7,83 (s, 1H), 7,78 (d, J = 8.6 Hz, 1H), 7,51 (d, J = 2.0 Hz, 1H), 6,97 (DD, J = 8,6, 2.0 Hz, 1H), 3,82 (s, 3H).

Mass spectrum (field desorption): 208.

Similarly receive benzo[b] thiophene-2-Bronevoy acid (a known compound).

Example 2

[6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene

< / BR>
To a solution of 6-methoxybenzo[b] thiophene-2-Bronevoy acid (1,00 g, to 4.81 mmol) in 20 ml of toluene added 4-iodoanisole (1.24 g, from 5.29 mmol), and then tetranitropentaerithrite (0.17 g, 0.15 mmol). To this solution add 5.0 ml solution of 2 n sodium carbonate. The resulting mixture is heated to the boiling temperature under reflux for 2 hours. After aniem and washed with ethyl acetate. The obtained filtrate is distributed between ethyl acetate and saturated sodium bicarbonate solution. The layers are separated and the organic layer dried over sodium sulfate. In the result, concentration in vacuo get a solid white color (optional [6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene), which is collected by filtration. The total yield of the product of 1.25 g (96%).

So melting 190-194oC.

1H-NMR (DMSO-d6) : 7,71-7,63 (m, 3H), to 7.61 (s, 1H), 7,53 (d, J = 2.0 Hz, 1H), 7,03 (d, J = 9.0 Hz, 2H), 6,99 (DD, J = 9,0, 2.0 Hz, 1H), 3,83 (s, 3H), 3,81 (s, 3H).

Elemental analysis for C16H14O2S:

Calculated: C 71,08; H 5,22;

Found: C 71,24; H 5,26.

Alternatively, purification typically reach chromatography on silica.

Example 3

6-methoxy-2-iodobenzoic[b]thiophene

< / BR>
To a solution of 6-methoxybenzo[b]thiophene (5,00 g, 30,49 mmol) in 200 ml anhydrous THF at -78oC add n-utility (20,0 ml, 32,01 mmol, 1.6 M solution in hexano). After stirring for 15 minutes injected dropwise via cannula a solution of I2(8,10 g, 32,01 mmol) in 25 ml anhydrous THF. The obtained mixture is allowed to gradually warm to ambient temperature. The reaction is quenched by distributing between ethyl acetate and rascone in vacuum get solid, yellowish-brown, which is recrystallized from hexanol obtaining 6,70 g (75%) of 6-methoxy-2-iodobenzoic[b]thiophene.

So melting point 75-77oC.

1H-NMR (CDCl3) : to 7.59 (d, J = 8.6 Hz, 1H), 7,42 (s, 1H), 7,22 (d, J = 2.0 Hz, 1H), 6,92 (DD, J = 8,6, 2.0 Hz, 1H), 3,86 (s, 3H).

Mass spectrum (field desorption): 290.

Elemental analysis for C9H7OSi:

Calculated: C 37,26; H 2,43;

Found: C 37,55; H 2,43.

6-methoxy-2-iodobenzoic[b] thiophene subjected to interaction with 4-methoxyphenylacetic acid according to the basic method described above, with the receipt of [6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene with yields of 80%.

1. The way to obtain 2-substituted benzo(b)thiophene of the formula I

< / BR>
where R1represents-H, -HE, or SIG or3where R3is hydroxyamino group;

R2represents-H, -HE or or SIG4where R4is hydroxyamino group

characterized in that

a) receive a derived Bronevoy acid of formula III from a compound of General formula II

< / BR>
< / BR>
where the values of R1above,

b) combining the product from step a) with the compound of the formula IV

< / BR>
where X represents bromine or iodine and R2above.

3. The method according to p. 2, wherein R3and R4each represent methyl.

4. The method according to p. 3, wherein X is iodine.

5. The method according to p. 4, characterized in that stage a) and (b) is carried out in the same reactor.

6. The method according to p. 1, characterized in that stage a) and (b) is carried out in the same reactor.

7. The way to obtain 2-substituted benzo[b]thiophene of the formula I

< / BR>
where R1represents-H, -HE or or SIG3where R3is hydroxyamino group;

R2represents-H, -HE or or SIG4where R4is hydroxyamino group

characterized in that

a) conduct selective bromination or iodination of compounds of formula II

< / BR>
where the values of R1above,

obtaining the compounds of formula V

< / BR>
where the values of R1indicated above and X is bromine or iodine,

b) combine the specified compound of formula V with the compound of the formula VI

< / BR>
values of R2above.

8. The method according to p. 7, wherein R1is or SIG3, R2is or SIG4 the same time, what R3and R4each represent methyl.

10. The method according to p. 9, characterized in that X represents iodine.

11. The method according to p. 10, characterized in that stage a) and (b) is carried out in the same reactor.

12. The method according to p. 7, characterized in that stage a) and (b) is carried out in the same reactor.

13. The method of obtaining derivatives of 2-phenyl-3-arovent[b]thiophene of formula VII

< / BR>
where R1represents-H, -HE or or SIG3where R3is hydroxyamino group;

R2represents-H, -OH or or4where R4is hydroxyamino group;

R5is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethylenimine,

characterized in that it consists of stages a) and b) under item 1 and further includes

(C) acylation of the compounds of formula I on p. 1 compound of formula VIII

< / BR>
where R6is bromine, chlorine, iodine or an activating ester group, R5specified above;

n = 2 or 3;

d) optionally removing R3and/or R4hydroxyamine groups

e) optional obtained the I, what R1and R2the compounds of formula VII, each represent IT.

15. The method according to p. 14, characterized in that n = 2, R5is 1-piperidinyl.

16. The method according to p. 15, characterized in that the pharmaceutically acceptable salt is a hydrochloride.

17. The method according to p. 16, wherein R6is bromine or chlorine.

18. The method of obtaining derivatives of 2-phenyl-arovent(b)thiophene of formula VII

< / BR>
where R1represents-H, -HE or or SIG3where R3is hydroxyamino group;

R2represents-H, -HE or or SIG4where R4is hydroxyamino group;

R5is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethylenimine,

characterized in that it consists of stages a) and b) under item 7 and further includes

(C) acylation of the compounds of formula I on p. 7 compound of formula VIII

< / BR>
where R6is bromine, chlorine, iodine or an activating ester group, R5specified above;

n = 2 or 3,

d) optionally removing R3and/or R4s VII.

19. The method according to p. 18, wherein R1and R2the compounds of formula VII, each represent IT.

20. The method according to p. 19, characterized in that n = 2 and R5is 1-piperidinyl.

21. The method according to p. 20, characterized in that the pharmaceutically acceptable salt is a hydrochloride.

22. The method according to p. 21, wherein R6is bromine or chlorine.

23. Derivatives of benzo(b)thiophene of formula IX

< / BR>
where R1'is HE or or SIG3where R3is hydroxyamino group, and Z represents bromine, iodine or-B(OH)2.

24. Connection on p. 23, R1'is-or SIG3.

25. Connection on p. 24, where R3is1- C4-alkyl.

26. Connection on p. 25, where R3represents methyl.

27. Connection on p. 26, where Z is bromine.

28. Connection on p. 26, where Z represents iodine.

29. Connection on p. 26 where Z is-B(OH)2.

30. Connection on p. 23, where Z is bromine.

31. Connection on p. 23, where Z represents iodine.

32. Connection on p. 23 where Z is-B(OH)2.

 

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< / BR>
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< / BR>
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