HU214106B - Process for producing intermediates of benzo[b]thiophene-5-yl derivatives - Google Patents

Abstract

(57) EXCLUSION [7] (b) thiophen-5-yl derivatives of general formula (7), from which R 2 is 2,2-dimethyl-1,3-dioxoanan-4-yn-5-yl or (8) or (10) generating a general-purpose tubular cortex, wherein R2a is a hydrogen atom or hydrofluoric acid coat, and R3 is hydrogen or a carboxy-protecting coat, and the preparation of its active esters and salts thereof is bromine (±) 5-benzo [b] thiophen-5-yl) -2,2-dimethyl. In the presence of racemization catalytic dye, supersaturated lithium of 1,3-diolane-4 is obtained with one of its optically active excipient crystals to obtain the optically pure excipients which, in the presence of an acid catalyst, are subjected to hydrosynthesis or lysis of (+) or (-) -2- (boron-thiol). 5-yl) -2-Hydroxy-acetic acid derivative, followed by the introduction of acid labile hydroxylic acid protecting powder and subsequent reduction of the azathion by (+) or (-) - 2- (benzo [b] thiophen-5-yl) -2 (protected) hydrogen hydroxide). ŕ

Description

The invention can be used as intermediates in [b] thiophen-5-yl derivatives which process benzo (7) compounds of the formula: - wherein ^R1 is a group or (8) or the group (10) of formula of formula (9) wherein R ^2a is a hydrogen atom or a hydroxy protecting group; and

R ³ is hydrogen or a carboxy protecting group

- for the preparation of optically active forms and their salts.

The compounds of the present invention are highly preferred intermediates for 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-dialkylamino) ethoxy] ethanol and their optical isomers which enhance brain function. and processes for the preparation of their salts as disclosed in JP 04-119740 and JP 05-090934, filed April 13, 1992 and JP 05-090934, filed March 25, 1993, and in U.S. Patent Application Serial No. P9301052, Hungarian patent application.

Through the intermediates of the invention, said 1- (benzo [b] thiophen-5-yl) -2- [2- (N, N-dialkylamino) ethoxy] ethanol derivatives and their salts, in particular the optically active isomers can be produced at low cost, high yield, and industrial scale.

Particularly preferred key intermediates are the optically active benzo [b] thiophen-5-yl derivatives of formula (7) wherein R ¹ is 2,2-dimethyl-4-oxo-1,3-dioxolane (9). 5-yl, the compounds of which are represented by the formulas 2a and 2b.

According to the invention of (7) A compound of formula - wherein R ¹ is (9) a group of formula - optical isomers thereof are prepared from the racemic compound [i.e., a compound (7) wherein R ¹ formula (1) (9) is added in the presence of a racemization catalyst to crystals of the optically active compound of formula (2a) or (2b), whereupon the desired optically active isomer corresponding to the seed crystal is precipitated out of solution by the racemization catalyst. racemization of the other isomer by a substantial shift in the steady state concentration (50-50%) of the desired isomer, which is constantly re-formed and removed from solution, in favor of the desired isomer.

Optically active compounds of formula (7) wherein R ¹ is a group of formula (8) wherein R ^2a is hydrogen and R ³ is hydrogen or a carboxy protecting group, such as (3a) or (3b). or a salt thereof wherein R ^2a is hydrogen and R ³ is hydrogen or a carboxy protecting group - can be prepared by hydrolysis of a compound of formula 2a or 2b in the presence of an acidic catalyst (R ³ = H). or, for example, alcoholysis (R ³ = carboxy protecting group).

A compound of Formula 7 wherein R ¹ is a group of Formula 8 wherein R ^2a is a hydroxy protecting group and R ³ is a carboxy protecting group - that is, a compound of Formula 3a or 3b; wherein R ^2a is a hydroxy protecting group and R ³ is a carboxy protecting group - can be prepared by reacting a compound of formula 3a or 3b wherein R ^2a is a hydrogen atom and R ³ is a carboxy protecting group, introducing a hydroxy protecting group in a known manner.

Optically active compounds of formula (7) wherein R ¹ is a group of formula (10) wherein R ^2a is a hydroxy protecting group, i.e. compounds of formula (4a) or (4b) wherein R ^2a is hydroxy. - protecting group - can be prepared by reducing compounds of formula (3a) or (3b) wherein R ^2a is a hydroxy protecting group and R ³ is a carboxy protecting group.

Further details and other advantageous aspects of the invention will be apparent from the following description.

The terms hydroxy protecting group for the definition of R ^2a and carboxy protecting group for the definition of R ³ mean conventional hydroxy protecting groups or carboxy protecting groups. Specific examples of these include the protecting groups mentioned in Theodora W. Greene's "Protective Groups in Organic Synthesis" (John Wiley & Sons, Inc., 1981) and Japanese Patent Application Publication No. 60-52,755 (Kokoku) and the like.

Among the hydroxy protecting groups, especially substituted methyl groups such as methoxymethyl, tert-butoxymethyl, (2-methoxyethoxy) methyl, (2,2,2-trichloroethoxy) methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, tetrahydrofuryl, and the like, substituted ethyl groups such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 2,2,2-trichloro; ethyl, tert-butyl, allyl, cinnamyl, p-chlorophenyl and the like, substituted benzyl groups such as 4-methoxybenzyl, diphenylmethyl and the like, silyl groups such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, di-tert-butylmethylsilyl and the like, and carboxy-protecting groups optionally substituted with one to six halogen atoms. alkyl groups such as methyl, ethyl, propyl, tert-butyl, 2-chloroethyl, 2,2,2-trichloroethyl and the like, aralkyl groups such as benzyl, diphenylmethyl, triphenylmethyl and the like, allyl group, cinnamyl group, silyl groups such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyldi- butyl) methylsilyl groups and the like, and C 1-6 alkyl groups optionally substituted with halogen atoms, such as methyl, ethyl, propyl, tert-butyl, 2-chloroethyl, and the like. , 2,2,2-trichloroethyl and the like, aralkyl groups such as benzyl, diphenylmethyl, triphenylmethyl and the like, allyl group, cinnamyl group, silyl groups such as trimethyl silyl, tert-butyldimethylsilyl, phenyldimethylsilyl and the like, phenacyl, lower alkylthio-substituted lower alkyl groups such as (methylthio) methyl, 2- ( methylthio) ethyl and the like, 4-piperonyl and the like. mentioned.

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The preparation of the compounds of the present invention is illustrated in Scheme [A]. In the formulas, R ^2a and R ³ are as defined above.

Salts of compounds of formulas 3a and 3b wherein R ³ is hydrogen, with alkali metals such as lithium, sodium, potassium and the like, alkaline earth metals such as barium, calcium and the like, organic amines such as propylamine, butyl. salts with amine, isobutylamine, octylamine, benzylamine, phenethylamine, diethylamine, diisopropylamine, triethylamine, methylpiperidine, methylpiperazine, aniline, leucine hydrazide and the like.

In the following, the process of the present invention is described in detail in Scheme [A] in a sequence of successive steps.

A process for the preparation of a compound of formula 2a or 2b (crystallization-friendly crystallization method).

An supersaturated solution of the compound of formula (1) is seeded with seed crystals of the same compound in the (+) or (-) configuration in the presence of a racemization catalyst, thus predominantly crystallizing the compound in optically active form in the seed crystal configuration.

The solvents useful in the above process are those in which the solubility of the compound of formula (I) is satisfactory. Examples of such solvents are aliphatic hydrocarbons such as petroleum ether, light naphtha, hexane, cyclohexane and the like, ethers such as diethyl ether, diisopropyl ether and the like, aromatic hydrocarbons such as benzene, toluene and the like, esters such as ethyl acetate and the like, secondary alcohols such as isopropyl alcohol, cyclohexanol and the like, tertiary alcohols such as tert-butanol, tert-pentanol and the like, ketones such as acetone, 2-butanone, cyclopentanone and the like, halogenated hydrocarbons such as dichloromethane, chloroform and the like, such as acetonitrile and the like, amides such as Ν, Ν-dimethylformamide and the like, sulfoxides such as dimethyl sulfoxide and the like, and mixtures of these solvents. Particularly preferred is a tertiary alcohol or a mixture of a tertiary alcohol and one of the solvents mentioned above.

Additionally, a solvent which controls the solubility, such as an aliphatic hydrocarbon such as petroleum ether, hexane, cyclohexane and the like, may be added.

The racemization catalyst may be an organic base such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non- 5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane, N-methylpiperazine and the like, and quatemeric ammonium salts soluble in organic solvents such as (tetrabutylammonium) fluoride and the like.

The racemization catalyst can be used in an amount of 0.001 to 0.10 mol per mole of the compound of formula (1).

The amount of seed crystal added and the particle size of the crystals are not critical to the process, but it is preferred that the seed crystals contain about 0.1 to about 10 weight percent crystals of the compound of formula (1) in solution or in the same solvent used to make the supersaturated solution. used as a suspension.

The operating temperature is not critical and the operation can be carried out at the boiling point of the solvent used. However, the temperature must be adjusted to obtain a stable supersaturated solution of compound (1) based on the solubility of the compound in solution.

A process for the preparation of a compound of formula 3a or 3b.

i) The compounds of formula 3a and 3b may be prepared by alcoholysis of a compound of formula 2a or 2b in the presence of an acidic catalyst and addition of a hydroxy protecting group to a product obtained by alcoholysis in a known manner.

The alcohol used in the aforementioned alcoholysis can be, for example, a C 1-6 alcohol such as methanol, ethanol and the like, an aralkyl alcohol such as benzyl alcohol and the like.

Acid catalysts useful in the above reaction include, for example, a protonic acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, dichloromethane sulfonic acid and the like, and a Lewis acid such as aluminum chloride, boron trifluoride, boron trichloride and similar.

The alcoholysis may be carried out in a solvent such as benzene, toluene, dichloromethane, diethyl ether, tetrahydrofuran and the like which does not adversely or interfere with the reaction.

The amount of alcohol used in the alcoholysis is preferably 1 mole or more per mole of the compound 2a or 2b, and the amount of the acidic catalyst used is preferably 0.1-30 mole per mole of the compound 2a or 2b calculated.

The above reaction can be carried out at a temperature of 0 to 120 ° C for a period of 1 to 24 hours.

The hydroxy protecting group used for subsequent introduction of the hydroxy protecting group is preferably a group which is stable against alkali and can be removed under acidic or neutral conditions. Examples include substituted methyl groups such as methoxymethyl, (2-methoxyethoxy) methyl, (2,2,2-trichloroethoxy) methyl, tetrahydropyranyl, tetrahydrofuryl and the like, substituted ethyl groups. such as 1-ethoxyethyl, tert-butyl and the like, a substituted benzyl group such as 4-methoxybenzyl, diphenylmethyl and the like, a silyl group such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like.

ii) The free carboxylic acid of formula 3a or 3b is obtained by hydrolysis of the compound of formula 2a or 2b.

3. A process for the preparation of compounds of formula 4a or 4b.

The compounds of formula (4a) or (4b) may be prepared from the compounds of formula (3a) or (3b) by standard ester reduction procedures.

The ester reduction is, for example, edited by Shin Jikken Kagaku Kouza (Maruzen, 1977) Vol. 15 (II) 29-216, edited by the Chemical Society of Japan. pages. Preferred reducing agents are lithium tetrahydroborate (1-)

The ester reduction may be carried out in the presence of a metal salt such as lithium chloride, lithium bromide, calcium chloride, cobalt chloride, nickel chloride or the like, or without it.

This reaction is usually carried out in the presence of a solvent. The solvent may be an alcohol such as methanol, ethanol, isopropyl alcohol and the like, an ether such as diethyl ether and the like, a nitrile such as acetonitrile and the like, an amide such as N, N-dimethylacetamide and the like. . These solvents may be used alone or may be a mixture of two or more solvents.

In the above reaction, preferably 0.75 to 5 moles of reducing agent are used per mole of compound (3a) or (3b) and the reaction is carried out at a temperature of 0 to 60 ° C for 1 to 48 hours.

The compound (1), 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one (11), benzo [b] thiophene, is described in detail below. Also starting from -5-carbaldehyde via 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid (12) or its salts as an intermediate.

The salts of the compounds of formula (12) include the salts of the compounds of formula (3a) or (3b) wherein R ³ is hydrogen.

I. A process for the preparation of a compound of formula 12 or salts thereof.

For example, the compound of formula (12) and its salts are described in J. Org. Chem.

33, 2565-2566 (1968). The (±) -2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid (compound 12) or its salt is the compound (11), i.e. benzo [b] thiophene-5-yl. by condensation with carbaldehyde bromoform in the presence of a base such as lithium hydroxide and subsequent hydrolysis of the condensation product.

II. An optical resolution process utilizing an optically active resolving agent is used to prepare an optically active form of compound (12) or a salt thereof.

The methods and the like described in Japanese Unexamined Patent Applications Nos. 54-24,849 and 55-147,236 (Kokai) may be used. In particular, an optically active compound or salt thereof may be prepared by reacting a compound of formula (12) or a salt thereof with an optically active amine such as optically active 2-aminobutanol or α-phenethylamine [(1-phenylethyl) amine ] and the desired diastereomeric salt is then decomposed with an acid.

III. Process for the preparation of compound (1).

For example, Bull. Soc. Chim. Fr., 332-340 (1970). In particular, the compound of formula (I) may be prepared by reacting the compound of formula (12) or a salt thereof with acetone, isopropenyl acetate or 2,2-dimethoxypropane in the presence or absence of an acidic catalyst.

The invention is further illustrated by the following examples. However, the examples are provided for illustrative purposes only and should not be construed as limiting the scope of protection.

The "% e.e." is the abbreviation for the percentage of enantiomeric excess known in the art.

Example 1:

A mixture of 100 g of benzo [b] thiophene-5-carbaldehyde, 195 g of bromoform and 400 ml of dioxane is added dropwise to a suspension of 129 g of lithium hydroxide water (1/1) in 400 ml of water with stirring at 50 ° C for 4 hours. The reaction mixture was stirred at the same temperature for 2 hours and then cooled to 20 ° C. The precipitated crystals were collected on a filter and suspended in a mixture of 768 ml of toluene and 256 ml of water. To the suspension was added 110 ml of 6M hydrochloric acid with stirring. The resulting mixture was stirred at reflux for 1 hour and then cooled to 20 ° C. The precipitated crystals were collected by filtration to give 107 g of colorless crystalline (±) -2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid. The crystals were recrystallized from isopropyl alcohol to give colorless crystals, m.p. 151-152 ° C.

Infrared spectrum (KBr): 3242, 1730, 1691 cm -1.

Example 2:

(1) 15.78 g of (±) -2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid and 7.11 ml of R- (-) - 2-amino- are suspended in 95 ml of acetone. butanol is added to the slurry to form a solution for heating. The solution is gradually cooled with stirring and the precipitated crystals are filtered off. 16.71 g of crude crystalline (-) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid salt of R (-) - 2-aminobutanol are obtained. (Yield: 74.2%). Recrystallization of the crude product from isopropyl alcohol gave 5.58 g of a colorless crystalline solid, m.p. 156-157 ° C. (Yield 24.8%). [Α] D = -78.3 ° (24 ° C; C = 1.0; water).

(2) Infrared (KBr) data 3386.2970, 1636, 1601 cm -1.

5.5 g of (-) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid R - (-) - 2-only butanol salt are added to a mixture of 56 ml of water and 56 ml of ethyl acetate then the pH of the mixture was adjusted to 1.0 with 6M hydrochloric acid and the organic layer was separated. The separated organic layer was washed thoroughly with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and diisopropyl ether was added to the resulting residue. The precipitated crystals were collected by filtration to give 3.78 g of crude crystalline (-) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid. The crystals were recrystallized from acetone / benzene (1: 2 by volume) to give a colorless crystalline solid, m.p. 167-168 ° C.

[α] D = -142.3 ° (24 ° C; c = 1.0; menthol).

IR (KBr): 3315, 1685 ^cm-1

Example 3

100 g of (±) -2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid is suspended in 500 ml of acetone and 5.12 ml of concentrated sulfuric acid are added dropwise at -10 ° C. The suspension is stirred at the same temperature for an additional 1 hour and then 60 ml of 3.2 M aqueous ammonium hydroxide solution are added dropwise at the same temperature. The precipitated crystals were filtered off to give 10.25 g of colorless crystals of (±) -5- (benzo [b] thiophen-5-yl) -2,2-dimethyl

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-1,3-dioxolan-4-one is obtained. (Yield: 86%). The crystals were recrystallized from isopropyl alcohol to give a colorless crystalline solid, m.p. 87-88 ° C.

IR (KBr): 1790 cm ^1st

Example 4:

100 g of (±) -5-benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one are dissolved in 300 ml of tert-amyl alcohol with heating. To the resulting solution was added 4.6 g of 8-diazabicyclo [5.4.0] -7-undecene at 50 ° C and 0.5 g of (-) - 5- (benzo [b] thiophene-5- ii) a suspension of -2,2-dimethyl-1,3-dioxolan-4-one in 1.5 ml of tert-amyl alcohol. The mixture was stirred at 50 ° C for 1 hour, then cooled gradually to 25 ° C over 4 hours and then stirred at this temperature for an additional 30 minutes. The precipitated crystals are filtered off, washed thoroughly with 150 ml of tertiary amyl alcohol and 135 ml of isopropyl alcohol, and then dried. 88 g of colorless crystals are obtained.

[α] D 20 = -71.0 ° (24 ° C; c = 1.0; chloroform).

Optical purity: 96.2% e.e.

Recrystallization from isopropyl alcohol gave 81 g of (-) - 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one with an optical purity of 99% e.e. or more. (Yield: 81%).

Melting point: 116-117 ° C.

[α] D = -73.8 ° (24 ° C; c = 1.0; chloroform).

IR (KBr): 1790 cm ^1st

Example 5:

Using (+) - 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one (6) (±) -5- (benzo [b] thiophene-5-yl) as the seed crystal. ii) -2,2-Dimethyl-1,3-dioxolan-4-one was worked up as described in Example 4. Yield: 5.37 g of crude crystalline melting point 114-116 ° C.

[α] D = + 72.0 ° (24 ° C, c = 1.0, chloroform).

Optical purity: 97.5% e.e.

Recrystallization from isopropyl alcohol gave 5.10 g of colorless crystalline (+) - 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one. optical purity 99% ee or more.

Melting point: 116-117 ° C.

[α] D = + 73.8 ° (24 ° C; c = 1.0; chloroform).

IR (KBr): 17980 cm ^1st

Example 6:

To a suspension of (-) - 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one (g) in methanol (20 ml) was added dropwise 1.07 ml of concentrated sulfuric acid. The resulting mixture was stirred at 25 ° C for 1.5 hours, then dichloromethane (50 ml) and water (40 ml) were added and the resulting mixture was neutralized with sodium bicarbonate. The organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and hexene was added to the resulting residue, and the precipitated crystals were then filtered off. so

8.77 g of colorless crystalline (-) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid methyl ester, m.p. 83-84 ° C, are obtained. (Yield: 98%). [Α] D = -136 ° (24 ° C; c = 1.0; menthol).

IR (KBr): 3440, 1726 cm ^1st

In a similar manner, methyl (+) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid was prepared.

[α] D = + 136 ° (24 ° C; c = 1.0; menthol).

Example 7:

(1) To a solution of 10 g of (-) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid methyl ester in 50 ml of dichloromethane, 4.92 g of 3,4-dihydro-2H Pyran and 1.13 g of pyridinium p-toluenesulfonate are added and the mixture is stirred at 25 ° C for 3 hours. The reaction mixture was washed thoroughly with water, saturated aqueous sodium bicarbonate solution and water again, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give (-) - 2- (benzo [b] thiophen-5-yl) -2-tetrahydropyranyloxy-acetic acid methyl ester as an oily residue.

(2) Methyl (-) - 2- (benzo [b] thiophen-5-yl) -2-tetrahydropyranyloxyacetic acid is dissolved in 41.3 ml of ethanol and 2.90 g of sodium are added. [tetrahydroborate] was added and the resulting mixture was stirred at 25 ° C for 8 hours. The reaction mixture was quenched with acetone (13.23 mL) dropwise under ice-cooling and excess sodium tetrahydroborate (138 mL) was added followed by dichloromethane (138 mL) and water (8.5) with 2M hydrochloric acid. set it. The organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with petroleum ether to give 12.0 g of a colorless (-) - 2- (benzo [b] thiophen-5-yl) -2- (tetrahydropyranyloxy) ethanol as a diastereomeric mixture. (Yield: 96%).

Mp 62-77 ° C.

IR (KBr): 3287, 2937, 1128, 1079, 1028, 986 cm in ^{the first}

The following compounds were prepared in a similar manner: (+) - 2- (benzo [b] thiophen-5-yl) -2- (tetrahydropyranyloxy) ethanol, (±) -2- (benzo [b] thiophene). 5-yl) -2- (tetrahydropyranyloxy) ethanol.

Example 8:

As in Example 3, 1 g of (-) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid was reacted to give 920 mg of colorless crystalline (-) - 5- (benzo [b]). thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one, m.p. 116-117 ° C. (Yield: 77.2%). [Α] 25 D = -73.8 ° (24 ° C; c = 1.0; chloroform).

IR (KBr): 1790 ^cm-1

Example 9:

The solvent obtained in Example 2 (1) from the filtrate obtained from the resolution of the racemate was then reacted as described in Example 2 (2) with 3.02 g of (+) - enriched 2- (benzo [b] thiophene-5). -yl) -2-hydroxyacetic acid is obtained. (Yield: 19.1%).

21 [α] ρ = + 32.5 ° (24 ° C; c = 1.0; methanol).

Optical purity: 22.8% e.e.

Subsequently, this material was reacted in a similar manner as in Example 3 to 2.52 g of colorless, crystalline (+) - enriched 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3 -dioxolan-4-one is obtained. (Yield 70%). [Α] D = + 29.1 ° (24 ° C; c = 1.0; chloroform).

Optical purity: 39.5% e.e.

The product was recrystallized from isopropyl alcohol by recrystallization from (+) - 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolane-4, m.p. 116-117 ° C. we get one.

[α] D = + 73.8 ° (24 ° C; c = 1.0; chloroform).

Infrared (KBr) Characteristics:

1790 cm ^-1 .

Example 10:

To a solution of (±) -2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid (6.90 g) in methanol (50 mL) was added concentrated sulfuric acid (6 mL). The solution was refluxed for 1 hour, then ethyl acetate (250 mL) and water (250 mL) were added and the mixture was neutralized with sodium bicarbonate. The organic layer was separated, washed well with water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and isopropyl alcohol was added to the resulting residue. The precipitated crystals were collected by filtration to give 6.25 g of colorless crystalline (±) -2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid methyl ester, m.p. 84-85 ° C.

Infrared (KBr) data 3440, 1726 cm ^-1 .

The following compounds were prepared in a similar manner: (+) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid methyl ester, (-) - 2- (benzo [b] thiophene). 5-yl) -2-hydroxy-acid-methyl-ester.

Example 11:

2.0 g of (-) - 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one are suspended in a mixture of 8.5 ml of tetrahydrofuran and 3 ml of water, and 0.60 g of sulfuric acid was added dropwise to the suspension under ice-cooling, and the resulting mixture was stirred at 20 ° C for 24 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and the solvent removed by distillation under reduced pressure to give 1.65 g of crystalline (-) - 2- (benzo [b] thiophen-5-yl) -2-hydroxyacetic acid. (Yield: 98.3%).

The crystals were recrystallized from isopropyl alcohol to give colorless needle crystals, m.p. 167.6-168.0 ° C.

[α] D = -142.3 ° (20 ° C, c = 1.0, methanol).

Infrared spectrum (KBr): 3315, 2641, 1648 cm ^-1 .

Example 12:

200 g of (±) -5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one are dissolved in 600 ml of tert-amyl alcohol with heating. The resulting solution was added at 54 ° C

9.2 g of 8-diazabicyclo [5.4.0] undec-7-ene and then the solution is seeded with 1.0 g of (-) - 5- (benzo [b] thiophen-5-yl) -2, Of 2-dimethyl-1,3-dioxolan-4-one in 3.0 ml of tert-amyl alcohol. The resulting mixture was stirred at the same temperature for 2 hours and then cooled gradually to 25 ° C over 4 hours, followed by stirring at this temperature for an additional 30 minutes. The crystals thus obtained are filtered off, washed thoroughly with 300 ml of tertiary amyl alcohol and 270 ml of isopropyl alcohol, and then dried to give 176 g of colorless crystals.

[α] D = -71.0 ° (24 ° C; c = 1.0; chloroform).

Optical purity: 96.2% e.e.

Recrystallization from isopropyl alcohol gave 162 g of (-) - 5- (benzo [b] thiophen-5-yl) -2,2-dimethyl-1,3-dioxolan-4-one with a purity of 99%. EE or higher. Melting point: 116-117 ° C.

[α] 25 D = -73.8 ° (24 ° C, c = 1.0, chloroform).

IR (KBr): 1790 cm ^1st

Claims (2)

PATENT CLAIMS A process for the preparation of benzo [b] thiophen-5-yl derivatives of the general formula (7): wherein: R ¹ is a group of formula (9) or a group of formula (8) or (10) in which R ^2a is hydrogen or a hydroxy protecting group; and R ³ is a hydrogen atom or a carboxy protecting group for the preparation of optically active forms and their salts, characterized in that: (a) in the preparation of optically active forms of compounds of formula (7) wherein R ¹ is a group of formula (9), 2,2-dimethyl-5- (benzo [b] thiophen-5-yl) - to the supersaturated solution of 1,3-dioxolan-4-one in the presence of a racemization catalyst, add crystals of the desired optically active compound of formula 2a or 2b and isolating the optically active isomer precipitated; and (b) for the preparation of optically active forms of compounds of formula (7) wherein R ¹ is a group of formula (8) in which: ba) R ^2a is hydrogen; and R ³ is hydrogen A compound of formula 2a or 2b is hydrolyzed in the presence of an acidic catalyst and the corresponding isomer of formula 3a or 3b wherein R ^2a is hydrogen; and R ^{3 is} hydrogen; or bb) R ^2a is hydrogen; and the carboxy protecting group R ^{3 is} subjected to an alcoholysis in the presence of an acidic catalyst of a compound of formula 2a or 2b and the corresponding isomer of formula 3a or 3b wherein HU 214 106 Β R ^2a is hydrogen; and R ^{3 is a} carboxy protecting group; or be) R ^2a is a hydroxy protecting group; and R ³ is a carboxy protecting group; a hydroxy protecting group is introduced into an isomer of formula (3a) or (3b) prepared according to bb) in a known manner; and c) in the preparation of optically active forms of compounds of formula 7 wherein R ¹ is a group of formula 10 wherein R ^2a is a hydroxy protecting group, a compound of formula 3a or 3b prepared according to b). isomer in which R ^2a is a hydroxy protecting group; and R ³ is a carboxy protecting group reduced to a corresponding compound of formula 4a or 4b; and optionally converting the resulting product into its salt. Process a) according to claim 1, characterized in that (-) - 2,2-dimethyl-5- (benzo [b] thiophen-5-yl) -1,3-dioxolan-4-one or (+) ) -2,2-dimethyl-5- (benzo [b] thiophen-5-yl) -1,3-dioxolan-4-one is prepared.