HU193230B - Process for producing /+/-threo-3-square bracket/2-amino-pfenyl/-thio-square bracket closed-2-hydroxy-3-/4-methoxy-phenyl/-propionic acid - Google Patents

Abstract

(+)-threo-3-(2'-amino-phenyl)-thio) -2-hydroxy-3-(4" -methoxy -phenyl)-propionic-acid (+A) is prepd. by resolving the diastereomer salts in the following reaction steps: (a) the alkali salt of (+A) is reacted in aq. soln. with 0.5-0.6 moleequivs. of the acid addition salt of (+) -alpha-phenyl -ethyle-amine at a temp. between room temp. and the b.p. of the reaction mixt., the mixt is subsequently cooled to 5-25 deg. C and the pptd. diastereomer is sepd. (b) the diastereomer salt obtd. in step a is decomposed in the known way with acid the pptd. (+A) is sepd. (c) the mother liquors obtd. in steps (a) and (b) are opt. combined, the pH of the mixt. is adjusted to 2-4 and the mixed (+A/-A) ppte. is sepd. (d) the (+A/-A) mixt. sepd. in step (c) is rich in (-A), it is kept in an alcohol with 1-3 carbons for at least 5 minutes at a temp. around the b.p. of the mixt., the nearly racemic (A) is sepd. at a temp. near the b.p. of the mixt. (e) the nearly racemic (A) obtd. in step d is reworked according to steps a and b. (f) steps (a) to

Description

The 'invention relates to method a / + / threo-3- [/ 2-aminophenyl / thio] -2-hydroxy-3- / 4-methoxyphenyl / -propionic acid ^- by resolution.

The process according to the invention is also suitable for use in a N-threo-3 - [(2-aminophenyl) thio} -2-hydroxy-3- (4-methoxyphenyl) propionic acid (hereinafter referred to as N - threo) from an amino acid / rich threo-3-] / 2-aminophenyl-thio] -2-hydroxy-3- (4-methoxyphenyl) -propionic acid (hereinafter "threo amino acid mixture") to obtain an approximately racemic threo amino acid mixture too.

An important raw material of the compound of this invention is the therapeutic / 2S, 3S / -3-acetoxy-5- (dimethylaminoethyl) -2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepine / 4 / 5H / -one hydrochloride, an antianginal agent known as Diltiazem, which acts as a calcium antagonist.

For the preparation of N +/- threo-3 - [(2'-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid (hereinafter - (-) - threo-amino acid) several methods are known in the literature.

German Patent Publication No. 3 337 176 discloses a resolution process using L-lysine as a resolving agent. Recovering the acid-free form of the extra expensive L-lysine from mother liquors is a very difficult and costly task.

Another method [Helv. Chim. Acta, 67, 916 (1984)] resolved racemic threo amino acids in ethanol with cinchonidine. This method is characterized by the use of extremely high amounts of alcohol as a solvent and a crystallization time of 48 hours.

The process described in U.S. Patent No. 4,416,819 is performed using an equivalent amount of the +/- a-phenylethylamine in both forms of the racemic acid for the resolution of the racemic threo amino acid in water. Resolution by this method followed by crystallization of the diastereoisomersal salt in 79% yield = + 302 ° / c = 0.3; ethanol / rotation / + / - threo amino acid having only 87% optical purity.

summing up the processes known so far, they either required more steps or resulted in lower yields or failed to provide a product with sufficient optical purity.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process which, in a simple manner, can be carried out in technological steps in high yield, high optical purity, and economically to provide the? -? -? - threo amino acid.

The invention is based on the recognition that

a.) ± (±) -Treo-3-] / 2-aminophenyl-thio] -2-hydroxy-3- (4-methoxyphenyl) -propionic acid (hereinafter referred to as ± ± -Treo-amino acid). aqueous solution of its alkali metal salt, preferably its sodium salt, and a solution of the acid addition salt of / - (- / -? - phenylethylamine, preferably with hydrochloric acid in a 1: 0.5-0.6 molar ratio with high selectivity / significantly less soluble / threo-amino acid (+) - diastereomeric salt formed with -α-phenylethylamine (hereinafter referred to as diastereomeric salt), thus eliminating the need to use a resolving agent for further processing of the sodium salt of - - / - threo-amino acid which remains in solution;

b.) there is a large difference in the solubility of the racemic or approximately racemic threo amino acid and the optically active / - / - threo amino acid in ethanol. Utilizing this recognition, most of the excess / - / - threo amino acid can be liberated from the acid mixture of / - (- / - threo amino acid and / - / - threo amino acid) from the mother liquor of the resolution and recrystallization to give approximately racemic threo amino acid , which may be the starting material for repeating the resolution step.

Based on the foregoing, an aqueous solution of the diastereomeric salt of 0.5 + 0.6 molar equivalent of the +/- a-phenylethylamine salt is carried out. This not only saves the expensive resolving agent but also simplifies the processing of the mother liquor obtained after the separation of the diastereomeric salt, since the mother liquor after the separation of the diastereomeric salt contains only a small proportion of the resolving agent, the alkaline (sodium) salt of threo amino acid. in solution.

As a result of our findings, the yield of / - (- / - threo-amino acid) is improved with higher yield and higher optical purity, while using less resolving agent and turning.

The present invention relates to a process for the preparation of N - (- / - threo-3-1 / 2-aminophenyl / thio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid by resolution

the. ) an alkali metal salt of N, N-threo-3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid in an amount of 0.5-0.6 molar equivalent / with an acid addition salt of (- / - α-phenylethylamine) in aqueous solution at room temperature to the reflux temperature of the reaction mixture, the reaction mixture is cooled to + 5 to 25 ° C and the precipitated diastereomeric salt is recovered and purified if desired;

b. ) cleaving the diastereomeric salt in a known manner with acid butter to recover the precipitated + + - threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid;

c. if desired, the mother liquors (resolution and recrystallization) obtained in step a) are combined and the pH of the resulting mixture is adjusted to 2-4, and the precipitated / - / - threo-3 - {/ 2-amino -phenyl (thio) -2-hydroxy-3- (4-methoxyphenyl) -propionic acid-rich threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxy) recovering the phenyl / propionic acid mixture;

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d. ) In a C 1 -C 3 alkanol for at least 5 minutes at about the reflux temperature and then with the approximately racemic, insoluble threo-3- [2-aminophenyl] thio-2-hydroxy-3- [4-methoxyphenyl] recovering the propionic acid at a temperature about the boiling point of the reaction mixture;

e. ) reprocessing the approximately racemic threo-3 - [(2-aminophenyl) -thio-2-hydroxy-3- (4-methoxyphenyl) -propionic acid product according to steps a./- b./;

f.) repeating steps a./-d./ if desired.

Thus, the present invention differs from known resolution techniques in that

the. ) Instead of / ± / -threo-amino acid, an alkali metal salt thereof, instead of / + / - a-phenylethylamine, an acid addition salt thereof is used as a resolving agent, therefore 0.5-0.6 molar equivalent of resolving agent is sufficient:

b. ) from the / - / - threo amino acid rich mother liquor mixture by treatment with hot ethanol gives an approximately racemic threo amino acid mixture, which can be the starting material for further resolution steps and thus significantly increase the yield of resolution.

The starting compound may be prepared, for example, by the procedure of Hiroshi Kugita et al., Chem. Pharm. Bull. 18, 2028 (1970).

Advantageously, the process according to the invention can be carried out by preparing an alkali metal salt of / ± threo amino acid with dilute alkali metal hydroxide, preferably 1 N sodium hydroxide solution, thereby forming an acid addition salt of +/- α-phenylethylamine. dilute acidic solution, preferably 1N hydrochloric acid. The two solutions are mixed under stirring at room temperature to the reflux temperature of the mixture, at higher temperatures even momentarily, at lower temperatures, preferably by slow addition. After stirring for 5-14 hours at + 5 to 25 ° C, the precipitated diastereomeric salt is recovered by recrystallization from water and liberated from the aqueous solution of the pure diastereomeric salt thus obtained with an equivalent amount of acid, preferably hydrochloric acid, the precipitated + + - threo amino acid is recovered, washed and dried (resolution step 1).

The mother liquors from the above steps are combined with the mother liquors of the diastereomeric salt and its recrystallization to a pH of 2 to 4, preferably 2.5 to 3.5, with a 1: 1 mixture of deionized water and concentrated hydrochloric acid. After drying, the resulting threo amino acid mixture containing about 20% +/- threo amino acids is refluxed in 1-3 pseudochannels, preferably ethanol, for at least 5 minutes, and the insoluble component is recovered hot. This gives a threo amino acid mixture containing approximately 40% (+) - threo amino acids, which can be resolved as described above (resolution step 2). The above two resolution steps may be repeated several times if desired.

The mother liquors containing some form of +/- α-phenylethylamine may be combined and the resulting solution basified to a pH of 11 to 13 with concentrated alkali metal hydroxide, preferably 30 to 50% sodium hydroxide. The resulting alkaline solution is extracted several times with an organic solvent, preferably chloroform. The combined organic phases are dried, evaporated, purified by conventional means, such as vacuum distillation, and the recovered +/- a-phenylethylamine can be used in further resolution steps.

In a preferred embodiment of the process of the invention, the resolution can be performed continuously to obtain a 95% yield of +/- threo-amino acid.

The following examples illustrate the process of the present invention without limiting it.

Example 1

31.9 g / l _0} mole / / ± / threo-amino acid 100.0 cm-1 N sodium hydroxide solution and 190 (0 cin ³ dissolved in deionized water, while the solution was heated to reflux. When the pH value not between 7 and 8, adjust to pH 7-8 with 1N sodium hydroxide solution or 1N hydrochloric acid solution In another flask, 7.25 g (0.06 mol) of +/- α-phenylethylamine 60.0 Dissolve cm ^{3 in} 1N hydrochloric acid and heat to boiling.

The two hot solutions were combined, cooled to room temperature with stirring, and stirred at this temperature for an additional 12 hours. The precipitated crystals were filtered off and washed with 2x15.0 cm ^{3 of} deionized water. The wet material was elucidated '0.5 g of charcoal was recrystallized 275.0 cm ³ of deionized water, and the precipitated crystals were filtered and washed 2x15,0 cm ³ deionized water, dried under infrared lamp.

16.18 g of diastereomeric salt are obtained.

158-159 ° C.

[a] 2o _{= +372} ° _{(c = Oi5,} ethanol)

The 16.18 g of diastereomeric salt was dissolved in dry 730.0 cm ³ hot deionized water, and 36.8 cm ³ of 1N hydrochloric acid was added with stirring. After cooling, the precipitated N - (- / - threo-amino acid) is filtered off, washed with 2 x 15 cm ^{3 of} deionized water and dried under an infrared lamp.

The first resolution step yield was 11.3 g of (+/-) - threo-amino acid (70.8%).

138-139 ° C.

_[Α] "= +347 ⁰ (c = 0.3, ethanol).

Second resolution step:

The diastereomeric salt filtrate and the recrystallization filtrate were combined and the mixture was adjusted to ρΗ by a 1: 1 mixture of concentrated hydrochloric acid and deionized water. The precipitate is filtered off, washed with neutral water and dried under an infrared lamp.

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18.74 g of a mixture of threo amino acids containing 20-22% of t- (- / - threo-amino acid) is obtained. 18.74 g of threo-amino acid are stirred in 45.0 cm ^{3 of} hot ethanol for 5 minutes and then the insoluble part is obtained. filtered hot, washed with ethanol and dried under an infrared lamp.

9.7 g of threo-amino acid are obtained, which contains 40-42% of +/- threo-amino acid.

Mp 170-172 ° C.

[Α] D = -78 ° (c = 0.2; DMF).

The filtrate was evaporated to give 9.0 g of (-) - threo-amino acid.

133-135 ° C.

[α] D = -330 ° (c = 0.3; ethanol).

The above 9.7 g (0.0305 mole) of threo amino acid calculated by its specific rotation

7.9 g (0.0248 mole) of / ± contains / threo-amino acids, 30.0 cm ³ of 1N sodium hydroxide solution and 47.0 cm ³ of deionized water is dissolved in a mixture, and then heated to reflux. If the pH of the solution thus obtained is not between 7 and 8, the required pH of 7 to 8 is adjusted with 1N sodium hydroxide solution or 1N hydrochloric acid solution. To the hot solution was added a hot solution of 1.8 g (0.0149 mol) of (+) - α-phenylethylamine in 14.9 cm ^{3 of} 1 N hydrochloric acid, cooled to room temperature with stirring, and then at this temperature for an additional 12 hours. stirred. The precipitated crystals are filtered off and washed with 2x 5.0 cm ^{3 of} deionized water. The nucleated moist material is recrystallized from deionized water with charcoal, filtered, washed, and dried under an infrared lamp.

3.6 g of the diastereomeric salt are obtained.

158-159 ° C.

= + 370 ° (c = 0.5; ethanol).

The above 3.6 g of dry diastereomeric salt were dissolved in 140.0 cm ^{3 of} hot deionized water and 8.2 cm ^{3 of} 1 N hydrochloric acid was added with stirring. After cooling, the precipitate is filtered off, washed with neutral water and dried under an infrared lamp.

The yield of the second resolution step is 2.5 g / - (- / - threo-amino acid. (63.3% based on the starting material of the second resolution step / - (- / - threo-amino acid)). The two resolution steps are combined. Yield: 86.5% The filtrates from the second resolution step were combined and the pH was adjusted to 3 with a 1: 1 mixture of concentrated hydrochloric acid solution and deionized water, filtered, washed with neutralized water and dried under an infrared lamp.

6.1 g of threo-amino acid are obtained, the main weight of which is / - / - threo-amino acid.

130-131 ° C.

[α] D = -200 ° (c = 0.3; ethanol).

Resolution of the resolving agent:

The diastereomeric salt decomposition filtrate of hydrochloric acid from the first resolution step and the filtrates from the second resolution step were combined and basified to pH 12 with 40% sodium hydroxide solution and extracted three times with 1000 cm ^{3 of} chloroform. The combined organic phases are dried and evaporated. The residue was fractionated by vacuum distillation. The resolving agent is recovered in a yield of 70-80%.

Example 2

31.9 g (0.1 mol) of / ± / threo-amino acid are dissolved in 100 cm ³ of 1 N sodium hydroxide solution and 190 cm ³ of deionized water at ambient temperature. A solution of 7.25 g (0.06 mol) of / - (- / -? - phenylethylamine in 60 cm @ ^{3 of} 1 N hydrochloric acid is added under stirring at room temperature for three hours. After the addition is complete, the mixture is stirred at + 10 ° C for four hours. The precipitated crystals are filtered off, recrystallized in 0.5 g of charcoal in deionized water, filtered, washed with deionized water, suspended in 260 cm ^{3 of} deionized water, and 40 cm ^{3 of} 1 N hydrochloric acid are added under stirring at room temperature. After stirring for 1 hour, the precipitated +/- threo-amino acid is filtered off, washed with neutralized water and dried.

Yield: 1.95 g / +/- threo-amino acid (75%).

M.p. 137-138 ° C.

[.alpha.] @ ²⁰ = + 346 DEG (c = 0.3; ethanol).

Second resolution step:

The diastereomeric salt filtrate and the recrystallization filtrate were combined and the pH was adjusted to 3 with a 1: 1 mixture of concentrated hydrochloric acid and deionized water. The precipitated material is filtered off, washed with neutral water and dried.

18.85 g of threo-amino acid are obtained, which contains approximately 20% of the - (- / - - threo-amino acid).

18.85 g of threo-amino acid are boiled in 40.0 cm <^{3> of} ethanol for fifteen minutes, the insoluble material is filtered hot, washed with ethanol and dried.

10.8 g of threo-amino acid are obtained, containing approximately 40% of / - (- / - threo-amino acid). resolved as described above.

The yield of the second resolution step is 2.5 g / - (- / - threo-amino acid. 67% based on the starting material of the second resolution step / - (- / - threo-amino acid). Combined yield of the two resolution steps. : 90.6%.

Claims (6)

PATENT CLAIMS CLAIMS 1. A process for the preparation of (+) - threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid by resolution a.) An alkali metal salt of ± ± 3-threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid is 0.5-0.6 molar equivalent. [+] - with an acid addition salt of α-phenylethylamine in the range from room temperature to the reflux temperature of the reaction mixture, The reaction mixture is cooled to + 5 to 25 ° C, the precipitated diastereomeric salt is recovered in a known manner, recrystallized if desired, and dried; b. ) the diastereomeric salt is decomposed with an acid in a known manner, the precipitated N - (- / - threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid recovering, drying; c. combining, if desired, the mother liquors of the diastereomeric salt formed in step a) and recrystallizing it, and then adjusting the pH of the resulting mixture 2-4, and threo-3-rich in precipitated N - threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid Recovering the mixture of [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) -propionic acid in a known manner; d. the resulting product is kept in a C 1-3 alkanol for about 5 minutes at about the boiling point of the mixture, followed by the addition of approximately racemic insoluble threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- [4-methoxy] recovering the phenyl-propionic acid in a manner known per se at the boiling point of the reaction mixture; e. ) reprocessing the approximately racemic threo-3 - [(2-aminophenyl) -thio] -2-hydroxy-3- (4-methoxyphenyl) -propionic acid product according to steps a./b./. f.) repeating steps a./-d./ if desired. Process according to claim 1, characterized in that it is rich in N-threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid keeping the mixture of threo-3 - [(2-aminophenyl) -thio] -2-hydroxy-3- (4-methoxyphenyl) -propionic acid in a C 1-3 alkanol for at least 5 minutes at about the reflux temperature of the mixture, and recovering the approximately racemic insoluble threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid at a temperature about the boiling point of the reaction mixture. ¹⁵ The process according to claim 1, wherein the N-threo-3 - [(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionic acid is an alkali metal. The salt of the salt is glazed with sodium salt. 4. A process according to claim 1 wherein the acid addition salt of N, N-α-phenylethylamine is an acid addition salt with hydrochloric acid. Process according to claim 1 or 2, characterized in that the combined mother liquors are adjusted to a pH of between 2.5 and 3.5. Process according to claim 1 or 2, characterized in that the alkanol having 1 to 3 carbon atoms is ethanol.