HU190943B - Process for preparing optically active p-hydroxy-phenyl-glycine - Google Patents

Abstract

Racemic p-hydroxy-phenyl -glycine-alkyl-esters having 1-4 carbons in the alkyl gp. are resolved with optically active tartaric-acid in the presence of carbonyl cpds. in an aq. medium by using for 1 mole racemic glycine deriv. 0.15-0.5 mole carbonyl cpd. and 0.3-3.0 mole water. The hemi-tartarat of the optically active glycine deriv. may appear in the solvated form, from it the optically active glycine deriv. is liberated in the known way. The mothe liquor and/or washing fluids resulting from this prepn. are reused 1-30 times in the same process.

Description

The D-isomer and its reactive acid derivatives are widely used acylating agents in the manufacture of semi-synthetic antibiotics such as amoxicillin, cefadroxil or cefaperazone. ¹⁰

The L-isomer of p-hydroxyphenylglycine is known per se as a component of artificial sweeteners and, more recently, its effect on carbohydrate metabolism control and myocardial infarction is disclosed in U.S. Patent No. 866,745. Belgian Patent Specification. Several methods are known for the resolution of racemic p-hydroxyphenylglycine.

No. 7,311,012. According to Dutch Pat. No. 4,015, 2- (4-hydroxyphenyl) -2-aminoacetonitrile is prepared from p-hydroxybenzaldehyde by Strecker synthesis, from which the D-isomer is separated by tartaric acid resolution and then acidically hydrolyzed.

A great disadvantage of the procedure, but starting from the difficult to access and therefore very expensive p-hydroxybenzaldehyde of the use and the methods ^five times extraction is not good. On an industrial scale, another disadvantage is the use of alkaline metal cyanides.

The above method was corrected by US authors in U.S. Patent No. 3,489,750. According to patent U.S. that started out substantially cheaper 4-methoxybenzaldehyde (anisaldehyde), and after the racemic 2- (4-methoxyphenyl) -2-aminoacetonitrile and hydrolysis as the last step by resolution demethylation is carried out ₃₅ hydrogen bromide ether cleavage . The economic efficiency of the procedure was thus improved, but safety and health conditions continued to deteriorate. Thus, alkali metal cyanides should continue to be used in the formation of racemic 2- (4-methoxyphenyl) -2-amino- _4Q nitrile, liberating highly toxic, odorless methyl bromide during ether cleavage, and use of concentrated hydrogen bromide under extreme corrosion conditions. create.

A process similar to that described above is described in U.S. Patent Nos. 173,824, 1, and 181, 479, ⁴⁵

Hungarian Patent No. 1. Each of these steps in the above reaction pathway is used in a different order.

According to Hungarian Patent Application Publication No. T / 19 371, a mixture of the racemic p-hydroxyphenylglycine methyl ester ⁵⁰ and the orthomethyl ester is reacted with an optically active tartaric acid in anhydrous alcoholic medium and the resulting optically active acidic acid of an optically active p-hydroxyphenylglycine methyl ester. is hydrolyzed in a manner known per se, and then the optically active p-hydroxyphenylglycine is liberated from its inorganic acid salt.

Other than the aforementioned manner could be resolved from the racemic p-hydroxyphenyl glycine (No. 2,309,180.) ⁶⁰ according to DE-patent specification. This process started from esters of racemic p-hydroxyphenylglycine obtained from the corresponding hydantoin. Their method was based on the discovery that ⁶⁵ azomethine derivatives of certain optically active amino acid esters were racemized under appropriate conditions while being isolated as an acid addition salt of tartaric acid in one of the isomers, thereby significantly improving the yield of the resolution reaction.

In this way, various ring-substituted phenylglycine esters were converted to the corresponding ester hemitartrate salt in absolute medium with 1 molar equivalent of tartaric acid and in the presence of 1-8 mol of a carbonyl compound (benzaldehyde, anisaldehyde, acetone).

The yield is 41-85%, however, the reaction time is very long and the product has a higher optical purity than the previous processes.

The resulting salts were converted to the corresponding phenylglycine by acidic or basic hydrolysis.

The present invention is based on the discovery that the asymmetric transformation of p-hydroxyphenylglycine esters with L- (+) tartaric acid does not require the use of 1-8 moles of benzaldehyde, but that catalytic amounts are sufficient, if not in anhydrous media.

The asymmetric transformation of the reaction mixture according to the invention has a water concentration of 0.3 to 10%, preferably 0.5 to 2%.

The presence of water in the reaction mixture is also advantageous because it increases the polarity of the mixture and thus the solubility of the racemic hemitartrate, thus obtaining a clear solution at a lower temperature even at the beginning of the resolution reaction and starting crystallization of one of the optical isomers. bigger.

The asymmetric transformation is performed in the presence of L (+) tartaric acid as a resolving agent. Of this, an equivalent amount of p-hydroxyphenylglycine alkyl ester is used. Racemic p-hydroxyphenylglycine methyl ester can be used to produce asymmetric transformation, depending on the solvent, D-hydroxyphenylglycine methyl ester L-hemitartarate or L-p-hydroxyphenylglycine methyl ester L-hemitartarate.

such as acetonitrile or methanol-benzene

D-p-hydroxyphenylglycine methyl ester L-hemitartrate, while methanol or ethanol-benzene mixture, L-p-hydroxyphenylglycine methyl ester L-hemitartrate precipitates in solvated form.

The optically active p-hydroxyphenylglycine can be prepared from the corresponding alkyl ester hemitartrate by liberating the optically active ester in an aqueous or organic solvent medium with two equivalents of alkali and by alkaline or acid hydrolysis of the ester. The whole process can be accomplished in 10-12 hours.

According to the present invention, one to four carbon atoms of the racemic p-hydroxyphenylglycine alkyl ester are reacted with optically active tartaric acid in the presence of benzaldehyde and water in a solvent medium, the optically active p-hydroxyphenylglycine -hemitartartrate, in a manner known per se, liberates the optically active phydroxyphenylglycine and the alkaline material formed in the above resolution process and / or. 190 943 washes were reused in the above process 1 to 30 times.

The advantages of the present invention over the prior art are summarized below: ⁵

By our method, optically active p-hydroxyphenylglycine antipodes can be obtained in quantitative yield.

- The optical purity of the obtained D-p-hydroxyphenylglycine 10 under operating conditions was improved by% compared to the prior art solutions.

Since no anhydrous solvent is needed in our process, it is easy to regenerate the solvents once the mother liquor circulation is complete.

Further details of our process are shown in the following examples discounted entrance ^15:

Example 1

164 kg of L (+) tartaric acid (1,093 km),

200 kg of DL-p-hydroxyphenylglycine methyl ester (1.105 km), kg of benzaldehyde (0.33 km), kg of benzene (1.025 km), ²⁵ kg of water (2.222 km) and

2000 liters of methanol are heated to "C" and maintained at this temperature until all solids are dissolved. The solution was then cooled to 40 ° C and stirred for 16 hours at this ³⁰ temperature. After cooling to 20 ° C, the product is filtered off, washed with a total of 400 liters of methanol and finally dried to give 340 kg (77%) of Dp-hydroxyphenylglycine methyl ester, L-hemitartarate salt, which is solvated. ³⁵ kb 1 molecule with methanol and ca. 0.45 molecule with benzene [α] D = -56 '(c = 1.140 in water).

The mother liquor obtained above and the washes of the washer are combined and added:

164 kg L (+) - tartaric acid (1,093 km),

200 kg of DL-p-hydroxyphenylglycine methyl ester (1.105 kmol), kg of benzaldehyde (0.160 kmol) and 50 kg of benzene (0.641 kmol). ⁴⁵

This reaction mixture was heated to 60 ° C, maintained at this temperature until complete dissolution, then cooled to 40 ° C and stirred at this temperature for 16 hours. The reaction mixture was cooled to 20 ', the product is filtered, washed with ⁵⁴⁰⁰ liters of methanol and dried. 420-450 kg (95-103%) of the same quality product are obtained. The quality of the product remains unchanged during this process.

(a] "= - 56 '(c = 1,140 in water) · ⁵⁵

The whole process is repeated at least twenty times.

Example 2 60

49.8 g DL-p-hydroxyphenylglycine methyl ester (0.275 mol),

40.5 g of L (+) - tartaric acid (0.270 mol), g of benzaldehyde (0.085 mol), 65 g of water (0.0556 mol) and 450 ml of acetonitrile are heated to 'C' and maintained at this temperature until all solids dissolved. The reaction mixture is then cooled to 40 'C and stirred at this temperature for 12 hours and then further cooled to 20' C and maintained at this temperature for 6 hours with stirring. The precipitated product is filtered off, washed with 150 ml of acetonitrile and dried. This gives 92-93 g (92-93%) of the L-hemitartarate salt of D-p-hydroxyphenylglycine methyl ester, which is solvated with 1 molecule of acetonitrile.

Example 3

16.4 g of L (+) tartaric acid (0.109 mol), g of DL-p-hydroxyphenylglycine methyl ester (0.110 mol), water (0.222 mol),

3.5 g of benzaldehyde (0.033 mol) and

200 ml of methanol are heated to 'C'. Keep here until complete dissolution and then cool to 40 ° C. After stirring at this temperature for 4 hours, it is further cooled to 20 'and kept at 20' with stirring for 12 hours. The product was then filtered, washed with methanol (40 mL) and dried. 25 g of 70% L-p-hydroxyphenylglycine methyl ester L-hemitartarate salt are obtained.

Example 4

16.4 g of L (+) tartaric acid (0.109 mol), g of DL-p-hydroxyphenylglycine methyl ester (0.110 mol), water (0.222 mol), benzene (0.102 mol),

3.5 g of benzaldehyde (0.03 mol) and

200 ml of ethanol were heated to 'C' and maintained at this temperature until all solids dissolved. The solution was then cooled to 40 ° C and stirred at this temperature for 16 hours.

It is then cooled to 20 'C, the product is filtered off, washed with 50 ml of ethanol and finally dried. This gave 34 g (77%) of the L-hemitartarate salt of L-p-hydroxyphenylglycine methyl ester.

[α] D = + 82 '(c = 1.140 in water).

EXAMPLE 5 Sodium hydroxide (20 g) was dissolved in water (ml) and 45 g of the powdered D-hydroxyphenylglycine methyl ester L-hemitartarate salt was added below 10 ° C. After stirring for half an hour at 20 ° C, dilute with 30 ml of water. Heat to 30 'C and maintain at this temperature for half an hour. Stir with 0.5 g of carbon and 0.3 g of perlite for 30 hours at 30 ° C and filter. The pH of the filtered solution was adjusted to 6.5 with concentrated hydrochloric acid at 30-40 ° C. The resulting slurry was stirred for 1 hour at 40 'C, cooled to 0' C and then filtered. The resulting crystals were washed with water and methanol 3 and dried under an infrared lamp. (17 g (97%) of D-p-hydroxyphenylglycine was obtained).

[α] D = -157 ° (C = 1 in INHCl)

Example 6 D-p-hydroxyphenylglycine methyl ester L-hemitartrate salt is dissolved in 110 ml of water. The solution is cooled to 0 ° C and at this temperature the pH is adjusted to 8 with concentrated ammonium hydroxide solution. After stirring for half an hour at this temperature, the resulting suspension was filtered. The solids remaining on the filter were resuspended twice in cold water, sucked well, and dried.

20.1 g (99%) of D-para-hydroxyphenylglycine methyl ester are obtained.

[o] "= - 146.5 '(C = 1 in INHCl)

Claims (5)

Claims CLAIMS 1. A process for the resolution of one to four carbon atoms of a p-hydroxyphenylglycine alkyl ester with optically active tartaric acid in the presence of benzaldehyde in a solvent medium, characterized in that the resolution is 0.15-0 per mole of racemic p-hydroxyphenylglycine alkyl ester. 5 mole performed benzaldehyde and 0.3 to 3 mol of the presence of water, optionally obtained as solvated forms, optically active p-hydroxy-phenylglycine one to four carbon atoms alkilészterhemitartarátból known manner the opti ⁵ kailag active p-hydroxy-phenylglycine liberating and reusing the mother liquor and / or washing liquids from the above resolution process 1 to 30 times in the above process. 2. A method according to claim 1 embodiment ⁰ mode, characterized in that racemic p-hydroxyphenyl-glycine alkilészterként one to four carbon atoms is a methyl ester. Third embodiment of the method according to claim 1, characterized in that the solvent is ⁵ nitrile, methanol, ethanol, benzene, methanol or ethanol, benzene-acetonitrile as eluent. 4. A process according to claim 1, wherein the reaction is carried out at 10-65 ° C. 5th embodiment The method according to claim 1, characterized in that use is Dp-hydroxyphenyl glycine methyl ester, L-hemitartrate preparation of acetonitrile as a solvent or a mixture of benzene and methanol _(mixture. ⁵ the sixth embodiment of the method according to claim 1, characterized in that L-p-hydroxyphenyl glycine methyl ester, L-hemitartrate of methanol or ethanol-benzene mixture used as solvent in the preparation.