HU182519B - Process for preparing alkakli metal salts of enamines in high optical purity - Google Patents

Abstract

The present invention relates to a process for the preparation of an alkali metal salt of the amines of formula IV wherein R1 is C1-6 alkyl having a high optical purity by reaction of p-hydroxyphenylglycine with an acetic acid alkyl ester such that p-hydroxylic acid is present. to a mixture of phenylglycine and a compound of formula (III) wherein R1 is as defined above, alkali metal hydroxide is added and the reaction mixture is refluxed, and if desired, the alkaline metal of formula IV has a high optical purity. its salt is isolated. Compounds of formula (IV) are useful intermediates for pharmaceutical use, from which known antibiotic penam-3-carboxylic acid and cephem-4-carboxylic acid derivatives are known to have greater optical purity than known methods. □ L-C-CH, -COOR, ii 1 0 hits. CH-COOH 1 NH HiC-C = CH-COOR, iv. 182519 -1-

Description

The present invention relates to a novel and improved process for the preparation of high optical purity alkali metal salts of enamines.

It is known that acylated derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid are widely used in medicine as a broad-spectrum antibiotic. A preferred representative of these compounds is D [(-) -? -Amino- (p-hydroxyphenyl) acetamido)] penicillanic acid (hereinafter referred to as "Amoxicillin").

Britich Pharmacopiea 1973

3-4. page describes the requirements for Amoxicillin; an important criterion is the optical rotation of the product, which is stated in the pharmacopoeia (a) P ₀ = (+ 290 °) - (+ 310 ^° ) (C = 0.2% w / v, water). Amoxicillin is prepared by reaction of 6-aminopenicillanic acid or a salt thereof with a functional derivative of p-hydroxyphenylglycine according to British Patent No. 978,178. No. 1,339,605. According to the British patent, 6-aminopenicillanic acid is used in the form of its silylated derivative and after the reaction the silyl group is removed. No. 3,674,776. U.S. Pat.

Among the functional derivatives formed on the amino group in the above patents, it is preferable to mention the mixed anhydrides (3-ketoesters) formed by condensation with alkyl acetic acetic acid. These compounds are prepared by reacting p-hydroxyphenylglycine with an alkali metal hydroxide. the resulting alkali metal salt is isolated, reacted with an alkyl acetate of acetic acid and then converted to the mixed anhydride, preferably with chloroformic acid. the optical rotation of the Amoxicillin produced in the examples is only (α) ο ° = = + 246.5 ° (c = 0.1% in water). In Example 1 of British Patent No. 1,339,605, the purity of Amoxicillin is 80%. are given.

The present invention relates to a process for the preparation of high-purity alkali metal salts of enamines of formula IV (wherein R 1 is C 1 -C 6 alkyl) by reacting p-hydroxyphenylglycine with an alkyl acetic acetic acid by reacting ρ-hydroxy of phenylglycine and a compound of formula III (wherein R 1 is as defined above), alkali metal hydroxide is added and the reaction mixture is refluxed and the high optical purity alkali metal salt of the enamine (IV) is isolated.

The alkali metal salts of the enamines of formula IV may be sodium or potassium salts.

The present invention is based on the discovery that when the alkali metal salt of p-hydroxyphenylglycine is reacted in situ with the alkyl acetate of acetic acid, the racemization of p-hydroxyphenylglycine is greatly suppressed and an amine of high optical purity is obtained. It has also been found that the optical purity of the amine prepared in this manner in the known manner is amoxicillin or other acylated 6-aminopenicillanic acid or 7-aminocephalosporanic acid derivatives which is superior to the optical purity of semi-synthetic antibiotics made by known methods. In the alkaline medium formed for the preparation of the alkali metal salt, D (-) - p-hydroxyphenylglycine is racemized more rapidly than the finished enamine.

According to our process, p-hydroxyphenylglycine is used in a molar equivalent of the alkyl acetic acid and the alkali metal hydroxide. Preferably, the alkyl acetic acid is methyl acetate or ethyl acetate, while the alkali metal hydroxide is preferably sodium hydroxide or potassium hydroxide. The reaction may be carried out in a water miscible organic solvent medium. Aliphatic alcohols (e.g. methanol, ethanol or acetone) can be used for this purpose.

In the process, an alkali metal hydroxide is added to an alcoholic solution of p-hydroxyphenylglycine and an alkyl acetic acid acetic acid. The alkali may be added in solid form or as an alcoholic solution.

The reaction may be carried out under heating, preferably under reflux. The reaction is complete within a few hours.

The reaction product can be isolated in various ways. Alternatively, the alcoholic reaction medium may be replaced by an organic solvent, such as toluene, which does not dissolve the enamine salt, then the toluene solution is cooled and the excellent enamine salt is isolated. Alternatively, the enamine is precipitated by cooling the alcoholic reaction mixture, the latter isolation process being particularly useful in the preparation of potassium salts of the compounds of formula (IV).

The enamine obtained by the process of the present invention is of high optical purity. Namely, in the process, the alkali metal salt of p-hydroxyphenylglycine formed is reacted in situ with the alkyl acetate of acetic acid, so that the alkalization of p-hydroxyphenylglycine by an alkaline medium is impossible or much less possible. This advantage is particularly significant in factory production; under industrial conditions, scaling and incomplete mixing may result in strong local alkali accumulation, which can greatly accelerate racemization.

The following experiments demonstrate that the optical purity of the materials in the alkaline medium is impaired when known methods are used to convert and isolate D-2- (4-hydroxyphenyl) glycine into an alkali metal salt by reaction with an alkali metal hydroxide.

Carry out the experiment as follows:

A mixture of D-2- (4-hydroxyphenyl) glycine (0.01 mol) in ethanol (30 ml) was heated to reflux with 0.01 molar sodium hydroxide and 0.01 molar potassium hydroxide. The rotation of the starting material and the aliquot sample was measured after 4 and 16 hours. The results are summarized in the following table:

Starting materials . Boiling time (hours) Forgatóké- tiveness D-2- (4-hydroxyphenyl) glycine 16 -165 ° D-2- (4-hydroxyphenyl) glycine + NaOH 4 -158 ° D-2- (4-hydroxyphenyl) glycine + NaOH 16 -137 ° D-2- (4-hydroxyphenyl) glycine + KOH 4 -155 ° D-2- (4-hydroxyphenyl) glycine ♦ KOH 16 -131 °

The enamines of formula (IV) thus obtained can, if desired, be converted into compounds of formula (I)

A is a \ _C / CH ₃ -ch | ^XCHj ^ _C-CH2 R

CH-COOH -C ^ ^z I

COOH;

R is hydrogen, acetoxy or a -S-He group and He is a heterocycle).

The optical purity of the 6-aminopenicillanic acid or 7-aminocephalosporanic acid derivative of formula (I) obtained thus far exceeds that of the final product obtained from the enamine prepared in a known manner.

The process may be carried out in a known manner. The enamine (IV) is converted to a mixed anhydride. Chloroformic acid esters, such as ethyl chloroformate, are preferably used for mixed anhydride formation. The reaction may be carried out in an organic solvent, preferably acetone or ether, preferably under cooling, usually at about 10 ° C. The compound of formula (V) (wherein A is as defined above) or a salt or reactive derivative thereof is dissolved in water and converted to a salt by addition of alkali metal hydroxides. The cold-cooled solutions are combined and the compound (I) formed after acid treatment of the reaction mixture is isolated in a manner known per se.

In the compounds of formula (I) and (V), where A and R are as defined above, within the meaning of R, the heterocycle is an optionally substituted heterocycle containing one or more heteroatoms, for example pyridyl, pyrimidyl , quinolyl, isoquinolyl, furyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, or substituted derivatives thereof, for example, may be halogen, alkyl, or alkoxy, such as 1-methyltetrazolyl.

Further details of the process are set forth in the Examples, without limiting the invention to the Examples.

EXAMPLES

1. Preparation of the sodium salt of N- (1-methyl-2-methoxycarbonyl-vinyl) -D-2- (425-hydroxyphenyl) glycine

A mixture of 133.7 g (0.8 mol) of D-2- (4-hydroxyphenyl) glycine, 1200 ml of methanol and 92.9 g (0.8 mol) of acetic acid 30-methyl ester is heated to reflux and then stirred under stirring. g (0.8 mol) of sodium hydroxide and refluxed for a further two hours. A light yellow, clear solution is obtained, after which 400 ml of solvent are evaporated off, the remaining distillate is replaced with an equal volume of toluene while controlling the vapor temperature. When it rises above 90 ° C, distillation is complete, the mixture is cooled to 15 ° and after stirring for one hour, the precipitate is filtered off, washed with toluene and dried.

Weight of the title product: 227.4 g.

Yield: 99.0%. Active ingredient content: 100.1%.

Optical rotation: (a) ™ = -90 ° (c = 2n, hydrochloric acid) Elemental analysis

date: C = 54.4%, N = 4.88% H = 4.88% found: C = 54.34%, H = 4.96% 50 N, 4.89%.

2. Preparation of the sodium salt of N- (1-methyl-2-ethoxycarbonylvinyl) -D-2- (4-hydroxyphenyl) glycine

133.7 g (0.8 mol) of D-2- (4-hydroxyphenyl) glycine,

A mixture of 1200 ml of ethanol and 104.2 g (0.8 mol) of ethyl acetate was heated to reflux, and 32 g (0.8 mol) of sodium hydroxide was added with stirring and refluxed for a further two hours.

In the following, the procedure of Example 1 is followed.

Weight of the title product: 232.0 g.

Yield: 96.6%.

-3182519

Active ingredient content: 100.0%.

Optical rotation: (a) = -84 ° (c = 2, n hydrochloric acid)

Calc'd: C, 55.80; H, 5.35.

N, 4.68. Found: C, 55.41; H, 5.19;

N, 4.68%.

3. Preparation of the potassium salt of N- (1-methyl-2-methoxycarbonyl-vinyl) -D-2- (4-hydroxyphenyl) glycine

16.71 g (0.1 mol) of D- (2- (4-hydroxyphenyl) glycine),

A mixture of methanol (300 mL) and methyl acetate (1.6 g, 0.1 mol) was heated to reflux, then potassium hydroxide (5.61 g, 0.1 mol) was added with stirring and refluxed for a further two hours. During boiling, a solution is formed temporarily and then precipitates again. The mixture was then cooled to 0 ° C and after stirring for one hour, the precipitate was collected, washed with chilled methanol and dried.

Weight of the title product: 29.2 g.

Yield: 96.3%.

Active ingredient content: 97.8%.

Optical rotation: (a) p ° = -85 ° (c = 2, n hydrochloric acid)

Calculated: C, 51.51; H, 4.66;

N, 4.63. Found: C, 50.90; H, 4.45;

N, 4.58%.

4. Preparation of the potassium salt of N- (1-methyl-2-ethoxycarbonyl-vinyl) -D-2- (4-hydroxyphenyl) glycine

16.71 g (0.1 mol) of D-2- (4-hydroxyphenyl) glycine,

A mixture of ethanol (300 mL) and ethyl acetate (13.02 g) was heated to reflux, then potassium hydroxide (5.61 g, 0.1 mol) was added with stirring and refluxed for a further two hours. During boiling, a solution is formed temporarily and then precipitates again. The mixture was then cooled to 0 ° C and after stirring for one hour, the precipitate was filtered off, washed with chilled anhydrous ethanol and dried.

Weight of the title product: 29.55 g.

Yield: 95.0%.

Active ingredient content: 99.4%.

Optical rotation: (α) θ ° = -82 ° (c = 2, n hydrochloric acid)

Calculated: C, 53.70; H, 5.12;

N, 4.47. Found: C, 52.50; H, 4.99;

N, 4.51%.

5. Preparation of amoxicillin trihydrate

28.7 g (0.1 mol) of the sodium salt of N- (1-methyl-2-methoxycarbonyl-vinyl) -D-2- (4-hydroxyphenyl) glycine are suspended in 300 ml of absolute acetone at -10 ° C. cool. 10 ml (0.1 mol) of ethyl chloroformate were added and the mixture was stirred at -10 ° C for one hour. In another flask, 21.5 g (0.1 mol)

6-Aminopenicillanic acid is suspended in 100 ml of water and 40% sodium hydroxide solution is added until dissolved. Keep the pH below 8.5 during the addition. To the resulting solution was added 50 ml of acetone, then cooled to -10 ° C and the two solutions were combined. The reaction mixture was reacted at -10 ° C for 3 hours. The pH was adjusted to 1 with concentrated hydrochloric acid and stirred for another hour. The resulting mixture was extracted with chloroform to remove the acetone. The aqueous phase was clarified with activated carbon and adjusted to pH 5-5.2 with 40% sodium hydroxide solution.

The mixture is stirred for 6 hours, filtered, washed with water and dried.

The product obtained was 28.6 g of Amoxicillin trihydrate.

[α] D = + 305 ° (c = 0.1% in water)

Active ingredient content calculated as iodometrically dry matter: 98.9%.

Water content (according to Kari Fischer: 12.5%). The product was homogeneous by layer chromatography.

R f = 0.424. Running mixture:

Polygram Syl G / UV 254.

Developer: ninhydrin.

6. Preparation of the potassium salt of N- (1-methyl-2-ethoxycarbonyl-vinyl) -D-2- (4-hydroxyphenyl) glycine

A mixture of 1.671 kg (10 moles) of D-2- (4-hydroxyphenyl) glycine, 30 liters of ethanol and 1.3 kg (10 moles) of ethyl acetate was heated to 55 ° C, stirred for half an hour and kg of potassium hydroxide (10 mol) was added and refluxed for a further 4 hours. The reaction mixture was cooled to 0-5 ° C, stirred for 2 hours, and the resulting precipitate was collected, washed with ethanol and dried at 50-60 ° C. 3.00 kg of the title compound are obtained.

Active substance content: 99.6%.

Optical rotation: [α] θ ° = -84 ° (c = 2, n hydrochloric acid) Water content: 0.3% (Kari Fischer)

IR spectrum: (KBr) appropriate.

Claims (3)

Patent claims: A process for the preparation of high-purity alkali metal salts of enamines of formula IV (wherein R 1 is C 1 -C 6 alkyl) by reaction of p-hydroxyphenylglycine with an alkyl acetate of acetic acid, characterized in that p-hydroxyphenylglycine and adding an alkali metal hydroxide to a mixture of a compound of Formula III (wherein R 1 is as defined above) and refluxing, and isolating the high optical purity alkali metal salt of the enamine of Formula IV. 9th January 1825 2. A process according to claim 1 wherein the compound of formula III is methyl acetic acid or ethyl acetic acid. 3. A process according to claim 1 or 2, wherein the reaction is carried out in an aliphatic alkanol, preferably methanol or ethanol. 1 drawing with 5 formulas Responsible for publishing: Director of Economic and Legal Publishing 85.4009 - Zrínyi Printing House, Budapest