HU203525B - Process for producing phenyl-glycine-chloride alt - Google Patents

Abstract

Phenyl-glycine -chloride-hydrochloride is prepd. from phenyl-glycine-hydrochloride and an acid chloride of formula A-Cl (III), in the presence of di:methylformamide. In formula (III), A = R1CO or R2SO2 gp. where: R1 = CCl3-, CF3- or chloro-carbonyl gp.; R2 = 4-methyl-phenyl- or methyl- gp

Description

The phenylglycine chloride salt of formula (I) is a known intermediate for various β-lactam antibiotics. These can be prepared with 6 amino-penicillanic acid (Ampicillin) 7-aminocephalosporanic acid (Cephaglycin, Cefatrizin).

Phenylglycine Chlorides. (Bér 382914 (190%)) is a general method for the preparation of amino acid chlorides. The amino acid was prepared by crystallization and reacted with phosphorus pentachloride in acetyl chloride. Yields were low - for example, 53% for glycine. The method (Chem. Soc. 76, 1954, 1342) was further developed and the production was improved to 75-80% for glycine by using carbon tetrachloride instead of the unpleasant corrosive acetyl chloride solvent.

Since α-aminophenylacetic acid and phosphorus pentachloride are insoluble in the solvent used, they are also converted into heterogeneous α-aminophenylacetyl chlorides in a heterogeneous reaction; therefore, the transformation reaction is not perfect, the products are contaminated and the production is unsatisfactory from an industrial point of view.

Alternatively, phenylglycine was suspended in dichloromethane to form the hydrochloride salt of the amino acid with dry hydrochloric acid gas, thereby protecting the amino group [Org. Chem. 31 (3): 897-99 (1966)]. A finely divided starting material was provided and then phosphorus pentachloride was added. Thus, the heterogeneous reaction can be conducted under more favorable conditions and significantly better yields can be achieved. The disadvantage of this process is that it requires the introduction of dry hydrochloric acid gas, which is a costly and cumbersome operation. A further disadvantage is that, since the formation of the amino acid hydrochloride salt is also a heterogeneous reaction, the reproducibility of the process and the quality of the product vary greatly.

The kinetics of this procedure is discussed in G. Philipp, Chemische Technik 31 (2) 6869 (1979). In a new process for the preparation of amino acid chlorides, amino acids were converted to N-carboxylic anhydrides with phosgene in dioxane and treated with carefully dried hydrochloric acid gas when the amino acid chloride hydrochlorides crystallized out.

[(Helv. Chim. 38, 1525-28 (1956))] The process yielded pure products, but at serious disadvantages. Due to the highly toxic nature of phosgene gas, its industrial use is subject to stringent conditions. production is relatively low, about 60% by weight. Excess phosgene has to be recovered from the reaction mixture, since N-carboxylic anhydride in the presence of phosgene has to be worked at 60-80 ° C under relatively strong conditions, which product deterioration (U.S. Patent Nos. 2364192 and 2500386, U.S. Patent Nos. 3923418).

Another possibility is to react the free phenylglycine with phosphorus pentachloride followed by hydrochloric acid gas (J. Org. Chem. European Patent 31,898,39086 and British Patent No. 1241844). However, the product thus produced has such poor physical properties that it is unsuitable for large-scale production (according to German Patent Publication No. 2537 235).

To overcome these problems, it has been recommended to react phenylglycine with a mixture of activated phosphorus oxychloride and phosphorus pentachloride using water, aqueous hydrochloric acid or organic acid as the activator. However, this process could not be used on a larger scale to produce a good quality product (Hungarian Patent Specification No. 183548).

No. 84,611. According to the method described in European Patent Application, p-hydroxyphenylglycyl chloride is prepared by reacting the corresponding amino acid with p-toluenesulfonic acid and thionyl chloride in dichloromethane. resolve. Therefore, the acid chloride thus produced is always inclusions. In the heterogeneous phase, two types of ammonium salts can be formed in the presence of two types of acid, thus the product is not uniform

The present invention relates to a process for the preparation of the phenylglycine chloride salt of the formula (I) by reacting the phenylglycine salt of the formula (Π) by reacting the phenylglycine salt of the formula (Π) with acid chloride (D1) in the presence of dimethylformamide. and then isolating the product in crystalline form from the reaction mixture, optionally in the form of a solvate.

In this specification, the variable substituent in the general formulas will always have the following meaning:

- R is CC1 ₃ -, CF ₃ -vagyklór carbonyl group.

The present invention is based on the discovery that by using chlorides of sufficiently strong acids, such as those represented by formula (ΠΙ), a homogeneous exchange reaction can be carried out in the presence of dimethylformamide using a reaction temperature of 20-30 ° C.

The homogeneous reaction mixture eliminates all the drawbacks that were mainly due to the heterogeneous reaction in earlier processes. The reaction is carried out in a good yield in a homogeneous liquid phase and sufficient equivalents or less of acid chloride are sufficient to effect the reaction.

Prior to the crystallization of the product, various solvents are preferably added to the reaction mixture, depending on which a hemi-solvated or unsolvated product is obtained. For example, in dioxane, in acetonitrile, the former in the presence of butyl acetate gives the latter

A more complete separation of the product can be facilitated by diluting the reaction medium with one of the following solvents: dichloromethane, dichloroethane, chloroform, benzene, n-hexane, ethyl acetate ether.

One embodiment of the present invention is to form the hydrochloric acid salt of the amino acid by introducing hydrochloric acid gas in one of the crystallization solvents (dioxane, acetonitrile, butyl acetate) and adding the acid chloride dissolved in dimethylformamide to the resulting suspension. After the reactants are pooled, the reaction proceeds at 20-30 ° C for 1030 minutes and the product crystallizes. This can be facilitated by cooling and addition of non-solvent solvents to the product.

HU 203 525 Β

One of the very advantageous possibilities of carrying out the present invention is to prepare the acid-Uorid in situ in the reaction mixture. A catalytic amount of less than one equivalent of acid chloride is then sufficient. Namely, if a small amount of the acid corresponding to the acid chloride is about 10% of dimethylformamide and phenylglycine. When used in an equimolar mixture of thionyl, sulfuryl, phosphorus di, or phosphorus tri-Moride, the acid chloride used in the decomposition reaction is continuously re-formed.

Accordingly, it is preferable to proceed as follows:

To the cooled thionyl chloride or sulfuryl chloride is added the catalyst acid dissolved in dimethylformamide so that the temperature does not rise above 5 ° C. The reaction mixture may be treated, for example, with a freshly prepared hydrochloric acid salt of phenylglycine. The reaction mixture was added to a solution of dioxane and reacted at 20-30 ° C. The product was cooled and diluted with reaction medium.

The process of the present invention provides the industrial production of the target compound without requiring extreme conditions and the product is free of impurities. This was checked by optical rotation, infrared spectrum, HPLC and GC.

Examples

Example 1

151 gD (-) - 2-aminophenylglycine is suspended in 450 ml of dioxane and the hydrochloric acid salt of the amino acid is formed at room temperature with dry hydrochloric acid gas (about 40 g). In another reaction vessel, 164 g of oxalyl chloride was cooled to 0 'C and 95 g of dimethylformamide was added dropwise at 0-5' C. The temperature was allowed to rise to 20 ° C and further stirred for 3 hours at this temperature. The dioxane amino acid hydrochloride salt suspension is cooled to 10 ° C and a solution of oxalyl chloride in dimethylformamide is added. The reaction mixture was stirred at 20-30 ° C for 30 minutes. It is then cooled to 20 'C and seeded with a few crystals of the D (-) - 2-aminophenylglycine chloride HCl salt. After crystallization started, the slurry was cooled to 0 'C and diluted dropwise with 300 ml of dichloromethane. After drying for 4 hours at 0 'C, 185 g of D (-) - 2-aminophenylglycine chloride HCl-dioxane hemisolvate salt are obtained. The quality of the prepared materials was confirmed by optical rotation, elemental analysis (sumschlorine and ionic chlorine). COC1 content: 98.9%; free acid: 0, free HCl: 0 Rotation: -93 * (c-0.2; water), Yield: 74%.

Example 2

151 g of D (-) - 2-aminophenylglycine are suspended in 450 ml of dry dioxane, which is suspended in ca. Saturate with 40 g of dry hydrochloric acid gas. The resulting amino acid hydrochloride salt was cooled to 10 ° C. In another reaction vessel, 156 g of thionyl chloride (or 185 g of sulfuryl chloride or 200 g of phosphorus oxychloride or 179 g of phosphorus trichloride) are cooled to 0 ° C and 5 g of anhydrous are added dropwise at 0-5 ° C. A solution of oxalic acid in 95 ml of dimethylformamide was stirred for 3 hours at 20 [deg.] C. The Apott solution was then added to a suspension of 10 [deg.] C. in dioxane and stirred for 15 minutes at 20 [deg.] C. The reaction mixture was seeded with a few crystals of acid chloride-HCl, cooled to 0 ° C and diluted with 300 ml of dichloromethane.

After stirring at 0 ° C for 1 hour, the crystalline material is filtered off, washed once with dioxane, twice with dichloromethane and dried at 30 ° C under vacuum.

184 g of D (-) - 2-aminophenylglycine chlorideHQ-dioxane hemisolvate salt are obtained.

Analysis: COCl content: 99.1%, free acid: 0, free HCl: 0, rotation: -92.5 '(c-0.2; water), lake yield 73.6%.

Example 3

Same as Example 2 except that 450 ml of butyl acetate was used instead of dioxane. The product was 178 g of D (-) - 2-aminophenylglycine chloride.HCl (unsolvated).

Analysis: COC1 content: 98.7%; free acid: 0; free HCl; 0th

Yield: 86.4%, Rotation: -110 '

Example 4

151 g of D (-) - 2-phenylglycine are suspended in 500 ml of dioxane and the hydrochloric acid salt of the amino acid is removed by the addition of dry hydrochloric acid gas (ca. 40 g). In another vessel, 182 g of trichloroacetic acid are added to 731 g of dimethylformamide at 0-5 ° C. The temperature is then allowed to rise to 20 ° C. The Apott. The solution is then added dropwise at 20-30 ° C to a suspension of the hydrochloride salt of phenylglycine at 20-30 ° C. After stirring for 30 minutes, the Apott solution was cooled to 20 ° C, seeded with a small amount of D (-) - 2-phenylglycochloride hydrochloride, and then cooled to 0 ° C. After stirring for 4 hours, the Apott slurry was filtered, washed well with dichloromethane and dried in vacuo. 178 g of the acid chloride are obtained in a yield of 71.2%. Active ingredient content: 98.9% free acid: HCl: -, OptiAi Rotation-91 '(c-0.2, water).

Claims (6)

A process for the preparation of the phenylglycine chloride salt of the formula (I) by chlorination of the phenylglycine salt of the formula (H), wherein the phenylglycine salt of the formula (Π) with the acid chloride of the formula (-) The reaction is carried out in the presence of CCl ₃ , CF ₃ , or chlorocarbonyl dimethylformamide, and the product, optionally in the form of a solvate, is isolated crystalline from the reaction mixture. Process according to Claim 1, characterized in that from the corresponding carboxylic acid with thionyl chloride, sulfuryl chloride, phosphorus trichloride or phosphorus oxychloride in the presence of dimethylformamide, EN 203 525 Β in situ in the reaction mixture - the acid chloride of the formula (ΙΠ) - R is as above -1 used as starting material. 3. A process according to claim 1 wherein the acid chloride is of formula (IH) - The R-report is used in equimolar amounts with respect to the phenylglycine salt. The process according to claim 2, wherein the starting material is an acid chloride of the formula (ΙΠ) R is a catalytic amount of less than the equivalent used above, which is continuously produced in situ from the catalytic amount of carbonic or sulfonic acid with phenylglycine hydrochloride for about one to two minutes. equimolar amounts of thionyl, phosphoryl, phosphorus oxy, 5 or phosphorus trichloride. 5. Process according to any one of claims 1 to 3, characterized in that at the end of the reaction, the product is isolated in the form of a solvate by adding acetonitrile, dioxane and / or dichloromethane. 6. Process according to any one of claims 1 to 3, characterized in that butyl acetate is added at the end of the reaction to crystallize the product in a solvate-free form.