DD264689A1 - PROCESS FOR PREPARING D (-) - PHENYLGLYCYLCHLORIDE HYDROCHLORIDE - Google Patents

Abstract

A process for producing D () -phenylglycyl chloride hydrochloride is described. After protection of the amino group of phenylglycine by hydrochloride formation is chlorinated with phosphorus trichloride / chlorine. A pure product is obtained in high yield, which can be used as an intermediate for semi-synthetic penicillins.

Description

Characteristic of the known state of the art

For the preparation of amino acid chloride hydrochlorides, in particular of (I), several processes have been proposed, which are both expensive and lead to unsatisfactory results.

Thus, using the highly toxic phosgene, one should arrive at the Df-M-hydroxyphenylglycyl chloride hydrochloride via a cyclic anhydride from the free amino acid (DE 2364192; DE 2527235). Another method for the preparation of Phonylglycylchlorid hydrochlorides leads via a compound of the general formula

^. COOH Ar - CII

\ NH - COOR

(R = lower alkyl or benzyl) which is reacted with a sulfur or phosphorus-containing acid chloride. The resulting intermediate is then treated with hydrogen chloride (EP 84611, DD 151446).

The disadvantage here is the complex reaction path with isolation of intermediates and required solvent changes.

Another method for the acid chlorination of amino acids based on the use voa chloromethyldimethylammonium chloride as a chlorinating agent (DE 2919450), wherein the chlorinating agent must be prepared in an upstream process stage of dimethylformamide and a standard chlorinating agent. It is an extremely hygroscopic hard-to-handle solid.

Also, the chlorination with phosphorus pentachloride has been proposed. In these processes, the amino group must be protected from the chlorinating agent. This happens mostly by hydrochloride formation. The proposed in GB 1241844 process for the preparation of DI-M-hydroxyphenylglycyl chloride hydrochloride by reaction with phosphorus pentachloride and hydrogen chloride, with a yield of only 50% d. Th. The difficulties encountered.

In DE 25 27 235 it is also found that the quality of the product prepared by this process for the technical production of penicillins and cephalosporin is insufficient.

The reaction of D (-) - phenylglycine with phosphorus pentachloride in indifferent solvents is described in BG 26730.

Da.'iouh required for the salt formation of phenylglycine hydrogen chloride is produced in a chlorination upstream of phosphorus pentachloride with aqueous solvents and only then added the amino acid.

The disadvantage of this method is that an approximately 50% excess of the already difficult to handle phosphorus pentachloride must be used. This leads to higher material costs, an additional environmental impact and quality impairments of the product due to reactions of the hydrolysis of the Phorphorpentachlorids with

Another general disadvantage of the known method is that the chlorination with cooling, usually between ^{0 0} C and 5 ° C, must be performed.

The chlorination of aromatic carboxylic acids by introducing chlorine into a mixture of carboxylic acid and phosphorus trichloride, as mentioned in DE 2831777 as prior art, has hitherto found no use for the chlorination of amino acids.

Object of the invention

The aim of the invention is to find a simple and economical process, which leads in high yield to a product of high quality.

Explanation of the essence of the invention

The invention is the task? to provide a process for the preparation of Dl-J-phenylglycyl chloride hydrochloride (Rl-AminophHnyless.gsäurechlorid hydrochloride) from D (-) - phenylglycine available without additional isolation of chlorinating agents or intermediates and avoiding the use Of phosphorus pentachloride bsi simple and economical technology in high yield leads to a product of high quality.

This object is achieved according to the invention in that first D (-) - phenylglycine in an inert solvent, preferably a chlorinated hydrocarbon such. Dichloromethane is suspended. By introducing hydrogen chloride, the hydrochloride of the phenylglycine is produced. It was found that came to a complete protection dor amino group of the phenylglycine be omitted by salt formation. A molar ratio of phenylglycine to hydrogen chloride, such as 1: 0.75 to 1: 1, leads to (I) in the required quality in the further reaction without yielding indium.

Dor obtained D (-) - phenylglycine hydrochloric * · suspension is added to phosphorus trichloride in a molar ratio of 1: 1.1 to 1: 1.3, based on phenylglycine. Thereafter, chlorine (1.1 moles to 1.3 moles of chlorine per mole of phenylglycine) is introduced to form the actual chlorinating agent phosphorus pentachloride. In this procedure it is achieved that the side reactions causing phosphorus pentachloride is always present only in low concentration. The complete conversion of the Phosphortiichlorids with chlorine can be accurately determined by measuring the redox potential, whereby overdose of chlorine can be avoided.

This Vorfahrwoiso also makes it possible to carry out the reaction at temperatures up to 20 ⁰ C, since the phosphorus and excess phosphorus and limited D (-) - phenylglycine hydrochloride is resistant to phosphorus trichloride. The retained (I) is then separated from the suspending agent by mechanical solid-liquid separation, washed with fresh solvent and dried under reduced pressure.

The product is obtained in a yield of 92% to 95% of theory won. It is white to pale pink and clear. I'm in water.

The keyword is [a \ l ° = -112 ° to -116 ° C (c = 6 in 1N HCl).

embodiment

56.5 g of D (-) - phenylglycine are suspended in 750 ml of dry dichloromethane in a sulphonation flask provided with a stirrer, thermometer and gas inlet and outlet tube.

Per mole of D (-) - phenylglycine 0.75 mol to 1.0 mol of hydrogen chloride are introduced in 30 min to 40 min in the temperature range between 0 ⁰ C and 5 ° C. 39 ml of phosphorus trichloride (1.2 moles per mole of D (-) - phonylglycine) are added to the D (-) - phonylgiycin hydrochloride suspension and elemental chlorine is introduced in 30 minutes to 60 minutes until the phosphorus trichloride has reacted completely. The end point of Phosphortrichloridumsotzung can be accurately determined by measuring the redox potential by the dead-stop method.

The reaction temperature should not exceed 20 ⁰ C. The chlorination dos D (-) - Phenylglycinhydrochlorides is completed after 3h to 4h, to recognize the cessation of hydrogen chloride evolution. Under exclusion of atmospheric moisture, the solid is separated, washed free with dichloromethane of phosphorus oxychloride and dried in vacuo at 40X.

Yield: 73 g (93% of theory)

Appearance: white to pale pink

Rotation: [a] g ° -112 ° C to -11 ° C, c = -6in1NHCI

Solubility: clearly soluble in water; c = 6 in 1N HCI

Claims (1)

Process for the preparation of Dl-J-phenylgycyl chloride hydrochloride, characterized in that hydrochloric acid is added in an molar ratio of 1: 0.75 to 1: 1 in an inductive solvent, preferably dichloro-ethane, suspended D (-) - phenylglycine, 1.1 moles to 1.3 moles of phosphorus trichloride per mole of phenylglycine are added and 1.1 moles to 1.3 moles of chlorine per mole of phenylglycine at a temperature between 0 ⁰ C and 2O ⁰ C are introduced. Field of application of the invention D (-) - phenylglycyl chloride hydrochloride (I) is an intermediate for the production of antibiotics. It is used as an acylating agent for 6- and 7-amino groups of 6-aminopenicillanic acid or 7-aminocephalosporanic acid or their salts or derivatives for the preparation of semisynthetic penicillins and cephalosporins.