CS258292B1 - Process for the preparation of the hydrochlorides of (Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) acetyl chlorides - Google Patents

Abstract

The solution relates to a method for preparing hydrochlorides of (Z)-2-alkoxyimino-2-(2-amino-4-thiazolyl)acetyl chloride of general formula I, used as intermediates in the preparation of effective beta-lactam antibiotics of the oxime type, by reacting (Z)-2-alkoxyimino-2-(2-amino-4-thiazolyl)acetic acids with a chlorinating agent in an inert solvent, optionally in the presence of a catalyst, for example dimethylformamide or dimethylacetamide and/or hydrogen chloride.

Description

The present invention relates to a process for the preparation of (Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) acetyl chlorides of the general formula I

NORWEGIAN

wherein R is C 2 -C 6 alkyl or C 4 -C 6 cycloalkyl. These substances are important intermediates in the preparation of beta-lactam antibiotics of the so-called oxime type (No. AO No. 242 018, No. AO No. 250 561). The advantage of using these intermediates is to shorten the process for the preparation of oxime-type beta-lactam antibiotics by two reaction steps, since there is no need to protect the amino group with, for example, trityl, chloroacetyl, trifluoroacetyl or formyl. (4,152,432).

The preparation of a compound of formula (I) wherein R is methyl is described in the literature by reacting a chlorinating agent with the anhydrous form of 2- (2-amino-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid in an inert solvent (U.S.A. No. 238). 950). However, depending on the reaction conditions, the reaction product is more or less contaminated with an admixture of the undesired (E) -isomer.

Surprisingly, it has now been found that in the preparation of compounds of formula I wherein R is C 2 -C 6 alkyl or C 4 -C 6 cycloalkyl according to the invention, the product is only in the form of the desired (Z) -isomer; This is essential because, as is well known, the (Z) -configuration of the alkoxyimino group is a prerequisite for the efficacy and hence the applicability of the oxime-type beta-lactam antibiotics.

The process for preparing the compounds of the formula I according to the invention consists in reacting the corresponding low-water (Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) acetic acids with a chlorinating agent, for example phosphorus pentachloride, in an inert chlorinated solvent an alkane having 1 to 2 carbon atoms, for example methylene chloride, an aromatic hydrocarbon or acetonitrile, optionally in the presence of a catalytic amount of dimethylformamide or dimethylacetamide and / or hydrogen chloride, at a temperature of -45 to 60 ° C, preferably at a temperature of -25 to 20 ° C.

Further details of the preparation process according to the invention will be apparent from the following examples which illustrate the process without limiting it.

Example 1

2- (2-Amino-4-thiazolyl) - (Z) -2-ethoxyiminoacetyl chloride hydrochloride

To a suspension of 4 g (0.02 mol) of 2- (2-amino-4-thiazolyl) - (Z) -2-ethoxyiminoacetic acid with a water content of 0.7% in 20 ml of anhydrous acetonitrile with a drop of dimethylformamide cooled to -25 ° 5 g (0.025 mol) of phosphorus pentachloride are added with stirring. The reaction mixture is stirred for 30 minutes without cooling, the precipitated product is filtered off with suction, washed with anhydrous benzene and petroleum ether.

After drying at 30 ° C under reduced pressure, 3.3 (64.8%) of the title compound are obtained as a yellowish product which decomposes when heated above 260 ° C. Chlorine content (argentometric) 99.9% of the calculated amount. The structure of the product was shown by NMR spectrum.

Example 2

2- (2-Amino-4-thiazolyl) - (Z) -2-isopropoxyiminoacetyl chloride hydrochloride

In a yield of 52.4%, the title compound is obtained as a colorless product as described in Example 1, which decomposes when heated above 260 ° C. Chlorine content 99.4% of the calculated amount.

Example 3

2- (2-Amino-4-thiazolyl) - (Z) -2-cyclopentyloxyiminoacetyl chloride hydrochloride

Following the procedure described in Example 1, the title compound is obtained in a yield of 84.5% as a colorless product which decomposes when heated above 260 ° C. Chlorine content (argentometric) 97.7% of the calculated amount.

Example 4

2- (2-Amino-4-thiazolyl) - (Z) -2-cyclohexyloxyiminoacetyl chloride hydrochloride

Following the procedure described in Example 1, the title compound was obtained in a yield of 66% as a colorless product which decomposes when heated above 260 ° C. Chlorine content 96% (argentometric) of the calculated amount.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of (Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) acetyl chlorides of the general formula X NORWEGIAN HCI.HjN COCI wherein R is C 2 -C 6 alkyl or C 4 -C 6 cycloalkyl, characterized in that the corresponding (Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) acetic acid is a low with a water content react with a chlorinating agent, for example phosphorus pentachloride, in a medium. an inert solvent of the chlorinated alkane type having 1 to 2 carbon atoms, for example methylene chloride, an aromatic hydrocarbon or acetonitrile at a temperature of -45 to 60 ° C. 2. Process according to claim 1, characterized in that the reaction is carried out in the presence of a catalytic amount of dimethylformamide or dimethylacetamide and / or hydrogen chloride.