CS238950B1 - Processing of 2-methoxyimino-2-/amino-1,3-thiazole/acetylchloride hydrochloride - Google Patents

Abstract

2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride hydrochloride salt and the method of its manufacture. The new one the substance is a very advantageous novel starting product synthesis of semi-synthetic, so-called aminothiazole beta-lactam antibiotics with a wide range of efficiency »is produced chlorination of the anhydrous 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid form.

Description

The present invention relates to 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride hydrochloride of the formula I

and a process for the preparation of this novel compound, which is also a novel, highly preferred intermediate of the synthesis of semi-synthetic antibiotics.

As is known, 2-alkoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acids with a substituted amino group in the 2-position, in particular the 2-methoxyiminoderivative, are key intermediates in the synthesis of cephalosporin or monobactam antibiotics. aminothiazole beta-lactam antibiotics having a broad spectrum of activity (see, e.g., R. Bucourt et al., Tetrahedron 34, 2233-2243, 1978).

By substitution of the amino group at the 2-position is meant substitution with a suitable protecting group which is introduced before the final stage of the synthesis and finally removed again. Commonly used protecting groups are trityl, formyl, trimethylsilyl or chloroacetyl / US Pat. No. 4,152,432} NSR Pat. No. 2,810,922].

The need to use and remove protecting groups is complicated by all known reaction schemes for the synthesis of aminothiazole beta-lactam antibiotics. It extends them by at least two reaction steps and accordingly increases production costs.

As mentioned, a simpler process for the preparation of aminothiazole beta-lactam antibiotics without the use of protecting groups is not yet known. The object of the invention was to find a new starting material which does not have the disadvantages of the starting materials which are as simple as possible to produce.

The novel starting material according to the invention is the syn-form of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride hydrochloride of formula I which can be acylated directly with suitable nuclei to give the desired semisynthetic antibiotic without the need prior deprotection and later deprotection.

The invention further relates to a process for the preparation of the 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) -acetyl chloride hydrochloride syn-form, characterized in that the anhydrous 2-methoxyimino- 2- (2-amino-1,3-thiazol-4-yl) acetic is reacted with a chlorinating agent in an inert inert solvent such as an aromatic hydrocarbon such as benzene, a C 1 -C 2 chlorinated alkane such as dichloromethane or acetonitrile in the presence of dimethylformamide or hydrogen chloride as a catalyst at a temperature of -10 ° C to 50 ° C.

Phosphorus pentachloride is preferably used as the chlorinating agent. The process according to the invention is very simple: the anhydrous form of the starting acid is suspended in the chosen solvent, after addition of the catalyst and the chlorinating agent, everything dissolves under slight spontaneous heating and upon cooling a crystalline, very pure syn-form 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride, which is again isolated very simply. It can be used without further cleaning for further work.

Further details of the process according to the invention will be apparent from the following examples, which are illustrative but not limiting.

Examples

2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride syn-form

1. 4 g of anhydrous 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid syn-form is suspended in 30 ml of anhydrous benzene with stirring, a drop of dimethylformamide and 5 g of triturated powder are added. phosphorus pentachloride.

The reaction mixture was warmed slightly and dissolved. The desired product soon crystallized. After stirring for 30 minutes, it is filtered off with suction, washed with 30 ml of benzene and 20 ml of petroleum ether and dried under vacuum at room temperature. 3 g of crystalline substance are obtained, with a chlorine content of 99 to 100.5% of theory.

2. 4 g of anhydrous acid II are suspended with stirring in 20 ml of acetonitrile (water content 0.22% w / w). A drop of dimethylformamide and 6 g of phosphorus pentachloride were added. The mixture is warmed slightly and upon cooling, the pure product crystallizes in a yield of 3.5 g. Isolation as above.

3. To 30 ml of methylene chloride, add 0.16 ml of concentrated hydrochloric acid, cool to -10 ° C and add, while stirring, 6.5 g of phosphorus pentachloride, then add 4 g of anhydrous acid at 0 ° C in one portion. II.

After about 30 minutes, it dissolves and the desired product crystallizes shortly. After about 3 hours of standing at 0-5 ° C, the product is filtered off with suction, washed with benzene and petroleum ether. Yield 4.0 g.

Claims (3)

Synthesis of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride hydrochloride of formula (i) 2. A process for the preparation of the 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride hydrochloride of the formula I according to claim 1, characterized in that the anhydrous 2-methoxyimino acid syn-form is obtained. -2- (2-amino-1,3-thiazol-4-yl) acetic acid II COOH n ^ OCH _3/11 / is reacted with a chlorinating agent in organic solvent the aromatic hydrocarbon, e.g., benzene, a chlorinated alkane having 1-2 carbon atoms such as dichloromethane or acetonitrile, or dimethylformamide in the presence of hydrogen chloride catalyst at -10 ° C to 50 ° C. 3. The process of claim 2 wherein the chlorinating agent is phosphorus pentachloride.