CS250578B1 - Method of 2-(2-chloracetamido-4-thiazolyl)-(z)-2-methoxy-iminoacetic acid's preparation - Google Patents

Abstract

The solution relates to a process for the preparation of an acid 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- -methoxyiminooetyl hydrolysis with ethyl or methyl esters in water by treatment with hydroxide sodium or potassium. Said compound is used as an intermediate in the preparation of the so-called amino-thiazole β-lactam antibiotics.

Description

The present invention relates to a process for the preparation of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid of the formula I

N - n - C-CCLh

/. And li

C O-Nn J q _Ch $ (i)

The compound is used as an intermediate for the preparation of so-called. aminothiazole antibiotics. The compound of formula I was obtained in 83% yield by hydrolysis of an ethanolic solution of the appropriate ethyl ester with sodium hydroxide followed by distillation of the solvent and extraction of the liberated acid (DOS 2,713,272).

Another method of preparation is the hydrolysis of the appropriate ethyl ester with 5 molar parts of potassium hydroxide for 2 hours in ethanol followed by distillation of the solvent and extraction after acidification of the liberated acid I. (DOS 2715 385 and DOS 2 805 655). M. Ochiai et al., J. Antibiotics 34, 160, (roll 1981), determined that for the hydrolysis of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid esters in ethanol, water at at least 5 times potassium hydroxide is required at room temperature.

Another method of obtaining 2- (2-chloroacetamido-4-thiazolyl) - (Z-2-methoxyiminoacetic acid) is to treat sodium carbonate for 16 hours to an aqueous ethanolic solution of acid I, followed by distilling off the solvent and extracting the acidic reaction mixture (US 4,196,205) When repeating the processes of the present invention, it has been found that the desired acid of formula (I) is accompanied by an impurity, as a product of reaction with a solvent, Another disadvantage of the prior art is the complex treatment of the reaction mixture to isolate the stream.

The reaction-based process for the preparation of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid according to the invention eliminates these disadvantages. 1 molar part of methyl or ethyl 2- (2-chloroacetamido-4-thiazolyl) - (Z) -methoxyiminoacetic acid with 1 to 5 molar parts of potassium hydroxide or sodium hydroxide, characterized in that the reaction is carried out in water, at a temperature of 0 to 100 ° C and after acidification with mineral acid, the product is isolated from the reaction medium.

It will be appreciated that the acid of formula I may exist either in the form given by formula I or in the form of formula I ₂

Μ N — _T - C C0 ₉ H i § ² i

Cl CmCO-N ^ ^SN ~ ° ^CH 3 ( ¹ °)

The process according to the invention is carried out by adding, in portions or simultaneously, 1 to 5 molar, to a molar portion of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid methyl or ethyl ester suspended in water. parts of sodium or potassium hydroxide dissolved in water. The mixing of the reaction components takes place at a temperature of 2 ° C to 100 ° C, preferably at 5 to 25 ° C. A time of 0.25 to 5 hours with a possible change of the temperature to room temperature is required to react. It will be appreciated by those skilled in the art that the process of adding the reaction components can be reversed and that the reaction is accelerated by the use of excess sodium or potassium hydroxide.

The amount of water used for the reaction is suitably selected to form a 5 to 60% solution of the sodium or potassium salt of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid. from the reaction mixture by adding a strong or medium mineral mineral acid such as hydrochloric acid and precipitated 2- (2-chloroacetamido-4-thiazolyl) - (Z) after purification, e.g. with activated carbon or by extracting impurities with a water-immiscible solvent. 2-Methoxyiminoacetic acid is isolated by conventional means, such as filtration or centrifugation, Another method of isolation is the precipitation of the sodium or potassium salt of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid from the reaction medium by addition of a water-miscible organic solvent such as ethanol or acetone or its salting-out by the addition of organic or inorganic salts such as lactate The precipitated sodium or potassium salt of 2- (2-chloroacetamino-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid is isolated after dissolution in water as described above.

An advantage of the process according to the invention, which is important from an industrial point of view, is that the organic solvents are replaced in comparison with the hitherto known processes, while simplifying the product isolation process.

An advantage of the process according to the invention is furthermore that, in comparison with the processes known to date, increased purity of the product and simple indication of the completion of the reaction by the formation of a solution from the reaction mixture are achieved.

The invention is further described in the examples. These examples describe some possibilities of preparing the compound of formula I without limiting the scope of the invention in any way.

Example 1

2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid

To 0.5 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid ethyl ester in 2 ml of water is added 0.56 g of potassium hydroxide in 10 ml of H 2 O and the reaction mixture is stirred for 0.25 h. The resulting solution was decolourised by the addition of activated carbon and adjusted to pH 2. The precipitate was dried to give 0.34 g of 2- (2-chloroacetamido-4-thiazolyl) - (from β-methoxyiminoacetic acid, m.p. 165-167%).

Example 2

To a solution of 13.7 g of sodium hydroxide in 840 ml of water is added 42 g of 2- (2-chloroacetamido-4-thiazolyl) - (2-methoxymethylamino) acetic acid methyl ester, and the mixture is stirred to 35-40 ° C until clear. 34.7 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid are obtained.

Example 3

To a solution of 122.4 g of sodium hydroxide in 7.4 l of water was added 370 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid ethyl ester. The mixture was stirred at room temperature until clear. After cooling to 2 degrees Celsius, it is acidified by the addition of 4 N sulfuric acid and the precipitate formed is filtered off. 284.5 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid are obtained.

Example 4

To a mixture of 10 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z-2-methoxyiminoacetic acid ethyl ester) in 100 ml of water at 0-2 ° C is added a solution of 5.81 g of sodium hydroxide in 20 ml of water. The mixture was stirred for 1 hour and the temperature was allowed to slowly rise to 20 ° C. The reaction mixture was filtered and acidified to pH 1 by the addition of 4 N sulfuric acid to give 8.37 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid.

Example 5

To 10 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid ethyl ester at room temperature was added a solution of 51.81 g of sodium hydroxide in 20 ml of water. The reaction mixture was stirred for 1 hour. After decolourising with charcoal, the filtrate was acidified to pH 1 by the addition of 4 N sulfuric acid. After cooling to 2 ° C, the precipitate was filtered off. 8.52 g of 2- {2-chloroacetamido-4-thiazolyl- (Z) -2-methoxyiminoacetic acid are obtained.

Claims (5)

Process for preparing 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid based on the reaction of 1 molar of methyl or ethyl 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2 methoxyiminoacetic acid is 1 to 5 molar parts of sodium hydroxide or potassium hydroxide, characterized in that the reaction is carried out in water at 0 to 100 ° C and, after acidification with a mineral acid, the product is isolated from the reaction medium.