CS264471B3 - Process for the preparation of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolacetoxyacetic acid - Google Patents

Abstract

The solution concerns an improved method of preparing l-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxyacetic acid, a known anti-inflammatory preparation. The essence of the invention is the reaction of in situ prepared indomethacin chloride with glycolic acid in the presence of amide compounds capable of binding the hydrogen chloride formed in the reaction. The previously used pyridine was replaced with Ν,Ν-dimethylacetamide and epsilon-caprolactam with very good results.

Description

The present invention relates to a process for the preparation of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolacetoxyacetic acid, an ester of the known anti-inflammatory drug indomethacin with glycolic acid, over which it has certain advantages, in particular better tolerability and less side effects . Said compound is known and a number of methods for its preparation are also known (DE 2 234 651, EP-87-654 to 657, EP-88-252, EP-126 942).

The intermediate of most syntheses is the glycolic acid ester, and this necessarily entails the need to remove the protecting group in an appropriate manner. A disadvantage of all the described processes is therefore the extension of the synthesis by introducing and removing protecting groups.

In one case, a very simple procedure is described, consisting in the direct reaction of indomethacin with glycolic acid (the reaction takes about 20 hours), but the yield is only about 25% of theory.

Although good yields are described in each of the synthesis reactions, the overall yield relative to the number of steps required is relatively low and the processes are technically laborious.

No. AES 174 052 describes the synthesis of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolacetoxyacetic acid by a simple procedure based on the reaction of indomethacin chloride with glycolic acid by reacting the - (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic (indomethacin) is first converted by the action of thionyl chloride in an inert solvent such as ether in the presence of a reagent capable of binding the resulting hydrogen chloride, preferably pyridine, to the chloride which without isolation, it is reacted after further addition of pyridine with glycolic acid to the desired ester.

Further research has also improved this process, in that pyridine, which is largely unpleasant to handle on a larger scale, has been replaced by less unpleasant reagents and, in addition, in substantially less quantities, with comparable yields and quality of the end product. In addition, the replacement of ether with toluene is a major benefit in terms of greater safety on an industrial scale.

The invention therefore relates to a process for the preparation of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolacetoxyacetic acid by converting 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid. (indomethacin) by treating thionyl chloride with an inert solvent such as toluene in the presence of a reagent capable of binding hydrogen chloride and reacting the formed chloride in situ with glycolic acid in the presence of the same reagent capable of binding hydrogen chloride. The reaction is carried out in the presence of amide compounds from the group consisting of Ν, Ν-dimethylacetamide, N-methylpyrrolidone, tetramethylurea, 1,3-dimethylethyleneurea, or epsilon-caprolactam is very preferred.

The advantage of the process according to the invention lies primarily in a certain increase in yields (using epsilon-caprolactam) and in a substantial improvement in the working environment.

Further details are given in the examples.

He did

To a suspension of 7.16 g of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid in 32 ml of toluene was added epsilon-caprolactam (g) at 20-30 ° C with stirring at 20-25 ° C. 1.48 ml of thionyl chloride is added dropwise. Stirring was continued for 20 minutes, 1.52 g of glycolic acid was added, the mixture was heated to 50 ° C and maintained at 45-50 ° C for 3 hours. After cooling to 20 ° C, it is diluted with toluene and the toluene solution is washed with water until neutral. Most of the toluene was distilled off under reduced pressure, gasoline was added to the residue, the product was filtered off with suction and recrystallized from nitromethane. 4.9 g of pure ester are obtained (59% of theory), m.p. M.p. 148-150 ° C.

Example 2

In the same manner as described in Example 1, except that 4 ml of dimethylacetamide was used instead of epsilon-caprolactam, 4.5 g (54% of theory) of pure ester was obtained.

Example 3

In the same manner as described in Example 1, except that 4.2 ml of N-methyl-2-parrolidone was used instead of epsilon-caprolactam, 4.7 g (56% of theory) of pure ester were obtained.

Example 4

In the same manner as described in Example 1, except that 2.5 ml of tetramethylurea was used instead of epsilon-caprolactam, 3.9 g (47% of theory) of pure ester were obtained.

Example 5

In the same manner as described in Example 1, except that 2.55 ml of 1,3-dimethylethyleneurea was used instead of epsilon-caprolactam, 3.5 g (42% of theory) of pure ester was obtained.

Claims (1)

I will invent the object A process for preparing 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolacetoxyacetic acid by converting 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid by thionyl chloride to chloride in an inert solvent such as toluene, in the presence of an agent capable of binding hydrogen chloride and by reacting the in situ formed chloride with glycolic acid in the presence of the same agent capable of forming hydrogen chloride, according to U.S. Pat. No. 174,052, characterized in that The reaction is carried out in the presence of aroid compounds selected from the group consisting of Ν, Μ-dimethylacetamide, N-methylpyrrolidone, tetramethylurea, 1,3-dimethylethylene urea or epsilon-caprolactam.