The way to get omeprazole

 

(57) Abstract:

Usage: in medicine as a drug. The inventive product is omeprazole. Reagent 1: 5-methoxy-2-[(4-methoxy-3,5-methyl-2-pyridinyl)] -methylthio-1H-benzimidazole. Reagent 2: m-chloroperoxybenzoic acid. Reaction conditions:methylene chloride pH 8.0 and 8.6, aqueous caustic soda. 6 C.p. f-crystals.

The invention relates to improved method for the synthesis of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl] -methyl] sulfinil] -1H-benzimidazole.

In U.S. patent N 4255431 describes a method for omeprazole, which includes stages of interaction of 5-methoxy-2 [(4-methoxy-3,5 - dimethyl-2-pyridinyl]-methylthio] -1H-benzimidazole in a solution of methylene chloride with m-chloroperoxybenzoic acid, resulting in omeprazole and m-chlorbenzene acid. Omeprazole is a highly sensitive and acids and the reaction mixture was kept at low temperature to prevent excessive decomposition in the reaction mixture.

The product distinguish, filtering m-chlorbenzoyl acid formed during the reaction. The filtrate is diluted with methylene chloride, extracted with sodium carbonate solution, dried and evaporated. Poluneesia is to develop an improved method for the synthesis of omeprazole, which eliminates the disadvantages of previously known methods.

This goal is achieved according to the present invention, which is characterised by that stage of the interaction of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) -methylthio] -1H-benzimidazole /indicated below, over connection 1/ chloroperoxybenzoic acid in a solution of methylene chloride is carried out at nearly constant pH of 8.0 to 8.6, the reaction mixture is extracted with aqueous sodium hydroxide, the aqueous phase is separated from the organic phase and added to the aqueous phase of alkylaryl, resulting crystallized omeprazole.

Usually m-chloroperoxybenzoic acid is used in amounts of 0.7 to 1.4 molar equivalents to the compound 1, and preferably in the amount of 0.9 to 1.2 molar equivalent.

In accordance with one variant of the invention alkylaryl is methylformate or ethylformate is preferred methylformate.

Alkylaryl usually used in the amount of 1.2 to 2.0 molar equivalents to the compound 1, and preferably in a quantity of 1.5 to 1.8 molar equivalents.

One essential feature of the method according to the invention is that unreacted sulfide does not go in the water PTA does not crystallize when adding methylformate to the aqueous phase, avoiding the need to filter the m-chlorbenzoyl acid in the previous stage.

the pH of the reaction mixture can be maintained in the range of 8.0 to 8.6 using the pH-static titration of NaOH or using a buffer. The preferred buffers are sodium bicarbonate and potassium bicarbonate.

A significant advantage of the method according to the invention is that the reaction takes place in the organic phase of methylene chloride, while formed during the reaction m-chlorbenzene acid is in an aqueous phase containing a buffer, in case of using a buffer. Due to this generated omeprazole is not in contact with the acid and the reaction can be conducted at temperatures above 0oC.

In accordance with one variant of the invention the pH of the aqueous caustic phase three is maintained above about 12. In accordance with another variant of the invention the crystallization of omeprazole is carried out at a pH above 9.

Example. Injected into the reaction 16.2 g /0,0492 mol/ 5-methoxy-2-[(4 - methoxy-3,5-dimethyl-2-pyridinyl)-methylthio] -1H-benzimidazole from 13.7 g /0,0537 mol/ m-chloroperoxybenzoic acid in methylene chloride acting as a solvent, at a pH of 8.6, which is supported by eribaum about 0oC.

Add dilute sodium hydroxide to a pH of about 12 and separated methylenchloride phase.

Download 4.7g of methylformate in the aqueous phase and maintain a pH of about 9, resulting crystallized omeprazole. Filtered off the crystals and wash them with water and methanol at a temperature of about 0oC. the Washed crystals are dried under vacuum. The output of 15.6 g /92%/.

1. The way to get omeprazole by reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)] -methylthio-1H-benzimidazole with m-chloroperoxybenzoic acid in a solution of methylene chloride and isolation of the target product, characterized in that the interaction is carried out at a constant pH value in the range of 8.0 to 8.6 using the buffer, perform the extraction of the reaction mixture of aqueous sodium alkali, separating the aqueous phase from the organic phase, add alifornia to the aqueous phase with obtaining crystalline omeprazole.

2. The method according to p. 1, characterized in that m-chloroperoxybenzoic acid is used in amount of 1 to 1.1 mol per 1 mol of the specified benzimidazole.

3. The method according to p. 1, characterized in that as alkylphosphate use methylformate.

4. The method according to p. 1, wherein t is, what is the pH of the aqueous phase sodium alkali support the above 12.

6. The method according to p. 1, characterized in that alifornia use in quantity of 1.47-1.5 mol per 1 mol of the specified benzimidazole.

7. The method according to p. 1, characterized in that the crystallization was carried out at pH above 9.

 

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