Method for synthesizing valsartan

Patent metadata

Field	Value
Publication number	US-11434210-B2
Application number	US-201817259292-A
Country	US
Kind code	B2
Filing date	Jul 17, 2018
Priority date	Jul 13, 2018
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

Abstract

A method for synthesizing valsartan, comprising the steps of: synthesizing a valsartan methyl ester intermediate to obtain a reaction mixture of the valsartan methyl ester intermediate; diluting the reaction mixture by salt water or water, and then using a first extraction solvent to extract the valsartan methyl ester intermediate; adding alkali to an organic layer containing the valsartan methyl ester intermediate for hydrolyzing, removing the organic layer, regulating pH of a water layer to be acidic by using acid, using the first extraction solvent to extract, concentrating a part of solvent, or distilling the solvent to dryness, and then adding a new solvent; finally, crystallizing, filtering, and drying to obtain the valsartan.

First claim

The invention claimed is:

1. A method for synthesizing valsartan, wherein the valsartan prepared does not comprise N-nitrosodimethylamine, valsartan impurity K and valsartan N-chloride; wherein the method comprises the following steps:
(1) synthesizing a valsartan methyl ester intermediate to obtain a reaction mixture containing the valsartan methyl ester intermediate;
wherein the step (1) comprises: dissolving a valsartan cyanide intermediate in N,N-dimethylformamide, then adding azide and a first acid, heating and stirring to carry out tetrazolium cyclization reaction to synthesize the valsartan methyl ester intermediate, thereby obtaining a reaction mixture containing the valsartan methyl ester intermediate;
(2) diluting the reaction mixture with salt water or water, adding a first extraction solvent, and heating extraction the valsartan methyl ester intermediate; obtaining a first organic layer containing the valsartan methyl ester intermediate by standing for layering and separating the water layer; washing the first organic layer at least once with salt water or water and separating the water layer to obtain a second organic layer containing the valsartan methyl ester intermediate;
(3) adding an alkaline solution to the second organic layer containing the valsartan methyl ester intermediate, stirring to hydrolysis, standing for layering; after separating the organic layer, adjusting the pH of the water layer to acidity with a second acid, and then adding a second extraction solvent to the water layer to extract valsartan compounds; standing for layering to obtain a third organic layer containing valsartan compounds; controlling the water content in the third organic layer to be lower than a target value by adding a desiccant or removing water by distillation; adding a new solvent when the solvent in the third organic layer is partially concentrated or the solvent in the third organic layer is evaporated, crystallizing and filtering to obtain a valsartan crude product; and
(4) adding the valsartan crude product to a crystallization solvent, heating to dissolve, cooling, crystallizing, and filtering, then washing the filter cake with the crystallization solvent and drying to obtain a finished valsartan product;
wherein the target value in step (3) is a mass fraction of 2%;
wherein the structures of the valsartan cyanide intermediate and the valsartan methyl ester intermediate are shown in the following Formula I and Formula II, respectively:

wherein the structure of the valsartan impurity K is as follows:

and the structure of the valsartan N-chloride is as follows:

2. The method according to claim 1 , wherein the azide described in step (1) is selected from the group consisting of sodium azide, potassium azide, lithium azide, cesium azide and trimethylsilicon azide or any combination thereof.

3. The method according to claim 1 , wherein the first acid in step (1) is a Lewis acid.

4. The method according to claim 1 , wherein the temperature of the tetrazole cyclization reaction in step (1) is 70-180° C.

5. The method according to claim 1 , wherein the salt water in step (2) is selected from the group consisting of one of sodium chloride aqueous solution, magnesium chloride aqueous solution, potassium chloride aqueous solution, calcium chloride aqueous solution, and sodium sulfate aqueous solution or any combination thereof.

6. The method according to claim 1 , wherein the first extraction solvent in step (2) is an organic solvent capable of dissolving valsartan methyl ester intermediates and immiscible with water.

7. The method according to claim 1 , wherein the temperature of heating extraction in step (2) is 35-140° C.

8. The method according to claim 1 , wherein the water layer separated in step (2) is combined, and the azide in the separated water layer can be quenched with a quenchant under acidic conditions, wherein the quenchant is selected from the group consisting of nitrite, hypochlorite and hypobromate or any combination thereof.

9. The method according to claim 1 , wherein, when the azide in the water layer is quenched, the acid used to form the acidic condition is an inorganic strong acid; after adding acid, the pH value range is 0-5.

10. The method according to claim 1 , wherein the alkaline solution in step (3) is one of hydroxide aqueous solution and carbonate aqueous solution or any combination thereof.

11. The method according to claim 1 , wherein the alkaline solution is added and then the hydrolysis reaction is carried out with stirring in step (3), wherein the hydrolysis reaction temperature is −10-40° C.

12. The method according to claim 1 , wherein in the step of adjusting the pH of the water layer to acidity with the second acid in step (3), the second add used is an inorganic strong acid.

13. The method according to claim 1 , wherein the second extraction solvent used in step (3) is a solvent that can be separated from the water layer.

14. The method according to claim 1 , wherein the new solvent in step (3) is a single solvent or a mixture of multiple solvents capable of dissolving valsartan.

15. The method according to claim 1 , wherein the desiccant in step (3) is selected from the group consisting of anhydrous metal chloride salts; and anhydrous metal sulfate or combination thereof.

16. The method according to claim 1 , wherein the crystallization solvent in step (4) is a single solvent or a mixture of multiple solvents capable of dissolving valsartan.

17. The method according to claim 1 , wherein the azide in step (1) is selected from the group consisting of sodium azide, potassium azide and trimethylsilicon azide.

18. The method according to claim 1 , wherein the first acid in step (1) is selected from the group consisting of triethylamine hydrogen halide, triethylamine sulfate, triethylamine hydrogen sulfate, triethylamine phosphate, triethylamine hydrogen phosphate, trimethylamine hydrogen halide, trimethylamine sulfate, trimethylamine hydrogen sulfate, trimethylamine phosphate, trimethylamine hydrogen phosphate, diisopropyl ethylamine hydrogen halide, diisopropyl ethylamine sulfate, diisopropyl ethylamine hydrogen sulfate, diisopropyl ethylamine phosphate, pyridine hydrogen halide, pyridine sulfate, pyridine hydrogen sulfate, pyridine phosphate, pyridine hydrogen phosphate, N-methyl morpholine hydrogen halide, N-methyl morpholine sulfate, N-methyl morpholine hydrogen sulfate, N-methyl morpholine phosphate, N-methyl morpholine hydrogen phosphate, N-methyl piperidine hydrogen halide, N-methyl piperidine sulfate, N-methyl piperidine hydrogen sulfate, N-methyl piperidine phosphate, N-methyl piperidine hydrogen phosphate, N-methyl tetrahydropyrrole hydrogen halide, N-methyl tetrahydropyrrole sulfate, N-methyl tetrahydropyrrole hydrogen sulfate, N-methyl tetrahydropyrrole phosphate, N-methyl tetrahydropyrrole hydrogen phosphate, tributyltin chloride, anhydrous zinc chloride, zinc chloride dihydrate, and anhydrous titanium tetrachloride, or any combination thereof.

Assignees

• Zhejiang Huahai Pharm Co Ltd

Inventors

• Zhou Xiaohui
• Zhu Xiaoren
• Zhu Yuanxun
• Dong Peng
• Wang Peng
• Lin Jinsheng
• Zhu Wenquan
• Li Min

Classifications

• C07D257/04 Primary

  Five-membered rings · CPC title