CN117624070A

CN117624070A - Preparation method of valsartan and intermediate thereof

Info

Publication number: CN117624070A
Application number: CN202210964957.2A
Authority: CN
Inventors: 张占涛; 孟艳华; 梁翠婷; 白明勇; 秦凤莲; 梁尊俊; 颜峰峰; 朱伟
Original assignee: Zhejiang Huahai Pharmaceutical Co Ltd
Current assignee: Zhejiang Huahai Pharmaceutical Co Ltd
Priority date: 2022-08-12
Filing date: 2022-08-12
Publication date: 2024-03-01

Abstract

The invention relates to a preparation method of valsartan and an intermediate thereof. In particular to a method for removing metal ions in the reaction and further preparing valsartan by using ammonium salt in the post-treatment process for preparing the compound II. The method provided by the invention can effectively remove the metal ions in the compound II, and ensures that the post-treatment in the valsartan preparation process is simple, the product yield is high and the purity is good.

Description

Preparation method of valsartan and intermediate thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of valsartan and an intermediate thereof.

Background

Valsartan (Valsartan, trade name "substituted text") is a drug developed by the company northwest for treating hypertension, which is a non-peptide angiotensin II (AT _II ) Receptor antagonist 1 having the chemical name N-pentanoyl-N- [ [2'- (1H-tetrazol-5-yl) [1,1' -biphenyl ]]-4-yl]Methyl group]L-valine having the structure shown below.

The preparation of valsartan has been disclosed in the prior art, wherein the conversion of cyano into tetrazole is an important ring for synthesizing valsartan in one step, and in industrial production, biphenyl cyano compound and azide are generally adopted to carry out cycloaddition reaction under the catalysis of Lewis acid to synthesize biphenyl tetrazole ring, and the reaction route is as follows:

although the use of lewis acid can improve the efficiency and yield of the reaction, the metal ions generated in the reaction process are easily complexed with the biphenyl tetrazole ring, and finally the metal ions in the valsartan finished product are out of standard. If hydrochloric acid is directly used for acidification in the post-treatment, highly toxic and explosive azido acid is generated, and the common post-treatment method is to quench excessive azide in the reaction by sodium nitrite firstly, and then adjust the pH of the solution to be acidic by hydrochloric acid to extract the product. The reaction process is complicated and is not suitable for industrial production. The solvent generally selects aprotic polar solvents such as DMF, NMP, diethylene glycol dimethyl ether and the like as the reaction solvent. However, these solvents are all water-soluble, and when the post-treatment water washes out excess inorganic salts such as azide, these solvents can enter the wastewater, producing a large amount of organic wastewater. In addition, the solvent such as DMF is used, dimethylamine is generated due to thermal decomposition, and the dimethylamine reacts with nitrite remained in the reagent such as sodium azide and the like, so that basic toxic impurities are generated.

Patent WO2012148148 discloses the use of toluene as the reaction solvent for the cyclization of tetrazoles with azide in the presence of two catalysts, a lewis acid and an organic amine such as tetramethyl ethylenediamine, and the post-treatment of the above patent uses aqueous ammonia or aqueous alkaline solutions such as sodium bicarbonate for washing.

Disclosure of Invention

In the process of preparing the compound II by using metal salt to carry out tetrazole reaction, if metal ions cannot be effectively removed, emulsification can occur during extraction operation and delamination is not easy in the subsequent post-treatment process of adding alkali to hydrolyze the compound II to obtain valsartan; and easily causes the problem that the metal ion residue of the final product is not qualified.

The invention aims to provide a novel method for effectively removing metal ions in a compound II, and valsartan with higher yield and purity, wherein the structural formula of the compound II is shown as follows:

the first aspect of the invention provides a method for removing metal ions in a compound II, which comprises the steps of adding an aqueous solution of an ammonium salt into a mixed solution containing metal ions, the compound II and a water-insoluble organic solvent, washing, and separating to obtain an organic layer containing the compound II, wherein the metal ions are zinc or copper ions.

The second aspect of the present invention provides a method for preparing compound II, which comprises the steps of:

(1) In a water-insoluble organic solvent, reacting the compound I with sodium azide, metal salt and amine ligand under heating, or directly reacting the compound I with an azide metal complex under heating;

the azide metal complex is a complex obtained by reacting sodium azide, metal salt and an amine ligand;

the metal salt is selected from: zinc chloride, zinc bromide, zinc triflate, copper chloride, cuprous chloride, preferably zinc chloride or zinc bromide;

(2) Adding an ammonium salt aqueous solution for washing after the reaction is finished, and collecting an organic layer containing the compound II;

the reaction route is as follows:

the third aspect of the present invention provides a method for preparing valsartan, which comprises the following steps:

(3) Adding an alkali aqueous solution into the organic layer containing the compound II for hydrolysis, and then acidizing and separating to obtain valsartan;

the reaction route is as follows:

in some embodiments, the ammonium salts described in the present invention include inorganic ammonium salts selected from the group consisting of: ammonium chloride, ammonium sulfate or ammonium bisulfate; the organic ammonium salt is selected from any one of ammonium formate and ammonium acetate or any mixture thereof; further preferred is ammonium chloride or ammonium sulfate. The molar ratio of the ammonium salt to the metal ion or metal salt is 1: 1-20: 1, a step of; further preferably 2:1 to 10:1.

in some embodiments, the water-insoluble organic solvent described in the present invention is an aromatic hydrocarbon solvent, preferably toluene, xylene or chlorobenzene; xylene or chlorobenzene is further preferred.

In some embodiments, after the organic layer containing compound II is collected, the organic layer is washed with water, preferably twice.

In some embodiments, the volume amount of the water-insoluble organic solvent of step (1) is 0.5 to 10ml, preferably 1 to 4ml, per gram of compound I.

In some embodiments, the amine ligand of step (1) is selected from the group consisting of: a compound having an ethylenediamine structure and a compound having a pyridine structure; preferably, the amine ligand is selected from tetramethyl ethylenediamine, pyridine or sparteine.

In some embodiments, the heating of step (1) is at a reaction temperature of 120 to 150 ℃; more preferably 125 to 135 ℃.

In some embodiments, the heating reaction of step (1) is for a period of time ranging from 12 to 20 hours.

In some embodiments, the operation mode of the step (3) comprises separating an aqueous layer after hydrolysis, adding acid into the aqueous layer to precipitate a solid, washing the solid with water, and then recrystallizing the solid in an organic solvent to obtain valsartan.

The beneficial technical effects of the invention are as follows:

the invention uses neutral or acidic ammonium salt aqueous solution to treat the organic layer containing the compound II, effectively removes metal ions, and simultaneously can avoid partial products from entering a water layer in the washing process of alkaline ammonia water or sodium bicarbonate in the prior art, so the invention can improve the yield of the products to a certain extent. The invention also simplifies the post-treatment process of valsartan, and the obtained product has high purity.

Detailed Description

Example one

Into a three-necked flask, 41.4g of a solution of compound I in xylene (150 mL) was added, followed by sequentially adding 24.9g of sodium azide, 21.9g of zinc chloride and 17.7 g of tetramethyl ethylenediamine, heating to 125-135℃and reacting at a constant temperature for 18 hours. HPLC showed less than 5% compound I content. After the reaction, an aqueous solution of ammonium chloride (53.5 g) was added and stirred, the mixture was transferred to separate the liquid, the lower aqueous layer was removed, and the upper organic phase was collected. The water wash was then repeated twice. The organic phase was added with aqueous sodium hydroxide solution and the reaction was stirred for 24 hours. And (5) transferring and separating liquid after the reaction is finished.

Slowly dropwise adding 6N hydrochloric acid into the lower layer to acidify until the pH value is=1-3, separating out solid, filtering, and washing with water. Ethyl acetate was added to stir the solution and washed with water. The washed organic phase is concentrated, crystallized, filtered and dried to obtain 36.4g of valsartan finished product, the yield of two steps is 82.2 percent, and the purity of HPLC: 99.7%. Valsartan isomer (D-valsartan) content: 0.41% and zinc was not detected.

Example two

Into a three-necked flask, 41.4g of a solution of compound I in xylene (150 mL) was added, followed by sequentially adding 24.9g of sodium azide, 21.9g of zinc chloride and 17.7 g of tetramethyl ethylenediamine, heating to 125-135℃and reacting at a constant temperature for 18 hours. HPLC showed less than 5% compound I content. After the reaction, an aqueous solution of ammonium sulfate (66.1 g) was added and stirred, the mixture was transferred to separate the liquid, the lower aqueous layer was removed, and the upper organic phase was collected. The water wash was then repeated twice. The organic phase was added with aqueous sodium hydroxide solution and the reaction was stirred for 24 hours. And (5) transferring and separating liquid after the reaction is finished.

Slowly dropwise adding 6N hydrochloric acid into the lower layer to acidify until the pH value is=1-3, separating out solid, filtering, and washing with water. Ethyl acetate was added to stir the solution and washed with water. The washed organic phase is concentrated, crystallized, filtered and dried to obtain 36.6g of valsartan finished product, the yield of two steps is 83.4 percent, and the purity of HPLC: 99.5%. Valsartan isomer (D-valsartan) content: 0.49% and zinc content 7ppm.

Example three

Into a three-necked flask, 41.4g of a solution of compound I in xylene (150 mL) was added, followed by sequentially adding 24.9g of sodium azide, 21.9g of zinc chloride and 22.7 g of pyridine, heating to 125-135℃and reacting at a constant temperature for 18 hours. HPLC showed less than 5% compound I content. After the reaction, an aqueous solution of ammonium chloride (53.5 g) was added and stirred, the mixture was transferred to separate the liquid, the lower aqueous layer was removed, and the upper organic phase was collected. The water wash was then repeated twice. The organic phase was added with aqueous sodium hydroxide solution and the reaction was stirred for 24 hours. And (5) transferring and separating liquid after the reaction is finished.

Slowly dropwise adding 6N hydrochloric acid into the lower layer to acidify until the pH value is=1-3, separating out solid, filtering, and washing with water. Ethyl acetate was added to stir the solution and washed with water. The washed organic phase is concentrated, crystallized, filtered and dried to obtain 35.2g of valsartan finished product, the yield of two steps is 79.5 percent, and the purity of HPLC is: 99.6%. Valsartan isomer (D-valsartan) content: 0.47% and zinc content 5ppm.

Example four

To the reaction flask were added 286g of zinc chloride and 400mL of water, and the mixture was dissolved by stirring at room temperature. 273g of sodium azide was dissolved in 750mL of water and slowly added to the reaction flask. The reaction solution is stirred and heated to 45-50 ℃, and 341g of pyridine is slowly added into a reaction bottle in a dropwise manner. After the completion of the dropwise addition, the reaction solution was stirred at 45 to 50℃for 3 hours. Cooled to room temperature, filtered, and the filter cake was washed with 1L of cold water and dried under nitrogen to give zinc azide complex.

Into a three-necked flask, 41.4g of a solution of Compound I in xylene (150 mL) was added, followed by 60g of zinc azide complex, and the temperature was raised to 125-135℃and the reaction was continued for 18 hours. HPLC showed less than 5% compound I content. After the reaction, an aqueous solution of ammonium chloride (53.5 g) was added and stirred, the mixture was transferred to separate the liquid, the lower aqueous layer was removed, and the upper organic phase was collected. The water wash was then repeated twice.

The organic phase was added with aqueous sodium hydroxide solution and the reaction was stirred for 24 hours. And (5) transferring and separating liquid after the reaction is finished.

Slowly dropwise adding 6N hydrochloric acid into the lower layer to acidify until the pH value is=1-3, separating out solid, filtering, and washing with water. Ethyl acetate was added to stir the solution and washed with water. The washed organic phase is concentrated, crystallized, filtered and dried to obtain 35.7g of valsartan finished product, the yield of two steps is 80.6 percent, and the purity of HPLC: 99.7%. Valsartan isomer (D-valsartan) content: 0.45%. Zinc content was 6ppm.

Claims

1. A method for removing metal ions from compound II, said method comprising the steps of: adding an aqueous solution of ammonium salt into a mixed solution containing metal ions, a compound II and a water-insoluble organic solvent, washing, and separating to obtain an organic layer containing the compound II, wherein the metal ions are zinc or copper ions, and the structural formula of the compound II is as follows:

2. a process for the preparation of compound II, said process comprising the steps of:

the reaction route is as follows:

3. a process for the preparation of valsartan, characterized in that it comprises the steps of:

the reaction route is as follows:

4. a method according to any one of claims 1-3, wherein the ammonium salt comprises an inorganic ammonium salt and an organic ammonium salt.

5. The process of claim 4, wherein the inorganic ammonium salt is selected from the group consisting of: ammonium chloride, ammonium sulfate or ammonium bisulfate; the organic ammonium salt is selected from any one of ammonium formate and ammonium acetate or any mixture thereof; further preferred is ammonium chloride or ammonium sulfate.

6. A method according to any one of claims 1-3, characterized in that the molar ratio of ammonium salt to metal ion or metal salt is 1: 1-20: 1, a step of; further preferably 2:1 to 10:1.

7. a process according to any one of claims 1 to 3, wherein the water-insoluble organic solvent is an aromatic hydrocarbon solvent, preferably toluene, xylene or chlorobenzene; xylene or chlorobenzene is further preferred.

8. A process according to any one of claims 1-3, characterized in that after the collection of the organic layer containing compound II, the organic layer is washed with water, preferably twice.

9. A process according to any one of claims 2-3, characterized in that the volume amount of the water-insoluble organic solvent of step (1) is required to be 0.5-10 ml, preferably 1-4 ml, per gram of compound I.

10. A method according to any one of claims 2 to 3, wherein the amine ligand of step (1) is selected from: a compound having an ethylenediamine structure and a compound having a pyridine structure; preferably, the amine ligand is selected from tetramethyl ethylenediamine, pyridine or sparteine.

11. A method according to any one of claims 2 to 3, wherein the heating in step (1) is at a reaction temperature of 120 to 150 ℃; more preferably 125 to 135 ℃.

12. A method according to any one of claims 2 to 3, wherein the heating reaction in step (1) is carried out for a period of time of from 12 to 20 hours.

13. A process according to claim 3, wherein the operation of step (3) comprises separating an aqueous layer after hydrolysis, adding acid to the aqueous layer to precipitate a solid, washing with water, and then recrystallizing in an organic solvent to obtain valsartan.