CN113993851B

CN113993851B - Valsartan refining method

Info

Publication number: CN113993851B
Application number: CN201980097597.7A
Authority: CN
Inventors: 王毅峰; 朱晓仁; 朱元勋; 颜峰峰; 王鹏
Original assignee: Zhejiang Huahai Pharmaceutical Co Ltd; Zhejiang Huahai Tiancheng Pharmaceutical Co Ltd; Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd
Current assignee: Zhejiang Huahai Pharmaceutical Co Ltd; Zhejiang Huahai Tiancheng Pharmaceutical Co Ltd; Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd
Priority date: 2019-08-07
Filing date: 2019-08-07
Publication date: 2024-02-09
Anticipated expiration: 2039-08-07
Also published as: CN113993851A; WO2021022516A1

Abstract

Relates to a valsartan refining method, which comprises the following steps: firstly, reacting valsartan and alkali or alkali weak acid salt in water to generate valsartan salt; then reacting with acid to regenerate valsartan; repeating the process to obtain a valsartan crude product again; dissolving the obtained valsartan crude product in ethyl acetate, separating to remove a water phase, performing organic phase drying treatment, cooling for crystallization, filtering and drying to obtain the purified valsartan. The method can effectively remove nitrosamine impurities in valsartan, reduce the nitrosamine impurities to less than or equal to 0.03ppm, is simple and easy to operate, does not use any organic solvent in the purification process, has the advantage of environmental protection, and is easy for industrial production.

Description

Valsartan refining method

Technical Field

The application belongs to the technical field of medicines, and particularly relates to a valsartan refining method.

Background

Valsartan (Valsartan), chemical name N- (1-pentanoyl) N- [ [2'- (1H-tetrazol-5-yl) [1,1' -biphenyl ] -4-yl ] methyl ] -L-valine, structural formula as follows:

valsartan was developed by novatics (Novatis), first approved for sale in germany at 7/1996, and is the second non-peptide angiotensin II (a-TII) type I receptor antagonist approved for the clinical treatment of hypertension. Valsartan can affect vasoconstriction and the antihypertensive effect of aldosterone by blocking the binding of angiotensin II to AT1 receptors in many tissues, such as vascular smooth muscle and glomeruli. Valsartan is used for various types of hypertension, has better protection effect on heart, brain and kidney, does not influence the heart rhythm, does not influence the total cholesterol, triglyceride, blood sugar and uric acid level of a hypertension patient, has small side effect, and has good application and market prospect.

The synthesis method of valsartan reported in the current literature mainly adopts the following route:

patent document WO2005021535A2 uses L-valine methyl ester hydrochloride and tetrazole-protected 2' -tetrazolyl-4-bromomethyl biphenyl as starting materials, and performs condensation, valerylation, saponification, acidification, deprotection and other operations to obtain valsartan.

Patent document US5399578 uses L-valine methyl ester hydrochloride and 4-formyl-2' -cyanobiphenyl as starting materials, and is subjected to reductive amination, n-valerylation, tetrazole cyclization, saponification and acidification to obtain valsartan.

Patent document WO2004026847A1 uses L-valine benzyl ester p-mesylate and 4-bromomethyl-2' -cyanobiphenyl as starting materials, and performs condensation, valerylation, cyclization and hydrogenation reduction to obtain valsartan.

The synthetic routes all relate to the synthesis of tetrazole ring, and the reaction principle is that organic nitrile and azide react under the action of a catalystAnd (3) cyclization reaction of sodium. Because of the high reaction temperature and long reaction time required for the cyclization reaction, a high boiling aprotic polar solvent DMF (N, N-dimethylformamide) is often used as a solvent to improve the reaction efficiency. However, at high temperature, DMF in the reaction system is at risk of decomposition into dimethylamine, and sodium nitrite is often used for quenching excessive sodium azide in the post-treatment step, and the decomposition product dimethylamine of sodium nitrite and DMF can generate trace by-product N-dimethylnitrosamine (formula C ₂ H ₆ N ₂ O, structure simple (CH) ₃ ) ₂ NNO, molecular weight 74.08, abbreviated NDMA). The relevant reaction mechanism is as follows:

NDMA is a typical nitrosamine compound, shows carcinogenesis to 7 animals such as rodents tested through different toxicological pathways (including oral and inhalation), and has been identified as animal carcinogen, and target organs are mainly liver and kidney. NDMA has been listed by the american society of government industry hygienists (ACGIH) as a suspected chemical carcinogen for humans.

The European pharmacopoeia Commission (EDQM) currently defines nitrosamines as genotoxic impurities with a warning structure according to ICH-M7 requirements, and tentatively sets the acceptable limit index of NDMA in valsartan to 0.3ppm, and requires a transition to the final 0.03ppm within a certain period of time.

The synthesis of tetrazole ring is an indispensable key step in valsartan synthesis process, while azide is taken as an indispensable cyclization reagent, and the azide must be quenched after the reaction is finished due to the special property of easy explosion; as the most widely used quencher, sodium nitrite can oxidize sodium azide into safe and harmless nitrogen under an acidic environment, and simultaneously terminate the reaction. Therefore, there is necessarily a risk of NDMA production in the valsartan synthesis process unless DMF is not used or other quenchers are used instead. DMF is used as a solvent for the cyclization reaction, so that the reaction efficiency can be greatly improved; other quenchers have poor quenching effect (such as a large amount of sodium hypochlorite solution can quench completely), so that a post-treatment method capable of effectively removing nitrosamine impurities is required to be designed, so that the limit on the production process is eliminated, and the quality safety of valsartan bulk drug is improved.

The post-treatment of valsartan described in patent document EP443983 is recrystallisation from ethyl acetate or isopropyl ether; the description of the work-up in patent document WO2005049586 is recrystallization in ethyl acetate or a mixed solvent of ethyl acetate and isopropyl ether; the post-treatment described in WO20055049588 is that after crystallization of valsartan in ethyl acetate, n-pentane is added and stirred, filtered and dried; the post-treatment described in patent document CN200810212026.7 is to wash valsartan in an aqueous alcohol solution, filter and dry.

The refining method mentioned in the above patent document mainly comprises recrystallization or beating, and the applicant finds that repeated operation is needed for a plurality of times to effectively reduce the impurity content through a large number of screening experiments, the yield loss is more, the recrystallization or beating of the mixed solvent can change the crystal form, and the change of the crystal form of the product can cause unexpected problems; therefore, the above method is not suitable for industrial production. In view of the above, it is an urgent technical problem to find a refining method which is simple, practical, low in cost and obvious in effect.

Disclosure of Invention

The purpose of the application is to provide a new valsartan refining method, which is mainly used for removing nitrosamine impurities in valsartan.

In order to achieve the above purpose, the present application adopts the following technical scheme:

a valsartan refining method, which can comprise the following steps:

step 1: carrying out salt forming reaction on valsartan to be refined and alkali or alkali weak acid salt in a solvent to obtain a valsartan salt solution;

step 2: mixing the valsartan salt solution obtained in the step 1 with acid to perform an acidification reaction to regenerate valsartan, and separating to obtain a primary purified crude product of valsartan;

step 3: sequentially repeating the step 1 and the step 2 for N times to obtain a valsartan multi-time purification crude product, wherein N is more than or equal to 1 and is an integer N;

step 4: dissolving the valsartan purified crude product obtained in the step 3 in ethyl acetate for multiple times, separating and removing a water phase, and reserving an organic phase;

step 5: and (3) carrying out cooling crystallization, filtering and vacuum drying on the organic phase obtained in the step (4) after the organic phase is subjected to drying and water removal treatment to obtain a valsartan refined product.

In the technical scheme of the application, the primary purification crude product obtained in the step 1 and the multi-purification crude product obtained in the step 2 are wet products, namely products which are not subjected to drying treatment.

In some embodiments of the present application, the base in step 1 may be an inorganic base and/or an organic base.

In some embodiments of the present application, the inorganic base may be selected from: alkali metal hydroxide and/or ammonia; the organic base may be selected from: one or at least two of phenethylamine, triethylamine, diethylamine and isopropylamine.

In some embodiments of the present application, the base is preferably an alkali metal hydroxide, more preferably one or both selected from sodium hydroxide and potassium hydroxide.

In some embodiments of the present application, the strong base weak acid salt in step 1 may be selected from: one or at least two of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.

In some embodiments of the present application, the solvent for the salt formation reaction in step 1 may be water; optionally, the ratio of the volume of solvent water to the mass of valsartan to be refined is (5-30) mL/g; preferably (10-15) mL/g.

In some embodiments of the present application, the reaction temperature of the salification reaction in step 1 is 5-30 ℃; preferably 5 to 15 ℃.

In some embodiments of the present application, the pH of the salt forming reaction in step 1 is pH 7 or more, preferably pH 7-12.

In some embodiments of the present application, the acid in step 2 may be an inorganic acid and/or an organic acid.

In some embodiments of the present application, the inorganic acid may be selected from one or at least two of strong protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like; the organic acid may be selected from one or at least two of formic acid, acetic acid, propionic acid, oxalic acid and citric acid.

In some embodiments of the present application, the acid in step 2 is preferably an inorganic acid, more preferably hydrochloric acid.

In some embodiments of the present application, the end point pH of the acidification reaction in step 2 is at a pH of 3 or less; preferably pH 0.5-2.

In some embodiments of the present application, step 3 may repeat steps 1 and 2 once; in other embodiments of the present application, step 3 may repeat steps 1 and 2 multiple times, e.g., 2 times, 3 times, 4 times, etc.

In some embodiments of the present application, the organic solvent used in step 4 is ethyl acetate; preferably, the ratio of the volume of ethyl acetate to the mass of valsartan to be refined is (5-10) mL/g.

In some embodiments of the present application, the drying means in step 5 may be selected from desiccant drying and/or distillation drying.

In some embodiments of the present application, step 2 may be performed by filtering the valsartan salt solution to remove insoluble impurities prior to mixing the valsartan salt solution with the acid.

In a specific implementation process, the valsartan refining method provided by the application can comprise the following steps:

step 1: dispersing valsartan to be refined in solvent water, then adding alkali or strong alkali weak acid salt, and regulating the pH value of the solution to be more than or equal to 7 so as to generate valsartan salt;

step 2: adding acid into the valsartan salt solution prepared in the step 1 to perform an acidification reaction to generate a valsartan precipitate, and filtering and collecting the precipitate to obtain a crude product of the primarily purified valsartan;

step 3: repeating the purification processes of the step 1 and the step 2 on the valsartan crude product prepared in the step 2 to obtain a re-purified valsartan crude product;

step 4: dissolving the valsartan crude product prepared in the step 3 in ethyl acetate, separating and removing a water phase, and reserving an organic phase;

According to the physicochemical properties of nitrosamine impurities, the valsartan to be refined is salified and dissolved in water through an acid-base conversion method, then acidified to obtain valsartan again, the process is repeated to improve the purification effect, the obtained crude product is dissolved in ethyl acetate, and after separation, dehydration and drying treatment, the valsartan refined product is finally obtained through cooling crystallization, filtration and drying. The method can simply and effectively refine valsartan, and provides a new method for industrialized production and improving the quality and safety of medicines.

Experiments prove that the method can efficiently eliminate nitrosamine impurities in valsartan, so that the nitrosamine impurities can be reduced below acceptable limits (less than or equal to 0.03 ppm) required by the official requirements of European pharmacopoeia committee (EDQM); can obtain the product with high yield and high purity.

Detailed Description

In order to make the technical problems, technical schemes and beneficial effects solved by the present application more clear, the present application is further described below with reference to specific embodiments. In the examples below, unless otherwise indicated, the specific conditions of the test methods described are generally carried out in accordance with conventional conditions or conditions recommended by the manufacturer; the raw materials and the reagents are all obtained by the market or prepared by using public information.

In the following examples, the valsartan to be refined used in step 1 is valsartan of an NDMA out-of-standard batch detected and identified in the process of optimizing and evaluating the production process of valsartan bulk drug.

In the following examples, NDMA was detected by GC-MS (gas chromatography-mass spectrometer), with the following detection conditions:

example 1:

step 1: preparation of valsartan salt solution

Adding 500mL of drinking water into a reaction bottle, cooling to 5 ℃, adding 50g of valsartan to be refined (NDMA content is 71 ppm), adding 30 mass percent sodium hydroxide solution, adjusting the pH value of the solution to 7, and stirring for reacting for 2 hours to obtain valsartan sodium salt solution;

step 2: preparation of valsartan primary purification crude product

Dropwise adding 6mol/L hydrochloric acid solution into the valsartan sodium salt solution prepared in the step 1 until the pH value is 0.5, separating out valsartan white solid, stirring for crystallization for 2 hours, and filtering to obtain a valsartan primary purification crude product;

step 3: preparation of valsartan re-purified crude product

Adding 500mL of drinking water into a reaction bottle, cooling to 5 ℃, adding the valsartan primary purified crude product obtained in the step 2, adding 30 mass percent sodium hydroxide solution, adjusting the pH value of the solution to 7, and stirring for reacting for 2 hours to obtain valsartan sodium salt solution; dripping 6mol/L hydrochloric acid solution into the valsartan sodium salt solution until the pH value is 0.5, separating out insoluble matters, stirring and crystallizing for 2 hours, and filtering to obtain a valsartan crude product for further purification;

step 4: preparation of valsartan crystallization liquid

Adding the valsartan prepared in the step 3 into a reaction bottle, purifying the crude product again, and 250mL of ethyl acetate, stirring and dissolving, separating to remove a water phase, and reserving an organic phase;

step 5: preparation of valsartan essence

And 5g of anhydrous magnesium sulfate is added into the organic phase prepared in the step 4, stirred for 1-2 hours, filtered, the filtrate is slowly cooled to 0-10 ℃, stirred and crystallized for 1-2 hours, filtered and dried in vacuum to obtain the refined valsartan product. Product yield 81%, HPLC purity 99.9%, NDMA content: less than 30ppb.

Example 2:

step 1: preparation of valsartan salt solution

750mL of drinking water is added into a reaction bottle, the temperature is reduced to 10 ℃, 50g of valsartan to be refined (the NDMA content is 100 ppm) is added, the pH value of the solution is adjusted to 9, and the solution is stirred and reacts for 1 hour to obtain valsartan triethylamine salt solution;

step 2: preparation of valsartan primary purification crude product

Dripping a phosphoric acid solution with the mass percentage of 30% and the pH value of 1 into the valsartan triethylamine salt solution prepared in the step 1, separating out valsartan white solid, stirring and crystallizing for 1 hour, and filtering to obtain a valsartan primary purification crude product;

step 3: preparation of valsartan re-purified crude product

Adding 750mL of drinking water into a reaction bottle, cooling to 10 ℃, adding the valsartan primary purification crude product prepared in the step 2, adding triethylamine, adjusting the pH value of the solution to 9, and stirring for reacting for 1 hour to obtain valsartan triethylamine salt solution; dropwise adding phosphoric acid solution with the mass percent of 30% into the obtained salt solution, wherein the pH value is 1, separating out insoluble matters, stirring and crystallizing for 1 hour, filtering to obtain valsartan, and purifying the crude product again;

step 4: preparation of valsartan crystallization liquid

Adding the valsartan prepared in the step 3 into a reaction bottle, purifying the crude product again, and 350mL of ethyl acetate, stirring and dissolving, separating to remove a water phase, and reserving an organic phase;

step 5: preparation of valsartan essence

And (3) distilling the organic phase obtained in the step (4) under reduced pressure to remove part of the solvent, adding fresh ethyl acetate, dissolving, clarifying, filtering, slowly cooling the filtrate to 10 ℃, stirring, crystallizing for 1-2 hours, filtering, and vacuum drying to obtain the refined valsartan product. Product yield 86%, HPLC purity 99.9%, NDMA content: less than 30ppb.

Example 3:

step 1: preparation of valsartan salt solution

Adding 500mL of drinking water into a reaction bottle, cooling to 15 ℃, adding 50g of valsartan to be refined (the NDMA content is 63 ppm), adding 30% potassium carbonate solution by mass fraction, adjusting the pH value of the solution to be 12, and stirring for reacting for 1.5 hours to obtain valsartan potassium salt solution;

step 2: preparation of valsartan primary purification crude product

Filtering the valsartan potassium salt solution prepared in the step 1, dropwise adding a 10% sulfuric acid solution into the filtrate, adjusting the pH to 2, separating out insoluble matters, stirring and crystallizing for 2 hours, and filtering to obtain a valsartan primary purified crude product;

step 3: preparation of valsartan crude product by multiple purification

Adding 500mL of drinking water into a reaction bottle, cooling to 15 ℃, adding the valsartan primary purification crude product prepared in the step 2, adding 30% of potassium carbonate solution by mass fraction, adjusting the pH value of the solution to 2, and stirring for reacting for 1.5 hours to obtain valsartan potassium salt solution; dropwise adding 10% sulfuric acid solution into the obtained salt solution, adjusting the pH to 2, separating out valsartan white solid, stirring and crystallizing for 2 hours, and filtering;

adding the wet product obtained by filtration into a reaction bottle again, adding 500mL of drinking water, cooling to 15 ℃, adding 30% potassium carbonate solution with mass fraction, adjusting the pH value of the solution to 2, and stirring for reacting for 1.5 hours to obtain valsartan potassium salt solution; dropwise adding 10% sulfuric acid solution into the obtained salt solution, adjusting the pH to 2, separating out insoluble matters, stirring and crystallizing for 2 hours, and filtering to obtain a valsartan multi-time purified crude product;

step 4: preparation of valsartan crystallization liquid

Adding the valsartan prepared in the step 3 into a reaction bottle, purifying crude products for many times, 300mL of ethyl acetate, stirring and dissolving, separating and removing a water phase, and reserving an organic phase;

step 5: preparation of valsartan essence

And (3) distilling the organic phase obtained in the step (4) under reduced pressure to remove part of the solvent, adding 5g of anhydrous magnesium sulfate after supplementing fresh ethyl acetate, stirring for 2 hours at 35 ℃, filtering, slowly cooling the filtrate to 0 ℃, stirring for crystallization for 2-4 hours, filtering, and drying in vacuum to obtain a valsartan refined product. Product yield 81%, HPLC purity 99.9%, NDMA content: less than 30ppb.

Example 4:

step 1: preparation of valsartan salt solution

1000mL of drinking water is added into a reaction bottle, the temperature is reduced to 25 ℃, 50g of valsartan to be refined (the NDMA content is 63 ppm) is added, saturated sodium bicarbonate solution is added, the pH value of the solution is regulated to 7-8, and the solution is stirred and reacts for 4 hours to obtain valsartan sodium salt solution;

step 2: preparation of valsartan primary purification crude product

Dripping glacial acetic acid with the mass fraction of 50% into the valsartan sodium salt solution prepared in the step 1 until the pH value is 3, precipitating valsartan white solid, stirring and crystallizing for 2 hours, and filtering and collecting precipitate to obtain a valsartan crude product;

step 3: preparation of valsartan re-purified crude product

1000mL of drinking water is added into a reaction bottle, the temperature is reduced to 25 ℃, the valsartan primary purification crude product prepared in the step 2 is added, saturated sodium bicarbonate solution is added, the pH value of the solution is regulated to 7-8, and the reaction is stirred for 4 hours, so as to obtain valsartan sodium salt solution; separating out insoluble matters from glacial acetic acid with the mass fraction of 50% of the sodium salt to a pH value of 3, stirring and crystallizing for 2 hours, filtering and collecting precipitate to obtain a valsartan crude product purified again;

step 4: preparation of valsartan crystallization liquid

Adding the valsartan prepared in the step 3 into a reaction bottle, purifying the crude product again, 300mL of ethyl acetate, stirring and dissolving, separating to remove a water phase, and reserving an organic phase;

step 5: preparation of valsartan essence

Distilling the organic phase obtained in the step 4 under reduced pressure to remove part of the solvent, and supplementing a proper amount of fresh solvent: then stirring for 2 hours at 35 ℃, filtering, slowly cooling the filtrate to 0 ℃, stirring and crystallizing for 2-4 hours, filtering, and vacuum drying to obtain the refined valsartan product. Product yield 80%, HPLC purity 99.9%, NDMA content: less than 30ppb.

Example 5:

step 1: preparation of valsartan salt solution

3000mL of drinking water is added into a reaction bottle, the temperature is reduced to 15 ℃, 50g of valsartan to be refined (the NDMA content is 63 ppm) is added, the pH value of the solution is adjusted to 10, and the solution is stirred and reacts for 3 hours to obtain valsartan ammonium salt solution;

step 2: preparation of valsartan primary purification crude product

Dropwise adding a citric acid solution with the mass fraction of 30% into the valsartan ammonium salt solution prepared in the step 1 until the pH value is 1, separating out valsartan white solid, stirring for crystallization for 1 hour, and filtering and collecting precipitate to obtain a valsartan crude product;

step 3: preparation of valsartan re-purified crude product

Adding 3000mL of drinking water into a reaction bottle, cooling to 15 ℃, adding the valsartan primary purification crude product prepared in the step 2, adding concentrated ammonia water, adjusting the pH value of the solution to 10, and stirring for reaction for 3 hours to obtain valsartan ammonium salt solution; dropwise adding 30% citric acid solution to the obtained ammonium salt solution until the pH value is 1, separating out insoluble substances, stirring for crystallization for 1 hour, filtering, collecting precipitate, and purifying the valsartan crude product again;

step 4: preparation of valsartan crystallization liquid

step 5: preparation of valsartan essence

Distilling the organic phase obtained in the step 4 under reduced pressure to remove part of the solvent, and supplementing a proper amount of fresh solvent: then stirring for 2 hours at 35 ℃, filtering, slowly cooling the filtrate to 0 ℃, stirring and crystallizing for 2-4 hours, filtering, and vacuum drying to obtain the refined valsartan product. Product yield 82%, HPLC purity 99.9%, NDMA content: less than 30ppb.

The above-described embodiments are provided for illustrating the essential content of the present application, but are not intended to limit the scope of the present application. It will be understood by those skilled in the art that various modifications and equivalent substitutions may be made to the technical solution of the present application without departing from the spirit and scope of the technical solution of the present application.

Claims

1. The valsartan refining method is characterized by comprising the following steps of:

step 1: carrying out salt forming reaction on valsartan to be refined and alkali or alkali weak acid salt in a solvent to obtain a valsartan salt solution; wherein the solvent for the salification reaction is water;

2. A valsartan purification process according to claim 1, characterized in that in step 1, the base is an inorganic base and/or an organic base.

3. A valsartan purification process according to claim 2, characterized in that the inorganic base is selected from: alkali metal hydroxide and/or ammonia; the organic base is selected from: one or at least two of phenethylamine, triethylamine, diethylamine and isopropylamine.

4. A valsartan purification process according to claim 1, characterized in that the base is an alkali metal hydroxide.

5. A valsartan refining process according to claim 4, characterized in that the base is one or both of sodium hydroxide and potassium hydroxide.

6. A valsartan purification process according to claim 1, characterized in that in step 1, the strong base weak acid salt is selected from: one or at least two of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.

7. A valsartan purification process according to claim 1, characterized in that in step 1 the ratio of the volume of solvent water to the mass of valsartan to be purified is (5-30) mL/g.

8. A valsartan purification process according to claim 7, characterized in that the ratio of the volume of solvent water to the mass of valsartan to be purified is (10-15) mL/g.

9. A valsartan refining process according to claim 1, characterized in that in step 1, the reaction temperature of the salification reaction is 5-30 ℃.

10. A valsartan refining process according to claim 9, characterized in that the reaction temperature of the salification reaction is 5-15 ℃.

11. A valsartan refining process according to claim 1, characterized in that the pH value of the salification reaction is pH > 7.

12. A process for refining valsartan according to claim 11, characterized in that the pH value of the salification reaction is 7-12.

13. A valsartan purification process according to claim 1, characterized in that in step 2, the acid is an inorganic acid and/or an organic acid.

14. A valsartan refining process according to claim 13, characterized in that the mineral acid is selected from one or at least two of hydrochloric acid, sulfuric acid, phosphoric acid; the organic acid is selected from one or at least two of formic acid, acetic acid, propionic acid, oxalic acid and citric acid.

15. A valsartan purification process according to claim 1, characterized in that in step 2, the acid is an inorganic acid.

16. A valsartan refining process according to claim 15, characterized in that the acid is hydrochloric acid.

17. A valsartan refining process according to claim 1, characterized in that in step 2, the end point pH value of the acidification reaction is pH is equal to or less than 3.

18. A valsartan purification process according to claim 17, characterized in that the end point pH of the acidification reaction is between 0.5 and 2.

19. A valsartan purification process according to any of claims 1 to 18, characterized in that in step 2 the valsartan salt solution is filtered to remove insoluble impurities before being mixed with the acid.

20. A process for the purification of valsartan according to claim 1, characterized in that the ratio of the volume of ethyl acetate to the mass of valsartan to be purified is (5-10) mL/g.

21. A valsartan purification process according to claim 1, characterized in that the manner of drying water removal in step 5 is selected from desiccant drying and/or distillation drying.