CN113993851A

CN113993851A - Valsartan refining method

Info

Publication number: CN113993851A
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: 2022-01-28
Anticipated expiration: 2039-08-07
Also published as: WO2021022516A1; CN113993851B

Abstract

Relates to a valsartan refining method, which comprises the following steps: firstly, valsartan reacts with alkali or strong base 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; and dissolving the obtained valsartan crude product in ethyl acetate, separating to remove a water phase, drying the organic phase, cooling, crystallizing, filtering and drying to obtain the purified valsartan. The method can effectively remove nitrosamine impurities in the valsartan to be 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 advantages 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), the chemical name of which is N- (1-valeryl) -N- [ [2 '- (1H-tetrazol-5-yl) [1, 1' -biphenyl ] -4-yl ] methyl ] -L-valine, has the following structural formula:

valsartan, developed by novartis (Novatis), was first approved for marketing in germany on 7/1.1996, and is the second non-peptide angiotensin II (a-TII) type I receptor antagonist approved for clinical treatment of hypertension. Valsartan can affect vasoconstriction and the hypotensive effect of aldosterone by blocking the binding of angiotensin II to AT1 receptors in many tissues, such as vascular smooth muscle and glomeruli. The valsartan is used for treating various types of hypertension, has a good protection effect on heart, brain and kidney, does not affect the heart rhythm, does not affect the levels of total cholesterol, triglyceride, blood sugar and uric acid of a hypertension patient, has small side effect, and has good application and market prospects.

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

in WO2005021535A2, valsartan is obtained by using L-valine methyl ester hydrochloride and 2' -tetrazolyl-4-bromomethylbiphenyl as starting materials and subjecting the starting materials to condensation, valerylation, saponification, acidification, deprotection and other operations.

In US5399578, L-valine methyl ester hydrochloride and 4-formyl-2' -cyanobiphenyl are used as starting materials, and subjected to reductive amination, n-valerylation, tetrazole cyclization, saponification and acidification to form valsartan.

In WO2004026847A1, valsartan is obtained by using L-valine benzyl ester p-methanesulfonate and 4-bromomethyl-2' -cyanobiphenyl as starting materials and performing condensation, valerylation, cyclization and hydrogenation reduction.

The synthesis routes all relate to the synthesis of tetrazole rings, and the reaction principle is the cyclization reaction of organic nitrile and sodium azide under the action of a catalyst. Since the cyclization reaction requires a high reaction temperature and a long reaction time, an aprotic polar solvent DMF (N, N-dimethylformamide) having a high boiling point is often used as a solvent to improve the reaction efficiency. However, at high temperature, DMF in the reaction system is at risk of decomposing into dimethylamine, and sodium nitrite is often used to quench excessive sodium azide in the post-treatment step, and dimethylamine, which is the decomposition product of sodium nitrite and DMF, generates trace amount of N-dimethylnitrosamine (formula C) as a byproduct under the acidic condition of Lewis acid catalyst (such as zinc chloride, etc.)₂H ₆N ₂O, structural formula (CH)₃) ₂NNO, 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 tested rodents through different contamination routes (including oral administration and inhalation), is determined to be an animal carcinogen, and target organs are mainly liver and kidney. The national association of government industry hygienists (ACGIH) has listed NDMA as a suspected chemical carcinogen in humans.

The european pharmacopoeia commission (EDQM) currently defines nitrosamines as genotoxic impurities with a warning structure as required by ICH-M7, and tentatively sets an acceptable limit index for NDMA in valsartan to 0.3ppm and requires a transition to the final 0.03ppm over a period of time.

The synthesis of the tetrazole ring is an indispensable key step in the valsartan synthesis process, and the azide is used as an indispensable cyclization reagent and must be quenched after the reaction is finished due to the explosive special property of the azide; sodium nitrite, as the most widely used quencher, can oxidize sodium azide into safe and harmless nitrogen gas in an acidic environment, and simultaneously terminate the reaction. Therefore, there is a certain risk of NDMA generation in the synthesis process of valsartan unless DMF is not used or other quenchers are exchanged. DMF as a solvent for cyclization reaction can greatly improve the reaction efficiency; other quenchers have poor quenching effects (for example, a large amount of sodium hypochlorite solution can be completely quenched), so a post-treatment method capable of effectively removing nitrosamine impurities needs to be designed, so that the limitation on the production process is eliminated, and the quality safety of valsartan bulk drugs is improved.

The work-up in EP443983 on valsartan is described by recrystallization from ethyl acetate or isopropyl ether; the post-treatment described in patent document WO2005049586 is recrystallization from ethyl acetate or a mixed solvent of ethyl acetate and isopropyl ether; the post-treatment in WO20055049588 is described as crystallizing valsartan in ethyl acetate, adding n-pentane, stirring, filtering and drying; patent document CN200810212026.7 describes the post-treatment by washing valsartan in an aqueous alcohol solution, filtering and drying.

The refining method mentioned in the patent literature is mainly recrystallization or pulping, and through a large number of screening experiments, the applicant finds that repeated operation is needed for effectively reducing the impurity content, the yield loss is high, the mixed solvent recrystallization or pulping 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 need to solve the technical problem of finding a simple and practical refining method with low cost and obvious effect.

Disclosure of Invention

The invention aims to provide a novel valsartan refining method which is mainly used for removing nitrosamine impurities in valsartan.

In order to achieve the purpose, the following technical scheme is adopted in the application:

a valsartan refining process, which may include the steps of:

step 1: carrying out salt forming reaction on the valsartan to be refined and alkali or strong base 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 carry out an acidification reaction, regenerating valsartan, and separating to obtain a first purified valsartan crude product;

and step 3: repeating the step 1 and the step 2N times in sequence on the primary purified valsartan crude product obtained in the step 2 to obtain a valsartan crude product which is purified for multiple times, wherein N is not less than 1 and is an N integer;

and 4, step 4: dissolving the valsartan crude product obtained in the step 3 after multiple purification in ethyl acetate, separating to remove the water phase and keeping the organic phase;

and 5: and (4) drying the organic phase obtained in the step (4) to remove water, cooling and crystallizing, filtering, and drying in vacuum to obtain a refined valsartan product.

In the technical scheme of the application, the primary purified crude product obtained in the step 1 and the multiple purified crude products obtained in the step 2 are wet products, namely products which are not dried.

In some embodiments herein, the base in step 1 can be an inorganic base and/or an organic base.

In some embodiments herein, the inorganic base may be selected from: hydroxides of alkali metals and/or aqueous 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 two selected from sodium hydroxide and potassium hydroxide.

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

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

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

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

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

In some embodiments herein, 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 pH ≦ 3; preferably, the pH value is 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 a plurality of times, e.g., 2 times, 3 times, 4 times, etc.

In some embodiments herein, the organic solvent used in step 4 is ethyl acetate; preferably, the volume ratio of the ethyl acetate to the mass of the 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, the valsartan refining method provided by the application can comprise the following steps:

step 1: dispersing valsartan to be refined in solvent water, adding alkali or strong base weak acid salt, and adjusting the pH value of the solution to be more than or equal to 7 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 preliminarily purified valsartan crude product;

and 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 purified valsartan crude product;

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

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

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

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects solved by the present application more apparent, the present application is further described below with reference to specific embodiments. In the following examples, unless otherwise indicated, the test method specific conditions described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the starting materials, reagents are either commercially available or prepared using published information.

In the following examples, all the valsartan to be refined used in the step 1 are the valsartan of an overproof batch in which NDMA impurities are detected and identified in the optimization and evaluation process of the production process of the valsartan raw material drug.

In the following examples, NDMA was measured by GC-MS (GC-MS) under the following 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 (the NDMA content is 71ppm), adding 30 mass percent of sodium hydroxide solution, adjusting the pH value of the solution to 7, and stirring for reaction for 2 hours to obtain a valsartan sodium salt solution;

step 2: preparation of valsartan primary purified 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 white valsartan solid, stirring and crystallizing for 2 hours, and filtering to obtain a primary purified crude product of valsartan;

and step 3: preparation of valsartan repurified crude product

Adding 500mL of drinking water into a reaction bottle, cooling to 5 ℃, adding the primary purified crude product of valsartan obtained in the step (2), adding a sodium hydroxide solution with the mass percentage of 30%, adjusting the pH value of the solution to 7, and stirring for reacting for 2 hours to obtain a valsartan sodium salt solution; dropwise adding 6mol/L hydrochloric acid solution into the obtained valsartan sodium salt solution until the pH value is 0.5, separating out insoluble substances, stirring for crystallization for 2 hours, and filtering to obtain a valsartan crude product which is purified again;

and 4, step 4: preparation of valsartan crystallization liquid

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

and 5: preparation of valsartan fine product

And (3) adding 5g of anhydrous magnesium sulfate into the organic phase prepared in the step (4), stirring for 1-2 hours, filtering, slowly cooling the filtrate to 0-10 ℃, stirring for crystallization for 1-2 hours, filtering, and vacuum drying to obtain a refined valsartan product. Product yield 81%, HPLC purity 99.9%, NDMA content: < 30 ppb.

Example 2:

step 1: preparation of valsartan salt solution

Adding 750mL of drinking water into a reaction bottle, cooling to 10 ℃, adding 50g of valsartan to be refined (the NDMA content is 100ppm), adding triethylamine, adjusting the pH value of the solution to 9, and stirring for reaction for 1 hour to obtain a valsartan triethylamine salt solution;

step 2: preparation of valsartan primary purified crude product

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

and step 3: preparation of valsartan repurified crude product

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

and 4, step 4: preparation of valsartan crystallization liquid

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

and 5: preparation of valsartan fine product

And (4) carrying out vacuum distillation on the organic phase obtained in the step (4) to remove part of the solvent, supplementing fresh ethyl acetate, dissolving, clarifying and filtering, slowly cooling the filtrate to 10 ℃, stirring, crystallizing for 1-2 hours, filtering, and carrying out vacuum drying to obtain a refined valsartan product. Product yield 86%, HPLC purity 99.9%, NDMA content: < 30 ppb.

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 63ppm), adding a potassium carbonate solution with the mass fraction of 30%, adjusting the pH value of the solution to be 12, and stirring for reacting for 1.5 hours to obtain a valsartan sylvite solution;

step 2: preparation of valsartan primary purified crude product

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

and step 3: preparation of valsartan crude product by multiple purification

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

adding the filtered wet product into a reaction bottle again, adding 500mL of drinking water, cooling to 15 ℃, adding a potassium carbonate solution with the mass fraction of 30%, adjusting the pH value of the solution to 2, and stirring for reaction for 1.5 hours to obtain a valsartan potassium salt solution; dropwise adding a 10% sulfuric acid solution into the obtained salt solution, adjusting the pH to 2, separating out insoluble substances, stirring for crystallization for 2 hours, and filtering to obtain a valsartan crude product subjected to multiple purification;

and 4, step 4: preparation of valsartan crystallization liquid

Adding the valsartan purified crude product prepared in the step 3 and 300mL of ethyl acetate into a reaction bottle, stirring for dissolving, separating and removing a water phase, and keeping an organic phase;

and 5: preparation of valsartan fine product

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

Example 4:

step 1: preparation of valsartan salt solution

Adding 1000mL of drinking water into a reaction bottle, cooling to 25 ℃, adding 50g of valsartan to be refined (the NDMA content is 63ppm), adding a saturated sodium bicarbonate solution, adjusting the pH value of the solution to 7-8, and stirring for reacting for 4 hours to obtain a valsartan sodium salt solution;

step 2: preparation of valsartan primary purified crude product

Dropwise adding 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, separating out a valsartan white solid, stirring for crystallization for 2 hours, filtering and collecting precipitates to obtain a valsartan crude product;

and step 3: preparation of valsartan repurified crude product

Adding 1000mL of drinking water into a reaction bottle, cooling to 25 ℃, adding the primary purified valsartan crude product prepared in the step (2), adding a saturated sodium bicarbonate solution, adjusting the pH value of the solution to 7-8, and stirring for reacting for 4 hours to obtain a valsartan sodium salt solution; adding glacial acetic acid with the sodium salt mass fraction of 50% to the pH value of 3, separating out insoluble substances, stirring and crystallizing for 2 hours, filtering and collecting precipitates to obtain a valsartan re-purified crude product;

and 4, 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 300mL of ethyl acetate, stirring, dissolving and clearing, separating and removing a water phase, and keeping an organic phase;

and 5: preparation of valsartan fine product

Removing part of the solvent by vacuum distillation of the organic phase obtained in the step 4, and supplementing a proper amount of fresh solvent: and then stirring for 2 hours at 35 ℃, filtering, slowly cooling the filtrate to 0 ℃, stirring for crystallization for 2-4 hours, filtering, and vacuum drying to obtain a refined valsartan product. Product yield 80%, HPLC purity 99.9%, NDMA content: < 30 ppb.

Example 5:

step 1: preparation of valsartan salt solution

Adding 3000mL of drinking water into a reaction bottle, cooling to 15 ℃, adding 50g of valsartan to be refined (the NDMA content is 63ppm), adding strong ammonia water, adjusting the pH value of the solution to 10, and stirring for reacting for 3 hours to obtain a valsartan ammonium salt solution;

step 2: preparation of valsartan primary purified 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 a valsartan white solid, stirring for crystallization for 1 hour, filtering and collecting precipitates to obtain a valsartan crude product;

and step 3: preparation of valsartan repurified crude product

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

and 4, step 4: preparation of valsartan crystallization liquid

and 5: preparation of valsartan fine product

Removing part of the solvent by vacuum distillation of the organic phase obtained in the step 4, and supplementing a proper amount of fresh solvent: and then stirring for 2 hours at 35 ℃, filtering, slowly cooling the filtrate to 0 ℃, stirring for crystallization for 2-4 hours, filtering, and vacuum drying to obtain a refined valsartan product. Product yield 82%, HPLC purity 99.9%, NDMA content: < 30 ppb.

The above-described embodiments are intended to illustrate the substance of the present application, but not to limit the scope of the present application. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the true spirit and scope of the present disclosure.

Claims

A valsartan refining method is characterized by comprising the following steps:

step 1: carrying out salt forming reaction on the valsartan to be refined and alkali or strong base 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 carry out an acidification reaction, regenerating valsartan, and separating to obtain a first purified valsartan crude product;

and step 3: repeating the step 1 and the step 2N times in sequence on the primary purified valsartan crude product obtained in the step 2 to obtain a valsartan crude product which is purified for multiple times, wherein N is not less than 1 and is an N integer;

and 4, step 4: dissolving the valsartan crude product obtained in the step 3 after multiple purification in ethyl acetate, separating to remove the water phase and keeping the organic phase;

and 5: and (4) drying the organic phase obtained in the step (4) to remove water, cooling and crystallizing, filtering, and drying in vacuum to obtain a refined valsartan product.
The method for refining valsartan according to claim 1, wherein in step 1, the base is an inorganic base and/or an organic base.
The method for refining valsartan according to claim 2, wherein the inorganic base is selected from the group consisting of: hydroxides of alkali metals and/or aqueous ammonia; the organic base is selected from: one or at least two of phenethylamine, triethylamine, diethylamine and isopropylamine.
The method for refining valsartan according to any one of claims 1 to 3, wherein the base is a hydroxide of an alkali metal, preferably one or two selected from the group consisting of sodium hydroxide and potassium hydroxide.
The method for refining valsartan according to claim 1, wherein in step 1, the salt of a strong base and a weak acid is selected from the group consisting of: one or at least two of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.
The method for purifying valsartan according to any one of claims 1 to 5, wherein in step 1, the solvent for the salt formation reaction is water; the ratio of the volume of the solvent water to the mass of the valsartan to be refined is (5-30) mL/g; preferably (10 to 15) mL/g.
The method for purifying valsartan according to any one of claims 1 to 6, wherein in step 1, the reaction temperature of the salt formation reaction is 5 to 30 ℃; preferably 5 to 15 ℃.
The method for purifying valsartan according to any one of claims 1 to 7, wherein the pH value of the salt formation reaction is 7 or more, preferably 7 to 12.
The method for refining valsartan according to any one of claims 1 to 8, wherein in step 2, the acid is an inorganic acid and/or an organic acid.
The method for refining valsartan according to claim 9, wherein the inorganic acid is one or at least two selected from the group consisting of hydrochloric acid, sulfuric acid, and 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.
The method for purifying valsartan according to any one of claims 1 to 10, wherein in step 2, the acid is an inorganic acid, preferably hydrochloric acid.
The method for purifying valsartan according to any one of claims 1 to 11, wherein the final pH of the acidification reaction in step 2 is pH 3 or less; preferably, the pH value is 0.5-2.
The process for refining valsartan according to any one of claims 1 to 12, wherein in step 2, the solution of valsartan salt is filtered to remove insoluble impurities before being mixed with the acid.
The method for purifying valsartan according to any one of claims 1 to 13, wherein the ratio of the volume of ethyl acetate to the mass of valsartan to be purified is (5 to 10) mL/g.
The process for refining valsartan according to any of claims 1 to 14, wherein the drying to remove water in step 5 is selected from desiccant drying and/or distillation drying.