CN110078640B

CN110078640B - Synthesis method of valsartan intermediate

Info

Publication number: CN110078640B
Application number: CN201910249453.0A
Authority: CN
Inventors: 余奎; 唐雪松; 黄勤; 张富荣; 黄想亮; 曹倩
Original assignee: Zhejiang Menovo Pharmaceuticals Co ltd
Current assignee: Zhejiang Menovo Pharmaceuticals Co ltd
Priority date: 2019-03-29
Filing date: 2019-03-29
Publication date: 2022-04-05
Anticipated expiration: 2039-03-29
Also published as: CN110078640A

Abstract

The invention relates to a synthesis method of a valsartan intermediate, which comprises the following steps: (1) dissolving a compound shown in the following formula II in an organic solvent, adding an acid binding agent, sodium chloride or potassium chloride and water, uniformly stirring, dropwise adding n-valeryl chloride, and carrying out heat preservation reaction; (2) after the reaction is finished, water is added for quenching, and the target product, namely the N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxo-pentyl) -L-valine methyl ester, is obtained by sequentially carrying out alkali washing, acid washing and alkali washing, and finally carrying out reduced pressure distillation. According to the method, a proper amount of sodium chloride or potassium chloride is added into a reaction system, and the occurrence of n-valeryl chloride hydrolysis reaction is inhibited by utilizing the same ion effect, so that the use amount of n-valeryl chloride is reduced, the purity and yield of a product are improved, the production cost is reduced, the pollution to the environment is reduced, and the method is more suitable for industrial production.

Description

Synthesis method of valsartan intermediate

Technical Field

The invention relates to the field of pharmaceutical preparation, in particular to a method for synthesizing a valsartan intermediate.

Background

Valsartan (Valsartan), chemical name: n- (1-oxypentyl) -N- [4- [2- (1H-tetrazol-5-yl) phenyl ] benzyl ] -L-valine, which is an angiotensin II receptor antagonist developed by Nowa company, and has the characteristics of stable blood pressure reduction, strong curative effect, long action time, good tolerance of patients and the like.

The compound N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxopentyl) -L-valine methyl ester is a key intermediate for synthesizing valsartan, and the structure of the compound is shown as a formula I.

In the prior art, the preparation of valsartan intermediate N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxopentyl) -L-valine methyl ester is carried out by reacting N- [ (2' -cyanobiphenyl-4-yl) methyl ] - (L) -valine methyl ester hydrochloride (structure shown in formula II) with N-valeryl chloride in the presence of an inorganic base aqueous solution and a suitable solvent to obtain (N- [ (2' -cyanobiphenyl-4-yl) -methyl ] -N-valeryl- (L) -valine methyl ester (formula I), wherein the synthetic route is shown as follows:

due to the presence of water in the reaction system, n-valeryl chloride undergoes hydrolysis, which leads to an increase in its amount. In addition, in the feeding molar ratio of the compound of the formula II to the n-valeryl chloride in the prior art, the dosage of the n-valeryl chloride is too high, the residue of n-valeric acid as an impurity in a product is increased, and ammonia water washing is needed for multiple times, so that the quality control of the product is not facilitated, the product purity and yield are lower, the production cost and the discharge amount of nitrogen-containing wastewater are increased, and the environmental pollution is greater.

Therefore, further improvement is needed for the current synthesis method of the valsartan intermediate.

Disclosure of Invention

The invention aims to solve the technical problem of the prior art and provides a synthesis method of a valsartan intermediate, which can effectively inhibit hydrolysis of n-valeryl chloride so as to reduce the dosage of the n-valeryl chloride, further improve the purity and yield of the product and reduce environmental pollution.

The technical scheme adopted by the invention for solving the technical problems is as follows: a synthetic method of a valsartan intermediate is characterized by comprising the following steps: comprises the following steps

(1) Dissolving a compound shown in the following formula II in an organic solvent, adding an acid binding agent, sodium chloride or potassium chloride and water, uniformly stirring, dropwise adding n-valeryl chloride, and carrying out heat preservation reaction;

(2) after the reaction is finished, adding water for quenching, sequentially carrying out alkali washing, acid washing and alkali washing, and finally carrying out reduced pressure distillation to obtain a target product, namely a compound shown as a formula I, namely N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxo-pentyl) -L-valine methyl ester;

preferably, the organic solvent in step (1) is any one of toluene, xylene and dichloromethane.

Preferably, the acid-binding agent in the step (1) is sodium carbonate or potassium carbonate.

Preferably, the feeding molar ratio of the sodium carbonate or the potassium carbonate to the compound of the formula II is 2.2-4: 1.

Preferably, the mass ratio of the sodium chloride or the potassium chloride to the compound of the formula II in the step (1) is 0.3-1: 1. By adopting the feed ratio, sodium chloride or potassium chloride can better inhibit the hydrolysis of the n-valeryl chloride.

Preferably, the feeding mass ratio of the water to the compound of the formula II in the step (1) is 3-5: 1.

Preferably, the feeding molar ratio of the compound of formula II in the step (1) to the n-valeryl chloride is 1: 1.05-1.2. Because the sodium chloride or the potassium chloride is adopted in the step (1), the hydrolysis of the n-valeryl chloride is effectively reduced, so that the dosage of the n-valeryl chloride can be reduced and controlled within the above charge ratio.

Preferably, the temperature of the heat preservation reaction in the step (1) is 15-35 ℃.

Preferably, in the step (2), the solvent used for alkali washing is an aqueous ammonia solution with a concentration of 2.5%, the solvent used for acid washing is an aqueous hydrochloric acid solution with a concentration of 5%, and the solvent used for alkali washing is a sodium bicarbonate solution with a concentration of 2%.

Compared with the prior art, the invention has the advantages that: according to the method, a proper amount of sodium chloride or potassium chloride is added into a reaction system, and the occurrence of n-valeryl chloride hydrolysis reaction is inhibited by utilizing the same ion effect, so that the use amount of n-valeryl chloride is reduced, the purity and yield of a product are improved, the production cost is reduced, the pollution to the environment is reduced, and the method is more suitable for industrial production.

Drawings

FIG. 1 is an HPLC profile of a valsartan intermediate of formula I of example 1 of the present invention;

FIG. 2 is an HPLC chromatogram of the valsartan intermediate of formula I in example 2 of the present invention;

fig. 3 is an HPLC profile of valsartan intermediate of formula I shown in example 3 of the present invention.

Detailed Description

The invention is described in further detail below with reference to the accompanying examples.

Example 1:

the synthesis method of the valsartan intermediate comprises the following steps:

(1) adding 30g of the compound shown in the formula II and 200mL of toluene into a 500mL four-mouth bottle, and uniformly stirring; adding 21g of sodium carbonate and 18g of sodium chloride into 120mL of water, stirring to dissolve the sodium carbonate and the sodium chloride, and then dropwise adding the sodium carbonate and the sodium chloride into the four-mouth bottle; controlling the internal temperature to be 20-28 ℃, slowly dripping 12g of n-valeryl chloride and 20mL of toluene mixed solution, keeping the temperature and stirring after dripping, and detecting the compound residue in the formula II by HPLC;

(2) detecting the residue of the compound shown in the formula II by HPLC (high performance liquid chromatography) to be less than or equal to 0.10%, adding 120mL of water, separating a water layer, washing an organic phase by using 120 mL2.5% ammonia water, and separating the water layer; the organic phase was washed with 50mL of 5% aqueous hydrochloric acid solution and the aqueous layer was separated; the organic phase was washed with 50mL of 2% sodium bicarbonate and the aqueous layer was separated; the organic layer was distilled under reduced pressure to give the compound of formula I, yield: 99.0%, as shown in fig. 1, purity (HPLC): 99.76 percent.

Example 2:

(1) adding 30g of the compound shown as the formula II and 200mL of dimethylbenzene into a 500mL four-mouth bottle, and uniformly stirring; adding 30g of potassium carbonate and 20g of sodium chloride into 150mL of water, stirring to dissolve, and then dropwise adding into the four-mouth bottle; controlling the internal temperature to be 20-28 ℃, slowly dripping 11g of n-valeryl chloride and 20mL of dimethylbenzene mixed solution, keeping the temperature and stirring after dripping, and detecting the residue of the compound shown in the formula II by HPLC;

(2) after HPLC detection shows that the residue of the compound shown in the formula II is less than or equal to 0.10%, 120mL of water is added, and a water layer is removed; washing the organic phase with 120ml of 2.5% ammonia water, and separating the water layer; the organic phase was washed with 50mL of 5% aqueous hydrochloric acid solution and the aqueous layer was separated; the organic phase was washed with 50mL of 2% sodium bicarbonate and the aqueous layer was separated; the organic layer was distilled under reduced pressure to give the compound of formula I, yield: 99.2%, as shown in fig. 2, purity (HPLC): 99.73 percent.

Example 3:

(1) adding 50g of the compound shown in the formula II and 335mL of dichloromethane into a 1000mL four-mouth bottle, and uniformly stirring; adding 35g of sodium carbonate and 39g of potassium chloride into 200mL of water, stirring to dissolve the sodium carbonate and the potassium chloride, and then dropwise adding the sodium carbonate and the potassium chloride into the four-mouth bottle; controlling the internal temperature to be 20-28 ℃, slowly dripping a mixed solution of 20g of n-valeryl chloride and 33.5mL of dichloromethane, keeping the temperature and stirring after dripping, and detecting the residue of the compound shown in the formula II by HPLC;

(2) after HPLC detection shows that the residue of the compound shown in the formula II is less than or equal to 0.10%, 200mL of water is added, and a water layer is removed; washing the organic phase with 200ml of 2.5% ammonia water, and separating the water layer; the organic phase was washed with 85mL of 5% aqueous hydrochloric acid solution and the aqueous layer was separated; the organic phase was washed with 85mL of 2% sodium bicarbonate and the aqueous layer was separated; the organic layer was distilled under reduced pressure to give the compound of formula I, yield: 98.8%, as shown in FIG. 3, purity (HPLC): 99.81 percent.

Claims

1. A synthetic method of a valsartan intermediate is characterized by comprising the following steps: comprises the following steps

；

wherein, the solvent adopted by the first alkali washing is ammonia water solution.

2. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the organic solvent in the step (1) is any one of toluene, xylene and dichloromethane.

3. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the acid-binding agent in the step (1) is sodium carbonate or potassium carbonate.

4. A process for the synthesis of valsartan intermediate according to claim 3, characterised in that: the feeding molar ratio of the sodium carbonate or the potassium carbonate to the compound of the formula II is 2.2-4: 1.

5. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: in the step (1), the feeding mass ratio of the sodium chloride or the potassium chloride to the compound of the formula II is 0.3-1: 1.

6. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the feeding mass ratio of the water to the compound of the formula II in the step (1) is 3-5: 1.

7. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the feeding molar ratio of the compound of the formula II in the step (1) to the n-valeryl chloride is 1: 1.05-1.2.

8. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the temperature of the heat preservation reaction in the step (1) is 15-35 ℃.

9. A method of synthesizing the valsartan intermediate as claimed in any one of claims 1 to 8, wherein: in the step (2), the solvent used for alkali washing is an ammonia water solution with the concentration of 2.5%, the solvent used for acid washing is a hydrochloric acid water solution with the concentration of 5%, and the solvent used for alkali washing is a sodium bicarbonate solution with the concentration of 2%.