A valsartan impurity and a method for preparing the same

Abstract

The application discloses a valsartan impurity (5-(4'-(chloromethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole) and a preparation method thereof. The structure of the valsartan impurity is shown as formula I. The preparation method takes compound 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole as a starting material, reacts with hydrochloric acid in a solvent, and obtains the valsartan impurity shown as formula I. The valsartan impurity has the advantages of mild reaction condition, simple process, short reaction time, good yield, high-purity 5-(4'-(chloromethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole, reliable impurity control sample for quality control research of a valsartan product, and great significance.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to 5-(4'-(chloromethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (a valsartan impurity) and a preparation method thereof. BACKGROUND

[0002] Valsartan, chemical name N-(1-pentanoyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine, has the following structural formula:

[0003]

[0004] Valsartan is an anti-hypertensive drug developed by Novartis, which is an angiotensin receptor antagonist and can be used for various types of hypertension and has good protection for heart, brain and kidney.

[0005] In the process of synthesizing valsartan, the present inventors found that the impurity of formula I is a potential genotoxic impurity, which has the structure shown in formula I:

[0006]

[0007] The impurity has a genotoxic warning structure, which has an important influence on the quality control of valsartan. At present, there is no literature report on the structure and preparation method of the impurity, so it is of great significance to synthesize the impurity and establish an analysis method for the impurity to control the quality of valsartan raw material. SUMMARY

[0008] One aspect of the present application provides a valsartan impurity, which has the structure shown in formula 1:

[0009]

[0010] Another aspect provides a method for synthesizing 5-(4'-(chloromethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole, which is simple in operation and low in cost. The method uses compound 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole as a starting material, reacts with hydrochloric acid in a solvent to prepare the valsartan impurity shown in formula I.

[0011]

[0012] The reaction solvent is one of methanol, acetone, tetrahydrofuran, ethyl acetate, water or a mixed solvent thereof.

[0013] The solvent is used in an amount of 5.0:1-20:1, preferably 8:1-12:1, by mass ratio of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole; the concentration of hydrochloric acid is 4-15 mol / L, preferably 10-12 mol / L; the amount of hydrochloric acid used is 0.5:1-3:1, preferably 0.8:1-2:1, by mass ratio of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole; and the reaction temperature is 20-100°C. DETAILED DESCRIPTION

[0014] The application is further described below in conjunction with examples, but these examples do not constitute any limitation on the application.

[0015] Example 1

[0016] Synthesis of 5-(4'-(chloromethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (valsartan impurity of Formula I):

[0017] Into a 350 mL thick-walled pressure-resistant flask, 10.0 g (0.03 mol) of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole, 100 g of ethyl acetate, and 10 g of 12 mol / L hydrochloric acid were sequentially added, the flask was tightly capped, and the temperature was raised to 80°C, and the reaction was allowed to proceed for 15 h. After cooling, the cap was opened, and the solvent was evaporated. The main product was separated by column chromatography to obtain 4.3 g of white solid of the valsartan impurity of Formula I, with a HPLC purity of 97% and a yield of 88%.1H NMR (DMSO-d6) δ 4.76 (s, 2H), 7.09 (d, 2H), 7.37 (d, 2H), 7.56-7.61 (m, 2H), 7.67-7.71 (m, 2H);

[0018] 13C NMR (DMSO-d6) δ 45.8, 123.2, 128.0, 128.8, 129.1, 130.7, 131.2, 136.8, 139.2, 140.9, 154.1.

[0019] Example 2

[0020] Synthesis of 5-(4'-(chloromethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (valsartan impurity of Formula I):

[0021] Into a 350 mL thick-walled pressure bottle, 10.0 g (0.03 mol) of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole, 120 g of tetrahydrofuran, 12 g of 12 mol / L hydrochloric acid were sequentially added, the bottle cap was tightened, and the temperature was raised to 60 °C, and the reaction was carried out for 12 h. After cooling, the cap was opened, and the solvent was evaporated. The main product was separated by column chromatography to obtain the valsartan impurity of formula I, which was a white solid 3.8 g, with a HPLC purity of 97% and a yield of 78%. NMR (DMSO-d6) δ 4.76 (s, 2H), 7.09 (d, 2H), 7.37 (d, 2H), 7.56-7.61 (m, 2H), 7.67-7.71 (m, 2H);

[0022] 13C NMR (DMSO-d6) δ 45.8, 123.2, 128.0, 128.8, 129.1, 130.7, 131.2, 136.8, 139.2, 140.9, 154.1.

[0023] Example 3:

[0024] Synthesis of 5-(4'-(chloromethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (valsartan impurity of formula I):

[0025] Into a 350 mL thick-walled pressure bottle, 10.0 g (0.03 mol) of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole, 150 g of acetone, 15 g of 10 mol / L hydrochloric acid were sequentially added, the bottle cap was tightened, and the temperature was raised to 70 °C, and the reaction was carried out for 18 h. After cooling, the cap was opened, and the solvent was evaporated. The main product was separated by column chromatography to obtain the valsartan impurity of formula I, which was a white solid 3.9 g, with a HPLC purity of 95% and a yield of 81%. 1 H NMR NMR (DMSO-d6) δ 4.76 (s, 2H), 7.09 (d, 2H), 7.37 (d, 2H), 7.56-7.61 (m, 2H), 7.67-7.71 (m, 2H);

[0026] 13C NMR (DMSO-d6) δ 45.8, 123.2, 128.0, 128.8, 129.1, 130.7, 131.2, 136.8, 139.2, 140.9, 154.1.

Claims

1. A method for preparing a valsartan impurity of structural formula I, which comprises reacting 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole with hydrochloric acid in a solvent to produce the valsartan impurity of formula I, wherein the solvent is ethyl acetate, the reaction temperature is 80°C, and the concentration of hydrochloric acid is 10-12 mol / L, the mass ratio of the amount of solvent to 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole is 5.0:1-20:1, and the mass ratio of the amount of hydrochloric acid to 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole is 0.5:1-3:

1.

2. The production method according to claim 1, characterized by, The mass ratio of the amount of solvent to 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole is 8:1-12:1, and the mass ratio of the amount of hydrochloric acid to 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole is 0.8:1-2:

1.

3. The production method according to claim 2, characterized by, The mass ratio of the amount of solvent to 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole is 8:1-12:1, and the mass ratio of the amount of hydrochloric acid to 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1-trityl-1H-tetrazole is 0.8:1-2:1.

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