Preparation of Valsartan

Abstract

The invention discloses a novel method for preparing valsartan, which comprises the steps: taking L-valine methyl ester or L-valine methyl ester hydrochloride and p-bromobenzaldehyde as raw materials, carrying out reductive amination and acidylation reaction to obtain an intermediate, and performing SUZUKI reaction on the intermediate so as to obtain the valsartan. The method is safely operated, and avoids a step of tetrazole synthesis, and azide and other explosible hazardous compounds are not necessarily used; and the used raw materials can be easily obtained, and most of the raw materials are conventional chemical raw materials. In the method, biphenyl derivatives are not required for preparing the valsartan, and biphenyl products are obtained mainly through the suzuki reaction.

Description

technical field

[0001] The present invention belongs to medicine synthesis. It specifically relates to a new preparation method of valsartan, namely its intermediate N-pentanoyl-N-[[2'-(N'-trityl-tetrazol-5-yl)-(1.1'-diphenyl Base)-4-base]-methyl]-L-valine methyl ester preparation method. Background technique

[0002] Valsartan is a popular non-peptide angiotensin II (AT II) receptor antagonist. The chemical name of valsartan is N-valeryl-N-[[2'-tetrazolium- 5-yl)-(1.1'-diphenyl)-4-yl]-methyl]-L-valine.

[0003] The key of existing valsartan and intermediate synthesis methods is tetrazole formation and biphenylation reaction.

[0004] The classic synthesis of valsartan patent US 5399578 is based on the synthesis of 2'-cyano-4-formylbiphenyl as a raw material, which is condensed with protected L-valine to form a Schiff base, and then reduced by alkali metal borohydride. N-valerylation reaction, into tetrazole, deprotection to get valsartan.

[0005] Among them, tetrazole...

Examples

Embodiment 1

[0020] step a

[0021] Preparation of N-[(4-bromo)-benzylidene]-L-valine methyl ester

[0022] Add 16ml of triethylamine to 14g, 0.082mol of L-valine methyl ester hydrochloride in 120ml of tetrahydrofuran, then add 15g of anhydrous magnesium sulfate, and after fully stirring the reaction, add 9.7g, 0.064mol of p-bromobenzene Formaldehyde, after the reaction was complete, the two phases were separated, the liquid phase was evaporated in vacuo and dried in high vacuum to give a pale yellow oil.

[0023] It was directly put into the next reaction without further treatment.

[0024] step b

[0025] Preparation of N-[(4-bromo)-benzyl]-L-valine methyl ester

[0026] The oil was dissolved in 150 ml of dry methanol. Cool the solution to 0°C, then slowly add sodium borohydride for one hour with stirring until the reaction of the imine is complete, add 40ml of water to the solution, evaporate the solution in a vacuum, add 700ml of water and 100ml of dihydrogen to the remaining liqui...

Embodiment 2

[0037] step a

[0038] Preparation of N-[(4-bromo)-benzylidene]-L-valine methyl ester

[0039] Add 16ml of triethylamine to 15g of L-valine tert-butyl ester hydrochloride, 0.082mol in 120ml of dichloromethane, then add 20g of anhydrous magnesium sulfate, after fully stirring the reaction, add 9.7g, 0.064mol of p-Bromobenzaldehyde, after the reaction is complete, the two phases are separated, the liquid phase is evaporated in vacuo and dried in high vacuum to give a pale yellow oil.

[0040] It was directly put into the next reaction without further treatment.

[0041] step b

[0042] Preparation of N-[(4-bromo)-benzyl]-L-valine tert-butyl ester

[0043] Dissolve the oil in 180ml of anhydrous methanol, cool the solution to 0°C, then slowly add sodium borohydride with stirring, and finish adding within one hour until the reaction of the imine is complete, add 40ml of water to the solution, and dissolve the solution Evaporate in vacuo, add 700ml of water and 100ml of dichloro...

technical field

[0001] The present invention belongs to medicine synthesis. It specifically relates to a new preparation method of valsartan, namely its intermediate N-pentanoyl-N-[[2'-(N'-trityl-tetrazol-5-yl)-(1.1'-diphenyl Base)-4-base]-methyl]-L-valine methyl ester preparation method. Background technique

[0002] Valsartan is a popular non-peptide angiotensin II (AT II) receptor antagonist. The chemical name of valsartan is N-valeryl-N-[[2'-tetrazolium- 5-yl)-(1.1'-diphenyl)-4-yl]-methyl]-L-valine.

[0003] The key of existing valsartan and intermediate synthesis methods is tetrazole formation and biphenylation reaction.

[0004] The classic synthesis of valsartan patent US 5399578 is based on the synthesis of 2'-cyano-4-formylbiphenyl as a raw material, which is condensed with protected L-valine to form a Schiff base, and then reduced by alkali metal borohydride. N-valerylation reaction, into tetrazole, deprotection to get valsartan.

[0005] Among them, tetrazole...

Examples

Embodiment 1

[0020] step a

[0021] Preparation of N-[(4-bromo)-benzylidene]-L-valine methyl ester

[0022] Add 16ml of triethylamine to 14g, 0.082mol of L-valine methyl ester hydrochloride in 120ml of tetrahydrofuran, then add 15g of anhydrous magnesium sulfate, and after fully stirring the reaction, add 9.7g, 0.064mol of p-bromobenzene Formaldehyde, after the reaction was complete, the two phases were separated, the liquid phase was evaporated in vacuo and dried in high vacuum to give a pale yellow oil.

[0023] It was directly put into the next reaction without further treatment.

[0024] step b

[0025] Preparation of N-[(4-bromo)-benzyl]-L-valine methyl ester

[0026] The oil was dissolved in 150 ml of dry methanol. Cool the solution to 0°C, then slowly add sodium borohydride for one hour with stirring until the reaction of the imine is complete, add 40ml of water to the solution, evaporate the solution in a vacuum, add 700ml of water and 100ml of dihydrogen to the remaining liqui...

Embodiment 2

[0037] step a

[0038] Preparation of N-[(4-bromo)-benzylidene]-L-valine methyl ester

[0039] Add 16ml of triethylamine to 15g of L-valine tert-butyl ester hydrochloride, 0.082mol in 120ml of dichloromethane, then add 20g of anhydrous magnesium sulfate, after fully stirring the reaction, add 9.7g, 0.064mol of p-Bromobenzaldehyde, after the reaction is complete, the two phases are separated, the liquid phase is evaporated in vacuo and dried in high vacuum to give a pale yellow oil.

[0040] It was directly put into the next reaction without further treatment.

[0041] step b

[0042] Preparation of N-[(4-bromo)-benzyl]-L-valine tert-butyl ester

[0043] Dissolve the oil in 180ml of anhydrous methanol, cool the solution to 0°C, then slowly add sodium borohydride with stirring, and finish adding within one hour until the reaction of the imine is complete, add 40ml of water to the solution, and dissolve the solution Evaporate in vacuo, add 700ml of water and 100ml of dichloro...

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