Synthesis method of valsartan

A synthesis method and valine technology, applied in directions such as organic chemistry, can solve the problems of high toxicity of trialkyltin azide, high cost, unreported chiral purity of valsartan, etc., and achieve easy industrial operation, The effect of stable raw materials and easy availability of raw materials

Active Publication Date: 2007-10-03
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantages of this method are: First, trialkyltin azide reacts with cyano group at 120-140°C to form tetrazole, but trialkyltin azide is highly toxic
The disadvantage of this method is: first, 2'-tetrazolyl-4-formyl biphenyl (or 2'-tetrazolyl-4-formyl biphenyl whose tetrazole has been protected) needs to be prepared separately ,high cost
In this patent report, the yield of the two-step reaction of tetrazolium protecting group and ester group hydrolysis is 50%, and the chiral purity of the obtained valsartan has not been reported

Method used

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  • Synthesis method of valsartan
  • Synthesis method of valsartan
  • Synthesis method of valsartan

Examples

Experimental program
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example 1

[0035]Example 1. N-[[2'-(N'-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L- Preparation of valine methyl ester (Val-1)

[0036] In a 1000mL four-neck flask equipped with a drying tube, a thermometer, a dropping funnel and a mechanical stirring paddle, add valine methyl ester (Val-OMe, 24.3g, 0.185mol), diisopropylethylamine (18.7g, 0.185mol), and dichloromethane (300mL), stir to dissolve, and cool down. At -10~0°C, a solution of N-trityl-2'-tetrazolyl-4-bromomethylbiphenyl (BBTT, 100g, 0.179mol) in dichloromethane (300mL) was added dropwise, and Complete, at 0-10 DEG C, continue to react for 4 to 5 hours, TLC (developing solvent, n-hexane: ethyl acetate = 5: 1) shows that the raw material basically disappears, add 5% sodium bicarbonate aqueous solution to wash, and saturated brine to wash , the organic phase was decompressed to remove dichloromethane to obtain N-[[2'-(N'-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4- Base]-methyl]-L-valine methyl ester crude product 110g (...

example 2

[0037] Example 2. N-[[2'-(N'-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L- Preparation of valine methyl ester (Val-1)

[0038] In a 100mL three-neck flask equipped with a drying tube, a thermometer, and a dropping funnel, add valine methyl ester hydrochloride (Val-OMe hydrochloride, 3.1g, 18.5mmol), diisopropylethylamine (3.74g , 37mmol), and dichloromethane (30mL), stirring and dissolving, cooling down. At -10~0°C, add N-trityl-2'-tetrazolyl-4-bromomethylbiphenyl (BBTT, 9.98g, 0.179mol) in dichloromethane (30mL) dropwise, After the addition was completed, the reaction was continued for about 5 hours at 0-10° C., TLC showed that the raw materials basically disappeared, and 5% aqueous sodium bicarbonate solution was added for washing, followed by washing with saturated brine, and the organic phase was decompressed to remove dichloromethane to obtain N-[ Crude product of [2'-(N'-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L-valine methyl ester 12.1g, the crud...

example 3

[0039] Example 3. N-(1-oxopentyl)-N-[[2'-(N'-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4 Preparation of -yl]-methyl]-L-valine methyl ester (Val-2)

[0040] In a 1000mL four-neck flask equipped with a drying tube, a thermometer, a dropping funnel and a mechanical stirrer, add the crude product obtained in Example 1, ethyl acetate (500mL), and triethylamine (21.2g, 0.21mol) after stirring and dissolving , cooled to about -10°C, and slowly added n-valeryl chloride (24.2 g, 0.20 mol) dropwise. After the addition was completed, the reaction was carried out at this temperature for 3 hours; then the temperature was raised, and the reaction was continued at 35° C. for 5 hours, and TLC showed that the reaction was complete. The reaction solution was washed successively with saturated saline, phosphate buffer (pH=7), and deionized water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N-(1-oxopentyl)-N-[[2'- (N'-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-...

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Abstract

This invention relates to a new synthetic method of valsartan, includes preparation method of intermediate N - ( 1 - oxygen amyl) - N - [ [ 2' - trityl - tetrazolium - 5 - group) - ( 1, 1' - dibenzyl) - 4 - group] - methyl] - L - valine. 2' - ( N - trityl) tetrazolium - 4 - bromoethyl Biphenyl and valine methyl ester ( or other salt) carry out alkylation reaction, after acidylation, by alkaline hydrolysis and acidification to obtain intermediate N - ( 1 - oxygen amyl) - N - [ [ 2' - trityl - tetrazolium - 5 - group) - ( 1, 1' - dibenzyl) - 4 - group] - methyl] - L - valine, then by protection solution to gain Valsartan. This invention belong to pharmaceutical chemistry and organic chemistry region, possess merits of raw material stabilization, yield higher, valsartan optical purity high, industrialization operating easy and so on.

Description

technical field [0001] [[ 2'-(N'-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L-valine (2) Preparation. [0002] Background technique [0003] Valsartan is a non-peptide angiotensin II (ATII) receptor antagonist, the chemical name of valsartan is N-(1-oxopentyl)-N-[[2'-(1H -tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L-valine, the chemical structure of valsartan is shown in formula (1). [0004] Known synthesis methods of valsartan and (or) intermediates such as patents US 5,399,578, US 5,965,592, WO 02 / 006253, CN 1317485, WO 04 / 026847, WO 04 / 111018, WO 05 / 049586, WO05 / 049587 and J . Med. Chem. 1991, 34(8), 2525-2574, Bioorganic & Med. Lett. 1994, 4(1), 29-34. [0005] The synthesis method of valsartan described in U.S. Patent No. 5,399,578 is shown in reaction formula (1), with 2'-cyano-4-formyl biphenyl (3) as raw material, and the p-toluene of L-valine benzyl ester The sulfonate (4) undergoes reductive amination reaction and n-valerylation reaction to form...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04
Inventor 屠勇军张毅程荣德李美君高伟
Owner ZHEJIANG TIANYU PHARMA
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