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Method for synthesizing Valsartan with high optical purity

A technology of optical purity and valsartan, which is applied in the field of drug synthesis, can solve the problems of high cost, cumbersome operation, and high toxicity of trialkyltin azide, and achieves the inhibition of racemization, the method is easy to operate, and has high optical purity Effect

Active Publication Date: 2010-07-14
LINHAI TIANYU PHARMA
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  • 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
The shortcoming of this method is: one, take off the protecting group of tetrazole and the carboxyl protecting group step by step, take off the protecting group of tetrazole under acidic condition, remove the carboxyl protecting group under alkaline condition, and the operation is loaded down with trivial details ; Second, under alkaline conditions, valsartan is prone to racemization reaction, resulting in a reduction in the optical purity of the crude product, which affects the total yield of synthetic valsartan. In this patent, the yield of the deprotection step is 50 %

Method used

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  • Method for synthesizing Valsartan with high optical purity
  • Method for synthesizing Valsartan with high optical purity
  • Method for synthesizing Valsartan with high optical purity

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0046] Example 1. N-[[2'-(2N-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L-valerian Amino acid methyl ester

[0047] (7, R 1 = Trityl, R 2 = methyl)

[0048] Add valine methyl ester (5, R 2 =Methyl, 24.3g), diisopropylethylamine (18.7g), and dichloromethane (300mL), stirred to dissolve, and lowered the temperature. At -10 to 0°C, drop N-trityl-2'-tetrazolyl-4-bromomethylbiphenyl (6, R 1 =trityl, 100g, 0.179mol) in dichloromethane (300mL) solution, add, at 0~10 ℃, continue to react for 4 to 5 hours, TLC (developing solvent, n-hexane: ethyl acetate=5 : 1) shows that the raw material disappears substantially, adding 5% aqueous sodium bicarbonate to wash, washing with saturated brine, removing dichloromethane from the organic phase under reduced pressure to obtain N-[[2'-(2N-trityl-tetrazole 105 g of crude product of oxazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L-valine methyl ester. The crude product was directly subjected to the next reaction without further purific...

example 2

[0049] Example 2. N-[[2'-(2N-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L-valerian Amino acid methyl ester

[0050] (7, R 1 = Trityl, R 2 = methyl)

[0051] In the 1000 milliliter four-neck bottle that is equipped with drying tube, thermometer, dropping funnel and mechanical stirring, add valine methyl ester hydrochloride (5, R 2 =methyl, 31.1 g), dichloromethane (300 ml), stirred and cooled. At -10~0°C, diisopropylethylamine (42.6 g) was added dropwise, and the reaction was stirred for 0.5 hours; N-trityl-2'-tetrazolyl-4-bromomethylbis Benzene (6, R 1 =trityl, 100 grams, 0.179mol) in dichloromethane (300 milliliters) solution; After adding, at 0~10 ℃, 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% aqueous sodium bicarbonate solution to wash, wash with saturated brine, remove methylene chloride from the organic phase under reduced pressure, and obtain N-[[2'-(2N-...

example 3

[0052] Example 3. N-[[2'-(2N-trityl-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methyl]-L-valerian Isopropyl Amino Acid

[0053] (7, R 1 = Trityl, R 2 = isopropyl)

[0054] In the 1000 milliliter four-necked bottle that is equipped with drying tube, thermometer, dropping funnel and mechanical stirring, add valine isopropyl ester (5, R 2 =isopropyl, 29.6 g), diisopropylethylamine (18.7 g), and dichloromethane (300 ml), stirred to dissolve, and cooled. At -10 to 0°C, drop N-trityl-2'-tetrazolyl-4-bromomethylbiphenyl (6, R 1 = trityl group, 100 grams) in dichloromethane (300 milliliters) solution; After adding, at 0~10 ℃, continue to react for 4 to 5 hours, TLC (developing solvent, n-hexane: ethyl acetate=5: 1) It shows that the raw material basically disappears; add 5% aqueous sodium bicarbonate solution to wash, wash with saturated brine, remove dichloromethane from the organic phase under reduced pressure, and obtain N-[[2'-(2N-trityl-tetrazolium -5-yl)-(1,1'-diphenyl)-4-yl]-me...

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Abstract

The invention relates to a synthesis of high optical purify N-[[2'-(1H- tetrazoline-5-group)- (1,1'- diphenyl)-4-group]-methyl-]-L-valine, and using it as raw material in the synthesis of high optical valsartan. Using the 2'- tetrazoline group-4-methyl bromide biphenyl protected by tetrazoline and esterification protected carboxyl of L- valine(its salt) as raw material, by nucleophilic substitution, doing deprotective reaction in acidic condition, getting high optical purify N-[[2'-(1H-tetrazoline-5-group)-(1,1'-diphenyl)-4-group]-methyl-]-L-valine; in the existence of lower aliphatic alcohol, condensing with n-valeryl chloride to synthesize the valsartan in temperature range -20deg C-40deg C, controlling pH value between 1.5-5.0.

Description

technical field [0001] The invention belongs to medicine synthesis. Specifically relate to a kind of synthetic method of the valsartan (Valsartan) of high optical purity. Background technique [0002] Valsartan (Valsartan) is a new type of 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 (1). [0003] [0004] There are existing synthetic methods of valsartan and (or) its 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, WO 05 / 049587 and J. Med. Chem. 1991, 34(8), 2525-2574, Bioorganic & Med. Lett. 1994, 4(1), 29-34. [0005] The valsartan synthesis method described in the existing patent US 5,399,578 is shown in Scheme 1, using 2'-cyano-4-formylbiphenyl (2) as raw material, and p-toluenesulfonic acid of L-valine benzyl ester Salt (3) undergoes reductive amination reaction...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D257/04
Inventor 屠勇军张毅程荣德
Owner LINHAI TIANYU PHARMA
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