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Improved preparation method of valsartan

A technology of valsartan and tetrazolium ring, applied in the field of synthesizing valsartan, can solve the problems of high price, high reflux temperature, toxicity and the like, and achieve the effects of simplifying operation, improving yield and reducing toxicity

Active Publication Date: 2011-04-13
鲁南新时代生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Its synthetic key step is the synthetic of tetrazole, and existing bibliography reports its method, adopts reaction scheme 1 to prepare valsartan as Organic Process R&D2007,11,892-898, and its defect is: one, used catalyst is expensive Tributyltin chloride, organotin has very strong toxicity, and is not friendly to the environment; Its two, the solvent used for reaction is dimethylbenzene, and reflux temperature is higher; Hydrogen equipment, as shown in reaction scheme 1:
[0010] In addition, in patents WO2004 / 101534, CN2005 / 0130401.x, US2005 / 0010053 A1, US2005 / 0059827A1, the synthesis of valsartan is also through tetrazole-protected 2'-tetrazolyl-4- Bromomethylbiphenyl is used to introduce the tetrazole ring, which also has the problem of high cost

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1. Azidotrimethylsilane (Me 3 SiN 3 ) preparation

[0028] Add trimethylchlorosilane (Me 3 SiCl, 66.6g, 0.616mol), sodium azide (NaN 3 , 48.0g, 0.739mol), n-butyl ether (300mL), heated to 100°C for 48 hours, distilled, and collected the fraction at 90°C-105°C, which was the crude product of azidotrimethylsilane, and the crude product was redistilled 56.7 g of colorless liquid was obtained, yield 80.0%, boiling point: 95°C-96°C.

Embodiment 2

[0029] Example 2. Azidotrimethylsilane (Me 3 SiN 3 ) preparation

[0030] In a 500mL four-neck reaction flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, add silicone oil (150mL), sodium azide (NaN 3 , 38.5g, 0.592mol) and polyethylene glycol (1.3g), the mixture was heated to 50°C-59°C, and trimethylchlorosilane (Me 3 SiCl, 64.3g, 0.592mol), after the dropwise addition, keep the reaction at 50°C-59°C for 2 hours. After the reaction is completed, heat the reaction solution to 105°C and distill to obtain azidotrimethylsilane, which is colorless Liquid 62.4g, yield 91.6%, boiling point: 95°C-96°C.

Embodiment 3

[0031] Example 3. N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)-(1,1'-diphenyl)-4-yl]-methanol Preparation of base]-L-valine methyl ester (II)

[0032] Add tetrabutylammonium fluoride trihydrate (TBAF.3H 2 O, 0.78g, 2.46mmol), azidotrimethylsilane (Me 3 SiN 3 , 5.67g, 49.3mmol, prepared in Example 1), N-(1-oxopentyl)-N-[[2'-cyano-(1,1'-diphenyl)-4-yl]- Methyl]-L-valine methyl ester (1, 10g, 24.6mmol), the mixture was vigorously stirred, and reacted at 80°C for 50 hours, TLC (petroleum ether: ethyl acetate=3:1) detected that the reaction was complete, and the reaction Cool the liquid to room temperature, add xylene (100mL) and water (20mL), stir for 30min, separate layers, wash the organic phase with 1mol / L HCl (25mL×3) to remove tributylammonium fluoride, and dry over anhydrous sodium sulfate N-(1-oxypentyl)-N-[[2'-cyano-(1,1'-diphenyl)-4-yl]-methyl]-L-valine methyl ester (II ) xylene solution, directly used for the next step hydrolysis reaction.

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Abstract

The invention provides an improved preparation method of valsartan, which is characterized in that triazo trimethylsilane is replaced with a triazo tin compound to be used as a source of triazo to ensure that the toxicity is greatly reduced, tetrazole is introduced by adopting a solvent-free reaction method when tetrabutylammonium fluoride is used as a catalyst, thus the operation is simplified, and the yield is improved and reaches above 80 percent.

Description

Technical field: [0001] The invention belongs to the field of medicine synthesis, and in particular relates to an improved method for synthesizing valsartan. Background technique: [0002] Valsartan (Valsartan 1) chemical name: N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)-(1,1'-diphenyl)- 4-yl]-methyl]-L-valine, is a novel non-peptide angiotensin II (AT II) receptor antagonist, is used for the chemical synthesis medicine of effective treatment hypertension, and its structural formula is as follows : [0003] [0004] Its synthetic key step is the synthesis of tetrazole, its method has been reported in the literature, as Organic Process R&D2007,11,892-898 adopts reaction scheme 1 to prepare valsartan, and its defect is: one, used catalyst is expensive Tributyltin chloride, organotin has very strong toxicity, unfriendly to environment; Its two, the solvent used for reaction is dimethylbenzene, and reflux temperature is higher; Hydrogen equipment, as shown in reaction scheme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04B01J31/02
Inventor 赵志全郭彦玲
Owner 鲁南新时代生物技术有限公司
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