Process for the manufacture of organic compounds

A compound and halide technology, applied in the field of synthesizing valsartan, can solve the problems such as the reduction of the yield of the desired product

Inactive Publication Date: 2012-07-18
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The formation of acyl-azide by-products is undesirable as their formation results in a reduced yield of the desired product

Method used

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  • Process for the manufacture of organic compounds
  • Process for the manufacture of organic compounds
  • Process for the manufacture of organic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment II

[0336] Embodiment II:Preparation of "acid-nitriles" via cleavage of benzyl esters of "benzyl-nitriles" with diethylaluminum chloride

[0337]

[0338] To a solution of 2.41 g (5 mmol) of "benzyl ester-nitrile" in 10 ml of anhydrous toluene was added a 1.8 M solution of diethylaluminum chloride in toluene (12.5 ml, 22.5 mmol) via syringe at room temperature under nitrogen and stirring. ). The addition was exothermic. After fully joining Et 2 After the AlCl solution the reaction mixture was warmed to 50 °C. After 2 hours the reaction mixture was cooled to 0°C and then quenched by the slow addition of 20 ml of 2M hydrochloric acid. Termination was largely exothermic and gas evolution was observed. The phases were separated and the organic phase was washed with 3 x 20 ml of water. The organic phase was evaporated in vacuo to give an oil. Spectral data is identical with embodiment 1.

[0339] Reference Example III: Preparation of valsartan via a one-pot process using ...

Embodiment IV

[0345] Embodiment IV: Preparation of valsartan: via the use of diethylaluminum chloride (for ester cleavage) and diethylaluminum azide (for cycloaddition) produced in situ by reacting diethylaluminum chloride with sodium azide into reaction) "one-pot method"

[0346]

[0347] 60 g of (S)-2-[(2'-cyanobiphenyl-4-ylmethyl)pentanoylamino]-3-methylbutanoic acid benzyl ester ("benzyl ester-nitrile" ) in xylene (67.1 mmol) was mixed with 33 g of diethylaluminum chloride (265.5 mmol) and stirred for 1 hour, the mixture was allowed to warm up to 50° C. by intermittent cooling. 8.82 g of sodium azide (134.3 mmol) were added and the mixture was heated to 110°C. After 4 hours the reaction mixture was carefully transferred to a flask containing 201.6 g of 12% by weight aqueous NaOH while raising the temperature of the mixture to 50°C. The upper organic phase was discarded, and the aqueous phase was washed with 60 g of xylene.

[0348] The oily phase containing product was separated...

Embodiment V

[0350] Embodiment V: Esterification of intermediate "acid-nitrile" with 3-methyl-1-(p-tolyl)triazene

[0351]

[0352] 9.8 g (65.56 mmol) of 3-methyl-1-(p-tolyl)triazene were dissolved in 100 ml of dichloromethane. To this solution was added 24.4 g (59.6 mmol) of a solution of "acid-nitrile" dissolved in 200 ml of dichloromethane via the dropping funnel within 45 minutes at room temperature with stirring. After 2 hours the reaction mixture was treated with 100 mL of 1M hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo to give a light yellow oil which was pure according to HPLC and H-NMR analysis.

[0353] 1 H-NMR (400MHz, CDCl 3 );δ H (ppm), a mixture of rotamers (6:4) at room temperature. 0.82-0.95 (5H, m, -CH 3 , 60%), 0.95-1.03 (4H, m, -CH 3 , 40%), 1.25-1.37 (1H, m, -CH-, 40%), 1.40-1.49 (1H, m, -CH-, 60%), 1.60-1.70 (1H, m, -CH-, 60 %), 1.70-1.82 (1H, m, -CH-, 40%), 2.22-2.65 (3H, br, copl.m, -CH- an...

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PUM

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Abstract

The present invention relates to processes for the manufacture of an angiotensin receptor blocker (ARB; also called angiotension II receptor antagonist or AT1 receptor antagonist) and salts thereof, to novel intermediates and process steps.

Description

field of invention [0001] The present invention relates to new methods, new process steps and new intermediates that can be used to synthesize valsartan. Background of the invention [0002] The present invention relates to the method for preparing valsartan. Valsartan, namely (S)-N-(1-carboxy-2-methylpropan-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-linked Phenyl-4-ylmethyl]amine, is an angiotensin II receptor antagonist used, for example, in the treatment of hypertension and has the following structure: [0003] [0004] Valsartan and its synthesis are described in EP-A-0443983 and US 5399578, especially in Examples 16, 37 and 54 thereof. [0005] One of the key structural units of valsartan is its tetrazole moiety. Various methods of preparing tetrazoles are described in the literature. For example, it is known in the art that tetrazole derivatives can be prepared by reacting a cyano group with an azide reagent, a method involving a [3+2] cycloaddition reaction, re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07D257/04
CPCC07C253/30C07D257/04A61P43/00A61P9/12C07C255/60C07C253/32C07C255/50C07C253/34
Inventor G·塞德尔迈尔F·A·拉姆普夫D·格里姆勒
Owner NOVARTIS AG
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