Preparation method of Aliskiren intermediate 3-amino-2,2-dimethylpropionamide

A technology of dimethylpropionamide and amino, which is applied in the field of preparation of aliskiren intermediate 3-amino-2,2-dimethylpropionamide, which can solve the difficulty of synthesis reaction that is not suitable for industrial production, has no industrial value, and Large and other problems, to achieve the effect of easy response, less loss, and short route

Active Publication Date: 2011-08-03
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are many kinds of synthetic methods disclosed at present, but they are not suitable for industrial production
BUCKL et al. reported the preparation of 3-amino-2,2-dimethylpropanamide by reduction of 3-nitro-2,2-dimethylpropanamide with Raney nickel, but the raw material 3-nitro-2,2- There is not a large amount of supply in the dimethylpropanecyanide market, and the synthesis reaction is difficult, so this route has no good industrial value; the disclosed patent CN1550491A of Novartis uses 3-amino-2,2-dimethylpropionic acid Ethyl ester reacts with benzyl chloroformate to protect the amino group, then reacts with ammonia for ammoniation, and then deprotects the group to prepare 3-amino-2,2-dimethylpropanamide
This route, synthetic step is longer, not economical, and this route has used benzyl chloroformate, and this route is more irritating, also very big to environmental pollution

Method used

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  • Preparation method of Aliskiren intermediate 3-amino-2,2-dimethylpropionamide
  • Preparation method of Aliskiren intermediate 3-amino-2,2-dimethylpropionamide
  • Preparation method of Aliskiren intermediate 3-amino-2,2-dimethylpropionamide

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Embodiment 1

[0023] Add 396g of sodium methoxide solution into 500ml of anhydrous methanol, stir for half an hour after adding, add 99g of methyl cyanoacetate, heat to 65°C and reflux for 2 hours, then cool to 20-30°C, add 290g of dimethyl sulfate, add After completion, the reaction was stirred overnight at 20-30°C. Evaporate the solvent to dryness, add 500ml of water, and then extract three times with 200ml of ethyl acetate, combine the ethyl acetate layers, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain 131.1g of yellow oil, namely 2,2-dimethylcyanoacetic acid Methyl ester, yield 93%.

Embodiment 2

[0025] Add 748g of sodium ethoxide solution into 500ml of absolute ethanol, stir for half an hour after adding, add 113g of ethyl cyanoacetate, heat to 80°C and reflux for 2 hours, then cool to 20-30°C, add 290g of dimethyl sulfate, add After completion, the reaction was stirred overnight at 20-30°C. Evaporate the solvent to dryness, add 500ml of water, then extract three times with 200ml of ethyl acetate, combine the ethyl acetate layers, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain 134.1g of yellow oily substance, namely 2,2-dimethylcyanoacetic acid Ethyl ester, yield 95%.

Embodiment 3

[0027] Add 88g of sodium hydride into 500ml of tetrahydrofuran, stir for half an hour after adding, add 113g of ethyl cyanoacetate, stir at room temperature for 2h, add 290g of dimethyl sulfate, and stir at room temperature overnight after adding. Add 500ml of acetic acid solution, then extract three times with 200ml of ethyl acetate, combine the ethyl acetate layers, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain 121.4g of yellow oil, namely ethyl 2,2-dimethylcyanoacetate , yield 86%.

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Abstract

The invention relates to an industrial preparation method of synthesizing a key intermediate 3-amino-2,2-dimethylpropionamide of an angiotonase inhibitor Aliskiren. In the method, 3-amino-2,2-dimethylpropionamide is obtained after a derivative of cyanoacetic acid is methylated, aminated and reduced. The method has the advantages of low cost, environmental friendliness, short reaction step, simple operation, high yield, high purity of product and the like, and is especially suitable for industrial production.

Description

Technical field: [0001] The present invention relates to the synthetic industrial preparation method of the key intermediate 3-amino-2,2-dimethylpropanamide of the hypertensive protease inhibitor Aliskiren (aliskiren) Background technique: [0002] Aliskiren is a new generation of non-peptide renin blocker. It is a new type of compound designed by applying the crystal structure analysis and computer model of the early renin blocker complex. There is no previous renin blocker. Extended peptide-like structures. Is a strong and effective, low molecular weight (relative molecular weight of 610), non-peptide, highly selective renin blocker. In March 2007, it was first approved for marketing in the United States, and it was used alone or in combination for the control of hypertension; in January 2008, the compound preparation composed of aliskiren and dihydrothiazide was also approved by the FDA. [0003] Aliskiren can block the RAS system in the first link, reduce the activity ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/06C07C231/12
CPCC07C231/12C07C237/06
Inventor 张文灵王鹏甘立新
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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