Method for preparing 3(R)/(S)-amidogen-1-butanol

A technology of -butanol and -amino, which is applied in the field of preparation of chiral drugs, can solve the problems of low yield, low yield of carboxyl group reduction reaction, high price of chiral phenylethylamine, etc., and achieve high yield and condensation reaction The effect of low yield and difficult waste liquid treatment

Active Publication Date: 2015-10-28
浙江宏康医药化工股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It has two disadvantages: one is that chiral phenylethylamine is more expensive; the other is that solvent recrystallization is required to split a pair of epimers, and in order to achieve a product with optical purity that meets the requirements, repeated crystalliz

Method used

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  • Method for preparing 3(R)/(S)-amidogen-1-butanol
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  • Method for preparing 3(R)/(S)-amidogen-1-butanol

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Embodiment 1

[0059] The preparation of embodiment 1 3-benzamido-2-butenoic acid ethyl ester (I)

[0060] Add 130g of ethyl acetoacetate, 127g of benzamide, 17.2g of p-toluenesulfonic acid and 400mL of cyclohexane into a three-necked reaction flask equipped with a thermometer, stirring and water separator in turn, heat, reflux, and add cyclohexane Bring water, after about 18g of water is separated, the reaction is over. Evaporate cyclohexane under reduced pressure (recoverable for mechanical use), cool to room temperature, add 150mL methyl tert-butyl ether, filter after stirring, then rinse the filter cake once with 20mL methyl tert-butyl ether, dry the filter cake Recover and apply mechanically (containing p-toluenesulfonic acid and a small amount of unreacted benzamide), combine the filtrate and washing liquid, wash twice with 10% aqueous sodium carbonate solution, then wash twice with water, evaporate the solvent methyl tert-butyl ether ( can be recycled and applied), add 50mL cyclohexa...

Embodiment 2

[0061] The preparation of embodiment 2 3-benzamido-2-butenoic acid methyl ester (I)

[0062] With the operating procedure and aftertreatment method of embodiment 1, by 128g methyl acetoacetate, 127g benzamide, 17.2g p-toluenesulfonic acid and 400mL cyclohexane, make 3-benzamido-2-butenoic acid Methyl ester (I), white solid, 199g, yield 91%, content 99.0% (HPLC method).

Embodiment 3

[0063] Example 3 Preparation of 3(R)-benzamido ethyl butyrate (II)

[0064] Take 150g 3‐benzamido‐2‐butenoic acid ethyl ester, 750mL methanol, put into a clean pressure reactor, under nitrogen protection, then add 60mg chiral rhodium‐bisphosphine ligand catalyst R‐xyl‐ BINAP-cymene-Rucl 2 . After sequentially replacing with nitrogen and hydrogen, under the conditions of hydrogen pressure 1.0MPa and temperature 70-80°C, catalytic hydrogenation for 24 hours, after the reaction is completed, cool to room temperature, replace with nitrogen, take out the reaction liquid, filter, and recover the filtrate by vacuum distillation Solvent methanol (can be used mechanically in the same procedure of this step in the next batch of reactions), add 1000mL methyl tert-butyl ether to the residue to make a slurry, filter (after the filtrate is distilled, the recovered methyl tert-butyl ether can be used in the next batch of reactions. Apply mechanically in the same procedure of step), filter ...

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Abstract

The invention provides a method for preparing 3(R)/(S)-amidogen-1-butanol. The method comprises the steps that firstly, benzamide reacts with acetoacetic ester under the catalyzing action of p-toluenesulfonic acid, so that 3-benzamido-2-butene acid ester is generated; secondly, catalytic hydrogenation is conducted by using a chiral rhodium-diphosphine ligand compound as a catalyst for enantioselective hydrogenation, so that 3(R)/(S)-benzamide butyrate is generated highly selectively; thirdly, benzoyl is removed by means of mixed solvent of concentrated hydrochloric acid and alcohol, so that 3(R)/(S)-amino-crotonic acid ester hydrochloride is generated; finally, optically pure 3(R)/(S)-amidogen-1-butanol is obtained after ester carbonyl is reduced by means of hydronoron. According to the method, the raw materials are low in cost and easy to obtain, the technological operation is easy and convenient, resolution is not needed, the yield is high, cost is low, environmental friendliness is achieved, the optical purity of product is high, and the method is more suitable for industrial production.

Description

technical field [0001] The present invention relates to the preparation of chiral drugs. In particular, it relates to a preparation method of a chiral drug intermediate 3(R) / (S)-amino-1-butanol. Background technique [0002] Optically active 3(R) / (S)‐amino‐1‐butanol is a key intermediate of many chiral drugs. Such as J.Org.Chem., 1977, 42:1650, it is reported that it is the key intermediate of the antineoplastic drug 4‐methyl cyclophosphamide; Teter.Lett., 1988, 29:231, it is reported that it can be derived into β‐ Lactam, so it is an important intermediate for the synthesis of penem antibiotics; Drugs.Of the Future 2012,37:697, it is reported that it is also the chirality of the anti-AIDS drug Dolutegravir (listed in the United States in 2013, trade name Tivicay) The key intermediate of the six-membered ring. [0003] The synthetic method of this compound mainly contains following several kinds: [0004] Tetrahedron Lett.1988,29(2), 231 reported the synthetic method sho...

Claims

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Application Information

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IPC IPC(8): C07C215/08C07C213/00
Inventor 叶宏灿魏河海
Owner 浙江宏康医药化工股份有限公司
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