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A kind of preparation method of optically pure 3-amino-1-butanol

An amino and optical technology, which is applied in the preparation of 3-amino-1-butanol and the field of chiral drug intermediates, can solve the problems of high price, low yield and low yield of carboxyl group reduction reaction of chiral phenylethylamine , to achieve the effects of high difficulty in waste liquid treatment, high yield, and low condensation reaction yield

Active Publication Date: 2016-09-07
浙江宏康医药化工股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 crystallization is required. times, leading to a decrease in yield
But its shortcoming is that the first step condensation reaction and the last step carboxyl reduction reaction yield are low, and the yield of these two parts is only 55-61% and 47-54% respectively

Method used

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  • A kind of preparation method of optically pure 3-amino-1-butanol
  • A kind of preparation method of optically pure 3-amino-1-butanol
  • A kind of preparation method of optically pure 3-amino-1-butanol

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Embodiment 1

[0056] The preparation of embodiment 1 3-benzamido-2-butenoic acid ethyl ester (I)

[0057] 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 ( After that, add 50mL cyclohexane, make a slurry,...

Embodiment 2

[0058] The preparation of embodiment 2 3-benzamido-2-butenoic acid methyl ester (I)

[0059] 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

[0060] Example 3 Preparation of 3(R)-benzamido ethyl butyrate (II)

[0061] Get 150g 3-benzamido-2-butenoic acid ethyl ester, 750mL methanol, drop into clean pressure reactor, under the protection of nitrogen, put into 60mg chiral ruthenium-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 applied mechanically in the same procedure of this step in the next batch reaction), add 1000mL methyl tert-butyl ether to the residue for beating, filter (after the filtrate is distilled, apply it mechanically in the same procedure of the next batch reaction step), filter cake vacuum Dry to obtain ethyl 3(R)-benzamidobutyrate...

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Abstract

The invention provides a method for preparing optically pure 3-amino-1-butanol. The method comprises the following steps: reacting benzamide and acetoacetate under the catalytic action of p-toluenesulfonic acid to generate 3-benzamido-2-crotonate; carrying out catalytic hydrogenation reaction by using a chiral rhodium-diphosphine ligand compound as an asymmetric hydrogenation catalyst to generate 3(R) / (S)-benzamidobutyrate at high selectivity; reducing ester carbonyl group with hydroborate to generate 3(R) / (S)-benzamido-1-butanol; and finally, carrying out hydrolysis and benzoyl removal with concentrated hydrochloric acid to obtain the optically pure 3(R) / (S)-amino-1-butanol. The method has the advantages of cheap and accessible raw materials, simple technical operation, no need of resolution, high yield, low cost, environment friendliness and high optical purity of the product, and 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 optically pure 3-amino-1-butanol as a chiral drug intermediate. Background technique [0002] Optically active 3-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 theFuture 2012,37:697, it is reported that it is also the chiral six of the anti-AIDS drug Dolutegravir (listed in the United States in 2013, trade name Tivicay) Key intermediates of metacyclics. [0003] The synthetic method of this compound mainly contains following several kinds: [0004] Tetrahedron Lett.1988,29(2), 231 reported the synthetic method shown in follo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/08C07C213/02
Inventor 叶宏灿魏河海
Owner 浙江宏康医药化工股份有限公司