Preparation method of (R)-3-amino butanol

A technology of aminobutanol and butanol, which is applied in the preparation of aminohydroxy compounds, the preparation of organic compounds, organic chemical methods, etc., can solve the problems of waste of raw materials in industrialized large-scale production, toxicity of raw materials, low yield, etc., and achieve environmental protection , short process route and high yield

CN107805205AActive Publication Date: 2018-03-16ZHEJIANG NHU CO LTD
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2018-03-16

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Abstract

The invention discloses a preparation method of (R)-3-amino butanol. The preparation method includes following steps: (1), allowing (R)-1-methylbenzylamine and butanone alcohol to be in ammoniation reduction reaction to obtain a mixture of (R,R)-3-(1'-methylbenzylamine)-butanol and (R,S)-3-(1'methylbenzylamine)-butanol; (2), adopting an acidic chiral resolution reagent to split the mixture to obtain (R,R)-3-(1'-methylbenzylamine)-butanol; (3), allowing (R,R)-3-(1'-methylbenzylamine)-butanol to be in debenzylation reduction reaction to obtain (R)-3-amino butanol. According to the preparation method, a pair of epimers can be obtained by enabling butanone alcohol to react with a chiral reagent (R)-1-methylbenzylamine, the chiral reagent is added for further resolution, then subsequent reduction is performed, and obtained (R)-3-amino butanol has high purity and ee value.
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Description

technical field

[0001] The invention relates to the preparation of chiral drugs, in particular to a method for preparing a chiral drug intermediate (R)-3-aminobutanol. Background technique

[0002] (R)-3-Aminobutanol is a key intermediate of many chiral drugs. As reported in the literature (J.Org.Chem., 1977, 42:1650), it is the key intermediate of the antineoplastic drug 4-methylcyclophosphamide; It can be derivatized into β-lactam, so it is an important intermediate for the synthesis of penem antibiotics; it is reported in the literature (Drug of the future 2012,37:697) that it is also used to construct the anti-AIDS drug Dolutegravir (U.S. in 2013 Listed, trade name Tivicay) the key intermediate of the chiral six-membered ring.

[0003] The preparation method of this compound can be divided into following several kinds according to the difference of starting material:

[0004] 1. Using crotonate as the starting material

[0005] 1.1, the literature (J.Org.Chem, 1977, ...

Examples

Embodiment 1

[0076] 1) Amination reduction reaction: In a reaction kettle, add 121g (R)-1-methylbenzylamine, 1184g ethanol, 105.6g butanol and 12.1g Pd / C catalyst (5%). After sequentially replacing with nitrogen and hydrogen, react at a pressure of 4 MPa and a temperature of 50° C. for 12 hours. GC analysis of the starting material is complete. After the reaction was completed, the Pd / C catalyst was filtered, and the filter cake was rinsed with 160 g of ethanol, and then vacuum-dried at 40° C. to obtain 12.2 g of recovered Pd / C. Combine the reaction liquid and washing liquid, rectify and recover ethanol under normal pressure to obtain 210g of light brown transparent viscous liquid, distill at 180-200°C and 1-2mmHg, collect fractions, and obtain light yellow transparent viscous liquid, namely 180.5 g of a mixture of (R,R)-3-(1'-methylbenzylamine)-butanol and (R,S)-3-(1'-methylbenzylamine)-butanol. After detection, RR / RS=82 / 18 in the mixture, 64%ee, reaction yield 93.5%, gas phase content ...

Embodiment 2

[0080] 1) Amination reduction reaction: In a reaction kettle, add 121g (R)-1-methylbenzylamine, 1184g n-hexane, 105.6g butanol and 45g Pt / C catalyst (5%). After sequentially replacing with nitrogen and hydrogen, react at 4MPa pressure and 50°C temperature for 8 hours. GC analysis of the starting material is complete. After the reaction was completed, the Pt / C catalyst was filtered, and the filter cake was rinsed with 160 g of n-hexane, and then vacuum-dried at 40° C. to obtain 45 g of recovered Pt / C. Combine the reaction liquid and washing liquid, rectify at normal pressure to recover n-hexane, obtain 208 g of light brown transparent viscous liquid, distill at 180-200 ° C, 1-2 mmHg, collect fractions, obtain light yellow transparent viscous liquid, That is, 179.5 g of a mixture of (R,R)-3-(1'-methylbenzylamine)-butanol and (R,S)-3-(1'-methylbenzylamine)-butanol. After detection, RR / RS=82 / 18 in the mixture, 64%ee, reaction yield 93.0%, gas phase content 98.6%.

[0081] 2) Re...

Embodiment 3

[0086] 1) Amination reduction reaction: In a reaction kettle, add 121g (R)-1-methylbenzylamine, 1184g n-hexane, 105.6g butanol and 45g Pd / C catalyst (5%). After sequentially replacing with nitrogen and hydrogen, react at 4MPa pressure and 50°C temperature for 8 hours. GC analysis of the starting material is complete. After the reaction was completed, the Pt / C catalyst was filtered, and the filter cake was rinsed with 160 g of n-hexane, and then vacuum-dried at 40° C. to obtain 45 g of recovered Pt / C. Combine the reaction liquid and washing liquid, rectify at normal pressure to recover n-hexane, obtain 208 g of light brown transparent viscous liquid, distill at 180-200 ° C, 1-2 mmHg, collect fractions, obtain light yellow transparent viscous liquid, That is, 181.5 g of a mixture of (R,R)-3-(1'-methylbenzylamine)-butanol and (R,S)-3-(1'-methylbenzylamine)-butanol. After testing, RR / RS=82 / 18 in the mixture, 64%ee, reaction yield 94.0%, gas phase content 98.4%

[0087] 2) Deben...