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Preparation method of (R)-3-aminobutanol

A technology of aminobutanol and amino, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of long reaction route, low overall yield, harsh process operation, etc., and achieve the effect of short reaction route, high optical purity and high yield

Active Publication Date: 2017-07-21
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The problems in the preparation of the intermediate in the prior art are mainly reflected in the following points: the reaction route is long, the overall yield is low, the process operation is relatively harsh, and highly toxic and explosive sensitive materials are required

Method used

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  • Preparation method of (R)-3-aminobutanol
  • Preparation method of (R)-3-aminobutanol

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preparation example Construction

[0025] The present invention provides a preparation method of dolutegravir intermediate (R)-3-aminobutanol, which uses 3-(Boc-amino)butyric acid as the starting material and undergoes chiral resolution to obtain the compound of formula I;

[0026]

[0027] Then through sodium borohydride and Lewis acid reduction to obtain the compound of formula II;

[0028]

[0029] Finally, the amino group is deprotected to obtain (R)-3-aminobutanol.

[0030] The method of the present invention is described in further detail below with examples.

Embodiment 1

[0032] Dissolve 20.3 g of 3-(Boc-amino)butyric acid in 40.6 mL of methanol, stir and heat to 40-50°C, slowly add 9.1 g of S-phenylethylamine in 10.2 mL of methanol solution dropwise at this temperature, and dropwise, Insulate and stir for 20-30 min, slowly cool to 10-15°C, suction filter, and dry to obtain 14 g of carboxylate; then add 14 g of carboxylate into 28 mL of ethanol, heat to 70-75°C, and keep warm for 15-20 min, slowly lowered to 10-15°C, suction filtered, and dried to obtain 13 g of carboxylate. Repeat this operation twice to obtain 12.2 g of carboxylate with an ee value of 99.7%; finally add 12.2 g of carboxylate to 36 mL In water, adjust the pH to 1-2 with concentrated hydrochloric acid, add 30 mL of ethyl acetate to extract twice, combine the organic phases and concentrate until there is no distillate to obtain 7.6 g of the compound of formula I.

Embodiment 2

[0034] Dissolve 30 g of 3-(Boc-amino)butyric acid in 60 mL of ethanol, stir and heat to 70-75°C, slowly add 14 g of S-phenylethylamine in 15 mL of ethanol solution dropwise at this temperature, and dropwise, Insulate and stir for 20-30 min, slowly cool to 10-15°C, suction filter, and dry to obtain 21.6 g of carboxylate; then add 21.6 g of carboxylate into 43.2 mL of ethanol, heat to 70-75°C, and keep warm for 15-20 min, slowly lowered to 10-15°C, filtered with suction, and dried to obtain 20 g of carboxylate. Repeat this operation twice to obtain 18.8 g of carboxylate with an ee value of 99.6%; finally add 18.8 g of carboxylate to 55 mL In water, adjust the pH to 1-2 with concentrated hydrochloric acid, add 50 mL of ethyl acetate to extract twice, combine the organic phases and concentrate until there is no distillate, and obtain 11.7 g of the compound of formula I.

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Abstract

The invention relates to the technical field of synthesis of drug intermediates and particularly relates to a preparation method of dolutegravir intermediate (R)-3-aminobutanol, comprising: using 3-(Boc-amino)butyric acid as a starting material, chirally splitting to obtain a compound of formula I; reducing with sodium borohydride and Lewis acid to obtain a compound of formula II; performing amino deprotection to obtain (R)-3-aminobutanol. The materials used herein are low in price and easy to obtain, the reaction conditions are mild, the safety is reliable, process stability is high, the yield is high, optical purity is high, and the preparation method is green and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Dolutegravir, also known as Derogevir, English name: Dolutegravir, trade name: Tivicay, is an anti-inflammatory drug developed jointly by the British pharmaceutical giant GlaxoSmithKline (GSK) and the Japanese Shionogi Pharmaceutical Company (Shionogi). New AIDS drugs. [0003] (R)-3-aminobutanol is an important intermediate for the synthesis of dolutegravir, and its structural formula is as follows: [0004] . [0005] The problems in the preparation of the intermediate in the prior art are mainly reflected in the following points: the reaction route is long, the overall yield is low, the process operation is relatively harsh, and highly toxic and explosive sensitive materials are required. Contents of the invention [0006] The technical problem to be solved in the present invention is to provide a preparation method of (R)-...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C215/08C07C269/06C07C271/22
CPCC07B2200/07C07C213/02C07C269/06C07C215/08C07C271/22
Inventor 刘劲松王平于淑玲张少平周文峰王辉
Owner CANGZHOU SENARY CHEM SCI TEC
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