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Preparation method of 2,2,2-trifluoro-N-[(1S,4S)-4-hydroxy tetrahydronaphthalene-1-yl]-acetamide

A technology of tetralin and acetamide, which is applied in the field of medicine and chemical industry, can solve the problems of complex post-processing, low synthesis efficiency, and a lot of waste, and achieve the effects of reducing waste discharge, low preparation cost, and simple reaction operation

Inactive Publication Date: 2018-09-21
浙江华贝药业有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to provide a 2,2,2-trifluoro-N- [( 1S , 4S )-4-hydroxyl-1,2,3,4-tetrahydronaphthalene-1-yl]-acetamide preparation method, comprises the following steps:

Method used

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  • Preparation method of 2,2,2-trifluoro-N-[(1S,4S)-4-hydroxy tetrahydronaphthalene-1-yl]-acetamide

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Embodiment 1

[0024] Embodiment 1: the synthesis of compound 1

[0025] Under nitrogen protection, add 500mL toluene to the reaction flask, start stirring, continue to add 80 g of compound 2, cool down to -20 ~ -10 ℃, add 32mL ( R )-2-methyl-CBS-oxazoborolane (1M), keep warm for 10 minutes, quickly add 45mL borane dimethyl sulfide (10M), keep warm at -20 ~ -10 ℃ for half an hour, heat up to 0 ~ 5 React at ℃ for half an hour, take a sample and control it. After passing the test, add 500mL of 3.6% dilute hydrochloric acid, stir at 0 ~ 5 ℃ for 1 hour, filter, beat the filter cake with water, dry the filter cake under reduced pressure at 50 ~ 60 ℃ to obtain 76.8 g of compound 1 , yield 95.2%, purity 99.2%, ee% value 99.1%. 1 HNMR (400 MHz, d 6 -DMSO): 1.61-1.84 (2H, m), 2.07-2.18 (2H, m), 4.61 (1H, m), 5.09 (1H, m), 5.29 (1H, d), 7.08 (1H, m), 7.24 (1H, dd), 7.51 (1H, dd), 9.77 (1H, d).

Embodiment 2

[0026] Embodiment 2: the synthesis of compound 1

[0027] Under nitrogen protection, add 500mL toluene to the reaction flask, start stirring, continue to add 80 g of compound 2, cool down to -20 ~ -10 ℃, add 32mL ( R )-2-n-butyl-CBS-oxazoborane (1M), keep warm for 10 minutes, quickly add 45mL borane dimethyl sulfide (10M), keep warm at -20 ~ -10 ℃ for half an hour, heat up to 0 ~ React at 5°C for half an hour, take a sample and control it. After passing the test, add 500mL of 3.6% dilute hydrochloric acid, stir at 0-5°C for 1 hour, filter, beat the filter cake with water, dry the filter cake under reduced pressure at 50-60°C to obtain 77.4 g of compound 1. The yield is 96.0%, the purity is 99.1%, and the ee% value is 99.0%.

Embodiment 3

[0028] Embodiment 3: the synthesis of compound 1

[0029] Under nitrogen protection, add 500mL toluene to the reaction flask, start stirring, continue to add 80 g of compound 2, cool down to -20 ~ -10 ℃, add 60mL ( R )-2-methyl-CBS-oxazoborolane (1M), keep warm for 10 minutes, quickly add 45mL borane dimethyl sulfide (10M), keep warm at -20 ~ -10 ℃ for half an hour, heat up to 0 ~ 5 React at ℃ for half an hour, take a sample and control it. After passing the test, add 500mL of 3.6% dilute hydrochloric acid, stir at 0 ~ 5 ℃ for 1 hour, filter, beat the filter cake with water, and dry the filter cake under reduced pressure at 50 ~ 60 ℃ to obtain 77.6 g of compound 1 , yield 96.3%, purity 99.1%, ee% value 99.2%.

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Abstract

The invention discloses a preparation method of 2,2,2-trifluoro-N-[(1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-yl]-acetamide. The preparation method comprises the following steps: performing asymmetric reduction on 2,2,2-trifluoro-N-[(S)-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-yl]-acetamide under the action of chiral oxazaborolidine derivative and borane-methyl sulfide to obtain a 2,2,2-trifluoro-N-[(1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-yl]-acetamide reaction solution; after the reaction ends, adding diluted hydrochloric acid for quenching, filtering, pulping with water, and carrying out solid drying to obtain a pure product, wherein the yield is 95.0% or higher, the purity is 99.0% or higher, and the ee% value is 99.0% or higher. According to the preparation method disclosed by the invention, the asymmetric reduction is carried out under the combined action of chiral oxazaborolidine derivative and borane-methyl sulfide, the reaction is simple in operation, the preparation period is shortened, the manufacturing cost is reduced, the generation of solid waste and solid water is greatly reduced, the preparation method is beneficial for environmental protection, and the investment of an enterprise for the disposal of waste is reduced.

Description

technical field [0001] The present invention relates to the technical field of medicine and chemical industry, specifically a kind of 2,2,2-trifluoro-N-[( 1S , 4S )-4-hydroxyl-1,2,3,4-tetrahydronaphthalene-1-yl]-acetamide preparation method. Background technique [0002] MOR is the target of opioid analgesics such as endogenous enkephalins and morphine. An oxygen heterocyclic derivative (general formula 1) reported in patent WO2017063509 is a receptor agonist of MOR. This compound 2, 2,2-trifluoro-N-[( 1S , 4S )-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-yl]-acetamide (compound 1) is one of the important structural fragments of oxygen heterocyclic derivatives (general formula 1). Its structural formula is as follows: [0003] [0004] The asymmetric reduction of ketones is one of the most basic reactions in asymmetric synthesis. The optically active alcohols, especially secondary alcohols, obtained from the asymmetric reduction of ketones are the basic structures of...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/23C07B53/00
CPCC07B53/00C07B2200/07C07C231/12C07C2602/10C07C233/23
Inventor 钱王科张三丰贡科斌冯爱军俞真益王红燕郑文瑾
Owner 浙江华贝药业有限责任公司
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