Efavirenz intermediate synthesizing method

A technology of efavirenz and an intermediate, which is applied in the field of organic chemical catalysis, can solve the problems of unfavorable industrial production, easy to absorb water again, high price and the like, and achieves the effects of easy recovery, beneficial to recovery and application, and easy operation.

Inactive Publication Date: 2017-07-14
WUHAN INSTITUTE OF TECHNOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This method synthesis efavirenz key intermediate has the following disadvantages: (1) when the solvent used is tetrahydrofuran, the miscibility between tetrahydrofuran and water is high. (2) zinc reagent uses diethyl zinc, which is expensive and unfavorable for industrial production; (3) adopting a large amount of organic ligands to react greatly increases the cost; (4) when adopting ether or tetrahydrofuran as solvent, during reaction A large amount of solvent needs to be supplemented to dissolve cyclopropynylmagnesium chloride and dilute the reaction solution

Method used

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  • Efavirenz intermediate synthesizing method

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Effect test

Embodiment 1

[0031] Add 3.2g of magnesium chips and 10mL of 2-methyltetrahydrofuran into a round-bottomed flask, add bromoethane to initiate the reaction, control the temperature at 40°C, and add dropwise a mixture of 17.8g of bromobutane and 40mL of 2-methyltetrahydrofuran liquid. After the addition is complete, keep the reaction at 40°C for 3 hours, and then lower the temperature to below 10°C. Slowly add 8.5 g of cyclopropyneacetylene dropwise. After the addition, keep stirring at 10-15° C. for 2 hours, and place the prepared cyclopropyne-magnesium bromide format solution for later use. 32.4 g of potassium hydride was put into another round bottom flask, and 30 mL of 2-methyltetrahydrofuran was added. After the addition, the temperature was lowered to 10°C. Add neopentyl alcohol (8.8g), toluene (20g) and (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (7g) under control within 20°C and mix Liquid, mixed evenly for later use, and stirred at 10-15°C for 2 hours after adding. Then the t...

Embodiment 2

[0033]Add 3.84g of magnesium chips and 10mL of 2-methyltetrahydrofuran into a round-bottomed flask, add bromoethane to initiate the reaction, control the temperature at 40°C, and dropwise add a mixture of 21g of bromobutane and 40mL of 2-methyltetrahydrofuran . After the addition is complete, keep the reaction at 43°C for 2 hours, and then lower the temperature to below 10°C. Slowly add 10.2 g of cyclopropyneacetylene dropwise. After the addition is complete, keep stirring at 15° C. for 2 hours. The prepared cyclopropynemagnesium bromide format solution is set aside for later use. Put 24g of sodium hydride into another round bottom flask, and add 30mL of 2-methyltetrahydrofuran. After the addition, the temperature was lowered to 10°C. Add neopentyl alcohol (10.73g), toluene (20g) and (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (8g) under control within 20°C and mix Liquid, mixed evenly for later use, and stirred at 14°C for 2 hours after the addition was complete. Then ...

Embodiment 3

[0035] Add 5.96g of magnesium chips and 10mL of 2-methyltetrahydrofuran into a round-bottomed flask, add bromoethane to initiate the reaction, control the temperature at 41°C, add dropwise a mixture of 34.1g of bromobutane and 50mL of 2-methyltetrahydrofuran liquid. After the addition is complete, keep the reaction at 42°C for 2 hours, and then lower the temperature to below 5°C. Slowly add 15.9 g of cyclopropyneacetylene dropwise. After the addition, keep stirring at 15° C. for 2 hours, and place the prepared cyclopropynemagnesium bromide format solution for later use. 36.7 g of sodium hydride was put into another round bottom flask, and 60 mL of 2-methyltetrahydrofuran was added. After the addition, the temperature was lowered to 10°C. Add neopentyl alcohol (16.4g), toluene (20g) and (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (13.1g) within 20°C The mixed liquid was mixed evenly for later use, and stirred at 13° C. for 2 hours after the addition was completed. Then t...

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Abstract

The invention relates to an efavirenz intermediate synthesizing method. The efavirenz intermediate synthesizing method comprises the following steps of: adding cyclopropyl acetylene magnesium bromide to a coordination compound prepared from neopentyl alcohol, a zinc salt or copper salt and (1R, 2S)-1-phenyl-2-(1-pyrrolidyl)-1-propyl alcohol by using 2-methyltetrahydrofuran as a solvent, reacting, adding 4-chlorine-2-(trifluoroacetyl) aniline, and carrying out heat-preservation stirring till ending; and transferring to a saturated citric acid solution for quenching, carrying out reduced pressure distillation after separating to obtain an organic phase, adding an polar organic solvent and L-amino acid after obtaining racemate, heating and mixing, carrying out cooling crystallization after resolution, and carrying out recrystallization after obtaining crystals to obtain white powder. Compared with the prior art, the efavirenz intermediate synthesizing method has the advantages that the 2-methyltetrahydrofuran which is a green solvent is used in reaction; the product with relatively high optical purity is obtained by using very few organic ligands; the yield is relatively high; the selectivity is good; the separation of products and the control of reaction conditions are easy; and the method conforms to green and environmental protection concept and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for synthesizing an efavirenz intermediate, belonging to the field of organic chemical catalysis. Background technique [0002] Efavirenz (Efavirenz) is an anti-HIV non-nuclear general reverse transcriptase inhibitor, developed by Merck, is the first-selected anti-HIV drug in the world, and its development has also received great attention. Its English Name: (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one, Chinese name is (4S)-6- Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one, the molecular formula is: C 14 h 9 CIF 3 NO 2 , the relative molecular mass is 315.678, the CAS registration number is 154598-52-4, the appearance is off-white powder, and the melting point is 139-141°C. Its chemical structure is shown below. [0003] [0004] The synthesis of efavirenz is by intermediate (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C213/10C07C215/70
CPCC07C213/00C07B2200/07C07C213/10C07C215/70
Inventor 吴广文胡争朋熊奇邹杨熊泽
Owner WUHAN INSTITUTE OF TECHNOLOGY
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