Synthesizing method of antiviral drug amprenavir intermediate

An antiviral drug and a synthesis method technology, applied in the direction of organic chemistry and the like, can solve the problems of cumbersome operation, difficult to reuse, large amount of organic solvent, etc., to reduce the use of organic solvents, reduce post-processing operations, and achieve high product yield. Effect

Inactive Publication Date: 2012-07-18
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In order to solve a series of problems in the prior art for the preparation of amprenavir raw materials, such as large amount of organic solvents, difficulty in repeated use, cumbersome operation, etc., and follow a more green and efficient synthesis concept, the present invention provides a new The synthetic method of the antiviral drug amprenavir intermediate reduces the use of solvent, and the reaction operation is simple, the solvent is easy to recover and the product yield is high

Method used

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  • Synthesizing method of antiviral drug amprenavir intermediate
  • Synthesizing method of antiviral drug amprenavir intermediate
  • Synthesizing method of antiviral drug amprenavir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0024] The raw material (2S, 3R)-3-hydroxyl-4-(isobutylamino)-1-phenyl-2-butylcarbamate tert-butyl ester (I) (34.0g, 0.1mol) and triethylamine (20.5g , 0.2mol) was dissolved in dichloromethane (150mL), and a dichloromethane solution (150mL) of 4-nitrobenzenesulfonyl chloride (27.0g, 0.12mol) was added dropwise at -10°C, and the reaction was stirred at 30°C for 20h Afterwards, the liquid chromatography analysis formula (I) peak disappears, cools down to 10 ℃, feeds hydrogen chloride gas (1mol) reaction within 6h, adds the sodium hydroxide aqueous solution 300mL alkali washing of 2mol / L three times, stands for stratification, takes the organic Layer was dried with anhydrous sodium sulfate (30g), and a dichloromethane solution (100mL) of (S)-3-tetrahydrofuryloxy-succinimidyl carbonate (23.0g, 0.1mol) was added dropwise at 20°C , After reacting for 20h, dichloromethane was removed under reduced pressure, washed with water and dried to obtain the described amprenavir intermediate (...

Embodiment 2

[0026]The starting material (2S, 3R)-3-hydroxyl-4-(isobutylamino)-1-phenyl-2-butylcarbamate tert-butyl ester (I) (34.0g, 0.1mol) and triethylamine (30.8g , 0.3mol) was dissolved in toluene (150mL), and a toluene solution (150mL) of 4-nitrobenzenesulfonyl chloride (33.8g, 0.15mol) was added dropwise at 10°C, stirred and reacted at 45°C for 30h, and the liquid chromatographic analysis formula (1) The peak disappears, and at this temperature, the flow rate in 20h feeds hydrogen chloride gas (2mol) to react, and the gained reaction solution adds 2mol / L potassium hydroxide aqueous solution 300mL alkali washes three times, leaves standstill and divides the water layer, and the organic layer is used Anhydrous magnesium sulfate (35g) was dried, and a toluene solution (100mL) of (S)-3-tetrahydrofuryloxy-succinimidyl carbonate (16.1g, 0.7mol) was added dropwise at 50°C, and after 20h of reaction, the Remove the toluene under pressure, wash and dry to obtain the described amprenavir inte...

Embodiment 3

[0028] Starting material (2S, 3R)-3-hydroxyl-4-(isobutylamino)-1-phenyl-2-butylcarbamate tert-butyl ester (I) (34.0g, 0.1mol) and pyridine (24g, 0.3mol ) was dissolved in dichloroethane (150mL), and 4-nitrobenzenesulfonyl chloride (27.0g, 0.12mol) in dichloroethane solution (150mL) was added dropwise at -10°C, stirred at 40°C for 20h, and the liquid phase The peak of chromatographic analysis formula (I) disappears, lower the temperature to -10°C, feed hydrogen chloride gas (1.2mol) to react within 6h, add 0.5mol / L sodium carbonate aqueous solution 1000mL alkali wash three times, let stand to separate the water layer, organic layer Dry with anhydrous calcium chloride (26g), add (S)-3-tetrahydrofuryloxy-succinimidyl carbonate (46.0g, 0.2mol) in dichloroethane solution (100mL) dropwise at 10°C , After reacting for 40h, dichloroethane was removed under reduced pressure, washed with water and dried to obtain the amprenavir intermediate (5) (3S)-3-tetrahydrofuryloxy N-[(1S, 2R)-3-( ...

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Abstract

The invention discloses a synthesizing method of an antiviral drug amprenavir intermediate. The synthesizing method is implemented according to the following steps: dissolving (2S, 3R)-3-hydroxy-4-( isobutyric amino)-1-phenyl-2-butyle amino tert-butyl carbamate shown in formula (I) and organic base into an organic solvent, dropping organic solution of 4-nitrobenzenesulfonyl chloride, stirring for reaction, introducing hydrogen chloride gas for reaction, alkali washing inorganic base, drying inorganic salt, dropping organic solution of (S)-3-tetrahydrofuran epoxide-disuccinimidyl carbonate, reacting completely, then reducing pressure to remove the solvent, washing by water, and drying to obtain amprenavir intermediate shown as formula (II). According to the method, the use of the organic solvent and the separation and purification step are reduced, and the product yield is high.

Description

(1) Technical field [0001] The invention relates to a synthesis method of an antiviral medicine amprenavir intermediate. (2) Background technology [0002] Amprenavir, systematically named (3S)-3-tetrahydrofuryloxy N-[(1S,2R)-3-(N-isobutyl N-4-aminobenzenesulfonyl)-1- Phenyl-2-hydroxypropyl] carbamate is the fifth-generation antiretroviral protease inhibitor developed by Glaxo-Smith Company in the United Kingdom, and it was launched in the United States and Japan in May 1999. It has strong antiviral activity and good drug resistance, so it has good clinical application value. The synthetic route of existing industrialization prospect is to be raw material with (2R, 3S)-2-epoxy-4-phenyl-3-butylcarbamate tert-butyl ester derived from L-phenylalanine, and isobutylamine Carry out amine alkylation reaction to obtain intermediate (I), then carry out sulfonylation reaction with 4-nitrobenzenesulfonyl chloride, deprotection, carry out with (S)-3-tetrahydrofuryloxy-succinimidyl car...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20
Inventor 罗书平郑鹛许丹倩徐振元
Owner ZHEJIANG UNIV OF TECH
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