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Method for preparing relative amino alcohol by borohydride-acid reduction system reducing amino ketone derivative

A technology of borohydride and aminoketone, which is applied in the field of borohydride-acid reduction system to reduce aminoketone derivatives to prepare corresponding aminoalcohols, which can solve the problems of poor stereoselectivity, cumbersome post-treatment, long reaction time, etc., and achieve conversion rate Complete, short reaction time, high selectivity effect

Inactive Publication Date: 2008-11-26
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The aluminum isopropoxide reduction method is characterized by high stereoselectivity, but due to the longer reaction time, more by-products, and more cumbersome post-treatment; the reported sodium borohydride reduction method is relatively poor in stereoselectivity, usually after purification lower yield

Method used

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  • Method for preparing relative amino alcohol by borohydride-acid reduction system reducing amino ketone derivative
  • Method for preparing relative amino alcohol by borohydride-acid reduction system reducing amino ketone derivative
  • Method for preparing relative amino alcohol by borohydride-acid reduction system reducing amino ketone derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1. Reduction of (R)-N-benzyloxyformyl-1-chloro-4-phenylthio-3-amino-2-butanone with sodium borohydride-methanesulfonic acid

[0021] (R)N-Benzyloxycarbonyl-1-chloro-4-phenylsulfanyl-3-amino-2-butanone 50mg (0.137mmol), sodium borohydride 6mg (0.151mmol), at -15°C, add ethanol 5 mL, 0.01 mL (0.137 mmol) of methanesulfonic acid, and the reaction was stirred for 30 min. With stirring, 5 mL of 10% potassium carbonate was added, the solvent was evaporated under reduced pressure, 8 mL of ethyl acetate and 8 mL of water were added. Divide the water layer. The organic phase was washed successively with water (8 ml) and saturated sodium chloride solution (8 mL). Dry over anhydrous sodium sulfate. filter. The solvent was evaporated under reduced pressure to obtain (2S,3R)N-benzyloxyformyl-1-chloro-4-phenylthio-3-amino-2-butanol (4a) and (2R,3R)N-benzyloxymethyl A mixture of acyl-1-chloro-4-phenylthio-3-amino-2-butanols (5a). The total yield of 4a and 5a determined b...

Embodiment 2

[0022] Example 2. Reduction of (R)-N-benzyloxyformyl-1-chloro-4-phenylthio-3-amino-2-butanone with sodium borohydride-trifluoroacetic acid

[0023] (R)-N-Benzyloxycarbonyl-1-chloro-4-phenylsulfanyl-3-amino-2-butanone 50mg (0.137mmol), sodium borohydride 6mg (0.151mmol), at -15°C, add Ethanol 5mL, trifluoroacetic acid 0.01ml (0.137mmol). The reaction was stirred for 30 min. Add 5 ml of 10% potassium carbonate with stirring. The solvent was evaporated under reduced pressure. 8 mL of ethyl acetate and 8 mL of water were added. Divide the water layer. The organic phase was washed with water (8 mL) followed by saturated sodium chloride solution (8 mL). Dry over anhydrous sodium sulfate. filter. The solvent was evaporated under reduced pressure to obtain (2S,3R)-N-benzyloxycarbonyl-1-chloro-4-phenylthio-3-amino-2-butanol (4a) and (2R,3R)-N-benzyl A mixture of oxyformyl-1-chloro-4-phenylthio-3-amino-2-butanol (5a). The total yield of 4a and 5a determined by HPLC internal sta...

Embodiment 3

[0024] Example 3. Potassium borohydride-methanesulfonic acid reduction of (R)-N-benzyloxycarbonyl-1-chloro-4-phenylthio-3-amino-2-butanone

[0025] (R)-N-benzyloxycarbonyl-1-chloro-4-phenylsulfanyl-3-amino-2-butanone 10g (27.4mmol), potassium borohydride 1.8g (30.2mmol), at -15°C, 40 mL of ethanol and 2 mL of methanesulfonic acid (27.4 mol) were added. The reaction was stirred for 60 min, and TLC detected the disappearance of the raw materials. With stirring, 15 mL of 10% potassium carbonate was added. The solvent was evaporated under reduced pressure. 30 mL of ethyl acetate and 30 mL of water were added. Divide the water layer. The organic phase was washed with water (20 mL) followed by saturated sodium chloride solution (20 mL). Dry over anhydrous sodium sulfate. filter. The solvent was evaporated under reduced pressure to give 9.82. Recrystallization from ethyl acetate / petroleum ether (1 / 3) gave (2S,3R)-N-benzyloxycarbonyl-1-chloro-4-phenylthio-3amino-2-butanol 7.64...

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Abstract

Amino amidation protected amino ketone derivative is reduced with borohydride-acid reduction system, which comprises sodium or potassium borohydride and organic acid or inorganic acid in the molar ratio of 1 to 0.5-1.5, and the molar ratio between basic reactant amino ketone and the reductant is 1 to 0.9-2.0. Amino ketone derivative and borohydride reacts in solvent at the temperature from -20 deg.c to +20 deg.c through stirring for 30-60 min, and through decompression distilling to eliminate solvent, extraction and re-crystallization to obtain product. The present invention has high selectivity, complete conversion, short reaction time and easy post-treatment, and especially the potassium borohydride-methylsulfonic acid system has low material cost and industrial application value.

Description

technical field [0001] The invention relates to a method for preparing a corresponding amino alcohol by diastereoselective reduction of a chiral amino ketone derivative by a borohydride-acid reduction system. Background technique [0002] Amino alcohols are the basic structural components of many important biologically active substances. For example: the anti-AIDS drugs nelfinavir (1) and saquinavir (2) (shown below) both contain this amino alcohol structure. [0003] [0004] An important method for the synthesis of such chiral amino alcohols is the preparation of the corresponding amino ketone derivatives by selective reduction. The schematic diagram of selective reduction of amino ketones is as follows: [0005] [0006] The main methods reported in the literature for the reduction of amino ketones to prepare amino alcohols are: NaBH 4 , LiAlH 4 , DIBALH, BU 4 NBH 4 , Me 4 NBH 4 , Li-9-BBNH, Zr( i PrO) 4 IPA, Al( i PrO) 3 Wait for the reduction of the re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C333/32C07C319/20C07C231/12C07B41/02
Inventor 靳立人王利娟谭斌
Owner XIAMEN UNIV
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