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Process for preparing 4.4-difluoro-2-amino butyric acid with optical activity and ester thereof

A technology of difluorocrotonate and optical activity, which is applied in the field of ester preparation, to achieve the effects of reasonable selection of reaction process, reduction of synthesis cost, and assurance of reproducibility and stability

Inactive Publication Date: 2007-07-04
上海药明康德新药开发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved in the present invention is: in the preparation process of 4,4-difluoro-2-amino-butyric acid and corresponding ester, avoid using expensive and difficult-to-prepare reagents, improve yield and reduce cost; provide a method for preparing 4 , 4-difluoro-2-amino-butyric acid and the corresponding ester method

Method used

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  • Process for preparing 4.4-difluoro-2-amino butyric acid with optical activity and ester thereof
  • Process for preparing 4.4-difluoro-2-amino butyric acid with optical activity and ester thereof
  • Process for preparing 4.4-difluoro-2-amino butyric acid with optical activity and ester thereof

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Experimental program
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Embodiment 1

[0036] 1. Synthesis of (S)-N-tert-butoxycarbonyl-4,4-difluoro-2-amino-butyric acid

[0037] Step 1: Synthesis of 1-ethoxy-2,2-difluoroethanol

[0038] Ethyl difluoroacetate (300 mL, 3 mol) was dissolved in anhydrous THF (600 mL), cooled to -78°C under nitrogen protection, and a suspension of LAH (29 g, 0.75 mol) in anhydrous THF (800 mL) was added dropwise. After the dropwise addition was completed, stirring was continued at -78°C for 3 h, and 98% ethanol (75 mL) was added. Then the reaction solution was naturally warmed to 25°C, poured into ice water, and concentrated sulfuric acid (230 mL) was added with stirring. The reaction liquid was extracted with ether (2000 mL*4), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and the filtrate was spin-dried under reduced pressure (keep the temperature of the water bath below 30°C). The residue was distilled under reduced pressure (vacuum degre...

Embodiment 2

[0057] 1. Synthesis of (S)-N-tert-butoxycarbonyl-4,4-difluoro-2-amino-butyric acid

[0058] The second step: the synthesis of ethyl 4,4-difluoro-2-butenoate

[0059] Will 1-ethoxy-2,2-difluoroethanol (147g, 1.167mol), ethoxycarbonylmethenyltriphenylphosphine (487g, 1.400mol), p-toluenesulfonic acid (24g, 0.140mol) and anhydrous toluene (2.5L) were heated to 120°C and refluxed overnight. The solvent was distilled off under reduced pressure, diethyl ether (500 mL) was added to the residue, filtered, and the filter layer was washed with diethyl ether (200 mL). The filtrates were combined, the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure (0.95Mpa), and the fraction above 50°C was collected to obtain a colorless transparent liquid, which was 4,4-Difluoro-2-butenoic acid ethyl ester (136 g, 0.858 mol, yield: 78%). 1 H NMR (400MHz, CDCl 3 ): δ6.675(m, J=60.8Hz, 1H), δ6.200(m, J=120Hz 1H), δ4.209(m, J=28.0Hz, 2H), δ3.891(m, J...

Embodiment 3

[0061] The second step: the synthesis of ethyl 4,4-difluoro-2-butenoate

[0062] Will 1-ethoxy-2,2-difluoroethanol (147g, 1.167mol), ethoxycarbonylmethenyltriphenylphosphine (487g, 1.400mol), acetic acid (8.4g, 0.140mol) and anhydrous tetrahydrofuran (2.5L) were stirred overnight at 25°C. The solvent was distilled off under reduced pressure, diethyl ether (500 mL) was added to the residue, filtered, and the filter layer was washed with diethyl ether (200 mL). The filtrates were combined, the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure (0.95Mpa), and the fraction above 50°C was collected to obtain a colorless transparent liquid, which was 4,4-Difluoro-2-butenoic acid ethyl ester (106.8 g, 0.712 mol, yield: 61%).

[0063] 1 H NMR (400MHz, CDCl 3 ): δ6.675(m, J=60.8Hz, 1H), δ6.200(m, J=120Hz1H), δ4.209(m, J=28.0Hz, 2H), δ3.891(m, J=30.4 Hz, 1H); δ3.643(m, J=67.4Hz, 1H); δ1.296(t, J=69.6Hz, 1H), Ms(M + +1, 151).

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Abstract

The invention relates to a method for preparing chiral alpha- aminobutyric acid with difluorobenzyl methyl function group, especially a method for preparing 4, 4- difluorobenzyl- 2- amino- butyrate and the relative ester. The invention solves problems of dear agent and low productivity in current process. The method comprises following steps: reducing difluorobenzyl acetate to get hemiacetal, catalyzing hemiacetal with organic acid and reacting with ylide phosphorous salt to get difluorobenzyl crotonic ester, hydrolyzing difluorobenzyl crotonic ester under basic condition and getting difluorobenzyl butenoic acid, catalytic hydrogenating difluorobenzyl butenoic acid and getting 4, 4- difluorobenzyl butyrate; directing 4, 4- difluorobenzyl butyrate with Evans ((S)-4- R2- 1, 3- oxygen nitrogen- zole- dione or (R)- 4- R2-1, 3- oxygen nitrogen- zole- dione ) to get chiral azides; hydrogenrating and protecting with amnio said azides and removing directing group from it and getting 4, 4- difluorobenzyl- 2- amino- butyrate of optical-purity; getting relative ester through normal deravitive reaction.

Description

Technical field: [0001] The invention relates to a preparation method of chiral-α-aminobutyric acid with difluoromethyl functional group, in particular to a preparation method of 4,4-difluoro-2-amino-butyric acid and corresponding ester. Background technique: [0002] 4,4-difluoro-2-amino-butyric acid and corresponding esters are relatively important drug intermediates, but so far there is no effective synthetic method to prepare this product. Two preparation methods have been reported in the literature. One method is to first react with N-bromosuccinimide (tetrahedron: Asymmetry; EN; 2003; 2919-2926) with N-acetyl glycine methyl ester, and then react with trimethyl phosphite (J.Chem .Soc.Perkin Trans.1 1995; 1603-1610), and then react with 2,2-difluoroethyl hemiacetal (Biorg.Chem.Lett.; 2004; 239-244) to obtain enamine, which in hand Hydrogenation (Biorg.Chem.Lett.; 2004; 239-244) in the presence of a neutral catalyst i-Pr-Duphos-R gives chiral 4,4-difluoro-2-amino-butyl e...

Claims

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Application Information

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IPC IPC(8): C07C227/12C07C229/20C07C213/00C07C219/04
Inventor 尹云星胡志刚施一峰马汝建唐苏翰陈曙辉李革
Owner 上海药明康德新药开发有限公司
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