Method for preparing chiral baclofen

A baclofen, chiral technology, applied in the field of preparation of chiral baclofen-baclofen,-baclofen), can solve the problems of expensive reagents, complicated operation, long reaction route, etc.

Active Publication Date: 2009-08-26
孟坤
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many disadvantages in these methods, such as the use of expensive reagent

Method used

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  • Method for preparing chiral baclofen
  • Method for preparing chiral baclofen
  • Method for preparing chiral baclofen

Examples

Experimental program
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Effect test

example 1

[0027] 3-(4-Chlorophenyl)glutaric acid (3.70 g, 15.29 mmol) was added into acetic anhydride (4.2 mL, 45.87 mmol), and refluxed until completely dissolved. Cool to room temperature, add diethyl ether (3 mL) dropwise, filter, wash with a little cold diethyl ether, and dry to obtain 2.77 g of 3-(4-chlorophenyl)glutaric anhydride, yield: 81%, mp: 128-129°C. 1 H NMR (500MHz, CDCl 3 ): δ2.81-2.87(m, 2H), 3.07-3.11(m, 2H), 3.40-3.45(m, 1H), 7.16(d, J=9.0Hz, 2H), 7.37(d, J=9.0 Hz, 2H); 13 C NMR (125MHz, CDCl 3 ): 33.51, 36.91(2C), 127.63(2C), 129.49(2C), 133.97, 137.52, 165.55(2C); FT-IR(KBr, cm -1 ): 1759 (CO); MS (m / z, %rel intensity): 226 (M + , 37 Cl, 6), 224 (M + , 35 Cl, 15), 140(33), 138(100), 115(9), 103(26), 77(9); HRMS(ESI) calcd for C 11 h 10 ClO 3 [M+H] + : 225.0313, found: 225.0316.

example 2

[0029] Under the protection of argon, add 3-(4-chlorophenyl)glutaric anhydride (0.32g, 1.43mmol) into 90mL of anhydrous ether, stir, cool, add (DHQD) 2 AQN (0.39g, 0.45mmol) was added dropwise to anhydrous methanol (0.46g, 14.30mmol) under temperature control at -40°C. After the addition was complete, the reaction was continued at temperature control at -40°C for 120h. Hydrochloric acid (1N, 42 mL) was added, warmed to room temperature, extracted with ethyl acetate (3×100 mL), dried and concentrated. Column chromatography (cyclohexane / ethyl acetate=15:1, then ethyl acetate) gave (S)-3-(4-chlorophenyl)glutaric acid monomethyl ester 0.27g, yield: 75%, 95%ee, mp: 103-104°C; [ α ] D 25 = - 8.0 ( c 0.88 , CHC l 3 ) . ...

example 3

[0031] At room temperature, (S)-3-(4-chlorophenyl)glutaric acid monomethyl ester (0.35g, 1.37mmol) was dissolved in anhydrous benzene (20mL), and diphenylphosphoryl azide (DPPA ) (0.57g, 2.00mmol) and Et 3 N (0.21g, 2.0mmol), reflux reaction for 7h, cooled to room temperature, room temperature reaction overnight. Anhydrous methanol (0.15 g, 4.67 mmol) was added dropwise, and the reaction was refluxed for 10 h. Cool to room temperature, concentrate under reduced pressure, add ethyl acetate, saturated NaHCO 3 washed, washed with water, washed with 5% HCl, washed with water, dried, and concentrated to obtain a crude product. Column chromatography (cyclohexane / ethyl acetate=3:1) gave yellow oil (S)-3-(4-chlorophenyl)-4-methoxycarbonylaminobutyric acid methyl ester 0.24g, yield : 62%. 1 H NMR (500MHz, CDCl 3 ): δ2.46-2.63(m, 2H), 3.20-3.22(m, 2H), 3.38(m, 1H), 3.49(s, 3H), 3.51(s, 3H), 4.70(brs, 1H), 7.04(d, J=8.5Hz, 2H), 7.18(d, J=8.5Hz, 2H); 13 CNMR (125MHz, CDCl 3 ): 38....

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Abstract

The invention relates to a method for preparing chiral baclofen, belonging to the synthesis field of chiral compounds. The synthetic route of the method is as follows: 3-(4-chlorphenyl) glutarate used as a starting material is condensed to prepare 3-(4-chlorphenyl) glutaric anhydride; a key intermediate (S)-3-(4-chlorphenyl) monoester glutarate is prepared by the 3-(4-chlorphenyl) glutaric anhydride under the action of chiral catalysts and the chiral baclofen is prepared by Curtius (or Hofmann) rearrangement reaction. The method of the invention has short reaction steps, convenient operation, high ee value of product, low cost and high yield.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of chiral baclofen ((S)-baclofen (I), (R)-baclofen (II)). Background technique [0002] γ-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system of mammals. It has important physiological functions, such as lowering blood pressure, promoting mental stability, promoting brain blood flow, increasing brain vitality, nutrition Nerve cells, increase the secretion of growth hormone, invigorate the liver and kidney, improve menopausal syndrome, etc. Baclofen (3-(4-chlorophenyl)-4-aminobutyric acid) is a known highly selective and highly active GABA B receptor agonist. According to literature reports (Eur.J.Pharmacol., 1978, 52, 133), (R)-baclofen is more active than (S)-baclofen, (see I, II for structural formula), but only its racemate is present listed. [0003] [0004] (S)-Baclofen(I) (R)-Baclofen(II...

Claims

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Application Information

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IPC IPC(8): C07C229/34C07C227/32C07C227/04B01J31/02
Inventor 李靖冀蕾
Owner 孟坤
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