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Preparation method of chiral baclofen

A baclofen and chiral technology, applied in the field of preparation of chiral baclofen (-baclofen, -baclofen), can solve the problems of expensive reagents, complicated operations, long reaction routes, etc.

Active Publication Date: 2013-01-09
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 reagents in the preparation, long reaction routes, low yields, complicated operations, etc.

Method used

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  • Preparation method of chiral baclofen
  • Preparation method of chiral baclofen
  • Preparation method of chiral baclofen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 3-(4-chlorophenyl)glutaric acid (3.70g, 15.29mmol) into acetic anhydride (4.2mL, 45.87mmol), and reflux until completely dissolved. Cool to room temperature, add diethyl ether (3mL) dropwise, filter, wash with a little cold diethyl ether, and dry to obtain 2.77g 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.

Embodiment 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) at a temperature of -40°C. After the addition was complete, the reaction was continued at a temperature of -40°C for 120h. Hydrochloric acid (1N, 42mL) was added, warmed to room temperature, extracted with ethyl acetate (3x 100mL), 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; 1 H NMR (500MHz, CDCl 3 ):δ2.59–2.78(m,4H),3.58(s,3H),3.59–3.62(m,1H),7.16(d,J=8.5Hz,2H),7.27(d,J=8.5Hz, 2H); 13 C NMR (125MHz, CDCl 3 ):37.33,39.97,40.25,51.71,128.61(2C),128.82(2C),132.81,140.70,171.73,176.85; FT-IR(KBr,cm -1 ):3035,1729,1700,1435,1273,1222,1162; MS(m / z,%rel intensity):258(M + , 37 Cl,4),256(M + ...

Embodiment 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 (0.15g, 4.67mmol) was added dropwise, and the reaction was refluxed for 10h. Cool to room temperature, concentrate under reduced pressure, add ethyl acetate, saturated NaHCO 3 washing, washing with water, washing with 5% HCl, washing with water, drying, and concentration 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 C NMR (125MHz, CDCl 3 ):38.00,41.68,45.8...

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Abstract

The invention relates to a preparation method of chiral baclofen, belonging to the field of synthesis of chiral compounds. The synthetic route of the method comprises the following steps: condensing the initial raw material 3-(4-chlorphenyl)glutaric acid to obtain 3-(4-chlorphenyl)glutaric anhydride; preparing the 3-(4-chlorphenyl)glutaric anhydride into a key intermediate (S)-3-(4-chlorphenyl)monoglutarate under the action of a chiral catalyst; and carrying out Curtius rearrangement (or Hofmann rearrangement) reaction to obtain the chiral baclofen. The method has the advantages of short reaction steps and is simple to operate; and the product has the advantages of high ee value, low cost and high yield.

Description

[0001] This application is a divisional application number 200910080236X technical field [0002] 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 [0003] 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 and II for the structural formula), but only its rac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C227/32
Inventor 李靖冀蕾
Owner 孟坤
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