Preparation of miglitol

A technology of benzylsuccinic acid monocarboxylic acid and derivatives, which is applied in the field of preparation of mitiglinide, can solve the problems of unavailability of R-isomer, high cost, low yield and the like, and achieves convenient industrial production, Mild process conditions and high optical purity

Inactive Publication Date: 2007-07-04
江苏省药物研究所有限公司
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Problems solved by technology

[0003] Half of the R-isomers cannot be utilized by the chemical resolution method, resulting in low yield and high cost (method 1)
The asymmetric hydrogenation method requires an expensive rhodium complex (rhodium / (2S,4S)-N-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine), making the production The cost is greatly improved, which is not conducive to industrial production (method 2)

Method used

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  • Preparation of miglitol
  • Preparation of miglitol
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] (S)-2-Chlorophenylpropionic acid

[0016] In a 5000ml reaction bottle, add 3000ml of 6N hydrochloric acid, add 330g (2mol) of L-phenylalanine under ice-salt bath cooling, stir, add 850g of 36% sodium nitrite aqueous solution dropwise below 0°C, and react overnight at room temperature, divide A light yellow organic layer was obtained, and the aqueous layer was extracted with ethyl acetate, combined and dried by adding an appropriate amount of anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain about 360 g of light yellow residue, [α] D 20 =+4.5° (methanol), yield 97.5% (direct reaction in next step).

[0017] (S)-Ethyl 2-chlorophenylpropionate

[0018] In a 3000ml reaction flask, add 351g (1.90mol) of (S)-2-chloro-3-phenylpropionic acid, 770ml of dichloromethane, 7.8ml of 98% sulfuric acid, add 1000ml of absolute ethanol dropwise under cooling in an ice bath, dropwise Stir the reaction at room temperature for 48 hours, wash with...

Embodiment 2

[0024] (S)-2-Benzylsuccinic acid

[0025] In a 1000ml reaction flask, add 625ml of anhydrous N,N-dimethylformamide, active methylene compound (0.4mol), cool in an ice-salt bath to below 0°C, add 48g (1mol) of 50% sodium hydrogen, and stir (S)-Ethyl 2-halo-3-phenylpropanoate (0.4mol) was added dropwise, and the mixture was kept stirring in an ice-salt bath for 30 minutes, and then stirred at room temperature. Pour the reaction solution into about 500g of crushed ice, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a yellowish brown residue, add 400ml of acetic acid and 400ml of 37% hydrochloric acid, heat to reflux for reaction, and concentrate under reduced pressure to a small volume, poured into crushed ice and crystallized overnight to obtain a white solid (results are shown in Table 1).

[0026]

[0027] Formula II

Embodiment 3

[0029] (S)-2-Benzylsuccinic anhydride

[0030] In a 1000ml reaction flask, add 62.5g (0.3mol) of (S)-2-benzylsuccinic acid and 220ml (2.33mol) of acetic anhydride, and react at 75-80°C for 1hr. After cooling, add about 415ml of isopropyl ether, put it in the refrigerator to crystallize overnight, and get 39.7g of white solid, mp122-125℃, yield 69.6%, [α] D 20 =+55.6° (ethyl acetate).

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Abstract

Production of miglina is carried out by providing chiral center by L-phenylalanine. It achieves high efficiency and good optical purity, and to avoid chemical resolution and asymmetric hydrogenation.

Description

technical field [0001] The invention relates to a preparation method of mitiglinide. Background technique [0002] Miglinide is a hypoglycemic drug, its mechanism of action is similar to that of sulfonylureas, and it mainly acts on the ATP-sensitive K of β-cells. + channel to promote insulin secretion. There are many preparation methods for mitiglinide, mainly chemical resolution method and asymmetric hydrogenation method. [0003] Half of the R-isomers cannot be utilized by the chemical resolution method, and the yield is low and the cost is high (method 1). The asymmetric hydrogenation method requires an expensive rhodium complex (rhodium / (2S,4S)-N-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine), making the production The cost is greatly improved, which is unfavorable for industrialized production (method 2). [0004] Method 1: chemical resolution method [0005] [0006] Method 2: Asymmetric Hydrogenation Method [0007] Contents of t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/44
Inventor 苏国强柴玉柱
Owner 江苏省药物研究所有限公司
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