Process for preparing (S)-2-(2-carbonyl-tetrahydropyrimidyl-1-(2H)-base)-3-methyl butyric acid

A technology of methylbutyric acid and ectoine, which is applied in the field of preparation of -2--yl)-3-methylbutyric acid, can solve the problems of serious environmental pollution, low product yield, poor selectivity, etc., and achieve product High purity, high yield, environment-friendly effect

Inactive Publication Date: 2013-05-22
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above-mentioned method has disadvantages such as poor selectivity and low product yield, and its total yield is lower than 45%. In addition, the above-mentioned method uses a stoichiometric amount of aluminum-nickel alloy as a catalyst for the reduction reaction, which has high cost and serious environmental pollution

Method used

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  • Process for preparing (S)-2-(2-carbonyl-tetrahydropyrimidyl-1-(2H)-base)-3-methyl butyric acid
  • Process for preparing (S)-2-(2-carbonyl-tetrahydropyrimidyl-1-(2H)-base)-3-methyl butyric acid
  • Process for preparing (S)-2-(2-carbonyl-tetrahydropyrimidyl-1-(2H)-base)-3-methyl butyric acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1 (S)-2-(2-cyanoethylamino)-3-synthesis of methylbutanoic acid (compound II)

[0023] Add 11.7g of L-valine, 40ml of water, and 6.0g of NaOH into a 100mL three-necked flask. Slowly add 5.3 g of acrylonitrile dropwise to the system under the condition that the temperature of the system is controlled to be lower than 20° C., and the dropwise addition is completed within 30 minutes. After the dropwise addition, the system was controlled to react at 5-20°C for 20 hours. After the reaction is completed, adjust the pH of the system to 6-7 with concentrated hydrochloric acid, stir for 30 minutes, and then filter with suction. The resulting solid was washed with 40 mL of water. Drying gave 15.2 g of white solid compound II, yield: 90%.

[0024] 1 HNMR (300MHz, D 2 O): δ0.87(m, 6H, C(CH 3 ) 2 ), 1.78(m, 1H, CH), 2.57(m, 2H, CH 2 ), 2.69(m, 1H, N-CH), 2.81(m, 2H, CH 2 ).

Embodiment 2

[0025] The synthesis of embodiment 2 (S)-2-(2-cyanoethylamino)-3-methylbutyric acid (compound II)

[0026] Add 11.7g L-valine, 58ml water, 13.8gK 2 CO 3 . Slowly add 5.3 g of acrylonitrile dropwise to the system under the condition that the temperature of the system is controlled to be lower than 20° C., and the dropwise addition is completed within 30 minutes. After the dropwise addition, the system was controlled to react at 5-20°C for 10 hours. After the reaction is completed, adjust the pH of the system to 6-7 with concentrated hydrochloric acid, stir for 30 minutes, and then filter with suction. The resulting solid was washed with 40 mL of water. Drying gave 15.2 g of white solid compound II, yield: 90%.

[0027] 1 HNMR (300MHz, D 2 O): δ0.87(m, 6H, C(CH 3 ) 2 ), 1.78(m, 1H, CH), 2.57(m, 2H, CH 2 ), 2.69(m, 1H, N-CH), 2.81(m, 2H, CH 2 ).

Embodiment 3

[0028] The synthesis of embodiment 3 (S)-2-(2-cyanoethylamino)-3-methylbutanoic acid (compound II)

[0029] Add 11.7g of L-valine, 35ml of water, and 4.0g of NaOH into a 100mL three-necked flask. Slowly add 5.3 g of acrylonitrile dropwise to the system under the condition of controlling the system temperature at 50° C., and the dropwise addition is completed within 30 minutes. After the dropwise addition, the system was controlled to react at 50° C. for 5 hours. After the reaction is completed, adjust the pH of the system to 6-7 with concentrated hydrochloric acid, stir for 30 minutes, and then filter with suction. The resulting solid was washed with 40 mL of water. Drying gave 14.6g of white solid compound II, yield: 86%.

[0030] 1 HNMR (300MHz, D 2 O): δ0.87(m, 6H, C(CH 3 ) 2 ), 1.78(m, 1H, CH), 2.57(m, 2H, CH 2 ), 2.69(m, 1H, N-CH), 2.81(m, 2H, CH 2 ).

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Abstract

The present invention relates to process of preparing (S)-3-methyl-2-(2-carbonyl-tetrahydropyrimidyl-1(2H)-yl) butyric acid. (S)-2-amido-3-methyl butyric acid as the material is condensated, reduced in the presence of W2-W7 Raney-Ni as catalyst, and cyclized to prepare (S)-3-methyl-2-(2-carbonyl-tetrahydropyrimidyl-1(2H)-yl) butyric acid. The process of the present invention has high yield, low cost, simplicity, environment friendship and other advantages.

Description

technical field [0001] The invention relates to a preparation method of (S)-2-(2-carbonyl-tetrahydropyrimidin-1(2H)-yl)-3-methylbutanoic acid. Background technique [0002] (S)-2-(2-carbonyl-tetrahydropyrimidin-1(2H)-yl)-3-methylbutanoic acid is an important intermediate for preparing the anti-AIDS drug lopinavir, and its structural formula is as follows: [0003] [0004] The prior art uses L-valine (compound I) as the initial raw material to react with acrylonitrile to generate compound N—(2-cyanoethyl)—L—valine (compound II), and then adds chloroformate to acylate Reaction obtains N-(2-cyanoethyl)-N-alkoxycarbonyl-L-valine (compound III), and compound III obtains (S)-2-( 2-carbonyl-tetrahydropyrimidin-1 (2H)-yl)-3-methylbutanoic acid (compound IV) (US patent application, publication number US5914332), its reaction scheme is as follows: [0005] [0006] The above-mentioned method has disadvantages such as poor selectivity and low product yield, and its total yield...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/10B01J25/02
Inventor 王立新彭焕庆杜振军兰海峰
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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