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Preparation method of 2S-(1-tetrahydropyramid-2-one)-3-methylbutanoic acid

A technology of ectoine and methylbutyric acid, applied in the direction of organic chemistry, can solve problems affecting the health of production personnel, polluting the environment, complicated procedures, etc., to save complicated procedures, maintain the production environment, and save operating time Effect

Active Publication Date: 2014-07-23
厦门蔚嘉制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the procedures of step 3) and step 4) of the above method are extremely complicated and cumbersome
In addition, the industrial ammonia water used is easy to volatilize ammonia gas that is irritating and corrosive to the eyes, nose and skin, which not only affects the health of production personnel but also pollutes the environment

Method used

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  • Preparation method of 2S-(1-tetrahydropyramid-2-one)-3-methylbutanoic acid
  • Preparation method of 2S-(1-tetrahydropyramid-2-one)-3-methylbutanoic acid
  • Preparation method of 2S-(1-tetrahydropyramid-2-one)-3-methylbutanoic acid

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Experimental program
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Effect test

Embodiment 1

[0042]1) Pour purified water (200kg) into the reaction tank, add L-valine (100kg) while stirring, cool down to 20-25°C after the addition is complete, and continue stirring for 15 minutes. 2) Add potassium hydroxide aqueous solution (57kgKOH mixed with 57kg water) dropwise, cool down to 20-25°C after the addition is complete, and continue stirring for 30 minutes until clarification. 3) Cool the solution to 0-5°C and add acrylonitrile (50kg) dropwise. After the addition is complete, keep the temperature at 0-5°C and react for 5 hours. The concentration of L-valine detected by TLC was 2.0%. 4) Add purified water (250kg). After the addition is complete, heat up to 10-15°C, and adjust the pH value to 10.0 with concentrated hydrochloric acid. 5) Slowly add methyl chloroformate (161kg) dropwise, and at the same time add 30% sodium hydroxide The pH value of the solution was maintained at 10.0. After the feeding was completed, the temperature was maintained at 10-15° C. and the pH va...

Embodiment 2

[0044] 1) Pour purified water (200kg) into the reaction tank, add L-valine (100kg) while stirring, cool down to 20-25°C after the addition is complete, and continue stirring for 15 minutes. 2) Add potassium hydroxide aqueous solution (57kgKOH mixed with 57kg water) dropwise, cool down to 20-25°C after the addition is complete, and continue stirring for 30 minutes until clarification. 3) Cool the solution to 0-5°C, add acrylonitrile (50kg) dropwise, and keep the temperature at 0-5°C for 7 hours after the addition is complete. The concentration of L-valine detected by TLC was 1.0%. 4) Add purified water (250kg). After the addition is complete, heat up to 10-15°C, and adjust the pH value to 10.0 with concentrated hydrochloric acid. 5) Slowly add methyl chloroformate (161kg) dropwise, and at the same time add 30% sodium hydroxide The pH value of the solution was maintained at 10.0. After the feeding was completed, the temperature was maintained at 10-15° C. and the pH value was m...

Embodiment 3

[0050] 1) Pour purified water (200kg) into the reaction tank, add L-valine (100kg) while stirring, cool down to 20-25°C after the addition is complete, and continue stirring for 15 minutes. 2) Add potassium hydroxide aqueous solution (57kgKOH mixed with 57kg water) dropwise, cool down to 20-25°C after the addition is complete, and continue stirring for 30 minutes until clarification. 3) Cool the solution to 0-5°C and add acrylonitrile (50kg) dropwise. After the addition is complete, keep the temperature at 0-5°C and react for 6 hours. The concentration of L-valine detected by TLC was 1.6%. 4) Add purified water (250kg). After the addition is complete, heat up to 10-15°C, and adjust the pH value to 10.0 with concentrated hydrochloric acid. 5) Slowly add methyl chloroformate (161kg) dropwise, and at the same time add 30% sodium hydroxide The pH value of the solution was maintained at 10.0. After the feeding was completed, the temperature was maintained at 10-15° C. and the pH v...

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Abstract

The invention discloses a preparation method of 2S-(1-tetrahydropyramid-2-one)-3-methylbutanoic acid. The method comprises the following steps: 1, reacting L-valine with acrylonitrile in an aqueous alkali at 0-5DEG C until the concentration of L-valine is not lower than 2.0%, adjusting the pH value of the obtained solution to 9.5-10.5, adding methyl chloroformate, reacting at 10-15DEG C until the concentration of methyl chloroformate is lower than 5.0%, and extracting a product I; and ,2 dissolving the product I in an alkaline solution with the concentration of 5-20%, introducing hydrogen under the catalysis of Raney Ni, reacting at 95-100DEG C under a pressure of 4.0-4.5kg / cm<2> until the concentration of the product I is lower than 1%, and crystallizing to obtain 2S-(1-tetrahydropyramid-2-one)-3-methylbutanoic acid. The preparation method can avoid the generation of viscous substances in hydrogenation and ring opening processes, greatly improves the product yield, saves the complicated steps of filtration, extraction and the like, and reduces the production cost; and ammonia water is not used in the preparation method, so it is beneficial for maintaining good production environment and the health of operators.

Description

technical field [0001] The invention relates to a preparation method of 2S-(1-tetrahydropyrimidin-2-one)-3-methylbutanoic acid. Background technique [0002] 2S-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid is an important intermediate of the anti-AIDS drug lopinavir, and its structural formula is as follows: [0003] [0004] Patent document US5914332A discloses a synthesis method of 2S-(1-tetrahydropyrimidin-2-one)-3-methylbutanoic acid. Its reaction circuit is as follows: [0005] [0006] Reaction of compound 11 (either the free carboxylic acid or carboxylic acid ester) with acrylonitrile yields aminonitrile 18 using standard conditions (e.g. the amine with the appropriate anhydrous methyl chloroformate) or in an inorganic base (e.g. NaOH, KOH,K 2 CO 3 etc.) or an organic base (eg, alkylamine or dialkylamine, etc.) to produce compound 19 directly or in an inert solvent (eg, water or THF, etc.). Hydrogenation of compound 19 in an inert solution (e.g., wate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/10
CPCC07D239/10
Inventor 侯鹏翼纪毅东
Owner 厦门蔚嘉制药有限公司
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