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Method for synthesizing D-biphenyl alanine

A technology of biphenylalanine and diethyl acetamidomalonate is applied in the field of synthesizing D-biphenylalanine, which can solve the problem of high chirality that cannot be solved by chemical methods, and is unfavorable for industrialized production and synthesis Problems such as low yield, to achieve the effect of easy industrialized large-scale production, simple environmental protection, and high chiral purity

Active Publication Date: 2017-02-15
NANJING REDWOOD FINE CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] 2) It is reported that biphenyl formaldehyde is used as a raw material to synthesize acylated amino acids, but the synthesis yield is very low and the cost is relatively high, which is not conducive to industrial production
[0011] This method can obtain mixed amino acids, but ordinary chemical methods cannot solve the problem of high chirality

Method used

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  • Method for synthesizing D-biphenyl alanine
  • Method for synthesizing D-biphenyl alanine
  • Method for synthesizing D-biphenyl alanine

Examples

Experimental program
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Effect test

Embodiment 1

[0031] 1) Add 1200kg of ethanol to the reaction kettle, start stirring, add 200kg of diethyl acetamidomalonate, and then add 28kg of sodium metal. Then add 150 kg of 4-bromomethyl biphenyl, keep the temperature at 50° C. for 2 hours, cool down and crystallize to obtain 320 kg of the condensate shown in Formula 1.

[0032] 2) Add 1100kg of 0.5mol / L hydrochloric acid into the reaction kettle, start stirring, add 320kg of the condensate shown in formula 1, stir at 25-30°C for 2 hours, cool down and crystallize to obtain N-acetyl-DL-biphenylalanine Acid 150kg.

[0033] 3) Add 1800kg of water to the reaction kettle, add 150kg of N-acetyl-biphenylalanine, adjust the pH to 7.6 with ammonia water, raise the temperature to 30°C, add L-aminoacylase and L-alanine for racemization Enzymes, a total of 0.15g, wherein the enzyme activity ratio of L-aminoacylase and L-alanine racemase is 1:2.1, reacted for 10 hours, a large amount of D-biphenylalanine crystallized out, centrifuged , rinsed ...

Embodiment 2

[0036] 1) Add 2500kg of ethanol to the reaction kettle, start stirring, add 416kg of diethyl acetamidomalonate, and then add 62.5kg of sodium metal. Then add 315 kg of 4-bromomethylbiphenyl, and keep the temperature at 50° C. for 2 hours. Cooling and crystallization gave 669 kg of the condensate shown in Formula 1.

[0037] 2) Add 2300kg of 0.5mol / L hydrochloric acid into the reaction kettle, start stirring, add 669kg of the condensate shown in formula 1 obtained in step 1, stir at 25-30°C for 2 hours, cool down and crystallize to obtain N-acetyl-DL-linked Phenylalanine 314kg.

[0038] 3) Add 3780kg of water to the reaction kettle, add 314kg of N-acetyl-biphenylalanine, adjust the pH to 7.6 with ammonia water, raise the temperature to 30°C, add L-aminoacylase and L-alanine for racemization Enzymes, a total of 0.471g, wherein, the enzyme activity ratio of L-aminoacylase and L-alanine racemase is 2.5, reacted for 10 hours, a large amount of D-biphenylalanine crystallized out, ...

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Abstract

The invention provides a method for synthesizing D-biphenyl alanine. The method comprises the following steps: 1) adding a solvent to a reaction kettle; during stirring, sequentially adding diethyl acetamidomalonate, metallic sodium and 4-bromomethyl biphenyl; after conducting a reaction, reacting a condensation product, which is obtained through cooling crystallization, and hydrochloric acid while conducting stirring, and conducting cooling crystallization so as to obtain N-acetyl-DL-biphenyl alanine; and 2) dissolving the N-acetyl-DL-biphenyl alanine in water; adjusting pH to 6.5-8.0 by virtue of ammonia water; adding catalyzing enzymes; and after a reaction, conducting centrifuging, rinsing with water and drying so as to obtain the D-biphenyl alanine, wherein the added catalyzing enzymes include L-aminoacylase and L-alanine racemase, and the total addition of the catalyzing enzymes is 0.1-0.15% of the mass of the N-acetyl-DL-biphenyl alanine. The method provided by the invention has the advantages that the method has fewer steps, and the method is mild in reaction, free from high temperature and high pressure, highly environment-friendly, high in yield and the like.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for synthesizing D-biphenylalanine. Background technique [0002] D-biphenylalanine is white crystalline powder, soluble in dilute hydrochloric acid, insoluble in ethanol and ether. It is the key intermediate of Sacubitril (AHU-377), which is one of the components of the new drug LCZ696. The existing industrial route is to use expensive D-tyrosine as the starting material to synthesize cheap D-linked Phenylalanine has a good market value. [0003] 1) The route with D-tyrosine is as follows: [0004] [0005] 2) It is reported that biphenyl formaldehyde is used as a raw material to synthesize acylated amino acids, but the synthesis yield is very low and the cost is relatively high, which is not conducive to industrial production. [0006] The reaction formula is as follows: [0007] [0008] 3) Biphenylalanine derivatives were prepared by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/04
CPCC12P13/04
Inventor 李钢吴法浩高仰哲
Owner NANJING REDWOOD FINE CHEM CO LTD
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