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Synthetic method of L-heterocyclic amino acid and pharmaceutical composition with L-heterocyclic amino acid

A technology of a heterocyclic amino acid and a synthesis method, which is applied in the field of synthesis methods and pharmaceutical compositions having the same, can solve the problems of high price, long synthesis routes, a large amount of organic solvents, etc., and achieves mild reaction conditions, simplified synthesis techniques, and chirality. Highly selective effect

Active Publication Date: 2013-09-04
ASYMCHEM LAB TIANJIN +4
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  • Abstract
  • Description
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Problems solved by technology

[0003] (1) Using precious metal asymmetric catalytic hydrogenation to realize the conversion of a single configuration of a key intermediate, the disadvantage is that the noble metal asymmetric catalyst is expensive, the reaction requires a large amount of organic solvent, and there may be heavy metal residues in the product and excessive Reduction by-products, and because the synthetic raw materials contain heterocycles, it often interferes with the combination of noble metals and ligands, resulting in low catalytic efficiency
[0004] (2) Using the traditional chiral resolution method to obtain a required isomer in the racemate will cause waste of the other half of the raw materials
[0005] (3) Asymmetric synthesis using chiral prosthetic groups or chiral raw materials involves expensive chiral raw materials, long synthetic routes and a large amount of organic solvents, and for the synthesis of certain heterocyclic amino acids, the obtained products The optical purity is not high, or the product and impurities are not easily separated
However, due to the special properties of heterocyclic amino acids, the prior art has not yet found suitable enzymes and corresponding reaction conditions to synthesize amino acids with chiral heterocyclic structures through biotransformation

Method used

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  • Synthetic method of L-heterocyclic amino acid and pharmaceutical composition with L-heterocyclic amino acid
  • Synthetic method of L-heterocyclic amino acid and pharmaceutical composition with L-heterocyclic amino acid
  • Synthetic method of L-heterocyclic amino acid and pharmaceutical composition with L-heterocyclic amino acid

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preparation example Construction

[0020] In a typical embodiment of the present invention, a method for synthesizing an L-heterocyclic amino acid is provided, comprising: step A, preparing a heterocyclic keto acid, wherein the heterocycle in the heterocyclic keto acid is selected from five-membered Any of heterocycle, six-membered monoheterocycle, seven-membered monoheterocycle, five-membered alkyl-substituted monoheterocycle, six-membered alkyl-substituted monoheterocycle, and seven-membered alkyl-substituted monoheterocycle, heterocyclic ketone The structural formula of the ketoacid group in an acid is and be located at any carbon position of the heterocycle; step B, combine the heterocyclic ketoacid with ammonium formate, phenylalanine dehydrogenase, formate dehydrogenase and coenzyme NAD + Mixing and performing reductive amination reaction to generate L-heterocyclic amino acid, wherein the amino acid sequence of phenylalanine dehydrogenase is SEQ ID No.1.

[0021] The above synthesis method utilizes the ...

Embodiment 1

[0040] Synthesis of L-4-pyridylalanine

[0041] 1) Add 904.2g, 1.5eq potassium tert-butoxide, 2L tetrahydrofuran and 500g 4-picoline to the four-necked flask, stir at room temperature for 2.5h, add 941.1g diethyl oxalate dropwise, and stir overnight at room temperature until the reaction is complete , the specific reaction is as follows. Temporary storage of the system goes directly to the second step.

[0042]

[0043] 2) Put the above system into the bottle, then add 1L methanol, 2L H 2 0, 783.6g potassium tert-butoxide, insulation reaction to no raw material, concrete reaction is as follows. Then concentrate, and lower the concentrated system to room temperature, adjust the pH value between 2 and 3 with 6mol / L hydrochloric acid, add 3 times the volume of water to it for dilution, and filter with suction, and the filtrate drops to 0 to 5°C. , to obtain 640g solid, two-step yield 72.2%. 1 H NMR (400 MHz, DMSO): δ 8.45 (d, 2H), 8.03 (d, 2H), 7.55 (d, 1H).

[0044]

...

Embodiment 2

[0048] Synthesis of L-2-pyridylalanine

[0049] 1) Add 800mL tetrahydrofuran and 152g (1.4eg) redistilled diisopropylamine to a 2L four-necked bottle, stir and cool down to -50~-40℃, add dropwise 590mL n-butyllithium (2.55 N, 1.4eq), then stirred for 0.5h, continued to cool down to -80~-70℃, added 100g of 2-picoline dropwise at -80~-70℃, kept it warm for 2h, followed TLC until the raw materials disappeared, and obtained System A;

[0050] Add 200mL tetrahydrofuran and 172g diethyl oxalate to a 3L four-neck flask, stir evenly, then cool down to -80~-70°C to obtain System B;

[0051] Press system A into system B at -80~-70°C, stir for 1 hour and follow TLC until the reaction is complete, return to -60°C, control the system temperature below -20°C, and use 2mol / L hydrochloric acid to adjust the system pH Adjust the temperature between 5 and 6, raise the temperature of the system to room temperature, and extract the aqueous phase with 300mL ethyl acetate three times after liquid ...

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Abstract

The invention provides a synthetic method of L-heterocyclic amino acid and a pharmaceutical composition with L-heterocyclic amino acid. The synthetic method comprises the steps that A, heterocyclic ketonic acid is prepared, wherein heterocycle in heterocyclic ketonic acid is selected from any one of pentabasic single heterocycle, hexabasic single heterocycle, heptabasic single heterocycle, pentabasic alkylation single heterocycle, hexabasic alkylation single heterocycle and heptabasic alkylation single heterocycle, and a structural formula of ketonic acid base in heterocyclic ketonic acid is as shown in the specification, and is positioned in any carbon position of heterocycle; and B, heterocyclic ketonic acid is mixed with ammonium formate, phenylalanine dehydrogenase, formate dehydrogenase and coenzyme NAD<+> to perform a reduced amination reaction to generate L-heterocyclic amino acid, wherein an amino acid sequence of phenylalanine dehydrogenase is SEQ ID No. 1 (sequence identifier number 1). Since special phenylalanine dehydrogenase, formate dehydrogenase and coenzyme NAD<+> are used for allowing heterocyclic ketonic acid to perform the reduced amination reaction to generate L-heterocyclic amino acid, the raw material conversion rate is high and the chiral selectivity is high.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a synthesis method of L-heterocyclic amino acid and a pharmaceutical composition thereof. Background technique [0002] At present, the synthesis of chiral non-natural heterocyclic amino acids mainly adopts chemical methods, including the use of noble metal asymmetric catalytic hydrogenation to realize the conversion of a single configuration of a key intermediate, the use of chiral reagents to resolve racemates, Asymmetric synthesis using chiral prosthetic groups, directional synthesis using chiral raw materials, etc. However, these methods have the following disadvantages: [0003] (1) Using precious metal asymmetric catalytic hydrogenation to realize the conversion of a single configuration of a key intermediate, the disadvantage is that the noble metal asymmetric catalyst is expensive, the reaction requires a large amount of organic solvent, and there may be heavy met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/04C12N15/53C12N15/63A61K31/381A61K31/444A61K31/4409A61K31/4402A61K31/4406A61K31/415
Inventor 洪浩郑长胜郭莉娜
Owner ASYMCHEM LAB TIANJIN
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