L-cyclic alkylamino acid synthesis method and medicinal composition containing L-cyclic alkylamino acid

A technology of alkyl amino acid and synthesis method, which is applied in the field of synthesis method and its pharmaceutical composition, can solve the problems of high price, long synthesis route, large amount of organic solvent, etc., achieve mild reaction conditions, simplify synthesis process, and convert raw materials high rate effect

Active Publication Date: 2013-10-23
ASYMCHEM LAB TIANJIN +4
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  • Abstract
  • Description
  • Claims
  • Application Information

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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

Method used

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  • L-cyclic alkylamino acid synthesis method and medicinal composition containing L-cyclic alkylamino acid
  • L-cyclic alkylamino acid synthesis method and medicinal composition containing L-cyclic alkylamino acid
  • L-cyclic alkylamino acid synthesis method and medicinal composition containing L-cyclic alkylamino acid

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preparation example Construction

[0029] In a typical embodiment of the present invention, a method for synthesizing an L-cyclic alkyl amino acid is provided, comprising: step A, preparing a cyclic alkyl ketoacid with structural formula (I) or structural formula (II) or Cyclic alkyl ketoacid; step B, combining cyclic alkyl ketoacid or cyclic alkyl ketoacid with ammonium formate, leucine dehydrogenase, formate dehydrogenase and coenzyme NAD + Mixed, carry out reductive amination reaction, generate L-cyclic alkyl amino acid, wherein, structural formula (I) is no 1 ≥1, m 1 ≥0, M 1 Is H or monovalent cation; Structural formula (II) is no 2 ≥0, m 2 ≥0, M 2 It is H or a monovalent cation; the amino acid sequence of leucine dehydrogenase is SEQ ID No.1.

[0030]The above synthesis method utilizes the specific leucine dehydrogenase, formate dehydrogenase and coenzyme NAD whose amino acid sequence is SEQ ID No.1 + Reductive amination reaction of cyclic alkyl keto acids is carried out to generate L-cyclic alky...

Embodiment 1

[0058] Synthesis of L-cyclopropylglycine

[0059] 1) At room temperature, add 500g cyclopropyl methyl ketone, 15.6g NaOH, and 8.7L water into a 20L four-necked bottle to form a mixed system. After heating the mixed system to 45-55°C, add 8.7L dropwise to the mixed system With 1864.8g KMnO 4 aqueous solution, undissolved KMnO 4 Then add it into the mixed system in batches, after about 10 hours, the reaction tracking raw materials reacted completely, the internal standard yield was 57.9%, and 10% NaHSO was added dropwise to the mixed system after the reaction was completed. 3 Destroy unreacted KMnO 4 ; Suction filtration, the filtrate is concentrated to 70% and then directly used in the next step. 1H NMR (500MHz, CD 3 Cl): δ 1.29 (m, 3H), 1.06 (m, 1H), 0.95 (m, 1H).

[0060]

[0061] 2) Add 1627g of 14.5% sodium cyclopropyloxyacetate aqueous solution, 193.3g of ammonium formate, and 2350mL of leucine dehydrogenase with an enzyme specific activity of 60U / ml to a 5L four-n...

Embodiment 2

[0064] Synthesis of L-cyclobutylglycine

[0065] 1) Add 15.13g of magnesium chips, 160ml of tetrahydrofuran, and 2 iodine particles into a 1L four-necked bottle, and then add 32ml of tetrahydrofuran solution with 8g of bromocyclobutane to it, and heat the four-necked bottle to make bromocyclobutane in the system Initiate with an alkane reagent; then cool the four-necked bottle to 40°C, add dropwise 288ml of tetrahydrofuran solution with 72g of bromocyclobutane to it, and after about 2.5 hours, the bromocyclobutane reacts according to the following reaction formula; The Grignard reagent was obtained after the temperature was kept at 40-50°C for about 1 hour, and the temperature was lowered to room temperature under nitrogen protection for later use.

[0066]

[0067] 2) Add 160ml of tetrahydrofuran solution containing 112.6g of diethyl oxalate into a 1L four-necked flask, and cool the four-necked flask to below -50°C with liquid nitrogen ethanol; The good 0.593mol Grignard ...

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Abstract

The invention provides an L-cyclic alkylamino acid synthesis method and a medicinal composition containing L-cyclic alkylamino acid. The synthesis method comprises the following steps: 1, preparing cyclic alkyl ketonic acid or cyclic alkyl ketonate having a structure represented by formula (I) or formula (II); and 2, mixing the cyclic alkyl ketonic acid or cyclic alkyl ketonate with ammonium formate, a leucine dehydrogenase, a formate dehydrogenase and a coenzyme NAD<+>, and carrying out a reduction amination reaction to generate the L-cyclic alkylamino acid, wherein n1 in the formula (I) is not lower than 1, m1 in the formula is not lower than 0, and M1 is H or a univalent cation; n2 in the formula (II) is not lower than 0, m2 in the formula (II) is not lower than 0, and M2 is H or a univalent cation; and the amino acid sequence of the leucine dehydrogenase is represented by SEQ ID No.1. The method utilizes specific leucine dehydrogenase, the formate dehydrogenase and the coenzyme NAD<+> to carry out the reduction amination reaction of the cyclic alkyl ketonic acid or cyclic alkyl ketonate, and has a high raw material conversion rate and a high chiral selectivity.

Description

technical field [0001] The present invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing an L-cyclic alkyl amino acid and a pharmaceutical composition thereof. Background technique [0002] At present, the synthesis of chiral unnatural cyclic alkyl 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, and the use of chiral reagents to resolve racemization. body, 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, ...

Claims

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Application Information

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IPC IPC(8): C12P13/04C12P17/06A61K31/195A61K31/351
Inventor 洪浩郑长胜郭莉娜
Owner ASYMCHEM LAB TIANJIN
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