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Biological synthesis method of atorvastatin intermediate

A biosynthetic technology of atorvastatin, which is applied in the field of preparation of raw materials and pharmaceutical intermediates, can solve the problems of unsuitability for industrialization, many by-products, long process flow, etc., and achieve easy control of reaction conditions, mild reaction conditions, The effect of simple process

Active Publication Date: 2018-07-24
ZHEJIANG HONGYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] According to the above route, using epichlorohydrin as raw material to synthesize (4R,6R)-6-(aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester requires 8 steps, the synthesis yield of the step (4) of the process is low, the noble metal lithium compound is needed in the step (5), the low temperature of -80°C is needed in the step (6), the process flow is long, and there are many by-products of the reaction, Therefore, the industrialization cost of the whole synthetic route is high, and the safety aspect is not easy to control
[0010] In the prior art, the synthesis of (4R,6R)-6-(aminoethyl)-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate requires the use of intermediates (R)-(-)-4-cyano-3-hydroxybutyric acid ethyl ester, this compound is difficult to obtain, and the subsequent process uses noble metal lithium, so it is not suitable for industrialization

Method used

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  • Biological synthesis method of atorvastatin intermediate
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  • Biological synthesis method of atorvastatin intermediate

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Experimental program
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Effect test

Embodiment 1

[0041] 1. Preparation of aldolase

[0042] Recombinant aldolase genetically engineered bacteria, the specific preparation method is: select the amino acid sequence of the aldolase derived from Escherichia coli, carry out artificial design, and synthesize the artificially designed sequence through the whole gene (commissioned by GenScript Biotechnology Co., Ltd. ), cloned into the Nde I and Xho I restriction sites of the expression vector pET28a, and transformed the host bacteria E.coliBL21 (DE3) competent cells; after picking the positive transformant and identifying it by sequencing, the recombinant expression vector was obtained; the recombinant expression vector Transform into E. coli BL21 (DE3) strain, obtain the recombinant aldolase gene engineering bacteria that can induce the expression of recombinant aldolase.

[0043] Inoculate the recombinant aldolase genetically engineered bacteria into LB medium containing kanamycin, and culture overnight at 37°C to obtain seed cul...

Embodiment 2

[0054] Formula VI compound (S)-6-tert-butoxy-4-hydroxyl-2,6-dicarbonylhexanoic acid is carried out by formula VII compound 3-carbonyl propionate tert-butyl ester and pyruvate under the effect of aldolase Catalyzed reaction generates, and the reaction formula is as follows:

[0055]

[0056] The specific reaction process is as follows: in a 500mL shake flask, the formula VII compound 3-oxopropionate tert-butyl ester (10g, 69.44mmol) was dissolved in 40mL of methanol, then pyruvic acid (17.6g, 0.200mol) was added in the shake flask, Add the aldolase of 160mL phosphate buffered saline solution, 40g again, the preparation of aldolase is as embodiment 1, add the PLP of 1mM again, the MgCl of 20mM 2 , control the pH value of the reaction system to be 7.5, react in a shaker for 14h, then extract the organic phase with ethyl acetate, and rotate to evaporate to obtain an oily liquid. The product is detected by gas chromatography, and the product formula VI compound (S)-6- The conce...

Embodiment 3

[0058] Formula V compound (S)-3-hydroxyl-1-carbonyl valeric acid tert-butyl ester is decarboxylated by formula VI compound (S)-6-tert-butoxy-4-hydroxyl-2,6-dicarbonylhexanoic acid Under the action of enzymes, the enzyme-catalyzed reaction is generated, and the reaction formula is as follows:

[0059]

[0060] The specific reaction process is as follows: in a 500mL shake flask, the formula VI compound (S)-6-tert-butoxy-4-hydroxyl-2,6-dicarbonylhexanoic acid (20g, 86.21mmol) was dissolved in 20mL of DMSO , then add 180mL phosphate buffer solution in the shake flask, then add 30g of ketoacid decarboxylase in the shake flask, the preparation of ketoacid decarboxylase is as in Example 1, then add 1mM TPP, 20mM MgCl 2 , control the pH value in the reaction system to be 8, control the temperature in the reaction system to be 6°C, react in a shaker for 22h, purify, and pass 1 H-NMR and 13 C-NMR and MS confirmed that the product V compound (S)-tert-butyl 3-hydroxy-1-oxopentanoate ...

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Abstract

The invention discloses a biological synthesis method of an atorvastatin intermediate. The biological synthesis method comprises the following step: carrying out enzyme catalysis reaction on a compound (4R,6R)-6-(1-amino-1-carboxylethyl)-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate under the action of amino acid decarboxylase to generate a compound (4R,6R)-6-(aminoethyl)-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate, i.e., the atorvastatin intermediate. The biological synthesis method disclosed by the invention has moderate reaction conditions and no special requirements on equipment; a chemical synthesis method is combined with an enzyme method and pollution to the environment is not caused; reaction conditions are easy to control, the operation is simple and convenient and a technological flow is simple.

Description

technical field [0001] The invention relates to a preparation method of a raw material drug and a drug intermediate, in particular to a biosynthesis method of an atorvastatin intermediate. Background technique [0002] Atorvastatin is a selective and competitive inhibitor of HMG-CoA reductase, which can reduce plasma cholesterol and lipoprotein levels by inhibiting the synthesis of HMG-CoA reductase and cholesterol in the liver, and increase liver LDL on the cell surface receptor to enhance LDL uptake and metabolism. At the same time, atorvastatin can also reduce low-density lipoprotein and triglyceride and increase high-density lipoprotein, which is of great significance to the prevention and treatment of atherosclerosis and coronary heart disease. Although simvastatin is still the dominant drug in the domestic blood lipid-regulating drug market, atorvastatin has attracted widespread attention from various domestic pharmaceutical companies because of its wider indications,...

Claims

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Application Information

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IPC IPC(8): C12P7/62
CPCC12P7/62
Inventor 梅光耀陈建华金辉胡磊林金荣汪海波林京都王飞
Owner ZHEJIANG HONGYUAN PHARMA
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