Micro-reaction system and method for continuously preparing (R)-3-hydroxyhex-5-enoate by using same

A hexenoate, micro-reaction technology, applied in sterilization methods, biochemical equipment and methods, sustainable manufacturing/processing, etc., can solve the problem of difficult recovery and reuse of enzyme catalysts, poor stability of free enzymes, and complicated processing operations. and other problems, to achieve the effect of saving the cost of catalyst separation and repeated use, shortening the reaction time, and improving the efficiency of the process.

Pending Publication Date: 2021-02-19
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above enzymatic catalysis methods all use crude enzyme liquid, which has outstanding disadvantages such as poor stability and easy inactivation of free enzymes, and the post-reaction treatment is complicated, the enzyme catalyst is difficult to recycle and reuse, and the process cost is high
Chinese patent application CN111686809A loaded carbonyl reductase and isopropanol dehydrogenase on an inert solid medium to make a co-immobilized catalyst. It was found that the immobilized enzyme could improve the stability and catalytic efficiency of the catalyst, but the reaction time was still as long as more than ten hours, the yield is low
Therefore, aiming at the deficiencies of the traditional batch-type enzyme-catalyzed method, a continuous preparation ( R )-3-hydroxyl-5-hexenoic acid ester is a problem to be solved urgently by those skilled in the art

Method used

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  • Micro-reaction system and method for continuously preparing (R)-3-hydroxyhex-5-enoate by using same
  • Micro-reaction system and method for continuously preparing (R)-3-hydroxyhex-5-enoate by using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Preparation of carbonyl reductase / isopropanol dehydrogenase co-immobilized catalyst

[0060] Weigh 5 g of polyvinyl alcohol, 3 g of polyethylene glycol and 35 mL of water into a reaction flask, heat until the solution is clear, cool down to below 50 °C, add 10 mL of crude enzyme solution of carbonyl reductase (15% w / v ) and 5 mL isopropanol dehydrogenase crude enzyme solution (15% w / v), mix well. After mixing, drop the solution onto the polyethylene film with a syringe, and then place it in a blast oven at 35°C to dry for 1 hour to obtain the carbonyl reductase / isopropanol dehydrogenase co-immobilized catalyst, which is stored in Store at 4°C for later use.

[0061] In this example, the preparation methods of the crude enzyme solution of carbonyl reductase and crude isopropanol dehydrogenase are incorporated herein for reference by citing Chinese patent application CN107119081A.

Embodiment 2

[0062] Embodiment 2 target product ( R ) Preparation of tert-butyl 3-hydroxy-5-hexenoate

[0063] use as figure 1 In the shown micro-reaction system, the micro-channel reactor 3 is a tubular micro-channel reactor. Weigh 5 g of the carbonyl reductase / isopropanol dehydrogenase co-immobilized catalyst prepared in Example 1, and fill it in a tubular microchannel reactor 3 with an inner diameter of 10 mm and a length of 200 mm. Before starting the reaction, pump disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution (pH 7.0) into the packed carbonyl reductase / isopropanol dehydrogenase co-immobilized solution through feed pump 2 at a flow rate of 5 mL / min. In the tubular microchannel reactor 3 of the catalyst 31, rinse for 5 min. Then, the substrate liquid containing 3-carbonyl-5-hexenoic acid tert-butyl ester is pumped into the tubular microchannel reactor 3 from the substrate liquid container 1 by the feed pump 2, and the back pressure of the back pressure ...

Embodiment 3

[0065] Embodiment 3 target product ( R ) Preparation of tert-butyl 3-hydroxy-5-hexenoate

[0066] use as figure 1 In the shown micro-reaction system, the micro-channel reactor 3 is a tubular micro-channel reactor. Weigh 2.5 g of the carbonyl reductase / isopropanol dehydrogenase co-immobilized catalyst prepared in Example 1, and fill it in a tubular microchannel reactor 3 with an inner diameter of 5 mm and a length of 200 mm. Before starting the reaction, pump disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution (pH 7.0) into the filled carbonyl reductase / isopropanol dehydrogenase co-immobilized catalyst through the feed pump 2 at a flow rate of 5mL / min 31 of the tubular microchannel reactor 3, rinse for 5 min. Then, the substrate liquid containing 3-carbonyl-5-hexenoic acid tert-butyl ester is pumped into the tubular microchannel reactor 3 from the substrate liquid container 1 by the feed pump 2, and the back pressure of the back pressure valve 4 is se...

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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a micro-reaction system and a method for continuously preparing (R)-3-hydroxyhex-5-enoate by using thesame. The method comprises the following steps: simultaneously loading carbonyl reductase and isopropanol dehydrogenase on an inert solid medium to prepare a carbonyl reductase / isopropanol dehydrogenase co-immobilized catalyst, then filling a micro-channel reactor with the carbonyl reductase / isopropanol dehydrogenase co-immobilized catalyst, and pumping a substrate solution containing 3-carbonylhex-5-enoate into the reactor, and carrying out continuous enzyme catalyzed asymmetric reduction reaction to obtain the (R)-3-hydroxyhex-5-enoate. Compared with the prior art, the method has the advantages that the reaction time is only several minutes, the yield of the product (R)-3-hydroxyhex-5-enoate is higher than 95%, the technological process is continuous, the automation degree is high, thespace-time yield is high, moreover, the operation is simple and convenient, the separation step of the reaction liquid and the catalyst is not needed, the cost is low, and the industrial production iseasy.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, in particular to a micro-reaction system and its continuous preparation ( R )-3-hydroxy-5-hexenoate method. Background technique [0002] ( R )-3-hydroxyl-5-hexenoic acid ester (I) has a structural formula of: [0003] , [0004] In the formula, R is straight-chain or branched C1-C8 alkyl or C3-C8 cycloalkyl, mono-substituted or multi-substituted aryl, or mono-substituted or multi-substituted aralkyl, referred to as compound (I). The compound (I) is a key chiral intermediate for the preparation of various drugs such as lipid-lowering drugs atorvastatin, rosuvastatin, pitavastatin and fluvastatin (international patent WO2016074324; international patent WO2003053950; Chinese patent CN101735272 ; Bennett et al., Methyl (3R)-3-hydroxyhex-5-enoate as a precursor to chiral mevinic acid analogues[J]. Journal of the Chemical Society, Perkin Transactions 1 , 1991, 133-140; Huang et al., Chiralsy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P41/00C12P7/62C12N11/089C12N11/084C12M1/40C12M1/38C12M1/24C12M1/00
CPCC12P41/002C12P7/62C12N11/089C12N11/084C12N9/0006C12Y101/01184C12Y101/0108C12M21/18C12M23/08C12M23/16C12M29/00C12M37/04C12M41/22C12P7/42Y02P20/50
Inventor 陈芬儿程荡黄则度胡辰姜梅芬刘敏杰黄华山
Owner FUDAN UNIV
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