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Method for preparing L-butylphthalide intermediate

An intermediate, butylphthalide technology, applied in the field of biocatalysis for the efficient preparation of L-butylphthalide intermediates, can solve the problems of high industrialization cost, high price, and inability to realize industrialization

Pending Publication Date: 2022-02-11
湖南引航生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Among the above synthetic methods, (Angew.Chem.Int.Ed.2018,57,13140–13144; Angew.Chem.Int.Ed.2011,50,7329–7332) the conditions of the reaction are relatively harsh, requiring high pressure and need to use expensive chiral bisphosphine ligands and noble metals as catalysts, which makes the industrialization of such methods more difficult
The method described in Tetrahedron Letters, Vol.37, No.13, pp.2205-2208, 1996 requires the use of equivalent chiral boron reagents, and the industrialization cost is higher, so it cannot be industrialized

Method used

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  • Method for preparing L-butylphthalide intermediate
  • Method for preparing L-butylphthalide intermediate
  • Method for preparing L-butylphthalide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Weigh 2 g of substrate ketone and 6 g of glucose into a 500 mL three-necked flask, and add 200 mL of PBS buffer solution with pH=6.5 and 0.2 M. Put the three-neck flask into the reaction pot, set the rotation speed to 850rpm and the temperature to 25-35°C. Then add 10 mg NAD, 100 mg ketoreductase (enzyme number YH2072), and 100 mg glucose dehydrogenase (enzyme number YH1901) respectively. Start the reaction, use 2M NaOH solution in the reaction process to maintain the pH at about 6.5-8, HPLC monitors the reaction, the conversion rate and enantioselectivity of the product intermediate are as shown in Table 1:

[0039] Table 1:

[0040]

[0041]

Embodiment 2

[0043] Weigh 2 g of substrate ketone and 1 g of sodium formate into a 500 mL three-necked flask, and add 200 mL of PBS buffer solution with pH=6.5 and 0.2 M. Put the three-neck flask into the reaction pot, set the rotation speed to 850rpm and the temperature to 25-35°C. Then add 10 mg NAD, 100 mg ketoreductase (enzyme number YH2072), and 100 mg formate dehydrogenase (enzyme number YH1805) respectively. Start reaction, with 20% formic acid solution in the reaction process, pH is maintained at about 6.5-8, HPLC monitors reaction, and the conversion ratio of product intermediate and enantioselectivity are as shown in table 2:

[0044] Table 2:

[0045] R Reaction time (h) Conversion rates(%) Enantioselectivity (ee%) H 8 98％ 97％ Me 11 96％ 97％ Et 11 96％ 97％ n-Pr 15 92％ 92％ i-Pr 14 90％ 93％ n-Bu 25 81％ 91％

Embodiment 3

[0047] Weigh 2 g of substrate ketone and 10 g of isopropanol into a 100 mL three-necked flask, and add 200 mL of 0.2 M PBS buffer solution with pH=6.5. Put the three-neck flask into the reaction pot, set the rotation speed to 850rpm and the temperature to 25-35°C. Then 10 mg NAD, 100 mg ketoreductase (purchased from Suzhou Pivot Biotechnology Co., Ltd., enzyme number YH2072), and 100 mg alcohol dehydrogenase (purchased from Suzhou Pivot Biotechnology Co., Ltd., enzyme number YH2023) were added respectively. Start reaction, HPLC monitors reaction, the conversion rate of product intermediate and enantioselectivity are as shown in table 3:

[0048] table 3:

[0049] R Reaction time (h) Conversion rates(%) Enantioselectivity (ee%) H 12 92％ 94％ Me 15 88％ 93％ Et 16 88％ 93％ n-Pr 20 85％ 92％ i-Pr 24 87％ 90％ n-Bu 24 76％ 88％

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Abstract

The invention relates to a method for synthesizing an L-butylphthalide intermediate. The method comprises the following steps: adding ketoreductase into a substrate ketone, and reacting in an enzyme reaction system to obtain the intermediate.

Description

technical field [0001] The invention relates to a biocatalytic method for efficiently preparing an intermediate of L-butylphthalide, belonging to the technical fields of biopharmaceuticals and biochemical industries. Background technique [0002] Butylphthalide (commodity name Enbipu) is the third chemical drug with independent intellectual property rights in my country after artemisinin and bicyclol, and it is also a new chemical drug specially used for the treatment of cerebrovascular diseases in the world. Butylphthalide has an excellent safety single-body structure, and has multiple pharmacological effects at the same time. It can comprehensively treat ischemic stroke, significantly reduce post-infarct neurological deficits, and improve the living ability of patients. Because it contains a chiral carbon atom, there are two optical isomers, and the medicinal (butylphthalide) is its artificially synthesized racemate. Recent studies have shown that the two isomers of the d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/62
CPCC12P7/62
Inventor 谢新开黄晓飞石利军
Owner 湖南引航生物科技有限公司