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Method for preparing brivaracetam intermediate

An intermediate and reaction system technology, applied in the field of biological enzyme catalysis, can solve the problem of high cost

Active Publication Date: 2019-06-07
ABIOCHEM BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] But the above are all chemical methods, and all use chiral raw materials, the cost is relatively high
In addition, because of the specificity of enzyme catalysis and high catalytic efficiency, the preparation of (R)-4-propyl-dihydrofuran-2-one by enzyme catalysis has also been favored, Org.ProcessRes.Dev, 2016, 20, 1566-1575 A method for preparing (R)-4-propyl-dihydrofuran-2-one using lipase and protease was reported, but the conversion rate was 50% and the ee value was 96%

Method used

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  • Method for preparing brivaracetam intermediate
  • Method for preparing brivaracetam intermediate
  • Method for preparing brivaracetam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] The synthesis of embodiment 1 compound 3

[0113]

[0114] Dissolve 30g (1.09eq) of morpholine in 90mL of n-heptane, cool down to 5°C, add dropwise 50% glyoxylic acid aqueous solution (46g, 1.0eq) to control the temperature not to exceed 40°C, and control the temperature for 25-30 ℃ reaction 2h. Slowly add 29g of n-valeraldehyde dropwise, and control the temperature not to be higher than 40°C, and react at 40°C for 16h after the drop is completed. Cool down to 20°C, add 50 mL of concentrated hydrochloric acid, extract with n-heptane, adjust the pH to 1.0 with aqueous sodium hydroxide solution, extract three times with tertiary methyl ether, combine the organic phases and concentrate under reduced pressure to obtain compound 3 (43 g, yield 96%). (refer to patent WO2005028435A1)

[0115] 1 H NMR (300MHz, CDCl 3 )δ6.00(s,1H),5.84(t,J=1.8Hz,1H),4.65(bs,1H,exchange with D 2 O),2.25–2.52(m,2H),1.52–1.77(m,2H),1.00(t,J=7.6Hz,3H).

[0116] 13 C NMR (75MHz, CDCl 3 )δ1...

Embodiment 2

[0117] The synthesis of embodiment 2 compound 2

[0118]

[0119] Compound 3 (14.2 g) was dissolved in 70 mL of ethanol, 0.7 g of palladium carbon (10% Pd) was added to replace the nitrogen, and then hydrogen gas (1 atmosphere) was introduced to react at room temperature for 6 h. The reaction was complete by GC detection. The palladium carbon was removed by filtration, and the ethanol was removed by concentration under reduced pressure to obtain compound 2 (14 g, yield 100%).

Embodiment 3

[0120] The preparation of embodiment 3 alcohol dehydrogenase

[0121] 3.1 Acquisition of enzyme gene

[0122] Alcohol dehydrogenase (ADH) in the following table was retrieved from NCBI, according to the sequence of the enzyme gene, the whole synthetase gene.

[0123] Table 1 Enzymes

[0124]

[0125]

[0126] 3.2 Expression of enzyme gene

[0127] Link the enzyme gene to pET28a, the restriction site NdeI&HindIII, and the carrier with the enzyme to transform the host Escherichia coli BL21 competent cells; the strain is inoculated with LB culture at 37°C, 200rpm shaker, when the OD600 reaches about 0.8, Take the bacterial solution and add sterile glycerol with a final concentration of 25%, after numbering, store it in a -80°C low-temperature refrigerator for future use.

[0128] 3.3 Cultivation of enzyme strains

[0129] The composition of LB liquid medium: peptone 10g / L, yeast powder 5g / L, NaCl 10g / L, dissolved in deionized water and then constant volume, sterilized a...

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Abstract

The invention provides a method for preparing a brivaracetam intermediate and particularly discloses preparation of the brivaracetam intermediate from part of alcohol dehydrogenase. The brivaracetam intermediate preparation method which is mild in reaction conditions, high in yield and low in cost is obtained on the basis.

Description

technical field [0001] The application belongs to the field of biological enzyme catalysis, and in particular relates to a method for preparing an intermediate of buvaracetam by enzyme catalysis. Background technique [0002] Brivaracetam is a new type of antiepileptic drug developed by UCB Company in Belgium, of which (R)-4-propyl-dihydrofuran-2-one is an important intermediate. [0003] [0004] There are many preparation methods for (R)-4-propyl-dihydrofuran-2-one, such as WO2016191435, which uses (R)-epichlorohydrin as raw material and prepares (R)-4-propyl through three-step reaction -Dihydrofuran-2-one, (R)-4-propyl-dihydrofuran-2-one can further prepare Buvaracetam. [0005] [0006] CN106588741A uses (R)-3-methoxycarbonylhexanoic acid as raw material, and prepares (R)-4-propyl-dihydrofuran-2-one through cyclization, (R)-4-propyl-dihydro Furan-2-one can be prepared through ring opening, substitution and cyclization to obtain Buvaracetam. [0007] [0008] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/04C07D307/33
Inventor 孙传民
Owner ABIOCHEM BIOTECH CO LTD
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