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Ketene reductase and preparation method of brivaracetam intermediate

A reductase and intermediate technology, applied in the field of pharmaceutical intermediates, can solve the problems of unpublished ene reductase information, difficult procurement of substrates, and many reaction steps, etc., and achieve broad industrial application prospects, easy implementation, and low cost effects

Active Publication Date: 2020-05-15
三明旻和医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the disadvantages of this method include: the dangerous operation of catalytic hydrogenation is also implemented, and there are many reaction steps, and the problem of waste salt will be generated by adjusting the pH after the reaction
However, the disadvantages of this method include starting from the substrate 4-n-propyl-2(5H)-furanone, which is not easily procurable, and no specific ene reductase information is disclosed

Method used

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  • Ketene reductase and preparation method of brivaracetam intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0054] Preparation of 5-hydroxy-4-n-propyl-2(5H)-furanone

[0055] At room temperature, add 15 mL of distilled water and 8.89 g of morpholine (molecular weight 87.1, 0.102 mol) into a 100 mL three-necked flask, cool to 0-5°C, and slowly add 14.8 g of 50% by volume glyoxylic acid solution (molecular weight 74, 0.1 mol), the temperature was controlled below 15°C during the dropwise addition, and the stirring was continued for 15 minutes after the dropwise addition was completed. Then slowly add 8.61g of valeraldehyde (molecular weight: 86.1, 0.1mol) dropwise at 15-25°C under temperature control. Note: there is no smell of aldehyde in the post-treatment process. The reaction solution was cooled to room temperature, and 12 mL of 37% hydrochloric acid (molecular weight 37.5, 0.14 mol) was added dropwise, and stirring was continued at 23-25° C. for 3 hours after the addition was completed. Subsequently, add 30mL tertiary methyl ether (thin-layer chromatography TLC), separate layers...

Embodiment 2

[0057] Preparation of 4-n-propyl-2(5H)-furanone

[0058] Add 50mL of anhydrous methanol and 6.9g of 5-hydroxy-4-n-propyl-2(5H)-furanone (molecular weight 142, 48.6mmol, 1eq) into a 100mL three-necked flask, cool to -5~0°C, and batch After adding 3.9g of sodium borohydride (molecular weight 37.8, 103mmol, 2.1eq), the temperature was raised to 0-10°C (note: gas was generated, exothermic violently and with delay), continued to stir for 30min, and then naturally rose to room temperature, and thin-layer chromatography The progress of the reaction was detected by TLC (developing solvent: n-hexane / ethyl acetate = 3:1). After the raw materials completely disappeared, cool to 0-5°C, slowly add 100mL of hydrochloric acid dropwise, and continue stirring for 5 minutes after the dropwise addition, and 80mL of acetic acid Extract with ethyl ester 3 times (note: the pH of the aqueous phase = 4.0-4.5), combine the organic phases, wash once with 100 mL of 5% sodium carbonate, wash once with sa...

Embodiment 3

[0060] Preparation of recombinant Escherichia coli wet cells

[0061] The expression vector pET-28a that has been digested with two endonucleases Nco I and EcoR I is connected with the nucleotide sequence of the enone reductase, the ketoreductase sequence, and the glucose dehydrogenase gene respectively with T4 ligase ,overnight. Add 1 microliter of the ligation product to the electroporation containing 50 microliters of E. coli electrocompetent cells, and immediately shock on the electroporator, then immediately transfer to ice, and add the broth preheated to 37°C respectively Mix 1mL of agar medium; transfer the mixed medium to 2mL culture tubes, and incubate at 200°C for one hour at 37°C; carry out on a broth agar plate containing 100 microliters per mL of kanamycin Streak culture, 37 ° C incubator overnight culture for 16 hours; the next day, pick a single clone on the inoculation plate and inoculate it into a Erlenmeyer flask containing 15 mL of kanamycin medium, 37 ° C ...

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Abstract

The invention relates to the technical field of medical intermediates, in particular to ketene reductase and a preparation method of a brivaracetam intermediate. The preparation method comprises the following steps of enabling valeraldehyde and glyoxylic acid to react under the catalysis of morpholine to generate 5-hydroxy-4-n-propyl-2(5H)-furanone; enabling the 5-hydroxy-4-n-propyl-2(5H)-furanoneto remove hydroxyl under the catalysis of sodium borohydride to generate 4-n-propyl-2(5H)-furanone; and in the presence of the ketene reductase, enabling the 4-n-propyl-2(5H)-furanone to have a reduction reaction to generate a target product namely the brivaracetam intermediate. The nucleotide sequence of the ketene reductase is as shown in SEQID NO.1, and the amino acid sequence of the ketene reductase is as shown in SEQID NO.2. According to the preparation method of the brivaracetam intermediate disclosed by the invention, only 3-step reactions are needed, the brivaracetam intermediate canbe prepared, additional chemical resolution is not needed, and the whole technology is environmentally-friendly, low in cost and easy to implement.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical intermediates, in particular to a method for preparing an enone reductase and a brivaracetam intermediate. Background technique [0002] Brivaracetam, namely (S)-2-(R)-3-propylpyrrolidin-1-ylbutyramide, is the third-generation broad-spectrum antiepileptic drug currently used in the treatment of epileptic seizures in the world one. Compared with levetiracetam, it has the advantages of high affinity and greatly reduced dosage. [0003] The brivaracetam intermediate is an important component for the synthesis of brivaracetam. The prior art provides many synthetic methods. For example, the patent application CN109134406A mentions that the brivaracetam intermediate undergoes one-step bromoacylation and one-step combination with S- Buvaracetam can be prepared from aminobutyramide under the action of base and phase transfer catalyst. [0004] [0005] Patent application CN109134406A disclose...

Claims

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Application Information

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IPC IPC(8): C12N9/02C12P17/04C12N15/70
CPCC12N9/001C12Y103/01031C12P17/04C12N15/70
Inventor 蔡宝琴张城孝章兆琪黄勇开马克·博科拉罗霄余梦娇崔琴燕
Owner 三明旻和医药科技有限公司
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