A kind of method for preparing orlistat intermediate by enzymatic method

A technology for orlistat and enzymatic preparation, which is applied in the field of enzymatic preparation of orlistat intermediates, can solve the problems of high production equipment requirements, high corrosiveness, and high catalyst cost, and achieve an environmentally friendly effect

Active Publication Date: 2021-09-17
ZHEJIANG OCEAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using the catalyst to prepare (R)-3-hydroxy-tetradecanoic acid methyl ester has a chiral ee value of less than 99%, the cost of the catalyst is relatively high, and the catalytic reaction needs to be carried out under strong acid and high pressure conditions, which requires high production equipment and highly corrosive

Method used

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  • A kind of method for preparing orlistat intermediate by enzymatic method
  • A kind of method for preparing orlistat intermediate by enzymatic method

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Experimental program
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Effect test

Embodiment 1

[0041] 5 g of the substrate β-carbonyltetradecanoic acid methyl ester was added to a 250 mL reactor, and subsequently, 100 mL containing 0.1 g / L NAD + , 30g / L cell disruption solution containing recombinant short-chain alcohol dehydrogenase, 10g / L cell disruption solution containing recombinant glucose dehydrogenase, 100g / L glucose, and 0.1M phosphate buffer (pH 7.0) were added to the reactor In the process, the solid-liquid ratio of β-carbonyltetradecanoic acid methyl ester to the mixed solution is 50g / L, and the pH automatic control system and 1M Na 2 CO 3 The solution controls the pH of the enzyme reaction to around 7.0. React at 35°C for 12h. The substrate conversion rate is greater than 98%, the product concentration is 49.0g / L, and the chiral ee value of the product is greater than 99%.

Embodiment 2

[0043] 7.5 g of the substrate β-carbonyltetradecanoic acid methyl ester was added to a 250 mL reactor, and subsequently, 100 mL containing 0.1 g / L NAD + , 35g / L cell disruption solution containing recombinant short-chain alcohol dehydrogenase, 10g / L cell disruption solution containing recombinant glucose dehydrogenase, 100g / L glucose, and 0.1M phosphate buffer (pH 7.0) were added to the reactor Among them, the solid-liquid ratio of β-carbonyltetradecanoic acid methyl ester to the mixed solution is 75g / L, and the pH automatic control system and 1M Na 2 CO 3 The solution controls the pH of the enzyme reaction to around 7.0. React at 35°C for 12h. The substrate conversion rate is greater than 96%, the product concentration is 72.0g / L, and the chiral ee value of the product is greater than 99%.

Embodiment 3

[0045] 10 g of the substrate β-carbonyltetradecanoic acid methyl ester was added to a 250 mL reactor, and subsequently, 100 mL containing 0.1 g / L NAD + , 30g / L cell disruption solution containing recombinant short-chain alcohol dehydrogenase, 10g / L cell disruption solution containing recombinant glucose dehydrogenase, 200g / L glucose, and 0.1M phosphate buffer (pH 7.0) were added to the reactor In the process, the solid-liquid ratio of β-carbonyltetradecanoic acid methyl ester to the mixed solution is 100g / L, and the pH automatic control system and 1M Na 2 CO 3 The solution controls the pH of the enzyme reaction to around 7.0. React at 35°C for 12h. The substrate conversion rate is greater than 78%, the product concentration is 78.0g / L, and the chiral ee value of the product is greater than 99%.

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Abstract

The invention relates to the field of medical technology, and discloses a method for enzymatically preparing an orlistat intermediate, including the synthesis of the original gene of short-chain alcohol dehydrogenase, the expression of short-chain alcohol dehydrogenase, cell disruption and enzyme catalysis, etc. Step, using short-chain alcohol dehydrogenase catalytic method to prepare orlistat intermediate (R)-3-hydroxy-tetradecanoic acid methyl ester with high chiral ee value (ee>99%), to replace traditional chemical synthesis method, reducing production costs and environmental pollution. The synthesis method of the orlistat intermediate provided by the invention has milder reaction conditions, faster reaction speed, high reaction yield and chiral ee value, and low production cost, and is suitable for industrial scale-up production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for enzymatically preparing an orlistat intermediate. Background technique [0002] Orlistat is currently the only OTC weight loss drug in the world. Orlistat is a long-acting and potent specific gastrointestinal lipase inhibitor, which acts by forming a covalent bond with the active serine site of gastric lipase and pancreatic lipase in the lumen of the stomach and small intestine to inactivate the enzymes Therapeutic effect, inactivated enzymes cannot hydrolyze the fat in food, mainly triglycerides, into absorbable free fatty acids and monoacylglycerols. Undigested triglycerides cannot be absorbed by the body, thereby reducing caloric intake and controlling weight. The drug does not need to be absorbed systemically to be effective. [0003] The structural formula of orlistat: [0004] [0005] According to the structural analysis of orlistat, (R)-β-hydroxy myri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/70C12N9/04C12P17/02
CPCC12N9/0006C12N15/70C12N2800/22C12P17/02
Inventor 唐云平周亚峰丁国芳余方苗杨最素黄芳芳陈艳
Owner ZHEJIANG OCEAN UNIV
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