Method for preparing orlistat intermediate

A technology of orlistat and intermediates, which is applied in the field of biosynthesis of -β-hydroxymyristate compounds, can solve the problems of ready-to-use catalysts, affecting ee value, and difficulty in guaranteeing process stability, etc. Achieve the effects of no heavy metal pollution, mild conditions, and simplified post-treatment steps

Active Publication Date: 2020-05-15
ZEIN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this type of method are: 1) expensive (R)-ligands and noble metal catalysts need to be used; 2) catalysts need to be made and used now, and process

Method used

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  • Method for preparing orlistat intermediate
  • Method for preparing orlistat intermediate
  • Method for preparing orlistat intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Weigh 1g of methyl β-carbonyltetradecanoate and 1.5g of glucose into a 100mL three-neck flask, then add 50mL of PBS buffer solution with a concentration of 50mM and a pH value of 7.0; put the three-necked flask into a constant temperature water bath , the stirring speed was adjusted to 800rpm, the temperature was 35°C, and then 10mg NADP was added + , 25mg of glucose dehydrogenase GDH enzyme powder (shown in SEQ ID NO:3), and 100mg of ketoreductase JR3789 enzyme powder (shown in SEQ ID NO:1), to obtain a mixed reaction solution, adjust the pH with 2M NaOH solution The temperature was maintained at 7.0-7.5, and the temperature was maintained at 35° C., and the reaction progress was monitored by HPLC. After 9 hours, the reaction was completed, and the conversion rate was measured to be >99%.

[0072] After the reaction, first raise the temperature to 60°C and keep it warm for 15min, then cool down to 20-25°C, add 80mL of ethyl acetate to extract and stir for 20min, filter...

Embodiment 2

[0074] Weigh 1g of ethyl β-carbonyltetradecanoate and 1.5g of glucose into a 100mL three-necked flask, and then add 50mL of PBS buffer solution with a concentration of 50mM and a pH value of 7.0; put the three-necked flask into a constant temperature water bath , the stirring speed was adjusted to 900rpm, the temperature was 35°C, and then 10mg NADP+, 35mg glucose dehydrogenase GDH enzyme powder (shown in SEQ ID NO:3), and 150mg ketoreductase JR3789 enzyme powder (shown in SEQ ID NO:1) were added respectively Shown), to obtain a mixed reaction solution, adjust the pH with 2M NaOH solution to maintain between 7.0-7.5, the temperature is maintained at 35 ° C, using HPLC to monitor the reaction process, 10h after the end of the reaction, and measured conversion> 99%.

[0075] After the reaction, first raise the temperature to 60°C and keep it warm for 15min, then cool down to 20-25°C, add 80mL of ethyl acetate to extract and stir for 20min, filter, and separate the filtrate to tak...

Embodiment 3

[0077] Weigh 5g of methyl β-carbonyltetradecanoate and 7.5g of glucose into a 100mL three-necked flask, then add 50mL of PBS buffer solution with a concentration of 50mM and a pH value of 7.0; put the three-necked flask into a constant temperature water bath , the stirring speed was adjusted to 800rpm, the temperature was 35°C, and then 50mg NADP+, 125mg glucose dehydrogenase GDH enzyme powder (shown in SEQ ID NO:3), and 500mg ketoreductase JR3789 enzyme powder (shown in SEQ ID NO:1) were added respectively Shown), the mixed reaction solution was obtained, the pH was adjusted with 2M NaOH solution to maintain between 7.0-7.5, the temperature was maintained at 35 ° C, the reaction progress was monitored by HPLC, the reaction was completed after 13 hours, and the conversion rate > 99% was measured.

[0078] After the reaction, first raise the temperature to 60°C and keep it warm for 15min, then cool down to 20-25°C, add 80mL of ethyl acetate to extract and stir for 20min, filter,...

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Abstract

The invention belongs to the technical field of biopharmaceuticals and biochemicals, and particularly relates to a method for synthesizing (R)-beta-hydroxyl-tetradecanoate compounds. The method includes the steps that beta-carbonyl-tetradecanoate is reacted in a mixed solution of ketoreductase, glucose, glucose dehydrogenase, NADP<+> and a buffer solution to obtain (R)-beta-hydroxyl-tetradecanoate. The method is an enzyme-catalyzed biosynthesis method, the operation is simple, the equipment is conventional equipment, the process is environmentally friendly, and obtained products are high in purity, high in yield and high in ee value.

Description

technical field [0001] The present invention belongs to the field of biopharmaceutical and biochemical technology, and specifically relates to a biosynthesis method of (R)-β-hydroxymyristate compounds. Background technique [0002] Drugs for the treatment of obesity are mainly divided into two categories, namely central nervous action weight loss drugs and non-central nervous action weight loss drugs. The weight-reducing effect of central nervous action weight-reducing medicine is obvious, but side effect is relatively large, and clinical application is greatly restricted. Among them, fenfluramine was withdrawn from the market in 1997 because it could cause pulmonary hypertension and hypertrophic heart valve disease. Sibutramine was announced by the State Food and Drug Administration in 2010 to stop its production, sales and use due to its possible increase in serious cardiovascular risks. Locaserin (trade name Belviq) was approved for marketing by the FDA in June 2012, bu...

Claims

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Application Information

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IPC IPC(8): C12N9/04C12P7/64
CPCC12N9/0006C12P7/6436C12Y101/01C12N15/62C12N15/52C07K2319/00C12P7/42C12Y101/01047
Inventor 徐天帅龚大勇王章洪黄治川黄山张磊高鑫沈军伟
Owner ZEIN BIOTECHNOLOGY CO LTD
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