Enzymatic synthesis method of chiral beta-hydroxyl ester compound

A synthesis method and compound technology are applied in the field of enzyme-catalyzed synthesis of chiral β-hydroxy ester compounds, and can solve the problems of high production cost of β-hydroxy ester, impractical and economical, expensive chiral reagents and the like, and achieve high practicality. Value, low production cost, high conversion effect

Inactive Publication Date: 2013-10-16
ENZYMEWORKS
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As described in this patent, this method of using chemical synthesis to synthesize chiral β-hydroxy ester compounds is not practical and economical in industry because: 1) The synthetic route is long, which makes the production cost of β-hydroxy ester High; 2) Chiral reagents to control the 5-hydroxyl group are relatively expensive, resulting in low practical value of this synthetic route

Method used

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  • Enzymatic synthesis method of chiral beta-hydroxyl ester compound
  • Enzymatic synthesis method of chiral beta-hydroxyl ester compound
  • Enzymatic synthesis method of chiral beta-hydroxyl ester compound

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preparation example Construction

[0018] A specific embodiment of the present invention is to prepare an intermediate (S)-3-hydroxytetradecanoic acid methyl ester for the synthesis of orlistat by an enzyme-catalyzed synthesis method, and the specific steps are as follows:

[0019] 1) Let lauroyl chloride Ⅰ and cycloisopropylidene malonate Ⅱ react for about 2 hours under the conditions of 0°C to room temperature, pyridine as an acid-binding agent, and dichloromethane as a solvent. The obtained product is extracted and concentrated, and then added Reflux in methanol for 4-6 hours, and then recrystallize to obtain methyl lauroyl acetate III. The synthetic route is as follows:

[0020]

[0021] 2) Add the methyl lauroyl acetate III, ketoreductase and coenzyme obtained in step 1) into the phosphate buffer solution with pH=6~8, and react at 15~40°C for 2~24 hours to obtain optically pure ( S)-Methyl 3-hydroxytetradecanoate IV. Among them, the amount of ketoreductase added is 1~50g / L, the amount of methyl lauroy...

Embodiment 1

[0027] 1) Preparation of methyl lauroyl acetate:

[0028] Under nitrogen protection and stirring in an ice bath at 0°C, 60 mL of dichloromethane, pyridine (9 mL, 0.1112 mol) and cycloisopropylidene malonate (8 g, 0.0556 mol) were added to a 250 mL reaction flask. Lauroyl chloride (13.6 mL, 0.059 mol) was slowly added dropwise to the reaction solution, and the reaction mixture was stirred in an ice bath at 0°C for 10 min, and the reaction solution was slowly raised to room temperature, and continued to stir for 2 h. After the reaction was completed, the reaction mixture was washed successively with hydrochloric acid (1M), water, and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.

[0029] Dissolve the concentrate in methanol (50 mL), heat the reaction solution under reflux for 5 hours, then slowly lower the reaction solution to room temperature, and then recrystallize at a low temperature of -30°C to obtain a light yel...

Embodiment 2

[0033] 1) Preparation of methyl lauroyl acetate:

[0034] With embodiment 1.

[0035] ) Preparation of (S)-3-hydroxy tetradecanoic acid methyl ester:

[0036] Add 9.4g methyl lauroyl acetate, 0.6L dimethyl sulfoxide, 6L phosphate buffer solution (Na 2 HPO 4 / NaH 2 PO 4 , 0.1M, pH=7.0), 60g ketoreductase ADH-RE, 20g glucose, 65g glucose dehydrogenase and 0.05g NADP, stirred in a water bath at 35℃, reacted for 12h to obtain optically pure (S)-3- Methyl tetradecanoate. Samples were taken for GC analysis, and the conversion rate was >90%; HPLC analysis was performed, and the ee value was greater than >95%.

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Abstract

The invention relates to an enzymatic synthesis method of a chiral beta-hydroxyl ester compound. The chiral beta-hydroxyl ester compound is compounded as the formula (1). The enzymatic synthesis method comprises the following steps: carrying out a reaction on a compound i and a compound ii at the temperature of 0 DEG C to the room temperature under the condition of using pyridine as an acid binding agent, enabling the resultants to backflow in R2OH after the resultants are extracted and concentrated, recrystallizing the resultants to obtain the compound iii, adding the compound iii, chalcone reductase and cozymase into a phosphate buffer with pH vale of 6-8, and reacting for 2-24 hours at the temperature of 15-40 DEG C to obtain the chiral beta-hydroxyl ester compound provided by the invention. The enzymatic synthesis method provided by the invention is used for preparing a chiral beta-hydroxyl ester compound, and expensive chiral reagents are not needed. The enzymatic synthesis method provided by the invention has the advantages of mildness in production process conditions, easiness for obtaining raw materials, high conversion rate, low production cost and the like, which is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to an enzyme-catalyzed synthesis method of chiral β-hydroxy ester compounds. Background technique [0002] An important use of chiral β-hydroxy esters is as an intermediate for the synthesis of Orlistat. Orlistat is a lipase inhibitor. With the participation of bile salts, it forms an inactive intermediate with gastrointestinal lipase, which irreversibly inhibits the enzyme, thereby weakening the digestion and absorption of fat, keeping the intestinal tract in an oil phase state for a long time, separating cholesterol and passing it through Fecal excretion, thereby reducing caloric intake and controlling body weight. Orlistat (Orlistat) has been widely studied by researchers from various countries due to its unique biological activity, and was approved for marketing in June 1999. [0003] The synthetic route for the preparation of orlistat intermediates was disclosed...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P7/62
Inventor 朱惠霖李斌鞠鑫王海艳
Owner ENZYMEWORKS
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