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Preparation method of cetilistat

A technology of new listat and compounds, applied in the field of drug preparation, can solve the problems of inconvenient industrial production and achieve the effect of cheap and easy-to-obtain reagents

Inactive Publication Date: 2016-06-15
北京修正创新药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The route adopts a one-pot method, using pyridine as a solvent and an acid-binding agent, 2-amino-5-methylbenzoic acid and a slight excess of hexadecyl chloroformate to react, and then adding phosphorus oxychloride for intramolecular ring closure Obtaining new lixistat, the yield reported in this document is 90%, but there is a shortcoming of using a large amount of strong irritant reagent pyridine, which brings inconvenience to industrialized production

Method used

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  • Preparation method of cetilistat
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  • Preparation method of cetilistat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation of embodiment 1 compound C

[0052]Disperse compound A (15.1g) with 250mL dichloromethane in a 500mL three-necked flask, add compound B (30.5g) under stirring, add pyridine (16.1mL) to the system under ice-water bath, drop it, and naturally rise to room temperature for reaction .

[0053] TLC (n-hexane: ethyl acetate: glacial acetic acid = 5:1:0.1) monitors the progress of the reaction. After the reaction is complete, add 80 mL of water to wash, extract the aqueous layer with an appropriate amount of dichloromethane, combine the organic layers, and add dilute hydrochloric acid to the system. Adjust the pH to 1-2, stir in an ice-water bath (0-10°C) to precipitate a solid, filter with suction, wash the filter cake with water, rinse the filter cake with dichloromethane, and dry it with air at 40°C to obtain 38.7 g of off-white solid, yield 92.3%.

Embodiment 2

[0054] The preparation of embodiment 2 compound C

[0055] Disperse compound A (15.1g) with 250mL dichloromethane in a 500mL three-necked flask, add compound B (30.5g) under stirring, add triethylamine (27.7mL) to the system under an ice-water bath, drop it, and naturally rise to React at room temperature.

[0056] TLC (n-hexane: ethyl acetate: glacial acetic acid = 5:1:0.1) monitored the progress of the reaction. After the degree of reaction no longer increased, 80 mL of water was added for washing, and the aqueous layer was extracted with an appropriate amount of dichloromethane. The organic layers were combined and poured into the system. Add dilute hydrochloric acid to adjust the pH to 1-2, stir and precipitate solids in an ice-water bath (0-10°C), filter with suction, wash the filter cake with water, rinse the filter cake with dichloromethane, and blow dry at 40°C to obtain 28.7g off-white Solid, yield 68.4%.

Embodiment 3

[0057] The preparation of embodiment 3 compound C

[0058] Disperse Compound A (15.1g) with 250mL ethyl acetate in a 500mL three-neck flask, add Compound B (30.5g) under stirring, add pyridine (16.1mL) to the system under ice-water bath, drop it, and naturally rise to room temperature for reaction .

[0059] TLC (n-hexane: ethyl acetate: glacial acetic acid = 5:1:0.1) monitors the progress of the reaction. After the reaction is complete, add 80 mL of water to wash, extract the aqueous layer with an appropriate amount of ethyl acetate, combine the organic layers, and add dilute hydrochloric acid to the system. Adjust the pH to 1-2, stir in an ice-water bath (0-10°C) to precipitate a solid, filter with suction, wash the filter cake with water, rinse the filter cake with ethyl acetate, and dry it with air at 40°C to obtain 24.6g of off-white solid, yield 58.7%.

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Abstract

The invention discloses a preparation method of cetilistat; the method has the advantages of concise process, easily obtained raw materials, and mild reaction conditions, and is suitable for industrialized production. According to a reaction route, 2-amino-5-methyl benzoic acid and hexadecyl chloroformate serve as starting raw materials, firstly, amino acylation is carried out, an intermediate is purified, then cyclization is carried out, and the target compound is obtained through a two-step reaction.

Description

technical field [0001] The invention relates to a preparation method of new lixistat, which belongs to the technical field of medicine preparation methods. Background technique [0002] New lisstat (2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one, cetilistat) is a long-acting and potent specific Sexual gastrointestinal lipase inhibitor, it forms 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, and the inactivated enzymes cannot detoxify the food Fats (mainly triglycerides) are hydrolyzed into absorbable free fatty acids and monoacylglycerols, and undigested triglycerides cannot be absorbed by the body, thereby reducing caloric intake and controlling body weight. The biggest advantage of the drug is that it does not act on the nervous system, does not affect other enzyme activities in the gastrointestinal tract, does not enter the blood without being absorbed, does n...

Claims

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Application Information

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IPC IPC(8): C07D265/26
CPCC07D265/26
Inventor 吕丹
Owner 北京修正创新药物研究院有限公司
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