Cetilistat preparation method

A technology of new lisstat and synthesis method, which is applied in the field of preparation of new lisstat, a drug for the treatment of obesity and its complications, can solve the problems of high equipment requirements, complicated operation, high risk factor, etc., and achieve economical and safe Improvement, post-processing is easy to operate, and the effect of low equipment requirements

Active Publication Date: 2017-02-01
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In the synthetic route of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-ketone disclosed in CN1785967A, the steps are more loaded down with trivial details, and in the synthesis of intermediates, a drastic Poisonous phosge

Method used

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  • Cetilistat preparation method
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  • Cetilistat preparation method

Examples

Experimental program
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Example Embodiment

[0034] Example 1

[0035] Weigh 12g (79.39mmol, 1.0eq) of 2-amino-5-methylbenzoic acid, 10.03ml (91.31mmol, 1.15eq) of N-methylmorpholine and join in a 500ml three-necked flask, add 100ml absolute ethanol, Stir to dissolve, and cool down in an ice bath. When the temperature of the reaction system is 5°C, start to slowly add 29.05g (95.27mmol, 1.2eq) of hexadecyl chloroformate dropwise, and control the temperature not to exceed 10°C. The dropwise addition is completed in about 30 minutes , a large number of light yellow solids are formed in the system, slowly raise the temperature to 30°C, keep the temperature for 30 minutes, then cool down to 0-5°C, start to slowly add 18.12ml (223.86mmol, 3.0eq) of sulfuryl chloride dropwise, and the dropwise addition is completed in about 20 minutes , during the dropping process, the temperature is controlled not to exceed 10°C. After the dropping is completed, continue to stir and react for 30 minutes, then slowly raise the temperature to 2...

Example Embodiment

[0036] Example 2

[0037] Weigh 12g (79.39mmol, 1.0eq) of 2-amino-5-methylbenzoic acid, 10.03ml (91.31mmol, 1.15eq) of N-methylmorpholine and join in a 500ml three-necked flask, add 100ml of anhydrous methanol, Stir to dissolve, and cool down in an ice bath. When the temperature of the reaction system is 5°C, start to slowly add 29.05g (95.27mmol, 1.2eq) of hexadecyl chloroformate dropwise, and control the temperature not to exceed 10°C. The dropwise addition is completed in about 30 minutes , a large number of light yellow solids are formed in the system, slowly raise the temperature to 30°C, keep the temperature for 30 minutes, then cool down to 0-5°C, start to slowly add 18.12ml (223.86mmol, 3.0eq) of sulfuryl chloride dropwise, and the dropwise addition is completed in about 20 minutes , during the dropping process, the temperature is controlled not to exceed 10°C. After the dropping is completed, continue to stir and react for 30 minutes, then slowly raise the temperature...

Example Embodiment

[0038] Example 3

[0039] Weigh 12g (79.39mmol, 1.0eq) of 2-amino-5-methylbenzoic acid, 10.03ml (91.31mmol, 1.15eq) of N-methylmorpholine and join in a 500ml three-necked flask, add 100ml isopropanol, Stir to dissolve, and cool down in an ice bath. When the temperature of the reaction system is 5°C, start to slowly add 29.05g (95.27mmol, 1.2eq) of hexadecyl chloroformate dropwise, and control the temperature not to exceed 10°C. The dropwise addition is completed in about 30 minutes , a large number of light yellow solids are formed in the system, slowly raise the temperature to 30°C, keep the temperature for 30 minutes, then cool down to 0-5°C, start to slowly add 18.12ml (223.86mmol, 3.0eq) of sulfuryl chloride dropwise, and the dropwise addition is completed in about 20 minutes , during the dropping process, the temperature is controlled not to exceed 10°C. After the dropping is completed, continue to stir and react for 30 minutes, then slowly raise the temperature to 25°, a...

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Abstract

The invention discloses a cetilistat preparation method. The cetilistat preparation method comprises the steps of allowing 2-amino-5-methyl benzoic acid to react with cetyl chloroformate and sulfonyl chloride one after another in alcohols solvent under the presence of acid binding agents to obtain cetilistat. The non-toxic and cheap ethanol is used as a reaction solvent, the preparation method is more economical, and the security of the preparation method is greatly improved. The sulfonyl chloride reacting fast is used as a cyclization reagent, reaction time is thus obviously reduced; postprocessing is simple and easy to operate, the requirement on equipment is low, and the industrial production of the cetilistat is facilitated.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a preparation method of new lixistat, a medicine for treating obesity and its complications. Background technique [0002] The new cetilistat, trade name OBLEAN, chemical name 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one, the structural formula is as follows: [0003] [0004] OBLEAN is an esterase inhibitor developed by Alizyme Therapeutics Ltd., UK. Norgine acquired the ownership of the Alizyme product in October 2009. In 2003, Takeda acquired the right to develop and market the drug in Japan. In 2013, Takeda announced that Japan approved 120mg OBLEAN tablets for the treatment of obesity and its complications. [0005] Neolistat is a long-acting and potent specific gastrointestinal lipase inhibitor that inactivates the enzymes by forming a covalent bond with the active serine sites of gastric and pancreatic lipases in the lumen of the stomach and small intestine To play a therap...

Claims

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Application Information

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IPC IPC(8): C07D265/26
CPCC07D265/26
Inventor 张理星谢印杰李莹
Owner LUNAN PHARMA GROUP CORPORATION
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