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A kind of one-pot method prepares the method for new lixistat

A new Lilistat and synthetic method technology, applied in the field of simple and efficient preparation of new Lilistat, can solve the problems of high equipment requirements, complicated operations, cumbersome steps, etc., and achieve simple and not cumbersome processes, simple post-processing, and product purity. high effect

Active Publication Date: 2019-12-31
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 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 phosgene and liquid bromine, expensive palladium catalysts, high requirements on equipment, complicated operation, and high-pressure equipment are used. Therefore, the production cost of this route is high and the risk factor is high.

Method used

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  • A kind of one-pot method prepares the method for new lixistat

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Experimental program
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Effect test

Embodiment 1

[0029] 5g (33.08mmol, 1.0eq) of 2-amino-5-methylbenzoic acid, pyridine (80ml) and tetrahydrofuran (40ml) were added in a 500ml three-necked flask, stirred and dissolved, the dissolution was complete, and the temperature was lowered. When the temperature of the reaction system was At 5°C, start to slowly add 12.10g (39.70mmol, 1.2eq) of hexadecyl chloroformate dropwise, control the temperature not to exceed 10°C, and complete the dropwise addition in about 30 minutes. 30°C, heat preservation reaction for 30 minutes, after the heat preservation is over, lower the temperature of the system to 0-5°C, start to slowly add 15.1ml (186.55mmol, 2.5eq) of methanesulfonyl chloride dropwise, and the dropwise addition is completed in about 20 minutes. The temperature does not exceed 10°C. After dropping, continue to keep warm and stir for 30 minutes. When the keep warm is over, move the reaction system to a water bath, slowly raise the temperature to 25°, keep warm for 1 hour, and when the ...

Embodiment 2

[0031] 5g (33.08mmol, 1.0eq) of 2-amino-5-methylbenzoic acid, pyridine (60ml) and tetrahydrofuran (60ml) were added in a 500ml three-necked flask, stirred and dissolved, the dissolution was complete, and the temperature was lowered. When the temperature of the reaction system was At 5°C, start to slowly add 12.10g (39.70mmol, 1.2eq) of hexadecyl chloroformate dropwise, control the temperature not to exceed 10°C, and complete the dropwise addition in about 30 minutes. 30°C, heat preservation reaction for 30 minutes, after the heat preservation is over, lower the temperature of the system to 0-5°C, start to slowly add 15.1ml (186.55mmol, 2.5eq) of methanesulfonyl chloride dropwise, and the dropwise addition is completed in about 20 minutes. The temperature does not exceed 10°C. After dropping, continue to keep warm and stir for 30 minutes. When the keep warm is over, move the reaction system to a water bath, slowly raise the temperature to 25°, keep warm for 1 hour, and when the ...

Embodiment 3

[0033] 5g (33.08mmol, 1.0eq) of 2-amino-5-methylbenzoic acid, pyridine (40ml) and tetrahydrofuran (80ml) were added in a 500ml three-necked flask, stirred and dissolved, the dissolution was complete, and the temperature was lowered. When the temperature of the reaction system was At 5°C, start to slowly add 12.10g (39.70mmol, 1.2eq) of hexadecyl chloroformate dropwise, control the temperature not to exceed 10°C, and complete the dropwise addition in about 30 minutes. 30°C, heat preservation reaction for 30 minutes, after the heat preservation is over, lower the temperature of the system to 0-5°C, start to slowly add 15.1ml (186.55mmol, 2.5eq) of methanesulfonyl chloride dropwise, and the dropwise addition is completed in about 20 minutes. The temperature does not exceed 10°C. After dropping, continue to keep warm and stir for 30 minutes. When the keep warm is over, move the reaction system to a water bath, slowly raise the temperature to 25°, keep warm for 1 hour, and when the ...

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Abstract

The invention discloses a method of preparing Cetilistat through a one-pot method. The method comprises the following steps that 2-amino-5-toluic acid is sequentially reacted with cetyl chloroformate and methane sulfonyl chloride in a mixed solution, and the Cetilistat is obtained through the one-pot method. According to the method, with selection of a mixed solution system as a reaction medium and the methane sulfonyl chloride as a lactonization reagent and adoption of the one-pot method to prepare the Cetilistat, an obtained product is high in yield and purity; the process is simple and not tedious, separation and purification of an intermediate are not needed, postprocessing is liable to operate, requirement on equipment is not high, the industrial production is facilitated.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to a simple and efficient method for preparing neolistat. 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 therapeutic role, inactivated enzymes cannot ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/26
CPCC07D265/26
Inventor 张则平周友春陈直金
Owner LUNAN PHARMA GROUP CORPORATION
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