Method for preparing important intermediate 2-(hexadecyloxy carbonyl)-amino-5-methylbenzoic acid of Cetilistat

A technology of methyl benzoic acid and new lixistat, which is applied in chemical instruments and methods, preparation of organic compounds, preparation of carbamic acid derivatives, etc., and can solve the problem of low conversion rate

Inactive Publication Date: 2016-06-08
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The technical purpose of the present invention is to provide a method for preparing the important intermediate 2-(hexadecyloxycarbonyl)-amino-5-methylbenzoic acid (I) of new lixistat, which mainly solves the process of producing compound I in the prior art Influence of the water generated in the reactant cetyl chloroformate (II) conversion rate is not high

Method used

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  • Method for preparing important intermediate 2-(hexadecyloxy carbonyl)-amino-5-methylbenzoic acid of Cetilistat
  • Method for preparing important intermediate 2-(hexadecyloxy carbonyl)-amino-5-methylbenzoic acid of Cetilistat
  • Method for preparing important intermediate 2-(hexadecyloxy carbonyl)-amino-5-methylbenzoic acid of Cetilistat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] The qualitative and quantitative detection method of the reaction substrate and product is: using KromasilC 18 Column (12.5cm×4.6mm×5μm), mobile phase: acetonitrile:acetic acid (100:0.1); UV detection wavelength 221nm; flow rate: 1.0mL / min; column temperature 30°C.

[0021] Put compound II, III, pyridine and solvent dichloromethane into the reaction kettle, wherein the molar ratio of compound II and III is 1:1, vigorously stir the reaction, during the reaction, the reaction feed liquid is pumped into two parallel molecular sieves In addition to the water column. After reacting for 1 hour, the product I was discharged from the bottom of the reaction kettle, heated and dissolved by adding ethyl acetate, and cooled to 10°C for recrystallization for 12 hours. The yield of the obtained product I was greater than 92.57%, and the chemical purity was greater than 99.76%.

Embodiment 2

[0023] Reaction substrate and product qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing the reactant molar ratio and each operating parameter are as follows:

[0024] Compound II, III, pyridine and solvent dichloromethane are loaded into the reactor, wherein the molar ratio of compound II and III is 1:1.5, and the reaction is vigorously stirred. During the reaction, the reaction feed liquid is pumped into three parallel packing In addition to the water column of calcium chloride. After 1.5 hours of reaction, the product I was released from the bottom of the reaction kettle, heated and dissolved by adding n-hexane, and cooled to 0°C for 20 hours of recrystallization. The yield of the obtained product I was greater than 95.73%, and the chemical purity was greater than 99.14%.

Embodiment 3

[0026] Reaction substrate and product qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing the reactant molar ratio and each operating parameter are as follows:

[0027] Compound II, III, pyridine and solvent dichloromethane are loaded into the reactor, wherein the molar ratio of compound II and III is 1:2, and the reaction is stirred vigorously. During the reaction, the reaction feed liquid is pumped into a single branch filled with anhydrous Sodium sulfate in the water column. After reacting for 2 hours, the product I was released from the bottom of the reactor, added ethanol to heat and dissolve, and cooled to 20°C for recrystallization for 15 hours. The yield of the obtained product I was greater than 93.29%, and the chemical purity was greater than 99.46%.

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Abstract

The invention relates to a method for preparing an important intermediate 2-(hexadecyloxy carbonyl)-amino-5-methylbenzoic acid (I) of Cetilistat and mainly aims to eliminate the influence of low conversion rate of a reactant hexadecyl chloroformate (II) by water produced in a compound I production process in the prior art. According to the method, an external-circulating water removing device is adopted to remove water produced in a nucleophilic substitution reaction of a compound II and 2-amino-5-methylbenzoic acid (III) in time, so that the conversion rate of the reaction material compounds II and III is greatly increased, simple and fast continuous production with low energy consumption is realized, the yield of the reaction product I is higher than 90%, and the chemical purity is higher than 99%.

Description

technical field [0001] The invention relates to a method for continuously producing the important intermediate of new lisstat 2-(hexadecyloxycarbonyl)-amino-5-methylbenzoic acid (I) by using an external circulation water removal device, and relates to a new method in the field of chemical industry Preparation technology of lixistat. Background technique [0002] Neolistat (Cetilistat, CAS: 282526-98-1), the chemical name is 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one, mainly used for Prevention and treatment of obesity and related diseases. The drug was first developed by the British company Alizyme. In September 2013, Takeda completed clinical trials in Japan and officially launched it under the trade name of Oblean. [0003] Neolistat is a long-acting and potent specific gastrointestinal lipase inhibitor, which exerts therapeutic effects by forming a covalent bond with the active serine site of lipase in the lumen of the stomach and small intestine to inactivate it ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/28C07C269/04
CPCC07C269/04
Inventor 卢定强严国荣王新仙凌岫泉吉文喆刘桐岐
Owner NANJING UNIV OF TECH
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