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Preparation method of cetilistat

A technology of lyse and hexadecane, which is applied in the preparation of cetiristat and the field of drug preparation, can solve the problems of unfavorable industrial production, harsh reaction conditions, and excessive discharge of three wastes, and achieve easy industrial production, convenient preparation, and side effects. The effect of less product

Inactive Publication Date: 2015-02-11
SHANDONG CHUANGXIN PHARMA RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method needs to use a large amount of glacial acetic acid, and there are defects such as more discharge of three wastes, harsh reaction conditions, high requirements for equipment, and unfavorable for industrial production.

Method used

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  • Preparation method of cetilistat
  • Preparation method of cetilistat
  • Preparation method of cetilistat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: Preparation of 2-(hexadecyloxycarbonylamino)-5-bromobenzoic acid methyl ester

[0054]

[0055] Add 4.9g of triphosgene to 50mL of dichloromethane, cool to 0°C, add dropwise a solution of 2-amino-5-bromobenzoic acid methyl ester (5g) and triethylamine (13.8mL) in dichloromethane (20mL) After the dropwise addition, keep at 0°C for 15 minutes, rise to room temperature and stir for 2 hours.

[0056] 5.26 g of cetyl alcohol was added to the above reaction liquid, and reacted at room temperature for 2 h. After the reaction is completed, filter, the filtrate is vacuum concentrated and spin-dried, the residue is beaten and washed with anhydrous methanol, filtered, and the filter cake is dried to constant weight. 9.1 g of white powder solid was obtained, which was methyl 2-(hexadecyloxycarbonylamino)-5-bromobenzoate; yield: 85%.

Embodiment 2

[0057] Embodiment 2: Preparation of 2-(hexadecyloxycarbonylamino)-5-methylbenzoate

[0058]

[0059] Under nitrogen protection, 10g of methyl 2-(hexadecyloxycarbonylamino)-5-bromobenzoate was dissolved in 1,4-dioxane (50mL) and water (5mL), and 11g of anhydrous potassium carbonate was added , 1.44g methylboronic acid, 0.731g Pd(dppf) 2 Cl 2 , and the mixture was reacted at 105°C for 3 hours. After the reaction is complete, cool down, filter, spin the filtrate to dry, wash the residue with anhydrous methanol, filter, and dry the filter cake to obtain 6.5 g of gray solid, which is 2-(hexadecyloxycarbonylamino)-5-methylbenzoic acid Methyl ester, yield 75%.

Embodiment 3

[0060] Embodiment 3: the preparation of 2-(hexadecyloxycarbonylamino)-5-methylbenzoic acid

[0061]

[0062] Add 7g of methyl 2-(hexadecyloxycarbonylamino)-5-methylbenzoate to a mixture of 35mL of tetrahydrofuran and 7mL of water, add 20.1g of lithium hydroxide, and react at 60°C for 3h. After the reaction was completed, the reaction solution was concentrated, the residue was added to 70 mL of ice water, the pH was adjusted to 7 with 6M hydrochloric acid, filtered, and the filter cake was dried to constant weight to obtain 6.2 g of a gray solid, namely 2-(hexadecyloxycarbonylamino)-5 -Methylbenzoic acid, yield 92%.

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PUM

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Abstract

The invention discloses a preparation method of cetilistat, which has the advantages of high yield, mild reaction conditions and the like and can easily implement industrial production. The method comprises the following steps: (1) reacting methyl 2-amino-5-halobenzoate with triphosgene to obtain 2-methoxycarbonyl-4-halophenylisocyanate; adding hexadecanol to generate methyl 2-(hexadecaalkoxycarbonylamino)-5-halobenzoate; (2) adding the methyl 2-(hexadecaalkoxycarbonylamino)-5-halobenzoate, methyl boron dihydroxide and alkali into water and an organic solvent, adding a palladium catalyst, and reacting to obtain methyl 2-(hexadecaalkoxycarbonylamino)-5-methylbenzoate; (3) carrying out esterolysis reaction on the methyl 2-(hexadecaalkoxycarbonylamino)-5-methylbenzoate to obtain 2-(hexadecaalkoxycarbonyl)-5-methylbenzoic acid; (4) suspending the 2-(hexadecaalkoxycarbonyl)-5-methylbenzoic acid in pyridine, and cyclizing under the action of a dehydrating agent; and purifying and carrying out crystal transformation to obtain the cetilistat.

Description

technical field [0001] The invention relates to a preparation method of cetiristat, which belongs to the technical field of medicine preparation methods. Background technique [0002] Cetilistat (2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one, cetilistat) is a long-acting and potent Specific gastrointestinal lipase inhibitors form covalent bonds with the active serine sites of gastric lipase and pancreatic lipase in the lumen of the stomach and small intestine to inactivate the enzymes, thereby achieving the therapeutic effect of reducing calorie intake and controlling body weight. The biggest advantage of this drug is that it does not act on the nervous system, does not affect other enzyme activities in the gastrointestinal tract, and is safer than the current similar drug orlistat. Its structural formula is as follows: [0003] [0004] The synthesis of cetiristat and its intermediates has been described in US2007232825 and US2003027821, but there is no relevant ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/26
CPCC07D265/26
Inventor 邢艳秋李运波杨冬霞齐玉威邵涛明娄艳华王发明马媛媛
Owner SHANDONG CHUANGXIN PHARMA RES & DEV
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