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Method for preparing cetilistat

A technology of Lise and compounds, which is applied in the field of drug preparation, can solve the problems of low yield and difficult separation and purification in the examples, and achieve the effects of excellent atom economy, high purity and simple route

Active Publication Date: 2016-06-01
ZHONGSHAN WANHAN PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned reasons cause low yields and difficulties in separation and purification in the aforementioned patents

Method used

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  • Method for preparing cetilistat
  • Method for preparing cetilistat
  • Method for preparing cetilistat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: Synthesis 2- ((( Hexadecyloxy)carbonyl)amino)5-methylbenzoic acid

[0048] Put 2-amino-5-methylbenzoic acid (3.0 g, 19.8 mmol, 1.0 equivalent, hereinafter abbreviated as eq) into 24 mL of dichloromethane, suspend, and start stirring. Pyridine was added dropwise, followed by cetyl chloroformate slowly. The specific results are shown in Table 1. figure 1 It is the HPLC spectrogram of 4# reaction terminal point. It can be seen from the table below that when the feeding sequence is 2-amino-5-methylbenzoic acid, pyridine, and cetyl chloroformate, the product has high purity and no specific impurities are formed, and can be directly used for feeding in the next step.

[0049] Table 1 Cetyl Chloroformate and Pyridine Feeding Quantity Investigation Statistical Table

[0050]

[0051] *: Cetyl chloroformate dosage is the molar ratio of cetyl chloroformate to 2-amino-5-methylbenzoic acid;

[0052] **: Pyridine dosage is the molar ratio of pyridine to 2-am...

Embodiment 2

[0054] Embodiment 2: the preparation of west for Li Sita

[0055] Add 36 mL of pyridine dropwise to the 6# reaction liquid in Example 1, and control the temperature at 0-5°C, then slowly add methyl chloroformate (7.5g, 79.2mmol, 4.0eq) dropwise, and control the internal temperature between 0-10°C, Insulated and stirred for 2.5 hours, at this time, the normalized content of cetiristat was 98.80%, such as figure 2 shown.

[0056] After the reaction was completed, 18 mL of water and 18 mL of dichloromethane were added, vigorously stirred for 10 minutes, then allowed to stand and separated. The organic phase was washed twice with 30 mL of 1 mol / L dilute hydrochloric acid, and then washed with purified water until pH = 6-7. The organic phase was concentrated under reduced pressure to a small volume, and then put into n-heptane to completely replace the dichloromethane. Then concentrated under reduced pressure to about 15-20mL, a large amount of solids precipitated, filtered, ...

Embodiment 3

[0058] Embodiment 3: the preparation of west for Li Sita

[0059] To the 4# reaction solution in Example 1, 33 mL of recovered pyridine was added dropwise, and the temperature was controlled at 0-5°C, and then ethyl chloroformate (10.7g, 99mmol, 5.0eq) was slowly added dropwise, and the internal temperature was controlled at 0-10°C. Insulated and stirred for 1 hour, at this time the normalized content of cetiristat was 98.86%.

[0060] After the reaction was completed, 18 mL of water and 18 mL of methylene chloride were recovered, vigorously stirred for 10 minutes, and then left to stand and separated. The organic phase was washed twice with 30 mL of 1 mol / L dilute hydrochloric acid, and then washed with purified water until pH = 6-7. The organic phase was concentrated under reduced pressure to a small volume, and then put into n-heptane to replace the dichloromethane. Then concentrated under reduced pressure to about 15-20mL, a large amount of solids precipitated, filtere...

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Abstract

The invention provides a method for preparing cetilistat. According to the method, 2-amidogen-5-methyl benzoic acid is adopted as an initial raw material, under existence of pyridine, the 2-amidogen-5-methyl benzoic acid reacts with chlorine acid cetyl alcohol ester in the first place, a midbody 2-(((hexadecane oxygroup) carbonyl) amidogen)-5-methyl benzoic acid is obtained, then dehydrogenation cyclization reagent is utilized to obtain the cetilistat, and the feeding sequence in step 1 is the 2-amidogen-5-methyl benzoic acid, alkali and the chlorine acid cetyl alcohol ester in sequence. The method has the remarkable advantages that the route is simple, operation is less, atom economy is better than that of other routes, and the cetilistat is suitable for large-scale production; the purity of the cetilistat at the reaction endpoint is larger than 98%, and through simple postprocessing, a final product which meets medical standards can be obtained, wherein the purity is larger than 99.5%, and the single impurity is smaller than 0.1%; the utilized solvent including dichloromethane and pyridine can be recycled for mechanical application, and the method is environmentally friendly.

Description

technical field [0001] The invention relates 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 Anti-gastrointestinal lipase inhibitors, non-systemic weight management drugs. Cetiristat mainly 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 enzyme and exert its therapeutic effect. Inactivated enzymes are unable to hydrolyze dietary fats (mainly triglycerides) into absorbable non-esterified fatty acids and monoacylglycerols. Unbroken triglycerides cannot be absorbed by the intestine, thereby reducing calorie intake and keeping weight under control. This medicine does not need to be absorbed throughout the body to be effective. The structural formula of cetilistat is as follows: [0003] [0004] Cetilistat is a kind of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/26
CPCC07D265/26
Inventor 王鹤然杜志博黄海石黄冠彬蔡明君彭韪
Owner ZHONGSHAN WANHAN PHARM CO LTD
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