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Process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as raw material

A technology of methyl benzoic acid and raw materials, which is applied in the field of organic synthesis, can solve the problems of large-scale industrial production limitations, difficult separation and purification of intermediates, and difficult industrial production, etc., and achieve the effect of fewer reaction steps, short reaction routes, and easy handling

Active Publication Date: 2020-03-24
HEFEI UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the process route is long, there are many side reactions, the intermediates are not easy to separate and purify, and the single-step yield is low, especially the conversion rate of the first step is very low.
In addition, this route is only suitable for small batch synthesis in the laboratory, and is limited for industrial mass production
[0018] In summary, the current existing methods have problems such as low yield, high cost, difficult product purification, and difficult industrial production.

Method used

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  • Process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as raw material
  • Process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as raw material
  • Process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as raw material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 1. Synthesis of intermediate c (6-methyl-2,4-dihydro-1H--3,1-benzoxazine-2,4-dione)

[0055] Put 2-amino-5-methylbenzoic acid (4g, 0.026mol) into a 250ml reaction flask, add 150ml of acetonitrile, heat the oil bath to 52°C, and dissolve triphosgene (2.57g, 0.0087mol) with 40ml of acetonitrile , and slowly drop triphosgene and pyridine (4.1g, 0.052mol) into the reaction flask at the same time, stir at 52°C for 5h, remove the solvent under reduced pressure, add H 2 O (100ml), suction filtered, the filter cake was washed with water and glacial dichloromethane successively, and dried in vacuo to obtain 4.27g of the product with a yield of 93%. 1 H NMR (400MHz, d 6 -DMSO): δ11.63(s,1H),7.72(s,1H),7.58.7.55(dd,J 1 =4.0Hz,J 2 =8.0Hz, 1H), 7.06(d, J=8.0Hz, 1H), 2.33(s, 3H)

[0056] 2, the preparation of intermediate f (sulfonate)

[0057] Add cetyl alcohol (5g, 0.021mol) in a 250ml reaction flask, dissolve in 150ml of dichloromethane, then add p-trifluoromethylbenzenesulfo...

Embodiment 2

[0061] 1. Synthesis of intermediate c (6-methyl-2,4-dihydro-1H--3,1-benzoxazine-2,4-dione)

[0062] Put 2-amino-5-methylbenzoic acid (4g, 0.026mol) into a 250ml reaction flask, add 150ml of acetonitrile, and dissolve triphosgene (2.57g, 0.0087mol) with 40ml of acetonitrile, and slowly drop it into the reaction flask Add triphosgene (2.57g, 0.0087mol) and pyridine (4.1g, 0.052mol), at room temperature for 5h, after removing the solvent under reduced pressure, add H 2 O (100ml), suction filtered, the filter cake was washed with water and ice dichloromethane successively, and dried in vacuo to obtain 3.0g of the product with a yield of 65%. 1 H NMR (400MHz, d 6 -DMSO): δ11.63(s,1H),7.72(s,1H),7.58.7.55(dd,J 1 =4.0Hz,J 2 =8.0Hz,1H),7.06(d,J=8.0Hz,1H),2.33(s,3H),1.69-1.64(m,3H),1.33-1.15(m,25H),0.84(t,J= 7.0Hz, 3H)

[0063] The synthesis of intermediate f and final product g is the same as in Example 1.

Embodiment 3

[0065] 1. The synthesis of intermediate c is the same as in Example 1;

[0066] 2, the preparation of intermediate f (sulfonate)

[0067] Add p-hexadecanol (5g, 0.021mol) into a 250ml reaction flask, add 150ml of dichloromethane to dissolve, then add p-toluenesulfonyl chloride (5.5g, 0.028mol), pyridine (4.8g, 0.0616mol) in sequence , DMAP (0.18g, 1.5mmol), after dropwise addition, heat up and reflux for 12h, after the reaction is completed, use successively the hydrochloric acid of 1mol / L of 50ml, the 1% NaOH of 50ml, the water washing reaction solution of 50ml to neutrality, The liquid was separated, and the aqueous layer was sequentially extracted three times with 40 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was removed in vacuo to obtain 5.95 g of off-white solid with a yield of 72%. 1 H NMR (400MHz, CDCl 3 ):d 7.78(d, J=8.4Hz, 2H), 7.34(d, J=8.0Hz, 2H), 4.02(t, J=6.4Hz, 2H), 2.44(...

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Abstract

The invention discloses a process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as a raw material. The process comprises the steps: taking 2-amino-5-methyl benzoic acid as a raw material, and carrying out transesterification on 2-amino-5-methyl benzoic acid and triphosgene under the action of organic base catalysis to generate an intermediate c, namely 6-methyl-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione; carrying out a reaction on sulfonyl chloride (d) with a specific structure with n-hexadecanol under the condition of base catalysis to generate an intermediatef; and finally, carrying out an alkylation reaction on oxygen atoms of the intermediate c and the intermediate f in the presence of organic base to generate the target product Cetilistat. According tothe method, the reaction steps for synthesizing the Cetilistat are few, the process route is short, side reactions are few, the yield of the final product is high, and the purity is more than 99%.

Description

technical field [0001] The invention relates to a synthesis method of a known compound, in particular to a process for efficiently synthesizing Cetilistat by using 2-amino-5-methylbenzoic acid as a raw material, and belongs to the technical field of organic synthesis. Background technique [0002] Obesity is a common nutritional problem in modern society. It is a state caused by excessive accumulation of body fat, especially triglycerides, which can easily lead to heart disease, high blood pressure, diabetes and other diseases. Cetilistat was jointly developed by Norgine and Takeda, and its English product name is Oblean. It was approved by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) on September 20, 2013, and was marketed in Japan by Takeda. , for the treatment of obesity. Celistat is essentially 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 a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/26
CPCC07D265/26
Inventor 冯乙巳朱天彩程俊浦同俊唐飞裴孝俊刘杰
Owner HEFEI UNIV OF TECH
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