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One-pot method for high-yield preparation of new lisstat

A technology of new listat and process, which is applied in the field of one-pot high-yield preparation of neolistat, which can solve the problems of high equipment requirements, high safety risks, and inability to recycle, and achieve good quality, simple post-treatment, and high-quality technology. The effect of easy operation

Active Publication Date: 2019-02-01
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, bromine and expensive palladium complex catalysts are used and cannot be recovered, and the discharge of "three wastes" is large. In addition, carbon monoxide gas needs to be used in the carboxylation reaction, and high temperature (115 ° C) and high pressure are used. (8bar) conditions, greater safety risks and higher requirements for equipment

Method used

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  • One-pot method for high-yield preparation of new lisstat
  • One-pot method for high-yield preparation of new lisstat
  • One-pot method for high-yield preparation of new lisstat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation one of embodiment 1 new lixistat

[0028] Add 2-amino-5-methylbenzoic acid (2.0g, 13.2mmol) and 20ml of pyridine in the reaction flask, stir and dissolve the mixture, add hexadecyl chloroformate (4.2g, 14.0mmol) dropwise under ice-bath cooling , after dropping, the ice bath was removed, and the reactant was stirred and reacted at room temperature for 2 hours, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.6g, 13.6mmol) was added, After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated to recover pyridine, the residue was added with 300 ml of water and stirred for 5 minutes, filtered, the solid was washed with water, and dried to obtain 5.2 g of off-white solid (98.1% yield). The crude product was recrystallized from methanol-ethyl acetate to obtain 4.6 g of white crystals (recrystallization yield 89.0%), mp76-78°C, HPLC purity 99.2%.

[0029] 1 H NMR (CDCl 3 ,400MHz): δ7.91(s,1H,Ar-H),7.51(d,J=8....

Embodiment 2

[0031] The preparation two of embodiment 2 new lixistat

[0032] Add 2-amino-5-methylbenzoic acid (10.0g, 66mmol) and 100ml pyridine in the reaction flask, the mixture is stirred and dissolved, and hexadecyl chloroformate (21g, 70mmol) is added dropwise under ice-bath cooling, and the dropwise After the ice bath was removed, the reactant was stirred at room temperature for 2 hours, and thionyl chloride (8.3 g, 70 mmol) was added dropwise. After the reaction mixture was stirred at room temperature for 1 hour, the pyridine solvent was recovered by concentration, and the residue was added with 500 ml of water and stirred for 10 minutes. Filter, wash the solid with water, and dry to obtain 25.7 g of a light yellow solid (97.0% yield). The crude product was recrystallized from ethyl acetate to obtain 23 g of white crystals (recrystallization yield 89.5%), mp76-78°C.

[0033] 1 H NMR (CDCl 3 ,400MHz): δ7.91(s,1H,Ar-H),7.52(d,J=8.0Hz,1H,Ar-H),7.32(d,J=8.4Hz,1H,Ar-H),4.42 (t, J=6....

Embodiment 3

[0034] Embodiment 3 The preparation three of new lixistat

[0035] Add 2-amino-5-methylbenzoic acid (10.0g, 66mmol) and 100ml pyridine in the reaction flask, the mixture is stirred and dissolved, and hexadecyl chloroformate (21g, 70mmol) is added dropwise under ice-bath cooling, and the dropwise After the ice bath was removed, the reactant was stirred and reacted at room temperature for 2 hours, and phosphorus oxychloride (8.2 g, 54 mmol) was added dropwise. After the reaction mixture was stirred at room temperature for 2 hours, the pyridine solvent was concentrated and recovered, and the residue was added with 600 ml of water and stirred for 10 minutes. Filter, wash the solid with water, and dry to obtain 25.3 g of white solid (95.5% yield). The crude product was recrystallized with 95% ethanol to obtain 22.5 g of white crystals (recrystallization yield 91.8%), mp 76-78°C.

[0036] 1 H NMR (CDCl 3 ,400MHz): δ7.91(s,1H,Ar-H),7.51(d,J=8.0Hz,1H,Ar-H),7.32(d,J=8.4Hz,1H,Ar-H),4...

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Abstract

The invention relates to a new process for one-pot preparation of cetilistat; the one-pot reaction is adopted, separation steps are sample, the product yield is high, the product quality is good, and the new process is especially suitable for industrialized production.

Description

Technical field: [0001] The invention relates to a high-yield one-pot process for preparing new lisstat. The biggest feature of the process is the one-pot process, which reduces purification steps and has high yield, and is especially suitable for large-scale industrial production. Background technique: [0002] New Lixistat (Cetilistat, Selistat, Cetilistat) is a new type of long-acting and potent specific gastrointestinal lipase inhibitor, with high safety and significant curative effect, and has a very broad prospect. Drugs for the treatment of obesity and related disorders. The molecule forms a covalent bond with the active serine site of gastrointestinal lipase and pancreatic lipase to inactivate the enzymes, thereby achieving the therapeutic effect of reducing calorie intake and controlling body weight. The biggest advantage of the drug is that it has no effect on the nervous system, does not affect other enzyme activities in the gastrointestinal tract, and is safer t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/26
Inventor 潘显道杨亚军沈玲珑闫琰
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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