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Method for preparing lorcaserin

A technology of green caserin and chlorophenyl, which is applied in the field of medicine, can solve problems such as potential safety hazards, cumbersome process operations, shortening the reaction time of Fuckers alkylation, etc., and achieve the effect of ensuring quality and safe and simple post-treatment process

Active Publication Date: 2016-09-07
LIANGJIANG MEDICINE CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0004] The most critical process point in the preparation process of green caserin is the step of preparing racemate by Friedel-Crafts alkylation reaction, but most of the synthesis methods of green caserin reported in existing patents and scientific literature are still the traditional solvent method for Friedel-Crafts alkylation. Chemical reaction, the process operation of this method is cumbersome, the solvent used is special (such as o-dichlorobenzene, nitrobenzene and other inert solvents), and it is not easy to remove it in the post-treatment process
[0005] The Friedel-Crafts alkylation reaction by the solvent-free method can shorten the Friedel-Crafts alkylation reaction time and avoid the use of special solvents in the solvent method. However, adding water directly in the post-treatment will cause a sharp exotherm and a great potential safety hazard. Therefore, this method Most of them only stay in the stage of small-scale preparation in the laboratory
There are reports in the literature of kilogram-level solid-phase scale-up tests, but the post-processing is also very cumbersome, and the product quality is poor, which cannot meet the requirements for use.

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  • Method for preparing lorcaserin

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preparation example Construction

[0023] The invention provides a preparation method of green caserin, comprising:

[0024] A) Using 1-[[2-(4-chlorophenyl)ethyl]amino]-2-chloropropane hydrochloride as a raw material, a green caserin racemate was synthesized by a solvent-free method;

[0025] B) Cool the reaction system to 70-80°C, add an organic solvent, stir evenly and cool to 0-5°C; the organic solvent is tetrachloroethylene, chlorobenzene, toluene or cyclohexane;

[0026] C) adding hydrochloric acid solution to the reaction system, separating liquids, removing the organic phase, and obtaining the aqueous phase;

[0027] D) adding NaOH solution to the above water phase, then adding cyclohexane or n-heptane for extraction, and concentrating the organic phase to obtain pure green caserin racemate.

[0028] After the solvent-free alkylation reaction, the present invention adds organic solvents such as tetrachlorethylene, chlorobenzene, toluene or cyclohexane, which solves the safety problem caused by the rapid...

Embodiment 1

[0055] 1-[[2-(4-chlorophenyl)ethyl]amino]-2-chloropropane hydrochloride 100g, anhydrous AlCl 3 (1.5eq.) 75.2g was added to (500mL) four-neck flask in turn, started stirring and heating, and raised the temperature to about 120°C for 12 hours. Sampling, TLC shows that the reaction is complete, stop heating, cool naturally, until T 内 When the temperature is 70°C, add chlorobenzene (400mL), stir to make the system evenly mixed, add ice-water bath, and cool the reaction system to 0-5°C. 1M HCl aqueous solution (360 mL) was added dropwise, and the temperature in the reaction flask was up to 80°C. Separate the liquid and remove the upper chlorobenzene phase. 30% NaOH aqueous solution (700g) was added dropwise to the aqueous phase, then cyclohexane (800mL) was added for extraction, the layers were separated, and the cyclohexane phase was left, and the aqueous phase was extracted once more with cyclohexane (200mL). Separate the liquids, combine the organic phases, and wash the organ...

Embodiment 2

[0057] 1-[[2-(4-chlorophenyl)ethyl]amino]-2-chloropropane hydrochloride 100g, anhydrous AlCl 3 (1.5eq.) 75.2g was sequentially added into (500mL) four-neck flask, stirring was started, heated, and the temperature was raised to about 120°C for 12h. Sampling, TLC shows that the reaction is complete, stop heating, cool naturally, until T 内 Add tetrachloroethylene (400mL) when the temperature is 70°C, stir to make the system evenly mixed, add ice-water bath, and cool the reaction system to 0-5°C. 1M HCl aqueous solution (360 mL) was added dropwise, and the temperature in the reaction flask was up to 40°C. Separate the liquid and remove the lower tetrachloroethylene phase. 30% NaOH aqueous solution (700g) was added dropwise to the aqueous phase, then cyclohexane (800mL) was added for extraction, the layers were separated, and the cyclohexane phase was left, and the aqueous phase was extracted once more with cyclohexane (200mL). Separate the liquids, combine the organic phases, a...

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Abstract

The present invention provides a method for preparing lorcaserin. The method is as below: A) synthesizing a lorcaserin racemate by using 1-[[2-(4-chlorphenyl) ethyl] amino]-2-chloropropane hydrochloride as a raw material by a solvent-free method; B) cooling the reaction system to 70-80 DEG C, adding an organic solvent, stirring well and cooling to 0 to 5 DEG C, wherein the organic solvent is tetrachloroethylene, chlorobenzene, toluene or cyclohexane; C) adding hydrochloric acid solution in the reaction system, dispensing the liquid, and removing an organic phase to obtain a water phase; and D) adding NaOH solution to the water phase, then adding cyclohexane or heptanes, and extracting and concentrating the organic phase to obtain a lorcaserin racemic pure product. After the solvent-free alkylation reaction, the organic solvent of tetrachloroethylene, chlorobenzene, toluene or cyclohexane is added, so as to solve the safety problem caused by rapid heat release due to direct addition of water; and the posttreatment process is simple and safe. The invention realizes industrial application of solvent-free synthesis of lorcaserin, at the same time ensures the quality of prepared lorcaserin.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a preparation method of chlorcaserin. Background technique [0002] Green caserin (8-chloro-1-methyl-2,3,4,5-tetrahydro-IH-3-benzazepine) is a drug that acts on the central nervous system to suppress appetite. Developed and developed by Nina Pharmaceuticals, its specific target is 5-HT2C, which has a strong effect on appetite control, but has no effect on 5-HT2A or 5-HT2B receptors, which are related to cardiovascular The disease is associated with causing hallucinations. [0003] Greencaserin is a highly selective serotonin agonist, and its selectivity for serotonin 5-HT2C receptors is 15 times and 100 times that of 5-HT2A receptors and 5-HT2B receptors, respectively. 5-HT2B receptor activation is one of the causes of heart valve disease and pulmonary hypertension. Greencaserin is highly selective for 5-HT2C receptors, and can avoid the occurrence of heart valve disease at t...

Claims

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Application Information

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IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 梁远鹏万昆霖冯立春贺耘
Owner LIANGJIANG MEDICINE CO LTD
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