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Method for preparing lorcaserin

A technology for lorcaserin and chlorophenyl, which is applied in the field of preparing lorcaserin, can solve the problems of complicated operation, many steps and high production cost, and achieves the effects of good reaction selectivity, high product purity and easy operation.

Active Publication Date: 2020-08-07
HEBEI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent WO2003086306 uses p-chlorophenethylamine as the starting material, undergoes aminolysis, iodination, allylation, Heck reaction, hydrogen reduction and alkali solution to deprotect, and splits into salt to obtain lorcaserin. This route has many steps , operation complex, Pd(OAc) 2 As a catalyst, it is expensive and the production cost is high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of p-chlorophenethylamine (IM1)

[0028] In a 250mL three-necked flask, add 15.16g (0.10mol) p-chlorophenylacetonitrile, add 180 mL cocatalyst ethanol, then add 5.87g (0.10mol) Raney Ni, 16.18g (0.30mol) KBH 4 , stirred at 25°C, the reaction was complete after 2 hours, stopped stirring, filtered with suction, and removed ethanol by rotary evaporation, added 200 mL of ethyl acetate, 200 mL of water, and adjusted the pH to 1 with 6 mol / L hydrochloric acid, separated the ethyl acetate layer, and water Add 200mL ethyl acetate to the layer, adjust the pH to 13 with 40% NaOH, separate the ethyl acetate layer, extract the water layer with 200mL ethyl acetate, combine the ethyl acetate layers, add anhydrous sodium sulfate to dry, filter with suction, spin Ethyl acetate was distilled off to obtain 14.32 g of light yellow oily liquid with a yield of 92.0%.

[0029] IM1 Characterization Data:

[0030] 1 H NMR (500 MHz, CDCl 3 ) δ 7.23 (d, J = 8.1 Hz, 2H), 7.09 (d, ...

Embodiment 2

[0032] Preparation of p-chlorophenethylamine (IM1)

[0033] In a 250mL three-necked flask, add 15.13g (0.10mol) of p-chlorophenylacetonitrile, add 150 mL of cocatalyst methanol, then add 5.88g (0.10mol) of Raney Ni, 11.36g (0.30mol) of NaBH 4 , stirred and reacted at 30°C for 3 hours, and the post-reaction treatment was the same as in Example 1, wherein the acid pH was adjusted to 2, and the base pH was adjusted to 12 after extraction and removal of impurities to obtain 13.23 g of light yellow oily liquid with a yield of 85.0%.

Embodiment 3

[0035] Preparation of N-(2-(4-chlorophenyl)ethyl))-4-methylbenzenesulfonamide (IM2)

[0036]In a 250mL three-necked flask, add 15.56g (0.10mol) of p-chlorophenethylamine, add 175mL of dichloromethane to dissolve it, add 14mL of triethylamine (0.10mol) under stirring at 25°C, and then add 19.07g in an ice bath (0.10mol) p-toluenesulfonyl chloride, stirred for 30 minutes and then moved to room temperature. After 4 hours, the reaction was complete and filtered with suction. After the filtrate was spin-dried, 50mL of ethanol was added and heated to 78°C for recrystallization to obtain 26.35g of IM2 white solid. 85.1%, HPLC purity 99.9%.

[0037] IM2 Characterization Data:

[0038] ESI-MS: m / z = 310[M+H] +

[0039] 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (d, J = 8.3 Hz, 2H), 7.28 (d, 2H), 7.21(d, 2H), 7.02 (d, J = 8.4 Hz, 2H), 4.79 (s, 1H), 3.18 (t , J = 7.0 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H).

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Abstract

The invention discloses a method for preparing lorcaserin. Specifically, the method comprises the steps: taking p-chlorophenylacetonitrile as an initial raw material, preparing p-chlorophenylethylamine through reduction; carrying out a reaction with p-toluenesulfonyl chloride to form an amino occupying intermediate; enabling the intermediate to carry out a reaction with monochloroacetone under analkaline condition to form N-(2-(4-chlorphenyl)ethyl)-4-methyl-N-(2-propionyl)benzenesulfonamide, and then carrying out reduction, chlorination, p-toluenesulfonyl removal and intramolecular Friedel-Crafts alkylation to synthesize 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzoazepine, carrying out L-(+)-tartaric acid resolution and alkalization on azepine to remove tartaric acid, and acting with hydrogen chloride diethyl ether to salify to prepare lorcaserin. The method has the characteristics of simple synthesis method, good reaction selectivity, high product purity, environmental protectionand low preparation cost.

Description

technical field [0001] The invention relates to a method for preparing lorcaserin, which belongs to the technical field of medicine and its preparation. Background technique [0002] Lorcaserin (English name: Lorcaserin) chemical name (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, is A new type of weight-loss drug developed by Arena Pharmaceuticals, which was approved by the FDA in 2012. Its target is 5-HT 2C , by specifically stimulating 5-HT 2C receptors increase appetite satiety and reduce caloric intake, while 5-HT 2A and 5-HT 2B There was no effect on the receptors, which are associated with cardiovascular disease and hallucinations, respectively. Phase III clinical results show that lorcaserin has no effect on heart valves and pulmonary arteries, and can also improve heart rate, blood pressure and low-density lipoprotein cholesterol levels. The advantages of lorcaserin are not limited to curative effect, and its safety is better than oth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 孙京国刘家伟孙辰龙瑶冯玉玲王玥蔡乐王涛王广威侯家宁王琳卢锡萌
Owner HEBEI NORMAL UNIV
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