Preparation method of weigh reducing drug lorcaserin hydrochloride and intermediate thereof

A technology of catalysts and compounds, which is applied in the field of preparation of weight-loss drug greencaserin hydrochloride and its intermediates, can solve the problems of inconvenient operation, high price of borane, relatively expensive price of 2-chloropropionyl chloride, etc., and achieve simple operation, reagent Cheap and easy to obtain, convenient and safe after-treatment

Active Publication Date: 2016-03-02
CHINA PHARM UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The 2-chloropropionyl chloride used in this reaction is more expensive; the bo...

Method used

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  • Preparation method of weigh reducing drug lorcaserin hydrochloride and intermediate thereof
  • Preparation method of weigh reducing drug lorcaserin hydrochloride and intermediate thereof
  • Preparation method of weigh reducing drug lorcaserin hydrochloride and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (1) Preparation of (4-chlorophenethyl) tert-butyl carbamate (III)

[0048]Add 2-(4-chlorophenyl)ethylamine (50.0g, 321.3mmol) into a 1L eggplant-shaped flask, add 200mL of dichloromethane, stir to dissolve, and add BOC anhydride (77.1g, 353.3mmol) dropwise at 0°C ) was dissolved in 300mL of dichloromethane, and a large amount of white solid was precipitated. After the addition was completed, it was raised to room temperature, and a catalytic amount of DMAP was added, and the solution gradually became colorless and clear. After stirring for about 5 hours (monitored by TLC, the reaction was complete), pour 400mL Extract in water, combine the organic phases, wash with water and saturated sodium chloride solution successively, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain 80.3 g of white solid with a yield of 97.7%.

[0049] 1 H-NMR (300MHz, CDCl 3 )δ7.29-7.24 (2H, m, ArH), 7.15-7.08 (2H, m...

Embodiment 2

[0066] (1) N-(4-chlorophenethyl) propyl-2-en-1-amine trifluoroacetate (V:HA=CF 3 CO 2 H) Preparation

[0067] Dissolve IV (12.0g, 40.6mml) in 25mL of dichloromethane, slowly add trifluoroacetic acid (6.0ml, 80.8mmol) dropwise, and stir the reaction at 25°C, gradually a white solid precipitates out, TLC monitors that the reaction of raw materials is complete, Cool, filter with suction, wash with a small amount of ethyl acetate to obtain a white solid, and dry to obtain intermediate V (HA=CF 3 COOH) 11.8g, yield 93.9%.

[0068] (2) 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Preparation of (VI)

[0069] Take anhydrous aluminum trichloride (8.6g, 64.5mmol), grind it into powder, put it into a 250mL four-necked bottle, add 60mL of o-dichlorobenzene, raise the temperature to 110°C under mechanical stirring, add N-(4-chloro Phenylethyl)propyl-2-en-1-amine trifluoroacetate (10.0g, 32.3mmol), after adding, stir the reaction until the raw material disappears (monitored ...

Embodiment 3

[0072] (1) Preparation of N-(4-chlorophenethyl)propyl-2-en-1-amine (VII)

[0073] IX(R=-COCF 3 , 20.0g, 68.6mmol) was dissolved in 100mL of methanol, 100mL of 15% NaOH solution was added, heated to 60°C for 3h, then concentrated under reduced pressure, the residue was extracted with dichloromethane (100mL×3), and the organic phases were combined, Wash with water and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain 11.9 g of a colorless oil, with a yield of 88.6%.

[0074] 1 H-NMR (300MHz, CDCl 3 )δ7.25(2H,dd,J=10.7,3.8Hz,ArH),7.11(2H,dd,J=14.1,8.3Hz,ArH),5.87(1H,m,CH),5.12(2H,m, CH 2 ),3.26(2H,d,J=6.0Hz,CH 2 ),2.91-2.70(4H,m,CH 2 CH 2 ).

[0075] (2) 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Preparation of (VI)

[0076]Take anhydrous aluminum trichloride (11.5g, 86.2mmol), grind it into powder, put it into a 250mL four-necked bottle, add 60...

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PUM

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Abstract

The present invention relates to the field of pharmaceutical chemistry, specifically to a preparation method of a weigh reducing drug lorcaserin hydrochloride and an intermediate thereof. The preparation method comprises: adopting p-chlorophenethylamine as a raw material, and sequentially carrying out acylation amino protection, allyl substitution, deprotection, Friedel-Crafts alkylation, splitting and salt forming to obtain the lorcaserin hydrochloride. According to the present invention, the preparation method has characteristics of low cost, simple operation and easy post-treatment, and is the economical and industrialized synthesis method.

Description

technical field [0001] The invention relates to the field of drug synthesis. It specifically relates to the preparation method of the weight-loss medicine greencaserin hydrochloride (I) and its intermediate. Background technique [0002] Lorcaserin Hydrochloride (I), the chemical name is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, In 2005, it was developed by American Arena Pharmaceuticals for obese patients. On June 27, 2012, it was officially approved by the U.S. Food and Drug Administration (FDA) to be marketed in the United States. Greencaserin is the first weight-loss drug approved by the FDA in 13 years since Orlistat was approved in 1999. Obese or overweight adults with a body mass index (BMI) >27, and at least one weight-related disease (such as hypertension, type II diabetes, or hyperlipidemia). Compared with previous weight-loss drugs, it has fewer side effects. At the same time, greencaserin can also improve heart rate, blood pre...

Claims

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Application Information

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IPC IPC(8): C07D223/16
Inventor 朱启华徐云根卞学国王均伟汪有亮魏萍何广卫
Owner CHINA PHARM UNIV
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