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Synthesis of Lorcaserin and preparation method of intermediate of Lorcaserin

A technology of intermediates and preparation steps, which is applied in the field of pharmaceuticals and can solve problems such as irritation and corrosion, environmental pollution, and no advantages in industrialized production

Inactive Publication Date: 2014-10-29
SHANGHAI SCIENPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this scheme is that 2-chloropropionyl chloride is too active, irritating and corrosive, and its decomposition will produce HCl and 2-chloropropionic acid, which will easily cause environmental pollution
[0012] The key intermediate 1-[[2-(4-chlorophenyl)ethyl]amino]-2-hydroxypropane (compound of formula I), the patent document CN200780045133.9 also reports another preparation method, but this method prepares The process of formula I compound is loaded down with trivial details, does not have industrialized production advantage

Method used

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  • Synthesis of Lorcaserin and preparation method of intermediate of Lorcaserin
  • Synthesis of Lorcaserin and preparation method of intermediate of Lorcaserin
  • Synthesis of Lorcaserin and preparation method of intermediate of Lorcaserin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1、1

[0021] Embodiment 1, the preparation of 1-[[2-(4-chlorophenyl) ethyl] amino]-2-hydroxypropane (formula I compound)

[0022] Add 30kg of water into a 50L reactor, stir, add 373.2g of propylene oxide at room temperature, stir evenly, then slowly add 1000g of p-chlorophenethylamine, stir slowly to 90±5°C, and react for 5 hours. Cool down to room temperature, add dichloromethane 15L×3 for extraction three times, combine the dichloromethane layers, dry with 1kg anhydrous sodium sulfate overnight, filter, and concentrate the filtrate to dryness to obtain 1250g of light yellow solid. Yield 91%.

[0023] 1 HNMR (d6-DMSO, 400Hz) δ (ppm): 8.44 (br, 1H), 7.39 ~ 7.41 (d, 2H), 7.28 ~ 7.30 (d, 2H), 5.33 (d, 1H), 3.92 (m, 1H ) 3.09-3.13 (t, 2H), 2.93-2.97 (m, 3H), 2.73-2.79 (m, 1H), 1.11-1.12 (d, 3H).

Embodiment 2、1

[0024] Embodiment 2, the preparation of 1-[[2-(4-chlorophenyl) ethyl] amino]-2-chloropropane hydrochloride

[0025] Add 500ml of toluene, 75g of 1-[[2-(4-chlorophenyl)ethyl]amino]-2-hydroxypropane, 40g of DMF, and 250g of thionyl chloride into a 2L three-necked flask, and mix well until the reaction is at 65°C , Dissolving clear (colorless) at 40 ° C, with the increase of temperature, the color gradually deepens. After reacting for three hours, TLC (DCM:MeOH=10:1) detected that the starting material was completely reacted. Stop heating, cool down in an ice-water bath to below 10°C, filter with suction, wash with 300ml*2 toluene, beat the filter cake with 1000ml isopropanol overnight. The next day, it was filtered with suction, washed with 200ml×2 isopropanol, and dried in an oven at 40°C for 4h to obtain 63g of white solid. Yield 73.8%.

[0026] 1 HNMR (d6-DMSO, 400Hz) δ (ppm): 9.58 (br, 1H), 9.19 (br, 1H), 7.39 (d, 2H), 7.31 (d, 2H), 4.54~4.59 (m, 1H), 3.39 (m, 1H), 3.24...

Embodiment 3、8

[0027] Example 3, Preparation of 8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine

[0028] Add 600ml of 1,2-dichlorobenzene to a 2000ml reaction flask, then add 60g of 1-[[2-(4-chlorophenyl)ethyl]amino]-2-chloropropane hydrochloride successively, and trichloride 80g of aluminum is heated up to 130°C for reaction. The raw material dissolves at 60°C, and dissolves at 110°C. TLC (DCM:MeOH=10:1) detected the disappearance of the starting material, stopped the heating, and naturally cooled to room temperature. Slowly add 800ml of 1N HCl solution and 400ml of methyl tert-butyl ether, stir, separate the layers, and extract the organic phase with 400mL of 1N HCl solution×2. Combine the aqueous phases, adjust the pH>11 with 30% sodium hydroxide solution, extract with 800ml×3 methyl tert-butyl ether, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry. 64 g of crude product were obtained.

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Abstract

The invention relates to the field of pharmaceutical chemistry and relates to a method for preparing (R)-8-chlorine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzodiazepine hydrochloride (Lorcaserin) and an intermediate of Lorcaserin. (R)-8-chlorine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzodiazepine hydrochloride (Lorcaserin) which is an active material of a weight-loss drug is prepared from epoxy propane and p-chlorophenyl ethylamine serving as starting raw materials through the steps of ring opening, chlorination, cyclization, tartaric acid splitting, dissociation, salification and the like.

Description

technical field [0001] The present invention relates to the pharmaceutical field, specifically, the present invention relates to a kind of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride Preparation method of salt (Lorcaserin) and intermediates. Background technique [0002] Lorcaserin is a weight-loss drug approved by the FDA on June 27, 2012. A selective 5-HT2c receptor agonist (5-HT2c receptor agonist) developed by Arena Pharmaceuti, activates the 5-HT2c receptor in the hypothalamus to satisfy appetite, thereby controlling appetite and achieving weight loss. Its trade name is Belviq. Obesity can cause various diseases, such as cerebral embolism, coronary heart disease, hypertension, fatty liver, cardiopulmonary failure, endocrine and metabolic diseases, etc. [0003] The patent documents CN03808272.1 and CN200480016780.3 applied by the original research company have four methods for preparing lorcarcillin. [0004] Method 1 uses p-chloropheneth...

Claims

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Application Information

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IPC IPC(8): C07C215/08C07C213/04C07D223/16
Inventor 姜春阳李惠陈俊谢军廖文胜
Owner SHANGHAI SCIENPHARM CO LTD
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