Synthesis methods of lorcaserin derivative and salt thereof

A technology of lorcaserin and a synthesis method, which is applied in the field of synthesis of active pharmaceutical ingredients of slimming drugs, can solve problems such as cumbersome splitting operation steps, and achieves improved splitting efficiency, simple splitting operation, high purity and yield. Effect

Inactive Publication Date: 2014-04-30
CHINA JILIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Wherein the resolution yield is only 27.1%, and its resolution operation steps are more loaded down with triv

Method used

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  • Synthesis methods of lorcaserin derivative and salt thereof
  • Synthesis methods of lorcaserin derivative and salt thereof
  • Synthesis methods of lorcaserin derivative and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040]Compound 1 (8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 8-chloro-1-methyl-2,3,4,5-tetrahydro -1H-benzo[d]azepine) (38.00g, 1.0eq), D-dibenzoyl tartaric acid (69.58g, 1.0eq) was dissolved in methanol (228ml), heated to 65°C, and kept for 1.5-2h. Then slowly cool down to 25-30°C for 3-5h, filter with suction, wash the filter cake with a small amount of methanol, collect the filter cake, and dry to obtain the crude product of compound 2 ((R)-8-chloro-1-methyl-2 , 3,4,5-tetrahydro-1H-3-benzazepine D-dibenzoyl tartrate, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro- 1H-benzo[d]azepine D-(+)-DBTA) (40.92g, ee=96.6%, Yield=38%).

[0041] Dissolve the crude white solid compound 2 obtained above in methanol (210ml), raise the temperature to 65°C and reflux, add water (12.3g) dropwise until clarification, complete the addition in 15 minutes, keep warm for 1-2h after the addition, and cool down to 55°C in 40 minutes , turbid, 2.5-3.5 hours down to room temperatu...

Embodiment 2

[0045]

[0046] Compound 1 (38.00g, 1.0eq), D-dibenzoyl tartaric acid (69.58g, 1.0eq) was dissolved in ethanol (260ml), and the temperature was raised to 78°C. Insulate for 3-4h, slowly cool down to 25-30°C over 3-5h, filter with suction, wash the filter cake with a small amount of ethanol, collect the filter cake, and dry to obtain the crude compound 2 as a white solid (40.8g, ee=95.6%, Yield= 37%).

[0047] Dissolve the crude white solid compound 2 obtained above in ethanol (230ml), raise the temperature to 65°C, add water (13.0g) dropwise until clarification, complete the addition in 15 minutes, keep warm for 1-2h after the addition, and cool down to 55°C in 40 minutes. After 2.5-3.5 hours, the temperature was lowered to 25°C, suction filtered, the filter cake was washed with a small amount of acetone, and the filter cake was collected to obtain pure compound 2 (33.5 g, ee=99.4%, Yield=90.5%).

[0048] Pure compound 2 (37.90g, ee>99%, 1.0eq) was dissolved in a 20% aqueo...

Embodiment 3

[0051]

[0052] Compound 1 (30.00g, 1.0eq), D-(+)-diacetyltartaric acid (35.90g, 1.0eq) was dissolved in acetone (250ml) and heated to 56°C. Insulate for 1.5-2h, slowly cool down to 20-25°C over 3-5h, filter with suction, wash the filter cake with a small amount of acetone, collect the filter cake, and dry to obtain the crude product of compound 4 ((R)-8-chloro-1- Methyl-2,3,4,5-tetrahydro-1H-3-benzazepine D-(+)-diacetyl tartrate, (R)-8-chloro-1-methyl-2,3, 4,5-tetrahydro-1H-benzo[d]azepine(2R,3R)-2,3-diacetoxysuccinic acid) (24g, ee=93%, Yield=36.5%).

[0053] Dissolve the crude white solid compound 4 obtained above in acetone (200ml), raise the temperature to 56°C and reflux, add water (10.0g) dropwise until clarification, complete the addition in 15 minutes, keep warm for 1-2h after the addition, and cool down to 55°C in 40 minutes , turbid, 2.5-3.5 hours down to room temperature 25°C, suction filtration, the filter cake was washed with a small amount of acetone, and th...

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PUM

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Abstract

The invention discloses a synthesis method of a lorcaserin derivative. The synthesis method comprises the following steps: resolving a compound shown as a formula (II) under the action of an optical resolving agent; performing post-treatment to obtain the lorcaserin derivative. In the formula (II), R is H, alkyl with 1-4 carbon atoms, halogen, methoxyl or nitryl; R2 is H, alkyl with 1-4 carbon atoms, methoxyl, carboxybenzyl, t-butyloxycarboryl, methylsulfonyl, tosyl and substituted or unsubstituted benzyl; the optical resolving agent is acyl-substituted tartaric acid. The revolving efficiency is increased by selecting the optical resolving agent having a specific structure, and an optical pure product of which the ee value is over 99 percent can be obtained by means of simple recrystallization; meanwhile, resolving operation is easy, a single solvent is used for resolving, materials are fed into one pot, and the method is suitable for industrial production. The invention further discloses a synthesis method of a salt of the lorcaserin derivative. The obtained salt of the lorcaserin derivative can be applied to preparation of novel weight-reducing medicaments.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to the synthesis of an active drug component of a weight loss drug. Background technique [0002] Lorcaserin (Lorcaserin, trade name Belviq) is a new type of weight loss drug approved by the US FDA for the first time in 13 years. On June 27, 2012, the US Food and Drug Administration (FDA) officially approved the new weight loss drug Lorcaserin of Arena Pharmaceuticals. (lorcaserin hydrochloride) listed. The drug is approved for obese or overweight adults with a body mass index (BMI) ≥ 27 and at least one weight-related disease (such as hypertension, type 2 diabetes, or hyperlipidemia). Its mechanism of action is to stimulate the serotonin receptors in the hypothalamus to control appetite. The activation of this receptor can help patients eat less and increase the feeling of fullness. Compared with other weight loss drugs currently on the market such as fenfluramine and phentermine, t...

Claims

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Application Information

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IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 周益峰蒋晗任峰波詹姆斯·李
Owner CHINA JILIANG UNIV
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