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Preparation method of maleic acid asenapine

A technology of asenapine maleate and asenapine maleate is applied in the research field of synthesis technology of new atypical antipsychotic drug asenapine maleate, which can solve the problems of low yield, Problems such as poor product quality and no production value can achieve the effect of improving purity and yield

Inactive Publication Date: 2016-06-22
AVENTIS PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The yield of changing the route is extremely low, the product quality is not good, and there is no production value

Method used

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  • Preparation method of maleic acid asenapine
  • Preparation method of maleic acid asenapine
  • Preparation method of maleic acid asenapine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: (3aS,12bS)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxazin[4,5 -c] Preparation of pyrrol-1-one (compound II).

[0026] Add 35.4g of compound Ⅰ (0.1mol), 12.3g of sodium acetate (0.15mol), 25.2g of acetic acid (0.42mol), and 350ml of absolute ethanol into a 500ml three-necked flask, reflux and stir, and react for 4 hours. TLC spotting test shows that the reaction is complete . Atmospheric pressure distillation removed 175 ml of the solvent, and the temperature was naturally lowered to obtain a cloudy ethanol solution of compound II. Add 175ml of water, continue to cool down, keep warm at 5°C for 3h, filter under reduced pressure, and wash the filter cake with a lot of water to obtain 28.4g of light yellow solid, yield: 95.0%. MS (+1): 300.1. 1 HNMR: δ (ppm, DMSO), 7.790 (dd, 1H), 7.139-7.784 (m, 6H), 4.059-4.089 (m, 1H), 3.865-3.885 (m, 1H), 3.524-3.849 (m, 2H) ), 2.894(s,3H).

Embodiment 2

[0027] Implementation example two: the preparation of asenapine maleate

[0028] Add 10g of compound II (33.43mmol) and 100ml of dichloromethane into a 500ml three-neck flask, at 0-5°C, under nitrogen protection for 10-15 minutes, add 5.1ml of triethylchlorosilane (40.12mmol), and continue stirring for 10- After 15 minutes, 19.5ml (46.81mmol) of lithium aluminum hydride tetrahydrofuran solution was added dropwise at 0-10°C, stirred at room temperature for 12h, and detected by TLC until the reaction was complete. 30ml of 2M sodium hydroxide solution was slowly quenched, extracted with 25ml of dichloromethane, collected the organic phase, washed with 20% sodium chloride solution, and distilled under reduced pressure to obtain the residue, dissolved in 50ml of isopropanol, and added 5.0g of maleic acid ( 43.46mmol) stirred at room temperature for 2-3h, lowered to 0-10°C and continued to stir for 2-3h. Filtered under reduced pressure, washed with 10ml of isopropanol, dried at 50-5...

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Abstract

The invention relates to an industrialization-suitable synthesis process for antipsychotic medicine asenapine. The synthesis process includes the following steps that in an organic solvent, a compound I is cyclized under an acidic condition to obtain an intermediate II; the intermediate II is subjected to a reduction reaction under the effect of a strong reducing agent, the intermediate II and maleic acid are salified, and the target compound maleic acid asenapine is obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the research on the synthesis technology of a novel atypical antipsychotic drug asenapine maleate. technical background [0002] Asenapine maleate (English name asenapine, trade name SAPHRIS, chemical name: trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2, 3:6,7]oxazin[4,5-c]pyrrole maleate), developed by OrganonBioSciences and produced by ScheringPlough. On August 14, 2009, the FDA approved the drug for the emergency treatment of adults with schizophrenia, mania, or mixed episodes with type I bipolar disorder. [0003] Its main preparation method is as follows at present: [0004] [0005] The preparation method has long reaction steps, difficulty in isomer resolution, low total yield of about 38%, severe post-treatment conditions, and difficult industrial production of the reaction. [0006] U.S. Patent No. 4,145,434 announces a general method for producing as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/044
CPCC07D491/044
Inventor 王娜赵国磊
Owner AVENTIS PHARMA HAINAN
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