The preparation method of asenapine maleate

A technology of asenapine maleate and organic acid, applied in the field of preparation of high-purity asenapine maleate, can solve problems such as low purity of finished product, complicated process, etc., and achieves improved reaction yield, simple operation, Good practical value and the effect of social and economic benefits

Active Publication Date: 2016-08-17
SICHUAN KELUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The object of the present invention is to overcome the defects that the existing technology is loaded down with trivial details, the finished product purity of preparation is lower, the preparation method of high-purity asenapine maleate is provided

Method used

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  • The preparation method of asenapine maleate

Examples

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Effect test

Embodiment 1

[0021] Example 1 Preparation of high-purity asenapine maleate from crude asenapine free base as raw material

[0022] (1) 1000mL of absolute ethanol is added to the crude product containing 318 grams of asenapine free base (C 17 h 16 ClNO, 1mol, HPLC purity is about 90%) in the pear-shaped flask of jelly, after warming (40-50 ℃) dissolves, then add 190 grams of p-toluenesulfonic acid (C 7 h 8 SO 3 , 1.1mol), after the reaction system is clarified, stop heating and stir for 6-12h, a large amount of white solid precipitates, filter, rinse with a small amount of cold ethanol (ethanol at a temperature of 0-10°C), and vacuum dry at 50°C for 8 hours, Obtain 437 grams of asenapine p-toluenesulfonate, yield 95.4%;

[0023] (2) Add 437 grams of the above-mentioned asenapine p-toluenesulfonate to 1 L of ethyl acetate, slowly add 1 L of 10% (g / mL) sodium hydroxide under stirring, continue stirring for 0.5 hours, and the solution becomes clear; Separate the organic phase, extract the...

Embodiment 2

[0026] Example 2 Preparation of high-purity asenapine maleate from crude asenapine free base as raw material

[0027] (1) 1000mL of absolute ethanol is added to the crude product containing 301 grams of asenapine free base (C 17 h 16 ClNO, 1mol, HPLC purity is about 95%) in the pear-shaped flask of jelly, after warming (40-50 ℃) dissolves, then add 224 grams of p-toluenesulfonic acid (C 7 h 8 SO 3 , 1.3mol), after the reaction system was clarified, stop heating and stir for 6-12h, a large amount of white solid precipitated, filtered, rinsed with a small amount of cold ethanol, and dried in vacuum at 50°C for 8 hours to obtain asenapine p-toluenesulfonate 440 grams, yield 96.1%;

[0028] (2) Add 440 grams of the above-mentioned asenapine p-toluenesulfonate to 1 L of ethyl acetate, slowly add 1 L of 10% (g / mL) sodium hydroxide under stirring, continue stirring for 0.5 hours, and the solution becomes clear; Separate the organic phase, extract the aqueous phase twice with eth...

Embodiment 3

[0030] Example 3 Purification and preparation of high-purity asenapine maleate from crude asenapine maleate as raw material

[0031] 447 grams (1mol, HPLC purity is about 90%) of unqualified asenapine maleate crude product that needs to be reworked in production, join in ethyl acetate (EA), with 10% (g / mL) NaOH, adjust The base pH is 10, extracted with ethyl acetate, the combined organic phases are washed with water, dried with anhydrous MgSO4, and the solvent is evaporated to dryness to obtain 260 grams of asenapine oil; then according to the method in Example 1, first use p-toluenesulfonic acid (TsOH) salification, crystallization and purification, then use alkali dissociation and then salify with maleic acid, obtain 346 grams of asenapine maleate after drying, the total yield is 86.1%, and the purity is greater than 99% (HPLC area is normalized chemical method).

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Abstract

The invention discloses a preparation method of high-purity asenapine maleate. The preparation method comprises the following steps: by taking an asenapine free alkali crude product and a asenapine maleate crude product as an initial raw material, reacting the asenapine free alkali crude product with an organic acid to generate salt or carrying out alkalifying dissociation on the asenapine maleate crude product to asenapine free alkali to be reacted with the organic acid to generate salt so as to obtain asenapine para-benzyl benzyl; crystallizing, filtering and carrying out alkalifying dissociation to obtain asenapine free alkali; then reacting the product obtained from the former step with maleic acid to obtain asenapine maleate; and crystallizing and filtering. The preparation method of high purity asenapine maleate is novel in process route, mild in process condition and simple to operate, and an acceptable product with the purity greater than or equal to 99% can be obtained by just one time without repeatedly recrystallizing operations. Meanwhile, the preparation method further improves the reaction yield, lowers the production cost, is suitable for being applied to industrial production on a large scale, and has good practical value and social and economic benefits.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of high-purity asenapine maleate. Background technique [0002] Asenapine, chemical name trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxa Zhuo[4,5-c]pyrrole has CNS-inhibitor activity, antihistamine and anti-serotonin activity, and its maleate is clinically used. Asenapine maleate (also known as asenapine maleate) can be made into pharmaceutical preparations for sublingual or oral administration (see international application patent WO / 23600), which is clinically applicable to adults with schizophrenia, Emergency treatment of psychiatric disorders such as mania or mixed episodes with type 1 bipolar disorder, the trade name is Saphris. The extensive clinical research and application of asenapine maleate necessitates the large-scale synthesis of the drug. [0003] A lot of research has been done on the synthesis of asenapine a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/044C07C51/41C07C57/145
CPCC07D491/044
Inventor 王朝阳李正林郭培良张生烈葛建华王利春胡思玉赵栋王晶翼程志鹏
Owner SICHUAN KELUN PHARMA CO LTD
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