Refining method of high-purity cariprazine

A refining method and cariprazine technology, applied in the refining field of high-purity cariprazine, can solve problems such as by-product X being difficult to remove

Active Publication Date: 2020-06-23
NHWA PHARMA CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] In order to solve the problem that the by-product X in the prior art is difficult to remove, the present invention provides a method for refining cariprazine, so that impurities can be effectively removed before cariprazine is salified, and the product purity is improved

Method used

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  • Refining method of high-purity cariprazine
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  • Refining method of high-purity cariprazine

Examples

Experimental program
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Effect test

Embodiment 1

[0037] (1) Cariprazine crude product 10g is joined in the 250ml reaction bottle, add 50ml dichloromethane, 30ml ethanol, heat to reflux, make the solution clarification;

[0038] (2) Slowly add 75ml of ethyl acetate and stir for 20 minutes; slowly cool down to 30°C.

[0039] (3) Ice-water bath, cooled to 0-10°C, stirred for 3 hours;

[0040] (4) Filter, and wash the filter cake with 30ml ethyl acetate, and vacuum-dry to constant weight at 50°C to obtain 8.1g cariprazine crystals, yield 81%, purity (HPLC) 99.79, impurity X (63.78min) The content of 0.02%, such as figure 2 mentioned.

Embodiment 2

[0042] (1) Cariprazine crude product 10g is joined in 250ml reaction bottle, add 30ml dichloromethane, 70ml ethanol, heat to reflux, make solution clarification;

[0043] (2) Slowly add 75ml of ethyl acetate and stir for 20 minutes; slowly cool down to 30°C.

[0044] (3) Ice-water bath, cooled to 0-10°C, stirred for 5 hours;

[0045] (4) filter, and wash the filter cake with 15ml ethyl acetate, and vacuum-dry to constant weight at 50 ℃, obtain 8.4g cariprazine crystal, yield 84%, purity (HPLC) 99.68, impurity X (63.33min) The content of 0.04%, such as image 3 shown.

Embodiment 3

[0047] (1) Add 20 g of cariprazine crude product into a 500 ml reaction flask, add 40 ml of methylene chloride and 60 ml of ethanol, and heat to reflux to make the solution clear;

[0048] (2) Slowly add 100ml of ethyl acetate and stir for 20 minutes; slowly cool down to 30°C.

[0049] (3) Ice-water bath, cooled to 0-10°C, stirred for 3 hours;

[0050] (4) filter, and wash the filter cake with 30ml ethyl acetate, and vacuum-dry to constant weight at 50 ℃, obtain 17.1g cariprazine crystal, yield 85.5%, purity (HPLC) 99.88, the content of impurity X 0.02% ,Such as Figure 4 shown.

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Abstract

The invention relates to a refining method of high-purity cariprazine. The refining method comprises the following steps: adding dichloromethane and alcohol into a cariprazine crude product, heating and stirring until the crude product is dissolved, adding an ester solvent or a ketone solvent; cooling, crystallizing, filtering, collecting cariprazine crystals, washing cariprazine crystals by ethylacetate, and drying cariprazine crystals in vacuum to obtain high-purity cariprazine. According to the refining method, the yield of cariprazine is 80% or above, the purity (HPLC) reaches 99.5%, andthe impurity content is reduced to about 0.1%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for refining high-purity cariprazine. Background technique [0002] Cariprazine hydrochloride, chemical name trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}- 3,3-Dimethylurea hydrochloride, a D 2 and D 3 Receptor partial agonists, especially for D 3 Receptors have high selectivity for 5-HT 1A Also has partial agonism, co-developed by Gedeon Richter and Forest Laboratories. On September 17, 2015, the FDA approved it for the treatment of schizophrenia and bipolar disorder. [0003] The structure of cariprazine is shown below: [0004] [0005] The preparation method of cariprazine disclosed at home and abroad mainly contains 2 classes at present: [0006] (1) Patent CN1829703 reports 2,3-dichlorophenylpiperazine (VII) and trans-tert-butyl (4-(2-oxoethyl)cyclohexyl)ammonium formate (X) as key intermediates , intermediate IX was obtained...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/135
CPCC07D295/135C07B2200/13
Inventor 曹龙吉张威杨相平
Owner NHWA PHARMA CORPORATION
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