A kind of refining method of high-purity cariprazine

Abstract

The invention relates to a method for purifying high-purity cariprazine. The crude cariprazine is added to dichloromethane and alcohol, heated and stirred until dissolved, and then an ester solvent or a ketone solvent is added; The oxazine crystals were washed with ethyl acetate and dried in vacuo to obtain high-purity cariprazine. The yield of cariprazine in the purification method is above 80%, the purity (HPLC) reaches 99.5%, and the impurities are 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...

Examples

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.

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...

Examples

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.

Images