SYNTHESIS METHOD FOR CARIPRAZINE

Abstract

The present application relates to a synthesis method for cariprazine, comprising performing an acylation reaction between a compound represented by formula (I) and dimethylcarbamoyl chloride in a reaction solvent in the presence of an aqueous solution of an inorganic base, so as to obtain the cariprazine compound represented by formula (II). The synthesis method overcomes defects in the prior art such as a long reaction time, large size impurities and the difficulty of purification, and provides a new method suitable for commercial production wherein the reaction is fast, impurity sizes are small, the product is easily purified, the purity of the product can reach 99.0% or more, and the yield is high.

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Claims

1. A method of synthesizing cariprazine represented by formula (II), comprising: in a reaction solvent, in the presence of an aqueous solution of an inorganic base, acylating a compound represented by formula (I) with dimethylcarbamoyl chloride to obtain cariprazine represented by formula (II), as shown in the reaction formula: ##STR00006##

2. The method according to claim 1, wherein the aqueous solution of the inorganic base is one or at least two selected from the group consisting of NaOH aqueous solution, KOH aqueous solution, Na.sub.2CO.sub.3 aqueous solution, K.sub.2CO.sub.3 aqueous solution; KHCO.sub.3 aqueous solution and NaHCO.sub.3 aqueous solution.

3. The method according to claim 2, wherein the aqueous solution of the inorganic base is Na.sub.2CO.sub.3 aqueous solution or K.sub.2CO.sub.3 aqueous solution.

4. The method according to claim 1, wherein the inorganic base has a concentration of 5-30% by weight in the aqueous solution of the inorganic base.

5. The method according to claim 1, wherein the reaction solvent is a solvent that is immiscible with water.

6. The method according to claim 5, wherein the reaction solvent is one or at least two selected from the group consisting of dichloromethane, toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

7. The method according to claim 5, wherein the reaction solvent is dichloromethane or 2-methyltetrahydrofuran.

8. The method according to claim 1, wherein a reaction temperature of the acylation reaction is 0-100° C.

9. The method according to claim 8, wherein the reaction temperature of the acylation reaction is 10-70° C.

10. The method according to claim 8, wherein the reaction temperature of the acylation reaction is 15-30° C.

11. The method according to claim 1, wherein a ratio in mole of the inorganic base to a sum of the compound represented by formula (I) and dimethylcarbamoyl chloride is greater than or equal to 1.

12. The method according to claim 1, further comprising: after completing the acylation reaction, removing a water phase, adding a crystallization solvent to an organic phase to precipitate cariprazine, and then filtering.

13. The method according to claim 12, wherein, before adding the crystallization solvent, if the reaction solvent in the organic phase is not dichloromethane, the reaction solvent in the organic phase is replaced with dichloromethane.

14. The method according to claim 12, wherein the crystallization solvent is n-heptane and/or cyclohexane.

15. The method according to claim 1, wherein the compound represented by formula (I) is added to the reaction solvent in the form of itself or salt thereof.

16. The method according to claim 11, wherein a ratio in mole of the inorganic base to the sum of the compound represented by formula (I) and dimethylcarbamoyl chloride is 2-6:1.

17. The method according to claim 14, wherein the crystallization solvent is n-heptane.

18. The method according to claim 15, wherein the salt of the compound represented by formula (I) is one or at least two selected from the group consisting of the dihydrochloride, sulfate, and dihydrobromide of the compound represented by formula (I).

19. The method according to claim 15, wherein the salt of the compound represented by formula (I) is dihydrochloride of the compound represented by formula (I).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0028] In order to make the technical problems solved by the present application, technical solutions and beneficial effects clearer, the following further describes the present application in combination with specific examples. In the following examples, unless otherwise specified, the specific conditions of the test method are usually implemented in accordance with conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents are commercially available or prepared using public information.

[0029] In the following examples and comparative examples, the content of double-condensation impurity is specifically detected by HPLC (High Performance Liquid Chromatography). The specific detection conditions are as follows:

[0030] Detection method and conditions: Mobile Phase: 25 mmol ammonium acetate aqueous solution, acetonitrile; Detection Wavelength: 220 nm; Flow Rate: 1.0 mL/min; Chromatographic Column: C18 50*2.1 mm, 3.5 μm.

[0031] The retention time of double-condensation impurity: RT 17 min.

Example 1: Preparation of Cariprazine

[0032] 20 g (56 mmol, 1.0 eq) of compound I, 300 ml of dichloromethane, and 60 ml of 20 wt % sodium hydroxide solution were added to a 1000 mL three-necked flask, and 9.1 g (84 mmol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 12 hours at 20-30° C. It was detected by HPLC that the raw materials had reacted completely, and the content of double-condensation impurity was 0.08%. After liquid separation of the reaction system and removal of a water phase, a dichloromethane phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate part of the dichloromethane. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 21.8 g of powdered solids (the cariprazine content was 99%, the purity was 99.5%, the double-condensation impurity content was 0.06%), with a yield of 90.9%.

Example 2: Preparation of Cariprazine

[0033] 10 g (28 mmol, 1.0 eq) of compound I, 200 ml of dichloromethane, and 470 ml of 10 wt % potassium carbonate solution were added to a 1000 mL three-necked flask, and 4.5 g (42 mmol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 15 hours at 20-30° C. It was detected by HPLC that the raw materials had reacted completely. After liquid separation of the reaction system and removal of a water phase, a dichloromethane phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate part of the dichloromethane. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 10.7 g of powdered solids (the cariprazine content was 99%, the purity was 99.3%, the double-condensation impurity content was 0.09%), with a yield of 89.2%.

Example 3: Preparation of Cariprazine

[0034] 20 g (56 mmol, 1.0 eq) of compound I, 500 ml of dichloromethane, 36 ml of 20 wt % sodium hydroxide solution and 500 ml of 10 wt % sodium carbonate were added to a 1000 mL three-necked flask, and 9.1 g (84 mmol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 13 hours at 15-25° C. It was detected by HPLC that the raw materials had reacted completely, and the content of double-condensation impurity was 0.07%. After liquid separation of the reaction system and removal of a water phase, a dichloromethane phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate part of the dichloromethane. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 22.3 g of powdered solids (the cariprazine content was 99%, the purity was 99.5%, the double-condensation impurity content was 0.06%), with a yield of 92.1%.

Example 4: Preparation of Cariprazine

[0035] 10 g (28 mmol, 1.0 eq) of compound I, 400 ml of toluene, and 900 ml of 5 wt % potassium carbonate solution were added to a 1000 mL three-necked flask, and 4.5 g (42 mmol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 15 hours at 20-45° C. It was detected by HPLC that the raw materials had reacted completely. After liquid separation of the reaction system and removal of a water phase, a toluene phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate toluene and the toluene was replaced with dichloromethane. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 10.5 g of powdered solids (the cariprazine content was 99%, the purity was 99.5%, the double-condensation impurity content was 0.10%), with a yield of 87.5%.

Example 5: Preparation of Cariprazine

[0036] 10 kg (28 mol, 1.0 eq) of compound I, 400 L of 2-methyltetrahydrofuran, and 400 L of 10 wt % sodium carbonate solution were added to a 1000 L reactor, and 4.5 Kg (42 mol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 14 hours at 20-50° C. It was detected by HPLC that the raw materials had reacted completely. After liquid separation of the reaction system and removal of a water phase, a 2-methyltetrahydrofuran phase was washed with water. Then the resultant was concentrated under reduced pressure to evaporate 2-methyltetrahydrofuran and the 2-methyltetrahydrofuran was replaced with dichloromethane. N-heptane was added to crystallize, then it was filtered with suction, and the filter cake was dried to obtain 10.2 kg of powdered solid (the cariprazine content was 99%, the purity was 99.2%, the double-condensation impurity content was 0.10%), with a yield of 85.0%.

Example 6: Preparation of Cariprazine

[0037] 1 kg (2.33 mol, 1.0 eq) of dihydrochloride of compound I, 20 kg of dichloromethane, and 15 kg of water to a 100 L reactor, and then 20 L of 10 wt % sodium hydroxide solution was added dropwise. 0.375 Kg (3.49 mol, 1.5 eq) of dimethylcarbamoyl chloride was added dropwise. Then the reaction mixture was stirred for 13 hours at 20-50° C. It was detected by HPLC that the raw materials had reacted completely. After separating the reaction system, washing it with water three times and removing the water phase. N-heptane was added to crystallize, then it was filtered, and the filter cake was dried to obtain 0.834 kg of powdered solids (the cariprazine content was 99.1%, the purity was 99.3%, the double-condensation impurity content was 0.09%), with a yield of 83.0%.

Comparative Example: Preparation of Cariprazine

[0038] 17.8 g of compound I (50 mmol, 1.0 eq), 300 ml of dichloromethane, 10.0 g of diisopropylethylamine (80 mmol, 1.6 eq) were added to a 1000 mL three-necked flask, and then 0.64 g (60 mmol, 1.2 eq) of dimethylcarbamoyl chloride was added dropwise. The reaction mixture was stirred for 12 hours at 20-30° C., and it was detected that the content of remaining raw materials were 25% and the content of double-condensation impurity was 0.23%. After further stirring for 36 hours, it was detected by HPLC that the raw materials had reacted completely, and the content of double-condensation impurity was 0.62%. The reaction solution was washed with 100 ml of 1% ammonia water and 100 ml of saturated brine successively. Then the resultant was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remainder was crystallized with n-heptane to obtain 14.1 g of white powdered solids cariprazine (II) (the content was 98%, the purity was 98.9%, the double-condensation impurity content was 0.56%), with a yield of 64.6%. After crystallization with ethyl acetate/n-heptane and methanol/dichloromethane system for several times, the content of double-condensation impurity was decreased to 0.15%, and 4.57 g of cariprazine (II) was obtained as off-white solids with a yield of 20.5%.

[0039] The purpose of the above-mentioned examples is to explain the substantive contents of the present application, but it does not limit the protection scope of the present application. Those skilled in the art should understand that the technical solution of the present application can be modified or equivalently replaced without departing from the essence and protection scope of the technical solution of the present application.