A preparation method of cariprazine and its intermediate

Abstract

The present invention provides a method for preparing cariprazine and an intermediate thereof. The present invention discloses a method for preparing a cariprazine intermediate 5, comprising the following steps: a) in a solvent, in the presence of a base, condensing 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 with an amino protecting agent to obtain a cariprazine intermediate 2; b) in a solvent, hydrolyzing the cariprazine intermediate 2 under alkaline conditions, and then acidifying to obtain a cariprazine intermediate 3; c) in an organic solvent, in the presence of a catalyst and a base, condensing the cariprazine intermediate 3 with 1-(2,3-dichlorophenyl)-piperazine 4 to obtain a cariprazine intermediate 5. The preparation method of the present invention has readily available raw materials, is simple to operate, has a high reaction yield, and is suitable for industrial production. #imgabs0#

Description

Technical Field

[0001] The invention relates to a preparation method of cariprazine and an intermediate thereof. Background Art

[0002] In 2015, the US FDA approved cariprazine (Vraylar) capsules for the treatment of schizophrenia and bipolar disorder in adults. Cariprazine is a dopamine D3 / D2 receptor partial agonist and an experimental atypical antipsychotic used for patients with schizophrenia and manic or mixed episodes associated with bipolar I disorder.

[0003]

[0004] Patent WO2005012266 first reported the synthesis of cariprazine. First, 1-(2,3-dichlorophenyl)piperazine and trans-2-{1-[4-(N-tert-butyloxycarbonyl)-amino]-cyclohexyl}-acetaldehyde were reacted for reductive amination to obtain trans-N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexyl}-carbamic acid tert-butyl ester. Then, the tert-butyloxycarbonyl group was removed for protection and the product was reacted with dimethyl-carbamoyl chloride to obtain cariprazine. The raw material trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetaldehyde is prepared by the reduction method described in Journal of Medicinal Chemistry, 2000, vol.43.9.1878-1885. The main disadvantage of this reduction is that the DIBAL-H reagent must be added to the reaction mixture in anhydrous toluene at -78°C, which is dangerous to operate, has high requirements for instruments and equipment, and is difficult to industrialize. The synthetic route is as follows:

[0005]

[0006] Patent WO2010070369 describes a route for N-alkylation with 2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate. 2-{trans-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate is reduced and then reacted with methanesulfonyl chloride to obtain 2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate, which is then N-alkylated with 1-(2,3-dichlorophenyl)piperazine to obtain N-tert-butoxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexylamine, which is then de-tert-butoxycarbonyl protected to obtain the key intermediate 4-{2-[-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexylamine dihydrochloride monohydrate. The disadvantage of this process is that the mesylate derivatives remain in the reaction mixture, which is considered as a potential genotoxic contamination, and the contamination level is maintained at the ppm level. In addition, methanesulfonyl chloride is highly toxic during production and use, which is not conducive to industrial production and labor protection. The synthesis route is as follows:

[0007]

[0008] Patent WO2018007986 describes a new preparation method of cariprazine, according to which trans-2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride is used as the starting material, which is hydrolyzed and acidified to obtain trans-2-[1-(4-amino]-cyclohexyl)-acetic acid hydrochloride, which is then reacted with dimethyl-carbamoyl chloride to obtain trans-4-{[(dimethylaminocarbonyl]amino}cyclohexyl)acetic acid, and then trans-4-{[(dimethylaminocarbonyl]amino}cyclohexyl)acetic acid is reacted with dimethyl-carbamoyl chloride to obtain trans-4-{[(dimethylaminocarbonyl]amino}cyclohexyl)acetic acid. [aminocarbonyl]amino}cyclohexyl)acetic acid is condensed with 1-(2,3-dichlorophenyl)-piperazine via acyl chloride or N,N-carbonyldiimidazole to obtain 1-dimethyl-3-[trans-4-(2-oxo-2-(4-(2,3-dichlorophenyl)piperazin-1-yl-ethyl)cyclohexyl]urea, and then the amide bond is reduced by sodium borohydride and boron trifluoride-etherate or sodium borohydride and anhydrous aluminum chloride to obtain cariprazine. The overall yield of this route is very low. The synthetic route is as follows:

[0009]

[0010] At present, there is an urgent need to develop a method for preparing cariprazine and its intermediates which is simple and safe to operate, has a high yield and is suitable for industrial production. Summary of the invention

[0011] The present invention provides a method for preparing cariprazine and its intermediates in order to overcome the defects of the preparation method of cariprazine in the prior art, such as complicated reaction steps, dangerous operation, strong equipment corrosion, low yield, and unsuitability for industrial production. The preparation method of the present invention has easy-to-obtain raw materials, short reaction steps, simple and safe operation, environmental friendliness, simple post-treatment, high yield, high purity of the obtained product, and is suitable for industrial production.

[0012] The present invention provides a cariprazine intermediate 5, the structure of which is shown below:

[0013]

[0014] Wherein, PG is an amino protecting group or hydrogen, and the amino protecting group is preferably tert-butyloxycarbonyl or acetyl.

[0015] The present invention also provides a method for preparing the cariprazine intermediate 5, which comprises the following steps:

[0016]

[0017] a) in a solvent, in the presence of a base, condensing ethyl 2-[1-(4-amino]-cyclohexyl)-acetate hydrochloride 1 with an amino protecting agent to obtain a cariprazine intermediate 2;

[0018] b) hydrolyzing the cariprazine intermediate 2 obtained in step a) under alkaline conditions in a solvent, and then acidifying to obtain the cariprazine intermediate 3;

[0019] c) In an organic solvent, in the presence of a catalyst and a base, the cariprazine intermediate 3 obtained in step b) is subjected to a condensation reaction with 1-(2,3-dichlorophenyl)-piperazine 4 to obtain a cariprazine intermediate 5.

[0020] In step a), the solvent is preferably water and / or an organic solvent. The organic solvent is preferably one or more of halogenated hydrocarbon solvents, alcohol solvents, ketone solvents, ether solvents, ester solvents, nitrile solvents, aromatic hydrocarbon solvents and amide solvents. The halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably one or more of dichloromethane, dichloroethane and chloroform. The alcohol solvent is preferably one or more of methanol, ethanol and tert-butanol. The ketone solvent is preferably acetone. The ether solvent is preferably tetrahydrofuran and / or 1,4-dioxane. The ester solvent is preferably ethyl acetate. The nitrile solvent is preferably acetonitrile. The aromatic hydrocarbon solvent is preferably toluene. The amide solvent is preferably N,N-dimethylformamide.

[0021] In step a), the volume mass ratio of the solvent to the ethyl 2-[1-(4-amino]-cyclohexyl)-acetic acid ethyl hydrochloride 1 is preferably 1 mL / g to 10 mL / g, more preferably 2 mL / g to 6 mL / g, for example 4 mL / g.

[0022] In step a), the base may be an organic base or an inorganic base, and the organic base is preferably one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine, and triethylamine is further preferred. The inorganic base is preferably one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate.

[0023] In step a), the molar ratio of the base to the ethyl 2-[1-(4-amino]-cyclohexyl)-acetic acid ethyl hydrochloride 1 is preferably 1 to 2, for example 1.

[0024] In step a), the amino protecting agent may be acetyl chloride, acetic anhydride or di(tert-butyl)dicarbonate, preferably di(tert-butyl)dicarbonate.

[0025] In step a), the molar ratio of the amino protecting agent to the ethyl 2-[1-(4-amino]-cyclohexyl)-acetic acid ethyl hydrochloride 1 is preferably 1 to 2, for example 1.

[0026] In step a), the temperature of the condensation reaction is preferably 0-40°C, more preferably 20-25°C.

[0027] In step a), the progress of the condensation reaction can be detected by conventional detection methods in the art (such as TLC, HPLC or NMR). Generally, the disappearance of the 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 is regarded as the end point of the reaction. The condensation reaction time is preferably 1 hour to 24 hours, more preferably 2 hours to 12 hours, for example 10 hours.

[0028] Step a) is preferably carried out under the protection of a protective gas, wherein the protective gas is preferably nitrogen and / or argon.

[0029] Step a) preferably adopts the following post-treatment steps: after the reaction is completed, add a base, extract, wash, dry, and remove the solvent to obtain the purified cariprazine intermediate 2. The base is preferably an inorganic base, and the inorganic base is preferably sodium bicarbonate. The amount of sodium bicarbonate used is preferably 10mL to 20mL of a saturated sodium bicarbonate solution. The washing is preferably done with water. The number of washings is preferably 1 to 3 times. The drying is preferably done with anhydrous sodium sulfate or anhydrous magnesium sulfate. The solvent removal is preferably done by removing the solvent under reduced pressure.

[0030] Step a) preferably adopts the following steps: adding a solution formed by an amino protecting agent and a solvent to a solution formed by 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1, a base and a solvent, and performing a condensation reaction to obtain the cariprazine intermediate 2. The temperature of the "solution formed by 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1, a base and a solvent" is preferably 5°C to 10°C. The preferred method of adding is dropwise addition. The speed of the dropwise addition is based on maintaining the temperature of the reaction system at no more than 10°C.

[0031] Step a) is further preferably the following steps: adding a base to a solution of 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 and a solvent, cooling the solution to 0-10°C (preferably 5°C to 10°C), dropping an amino protecting agent, and after the dropping is complete, raising the temperature to 20-25°C. After the reaction is complete, adding a saturated sodium carbonate solution, separating the phases, drying with Na2SO4, and concentrating to obtain a cariprazine intermediate 2.

[0032] In step b), the solvent is preferably a mixed solvent of an organic solvent and water. The organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran. The volume ratio of the organic solvent to the water is preferably 1 to 10, more preferably 2 to 6, for example 4.

[0033] In step b), the volume mass ratio of the solvent to the cariprazine intermediate 2 is preferably 1 ml / g to 20 ml / g, more preferably 10 ml / g to 15 ml / g, for example 12.5 ml / g.

[0034] In step b), the base is preferably an inorganic base; the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and lithium hydroxide is further preferred. The lithium hydroxide can be a conventional commercially available lithium hydroxide monohydrate reagent.

[0035] In step b), the molar ratio of the base to the cariprazine intermediate 2 is preferably 1.0 to 5.0, more preferably 1.1 to 3.0, such as 2.0.

[0036] In step b), the temperature of the hydrolysis reaction is preferably 10°C to 60°C, more preferably 20°C to 50°C, for example 40°C.

[0037] In step b), the progress of the hydrolysis reaction can be detected by conventional detection methods in the art (such as TLC, HPLC or NMR). Generally, the disappearance of the cariprazine intermediate 2 is taken as the end point of the reaction. The time of the hydrolysis reaction is preferably 1 hour to 12 hours, more preferably 2 hours to 10 hours, for example 6 hours.

[0038] In step b), the acid is preferably an inorganic acid. The inorganic acid is preferably hydrochloric acid. The hydrochloric acid can be a conventional commercially available hydrochloric acid reagent, and the concentration of the hydrochloric acid is preferably 1 mol / L to 12 mol / L, more preferably 2 mol / L to 10 mol / L, for example 6 mol / L.

[0039] In step b), the molar ratio of the acid to the cariprazine intermediate 2 is preferably 1 to 10, more preferably 2 to 6, for example 5.

[0040] In step b), the acidification temperature is preferably -5°C to 25°C, more preferably 0°C to 5°C.

[0041] In step b), the progress of the acidification can be detected by conventional detection methods in the art (such as TLC, HPLC or NMR), and the acidification time is preferably 0.5 hour to 5.0 hours, more preferably 1.0 hour to 3.0 hours, for example 1.0 hour.

[0042] In step c), the organic solvent is preferably one or more of a ketone solvent, a halogenated hydrocarbon solvent and an alcohol solvent. The ketone solvent is preferably acetone. The halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the alcohol solvent is preferably isopropanol.

[0043] In step c), the volume mass ratio of the organic solvent to the cariprazine intermediate 3 is preferably 1.0 ml / g to 20.0 ml / g, more preferably 2.0 ml / g to 8.0 ml / g, such as 5.2 ml / g, 5.7 ml / g or 6.0 ml / g.

[0044] In step c), the catalyst is preferably ethyl chloroformate, isobutyl chloroformate, N,N-carbonyldiimidazole, methanesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, di-tert-butyl dicarbonate, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride , 4-N,N-dimethylpyridine, 1-hydroxybenzotriazole, 4-pyrrolidinylpyridine, O-(7-azabenzotriazole-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(benzotriazole-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(5-chlorobenzotriazole-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(benzotriazole-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate Triazole-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate, benzotriazole-1-yloxy-tri(dimethylamino)phosphonium hexafluorophosphate, benzotriazole-1-yloxy -tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate, diphenylphosphoryl chloride, diethyl cyanophosphate, diphenylphosphoryl azide thiodimethylphosphoryl azide and di(2-oxo-3-oxazolidinyl)phosphoryl chloride, one or more thereof, further preferably N,N-carbonyldiimidazole, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0045] In step c), the molar ratio of the catalyst to the cariprazine intermediate 3 is preferably 1.0 to 2.0, more preferably 1.1 to 1.5, such as 1.2.

[0046] In step c), the base may be an organic base and / or an inorganic base. The organic base is preferably one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine, and triethylamine and / or N,N-diisopropylethylamine are further preferred. The inorganic base is preferably one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate.

[0047] In step c), the molar ratio of the base to the cariprazine intermediate 3 is preferably 1.0 to 3.0, more preferably 1.0 to 2.0, such as 1.0 or 1.1.

[0048] In step c), the molar ratio of the 1-(2,3-dichlorophenyl)-piperazine 4 to the cariprazine intermediate 3 is preferably 1.0 to 3.0, more preferably 1.0 to 2.0, for example 1.0.

[0049] In step c), the temperature of the condensation reaction is preferably 0-40°C, more preferably 10-30°C; and even more preferably 20-25°C.

[0050] In step c), the progress of the condensation reaction can be detected by conventional detection methods in the art (such as TLC, HPLC or NMR). Generally, the disappearance of the cariprazine intermediate 3 is regarded as the end point of the reaction. The condensation reaction time is preferably 1 hour to 24 hours, more preferably 6 hours to 12 hours, for example 12 hours.

[0051] The present invention also provides a method for preparing a cariprazine intermediate 7, characterized in that after the cariprazine intermediate 5 is prepared according to the above method, the method further comprises the following steps:

[0052] d) dissolving the cariprazine intermediate 5 in an organic solvent and performing a reduction reaction with a reducing agent to obtain a cariprazine intermediate 6, and then performing a reaction with an acid to remove the amino protecting group to obtain a cariprazine intermediate 7;

[0053]

[0054] Wherein, PG is an amino protecting group or hydrogen, and the amino protecting group is preferably tert-butyloxycarbonyl or acetyl.

[0055] In step d), the organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

[0056] In step d), the volume mass ratio of the organic solvent to the cariprazine intermediate 5 is preferably 1.0 ml / g to 20.0 ml / g, more preferably 2.0 ml / g to 8.0 ml / g, for example 6.0 ml / g.

[0057] In step d), the reducing agent may be boron trifluoride etherate and / or sodium borohydride.

[0058] In step d), the molar ratio of the reducing agent to the cariprazine intermediate 5 is preferably 1.0 to 5.0, more preferably 1.5 to 3.0, such as 1.9 or 2.9.

[0059] In step d), the temperature of the reduction reaction is preferably 0-25°C, more preferably 0-10°C, such as 0-5°C.

[0060] In step d), the progress of the reduction reaction can be detected by conventional detection methods in the art (such as TLC, HPLC or NMR). Generally, the disappearance of the cariprazine intermediate 5 is regarded as the end point of the reaction. The time of the reduction reaction is preferably 0.5 hour to 24 hours, more preferably 2 hours to 10 hours, for example 5 hours.

[0061] In step d), the acid is preferably an inorganic acid. The inorganic acid is preferably hydrochloric acid and / or sulfuric acid. The hydrochloric acid can be a conventional commercially available hydrochloric acid reagent; the molar concentration of the hydrochloric acid is preferably 1 mol / L to 12 mol / L, more preferably 2 mol / L to 6 mol / L, for example 4 mol / L. The sulfuric acid can be a conventional commercially available sulfuric acid reagent; the molar concentration of the sulfuric acid is preferably 1 mol / L to 18 mol / L.

[0062] In step d), the molar ratio of the acid to the cariprazine intermediate 5 is preferably 1 to 20, more preferably 2 to 15, for example 8.

[0063] In step d), the reaction temperature for removing the amino protecting group is preferably 10°C to 80°C, more preferably 20°C to 60°C, for example 50°C.

[0064] In step d), the progress of the reaction of removing the amino protecting group can be detected by conventional detection methods in the art (such as TLC, HPLC or NMR). Generally, the disappearance of the cariprazine intermediate 5 is regarded as the end point of the reaction. The reaction time of removing the amino protecting group is preferably 1.0 hour to 10.0 hours, more preferably 2.0 hours to 6.0 hours, for example 3.0 hours.

[0065] The present invention also provides a method for preparing cariprazine, which is characterized in that after preparing the cariprazine intermediate 7 according to the above method, it also includes the following steps:

[0066] e) in an organic solvent, subjecting the cariprazine intermediate 7 obtained in step d) to a condensation reaction with a base and dimethyl-carbamoyl chloride to obtain cariprazine (trans-N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexyl}-urea);

[0067]

[0068] In step e), the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.

[0069] In step e), the volume mass ratio of the organic solvent to the cariprazine intermediate 7 is preferably 1.0 ml / g to 20.0 ml / g, more preferably 2.0 ml / g to 8.0 ml / g, for example 6.0 ml / g.

[0070] In step e), the base is preferably an organic base or an inorganic base; the organic base is preferably one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine, and triethylamine is further preferred. The inorganic base is preferably one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate.

[0071] In step e), the molar ratio of the base to the cariprazine intermediate 7 is preferably 1.0 to 5.0, more preferably 1.5 to 3.0, such as 2.0.

[0072] In step e), the molar ratio of the dimethylcarbamoyl chloride to the cariprazine intermediate 7 is preferably 1.0 to 2.0, more preferably 1.0 to 1.5, for example 1.0.

[0073] In step e), the temperature of the condensation reaction is preferably 0-40°C, more preferably 20-30°C, for example 25°C.

[0074] In step e), the progress of the condensation reaction can be detected by conventional detection methods in the art (such as TLC, HPLC or NMR). Generally, the disappearance of the cariprazine intermediate 7 is regarded as the end point of the reaction. The condensation reaction time is preferably 2 hours to 24 hours, more preferably 6 hours to 12 hours, for example 10 hours.

[0075] In the present invention, the preparation method of cariprazine preferably adopts the following synthetic route:

[0076] The reagents and raw materials used in the present invention are commercially available.

[0077] The positive and progressive effects of the present invention are: the raw materials are easily available, the operation is simple, the intermediates and products are easy to purify, the quality of the finished product is effectively controlled, the quality of the drug is guaranteed to be safe and controllable, the reaction yield is high, and it is suitable for industrial production. DETAILED DESCRIPTION

[0078] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0079] Example 1 Preparation of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate (Cariprazine intermediate 2)

[0080] 4g (0.018mol) of trans-2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 and 16mL of dichloromethane were added to a 50mL three-necked flask, and then 1.8g (0.018mol) of triethylamine was added. The mixture was cooled to 5-10°C, and then 4.0g (0.018mol) of di(tert-butyl) dicarbonate in 10mL of dichloromethane solution was added dropwise under nitrogen protection. After the addition, the mixture was stirred at 20°C. After 10h, the reaction was completed, and 20mL of saturated sodium bicarbonate solution was added to separate the phases. The organic layer was washed with 10mL of water, the phases were separated, and the organic phase was dried with anhydrous Na2SO4, the solvent was removed under reduced pressure, and the mixture was dried under reduced pressure at 30°C to obtain 4.64g of the target compound with a yield of 90.0%. HPLC purity was 98.5%.

[0081] Example 2 Preparation of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetic acid (cariprazine intermediate 3)

[0082] In a 50mL three-necked flask, 4.0g (0.014mol) of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate (cariprazine intermediate 2), 40mL of tetrahydrofuran, 10mL of distilled water and 1.18g (0.028mol) of lithium hydroxide monohydrate were added. The mixture was stirred at 40°C for 6h. After the reaction, tetrahydrofuran was removed under reduced pressure. 14mL (6M) of hydrochloric acid was added for acidification. After stirring in an ice bath for 1h, the mixture was filtered, washed with 10mL of distilled water, and dried under reduced pressure at 50°C to obtain 1.8g of the target compound with a yield of 90.0% and a HPLC purity of 99.0%.

[0083] Example 3 Preparation of tert-butyl (1R, 4R-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl)-2-oxoethyl) cyclohexyl) carbamate (cariprazine intermediate 5)

[0084] Method a: In a 50 mL three-necked flask, add 3.86 g (0.015 mol) of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetic acid (cariprazine intermediate 3), 20 mL of acetone and 2.9 g (0.018 mol) of N,N-carbonyldiimidazole, stir at 25°C for 4 h, add 2 mL of isopropanol, stir at 25°C for 1 h, then add 2.1 mL of triethylamine and 3.47 g (0.015 mol) of 1-(2,3-dichlorophenyl)-piperazine 4, stir at room temperature for 12 hours, after the reaction is completed, add 80 mL of distilled water, stir for 1 h, filter, and wash with 40 mL of distilled water. Dry under reduced pressure at 45°C to obtain 6.4 g of the target compound, with a yield of 90.0% and a HPLC purity of 99.5%.

[0085] Method b: Add 5 g (0.019 mol) of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetic acid (cariprazine intermediate 3), 30 mL of dichloromethane, 4.5 g (0.019 mol) of 1-(2,3-dichlorophenyl)-piperazine 4, 2.46 g (0.021 mol) of N,N-diisopropylethylamine to a 50 mL three-necked flask, cool to 0 ° C, stir, add 2.89 g (0.021 mol) of 1-hydroxybenzotriazole and 3.4 g (0.0177 mol) of ol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stirred at 0°C for 1h, then at 25°C for 12h. After the reaction was completed, 30mL of 10% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the total mass of the hydrochloric acid solution) was added, the phases were separated, washed with 10mL of saturated sodium bicarbonate, the phases were separated, 50mL of saturated sodium chloride solution was added, the phases were separated, dried over anhydrous sodium sulfate, and dichloromethane was removed under reduced pressure to obtain 8g of the target compound with a yield of 83.0% and a HPLC purity of 99.3%.

[0086] Example 4 Preparation of tert-butyl ((1R, 4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (cariprazine intermediate 6)

[0087] In a 100 mL three-necked flask, 5 g (0.011 mol) of tert-butyl (1R, 4R-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl)-2-oxoethyl) cyclohexyl) carbamate and 30 mL of tetrahydrofuran were added, and the mixture was stirred at 0-5°C. Then, 2 g (0.021 mol) of sodium borohydride and 4.53 g (0.032 mol) of boron trifluoride etherate were added, and the mixture was stirred at 0-5°C for 1 h, and then stirred at room temperature for 5 hours. After the reaction was completed, 20 mL of water was added, and the temperature was raised to reflux. After the reaction was completed, tetrahydrofuran was removed under reduced pressure, the solid was filtered, and recrystallized from tert-butanol to obtain 4 g of the target compound with a yield of 82.0% and a HPLC purity of 99.3%.

[0088] Example 5 Preparation of (1R, 4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexane-1-amine hydrochloride (Cariprazine intermediate 7)

[0089] In a 100mL three-necked flask, 5g (0.011mol) of tert-butyl ((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate and 15mL of ethanol were added, stirred at room temperature, 22mL of hydrochloric acid (4mol / L) was added, and the mixture was heated to 50°C. After reacting for 3h, the ethanol was removed under reduced pressure, and the mixture was cooled to 0-5°C, filtered, washed, and dried under reduced pressure at 40°C to obtain 4.1g of the target compound with a yield of 95.0%.

[0090] Example 6 Preparation of trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl}-N',N'-dimethylurea (cariprazine)

[0091] In a 50mL three-necked flask, 5g (0.013mol) of (1R, 4R)-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclohexane-1-amine hydrochloride (cariprazine intermediate 7), 30mL of dichloromethane and 2.58g (0.026mol) of triethylamine were added, and the mixture was stirred at 0-5°C. A solution of 1.37g (0.013mol) of dimethylcarbamoyl chloride in 5mL of dichloromethane was added dropwise. After the addition was completed, the mixture was reacted at 25°C for 10h. After the reaction was completed, 30mL of saturated sodium chloride solution was added, the phases were separated, and the mixture was dried over anhydrous sodium sulfate. The dichloromethane was removed under reduced pressure, and the mixture was recrystallized from methanol to obtain 4.5g of the target compound with a yield of 83.0% and a HPLC purity of 99.5%.

Claims

1. A method for preparing cariprazine, characterized in that: The preparation method comprises the following steps: Wherein, PG is an amino protecting group, and the amino protecting group is tert-butyloxycarbonyl or acetyl; a) in a solvent, in the presence of a base, condensing ethyl 2-[1-(4-amino]-cyclohexyl)-acetate hydrochloride 1 with an amino protecting agent to obtain a cariprazine intermediate 2; b) hydrolyzing the cariprazine intermediate 2 obtained in step a) under alkaline conditions in a solvent, and then acidifying to obtain the cariprazine intermediate 3; c) in an organic solvent, in the presence of a catalyst and a base, condensing the cariprazine intermediate 3 obtained in step b) with 1-(2,3-dichlorophenyl)-piperazine 4 to obtain a cariprazine intermediate 5; d) dissolving the cariprazine intermediate 5 in an organic solvent and reacting it with a reducing agent to obtain a cariprazine intermediate 6, and then reacting it with an acid to remove the amino protecting group to obtain a cariprazine intermediate 7; e) in an organic solvent, subjecting the cariprazine intermediate 7 obtained in step d) to a condensation reaction with a base and dimethyl-carbamoyl chloride to obtain cariprazine (trans-N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexyl}-urea); In step e, the organic solvent is dichloromethane; In step e, the molar ratio of the base to the cariprazine intermediate 7 is 1.5 to 3.0; In step e, the molar ratio of the dimethyl-carbamoyl chloride to the cariprazine intermediate 7 is 1.0 to 1.5; In step e, the temperature of the condensation reaction is 20°C to 30°C.

2. The method for preparing cariprazine according to claim 1, characterized in that: In step e): The volume mass ratio of the organic solvent to the cariprazine intermediate 7 is 2.0 ml / g to 8.0 ml / g; The base is an organic base, and the molar ratio of the base to the cariprazine intermediate 7 is 1.5 to 3.0; The condensation reaction time is 6 hours to 12 hours.

3. The method for preparing cariprazine according to claim 1, characterized in that: In step e): The volume mass ratio of the organic solvent to the cariprazine intermediate 7 is 6.0 ml / g; The base is one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine; The molar ratio of the base to the cariprazine intermediate 7 is 2.0; The molar ratio of the dimethyl-carbamoyl chloride to the cariprazine intermediate 7 is 1.0; The condensation reaction time is 10 hours.

4. The preparation method according to any one of claims 1 to 3, characterized in that: In step a), the solvent is water and / or an organic solvent; and / or, In step a), the volume mass ratio of the solvent to the ethyl 2-[1-(4-amino]-cyclohexyl)-acetic acid ethyl hydrochloride 1 is 1 mL / g to 10 mL / g; and / or, In step a), the base used in the alkaline condition is an organic base or an inorganic base; and / or, In step a), the molar ratio of the base used in the alkaline condition to the 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 is 1 to 2; and / or, In step a), the amino protecting agent is acetyl chloride, acetic anhydride or di(tert-butyl) dicarbonate; and / or, In step a), the molar ratio of the amino protecting agent to the 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 is 1 to 2; and / or, In step a), the condensation reaction temperature is 0 to 40°C; and / or, In step a), the condensation reaction time is 1 hour to 24 hours; and / or, In step b), the solvent is a mixed solvent of an organic solvent and water; and / or, In step b), the volume mass ratio of the solvent to the cariprazine intermediate 2 is 1 ml / g to 20 ml / g; and / or, In step b), the base is an inorganic base; and / or, In step b), the molar ratio of the base to the cariprazine intermediate 2 is 1.0 to 5.0; and / or, In step b), the temperature of the hydrolysis reaction is 10°C to 60°C; and / or, In step b), the hydrolysis reaction time is 1 hour to 12 hours; and / or, In step b), the acid used for acidification is an inorganic acid; and / or, In step b), the molar ratio of the acid used in the acidification to the cariprazine intermediate 2 is 1 to 10; and / or, In step b), the acidification temperature is -5°C to 25°C; and / or, In step b), the acidification time is 0.5 hours to 5.0 hours; and / or, In step c), the organic solvent is one or more of a ketone solvent, a halogenated hydrocarbon solvent and an alcohol solvent; and / or, In step c), the volume mass ratio of the organic solvent to the cariprazine intermediate 3 is 1.0 ml / g to 20.0 ml / g; and / or, In step c), the catalyst is ethyl chloroformate, isobutyl chloroformate, N,N-carbonyldiimidazole, methanesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, di-tert-butyl dicarbonate, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-N,N-lutidine, 1-hydroxybenzotriazole, 4-pyrrolidinylpyridine, O-(7-azabenzotriazole-1-yl)-di(dimethylamino)carbonium hexafluorophosphate, O-(benzotriazole-1-yl)-di(dimethylamino)carbonium hexafluorophosphate, O-(5-chlorobenzotriazole-1-yl)-di(dimethylamino)carbonium hexafluorophosphate, one or more of: benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate, diphenylphosphoryl chloride, diethyl cyanophosphate, diphenylphosphoryl azide thiodimethylphosphoryl azide and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride; and / or, In step c), the molar ratio of the catalyst to the cariprazine intermediate 3 is 1.0 to 2.0; and / or, In step c), the base is an organic base and / or an inorganic base; and / or, In step c), the molar ratio of the base to the cariprazine intermediate 3 is 1.0 to 3.0; and / or, In step c), the condensation reaction temperature is 0 to 40°C; and / or, In step c), the condensation reaction time is 1 hour to 24 hours.

5. The preparation method according to claim 4, characterized in that: In step a), the organic solvent is one or more of a halogenated hydrocarbon solvent, an alcohol solvent, a ketone solvent, an ether solvent, an ester solvent, a nitrile solvent, an aromatic hydrocarbon solvent and an amide solvent; and / or, In step a), the volume mass ratio of the solvent to the ethyl 2-[1-(4-amino]-cyclohexyl)-acetic acid ethyl hydrochloride 1 is 2 mL / g to 6 mL / g; and / or, In step a), the organic base is one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine; and / or, In step b), the organic solvent is an ether solvent; and / or, In step b), the volume ratio of the organic solvent to the water is preferably 1 to 10; and / or, In step b), the volume mass ratio of the solvent to the cariprazine intermediate 2 is 10 ml / g to 15 ml / g; and / or, In step b), the inorganic base is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; and / or, In step b), the molar ratio of the base to the cariprazine intermediate 2 is 1.1 to 3.0; and / or, In step b), the temperature of the hydrolysis reaction is 20°C to 50°C; and / or, In step b), the hydrolysis reaction time is 2 hours to 10 hours; and / or, In step b), the inorganic acid is hydrochloric acid; and / or, In step b), the molar ratio of the acid used in the acidification to the cariprazine intermediate 2 is 2 to 6; and / or, In step b), the temperature of the acidification reaction is 0°C to 5°C; and / or, In step b), the acidification reaction time is 1.0 hour to 3.0 hours; and / or, In step c), the ketone solvent is acetone; and / or, In step c), the halogenated hydrocarbon solvent is a chlorinated hydrocarbon solvent; and / or, In step c), the alcohol solvent is isopropanol; and / or, In step c), the volume mass ratio of the organic solvent to the cariprazine intermediate 3 is 2.0 ml / g to 8.0 ml / g; and / or, In step c), the molar ratio of the catalyst to the cariprazine intermediate 3 is 1.1 to 1.5; and / or, In step c), the organic base is one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine; and / or, In step c), the inorganic base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate; and / or, In step c), the molar ratio of the base to the cariprazine intermediate 3 is 1.0 to 2.0; and / or, In step c), the condensation reaction temperature is 10°C to 30°C; and / or, In step c), the condensation reaction time is 6 hours to 12 hours.

6. The preparation method according to claim 5, characterized in that: In step a), the halogenated hydrocarbon solvent is a chlorinated hydrocarbon solvent; and / or, In step a), the alcohol solvent is one or more of methanol, ethanol and tert-butanol; and / or, In step a), the ketone solvent is acetone; and / or, In step a), the ether solvent is tetrahydrofuran and / or 1,4-dioxane; and / or, In step a), the ester solvent is ethyl acetate; and / or, In step a), the nitrile solvent is acetonitrile; and / or, In step a), the aromatic hydrocarbon solvent is toluene; and / or, In step a), the amide solvent is N,N-dimethylformamide; and / or, In step a), the volume mass ratio of the solvent to the 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 is 4 mL / g; and / or, In step a), the inorganic base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate; and / or, In step b), the ether solvent is tetrahydrofuran; and / or, In step b), the volume mass ratio of the solvent to the cariprazine intermediate 2 is 12.5 ml / g; and / or, In step b), the volume ratio of the organic solvent to the water is preferably 2 to 6; and / or, In step b), the molar ratio of the base to the cariprazine intermediate 2 is 2.0; and / or, In step b), the temperature of the hydrolysis reaction is 40°C; and / or, In step b), the hydrolysis reaction time is 6 hours; and / or, In step b), the concentration of hydrochloric acid is 1 mol / L to 12 mol / L; and / or, In step b), the molar ratio of the acid used in the acidification to the cariprazine intermediate 2 is 5; and / or, In step b), the acidification reaction time is 1.0 hour; and / or, In step c), the chlorinated hydrocarbon solvent is dichloromethane; and / or, In step c), the volume mass ratio of the organic solvent to the cariprazine intermediate 3 is 5.2 ml / g, 5.7 ml / g or 6.0 ml / g; and / or, In step c), the molar ratio of the catalyst to the cariprazine intermediate 3 is 1.2; and / or, In step c), the molar ratio of the base to the cariprazine intermediate 3 is 1.0 or 1.1; and / or, In step c), the condensation reaction temperature is 20°C to 25°C; and / or, In step c), the condensation reaction time is 12 hours.

7. The preparation method according to claim 1, characterized in that: Step a) is carried out under the protection of protective gas; and / or, Step a) adopts the following post-treatment steps: after the reaction is completed, adding a base, extracting, washing, drying, and removing the solvent to obtain a purified cariprazine intermediate 2; and / or, Step a) adopts the following steps: adding a solution formed by an amino protecting agent and a solvent to a solution formed by 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1, a base and a solvent, and performing a condensation reaction to obtain the cariprazine intermediate 2.

8. The preparation method according to any one of claims 1 to 3, characterized in that: In step d), the organic solvent is an ether solvent; and / or, In step d), the volume mass ratio of the organic solvent to the cariprazine intermediate 5 is 1.0 ml / g to 20.0 ml / g; and / or, In step d), the reducing agent is boron trifluoride etherate and / or sodium borohydride; and / or, In step d), the molar ratio of the reducing agent to the cariprazine intermediate 5 is 1.0 to 5.0; and / or, In step d), the temperature of the reduction reaction is 0 to 25°C; and / or, In step d), the reduction reaction time is 0.5 hours to 24 hours; and / or, In step d), the acid is an inorganic acid; and / or, In step d), the molar ratio of the acid to the cariprazine intermediate 5 is 1 to 20; and / or, In step d), the temperature of the reaction for removing the amino protecting group is 10° C. to 80° C.; and / or, In step d), the reaction time for removing the amino protecting group is 1.0 hour to 10.0 hours.

9. The preparation method according to claim 8, characterized in that: In step d), the ether solvent is tetrahydrofuran; and / or, In step d), the volume mass ratio of the organic solvent to the cariprazine intermediate 5 is 2.0 ml / g to 8.0 ml / g; and / or, In step d), the molar ratio of the reducing agent to the cariprazine intermediate 5 is 1.5 to 3.0; and / or, In step d), the temperature of the reduction reaction is 0 to 10°C; and / or, In step d), the reduction reaction time is 2 hours to 10 hours; and / or, In step d), the inorganic acid is hydrochloric acid and / or sulfuric acid; and / or, In step d), the molar ratio of the acid to the cariprazine intermediate 5 is 2 to 15; and / or, In step d), the temperature of the reaction for removing the amino protecting group is 20°C to 60°C; and / or, In step d), the reaction time for removing the amino protecting group is 2.0 hours to 6.0 hours.

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