A process for the preparation of cariprazine and intermediates thereof

Abstract

A method for preparing cariprazine and its intermediates, belonging to the field of pharmaceutical preparation, synthesizes cariprazine from ethyl 2-(4-oxocyclohexyl)ethyl acetate through a three-step reaction. The synthetic route is as follows: This invention features high yield, short steps, low cost, and suitability for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically designing a method for preparing cariprazine and its intermediates. Background Technology

[0002] Cariprazine, chemically known as trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylformyl-cyclohexylamine, is a D3 / D2 receptor partial agonist jointly developed by Gedeon Richter of Hungary and Forest Laboratories of the United States. It is used to treat schizophrenia, bipolar disorder, bipolar depression, and major depressive disorder. It was approved by the US FDA on September 17, 2015. Its structural formula is shown below:

[0003] .

[0004] The following preparation routes for cariprazine have been reported in the prior art:

[0005] Route 1:

[0006] ;

[0007] In route 1, compound 1 undergoes a Buchwald-Hartwig metal coupling reaction catalyzed by Pd2(dba)3 to yield intermediate 2. Intermediate 2 is then deprotected under acidic conditions to yield intermediate 3. Intermediate 3 is reductively amination with intermediate 4 to yield intermediate 5, which is then deprotected to generate intermediate 6. This intermediate 6 then reacts with compound 7 (N,N-dimethylcarbamoyl chloride) to generate carrillazine. This route utilizes the noble metal Pd2(dba)3, as compound 4 is not readily available.

[0008] Route 2:

[0009] ;

[0010] In route 2, compound 1 undergoes a Wittig and hydrogenation reaction to obtain intermediate compound 3, which is then reduced to obtain compound 4. After activation of the hydroxyl group, compound 4 forms a CN bond with intermediate 6. Finally, after deprotection, it undergoes ureation to obtain carilarazine. This reaction involves expensive raw materials and a long reaction route, making it unsuitable for industrial production. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art, such as the high price of starting materials and the long reaction process, and to provide a method for preparing cariprazine and its intermediates. The present invention uses ethyl 4-oxocyclohexane as the starting material for the preparation of cariprazine. The reaction cost is low, the reaction process is short, and it is suitable for industrial production.

[0012] A method for preparing cariprazine and its intermediates includes the following steps:

[0013] (1) 4-oxocyclohexane ethyl acetate, i.e., compound I, undergoes a reductive amination reaction with tert-butylsulfinamide under the conditions of a catalyst and a reducing agent to generate trans-tert-butylsulfinamide-substituted cyclohexane ethanol, i.e., compound II.

[0014] (2) The trans-tert-butylsulfinylamino-substituted cyclohexane ethanol, i.e., compound II, reacts with 1-(2,3-dichlorophenyl)piperazine hydrochloride in the presence of a betaine intermediate and a base to give N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide, i.e., compound III;

[0015] (3) N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide, i.e., compound III, is deamino protected under acid to give (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride, i.e., compound IV;

[0016] (4) (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride, i.e., compound IV, undergoes an acylation reaction with the acylation reagent dimethylcarbamoyl chloride under the action of a base to give the final product carilarazine.

[0017] The corresponding synthesis route is:

[0018]

[0019] In one implementation, the reductive amination reaction described in step (1) is carried out in the presence of a catalyst, such as one or more of tetraethyl titanate and tetraisopropyl titanate, with an equivalent of 1-4 eq.;

[0020] The reductive amination reaction described in step (1) above is carried out under the action of a reducing agent, which is a NaBH4 / ZnCl2 composite reducing agent, a NaBH4 / CaCl2 composite reducing agent, a NaBH4 / AlCl3 composite reducing agent or a LiBH4 reducing agent, with an equivalent of 2-3 eq.;

[0021] The reductive amination reaction described in step (1) above is carried out in a solvent, wherein the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate and toluene;

[0022] The reductive amination reaction temperature in step (1) above is 50-90℃, and the reaction time is 4-12 h.

[0023] Further, in step (1) above: 4-oxocyclohexane ethyl acetate, tert-butylsulfonamide and catalyst are added to the reaction flask, dissolved in solvent, and refluxed at 50-90℃ for 1.5-3 h; the reaction is cooled to room temperature, and NaBH4 is slowly added, and refluxed at 50-90℃ for 0.5-1.5 h; the reaction is cooled, and the other component of the composite reducing agent is slowly added or the reaction is carried out without the composite reducing agent (the addition temperature and reaction temperature of the other component of the composite reducing agent can be adjusted as needed). The reaction system is added dropwise to a sodium bicarbonate aqueous solution stirred at 0℃, the insoluble matter is removed by filtration, and the solution is washed with an organic solvent. The organic phase of the filtrate is retained, and the aqueous phase is washed with an organic solvent. The organic phases are combined, concentrated under reduced pressure to remove the solvent, and the obtained solid is recrystallized from ethyl acetate:n-hexane = 1:1 to obtain a white solid product.

[0024] The photoelectrophoresis reaction described in step (2) is carried out under the action of a betaine intermediate and an alkali;

[0025] The base mentioned in step (2) above is triethylamine or N,N-diisopropylethylamine, with an equivalent of 1.5-3 eq;

[0026] The betaine intermediate described in step (2) above is prepared by azo reagent, organophosphorus reagent and trifluoromethanesulfonic acid in a molar ratio of 1:1:1. The organophosphorus reagent is placed in an organic solvent, cooled to -5°C, and azo reagent is added dropwise, followed by trifluoromethanesulfonic acid. The mixture is then heated to room temperature and stirred for 1 h.

[0027] The azo reagent is diethyl azodiacetic acid, diisopropyl azodiacetic acid, ditert-butyl azodiacetic acid, or di-p-chlorobenzyl azodiacetic acid.

[0028] The organophosphorus reagent is triphenylphosphine, tri-n-butylphosphine, trimethylphosphine, (cyanomethylene)tri-n-butylphosphine, or (cyanomethylene)trimethylphosphine.

[0029] In step (2) above, the molar ratio of compound II, 1-(2,3-dichlorophenyl)piperazine hydrochloride, betaine intermediate and alkali in the reaction is 1:1-1.5:1-1.5:1.5-3.

[0030] In step (3), the N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide is deprotected under the action of acid, and the acid used is hydrochloric acid with an equivalent of 6-12 eq;

[0031] The deprotection reaction described in step (3) above is carried out in a solvent, which is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, dichloromethane, ethyl acetate and isopropanol;

[0032] The acylation reaction described in step (4) is an organic base or an inorganic base; the organic base is selected from N,N-diisopropylethylamine, triethylamine, and pyridine, and the inorganic base is a 30% sodium hydroxide solution.

[0033] The molar ratio of the acylation reaction compound IV and the organic base, N,N-dimethylcarbamoyl chloride in step (4) above is 1.0:1.0-2.0:1.0-2.0;

[0034] The acylation reaction described in step (4) above is carried out in a solvent, which is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and ethyl acetate;

[0035] When an inorganic base is used for the acylation reaction in step (4) above, the volume ratio of the solvent to the inorganic base 30% sodium hydroxide solution is 1.0:1.0-2.0.

[0036] Due to the adoption of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0037] 1. The preparation method of this invention uses readily available raw materials, is simple to operate, has relatively mild reaction conditions, and requires minimal equipment, making it suitable for industrial production;

[0038] 2. This invention addresses the construction of trans-cyclohexane by reducing the ester to an alcohol based on a reductive amination reaction, directly yielding trans-cyclohexane, which greatly reduces unit operation reactions and is suitable for industrial production;

[0039] 3. This invention employs photoelectrophoresis for the construction of CN bonds. The introduction of the betaine intermediate overcomes the pKa effect of the piperazine structure, avoids the use of precious metal catalysts, reduces reaction costs, and greatly shortens the reaction steps.

[0040] 4. The preparation method of this invention yields cariprazine with a high yield and a crystal structure that meets the expected pharmaceutical requirements. Attached Figure Description

[0041] Figure 1 The 1H NMR spectrum of the intermediate N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (II) of this invention.

[0042] Figure 2 MS of the intermediate N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (II) of the present invention.

[0043] Figure 3 The 1H NMR spectrum of the intermediate N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide (III) of this invention.

[0044] Figure 4 MS of the intermediate N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide (III) of the present invention.

[0045] Figure 5 The 1H NMR spectrum of (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride (IV), an intermediate of this invention.

[0046] Figure 6 The 1H NMR spectrum of (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride (IV), an intermediate of this invention.

[0047] Figure 7 MS of (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride (IV), an intermediate of the present invention.

[0048] Figure 8 The 1H NMR spectrum of cariprazine (V), the end product of this invention.

[0049] Figure 9 The 1H NMR spectrum of cariprazine (V), the end product of this invention.

[0050] Figure 10 MS of cariprazine (V), the end product of this invention.

[0051] Figure 11 Crystal structure Detailed Implementation

[0052] The present application will be further described below with reference to the embodiments, but the present application is not limited to the following embodiments.

[0053] Example 1

[0054] (1) Synthesis of N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (II)

[0055] Ethyl 4-oxocyclohexane (10.0 g, 54.3 mmol), tert-butylsulfinamide (6.6 g, 54.3 mmol), and ethyl titanate (12.4 g, 54.3 mmol) were added to a 500 mL three-necked flask, dissolved in 200 mL of THF, and refluxed at 70 °C for 2 h. The reaction mixture was cooled to room temperature, and NaBH4 (5.1 g, 135.7 mmol) was slowly added, refluxed at 70 °C for 1 h. The reaction mixture was then cooled to room temperature, and ZnCl2 (18.5 g, 135.7 mmol) was slowly added, refluxed at 70 °C for 8 h. The reaction mixture was then cooled to room temperature, and the reaction mixture was added dropwise to 200 mL of stirred sodium bicarbonate aqueous solution at 0 °C. The insoluble matter was removed by filtration and washed with 200 mL of dichloromethane. The organic phase of the filtrate was retained, and the aqueous phase was washed with 200 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to remove the solvent. The resulting solid was recrystallized from ethyl acetate and n-hexane in a 1:1 ratio to give 12.7 g of white solid product, with a yield of 95%.

[0056] Compound II was obtained through the above experiments, and its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.69 (t, J = 6.6 Hz, 2H), 3.14 (ddt, J = 15.3, 11.2, 4.0 Hz, 1H), 3.03 (d, J = 5.4 Hz, 1H), 2.05 (tdd, J = 13.3, 6.2, 3.1 Hz, 2H), 1.82(dp, J = 11.9, 2.7 Hz, 2H), 1.49 (q, J = 6.7 Hz, 2H), 1.43 – 1.28 (m, 2H), 1.22 (d, J = 11.4 Hz, 10H), 1.15 – 0.94 (m, 2H).

[0057] See the 1H NMR spectrum data. Figure 1 .

[0058] ESI-MS m / z: ([M+H) + )cald. For C 12 H 26 NO2S + :248.2, Found:248.2.

[0059] See MS data chart. Figure 2 .

[0060] (2) Synthesis of N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide (III)

[0061] Triphenylphosphine (12.7 g, 48.5 mmol) was dissolved in 100 mL of dichloromethane, cooled to -5 °C, and diethyl azodicarboxylate (8.5 g, 48.5 mmol) was added dropwise, followed by trifluoromethanesulfonic acid (7.28 g, 48.5 mmol). The mixture was heated to room temperature and stirred for 1 h. Then, N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (i.e., compound II, 10.0 g, 40.4 mmol), 1-(2,3-dichlorophenyl)piperazine hydrochloride (10.8 g, 40.4 mmol), and triethylamine (12.3 g, 121.3 mmol) were added sequentially, and the mixture was stirred at room temperature for 7 h. After the reaction was complete, 100 mL of n-hexane was added, the mixture was filtered to retain the solid, and dried at 60 °C under blast heat to give 14.5 g of a white solid product, with a yield of 78%.

[0062] Compound III was obtained through the above experiments, and its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (ddt, J = 12.0, 6.8, 1.4 Hz, 1H), 7.48 (ddd, J = 8.5,6.6, 3.0 Hz, 1H), 7.21 – 7.11 (m, 2H), 6.98 (dd, J = 6.6, 3.0 Hz, 1H), 3.11(d, J = 6.4 Hz, 4H), 3.02 (d, J = 5.2 Hz, 1H), 2.66 (s, 4H), 2.46 (t, J = 8.0Hz, 2H), 2.07 (tq, J = 13.9, 3.1 Hz, 2H), 1.83 (ddq, J = 11.1, 5.6, 2.8 Hz, 2H), 1.46 (t, J = 8.0 Hz, 2H), 1.34 – 1.26 (m, 2H), 1.21 (s, 10H), 1.10 –0.97 (m, 2H).

[0063] See the 1H NMR spectrum data. Figure 3 .

[0064] ESI-MS m / z: ([M+H]+) cald.For C 22 H 36Cl2N3OS + :460.2 Found:460.2.

[0065] See MS data chart. Figure 4 .

[0066] (3) Synthesis of (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride (IV)

[0067] N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide (III) (10.0 g, 21.7 mmol) was dissolved in 100 mL of dichloromethane, and 16.3 mL of 4 M ethyl acetate-hydrochloric acid solution was added. The mixture was stirred at room temperature for 8 h. The solid was filtered under reduced pressure, washed with 20 mL of ethyl acetate, and dried over a blast furnace at 60 °C to give 8.1 g of a white solid product, with a yield of 95%.

[0068] Compound III was obtained through the above experiments, and its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (d, J = 7.4 Hz, 1H), 8.15 – 8.09 (m, 2H), 7.42 – 7.32 (m,2H), 3.56 (d, J = 10.8 Hz, 2H), 3.45 – 3.31 (m, 5H), 3.25 (d, J = 10.9 Hz, 2H), 3.15 (dq, J = 11.9, 4.0, 3.1 Hz, 4H), 2.92 (q, J = 11.8, 9.3 Hz, 1H), 2.02 – 1.92 (m, 2H), 1.78 (dd, J = 13.8, 3.5 Hz, 2H), 1.65 (dd, J = 10.4, 6.0Hz, 2H), 1.42 – 1.25 (m, 3H), 1.08 – 0.93 (m, 2H).

[0069] See the 1H NMR spectrum data. Figure 5 .

[0070] Its carbon NMR data are as follows: 13C NMR (101 MHz, DMSO) δ 150.01, 133.21, 129.13,126.50, 125.75, 120.24, 54.13, 51.47, 49.67, 48.13, 34.23, 30.48, 30.37,21.41.

[0071] See the carbon NMR data graph. Figure 6 .

[0072] ESI-MS m / z: ([M+H) + ) cald.For C 18 H 28 Cl2N3 + :356.2 Found:356.2

[0073] See MS data chart. Figure 7 .

[0074] (4) Synthesis of cariprazine (V)

[0075] At room temperature, (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride (IV) (10.0 g, 25.5 mmol) was dissolved in 50 mL of THF and 50 mL of 30% sodium hydroxide solution. Dimethylcarbamoyl chloride (3.3 g, 30.6 mmol) was added dropwise, and the mixture was stirred at room temperature for 8 h. 50 mL of n-hexane was added, the mixture was cooled to 5 °C, filtered to retain the solid, washed with 20 mL of n-hexane, and dried at 60 °C under blast heat to give 9.9 g of a white solid product, with a yield of 91%.

[0076] Compound V was obtained through the above experiments, and its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.43 – 7.31 (m, 2H), 7.22 (dd, J = 7.2, 2.4 Hz, 1H), 5.89 (d, J = 7.8 Hz, 1H), 3.57 (d, J = 8.5 Hz, 2H), 3.44 (s, 2H), 3.21 – 3.12(m, 5H), 2.76 (s, 6H), 1.81 – 1.70 (m, 4H), 1.63 (dd, J = 10.3, 5.7 Hz, 2H), 1.28 – 1.15 (m, 3H), 1.10 – 0.93 (m, 2H).

[0077] See the 1H NMR spectrum data. Figure 8 .

[0078] Its carbon NMR data are as follows: 13 C NMR (101 MHz, CDCl3) δ 157.82, 151.29,134.00, 127.45, 124.54, 118.60, 56.65, 53.38, 51.28, 49.83, 36.14, 35.63,34.02, 33.88, 32.10.

[0079] See the carbon NMR data graph. Figure 9 .

[0080] ESI-MS m / z: ([M+H) + )cald.For C 21 H 33 Cl2N4O + :427.2, Found:427.2.

[0081] See MS data chart. Figure 10 .

[0082] Example 2

[0083] Synthesis of N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (II)

[0084] Ethyl 4-oxocyclohexane (10.0 g, 54.3 mmol), tert-butylsulfinamide (6.6 g, 54.3 mmol), and tetraisopropyl titanate (15.4 g, 54.3 mmol) were added to a 500 mL three-necked flask, dissolved in 200 mL of THF, and refluxed at 70 °C for 2 h. The reaction mixture was cooled to room temperature, and NaBH4 (5.1 g, 135.7 mmol) was slowly added, refluxed at 70 °C for 1 h. The reaction mixture was then cooled to room temperature, and ZnCl2 (18.5 g, 135.7 mmol) was slowly added, refluxed at 70 °C for 8 h. The reaction mixture was then cooled to room temperature, and the reaction mixture was added dropwise to 200 mL of stirred sodium bicarbonate aqueous solution at 0 °C. The insoluble matter was removed by filtration and washed with 200 mL of dichloromethane. The organic phase of the filtrate was retained, and the aqueous phase was washed with 200 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to remove the solvent. The resulting solid was recrystallized from ethyl acetate:n-hexane in a 1:1 ratio to give 12.4 g of a white solid product, with a yield of 93%.

[0085] Other simultaneous embodiment 1.

[0086] Example 3

[0087] Synthesis of N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (II)

[0088] Ethyl 4-oxocyclohexane (10.0 g, 54.3 mmol), tert-butylsulfinamide (6.6 g, 54.3 mmol), and ethyl titanate (12.4 g, 54.3 mmol) were added to a 500 mL three-necked flask, dissolved in 200 mL of THF, and refluxed at 70 °C for 2 h. The reaction mixture was cooled to room temperature, and NaBH4 (5.1 g, 135.7 mmol) was slowly added, followed by reflux at 70 °C for 1 h. The reaction mixture was then cooled to -30 °C, and AlCl3 (18.1 g, 135.7 mmol) was slowly added, followed by a warming to room temperature for 1 h. The reaction mixture was then cooled to room temperature, and the reaction mixture was added dropwise to 200 mL of stirred sodium bicarbonate aqueous solution at 0 °C. The insoluble matter was removed by filtration and washed with 200 mL of dichloromethane. The organic phase of the filtrate was retained, and the aqueous phase was washed with 200 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to remove the solvent. The resulting solid was recrystallized from ethyl acetate and n-hexane in a 1:1 ratio to give 12.5 g of white solid product, with a yield of 93%.

[0089] Other simultaneous embodiment 1.

[0090] Example 4

[0091] Synthesis of N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide (III)

[0092] Triphenylphosphine (12.7 g, 48.5 mmol) was dissolved in 100 mL of dichloromethane, cooled to -5 °C, and diethyl azodicarboxylate (8.5 g, 48.5 mmol) was added dropwise, followed by trifluoromethanesulfonic acid (7.28 g, 48.5 mmol). The mixture was heated to room temperature and stirred for 1 h. N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (10.0 g, 40.4 mmol), 1-(2,3-dichlorophenyl)piperazine hydrochloride (10.8 g, 40.4 mmol), and N,N-diisopropylethylamine (15.6 g, 121.3 mmol) were added, and the mixture was stirred at room temperature for 7 h. After the reaction was complete, 100 mL of n-hexane was added, the mixture was filtered to retain the solid, and dried at 60 °C under blast heat to give 13.5 g of a white solid product, with a yield of 73%.

[0093] Other simultaneous embodiment 1.

[0094] Example 5

[0095] In step (1) of Example 1, the reaction solvent was changed to 2-methyltetrahydrofuran, and the other steps were the same as in Example 1, yielding 7.9 g of N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (II) with a yield of 58%.

[0096] Example 6

[0097] In step (1) of Example 1, the reaction solvent was changed to ethyl acetate, and the other steps were the same as in Example 1, yielding 7.7 g of N-((1R,4R)-4-(2-hydroxyethyl)cyclohexyl)-2-methylpropane-2-thioamide (II) with a yield of 57%.

[0098] Example 7

[0099] In step (3) of Example 1, the reaction solvent was changed to ethyl acetate, and the other steps were the same, yielding 8.3 g of (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride (IV) with a yield of 97%.

Claims

1. A process for the preparation of cariprazine, characterized by, Includes the following steps: (1) 4-oxocyclohexane ethyl acetate, i.e., compound I, undergoes a reductive amination reaction with tert-butylsulfinamide under the conditions of a catalyst and a reducing agent to generate trans-tert-butylsulfinamide-substituted cyclohexane ethanol, i.e., compound II. (2) The trans-tert-butylsulfinylamino-substituted cyclohexane ethanol, i.e., compound II, reacts with 1-(2,3-dichlorophenyl)piperazine hydrochloride in the presence of a betaine intermediate and a base to give N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide, i.e., compound III; (3) N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide, i.e., compound III, is deamino protected under acid to give (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride, i.e., compound IV; (4) (1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl-1-amine hydrochloride, i.e., compound IV, undergoes an acylation reaction with the acylation reagent dimethylcarbamoyl chloride under the action of a base to give the final product carlirazine; The corresponding synthesis route is: 。 2. The method of claim 1, wherein, The reductive amination reaction described in step (1) is carried out in the presence of a catalyst, such as one or more of tetraethyl titanate and tetraisopropyl titanate, with an equivalent of 1-4 eq.; The reductive amination reaction described in step (1) is carried out under the action of a reducing agent, which is a NaBH4 / ZnCl2 composite reducing agent, a NaBH4 / CaCl2 composite reducing agent, a NaBH4 / AlCl3 composite reducing agent or a LiBH4 reducing agent, with an equivalent of 2-3 eq.; The reductive amination reaction described in step (1) is carried out in a solvent selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate and toluene; The reductive amination reaction temperature in step (1) above is 50-90℃, and the reaction time is 4-12 h.

3. The method of claim 2, wherein, Step (1): Add ethyl acetate of 4-oxocyclohexane, tert-butylsulfonamide and catalyst to the reaction flask, add solvent to dissolve, and reflux at 50-90℃ for 1.5-3 h; cool the reaction to room temperature, then slowly add NaBH4, and reflux at 50-90℃ for 0.5-1.5 h; cool the reaction, and slowly add the other component of the composite reducing agent or without the composite reducing agent and continue the reaction. The addition temperature of the other component of the composite reducing agent and the reaction temperature can be adjusted as needed. Add the reaction system dropwise to a sodium bicarbonate aqueous solution stirred at 0℃, filter to remove insoluble matter, and wash with organic solvent. Retain the organic phase of the filtrate, wash the aqueous phase with organic solvent, combine the organic phases, concentrate under reduced pressure to remove the solvent, and recrystallize the obtained solid with ethyl acetate:n-hexane = 1:1 to obtain a white solid product.

4. The method according to claim 1, characterized in that, The reaction described in step (2) is carried out under the action of a betaine intermediate and a base; The base mentioned in step (2) above is triethylamine or N,N-diisopropylethylamine, with an equivalent of 1.5-3 eq; The betaine intermediate mentioned in step (2) above is prepared by azo reagent, organophosphorus reagent and trifluoromethanesulfonic acid in a molar ratio of 1:1:

1. The organophosphorus reagent is placed in an organic solvent, cooled to -5°C, and azo reagent is added dropwise, followed by trifluoromethanesulfonic acid. The mixture is then heated to room temperature and stirred for 1 h. The azo reagent is diethyl azodiacetic acid, diisopropyl azodiacetic acid, ditert-butyl azodiacetic acid, or di-p-chlorobenzyl azodiacetic acid. The organophosphorus reagent is triphenylphosphine, tri-n-butylphosphine, trimethylphosphine, (cyanomethylene)tri-n-butylphosphine, or (cyanomethylene)trimethylphosphine.

5. According to the method of claim 1, the molar ratio of compound II, 1-(2,3-dichlorophenyl)piperazine hydrochloride, betaine intermediate and base in the reaction of step (2) is 1:1-1.5:1-1.5:1.5-3.

6. The method of claim 1, wherein, In step (3), the N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide is deprotected under the action of acid, and the acid used is hydrochloric acid with an equivalent of 6-12 eq; The deprotection reaction in step (3) is carried out in a solvent selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, dichloromethane, ethyl acetate and isopropanol.

7. The method of claim 1, wherein, The acylation reaction described in step (4) is an organic base or an inorganic base; the organic base is selected from N,N-diisopropylethylamine, triethylamine, and pyridine, and the inorganic base is a 30% sodium hydroxide solution. The molar ratio of the acylation reaction compound IV and the organic base, N,N-dimethylcarbamoyl chloride in step (4) above is 1.0:1.0-2.0:1.0-2.0; The acylation reaction described in step (4) above is carried out in a solvent, which is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and ethyl acetate; When an inorganic base is used for the acylation reaction in step (4) above, the volume ratio of the solvent to the inorganic base 30% sodium hydroxide solution is 1.0:1.0-2.

0.

8. An intermediate compound, characterized in that, N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2- methylpropane-2-sulfonamide, i.e., Compound III, having the structural formula: .

9. The method for preparing the intermediate compound according to claim 8, characterized in that, The reaction of trans-tert-butylsulfinylamino-substituted cyclohexaneethanol, i.e., compound II, with 1-(2,3-dichlorophenyl)piperazine hydrochloride in the presence of a betaine intermediate and a base yields N-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylpropane-2-sulfinamide, i.e., compound III. The reaction is carried out in the presence of a betaine intermediate and a base. The base is triethylamine or N,N-diisopropylethylamine, with an equivalent of 1.5-3 eq; The betaine intermediate was prepared by azo reagent, organophosphorus reagent and trifluoromethanesulfonic acid in a molar ratio of 1:1:

1. The organophosphorus reagent was placed in an organic solvent, cooled to -5°C, and azo reagent was added dropwise, followed by trifluoromethanesulfonic acid. The mixture was then heated to room temperature and stirred for 1 h. The azo reagent is diethyl azodiacetic acid, diisopropyl azodiacetic acid, ditert-butyl azodiacetic acid, or di-p-chlorobenzyl azodiacetic acid. The organophosphorus reagent mentioned above is triphenylphosphine, tri-n-butylphosphine, trimethylphosphine, (cyanomethylene)tri-n-butylphosphine, or (cyanomethylene)trimethylphosphine; The molar ratio of compound II, 1-(2,3-dichlorophenyl)piperazine hydrochloride, betaine intermediate, and alkali in the reaction is 1:1-1.5:1-1.5:1.5-3.

10. The use of the intermediate compound of claim 8 for the preparation of carilarazine.

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