Preparation method of cariprazine

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of cariprazine. According to the method, trans-4-Boc-aminocyclohexylethyl methanesulfonate is taken as a starting material, an acylation step using N, N-dimethylformyl chloride is carried out at the middle position of the process, dimer impurities generated during the acylation step can be removed through subsequent steps, the quality of a cariprazine raw material medicine is ensured, and the method can be applied to a process route of industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing cariprazine. Background Art

[0002] Cariprazine, whose Chinese chemical name is trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-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 for marketing by the US FDA on September 17, 2015. Its structural formula is shown below:

[0003]

[0004] There have been many reports on the synthesis method of cariprazine. World patent WO 2015 / 05616A1 reports a synthesis method such as the formula, which uses trans-4-aminocyclohexyl ethyl acetate as a raw material, reacts with CDI to obtain trans-4-(imidazolyl-1-formamido) cyclohexyl ethyl acetate (compound Int-1), and compound Int-1 reacts with dimethylamine hydrochloride to obtain trans-4-(dimethylaminoformamido) cyclohexyl ethyl acetate (compound Int-2), and compound Int-2 is reduced by DIBAL-H to obtain trans-4-(dimethylaminoformamido) cyclohexylethanol (compound Int-3), and finally compound Int-3 reacts with 1-(2,3-dichlorophenyl) piperazine under the catalysis of dodecacarbonyltriruthenium and Xantphos to obtain cariprazine. Although the reaction conditions of this method are relatively mild, the yields in the preparation of compound Int-1 and the finished product steps are only 36% and 52%, respectively, which are low and not suitable for industrial production.

[0005]

[0006] In addition, the original world patents WO 2010 / 070369A1, WO 2010 / 070370A1 and WO 2010 / 070371A1 reported another method for preparing cariprazine. As shown in the formula, the method uses trans-4-Boc-aminocyclohexyl ethyl acetate as a raw material to obtain trans-4-Boc-aminocyclohexyl ethanol compound (Int-1), and compound Int-1 reacts with methanesulfonyl chloride to obtain trans-4-Boc-aminocyclohexyl ethyl methanesulfonate (compound Int-2), and compound Int-2 is then reacted with 1-(2,3- The preparation method comprises the following steps: alkylation of 2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexylamine (compound Int-3), de-Bocation of compound Int-3 to obtain trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexylamine hydrochloride (compound Int-4), and finally compound Int-4 reacts with N,N-dimethylformyl chloride to obtain cariprazine. The yield of each step of the preparation method is relatively high, but in the last step, when compound Int-4 reacts with N,N-dimethylformyl chloride, it is very easy to produce a difficult-to-remove dimer impurity as shown in the formula. This impurity is produced at the end of the process, posing a significant potential risk to the quality of the finished product.

[0007] Summary of the invention

[0008] In order to overcome the shortcomings of the prior art, the present invention provides a method for preparing cariprazine as shown in Formula V. In the synthetic route, the applicant selects trans-4-Boc-aminocyclohexylethyl methanesulfonate as the starting material, and places the acylation step using N,N-dimethylformyl chloride in the middle of the process. The dimer impurities generated during the process can be removed by subsequent steps, thereby ensuring the quality of the cariprazine raw material.

[0009]

[0010] To achieve the above purpose, the technical solution steps adopted by the present invention are as follows:

[0011] Step (1), preparation of intermediate II: add organic solvent A, purified water and compound SM into a reaction flask, stir, add hydrochloric acid, stir at room temperature until the reaction end, cool, stir, filter, wash the filter cake, and vacuum dry to obtain compound II.

[0012] Step (2), preparation of intermediate III: organic solvent B, compound II and base are added to a reaction flask, stirred until completely dissolved, N, N-dimethylaminoformyl chloride is added, the temperature is raised to T1, the temperature is kept to react until the reaction is completed, purified water is added, stirred, filtered, the filter cake is washed, and vacuum dried to obtain compound III.

[0013] Step (3), preparation of cariprazine: adding organic solvent C, compound III, 1-(2,3-dichlorophenyl)-piperazine hydrochloride and alkali into a reaction flask, heating to T2, keeping the temperature to react until the reaction is completed, cooling the temperature to room temperature, adding purified water, stirring, filtering, washing, and vacuum drying to obtain cariprazine.

[0014] Preferably, the molar ratio of the compound SM in step (1) to the hydrochloric acid is 1.0:1.0-2.0, with 1:1.2 being particularly preferred.

[0015] Preferably, the organic solvent A in step (1) is selected from acetonitrile, tetrahydrofuran, dichloromethane and toluene, among which acetonitrile is particularly preferred.

[0016] Preferably, the cooling temperature in step (1) is -5°C to 15°C, with 0°C to 5°C being particularly preferred.

[0017] Preferably, the base in step (2) is selected from N,N-diisopropylethylamine, triethylamine, pyridine, and sodium methoxide, and N,N-diisopropylethylamine is particularly preferred.

[0018] Preferably, the molar ratio of compound II to base and N,N-dimethylcarbamoyl chloride in step (2) is 1.0:3.5-4.5:1.2-2.0, particularly preferably 1:4.0:1.5; the reaction temperature T1 is 30-70°C, particularly preferably 45-50°C.

[0019] Preferably, the organic solvent B in step (2) is selected from tetrahydrofuran, acetonitrile, methanol and toluene, among which tetrahydrofuran is particularly preferred.

[0020] Preferably, the base in step (3) is selected from potassium carbonate, sodium carbonate, sodium methoxide and sodium hydroxide, and potassium carbonate is particularly preferred.

[0021] Preferably, the molar ratio of compound III to 1-(2,3-dichlorophenyl)-piperazine hydrochloride and base in step (3) is 1.0:1.0-2.0:3.5-4.5, with 1:1.1:4.0 being particularly preferred.

[0022] Preferably, the organic solvent C in step (3) is selected from acetonitrile, toluene and DMF, among which tetraacetonitrile is particularly preferred.

[0023] Preferably, the reaction temperature T2 in step (3) is 70-100°C, particularly preferably 80-85°C.

[0024] The advantages of the present invention compared with the prior art are:

[0025] The acylation step using N,N-dimethylformyl chloride is placed in the middle of the process, and the dimer impurities produced during the process can be removed through subsequent steps, thus ensuring the quality of the cariprazine raw material. DETAILED DESCRIPTION

[0026] The present invention is further described by the following examples to make the present invention clearer and easier to understand. It should be understood that these examples are only for illustrative purposes and do not limit the scope of the present invention. The obvious changes and modifications made by those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.

[0027] Preparation of Compound II

[0028] Example 1

[0029] Acetonitrile (150 mL), purified water (50 mL) and compound SM (39.75 g, 100 mmol) were added to a reaction flask. Concentrated hydrochloric acid (4.37 g, 120 mmol, calculated as the amount of hydrochloric acid) was slowly added dropwise under stirring. After the addition was completed, the mixture was stirred at room temperature for 2 to 3 h. After the reaction was complete, the mixture was cooled to 0 to 10°C, stirred at this temperature for 1 to 2 h, filtered, and the filter cake was washed with cold acetonitrile (12.5 mL). The mixture was dried in vacuo to obtain a light yellow solid with a yield of 97.8% and a purity of 99.92%.

[0030] Example 2

[0031] Tetrahydrofuran (150 mL), purified water (50 mL) and compound SM (39.75 g, 100 mmol) were added to a reaction flask. Concentrated hydrochloric acid (3.65 g, 100 mmol, calculated as the amount of hydrochloric acid) was slowly added dropwise under stirring. After the addition was completed, the mixture was stirred at room temperature for 2 to 3 h. When the reaction was complete, the mixture was cooled to -5 to 0°C, stirred at this temperature for 1 to 2 h, filtered, and the filter cake was washed with cold tetrahydrofuran (12.5 mL). The mixture was dried in vacuo to obtain a light yellow solid with a yield of 94.6% and a purity of 99.65%.

[0032] Example 3

[0033] Dichloromethane (150 mL), purified water (50 mL) and compound SM (39.75 g, 100 mmol) were added to a reaction flask. Concentrated hydrochloric acid (7.30 g, 200 mmol, calculated as the amount of hydrochloric acid) was slowly added dropwise under stirring. After the addition was completed, the mixture was stirred at room temperature for 2 to 3 h. When the reaction was complete, the temperature was lowered to 10 to 15°C, and the mixture was stirred at this temperature for 1 to 2 h. The mixture was filtered, and the filter cake was washed with cold dichloromethane (12.5 mL). The mixture was dried in vacuo to obtain a light yellow solid with a yield of 95.5% and a purity of 99.59%.

[0034] Example 4

[0035] Toluene (150 mL), purified water (50 mL) and compound SM (39.75 g, 100 mmol) were added to a reaction flask. Concentrated hydrochloric acid (8.03 g, 220 mmol, calculated as the amount of hydrochloric acid) was slowly added dropwise under stirring. After the addition was completed, the mixture was stirred at room temperature for 2 to 3 h. When the reaction was complete, the temperature was lowered to 15 to 20°C, and the mixture was stirred at this temperature for 1 to 2 h. The mixture was filtered, and the filter cake was washed with cold toluene (12.5 mL). The mixture was dried in vacuo to obtain a light yellow solid with a yield of 89.6% and a purity of 98.71%.

[0036] Preparation of Compound III

[0037] Example 5

[0038] Tetrahydrofuran (400 mL), compound II (33.38 g, 100 mmol) and N,N-diisopropylethylamine (51.70 g, 400 mmol) were added to a reaction flask and stirred until completely dissolved. N,N-dimethylaminoformyl chloride (16.13 g, 150 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 45-50°C and the reaction was kept warm for 3-5 hours. After the reaction was complete, purified water (100 mL) was added dropwise. After the addition was completed, the temperature was lowered to room temperature, and the mixture was kept warm and stirred for 1-2 hours. Filtered with suction, the filter cake was washed with tetrahydrofuran aqueous solution, and the filter cake was vacuum dried to obtain a white solid, which was compound III, with a yield of 97.8% and a HPLC purity of 99.96%.

[0039] Example 6

[0040] Add acetonitrile (200 mL), compound II (33.38 g, 100 mmol) and N,N-diisopropylethylamine (45.24 g, 350 mmol) into a reaction flask and stir until completely dissolved. Slowly drop N,N-dimethylaminoformyl chloride (16.13 g, 150 mmol). After the addition is complete, raise the temperature to 30-35°C and keep the temperature for reaction for 3-5 hours. After the reaction is complete, drop purified water (100 mL). After the addition is complete, cool to room temperature and keep the temperature for stirring for 1-2 hours. Filter with suction, wash the filter cake with acetonitrile aqueous solution, and vacuum dry the filter cake to obtain a white solid, which is compound III, with a yield of 93.8% and a HPLC purity of 99.62%.

[0041] Example 7

[0042] Toluene (200 mL), compound II (33.38 g, 100 mmol) and N,N-diisopropylethylamine (58.16 g, 450 mmol) were added to a reaction flask and stirred until completely dissolved. N,N-dimethylaminoformyl chloride (16.13 g, 150 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 65-70°C and the reaction was kept warm for 3-5 hours. After the reaction was complete, purified water (100 mL) was added dropwise. After the addition was completed, the temperature was lowered to room temperature and stirred for 1-2 hours. Filtered with suction, the filter cake was washed with toluene aqueous solution, and the filter cake was vacuum dried to obtain a white solid, which was compound III with a yield of 94.8% and a HPLC purity of 99.69%.

[0043] Example 8

[0044] Methanol (400 mL), compound II (33.38 g, 100 mmol) and triethylamine (40.48 g, 400 mmol) were added into a reaction flask and stirred until completely dissolved. N,N-dimethylaminoformyl chloride (12.90 g, 120 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 45-50°C and kept warm for reaction for 3-5 h. After the reaction was complete, purified water (100 mL) was added dropwise. After the addition was completed, the temperature was lowered to room temperature and stirred for 1-2 h. The filter cake was filtered and washed with toluene aqueous solution. The filter cake was vacuum dried to obtain a white solid, which was compound III with a yield of 95.6% and a HPLC purity of 99.61%.

[0045] Example 9

[0046] Acetonitrile (400 mL), compound II (33.38 g, 100 mmol) and pyridine (31.64 g, 400 mmol) were added to a reaction flask and stirred until completely dissolved. N, N-dimethylaminoformyl chloride (21.51 g, 200 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 45-50°C and the reaction was kept warm for 3-5 hours. After the reaction was complete, purified water (100 mL) was added dropwise. After the addition was completed, the temperature was lowered to room temperature, and the mixture was kept warm and stirred for 1-2 hours. Filtered with suction, the filter cake was washed with acetonitrile aqueous solution, and the filter cake was vacuum dried to obtain a white solid, which was compound III, with a yield of 96.9% and a HPLC purity of 99.70%.

[0047] Example 10

[0048] Tetrahydrofuran (400 mL), compound II (33.38 g, 100 mmol) and N,N-diisopropylethylamine (42.65 g, 330 mmol) were added to a reaction flask and stirred until completely dissolved. N,N-dimethylaminoformyl chloride (10.75 g, 100 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 25-30°C and the reaction was kept warm for 3-5 hours. After the reaction was complete, purified water (100 mL) was added dropwise. After the addition was completed, the temperature was lowered to room temperature, and the mixture was kept warm and stirred for 1-2 hours. Filtered with suction, the filter cake was washed with tetrahydrofuran aqueous solution, and the filter cake was vacuum dried to obtain a white solid, which was compound III, with a yield of 85.3% and a HPLC purity of 98.75%.

[0049] Embodiment 11

[0050] Toluene (400 mL), compound II (33.38 g, 100 mmol) and sodium methoxide (25.39 g, 470 mmol) were added into a reaction flask and stirred until completely dissolved. N,N-dimethylaminoformyl chloride (23.66 g, 220 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 70-75°C and the reaction was kept warm for 3-5 hours. After the reaction was complete, purified water (100 mL) was added dropwise. After the addition was completed, the temperature was lowered to room temperature and stirred for 1-2 hours. The filter cake was filtered and washed with toluene aqueous solution. The filter cake was vacuum dried to obtain a white solid, which was compound III with a yield of 88.6% and a HPLC purity of 97.89%.

[0051] Preparation of Cariprazine

[0052] Example 12

[0053] Acetonitrile (300 mL), compound III (36.85 g, 100 mmol), 1-(2,3-dichlorophenyl)-piperazine hydrochloride (29.43 g, 110 mol) and potassium carbonate (55.28 g, 400 mmol) were added to a reaction flask, stirred and heated to 80-85°C, and kept warm for 12-15 h. After the reaction was completed, the temperature was lowered to 20-30°C, purified water (200 mL) was added, and the mixture was stirred for 1-2 h. The filter cake was washed with purified water until it was neutral, and the filter cake was vacuum dried to obtain white solid cariprazine with a yield of 98.5% and a HPLC purity of 99.95%.

[0054] Embodiment 13

[0055] Acetonitrile (300 mL), compound III (36.85 g, 100 mmol), 1-(2,3-dichlorophenyl)-piperazine hydrochloride (26.76 g, 100 mol) and sodium carbonate (42.40 g, 400 mmol) were added to a reaction flask, heated to 80-85° C. with stirring, and kept warm for 12-15 h. After the reaction was completed, the temperature was lowered to 20-30° C., purified water (200 mL) was added, and the mixture was stirred for 1-2 h. The mixture was filtered, and the filter cake was washed with purified water until it was neutral. The filter cake was vacuum dried to obtain white solid cariprazine with a yield of 94.4% and an HPLC purity of 99.62%.

[0056] Embodiment 14

[0057] Acetonitrile (300 mL), compound III (36.85 g, 100 mmol), 1-(2,3-dichlorophenyl)-piperazine hydrochloride (53.52 g, 200 mol) and sodium methoxide (21.61 g, 400 mmol) were added to a reaction flask, stirred and heated to 80-85°C, and kept warm for 12-15 h. After the reaction was completed, the temperature was lowered to 20-30°C, purified water (200 mL) was added, and the mixture was stirred for 1-2 h. The mixture was filtered, and the filter cake was washed with purified water until it was neutral. The filter cake was vacuum dried to obtain white solid cariprazine with a yield of 95.5% and an HPLC purity of 99.58%.

[0058] Embodiment 15

[0059] Toluene (300 mL), compound III (36.85 g, 100 mmol), 1-(2,3-dichlorophenyl)-piperazine hydrochloride (29.43 g, 110 mol) and potassium carbonate (48.37 g, 350 mmol) were added to a reaction flask, heated to 70-75° C. with stirring, and kept warm for 12-15 h. After the reaction was completed, the temperature was lowered to 20-30° C., purified water (200 mL) was added, and the mixture was stirred for 1-2 h. The filter cake was washed with purified water until it was neutral, and the filter cake was vacuum dried to obtain white solid cariprazine with a yield of 95.1% and an HPLC purity of 99.65%.

[0060] Example 16

[0061] DMF (300 mL), compound III (36.85 g, 100 mmol), 1-(2,3-dichlorophenyl)-piperazine hydrochloride (29.43 g, 110 mol) and potassium carbonate (62.19 g, 450 mmol) were added to a reaction flask, heated to 95-100° C. with stirring, and kept warm for 12-15 h. After the reaction was completed, the temperature was lowered to 20-30° C., purified water (200 mL) was added, and the mixture was stirred for 1-2 h. The mixture was filtered, and the filter cake was washed with purified water until it was neutral. The filter cake was vacuum dried to obtain white solid cariprazine with a yield of 96.3% and a HPLC purity of 99.60%.

[0062] Embodiment 17

[0063] DMF (300 mL), compound III (36.85 g, 100 mmol), 1-(2,3-dichlorophenyl)-piperazine hydrochloride (58.86 g, 220 mol) and sodium hydroxide (18.80 g, 470 mmol) were added to a reaction flask, stirred and heated to 100-105° C., and kept warm for 12-15 h. After the reaction was completed, the temperature was lowered to 20-30° C., purified water (200 mL) was added, and the mixture was stirred and kept warm for 1-2 h. The filter cake was washed with purified water until it was neutral, and the filter cake was vacuum dried to obtain white solid cariprazine with a yield of 87.6% and a HPLC purity of 98.65%.

Claims

1. A method for preparing cariprazine, characterized in that: The preparation method comprises the following steps: Step 1: Add organic solvent A, purified water and compound SM into a reaction flask, stir, add hydrochloric acid, stir at room temperature until the reaction end point, cool, stir, filter, wash the filter cake, and vacuum dry to obtain compound II; Step 2: Add organic solvent B, compound II and base into a reaction bottle, stir until completely dissolved, add N,N-dimethylaminoformyl chloride, raise the temperature to T1, keep the temperature to react until the reaction is completed, add purified water, stir, filter, wash the filter cake, and vacuum dry to obtain compound III; Step 3: Add organic solvent C, compound III, 1-(2,3-dichlorophenyl)-piperazine hydrochloride and base to a reaction bottle, raise the temperature to T2, keep the temperature to react until the reaction is completed, cool the reaction to room temperature, add purified water, stir, filter, wash, and vacuum dry to obtain cariprazine; The synthetic route is as follows 2. The preparation method according to claim 1, characterized in that: The molar ratio of the compound SM in step 1 to hydrochloric acid is 1.0:1.0-2.

0.

3. The preparation method according to claim 1, characterized in that: The organic solvent A described in step 1 is selected from one of acetonitrile, tetrahydrofuran, dichloromethane and toluene.

4. The preparation method according to claim 1, characterized in that: The cooling temperature in step 1 is -5°C to 15°C.

5. The preparation method according to claim 1, characterized in that: The base described in step 2 is selected from one of N,N-diisopropylethylamine, triethylamine, pyridine and sodium methoxide.

6. The preparation method according to claim 1, characterized in that: In step 2, the molar ratio of compound II to base and N,N-dimethylcarbamoyl chloride is 1.0:3.5-4.5:1.2-2.

0.

7. The preparation method according to claim 1, characterized in that: The organic solvent B described in step 2 is selected from one of tetrahydrofuran, acetonitrile, methanol and toluene.

8. The preparation method according to claim 1, characterized in that: The base described in step 3 is selected from one of potassium carbonate, sodium carbonate, sodium methoxide and sodium hydroxide.

9. The preparation method according to claim 1, characterized in that: In step 3, the molar ratio of compound III to 1-(2,3-dichlorophenyl)-piperazine hydrochloride and base is 1.0:1.0-2.0:3.5-4.

5.

10. The preparation method according to claim 1, characterized in that: The organic solvent C in step 3 is selected from acetonitrile, toluene and DMF; the reaction temperature T2 is 70-100°C.

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