PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE LAUROXIL

Abstract

It is provided a process for the preparation of aripiprazole lauroxil that comprises reacting 1-(hydroxymethyl) aripiprazole with lauric anhydride in the presence of DMAP and a solvent.

##STR00001##

Claims

1-13. (canceled)

14. A process for the preparation of a compound of formula (I) ##STR00010## which is aripiprazole lauroxil, which comprises the following steps: reacting a compound of formula (II) ##STR00011## with lauric anhydride in the presence of DMAP and a solvent, to obtain aripiprazole lauroxil; and optionally isolating the obtained compound of formula (I).

15. The process according to claim 14, wherein the solvent is selected from the group of dichloromethane, toluene, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, acetonitrile, and mixtures thereof.

16. The process according to claim 15, wherein the solvent is dichloromethane.

17. The process according to claim 14, wherein the reaction temperature is in the range of room temperature and the boiling point of the solvent.

18. The process according to claim 17, wherein the reaction is performed at room temperature.

19. The process according to claim 14, wherein the amount of DMAP used is 0.2 to 0.3% molar with respect to the compound of formula (II).

20. The process according to claim 14, wherein the molar ratio of the compound of formula (II) to lauric anhydride is 1:1.3.

21. The process according to claim 16, wherein step b) is carried out by distilling the solvent at atmospheric pressure.

22. The process according to claim 14, further comprising, before the step of reacting the compound of formula (II), a step of preparing the compound of formula (II) ##STR00012## by reacting a compound of formula (III) ##STR00013## which is aripiprazole or a hydrate thereof, with paraformaldehyde in the presence of an organic solvent and a suitable base, wherein the process is carried out either in the absence of water or in the presence of a content of water which comes from either the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of a hydrated form of aripiprazole, without addition of further water.

23. The process according to claim 22, wherein the organic solvent is selected from the group of toluene, ethyl acetate, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, acetonitrile, and mixtures thereof.

24. The process according to claim 22, wherein the base is selected from the group of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and diisopropylethylamine.

25. The process according to claim 22, wherein the amount of water in the reaction mixture comprising aripiprazole and paraformaldehyde is equal to or lower than 1 wt %.

26. The process according to claim 22, wherein aripiprazole or a hydrate thereof, and paraformaldehyde are in a molar ratio of from 1:1 to 1:3.

27. The process according to claim 15, wherein the reaction temperature is in the range of room temperature and the boiling point of the solvent.

28. The process according to claim 15, wherein the amount of DMAP used is 0.2 to 0.3% molar with respect to the compound of formula (II).

29. The process according to claim 15, wherein the molar ratio of compound of formula (II) to lauric anhydride is 1:1.3.

30. The process according to claim 15, further comprising, before the step of reacting the compound of formula (II), a step of preparing the compound of formula (II) ##STR00014## by reacting a compound of formula (III) ##STR00015## which is aripiprazole or a hydrate thereof, with paraformaldehyde in the presence of a organic solvent and a suitable base, wherein the process is carried out either in the absence of water or in the presence of a content of water which comes from either the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of a hydrated form of aripiprazole, without addition of further water.

31. The process according to claim 17, wherein the reaction temperature is in the range of 15-25° C.

32. The process according to claim 27, wherein the reaction temperature is in the range of 15-25° C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0021] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0022] In the first aspect of the invention, the process of preparing aripiprazole lauroxil comprises a first step a) of reacting a compound of formula (II) with lauric anhydride in the presence of DMAP and a solvent.

[0023] Examples of solvents to carry out the reaction of compound of formula (II) with lauric acid include, without being limited to, toluene, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), tetrahydrofuran (THF), acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), dichloromethane (DCM), acetonitrile (ACN), and mixtures thereof. Preferably the solvent is selected from toluene, tetrahydrofuran and dichloromethane. Particularly, the reaction is carried out in dichloromethane.

[0024] In a particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the solvent is selected form toluene, tetrahydrofuran and dichloromethane, and preferably is dichloromethane.

[0025] In another embodiment of the invention, the amount of DMAP used in the reaction between the compound of formula (II) and lauric anhydride can be from 0.1 to 1% molar respect to compound of formula (II). More particularly 0.2 to 0.3% molar respect to compound of formula (II).

[0026] In another embodiment of the invention, the molar ratio of compound of formula (II) to lauric anhydride can be from 1:1 to 1:3. More particularly the molar ratio is 1:1.3.

[0027] In another embodiment of the invention, the reaction temperature is in the range of 0° C. to the temperature of the boiling point of the solvent, still more particularly, at room temperature. For the purposes of the invention, room temperature is 15-25° C.

[0028] In the first aspect of the invention, the process of preparing aripiprazole lauroxil comprises a step b) of optionally isolating the product.

[0029] The product obtained in step a) can be isolated by conventional methods. The solvent can be directly removed to obtain aripiprazole lauroxil crude.

[0030] A filtration step to separate N,N-dicyclohexylurea form the reaction mixture is not needed before removal of the solvent in comparison to the process disclosed in the prior art when the reaction is carried out with lauric acid, DCC and 4-dimethylaminopyridine. The solvent can be removed by standard techniques used in organic chemistry as for example distillation. The solvent is preferably removed by distillation at atmospheric pressure. When a toxic solvent, as dichloromethane, is removed at atmospheric pressure, it has the advantage that the emission of volatiles to the atmosphere are reduced and they can be completely collected and recycled.

[0031] Thus, in a particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, step b) is carried out by distilling the solvent at atmospheric pressure.

[0032] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the solvent is dichloromethane and step b) is carried out by distilling the solvent at atmospheric pressure.

[0033] With the process of the invention aripiprazole lauroxil is obtained with high purity and very good yields. Particularly, aripiprazole lauroxil with a purity of at least 95% is obtained.

[0034] Additionally, the yield from compound of formula (II) to crude aripiprazole lauroxil range from 80% to 90%.

[0035] Aripiprazole lauroxil with a purity of at least 99.8% HPLC can be obtained by submitting the reaction crude to conventional purification techniques or other techniques described in the prior art such as crystallization, chromatography, or a combination thereof. Particularly, purification is carried out by crystallization, more particularly in isopropanol.

[0036] Previously, compound of formula (II) can be obtained by reacting aripiprazole of formula (III) or a hydrate thereof such as aripiprazole monohydrate with paraformaldehyde in the presence of an organic solvent and a suitable base, wherein the reaction is carried out either in the absence of water or in the presence of a content of water which comes from either the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of a hydrated form of aripiprazole, without addition of further water, accordingly as described in WO2019020821.

[0037] Thus, in a particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the process of preparing aripiprazole lauroxil further comprises a previous step i) to prepare a compound of formula (II)

##STR00006##

[0038] by reacting a compound of formula (III)

##STR00007##

[0039] which is aripiprazole, or a hydrate thereof, with paraformaldehyde in the presence of an organic solvent and a suitable base, wherein the reaction is carried out either in the absence of water or in the presence of a content of water which comes from either the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of a hydrated form of aripiprazole, without addition of further water.

[0040] Examples of organic solvents in step i) include, without being limited to, toluene, ethyl acetate, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), tetrahydrofuran (THF), acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), dichloromethane (DCM), acetonitrile (ACN), and mixtures thereof. Particularly, the organic solvent is toluene.

[0041] Examples of bases include, without being limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and diisopropylethylamine. Particularly, the base is DBU.

[0042] In a particular embodiment, as mentioned above, the amount of water present in the reaction mixture comprising aripiprazole and paraformaldehyde is equal to or lower than 1 wt %.

[0043] The reaction can be carried out with a molar ratio of aripiprazole, or a hydrate thereof such as the monohydrate, to paraformaldehyde of from 1:1 to 1:3. More particularly the molar ratio is 1:1:1.7.

[0044] Aripiprazole used as the starting material as such or in form of a monohydrate, paraformaldehyde, and lauric anhydride are commercially available. Paraformaldehyde (CAS Number 30525-89-4), also known as polyoxymethylene, is a polymer of formaldehyde and can be represented by the chemical formula (CH.sub.2O).sub.n, wherein n is an integer from 8 to 100.

[0045] Throughout the description and claims the word “comprise” and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”.

[0046] The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

EXAMPLES

Example 1. Preparation of Compound of Formula (I) in Dichloromethane

Step 1: Preparation of 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one (Compound of formula (II)) in toluene and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

[0047] ##STR00008##

[0048] 500 mL of toluene (5V), 100.0 g of aripiprazole (as monohydrate) (214 mmol), 10.6 g paraformaldehyde (343 mmol) and 0.65 g DBU (4.29 mmol) were charged into a 1 L reactor, heated to 30-40° C. and kept under stirring and nitrogen atmosphere during 16 hours (until aripiprazole in the reaction mixture is s 16.0% HPLC).

[0049] The reaction mixture was cooled to T s 5.0° C. and kept for 2 hours at these conditions. The solid was filtered from the mixture, washed once with 100 mL cool toluene. The solid was dried at 30° C. in a vacuum oven for 6 hours to obtain 96.9 g of the title compound (94% yield based on aripiprazole (as monohydrate)). Its purity, analyzed by HPLC was 87.6%, which means a conversion of 82.3%.

[0050] The HPLC analysis was carried out in the following column and conditions: [0051] Chromatographic column: XBridge RP Shield C18 (150×3 mm, 3.5 μm); [0052] Column temperature: 40° C.; [0053] Mobile phase: A: 2.3 g K.sub.2HPO.sub.4+3H.sub.2O/1 L H.sub.2O pH=6.6 H.sub.3PO.sub.4 10%, B: Acetonitrile [0054] Gradient elution conditions:

[0055] The chromatograph was programmed as follows:

TABLE-US-00001 Time Solution Solution (minutes) A (%) B (%) Elution 0 75 25 Isocratic 1.87 75 25 Isocratic 18.87 15 85 Gradient 22 15 85 Isocratic 22.5 75 25 Return to initial Post-time: 5 min Re-equilibrate

[0056] Main peak retention time: around 15.6 min; Sample volume 2μL; Detection wavelength: 254 nm; running time: 22 min; Test solution: 1 mg/mL, Solvent: Acetonitrile: Milli-Q water at 10% AcOH (1:2); Column flow: 0.51 ml/min.

Step 2: Purification of Compound of Formula (II)

[0057] 896 mL of deionized water (10V), 89.6 g of crude (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one are charged into a 2 L reactor, heated to 18-28° C. and kept under stirring and nitrogen atmosphere during at least 30 minutes.

[0058] The solid is filtered from the reaction mixture, washed twice with 270 mL deionized water. The solid is dried at 30° C. in a vacuum oven for 16 hours. It is obtained 88.38 g of pure 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one (98.6% yield from crude).

Step 3: Preparation of Aripiprazole Lauroxil (Compound of Formula (I) in Dichloromethane

[0059] ##STR00009##

[0060] Dichloromethane 100 mL, 8.8 g of lauric anhydride (23.0 mmol), 10.0 g of compound of formula (II) obtained in step 1 or 2 (20.9 mmol) and 0.51 g 4-dimethylaminopyridine (4.18 mmol) were charged into a 250 mL reactor and kept under stirring at room temperature (15-25° C.) for a minimum of 2 hours (until compound of formula (II) in the reaction mixture was ≤0.5% HPLC). Results: 0% of unreacted starting material compound of formula (II), 11.24% of aripiprazole and 86.0% of aripiprazole lauroxil.

[0061] Dichloromethane was distilled at atmospheric pressure. 10 mL of solvent were left in the reaction mixture. Then, 140 mL of isopropanol were charged and 100 mL of solvent were distilled at reduced pressure. The reaction mixture was cooled to 0-10° C. It was kept 2 hour at 0-10° C. The mixture was filtered and the solid was washed twice with isopropanol (10 mL). The solid was dried under vacuum at 40° C. for 4 hours to obtain 12.4 g of aripiprazole lauroxil of 95.7% purity (analysed by HPLC).

[0062] Three recrystallizations were performed on aripiprazole lauroxil crude using isopropanol as solvent (200 mL). Finally, 10.4 g of aripiprazole (API quality) having a purity of 99.8% (analysed by HPLC) was obtained (75% overall yield from compound of formula (II)).

[0063] The HPLC analysis was carried out in the following column and conditions: [0064] Chromatographic column: Gemini C6-phenyl C18 (150×4.6 mm, 3.0 μm); [0065] Column temperature: 40° C.; [0066] Mobile phase: A: Acetonitrile B: Ammonium acetate pH=7.5 [0067] Gradient elution conditions:

[0068] The chromatograph was programmed as follows:

TABLE-US-00002 Time (minutes) Solution A (%) Solution B (%) 0 15 85 5 50 50 18 75 25 25 90 10 35 90 10 35.5 15 85 Post-time: 5 min

[0069] Main peak retention time: around 26.7 min; Sample volume 5 μL; Detection wavelength: 215 nm; running time: 35 min; Test solution: 1 mg/mL, Solvent: Acetonitrile:methanol (1:1); Column flow: 1.5 ml/min.

Example 2. Preparation of Compound of Formula (I) in Toluene

[0070] Toluene 50 mL, 5.2 g of lauric anhydride (13.6 mmol), 5.0 g of compound of formula (II) obtained in step 1 (10.5 mmol) and 0.26 g 4-dimethylaminopyridine (2.1 mmol) were charged into a 250 mL reactor and kept under stirring at room temperature (15-25° C.) for a minimum of 4 hours (until compound of formula (II) in the reaction mixture was s 0.5%). Results: 0% of unreacted starting material compound of formula (II), 10.0% of aripiprazole and 86.0% of aripiprazole lauroxil.

[0071] 45 mL of toluene are distilled under reduced pressure (80° C., 600-700 mbar). 5 mL of solvent was left in the reaction. Then, 110 mL of isopropanol were charged and 90 mL of solvent were distilled at reduced pressure.

[0072] The reaction mixture was cooled to 0-10° C. It was kept 2 hours at 0-10° C. The mixture was filtered and the solid was washed twice with isopropanol (5 mL). The solid was dried under vacuum at 40° C. for 4 hours to obtain 5.6 g of aripiprazole lauroxil of 95.3% purity (analysed by HPLC) (82% yield).

Example 3. Preparation of Compound of Formula (I) in Tetrahydrofuran

[0073] 40 mL of anhydrous THF, 3.5 g of lauric anhydride (9.2 mmol), 4.0 g of compound of formula (II) obtained in step 1 (8.4 mmol) and 0.20 g 4-dimethylaminopyridine (1.7 mmol) were charged into a 250 mL reactor and kept under stirring at room temperature (15-25° C.) for a minimum of 5 hours (until compound of formula (II) in the reaction mixture was s 0.5%). Results: 0% of unreacted compound of formula (II), 10.0% of aripiprazole and 85.6% of aripiprazole lauroxil.

Comparative Example 2. Preparation of Aripiprazole Lauroxil from Compound of Formula (II) and Lauric Anhydride According to U.S. Pat. No. 8,431,576

[0074] 30 mL of anhydrous THF, 5.0 g of compound of formula (II) obtained in step 1 of example 1 (10.45 mmol), 6.08 g of lauric anhydride (15.89 mmol) and 0.137 g of trimethylamine (1.36 mmol) were charged into a 100 mL reactor and kept under stirring for 16 hours. It was performed an HPLC analysis on the reaction mixture. Results: 32.8% of unreacted starting material compound of formula (II), 35.3% of aripiprazole and 26.7% aripiprazole lauroxil.