Process for the preparation of aripiprazole lauroxil

Abstract

A process for the preparation of aripiprazole lauroxyl is provided, which comprises reacting 1-(hydroxymethyl)aripiprazole with lauric anhydride in the presence of DMAP and a solvent. [Formula 1] JPEG2022543990000016.jpg49162

Description

Technical Field

[0001] This application claims the benefit of European Patent Application No. EP19382592.4, filed on July 12, 2019.

[0002] The present invention relates to an improved process for the preparation of aripiprazole lauroxil.

Background Art

[0003] Aripiprazole lauroxil is the common name of the compound 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate, and its chemical structure is as follows:

Chemical Formula

[0004] 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate was first disclosed in US8431576.

[0005] US8431576 discloses a process for the preparation of aripiprazole lauroxil in two synthetic steps from aripiprazole, which has a low yield and lower purity.

[0006] Aripiprazole is reacted with formaldehyde in the presence of triethylamine and dimethylformamide to obtain 1-hydroxymethylaripiprazole of formula (II). By the conversion of aripiprazole to 1-hydroxymethylaripiprazole in the presence of formaldehyde and triethylamine, 65% of 1-hydroxymethylaripiprazole and 25% of aripiprazole are obtained. Subsequently, 1-hydroxymethylaripiprazole of formula (II) is reacted with lauric anhydride in tetrahydrofuran in the presence of triethylamine to obtain a crude compound of formula (I), which is then purified using chromatography to obtain pure aripiprazole lauroxil. The desired product was isolated as a crystalline solid in 21% yield. The overall yield of aripiprazole lauroxil from aripiprazole was 13.7%.

[0007] [Chemical formula]

[0008] The inventors filed WO2019020821. This discloses an improved process for the preparation of aripiprazole lauroxil. In Step I, a conversion higher than 77% is obtained when a compound of formula (II) is obtained by reacting aripiprazole with paraformaldehyde (instead of formaldehyde) without water. In Step II, aripiprazole lauroxil is prepared by reacting 1-hydroxymethylaripiprazole of formula (II) with lauric acid, N,N-dicyclohexylcarbodiimide, 4-dimethylaminopyridine in dichloromethane.

[0009] WO2018104953 and WO2018169491 also disclose, among several processes, the preparation of aripiprazole lauroxil from 1-hydroxymethylaripiprazole of formula (II) by reacting it in the presence of lauric acid, N,N-dicyclohexylcarbodiimide and 4-dimethylaminopyridine.

[0010] In the above process, N,N-dicyclohexylurea, which is a by-product in the reaction, needs to be separated from the reaction mixture to isolate crude aripiprazole. Therefore, a filtration step is required in the manufacturing process before the removal of the solvent.

[0011] The solvent is then distilled under reduced pressure and the reaction product is isolated. The inventors have found that a mixture containing aripiprazole lauroxil and N,N-dicyclohexylurea is unstable when heated above 30 °C. This is because the product decomposes into aripiprazole. Therefore, the solvent needs to be evaporated at room temperature and under reduced pressure to avoid such decomposition.

[0012] When the process is carried out on an industrial scale and the solvent used is dichloromethane, distillation of the solvent at atmospheric pressure is always desirable to completely collect it and avoid solvent release into the atmosphere. On the other hand, sometimes it is desirable to crystallize the product from the reaction mixture by partial evaporation of the solvent to a certain amount to obtain an optimal crystallization yield. In an industrial process, the calculation of the remaining solvent in the reaction mixture is carried out by measuring the evaporated solvent. Evaporation of the solvent at atmospheric pressure ensures the total collection of the solvent, and thereby the amount of the collected solvent and, as a result, the remaining amount in the reaction mixture can be accurately measured. This is not possible in the above process.

[0013] Considering the above, there is still a need to find a new process that can prepare aripiprazole lauroxil with good yield and purity, is easy to scale up, and is environmentally friendly. SUMMARY OF THE INVENTION

[0014] The present disclosure provides a novel process for the preparation of aripiprazole lauroxil, which works with good yield and purity, is easy to industrialize, and avoids the release of toxic solvents into the atmosphere.

[0015] The first aspect of the invention relates to a process for the preparation of a compound of formula (I) which is aripiprazole lauroxil [Chemical formula] This process comprises the following steps: a) reacting a compound of formula (II) [Chemical formula] with lauric anhydride in the presence of DMAP and a solvent to obtain aripiprazole lauroxil; and b) optionally, isolating the obtained compound of formula (I).

[0016] The inventors have surprisingly observed that when the compound of formula (I) is prepared by reacting the compound of formula (II) with lauric anhydride in the presence of DMAP instead of triethylamine, a higher conversion is obtained compared to the process described in US8431576. In particular, in Example 12 of US8431576, the preparation of dodecanoic acid (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl is carried out in the same manner as described in Example 11 for the acetate analogue. The desired compound is obtained by reacting compound - A1 in anhydrous tetrahydrofuran with lauric anhydride and heated at 60 °C (oil bath) for 2.0 hours. Then, triethylamine is added to the above solution and stirred at 60 °C for 16 hours. The product is isolated after work-up and purification by silica gel column chromatography. In Example 12, aripiprazole lauroxil is isolated as a crystalline solid with a yield of 21%. By following this example, the conversion of the compound of formula (II) to the compound of formula (I) is only 26.7% as shown in Comparative Example 2. In contrast, using the process of the present invention, as can be seen in Examples 1 - 3 of the present disclosure, a conversion higher than 85% is obtained. The product can be easily isolated after solvent evaporation and crystallization in a suitable solvent.

[0017] Therefore, surprisingly, the inventors have found that, as can be seen from the examples and comparative examples, through the process of the invention, aripiprazole lauroxil can be obtained in good yield and at the same time with high purity. The process is easy to scale up to an industrial level; the product can be obtained simply by evaporating the solvent after the end of the reaction and purifying it, for example, by crystallization. The process avoids the filtration step after the end of the reaction.

BRIEF DESCRIPTION OF THE INVENTION

[0018] All terms used herein in this application shall be understood in their ordinary meaning as known in the art, unless otherwise specified. Other more specific definitions for certain terms used in this application are as specified below, and it is intended that, unless otherwise explicitly set, the definitions shall be uniformly applied throughout the specification and the claims, provided that the broader definitions are not provided.

[0019] In a first aspect of the invention, the process for 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.

[0020] Examples of solvents for carrying out the reaction of the compound of formula (II) with lauric acid include, but are not limited to, toluene, dimethyl sulfoxide (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. In particular, the reaction is carried out in dichloromethane.

[0021] In certain embodiments, optionally, in combination with one or more features of the specific embodiments defined above or below, the solvent is selected from toluene, tetrahydrofuran, and dichloromethane, preferably dichloromethane.

[0022] 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 0.1 - 1% mol relative to the compound of formula (II). More specifically, 0.2 - 0.3% mol relative to the compound of formula (II).

[0023] In another embodiment of the invention, the molar ratio of the compound of formula (II) to lauric anhydride can be 1:1 - 1:3. More specifically, the molar ratio is 1:1.3.

[0024] In another embodiment of the invention, the reaction temperature ranges from 0 °C to the boiling point of the solvent, and even more specifically, it is room temperature. For the purposes of the invention, room temperature is 15 - 25 °C.

[0025] In a first aspect of the invention, the process for preparing aripiprazole lauroxil optionally includes step b) of isolating the product.

[0026] The product obtained in step a) can be isolated by conventional methods. The solvent can be removed directly, and crude aripiprazole lauroxil is obtained.

[0027] The filtration step of separating N,N-dicyclohexylurea from the reaction mixture is not required prior to the removal of the solvent compared to the processes disclosed in the prior art when the reaction is carried out using lauric acid, DCC, and 4-dimethylaminopyridine. The solvent can be removed by standard techniques used in organic chemistry, such as distillation. The solvent is preferably removed by distillation at atmospheric pressure. When a toxic solvent, such as dichloromethane, is removed at atmospheric pressure, the release of volatile substances into the atmosphere is reduced, and they have the advantage that they can be completely collected and recycled.

[0028] Thus, in certain embodiments, optionally, in combination with one or more features of certain embodiments defined above or below, step b) is carried out by distilling the solvent at atmospheric pressure.

[0029] In another particular embodiment, optionally, in combination with one or more features of certain embodiments defined above or below, the solvent is dichloromethane and step b) is carried out by distilling the solvent at atmospheric pressure.

[0030] Using the process of the invention, aripiprazole lauroxil is obtained in high purity and very good yield. In particular, aripiprazole lauroxil having a purity of at least 95% is obtained.

[0031] In addition, the yield from the compound of formula (II) to crude aripiprazole lauroxil is in the range of 80% to 90%.

[0032] Aripiprazole lauroxil having a purity of at least 99.8% HPLC can be obtained by subjecting the crude reaction product to conventional purification techniques or other techniques described in the prior art, such as crystallization, chromatography, or combinations thereof. In particular, the purification is carried out more specifically by crystallization in isopropanol.

[0033] Previously, the compound of formula (II) could be obtained by reacting an 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, and the reaction was carried out either without water or in the presence of a certain amount of water, which was brought about by the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of a hydrated form of aripiprazole, and there was no further addition of water, thus as described in WO2019020821.

[0034] Thus, in certain embodiments, optionally, in combination with one or more features of the specific embodiments defined above or below, the process for preparing aripiprazole lauroxil comprises a compound of formula (II) [Chemical Formula] reacting with a compound of formula (III) which is aripiprazole or its hydrate [Chemical Formula] in the presence of paraformaldehyde, an organic solvent and a suitable base, further comprising the previous step i) for preparation, and the reaction is carried out either without water or in the presence of a certain amount of water, which is brought about by the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of a hydrated form of aripiprazole, and there is no further addition of water.

[0035] Examples of the organic solvent in step i) include, but are not limited to, toluene, ethyl acetate, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), tetrahydrofuran (THF), acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIK), dichloromethane (DCM), acetonitrile (ACN), and mixtures thereof. In particular, the organic solvent is toluene.

[0036] Examples of the base include, but are not 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. In particular, the base is DBU.

[0037] In certain embodiments, as described above, the amount of water present in the reaction mixture containing aripiprazole and paraformaldehyde is 1 wt% or less.

[0038] The reaction can be carried out at a molar ratio of aripiprazole, or its hydrates such as the monohydrate, to paraformaldehyde of 1:1 to 1:3. More specifically, the molar ratio is 1:1:1.7.

[0039] As starting materials, aripiprazole, paraformaldehyde, and lauric anhydride, which are used by themselves or in the form of the monohydrate, 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 (CH2O) n wherein n is an integer from 8 to 100.

[0040] Throughout the description and claims, the word "comprising" and variations of that word are not intended to exclude other technical features, additives, components, or steps. Further, the word "comprising" encompasses the case of "consisting of".

[0041] The following examples are provided by way of example and are not intended to limit the present invention. Further, the present invention encompasses all possible combinations of the specific and preferred embodiments described herein.

[0042] Examples Example 1. Preparation of the 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)

Chemical formula

[0043] The reaction mixture was cooled to T ≤ 5.0 °C and maintained under these conditions for 2 hours. The solid was filtered from the mixture and washed once with 100 mL of cold toluene. The solid was dried in a vacuum oven at 30 °C for 6 hours to obtain 96.9 g of the title compound (94% yield based on aripiprazole (as the monohydrate)). Its purity analyzed by HPLC was 87.6%, which means an 82.3% conversion.

[0044] HPLC analysis was carried out under the following column and conditions: - Chromatographic column: XBridge RP Shield C18 (150 × 3 mm, 3.5 μm); - Column temperature: 40 °C; - Mobile phase: A: 2.3 g K2HPO4·3H2O / 1 L H2O pH = 6.6 H3PO4 10%, B: Acetonitrile - Gradient elution conditions:

[0045] The chromatograph was programmed as follows:

Table 1

[0046] Step 2: Purification of the compound of formula (II) 896 mL of deionized water (10 V), 89.6 g of crude 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one are placed in a 2 L reactor, heated to 18 - 28 °C, and maintained for at least 30 minutes under a nitrogen atmosphere with stirring.

[0047] The solid is filtered from the reaction mixture and washed twice with 270 mL of deionized water. The solid is dried in a vacuum oven at 30 °C for 16 hours. 88.38 g of pure 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one is obtained (98.6% yield from the crude).

[0048] Step 3: Preparation of Aripiprazole Lauroxil (Compound of Formula (I)) in Dichloromethane

Chemical formula

[0049] Dichloromethane is distilled off at atmospheric pressure. 10 mL of the solvent remains in the reaction mixture. Then, 140 mL of isopropanol is added and 100 mL of the solvent is distilled off under reduced pressure. The reaction mixture is cooled to 0 - 10 °C and maintained at 0 - 10 °C for 2 hours. The mixture is filtered and the solid is washed twice with isopropanol (10 mL). The solid is dried under vacuum at 40 °C for 4 hours to obtain 12.4 g of aripiprazole lauroxil with a purity of 95.7% (analyzed by HPLC).

[0050] Three recrystallizations were carried out on crude aripiprazole lauroxil using isopropanol as the solvent (200 mL). Finally, 10.4 g of aripiprazole (API quality) with a purity of 99.8% (analyzed by HPLC) was obtained (75% overall yield from the compound of formula (II)).

[0051] HPLC analysis was performed under the following column and conditions: - Chromatographic column: Gemini C6 - phenyl C18 (150×4.6 mm, 3.0 μm); - Column temperature: 40 °C; - Mobile phase: A: Acetonitrile B: Ammonium acetate pH = 7.5 - Gradient elution conditions:

[0052] The chromatograph was programmed as follows:

Table 2

[0053] Example 2. Preparation of the compound of formula (I) in toluene 50 mL of toluene, 5.2 g of lauric anhydride (13.6 mmol), 5.0 g of the compound of formula (II) obtained in Step 1 (10.5 mmol) and 0.26 g of 4 - dimethylaminopyridine (2.1 mmol) were placed in a 250 mL reactor and maintained at room temperature (15 - 25 °C) with stirring for at least 4 hours (until the compound of formula (II) in the reaction mixture was ≤ 0.5%). Results: 0% of the unreacted starting material compound of formula (II), 10.0% of aripiprazole and 86.0% of aripiprazole lauroxil.

[0054] 45 mL of toluene was distilled under reduced pressure (80 °C, 600 - 700 mbar). 5 mL of the solvent remained in the reaction mixture. Then, 110 mL of isopropanol was added and 90 mL of the solvent was distilled under reduced pressure.

[0055] The reaction mixture was cooled to 0 - 10 °C. This was maintained at 0 - 10 °C for 2 hours. 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 with a purity of 95.3% (analyzed by HPLC) (82% yield).

[0056] Example 3. Preparation of the compound of formula (I) in tetrahydrofuran 40 mL of anhydrous THF, 3.5 g of lauric anhydride (9.2 mmol), 4.0 g of the compound of formula (II) obtained in Step 1 (8.4 mmol), and 0.20 g of 4-dimethylaminopyridine (1.7 mmol) were placed in a 250 mL reactor and maintained at room temperature (15 - 25 °C) with stirring for at least 5 hours (until the compound of formula (II) in the reaction mixture was ≤ 0.5%). Results: 0% unreacted compound of formula (II), 10.0% aripiprazole, and 85.6% aripiprazole lauroxil.

[0057] Comparative Example 2. Preparation of aripiprazole lauroxil from the compound of formula (II) and lauric anhydride according to US8431576 30 mL of anhydrous THF, 5.0 g of the 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 placed in a 100 mL reactor and maintained with stirring for 16 hours. HPLC analysis was performed on the reaction mixture. Results: 32.8% unreacted starting material compound of formula (II), 35.3% aripiprazole, and 26.7% aripiprazole lauroxil.

Claims

1. A process for the preparation of a compound of formula (I) which is aripiprazole lauroxil, comprising the following steps: 【Chemical 1】 The following steps: a) reacting a compound of formula (II) with lauric anhydride in the presence of DMAP and a solvent to obtain aripiprazole lauroxil; and 【Chemical 2】 b) optionally, isolating the obtained compound of formula (I), wherein the solvent is selected from the group consisting of dichloromethane, toluene, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, and mixtures thereof.

2. The process according to claim 1, wherein the solvent is dichloromethane.

3. The process according to claim 1 or 2, wherein the reaction temperature ranges from room temperature to the boiling point of the solvent.

4. The process according to any one of claims 1 to 3, wherein the reaction is carried out at room temperature.

5. The process according to any one of claims 1 to 4, wherein the amount of DMAP used is 0.2 to 0.3% mol based on the compound of formula (II).

6. The process according to any one of claims 1 to 5, wherein the molar ratio of the compound of formula (II) to lauric anhydride is 1:1.

3.

7. The process according to claim 2, wherein step b) is carried out by distilling the solvent at atmospheric pressure.

8. The process according to any one of claims 1 to 7, further comprising a previous step i) for preparing a compound of formula (II) which is aripiprazole or its hydrate by reacting it with paraformaldehyde in the presence of an organic solvent and a suitable base, wherein step i) is carried out either without water or in the presence of a certain amount of water, which is brought about by the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of the hydrated form of aripiprazole, and no further addition of water is made.

9. The process according to claim 8, wherein the organic solvent is selected from the group consisting of toluene, ethyl acetate, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, acetonitrile, and mixtures thereof. 【Chemical Formula 3】

10. ​ 【Chemical 4】 ​ ​ ​ ​ ​ The base is selected from the group consisting 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, the process according to claim 8 or 9.

11. The amount of water in the reaction mixture containing aripiprazole and paraformaldehyde is 1 wt% or less, the process according to any one of claims 8 to 10.

12. Aripiprazole or its hydrate, and paraformaldehyde are present in a molar ratio of 1:1 to 1:3, the process according to any one of claims 8 to 11.

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