Patent Description:
The present invention relates to an improved process for the preparation of aripiprazole lauroxil.

Aripiprazole lauroxil is the generic name of compound <NUM>-[<NUM>-[<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>-piperazinyl]-butoxy]-<NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>-quinolin-1yl)methyl dodecanoate, which chemical structure is:
<CHM>.

Aripiprazole lauroxil is an atypical antipsychotic agent developed by Alkermes under the trade name Aristada® for the treatment of schizophernia.

<NUM>-{<NUM>-[<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>-piperazinyl]butoxy}-<NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>-quinolin-<NUM>-yl)methyl dodecanoate was first disclosed in <CIT>.

<CIT> discloses a process for the preparation of aripiprazole lauroxil in two synthetic steps from aripiprazole with low yields and less purity.

Aripiprazole is reacted with formaldehyde in the presence of triethylamine and dimethylformamide to give <NUM>-hydroxymethyl aripiprazole of formula (II). Conversion of aripiprazole to <NUM>-hydroxymethyl aripiprazole in the presence of formaldehyde and triethyl amine, results <NUM> % of <NUM>-hydroxymethyl aripiprazole and <NUM> % of aripiprazole. Then <NUM>-hydroxymethyl aripiprazole of formula (II) is reacted with lauric anhydride in tetrahydrofuran in the presence of triethylamine to give the crude compound of formula (I), followed by purification using chromatography to obtain pure Aripiprazole lauroxil. The desired product was isolated in <NUM>% yield as a crystalline solid. The overall yield form aripiprazole to aripiprazole lauroxil was <NUM>%.

The present inventors filed <CIT> which discloses an improved process of preparation of aripiprazole lauroxil. In step I, when compound of formula (II) is obtained in the absence of water by reacting aripiprazole with paraformaldehyde (instead of formaldehyde) conversion higher than <NUM>% are obtained. In step II aripiprazole lauroxil is prepared by reacting <NUM>-hydroxymethyl aripiprazole of formula (II) with lauric acid, N,N-dicyclohexylcarbodiimide, <NUM>-dimethylaminopyridine in dichloromethane.

<CIT> and <CIT> also disclose, among other processes the preparation of aripiprazole lauroxil from <NUM>-hydroxymethyl aripiprazole of formula (II) by reacting it with lauric acid in the presence of N,N-dicyclohexylcarbodiimide and <NUM>-dimethylaminopyridine.

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

The solvent is then distilled at reduced pressure to isolate the reaction product. The present inventors have found that mixtures containing aripiprazole lauroxil and N,N-dicyclohexylurea are not stable when heated above <NUM> <NUM>C since the product decomposes to aripiprazole. Therefore, the solvent needs to be evaporated at room temperature and reduced pressure to avoid such degradation.

When a process is carried out at industrial scale and the solvent used is dichloromethane, distillation of the solvent at atmospheric pressure is always desirable to collect it completely and avoid solvent emissions to 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 get an optimum crystallization yield. In an industrial process the calculation of the remaining solvent in the reaction mixture is performed by measuring the evaporated solvent. The evaporation of the solvent at atmospheric pressure ensures the total collection of the solvent, which allows to accurately measure the amount of solvent collected and consequentially the remainder in the reaction mixture. In the process mentioned above this is not possible.

In view of the above, there is still the need of finding new processes that allow preparing aripiprazole lauroxil in good yields and purity, easy to scale-up and which are environmentally friendly.

The present disclosure provides a new process for the preparation of aripiprazole lauroxil which works with good yields and purity, easy to industrialize and which avoids emission of toxic solvents to the atmosphere.

A first aspect of the invention refers to a process for the preparation of a compound of formula (I)
<CHM>
which is aripiprazole lauroxil, which comprises the following steps:.

The inventors have surprisingly observed that when compound of formula (I) is prepared by reacting compound of formula (II) with lauric anhydride in the presence of DMAP, instead of triethylamine, higher conversions are obtained compared with the processes described in <CIT>. Particularly, in Example <NUM> of <CIT> the preparation of (<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichlorophenyl)piperazin-<NUM>-yl)butoxy)-<NUM>-oxo-<NUM>,<NUM>-dihydroquinolin-<NUM> (<NUM>)-yl)methyl dodecanoate is carried out in an analogous fashion as described in Example <NUM> for the acetate analogue. The desired compound is obtained by reacting Compound-A1 in anhydrous tetrahydrofuran with lauric anhydride and heated for <NUM> hours at <NUM> <NUM>C (oil-bath). Then, triethylamine is added to the above solution, and stirred for <NUM> hours at <NUM> <NUM>C. The product is isolated after work-up and purification by silica gel column chromatography. In Example <NUM> aripiprazole lauroxil was isolated as a crystalline solid with <NUM>% yield. By following this example, the conversion of the compound of formula (II) into a compound of formula (I) is only of <NUM>%, as shown in Comparative Example <NUM>. Conversely, with the process of the present invention conversions higher than <NUM>% are obtained, as can be seen in Examples <NUM> to <NUM> of the disclosure. The product can be isolated easily after solvent evaporation and crystallization in a suitable solvent.

Thus, surprisingly, inventors have found that the process of the invention allows obtaining aripiprazole lauroxil with good yields and at the same time with a high purity, as can be seen from the Examples and Comparative Example. The process is easy to scale-up to an industrial level; the product can be obtained after the end of reaction by simply evaporating the solvent and purifying it, for instance by crystallization. The process avoids any filtration step after the end of reaction.

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.

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.

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.

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.

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 <NUM> to <NUM>% molar respect to compound of formula (II). More particularly <NUM> to <NUM>% molar respect to compound of formula (II).

In another embodiment of the invention, the molar ratio of compound of formula (II) to lauric anhydride can be from <NUM>:<NUM> to <NUM>:<NUM>. More particularly the molar ratio is <NUM>:<NUM>.

In another embodiment of the invention, the reaction temperature is in the range of <NUM> 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 <NUM>-<NUM> <NUM>C.

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

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

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 <NUM>-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.

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.

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.

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 <NUM>% is obtained.

Additionally, the yield from compound of formula (II) to crude aripiprazole lauroxil range from <NUM>% to <NUM>%.

Aripiprazole lauroxil with a purity of at least <NUM>% 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.

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 <CIT>.

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)
<CHM>
by reacting a compound of formula (III)
<CHM>
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.

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.

Examples of bases include, without being limited to, <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene, <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]octane, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, and diisopropylethylamine. Particularly, the base is DBU.

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 <NUM> wt%.

The reaction can be carried out with a molar ratio of aripiprazole, or a hydrate thereof such as the monohydrate, to paraformaldehyde of from <NUM>:<NUM> to <NUM>:<NUM>. More particularly the molar ratio is <NUM>:<NUM>:<NUM>.

Aripiprazole used as the starting material as such or in form of a monohydrate, paraformaldehyde, and lauric anhydride are commercially available. Paraformaldehyde (<NPL>), also known as polyoxymethylene, is a polymer of formaldehyde and can be represented by the chemical formula (CH<NUM>O)n, wherein n is an integer from <NUM> to <NUM>.

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".

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.

<NUM> of toluene (5V), <NUM>,<NUM> of aripiprazole (as monohydrate) (<NUM> mmol), <NUM>,<NUM> paraformaldehyde (<NUM> mmol) and <NUM>,<NUM> DBU (<NUM>,<NUM> mmol) were charged into a <NUM> reactor, heated to <NUM>-<NUM> and kept under stirring and nitrogen atmosphere during <NUM> hours (until aripiprazole in the reaction mixture is ≤ <NUM>% HPLC).

The reaction mixture was cooled to T ≤ <NUM> and kept for <NUM> hours at these conditions. The solid was filtered from the mixture, washed once with <NUM> cool toluene. The solid was dried at <NUM> in a vacuum oven for <NUM> hours to obtain <NUM> of the title compound (<NUM>% yield based on aripiprazole (as monohydrate)). Its purity, analyzed by HPLC was <NUM>%, which means a conversion of <NUM>%.

The HPLC analysis was carried out in the following column and conditions:.

- Chromatographic column: XBridge RP Shield C18 (150x3 mm, <NUM>);
- Column temperature: <NUM>;
- Mobile phase: A: <NUM> K<NUM>HPO<NUM> × <NUM><NUM>O / <NUM> H<NUM>O pH = <NUM><NUM>PO<NUM> <NUM>%,
B: Acetonitrile
- Gradient elution conditions:
The chromatograph was programmed as follows:.

<NUM> of deionized water (10V), <NUM>,<NUM> of crude (<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichlorophenyl)piperazin-<NUM>-yl)butoxy)-<NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydroquinolin-<NUM>(<NUM>)-one are charged into a <NUM> reactor, heated to <NUM>-<NUM> and kept under stirring and nitrogen atmosphere during at least <NUM> minutes.

The solid is filtered from the reaction mixture, washed twice with <NUM> deionized water. The solid is dried at <NUM> in a vacuum oven for <NUM> hours. It is obtained <NUM> of pure <NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichlorophenyl)piperazin-<NUM>-yl)butoxy)-<NUM>-(hydroxymethyl)-<NUM>,<NUM>-dihydroquinolin-<NUM>(<NUM>)-one (<NUM> % yield from crude).

Dichloromethane <NUM>, <NUM> of lauric anhydride (<NUM> mmol), <NUM> of compound of formula (II) obtained in step <NUM> or <NUM> (<NUM> mmol) and <NUM> <NUM>-dimethylaminopyridine (<NUM> mmol) were charged into a <NUM> reactor and kept under stirring at room temperature (<NUM>-<NUM>) for a minimum of <NUM> hours (until compound of formula (II) in the reaction mixture was ≤ <NUM>% HPLC). Results: <NUM>% of unreacted starting material compound of formula (II), <NUM>% of aripiprazole and <NUM>% of aripiprazole lauroxil.

Dichloromethane was distilled at atmospheric pressure. <NUM> of solvent were left in the reaction mixture. Then, <NUM> of isopropanol were charged and <NUM> of solvent were distilled at reduced pressure. The reaction mixture was cooled to <NUM>-<NUM>. It was kept <NUM> hour at <NUM>-<NUM>. The mixture was filtered and the solid was washed twice with isopropanol (<NUM>). The solid was dried under vacuum at <NUM> for <NUM> hours to obtain <NUM> of aripiprazole lauroxil of <NUM>% purity (analysed by HPLC).

Three recrystallizations were performed on aripiprazole lauroxil crude using isopropanol as solvent (<NUM>). Finally, <NUM> of aripiprazole (API quality) having a purity of <NUM>% (analysed by HPLC) was obtained (<NUM>% overall yield from compound of formula (II)).

- Chromatographic column: Gemini C6-phenyl C18 (150x4. <NUM>, <NUM>);
- Column temperature: <NUM>;
- Mobile phase: A: Acetonitrile B: Ammonium acetate pH=<NUM>
- Gradient elution conditions:
The chromatograph was programmed as follows:.

Toluene <NUM>, <NUM> of lauric anhydride (<NUM> mmol), <NUM> of compound of formula (II) obtained in step <NUM> (<NUM> mmol) and <NUM> <NUM>-dimethylaminopyridine (<NUM> mmol) were charged into a <NUM> reactor and kept under stirring at room temperature (<NUM>-<NUM>) for a minimum of <NUM> hours (until compound of formula (II) in the reaction mixture was ≤ <NUM>%). Results: <NUM>% of unreacted starting material compound of formula (II), <NUM>% of aripiprazole and <NUM>% of aripiprazole lauroxil.

<NUM> of toluene are distilled under reduced pressure (<NUM>, <NUM>-<NUM> mbar). <NUM> of solvent was left in the reaction. Then, <NUM> of isopropanol were charged and <NUM> of solvent were distilled at reduced pressure.

The reaction mixture was cooled to <NUM>-<NUM>. It was kept <NUM> hours at <NUM>-<NUM>. The mixture was filtered and the solid was washed twice with isopropanol (<NUM>). The solid was dried under vacuum at <NUM> for <NUM> hours to obtain <NUM> of aripiprazole lauroxil of <NUM>% purity (analysed by HPLC) (<NUM>% yield).

<NUM> of anhydrous THF, <NUM> of lauric anhydride (<NUM> mmol), <NUM> of compound of formula (II) obtained in step <NUM> (<NUM> mmol) and <NUM> <NUM>-dimethylaminopyridine (<NUM> mmol) were charged into a <NUM> reactor and kept under stirring at room temperature (<NUM>-<NUM>) for a minimum of <NUM> hours (until compound of formula (II) in the reaction mixture was ≤ <NUM>%). Results: <NUM>% of unreacted compound of formula (II), <NUM>% of aripiprazole and <NUM>% of aripiprazole lauroxil.

Claim 1:
A process for the preparation of a compound of formula (I)
<CHM>
which is aripiprazole lauroxil, which comprises the following steps:
a) reacting a compound of formula (II)
<CHM>
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).