This application claims priority to Indian patent applications numbered IN 1972/CHE/2015, filed on April 16, 2015 and IN 6463/CHE/2015, filed on Dec 1, 2015.
FIELD OF THE INVENTION:
The present invention relates to a process for the purification of Aripirprazole lauroxil and further relates to process for the preparation of Aripirpazole Lauroxil.
BACKGROUND OF THE INVENTION:
Aripiprazole Lauroxil is chemically known as (7-(4-(4-(2,3-Dichlorophenyl)piperazin-l-yl)butoxy)-2-oxo-3,4-dihydroquinolin-l(2H)-yl)methyl dodecanoate and structurally represented as below:
Aripiprazole Lauroxil is an Antipsychotic drug. It is indicated for the treatment of Schizophrenia.
U.S. patent No. US8431576 disclosed Aripiprazole Lauroxil and/or its geometric isomers, . enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof. This patent also disclosed purification of Aripiprazole Lauroxil by column chromatography.
US 20150274670, US 9126936, US 8536328 discloses process for the preparation of Aripiprazole lauroxil.
The present invention provides an improved process for the preparation of pure Aripiprazole Lauroxil. The present process is simple, cost effective and.avoid use of column chromatography which is otherwise not feasible at Industrial scale.

SUMMARY OF THE INVENTION:
The present invention relates to a process for the purification of Aripirprazole lauroxil comprising the steps of:
a) dissolving Aripirprazole lauroxil in an organic solvent,
b) adding an aqueous inorganic acid,
c) isolating pure Aripiprazole lauroxil.
One aspect of the present disclosure relates to a process for the preparation of Aripiprazole lauroxil as depicted in the scheme -1 below

One another aspect of the present disclosure relates to a process for the preparation of Aripiprazole lauroxil as depicted in the scheme - II below.
Another aspect of the present disclosure relates to a process for the preparation of Aripirprazole lauroxil as depicted in the scheme - III below.

Yet another aspect of the present disclosure relates to a process for the preparation of Aripirprazole lauroxil or its pharmaceutically acceptable salts as depicted in the scheme - IV below.
Yet another aspect of the present disclosure relates to novel intermediates of Aripirprazole lauroxil selected from

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a process for the purification of Aripiprazole lauroxil.
In one embodiment, the present invention relates to a process for the purification of aripiprazole lauroxil comprising the steps of:
a) dissolving Aripirprazole lauroxil in an organic solvent,
b) adding an aqueous inorganic acid,
c) isolating pure Aripiprazole lauroxil.
According to the present invention, Aripirprazole lauroxil may be dissolved in an organic solvent selected from cyclohexane, xylene or toluene preferably toluene and added with aqueous inorganic acid selected from hydrochloric acid, nitric acid, sulfuric acid preferably hydrochloric acid. Separating the layers and concentrating the organic layer leaves an oily residue which is taken in an appropriate solvent such as n- heptane, hexanes, 1,4 dioxane preferably n-heptane. The solid obtained may be filtered to get pure aripiprazole lauroxil.
According to the present invention, the aqueous layer containing Aripiprazole acid salt may be neutralized using appropriate base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate and upon extraction with suitable solvent like dichloromethane obtains Aripiprazole, which may be reused.
The process for the preparation of Aripiprazole Lauroxil is schematically represented scheme I as shown below:

In another embodiment, the present invention relates a process for the preparation of Aripiprazole lauroxil or its pharmaceutically acceptable salts comprising the steps of:
a) reacting compound of formula I with aldehyde to get Formula II

b) reacting Formula II with Laurie acid chloride to get compound of the formula III
c) condensing the compound of formula III with 1 -(2,3-dichlorophenyl) piperazine to get Aripiprazole Lauroxil.
According to the present invention, compound of the formula I may be converted to compound of formula II in the presence of formaldehyde, base and a suitable solvent. The base is selected from triethylamine, pyridine or N, N-diisopropylethylamine and solvent is selected from dimethyl formamide, acetone, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran.
According to present invention, Formula II may be reacted with lauric acid chloride in presence of a base and solvent to get compound of the formula III. The base is selected triethylamine, pyridine

orN, N-diisopropylethylamine and solvent is selected from dichloromethane, dichloroethane or chloroform and the like.
According to present invention, compound of the formula III may be reacted with l-(2,3-dichlorophenyl) piperazine in presence of a base to get Aripiprazole Lauroxil. The base is selected from triethylamine, pyridine or N, N-diisopropylethylamine. Optionally an alkali metal iodide selected from the group consisting of sodium iodide, lithium idoide and potassium iodide preferably sodium iodide may be added in this reaction.
In yet another embodiment, the present invention relates to a process for the preparation of Aripipraozole lauroxil or a pharmaceutical^ acceptable salt comprising the steps of:
a) converting compound of the formula I into Formula II,
b) reacting Formula II with l-(2,3-dichlorophenyl)piprazine to get compound of the formula IV
c) reacting compound of the formula IV with lauric acid chloride to get Aripiprazole lauroxil

According to the present invention, compound of the formula I may be converted to compound of formula II in the presence of formaldehyde, base and a suitable solvent. The base is selected from triethylamine, pyridine or N, N-diisopropylethylamine and solvent is selected from dimethyl formamide, acetone, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran.
According to present invention, compound of the formula II may be reacted with l-(2,3-dichlorophenyl) piperazine in presence of a base to get compound of formula IV. The base is selected from triethylamine, pyridine or N, N-diisopropylethylamine. Optionally an alkali metal iodide selected from the group consisting of sodium iodide, lithium idoide and potassium iodide preferably sodium iodide may be added in this.reaction.
According to the present invention, compound of the formula IV may be reacted with lauric acid chloride in presence of a base and solvent to get Aripiprazole lauroxil. The base is selected from triethylamine, pyridine or N, N-diisopropylethylamine and solvent is selected1 from dichloromethane, dichloroethane, chloroform.
In yet further embodiment, the present invention relates to. a process for the preparation of Aripipraozole lauroxil or a pharmaceutical^ acceptable salt comprising the steps of:
a) converting Lauric acid chloride into Lauric acid chloromethyl ether
b) reacting Lauric acid chloromethyl ether with formula I to get compound of the formula III

c) reacting compound of the formula III with l-(2,3-dichlorophenyl) piprazine to get Aripiprazole lauroxil
According,to the present invention, lauric acid chloride is converted to lauric acid chloromethyl ether in presence of BF3 complex and paraformaldehyde. The BF3 complex is preferably Boron trifluoride etherate in diethylether.
According to the present embodiment, lauric acid chloromethyl ether may be reacted with . compound of the formula I in presence of a base and solvent to obtain compound of the formula III. The base in this reaction is selected from sodium hydride, triethylamine, pyridine or N, N-diisopropylethylamine and solvent is selected from dichloromethane, dichloroethane, chloroform or mixtures thereof.

According to the present invention, compound of the formula III may be reacted with l-(2,3-dichlorophenyl) piperazine in the presence of alkali metal iodide and a base to get Aripiprazole lauroxil. The base in this reaction is selected triethylamine, pyridine or N, N-diisopropylethylamine and alkali metal iodide is selected from sodium iodide, lithium idoide and potassium iodide.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in anyway.
EXAMPLES Synthetic process:
Stage-I: Preparation of 7-(4-(4-(2v3-Dichlorophenyl)Piperazine-l-YL)Butoxy)-l-(Hydroxymethyl)-3,4-Dydro-quinolin-2(lH)-one (Hemiaminal) :
A mixture of Aripiprazole (20g, 45mmol), triethylamine (1ml, 7.1 mmol), formaldehyde (37% aqueous solution, 70mL) and dimethylformamide (200mL) was heated to 80°C for 20-24hours. The reaction mixture was cooled and diluted with ethyl acetate (400mL) and washed the organic layer with water/brine (1; 1 3X500 mL). The separated organic layer was dried over sodium sulphate, filtered and evaporated to dryness under vacuum to get hemi-aminal as a white solid (Yield: 18.6g containing -70-75% hemi-aminal &25-30 % Aripiprazole, 65% Yield based hemi¬aminal)
Stage-II: Preparation of 7-(4-(4-(2, 3-dichlorophenyl) Piperazine-1-yl) butoxy)-2-oxo-3,4-dihydroquinolin-l(2H)-yl)methyl dodecanoate :
Step I: Thionyl chloride (7.12g,- 59.9 mmol) and catalytic amount of N,N-dimethylformamide (DMF,0.1 mL) was added to a solution of Laurie acid (10 g, 49.9 mmol) in dichloromethane (DCM, 100 mL) at 5-10°C. Heated the reaction solution to 25-30°C temperature and maintained for 3 hours under nitrogen atmosphere. On completion of reaction, the volatiles were evaporated under reduced pressure below 40°C to obtain a viscous liquid material, lauric acid chloride (about 10.9
g)-
Step II: To a suspension of hemiaminal obtained from stage-I (20g, .41.8 mmol ) in dichloromethane (lOOmL) was added triethylamine (7.03 mL, 50 mmol) and Lauric acid chloride

(10.97g , 50.13 mmol) solution in dichloromethane (40 mL ) over 15 min at a temperature of about 5-10°C under nitrogen atmosphere. The reaction mixture was stirred at 5-10°C for 1 hour, . further stirred at 25-30°C for 3- 4 hours. Water (200 mL) was added under stirring and separated the dichloromethane layer. Aqueous layer was washed with dichloromethane (100ml). Combined organic layer was washed with water (200ml and dried over sodium sulphate, filtered and evaporated. To the oily residual mass charged n-Heptane (50ml) and stirred for 30 min. Solid obtained was filtered and dried under vacuum wt.: 24 g (crude, containing unreacted Aripiprazole from step-I)
Purification:
Charged crude solid (20.5 g) obtained from stage II and toluene (300 mL) and stirred for 15 min. Added 5% V/V dil. HC1 (200 mL, 10 vol) and stirred for 30 min. Separated organic and aqueous layers. Organic layer was stirred with 2.5% V/V dil. HC1 (200 mL, lOvol) for 30 min and separated the organic layer stirred with water (200ml X 3) for 1 hour. Combined aqueous layer was washed with toluene (100ml X2) for 1 hour. Combined organic layer was stirred with 2.5 % dil. HC1 (200 mL) for 30 min. Separated organic layer was washed with water (200 ml x3) for 30min. Combined organic layers were dried over sodium sulphate, filtered and evaporated under vacuum at 50-55°C. Charged n-heptane (50 mL) and stirred fori hour to get solid. Filtered the solid and dried at 50-. 55°C under vacuum. Dry wt. 12 g.
Recovery of Aripiprazole: Aqueous layer basified by carbonate and recovered unreacted Aripiprazole and which can be reused (~60-65 % recovery of Aripiprazole).

We Claim: ?
1. A process for the purification of aripiprazole lauroxil comprising the steps of:
a) dissolving Aripirprazole lauroxil in an organic solvent,
b) adding an aqueous inorganic acid,
c) isolating pure Aripiprazole lauroxil.
2. The process of claim 1, wherein organic solvent selected from cyclohexane, xylene or toluene
or mixtures thereof.
3. The process of claim 1, wherein the organic solvent is toluene.
4. The process of claim 1, wherein inorganic acid selected from hydrochloric acid, nitric acid,
Sulfuric.
5. The process of claim 1, wherein the inorganic acid is hydrochloric acid.
6. Compound of formula