Title of the Invention
Improved process for the preparation of Aripiprazole Lauroxil.
Field of the invention
The present invention relates to an improved process for the preparation of Aripiprazole Lauroxil of formula
(D.
The present invention also relates to an improved process for the purification of Aripiprazole Lauroxil of formula (I).
Background of the Invention
Aripiprazole Lauroxil (ARISTADA®) is a prodrug of Aripiprazole. The chemical name of Aripiprazole Lauroxil is 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l-yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate. The empirical formula is CjsHsiCrcNjQiand its molecular weight is 660.7 g/mol. The chemical structure is:

Aripiprazole Lauroxil is available as an extended-release injectable suspension and is a long-acting atypical antipsychotic that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia. Aripiprazole Lauroxil is available in three dose strengths with once-monthly dosing and a six-week dosing option.
Aripiprazole Lauroxil was first described and claimed in US 8,431,576. This patent describes a specific method for producing Aripiprazole Lauroxil by the reaction of Aripiprazole of formula (2) with formaldehyde in the presence of triethylamine and dimethylformamide to give N-hydroxymethyl aripiprazole of formula

(3), which is then reacted with Laurie anhydride in tetrahydrofuran to give crude Aripiprazole Lauroxil of formula (1-1), followed by purification using chromatography to obtain pure Aripiprazole Lauroxil of formula (I). The above process is shown in the scheme - 1 given below:

In Step-I: Conversion of Aripiprazole to N-hydroxymethyl Aripiprazole in the presence of formaldehyde and
triethyl amine, which results 65 % of N-hydroxymethyl aripiprazole and 25 % of Aripirpazole. Therefore,
there is a need of increasing yield of N-hydroxymethyl aripiprazole and less amount of Aripiprazole. Triethyl
amine is used, which is not environmental friendly. Therefore, there is a need of using environmental friendly
base.
In Step-II: Laurie anhydride is used for conversion of N-hydroxymethyl aripiprazole to Aripiprazole lauroxil,
which is very expensive. Therefore, there is a need of using cheaper reagent.
In Step-IIl: column chromatography is used for the purification of Aripiprazole lauroxil, which is not feasible
for commercial scale.
Hence, there is a need for an improved process for the preparation of Aripiprazole Lauroxil; which is simple, eco-friendly, inexpensive, reproducible and well suited for commercial scale.
Summary of the Invention
In one aspect, the present invention provides an improved process for the preparation of crude Aripiprazole Lauroxil of formula (1-1)


which comprises: i) reacting Aripiprazole of formula (2)

with formaldehyde and 4-dimethylaminopyridine in the presence of organic solvent to give N-hydroxym ethyl
Aripiprazole of formula (3);
D ii) reacting N-hydroxvmethvl Aripiprazole of formula (3)
D
i
5
I
5
^ with Laurie acid in the presence of base, solvent and pivaloyl chloride to obtain crude Aripiprazole lauroxil
■| of formula (1-1).
1)
f In another aspect, the present invention provides an improved process for the preparation of pure Aripiprazole
? Lauroxil of formula (I).
r >
r •>
•> j
4 ) >
which comprises:
J i) reacting Aripiprazole of formula (2)
I


with formaldehyde and 4-dimethylaminopyridine in the presence of organic solvent to give N-hydroxymethyl Aripiprazole of formula f3V
ii) reacting N-hydroxymethyl Aripiprazole of formula (3) with Laurie acid in the presence of base, solvent and pivaloyl chloride to obtain crude Aripiprazole Lauroxil of formula (1-1);

iii) purifying crude Aripiprazole Lauroxil of formula (1-1) with organic solvent or mixture of organic solvents to obtain pure Aripiprazole Lauroxil of formula (I).
In another aspect, the present invention provides Aripiprazole Lauroxil of formula (I) is free from impurities of formulae (4);
wherein, n=l, 2,4 &. J
In further aspect, the present invention provides a pharmaceutical composition comprising:

(a) Aripiprazole Lauroxil of formula (I) having purity greater than 99.8 %.

(b) sorbitan laurate;
(c) polysorbate 20; and
(d) an aqueous vehicle
wherein, the composition forms an aqueous, flocculated, injectable composition.
Detailed description of the Invention
The main embodiment of present invention provides an improved process for the preparation of pure Aripiprazole Lauroxil of formula (I) as shown in the Scheme - 2 given below;

Step 1:
Reacting Aripiprazole of formula (2) with formaldehyde and 4-dimethylaminopyridine in the presence of organic solvent to give N-hydroxymethyl Aripiprazole of formula (3);
The solvent used is selected from the group consisting of dimethylformamide, dimethylacetamide, 1,4-dioxane, dimethylsulfoxide, lutidine or pyridine. Preferably, the solvent used is dimethylformamide. The

reaction temperature may range from 20 °C to 40 °C and preferably at 25 °C to 35 °C. The duration of the
reaction may range from 5 hours to 7 hours, preferably for a period of 6 hours.
Step 2:
Reacting N-hydroxymethyl Aripiprazole of formula (3) with Laurie acid in the presence of base, solvent and
pivaloyl chloride to give crude Aripiprazole Lauroxil of formula (1-1);
The base used is selected from the group consisting of triethylamine, pyridine, diisopropylethylamine,
potassium hydroxide, l,8-Diazabicycloundec-7-ene (DBU) or 4-dimethylamino pyridine and mixture
thereof. Preferably, the base used is mixture of triethylamine and 4-dimethylaminopyridine. The solvent used
is selected from the group consisting of dichloromethane, dimethylformamide, chloroform, 1,4-dioxane,
dimethylsulfoxide, lutidine or pyridine. Preferably, the solvent used is dichloromethane. The reaction
temperature may range from 20 °C to 40 °C and preferably at a temperature of 25 °C to 35 °C. The duration
of the reaction may range from 4 hours to 6 hours, preferably for a period of 5 hours.
Step 3:
Purifying crude Aripiprazole Lauroxil of formula (1-1) with organic solvent or mixture of organic solvents
to obtain pure Aripiprazole Lauroxil of formula (I).
The organic solvent or mixture of organic solvents are selected from the group consisting of acetone,
propanone, butanone, methanol, ethanol, propanol, isopropanol, butanol, toluene, dimethyl formamide
(DMF), dimethyl sulfoxide (DMSO), ethyl acetate or hexane. Preferably, the solvent used is dimethyl
sulfoxide (DMSO).
In another embodiment, the present invention provides an improved process for the preparation of crude Aripiprazole Lauroxil of formula (1-1)

which comprises: i) reacting N-hydroxymethyl Aripiprazole of formula (3)


with Laurie acid in the presence of base, solvent and pivaloyl chloride to obtain crude Aripiprazole Lauroxil of formula (1-1).
In another embodiment, the present invention provides an improved process for the preparation of pure Aripiprazole Lauroxil of formula (I) from crude Aripiprazole Lauroxil of formula (1-1)

which comprises:
purifying crude Aripiprazole Lauroxil of formula (1-1) with organic solvent or mixture of organic solvents
to obtain pure Aripiprazole Lauroxil of formula (I).
In another embodiment, the present invention provides an improved process for the preparation of pure
Aripiprazole Lauroxil of formula (I)
which comprises:
i) reacting Aripiprazole of formula (2)


with formaldehyde and 4-dimethylaminopyridine in the presence of dimethyl form amide to give N-hydroxymethyl Aripiprazole of formula (3);

ii) reacting N-hydroxymethyl Aripiprazole of formula (3) with Laurie acid in dlchloromethane in the presence of triethylamine, 4-dimethylaminopyridine and pivaloyl chloride to obtain crude Aripiprazole Lauroxil of formula (1-1);
iii) purifying crude Aripiprazole Lauroxil of formula (1-1) with dimethyl sulfoxide (DMSO) to obtain pure Aripiprazole Lauroxil of formula (I).
In further embodiment, alternative process for preparation of Aripiprazole Lauroxil of formula (I) is shown

Reaction of compound of formula (5) with 1,4-dichlororbutane to give compound of formula (6)} followed by hydroxyl methylation using aldehyde or ketone to give compound of formula (7), which on further

coupling with compound of formula (8) to give compound of formula (9), followed by reaction with Laurie acid in presence of base and solvent to give Aripiprazole Lauroxil of formula (I).
In further embodiment, another alternative process for preparation of Aripiprazole Lauroxil of formula (I) is shown Scheme - 4 given below:
Reaction of compound of formula (10) with Laurie acid in presence of base and solvent to give compound of formula (11), followed by coupling with compound of formula (12) to obtain Aripiprazole Lauroxil of formula (I).
In further embodiment, another alternative process for preparation of Aripiprazole Lauroxil of formula (I) is
shown Scheme - 5 given below: • ...


Reaction of compound of formula (13) with Laurie acid in presence base, solvent and aldehyde or ketone to give compound of formula (14), followed by deprotection to give compound of formula (15), which on further coupling with compound of formula (16) to obtain compound of formula (I).
Exam pie-1: Preparation of pure Laurie acid
Commercially obtained Laurie acid was purified by using heptane, to control homologues acids with specifications limit less than 0.10 %. Purity: > 99.7 %.
Example-2: Preparation of 7-(4-(4-(2, 3-dichlorophenyl) piperazin-1-yl) butoxide)-2-oxo-3, 4-
dihydroquinolin-l(2H)-yl) methyl dodecanoate (Aripiprazole Lauroxil)
Step 1: Preparation of 7-(4-(4-(2, 3-dichtorophenyl) piperazin-1-yl) butoxy)-l-(hydroxymethyl)-3, 4-
dihydroquinolin-2(lH)-one.
To the round bottom flask, charge Aripiprazole (100 grams, 223 m mole), dimethylformamide (DMF) (500 mL), formaldehyde (37 % aqueous solution, 400 mL), 4-dimethylaminopyridine (5.4 grams, 44,64 mmol). The mixture was stirred at 25-35 °C for 6-10 hours. Slowly add 500 mL of water to the reaction mixture and filtered, dried under oven to give 7-(4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butoxy)-l-(hydroxymethyl)-3,4-dihydroquinolin-2(lH)-one as a white solid. Yield: 87%; Purity: 92%.
H1 NMR(CDCh): 8 1.57-1.79 (m, 4H), 2.37-2.42 (m, 2H), 2.48-2.55 (m, 5H), 2.71-2.76 (m, 2H), 2.78-2.98 (m, 5H), 3.87-3.94 (t, 2H), 5.22-5.32 (d, 2H), 5.86 (bs,lH), 6.39-6.48 (m, 1H), 6.85-6.97 (m, 3H), 7.06-7.13 (d, 2H).
Step 2: Preparation of 7-(4-(4-(2, 3-dichlorophenyl) piperazin-1-yl) butoxide)-2-oxo-3, 4-dihydroquinolin-l(2H)-yl) methyl dodecanoate.
To a solution of Step-1 compound (50 grams, 104 mmol), charge Laurie acid (25.0 grams, 125 mmol) in dichloromethane (500 mL), triethylamine (17 grams, 167 mmol), 4-dimethylaminopyridine (2.5 grams, 20 mmol) and pivaloyl chloride (18.8 grams, 156 mmol). The reaction mixture was stirred for 5 hours at 25-30 °C. The crude reaction mixture was washed with water (250 mL) followed by 10 % sodium bi carbonate solution (200 mL), upon solvent evaporation under vacuum provided crude oil which on stirring with methanol (150 mL) results crude title compound as white solid (53 grams) which was further purified by using dimethyl sulfoxide (DMSO) to obtain pure compound as a white solid. Yield: 72%; Purity: > 99 % H1 NMR (CDCb): 5 0.88 (t, 3H), 1.25 (m, 20H), 1.64 (m, 2H), 1.72 (m, 2H), 1.84 (m,2H), 2.36 (t,2H), 2.49 (t, 2H), 2.68 (m, 6H), 2.86 (dd,2H), 3.08 (m, 4H), 3.97 (t,2H), 5.92 (brs, 2H), 6.59 (dd.lH), 6.60 (s, 1H), 6.96 (dd,lH), 7.07 (d, 1H), 7.14 (m,.2H).

Advantages of the invention:
1. The process of the present invention is simple and employs the use of readily available starting material thereby making the process economical and industrially viable.
2. The process involves the use of commercially available and cheaper reagents like Laurie acid unlike the use of the expensive reagents like Laurie anhydride used in prior art patent.
3. The process of the present invention avoids the use of lengthy column chromatography and involves the purification by crystallization techniques."" 7001363/^
We claim:
l. An improved process for the preparation of pure Aripiprazole Lauroxil of formula (I)

which comprises;
i) reacting Aripiprazole of formula (2)

with formaldehyde and 4-dimethylaminopyridine in the presence of organic solvent, to give N-
hydroxymethyl Aripiprazole of formula (3);
ii) reacting N-hydroxymethyl Aripiprazole of formula (3)

with Laurie acid in the presence of base, solvent and pivaloyl chloride to obtain crude Aripiprazole Lauroxil of formula (1-1);
iii) purifying crude Aripiprazole lauroxil of formula (1-1) with organic solvent or mixture of organic solvents to obtain pure Aripiprazole lauroxil of formula (I).

2. The.process as claimed in claim 1, wherein Laurie acid used in the preparation of crude Aripiprazole Lauroxil having purity greater than 99.7% and pure Aripiprazole Lauroxil obtained from crude Aripiprazole Lauroxil having purity greater than 99.8 %.
3. The process as claimed in claim 1, wherein said Aripirpazole Lauroxil of formula (I) prepared by the process of the present invention is free from impurities of formulae (4),

wherein, n=l,2, 4&5
4. The process as claimed in claim I, wherein,
In step i) the solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, 1,4-dioxane, dimethylsulfoxide, lutidine or pyridine;
' In step ii) the base is selected from the group consisting of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, potassium hydroxide, l,8-Diazabicycloundec-7-ene, pyridine or their mixtures; the solvent is selected from the group consisting of dichloromethane, trichloromethane, dimethylformamide, 1,4-dioxane, dimethylsulfoxide, lutidine or chloroform;
In step iii) the solvent is selected from the group consisting of acetone, propanone, butanone, methanol, ethanol, propanol, isopropanol, butanol, dimethyl formamide, dimethyl sulfoxide, ethyl acetate, hexane or their mixtures.

5. The process as claimed in claim 1, wherein crude Aripiprazole Lauroxil of formula (1-1) is formed by
reacting hydroxymethyl aripiprazole of formula (3)

with Laurie acid in the presence of base, solvent and pivaloyl chloride.
6. The process as claimed in claim 5, wherein, solvent used in the reaction is dichloromethane and base used in the reaction is mixture of triethylamine and 4-d i methyl am inopyri dine.
7. A pharmaceutical composition comprising:
(a) Aripiprazole Lauroxil of formula (I) having purity greater than 99.8 %

(b) sorbitan laurate;
(c) polysorbate 20; and
(d) an aqueous vehicle
wherein the composition forms an aqueous, flocculated, injectable composition.
8. The process as claimed in claim I, wherein purification of crude Aripiprazole Lauroxil of formula (1-1)
with organic solvent or mixture of organic solvents to obtain pure Aripiprazole Lauroxil of formula (I);


9. The process as claimed in claim 8, wherein organic solvent is dimethyl sulfoxide.
10. The process for the preparation of Aripiprazole Lauroxil of the formula (I) as claimed in claim I- is
substantially as herein described with reference to the Example 1.