DESC:FIELD OF INVENTION:

The present invention relates to an improved process for the preparation of Brexpiprazole and its pharmaceutically acceptable salt.

The present invention further relates to a process for purification of Brexpiprazole to reduce or eliminate all known and unknown impurities.

BACKGROUND OF THE INVENTION:

The compound 7-(4-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one commonly known as Brexpiprazole represented below as the compound of formula I, is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM). Brexpiprazole differs from the other available D2 partial agonist, as it is more potent at serotonin 5-HT1A and 5-HT2A recep¬tors and displays less intrinsic activity at D2 receptors, which could mean better tolerability.

Formula I
Brexpiprazole is a once-daily, second-generation (atypical) oral antipsychotic that was discovered by Otsuka and co-developed by Otsuka and Lundbeck. It is marketed by Otsuka under the trade name Rexulti? in U.S. for the treatment of Acute Schizophrenia.

Brexpiprazole and its pharmaceutical acceptable salts and process for their preparation are described in the patent, US 7,888,362 (“US’362 Patent). The process described in US’362 patent involves reaction of 4-bromobenzo[b]thiophene with anhydrous piperazine in presence of reagents sodium tert-butoxide, (R)-(+)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP), tris(dibenzylideneacetone)dipalladium(0), in toluene solvent to give 1-(benzo[b]thiophen-4-yl)piperazine, which is treated with concentrated hydrochloric acid in methanol to isolate the hydrochloride salt of 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride compound of formula II. The hydrochloride salt of formula II is reacted with 7-(4-chlorobutoxy)-1H-quinolin-2-one compound of formula III in presence of base potassium carbonate, reagent sodium iodide in dimethylformamide solvent at 80°C to get crude 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole).

The crude compound was purified by silica gel column chromatography using eluent (MDC:MeOH = 100:3) and recrystallized from ethanol, to get pure compound 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole) of formula I. The reaction is schematically represented in the following scheme I;

Scheme I
The drawback of the process described in the patent US’362 is the formation of impurities during the reaction which affects the yield and purity of the compound of formula I. To get rid of the impurities formed during the process column chromatographic purification is carried out at intermediate stage as well as at final stage followed by recrystallisation of the crude compound from solvent ethanol to get pure Brexpiprazole. It is not possible to carry out column chromatographic purification on industrial scale production of Brexpiprazole compound and therefore, it is desired to have chemical purification process especially for large scale production.

Another route of synthesis for the preparation of 4-(1-piperazinyl)benzo[b]thiophene is disclosed in the PCT application WO2013015456 as shown in Scheme II.

Scheme II
wherein X1 is a leaving group; and Pg is a hydrogen atom or a protecting group.

4- (1-Piperazinyl)benzo[b] thiophene is reacted with 7-(4-chlorobutoxy)quinolin-2(1H)-one to obtain Brexpiprazole. The reagents used in this route are relatively expensive; making this route of synthesis is costly, and not suitable for industrial scale up.

Therefore, there remains a need in the art to develop a safe and cost effective process for the preparation of Brexpiprazole compound of formula I by using economical reagents and by controlling the formation of impurities, which makes the process industrially viable and overcomes the problems associated with the processes known in the art. The present invention therefore seeks to address these issues.

The present inventors ameliorates the problems of the prior art processes by using cost effective starting materials, controlling the reaction temperature and formation of impurities, and avoiding the use of column chromatography for the purification of the intermediates and the product Brexpiprazole of formula I.

OBJECTIVES OF THE INVENTION:

The main objective of the present invention is to prepare highly pure compound 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole) of formula I with an industrially useful cost effective process.

Another objective of the present invention is to provide a process for preparation of compound Brexpiprazole of formula I with controlled formation of Impurity.

Yet another objective of the present invention is to provide an efficient process for the purification of Brexpiprazole.

SUMMARY OF THE INVENTION:

Accordingly the present invention provides an improved process for the preparation and purification of compound 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole) of formula I,

Formula I
which process comprises of;
a) oxidising compound 7-hydroxy-3,4-dihydroquinolin-2(1H)-one of formula IV to get compound 7-hydroxyquinolin-2(1H)-one of formula V;

Formula IV Formula V
b) reacting the compound of formula V with 1-bromo-4-chlorobutane in presence of a polar protic solvent to get the compound 7-(4-chlorobutoxy)quinolin-2(1H)-one of formula III;

Formula III
c) reacting the compound of formula III with 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride of formula II

Formula II
in presence of a base and a polar aprotic solvent optionally in presence of a
catalyst to isolate crude compound Brexpiprazole of formula I;
d) suspending the crude Brexpiprazole in a polar protic solvent, said solvent being in an amount sufficient to leach the compound in hot condition followed by isolating the crude compound after cooling; and
e) purifying the crude Brexpiprazole in presence of a single or mixed solvent system to isolate pure Brexpiprazole compound of formula I.

In another aspect, the process according to the present invention provides a purification method which comprises;
i. suspending crude Brexpiprazole in a single or mixed solvent system sufficient to achieve complete dissolution to get clear solution in hot condition;
ii. treating with activated charcoal followed by filtering hot;
iii. stirring and cooling gradually to crystallise out solid completely; and
iv. isolating the pure crystalline Brexpiprazole of formula I.

In yet another aspect, the present invention provides a process for the preparation of Brexpiprazole compound of formula I having the following impurities namely compound of formula A, compound of formula B, compound of formula C, compound of formula D and compound of formula E in less than 0.2%;

Compound A Compound B

Compound C

Compound D Compound E

These and the other objects of the present invention will be apparent from the following detailed description.

DETAILED DESCRITION OF THE INVENTION:

The present invention describes a cost-effective process for preparing Brexpiprazole, the compound of formula I that is substantially devoid of known and unknown impurities.

In an aspect, the present invention provides a process for the preparation of Brexpiprazole compound of formula I, which comprises the steps of;
a) oxidising compound 7-hydroxy-3,4-dihydroquinolin-2(1H)-one of formula IV to get compound 7-hydroxyquinolin-2(1H)-one of formula V;

Formula IV Formula V
b) reacting the compound of formula V with 1-bromo-4-chlorobutane in presence of polar aprotic solvent and a base to get the compound 7-(4-chlorobutoxy)quinolin-2(1H)-one of formula III;

Formula III
c) reacting the compound of formula III with 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride of formula II

Formula II
in presence of a base and a polar aprotic solvent optionally in presence of a
catalyst to isolate crude compound Brexpiprazole of formula I;
d) suspending crude Brexpiprazole in a polar protic solvent, said solvent being in an amount sufficient to leach the compound in hot condition followed by isolating crude compound after cooling; and
e) purifying the compound crude Brexpiprazole in presence of single or mixed solvent system to isolate pure Brexpiprazole compound of formula I.

In an embodiment of the present invention, the oxidation reaction in step (a) is carried out using a reagent selected from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 3,4,5,6-tetrachloro-1,2-benzoquinone (TCQ) in presence of an acid and solvent.

In an embodiment of the present invention, the acid used in the oxidation reaction in step (a) is selected from the group consisting of acetic acid and trifluoroacetic acid.

In an embodiment of the present invention, the solvent used in the oxidation reaction in step (a) is selected from the group consisting of tetrahydrofuran, dichloromethane and N,N-dimethylformamide.

In an embodiment of the present invention, the oxidation reaction of step (a) is carried out at a suitable temperature, preferably at a temperature ranging from 20°C to 80°C.

The compound 7-hydroxyquinolin-2(1H)-one of formula V obtained in step (a) is optionally purified using C1-C4 linear or branched alcohol. The linear or branched alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and secondary butanol.

In another embodiment of the present invention, in the reaction of step (b), the compound 7-hydroxyquinolin-2(1H)-one of formula V, as obtained in the above step (a) is reacted with 1-bromo-4-chlorobutane in the presence of a polar protic solvent and a base to obtain the compound 7-(4-chlorobutoxy)quinolin-2(1H)-one of formula III.

In an embodiment of the present invention, the base used in the reaction of step (b) is selected from the group consisting of potassium carbonate, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine.

In an embodiment of the present invention, the polar aprotic solvent used in the reaction of step (b) is selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide and N,N-dimethylacetamide; or a mixture thereof.

In an embodiment of the present invention, the reaction of step (b) is carried out at a suitable temperature, preferably at a temperature ranging from 20°C to 80°C.

In an embodiment of the present invention, after the completion of reaction, the reaction mass is quenched with mixture of solvents such as cyclohexane and water. The compound 7-(4-chlorobutoxy)quinolin-2(1H)-one of formula III is isolated by filtration. Optionally the compound is purified by using polar solvent selected from methanol, ethanol, isopropanol and n-propanol.

In a further embodiment of the present invention, in the reaction of step (c), the compound 7-(4-chlorobutoxy)quinolin-2(1H)-one of formula III, as obtained in the above step (b) is reacted with 1-(benzo[b]thiophen-4-yl)piperazine free base or its hydrochloride salt of formula II in presence of base and polar aprotic solvent optionally in presence of a catalyst to isolate crude compound Brexpiprazole of formula I.
In an embodiment of the present invention, the base used in the reaction of step (c) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

In an embodiment of the present invention, the solvent used in the reaction of step (c) is polar aprotic solvent selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide and N,N-dimethylacetamide; or a mixture thereof.

In an embodiment of the present invention, the reaction of step (c) is carried out in the presence of a catalyst selected from potassium iodide, sodium iodide, ammonium iodide and tetrabutylammonium iodide.

In an embodiment of the present invention, the reaction of step (c) is carried out at a temperature in the range of 30°C to 80°C.

The compound 1-(benzo[b]thiophen-4-yl)piperazine free base or its hydrochloride salt of formula II used in the present invention in step (c) is readily available commercial compound or can be freshly prepared as per the process disclosed in the prior art.

In an embodiment of the present invention, the step (d) process comprises of suspending crude Brexpiprazole in a polar aprotic solvent, said solvent being in an amount sufficient to leach the compound in hot condition and to isolate crude compound after cooling.

In an embodiment of the present invention, the polar aprotic solvent used in the reaction of step (d) is selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and N,N-dimethylacetamide or a mixture thereof. Further leaching of the crude compound is carried out at temperature in the range of 70°C to 90°C.
In an embodiment of the present invention the purification of crude Brexpiprazole of formula I in step (e) comprises the steps of;
i. suspending crude Brexpiprazole in single or mixed solvent system sufficient to achieve complete dissolution in hot condition;
ii. treating the solution with activated charcoal and filtering hot;
iii. stirring and cooling gradually to crystallise out solid completely; and
iv. isolating the pure crystalline Brexpiprazole of formula I.

The solvent used for the dissolution of crude Brexpiprazole in step (i) is selected from the group of polar and non-polar solvents.

In an embodiment of the present invention the polar solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and butanol where as the non-polar solvent may be selected from the group consisting of chlorobenzene, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, xylene, cyclohexane, hexane and heptane.

In an embodiment of the present invention the charcoalisation in step (ii) is carried out at the temperature in the range of 70°C to 80°C. The reaction mass is filtered hot through hyflow bed and cooled gradually to 20° to 30°C to crystallize out the product followed by isolation by filtration to obtain pure Brexpiprazole compound of formula I.

In an embodiment of the present invention, pure compound brexpiprazole of Formula I is optionally further purified by leaching using the solvents may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and butanol.

In another aspect, the present invention provides a process for the preparation of Brexpiprazole compound of formula I that is devoid of the impurities of compound of formula A, compound of formula B, compound of formula C, compound of formula D and compound of formula E, which otherwise normally formed during the process.

Compound A Compound B

Compound C

Compound D Compound E

Further according to the present invention the compound Brexpiprazole prepared as per the process having less than 0.2% of individual impurities such as compound of formula A, compound of formula B, compound of formula C, compound of formula D and compound of formula E.

The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.

Examples:

Example 1: Synthesis of 7-hydroxyquinolin-2(1H)-one
7-Hydroxy-3,4-dihydroquinolin-2(1H)-one (200 gm, 1.2257 mole) was added to dichloromethane (2.0 lit) and acetic acid (147 gm, 2.45 mole), which was stirred to form a solution. DDQ (334 gm, 1.47 mole) was added and stirred at 25-30°C and the reaction was monitored on HPLC. After 8 hrs, the reaction was completed, and the reaction mass was quenched with water (1.0 lit) and the product was isolated by filtration. The wet cake was leached in methanol (2.0 lit) to obtain pure 7-hydroxyquinolin-2(1H)-one (173 gm, 87.58%).

Example 2: Synthesis of 7-(4-Chlorobutoxy)quinolin-2(1H)-one
7-Hydroxyquinolin-2(1H)-one (100 gm, 0.6205 mole) was dissolved in N,N-dimethylacetamide (1.0 lit), then added water (15 ml, 15% w/v) and potassium carbonate (175.5 gm, 1.2409 mole) at 25-30°C, stirred for 15 min. Then added 1-bromo-4-chlorobutane (319.16 gm, 1.8614 mole) to the reaction mass and stirred for 5-6 hrs at 25-30°C, and the reaction was monitored on HPLC. After the reaction was completed, the reaction mass was quenched with water (3.0 lit) and cyclohexane (300 ml). The solid was isolated by filtration and recrystallised in methanol (700 ml) to obtain 7-(4-chlorobutoxy)quinolin-2(1H)-one (122.6 gm, 78.37%).

Example 3: Synthesis of 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride
A mixture of 4-bromobenzo[b]thiophene (50 gm, 0.235 mole), piperazine anhydride (101.09 gm, 1.173 mole), sodium tert-butoxide (31.82 gm, 0.3309 mole), BINAP (1.0 gm, 0.0016 mole), tris(dibenzylideneacetone)dipalladium(0) (1.0 gm, 0.00109 mole) and toluene (500 ml) was refluxed for 1 hour under nitrogen atmosphere, and the reaction was monitored on HPLC. After the reaction completed, the reaction mass was cooled to 25-30°C and the reaction mass was quenched with water (150 ml), which was extracted with ethyl acetate (100 ml), solvent was evaporated under reduced pressure. The product was isolated by preparing hydrochloride salt by treating with HCl in methanol (250 ml) to obtain 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (54.5 gm, 79.79%).

Example 4: Synthesis of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (Brexpiprazole)
7-(4-Chlorobutoxy)quinolin-2(1H)-one (50 gm, 0.199 mole), 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (50.7 gm, 0.199 mole), potassium carbonate (61.89 gm, 0.4478 mole), sodium iodide (32.80 gm, 0.219 mole) and N,N-dimethylformamide (500 ml) was stirred for 2-3 hrs at 75-80°C, and the reaction was monitored on HPLC. After the reaction was completed, the reaction mass was quenched with water at 70-75°C, then the reaction mass was cooled to room temperature. The product was isolated by filtration and then wet cake of product was leached into N,N-dimethylformamide (150 ml) at 80-85°C for 2 hrs, cooled the reaction mass to 20°C to 30°C and filtered the solid to obtain crude 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (70 gm, 69.68%).
Purification of crude 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (Brexpiprazole)
7-(4-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (100 gm, 0.2306 mole) and toluene (500 ml) was heated to 75-80°C. Added methanol (100 ml) to form a clear solution and then charged activated charcoal, stirred for 30 min under this condition. Charcoal was filtered through Hyflo bed, the reaction mass was cooled gradually to 25-30°C, and the solid was filtered to obtain pure Brexpiprazole (75 gm, 75.0%).
,CLAIMS:1. A process for the preparation and purification of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole) of formula I,

Formula I
which process comprises of;
a) oxidising compound 7-hydroxy-3,4-dihydroquinolin-2(1H)-one of formula IV to get compound 7-hydroxyquinolin-2(1H)-one of formula V using a reagent selected from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 3,4,5,6-tetrachloro-1,2-benzoquinone (TCQ) in presence of an acid and solvent at a temperature ranging from 20° to 80°C;

Formula IV Formula V
b) reacting the compound of formula V with 1-bromo-4-chlorobutane in presence of a polar protic solvent and a base to get the compound 7-(4-chlorobutoxy)quinolin-2(1H)-one of formula III;

Formula III
c) reacting the compound of formula III with 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride of formula II

Formula II
in presence of a base and a polar aprotic solvent optionally in presence of catalyst to isolate crude compound Brexpiprazole of formula I;
d) suspending the crude Brexpiprazole in a polar protic solvent, said solvent being in an amount sufficient to leach the compound in hot condition followed by isolating the crude compound after cooling; and
e) purifying the crude Brexpiprazole in presence of a single or mixed solvent system to isolate pure Brexpiprazole compound of formula I.
2. The process as claimed in claim 1, wherein the acid used in step (a) is selected from the group consisting of acetic acid and trifluoroacetic acid and the solvent is selected from the group consisting of tetrahydrofuran, dichloromethane and N,N-dimethylformamide.
3. The process as claimed in claim 1, wherein the base used in the reaction step (b) and the reaction step (c) is selected from the group consisting of potassium carbonate, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine and the polar aprotic solvent is selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide and N,N-dimethylacetamide or a mixture thereof.
4. The process as claimed in claim 1, wherein the reaction of step (c) is carried out in the presence of a catalyst selected from potassium iodide, sodium iodide, ammonium iodide and tetrabutylammonium iodide at a temperature in the range of 30°C to 80°C.

5. The process as claimed in claim 1, wherein the polar aprotic solvent used in the reaction of step (d) is selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and N,N-dimethylacetamide or a mixture thereof and the leaching of the crude compound is carried out at temperature in the range of 70°C to 90°C.
6. The process as claimed in claim 1, wherein the purification method of step e) comprises;
i. suspending crude Brexpiprazole in a single or mixed solvent system sufficient to achieve complete dissolution to get clear solution in hot condition;
ii. treating with activated charcoal followed by filtering hot;
iii. stirring and cooling gradually to crystallise out solid completely; and
iv. isolating the pure crystalline Brexpiprazole of formula I.
7. The process as claimed in claim 6, wherein the solvent used for the dissolution of crude Brexpiprazole in step (i) is a polar solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and butanol and a non-polar solvent selected from the group consisting of chlorobenzene, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, xylene, cyclohexane, hexane and heptane.
8. The process as claimed in claim 6, wherein the charcoalisation in step (ii) is carried out at the temperature in the range of 70°C to 80°C.
9. The process as claimed in claim 6, wherein the reaction mass is cooled gradually to 20° to 30°C to obtain the crystalline Brexpiprazole of formula I.
10. The process as claimed in any one of the preceding claims, wherein the Brexpiprazole prepared as per the process having less than 0.2% of individual impurities such as compound of formula A, compound of formula B, compound of formula C, compound of formula D and compound of formula E.

Compound A Compound B

Compound C

Compound D Compound E