DESC:FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of 7-[4-n(4-benzo[b]nthiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one (Brexpiprazole) of Formula (II). More particularly the present invention provides a process for synthesis of 7-hydroxyquinolin-2(1H)-one compound of formula (I) comprising a step of oxidative dehydrogenation to convert 7-hydroxy-3,4-dihydroquinolin-2(1H)-one compound of formula (IV) to compound of formula I.

BACKGROUND OF THE INVENTION:

Brexpiprazole (II) is a serotonin-dopamine activity modulator (SDAM) for the treatment of schizophrenia and is used as adjunctive therapy for the treatment of clinical depression. Its new drug application (NDA) has recently been approved by the US Food and Drug Administration (FDA) and clinical trials for its application in attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and agitation associated with dementia of the Alzheimer's type are currently underway.

A preparation route of brexpiprazole is disclosed in the PCT application WO2006112464 A1 by Otsuka Pharmaceutical Co., Ltd., the disadvantage of this route is that by-products formed cannot be easily separated, are produced in the first step of the reaction, intermediates with high purity cannot be easily obtained even by column chromatography. Thus process suffered from reduced purity and yield of the final product Brexpiprazole (II).

US Patent 20130137679 disclosed two steps process for synthesis of 7-hydroxyquinolin-2(1H)-one compound of formula (I) where in 3-methoxy aniline is condensed with cinnamoyl chloride followed by cyclization of corresponding anilide in presence of AIC13 in chlorobenzene to yield 7- hydroxyquinolin-2(1H)-one compound of formula (I) in 40% overall yield. Disadvantage of the above process is during the cyclization 5-hydroxyquinolin-2(1H)-one compound of formula (III) is also formed along with 7- hydroxyquinolin-2(1H)-one, even after several crystallization with different solvents and mixture of solvents it could not be reduced to below 1%. This 5-hydroxyquinolin-2(1H)- one compound of formula (III) being a reactive impurity for the Brexpiprazole (II) synthesis, will ends up with corresponding positional isomeric impurity in the Brexpiprazole (II).

There are disadvantages of high-cost, formation of impurities which are hard to separate and eliminate during above preparative method. Thus it is necessary to find a new route which is economic, practically viable and environment benign, so as to improve process stability, reduce the cost and improve the product quality.

Moreover, the content of undesired impurities in the final product is always a cause of concern with respect to Food and Drug Authorities (FDA) requirement. Therefore, it is required to have the undesired impurity content well below the level specified in the International Conference on Harmonization (ICH) guideline as per regulatory authority. Particularly with respect to the known impurity the acceptable limit 0.15%. Therefore it is extremely important to control the level of impurity to comply with the regulatory requirement.

In summary, process disclosed in prior art for the preparation of 7-hydroxyquinolin-2(1H)-one compound of formula (I), are tedious and requires laborious column chromatography. Moreover, 7-hydroxyquinolin-2-(1H)-one compound of formula (I) obtained by prior art process, involves the formation of impurities, which causes low yield and purity.

Therefore, there is a need to develop a process which provides an intermediate of high purity specifically with less content of impurities which is difficult to control as per the method known in the art.

With an objective of reducing the content of impurity from the intermediate, the present inventors has directed the research work towards developing a process for preparing of 7-hydroxyquinolin-2(1H)-one compound of formula (I) having high purity and less impurity.

In the preparation of Brexpiprazole (II), 7-hydroxyquinolin-2(IH)-one (I) is one of the key starting material or key intermediate, and therefore the quality/purity of the 7- hydroxyquinolin-2(1-H)-one compound of formula (I) directly effects the quality of the API.

The present invention is directed to the above drawbacks and the purpose is to provide improved process for the preparation of 7- hydroxyquinolin-2(1H)-one compound of formula (I) which is a mild reaction conditions, simple operation, less expensive & ultimately cost effective outcome.

OBJECTIVE OF THE INVENTION

It is an objective of the invention to provide a process for the preparation of Brexpiprazole (II) comprising a step of oxidative-dehydrogenation of 7-hydroxy-3,4-dihydroquinol in-2(1H)-one compound of formula (IV) to 7-Hydroxyquinolin-2(1H)-one of Formula (I).

Further objective of the present invention is to provide novel process for the preparation of 7-Hydroxyquinolin-2(1H)-one of Formula (I).

A yet another objective of the present invention is to provide an improved process for the preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole) of Formula (II) comprises reacting pure compound of Formula (V)

with 1-Benzo [b] thiophene-4-yl-piperazine dihydrochloride of Formula (VI) or it’s salts

in presence of base and water as solvent, without alkali iodide to produce 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one of Formula (II).

DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to an improved process for the preparation of Brexpiprazole (II) that results in a reproducible manner and without the need for laborious purification in 7- hydroxyquinolin-2(1H)-one compound of formula (I) of at least 99%.

Unlike the difficulties encountered with process described in patent US Patent 20130137679, the present invention provides a process comprising oxidative-dehydrogenation of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one compound of formula (IV) to yield 7-hydroxyquinolin-2(1H)-one compound of formula (I) in quantitative yield and in very high purity.

In another embodiment of the present invention is to provide an improved process for the preparation of 7- hydroxyquinolin-2(1H)-one compound of formula (I) comprises oxidative-dehydrogenation of 7-hydroxy-3,4-dihydroquinol in-2(1H)-one compound of formula (IV) in presence of oxidative-dehydrogenation reagent as hydrogen acceptor in the presence base and solvent.

In a preferred embodiment of the present invention, the oxidative-dehydrogenation inorganic base are selected from sodium hydroxide, Potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, or mixtures thereof.

In a preferred embodiment of the present invention, the oxidative-dehydrogenation, the solvents used for dehydrogenation includes but are not limited to water, ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and the like or mixture thereof; aromatic hydrocarbons such as toluene, xylene and the like or mixture thereof; lower alcohols such as methanol, ethanol, isopropanol and the like or mixture thereof; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide and the like; The amount of solvent that preferably used in this step may range from about 3 to 10 volumes to compound of (IV).

The oxidative-dehydrogenation reagent as hydrogen acceptor are selected form the group not limited to Pd/C- acrylic acid or Pd/C- Meth acrylic acid or Pd/C- vinylic acid (C1-C6) straight or branched or DDQ (2, 3-dichloro-5, 6-dicyano-1,4-benzoquinone) or DDHQ/NaNO2/O2.

The reaction of oxidative-dehydrogenation the most preferred reagent is Pd/C-acrylic acid or Pd/C-Methacrylic acid or Pd/C- vinylic acid (C1-C6) straight or branched wherein the amount of acid that may be used ranges from about 0.1 to 10 mole eq. to compound of formula (IV). Preferably the amount of acid that may be used ranges from about 0.5 to 5 mole eq. to compound of formula (IV), and most preferably the amount of acid that may be used ranges from about 1.0 to 3 mole eq. to compound of formula (IV)

The reaction of oxidative-dehydrogenation the amount of the amount of Pd/C that may be used ranges from about 0.001 to about 1.0 mole eq to compound of formula (IV). Preferably the amount of Pd/C that may be used ranges from about 0.05 to 0.5 mole eq. to compound of formula (IV), and most preferably the amount of Pd/C that may be used ranges from about 0.01 to 0.1 mole eq. to compound of formula (IV).

In the present invention, the oxidative-dehydrogenation of 7-hydroxy-3,4-dihydroquin-2(1H)-one compound (IV) to obtain 7- hydroxyquinolin-2(1H)-one of formula (I) wherein catalyst as hydrogen acceptor are Pd/C- acrylic acid or Pd/C-Methacrylic acid or Pd/C-vinylic acid (C1-C6) straight or branched or DDQ (2, 3-dichloro-5, 6-dicyano-1,4-benzoquinone) or DDHQ/NaNO2/O2 reagent used in the above step is preferably Pd/C and acrylic acid or methacrylic acid or vinylic acid (C1-C6) straight or branched in the presence of inorganic base like sodium hydroxide, Potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate etc. The amount of acrylic acid methacrylic acid or vinylic acid (C1-C6) straight or branched that may be used ranges from about 1 to 3 mole eq. to compound (IV). The amount of Pd/C that may be used ranges from about 0.01 to about 0.1 mole eq. to compound (IV). Solvents used for dehydrogenation includes but are not limited to water, alcoholic solvent such as methanol, ethanol, isopropanol and the like; The amount of solvent that preferably used in this step may range from about 3 to 10 volumes to compound of (IV).

In the present invention, the oxidative-dehydrogenation reaction is generally performed at suitable reaction temperature in the range of -10°C to 150°C, or preferably reaction temperatures is 50°C to 100°C, or more preferably reaction temperatures is 25°C to 60°C or, or more preferably reaction temperatures is 10°C to 20°C, and most preferably less than about 0°C or any other suitable temperatures. The present invention, the Oxidative dehydrogenation the reaction time is 30 minutes to 24 hours, preferably 1 hour to 15 hours.

After completion of the reaction the compound of formula (I) may optionally be isolated and purified or the reaction mass comprising the compound of formula (I) may be taken for next step of the process. In an embodiment the reaction mass comprising the compound of formula (I) further be purified by a process involving acidification and basification steps, in any order, crystallization and combination thereof, to enhance the purity.

In a preferred embodiment of the present invention 7-Hydroxyquinolin-2(1H)-one compound of formula (I) reacted with 1-4-dihalobutane preferably 1-Bromo-4-chloro butane in presences of solvent and base to obtain 7-(4-Chlorobutoxy)quinolin-2(1H)-one compound of formula (V).

The above reaction is conducted in the presence of a base, in particular, it is conducted in the presence of an inorganic base (e.g. sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride, etc.).

The above reaction is conducted in a suitable solvent, the solvent is one or more selected from the group consisting of water, C1-C5 lower alcohol (such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, ethylene glycol, propylene glycol, glycerol), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or ethylene glycol monomethyl ether, and the like, preferably, the solvent is one or more selected from the group consisting of water, methanol, ethanol, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane or ethylene glycol dimethyl ether; and most preferably N,N-Dimethylacetamide. The reaction time is 1 hour to 24 hours, preferably 2 hours to 12 hours. The reaction temperature is 0°C to 150°C, preferably from room temperature to 100°C.

In a preferred embodiment of the present invention process for preparing of Brexpiprazole (II) comprises:
7-(4-chlorobutoxy)-1H-quinolin-2-one compound of formula (V) is reacted with 1-Benzo [b] thiophene-4-yl-piperazine dihydrochloride compound of formula (VI) in presence of base selected from sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate or mixtures thereof and alkali iodide selected from sodium iodide, potassium iodide, calcium iodide, in a solvent selected from water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, N,N-dimethylacetamide and the like or mixture thereof. The reaction solvent is water, reaction is carried without alkali iodide. The reaction temperature is of about 75 to about 100°C for 1 hr to about 20 hr. After completion of addition, the reaction mass was monitored on TLC. The precipitated solid was filtered and washed with water and filtered to remove insoluble material. The resulting solid was dissolved in mixed solvent of dichloromethane and methanol, dried over sodium sulphate and solvent was evaporated under reduced pressure and filter the precipitated crude Brexpiprazole (II). Crude Brexpiprazole (II) is recrystallised from alcohols such as ethanol and methanol.

In a preferred embodiment of the present invention process for preparing of Brexpiprazole (II) comprises reaction of 7-(4-chlorobutoxy)-1H-quinolin-2-one compound of formula (V) with 1-Benzo [b] thiophene-4-yl-piperazine dihydrochloride compound of formula (VI) in presence of base and water as solvent, without alkali iodide.

The above reaction is conducted in a suitable base selected from sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate or mixtures thereof and alkali iodide selected from sodium iodide, potassium iodide, calcium iodide.

The above process can be represented stepwise as shown below:

The process of the invention is illustrated with reference to the following working Examples and is not intended to limit or enlarge the scope of the invention.

Example 1:-
Process for preparation of 7-Hydroxyquinolin-2(1H)-one:

To a stirred solution of 7-Hydroxy-3,4-dihydroquinolin-2(1H)-one (100.0 g, 0.61 mole) in water (700 ml) was added sodium hydroxide flakes (70.0 g, 1.75 mole) slowly at room temperature within 10-15 min. Exotherm was observed up to 65oC. Addition of vinylic acid (66.3 g, 0.92 mole) was done within 5-10 min at the same temperature. Reaction mixture was refluxed in the presence of 10% Pd/C (6.0 g) and reaction was monitored by TLC. After completion of the reaction, reaction mixture was filtered at 60oC through celite bed to remove Pd/C and bed was washed with water (100 ml). Filtrate was diluted with water (400 ml), cooled up to 10oC and acidified using Conc. HCl to isolate the crude product. Filter the product, washed with water (2 X100 ml) and suck dry. Wet cake was then dried at 60oC to afford 90.0 g (91%) of desired product.
IR (KBR): ? 2825, 1633, 1554, 1506 cm-1.
1H-NMR (DMSO-d6, 300 MHz): ? 6.20 (d, 1H), 6.58 – 6.61 (m, 1H), 6.68 (d, 1H), 7.42 (d, 1H), 7.71 (d, 1H), 10.11 (s, 1H), 11.52 (s, 1H).

13C-NMR (DMSO-d6,100 MHz): ?????????????????????????????????????????????????????????????????

Mass (m/z): 162.0 (100, M+1)

Example 2:-
Process for preparation of 7-(4-Chlorobutoxy)quinolin-2(1H)-one:

To a stirred clear solution of 7-Hydroxyquinolin-2(1H)-one (80.0 g, 0.49 mole) in N,N-Dimethylacetamide (1600 ml) was charged 1-Bromo-4-chloro butane (102.1 g, 0.59 mole) at 30-35oC. Sodium hydroxide powder (25.8 g, 0.64 mole) was added portion wise to the pre-cooled reaction mixture and maintained temperature less than 10oC by applying external cooling. The reaction mixture was maintained at 8-10oC for 7-8 h. Reaction was monitored by TLC. After completion of the reaction, water (2000 ml) was added slowly to the reaction mixture below 15oC. Stir the reaction mixture at 15oC for additional 1 h then filter the resulting crude solid, wash with water (160 ml) and suck dry well. Crude product was dried at 70-75oC for 8-10 h. Stir crude product in dichloromethane (880 ml) and stir resulting suspension at 30-35oC for 30-40 min. Filter the above solution through celite bed, wash celite bed with dichloromethane and combined filtrate was distilled up to recovery of dichloromethane (800 ml). Cool resulting slurry between 0-5oC, filter, wash the solid with dichloromethane (80 ml) and suck dry well. Solid product was dried at 70-75oC for 5-6 h to yield 96 g (77%) of the desired product.
IR (KBR): ? 2826, 1645, 1550, 725cm-1.
1H-NMR (CDCl3, 300 MHz): ? 1.96 – 1.98 (m, 4H), 3.60 – 3.64 (m, 2H), 4.06 – 4.09 (m, 2H), 6.56 (s, 1H), 6.81 (d, 1H), 6.86 (dd, 1H), 7.43 (d, 1H), 7.73, (s, 1H), 12.82 (s, 1H).
13C-NMR (CDCl3, 100 MHz): ???????????????????????????????????????????????????????????????????????????????????????

Mass (m/z): 252 (100, M), 254 (M+2)

Example 3:- Process for preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole)

A mixture of 7-(4-chlorobutoxy)-1H-quinolin-2-one (50 g, 0.20 mole), 1-Benzo [b] thiophene-4-yl-piperazine dihydrochloride (69.4 g, 0.24 mole), potassium carbonate (108 g, 0.79 mole) and water (400 ml) was stirred for 8-10 hours at 100-110oC. Reaction was monitored on TLC, precipitated solid was filtered and washed with water (100 ml). The resulting solid was dissolved in mixed solvent of dichloromethane and methanol, dried over sodium sulphate and solvent was evaporated under reduced pressure. The resulting solid was re-crystallized from ethanol to afford desired compound in 65 g (75%) yield.

Example 4:- Process for preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole)

A mixture of 7-(4-chlorobutoxy)-1H-quinolin-2-one (50 g, 0.20 mole), 1-Benzo [b] thiophene-4-yl-piperazine dihydrochloride (69.4 g, 0.24 mole), potassium carbonate (108 g, 0.79 mole), potassium iodide (33.0 g, 0.20 mole) and N,N-Dimethylformamide (400 ml) was stirred for 3-4 hours at 80oC. Reaction was monitored on TLC, water (100 ml) was added to the reaction mixture and precipitated solid was filtered and washed with water (100 ml). The resulting solid was dissolved in mixed solvent of dichloromethane and methanol, dried over sodium sulphate and solvent was evaporated under reduced pressure. The resulting solid was re-crystallized from ethanol to afford desired compound in 65 g (75%) yield.

IR (KBR): ? 2940, 2815, 1937, 1729, 1479, 1097, 767, 623 cm-1.
1H-NMR (DMSO-d6, 400 MHz): ? 1.60 – 1.67 (m, 2H), 1.77 – 1.83 (m, 2H), 2.44 – 2.50 (t, 2H), 2.68 – 2.68 (m, 4H), 3.06 (m, 4H), 4.04 – 4.07 (m, 2H), 6.30 (d, 1H), 6.79 – 6.81 (m, 2H), 6.80 (d, 1H), 7.25 – 7.29 (m, 1H), 7.40 (d, 1H), 7.54 – 7.56 (m, 1H), 7.61 (d, 1H), 7.69 (d, 1H), 7.80 (d, 1H), 11.59 (s, 1H).
13C-NMR (DMSO-d6, 100 MHz) ?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????
Mass (m/z): 434 (100, M+1)
,CLAIMS:[Claim 1] An improved process for the preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (Brexpiprazole) of Formula (II)

which comprises:
(i) Oxidative-dehydrogenation of 7-Hydroxy-3,4-dihydroquinolin-2(1H)-one compound of formula (IV) in presences of oxidative-dehydrogenation reagent, base and solvent to produce 7-Hydroxyquinolin-2(1H)-one compound of formula (I)

(ii) reacting the compound of Formula (I) with 1-4-dihalo butane in presence of base and solvent to produce compound of formula (V)

(iii) reacting pure compound of Formula (V) with 1-Benzo [b] thiophene-4-yl-piperazine dihydrochloride compound of formula (VI) or its salt

in presence of presence of base and solvent as water, without alkali iodide to produce 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one compound of formula (II).

[Claim 2] An improved process according to claim 1 , wherein the base is selected from sodium hydroxide, Potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate or mixtures thereof.

[Claim 3] An improved process according to claim 1, wherein the oxidative dehydrogenation reagent selected from Pd/C- acrylic acid or Pd/C-Methacrylic acid or Pd/C-vinylic acid (C1-C6) straight or branched or DDQ (2, 3-dichloro-5, 6-dicyano-1,4-benzoquinone) or DDHQ/NaNO2/O2.

[Claim 4] An improved process according to claim 1, wherein the solvent is selected from water, ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and the like or mixture thereof; aromatic hydrocarbons such as toluene, xylene and the like or mixture thereof; lower alcohols such as methanol, ethanol, isopropanol and the like or mixture thereof; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide and the like or mixture thereof.

[Claim 5] An improved process for the preparation of 7-Hydroxyquinolin-2(1H)-one of Formula (I)

which comprises:
oxidative dehydrogenation of 7-Hydroxy-3,4-dihydroquinolin -2(1H)-one of Formula (IV) in presences of oxidative dehydrogenation reagent selected from Pd/C-acrylic acid or Pd/C-Methacrylic acid or Pd/C-vinylic acid (C1-C6) straight or branched or DDQ (2, 3-dichloro-5, 6-dicyano-1,4-benzoquinone) or DDHQ/NaNO2/O2 , base and solvent.

[Claim 6] An improved process according to claim 5, wherein oxidative dehydrogenation reagent is preferably Pd/C-acrylic acid or Pd/C-Methacrylic acid or Pd/C-vinylic acid (C1-C6) straight or branched and it ranges from about 1 to 3 mole eq. to compound (IV) and Pd/C in ranges from about 0.01 to about 0.1 mole eq to compound (IV).

[Claim 7] An improved process for the preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin -2-one (Brexpiprazole) of Formula (II) comprises reacting pure compound of Formula (V)

with 1-Benzo [b] thiophene-4-yl-piperazine dihydrochloride of Formula (VI) or its salt

in presence of presence of base and solvent as water, without alkali iodide to produce 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one of Formula (II).

[Claim 8] An improved process according to claim 7, wherein the base used in step (iii) is selected from sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate or mixture thereof.

[Claim 9] An improved process according to claim 7, wherein the alkali iodide is selected from sodium iodide, potassium iodide, calcium iodide or mixture thereof.

[Claim 10] An improved process according to claim 7, wherein the solvent is selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, dimethylacetamide and the like or mixture thereof.