DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL PROCESS FOR THE PREPARATION OF BREXPIPRAZOLE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it has to be performed:
FIELD OF THE INVENTION
The present invention relates to the novel process for the preparation of Brexpiprazole of formula (I) and intermediate thereof.

BACKGROUND OF THE INVENTION
Brexpiprazole, sold under the brand name REXULTI® is available in six strengths of tablet. It’s chemical name is 7-[4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butoxy]-1H-quinolin-2-one.

Brexpiprazole is useful for adjunctive treatment of major depressive disorder and treatment of schizophrenia.

The US Patent 7,888,362 covers Brexpiprazole as a product and process for preparation thereof. The US Patent ’362 describes a process for preparation of Brexpiprazole comprising 1-benzo[b]thiophene-4-yl-piperazine hydrochloride (IIIa) with 7-(4-chlorobutoxy)-1H-quinolin-2-one (II) in presence of potassium carbonate and sodium iodide in dimethylformamide. However, this process emphasizes on use of column chromatography for purification of intermediates and may lead to low yield quality product which makes the process not suitable for industrial scale. The process is schematically represented by scheme I.

Scheme-1

The US Patent 9,206,169 describes a process for preparation of Brexpiprazole comprising reaction of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride (IIIa) with 7-(4-chlorobutoxy)-1H-quinolin-2-one (II). The intermediate 1-benzo[b]thiophen-4-yl-piperazine hydrochloride (IIIa) prepared in this patent involves use of palladium compound and tertiary phosphines or palladium carbine complex which is schematically represented by scheme II. However, use of palladium compound and tertiary phosphines or palladium carbine complex poses problems such as reagent handling, laborious purification requirements, as well as the inherent complexity of the reaction system.
Scheme-II

Hence, there is a need for environmentally friendly, simple, cost effective, commercially feasible, and industrially scalable process for the preparation of Brexpiprazole and intermediates thereof.
OBJECTIVE OF INVENTION
The primary object of the present invention is to provide efficient, economic and industrially viable novel process for preparation of Brexpiprazole (I).

Another objective of the present invention is to provide a novel intermediate i.e. 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene or its (VI) salt, which is useful compound for the preparation of Brexpiprazole (I).

Another objective of the present invention is to provide a process for preparation of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene or its salt (VI), which is useful compound for the preparation of Brexpiprazole (I).

SUMMARY OF THE INVENTION
The present invention relates to tosyl salt of 8-aza-5-azoniaspiro[4.5]decane-8-Benzo[b]thiophene i.e. spiro compound of formula (VI) as a product.

In another embodiment of the present invention relates to a process for the preparation of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene or its i.e. spiro compound of formula (VI), the process comprising reacting piperazine-1-benzo[b]thien-4-yl or its acid addition salt (III) with a compound of formula (VII) in a solvent and in presence of a base to give tosyl salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene (VI).

In another embodiment of the present invention relates to a process for the preparation of Brexpiprazole, the process comprising the step of reacting tosyl salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene (VI) with 7-hydroxy-2-(1H)-quinolinone of formula (VIII) in a solvent and in presence of a base to obtain Brexpiprazole (I).

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to tosyl salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene i.e. spiro compound of formula (VI).

In an embodiment of the present invention relates to a process for the preparation of tosyl salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene i.e. spiro compound of formula (VI), the process comprising the step of reacting piperazine-1-benzo[b]thien-4-yl or its salt (III) with a compound of formula (VII) in a solvent and in presence of a base to give salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene (VI).

Spiro intermediate of the present invention can be prepared by reacting piperazine-1-benzo[b]thien-4-yl or its acid addition salt of formula (III), wherein salt is hydrochloride, hydrobromide or organic acids; with a compound of formula (VII) in the solvent and in the presence of base at a temperature in the range of from 0°C to 120°C.

Piperazine-1-benzo[b]thien-4-yl or its acid addition salt of formula (III) used in the foregoing process wherein the acid is selected from inorganic or organic acid preferably hydrochloric acid or hydrobromic acid.

The tosylate in the compound of formula (VII) used in foregoing process can also be replaced by an anion of conjugate base selected from acetate, benzenesulfonate, benzoate, bisulfate, bitartrate, camsylate, clavulanate, citrate, edetate, edisylate, esylate, fluoride, fumarate, gluceptate, glutamate, isothionate, laurate, malate, mandelate, mesylate, methylsulfate, mucate, oleate, oxalate, palmitate, pantothenate, phosphate, salicylate, stearate, subacetate, succinate, tartrate, trifluoroacetate, trifluoromethane sulfonate, nosylate, brosylate and valerate.

The solvent(s) used in the foregoing process is an organic solvent may be selected from the group comprises of alkyl acetate such as ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as dimethyl formamide; ethers such as methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers such as 2-methyl tetrahydrofuran and the like; alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, diethylene glycol and the like; esters; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; dialkylsulfoxides such as dimethyl sulfoxide; dialkylacetamides such as ?,?,-dimethyl acetamide; nitriles such as acetonitrile, and propionitrile; ionic liquids, hexamethylphosphorous triamide, hexamethylphosphoramide; water or mixtures thereof.

The bases used in the foregoing process are selected from either organic or inorganic bases; organic bases include primary amines such as methylamine, ethylamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; secondary amines such as N,N- diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ?,?-dimethyl aniline, ?,?-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, ?,?-dimethylethyl amine and the like; tetra alkyl ammonium and phosphonium hydroxides; Metal alkoxides and amides; metal silanoates and the like and inorganic bases such as alkali metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal hydrides, metal alkoxides such as sodium methoxide, sodium ethoxide, lithium tert. butoxide, potassium tert butoxide and the like; alkali metal amide such as lithium amide, sodium amide, potassium amide, cesium amide and rubidium amide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium and calcium hydride and the like. alkali metal amide such as lithium amide, sodium amide, potassium amide, cesium amide and rubidium amide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium and calcium hydride and the like.

According to the present invention, the spiro compound of formula (VI) can be purified using known techniques available in art such as re-crystallization, re- saltification, washing with solvent with the help of above mentioned solvent or mixture of solvents thereof.

According to the present invention, the obtained spiro compound (VI) could be further used for the preparation of Brexpiprazole.

According to another embodiment of the present invention relates to a novel process for the preparation of Brexpiprazole comprising the step of reacting tosyl salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene (VI) with 7-hydroxy-2-(1H)-quinolinone of formula (VIII) in a solvent and in presence of a base to obtain Brexpiprazole (I).

The whole synthetic scheme of preparation of Brexpiprazole according to the present invention can be represented as below:

Brexpiprazole can be prepared by reacting tosyl salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene (VI), with 7-hydroxy-2-(1H)-quinolinone (VIII) in a solvent and in presence of base at a temperature ranging from 0 °C to 120 °C.

The solvent(s) used in the foregoing process is an organic solvent may be selected from the group comprises of alkyl acetate such as ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as dimethyl formamide; ethers such as methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers such as 2-methyl tetrahydrofuran and the like; alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, diethylene glycol and the like; esters; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; dialkylsulfoxides such as dimethyl sulfoxide; dialkylacetamides such as ?,?,-dimethyl acetamide; nitriles such as acetonitrile, and propionitrile; ionic liquids, hexamethylphosphorous triamide, hexamethylphosphoramide; water or mixtures thereof.

The bases used in the foregoing process may be same or different and are selected from either organic or inorganic bases; organic bases include primary amines such as methylamine, ethylamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; 'secondary amines such as N,N- diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ?,?-dimethyl aniline, ?,?-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, ?,?-dimethylethyl amine and the like; tetra alkyl ammonium and phosphonium hydroxides; Metal alkoxides and amides; metal silanoates and the like and inorganic bases such as alkali metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal hydrides, metal alkoxides such as sodium methoxide, sodium ethoxide, lithium tert. butoxide, potassium tert butoxide and the like; alkali metal amide such as lithium amide, sodium amide, potassium amide, cesium amide and rubidium amide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium and calcium hydride and the like. alkali metal amide such as lithium amide, sodium amide, potassium amide, cesium amide and rubidium amide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium and calcium hydride and the like.

According to another specific embodiment of the present invention provides a novel process for the preparation of Brexpiprazole, comprising of:
a) reacting piperazine-1-benzo[b]thien-4-yl hydrochloride with butane ditosylate in acetonitrile and in presence of potassium carbonate to provide spiro compound of formula (VIa) i.e. tosylate salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene, and optionally isolating compound of formula (VIa);
b) reacting spiro compound of formula (VIa) i.e. tosylate salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene with 7-hydroxy-2-(1H)-quinolinone of formula (VIII) in dimethylacetamide (DMAc or DMA) and in presence of potassium carbonate to obtain Brexpiprazole (I).

The obtained product by the process disclosed herein i.e. Brexpiprazole may be purified with known techniques available in the art with the use of above mentioned solvent or mixture of solvents thereof.

Further, the specific embodiment of the present invention is represented schematically as follows:

The spiro intermediate of formula (VI) obtained in the present invention may or may not be isolated and can be directly converted into Brexpiprazole.

The novel spiro intermediate of formula (VI) of the present invention offers good control over the level of impurities which are commonly observed during the preparation of Brexpiprazole. The impurities are controlled at intermediate stage would lead to better quality of final compound and ultimately avoiding extensive purification procedure.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention in any manner whatsoever.

EXAMPLE-1
Preparation of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene chloride (Spiro intermediate):

Acetone (700ml) was charged in a round bottom flask followed by piperazine-1-benzo[b]thien-4-yl hydrochloride (100 g, 0.3929 moles) at 25-30°C. Further, potassium carbonate (124.7 g, 0.9036 moles) was added to the reaction mass and stirred for 20-30 min. 1,4-Chlorobutane (100 g, 0.4631 moles) was added and the reaction mass was heated to reflux temperature (55-57°C) for 6 hrs. The reaction mass was cooled at 25-30°C and stirred for 30 min. The solid was filtered and washed with acetone (100ml) at 25-30°C. The solid was dried in vacua to a constant weight, affording 280 g of titled product.
1H-NMR (D2O, 300MHz) d: 2.24 (m, 4H), 3.43 (m, 4H), 3.71 (m, 8H), 7.09-7.82 (m, 5H). MS: molecular ion at m/z: 273.1 [(M+H)].
EXAMPLE-2
Preparation of Brexpiprazole:

Brexpiprazole Stage-I spiro compound prepared in example 1 (12 g, 0.0339 moles, including inorganic salts) was charged followed by and methyl isobutyl ketone (60 ml) and N,N-dimethylformamide (9 ml) into a round bottom flask at 25-30°C and it was stirred for 5-10 min. 7-Hydroxy-2-(1H)-quinolinone (2.1 g, 0.0130 moles) was added to the reaction mass and stirred for 15-20 min. Potassium carbonate (2.4 g, 0.0173 moles) was added and heated to reflux temperature (~110°C) for 16 hrs. The reaction mass was cooled to 25-30°C, DM water was added and stirred for 10-15 min. The layers were separated and the aqueous layer was extracted with methyl isobutyl ketone. The organic layer was concentrated at 60-65°C under vacuum till no more solvent distills. Ethanol was added to the concentrated mass at 50-55°C and stirred for 20-30 min. The reaction mass was cooled to 25-30°C and stirred for 1hr. The solid was filtered and washed with ethanol. The solid was dried in vacua to a constant weight, affording 2.08 g of titled product.
1H-NMR (DMSO-d6, 300MHz) d: 1.62-1.69 (m, 2H), 1.76-1.83 (m, 2H), 2.55-2.62 (m, 4H), 3.0-3.6 (m, 4H), 4.04-4.08 (m, 2H), 6.27-6.31 (d, 1H), 6.78-6.82 (d, 2H), 6.87-6.89 (d, 1H), 7.24-7.3 (m, 1H), 7.39-7.41 (m, 1H), 7.54-7.55 (m, 1H), 7.57-7.62 (m, 2H), 7.68-7.70 (d, 1H), 7.78-7.81 (d, 1H), 11.57 (br, 1H). MS: molecular ion at m/z: 434.2 [(M+H)].

EXAMPLE-3
Preparation of 1, 4-butanediol ditosylate:

P-Toluenesulfonyl chloride (132.2 g, 0.6935moles) was dissolved in methylene chloride (500 ml) at 20-30°C under nitrogen atmosphere and stirred for 5-10 min. Triethyl amine (84.21 g, 0.8322 moles) was added to reaction mass at 20-30°C and cooled the reaction mass to 0-5°C. 1, 4-Butanediol (25 g, 0.2774 moles) was added to the reaction mass at 0-5°C for 30 min. Reaction mass temperature was slowly raised to 20-30°C over a period of 2 hr and stirred for 15 hr at 20-30°C. Reaction mass was cooled to 0-5°C and DM water (300 ml)was added into reaction mass, stirred for 5 min at 0-5°C. Reaction mass temperature was raised to 20-30°C and stirred for another 10-15 min. The layers were separated and the aqueous layer was extracted with methylene chloride (150 ml) at 25-30°C.Combined organic layer was washed with DM water (2 x 300 ml) and followed by 0.4 M hydrochloride solution (2 x 200 ml)at 25-30°C.The organic layer was concentrated at 30-35°C under vacuum till no more solvent distills. The concentrated solid (98.4 g) was slurry washed with hexane (500 ml) at 20-30°C. The solid mass filtered at 20-30°C and washed with hexane (20 ml). It was dried at 40-45°C under vacuum for 5 hrs to get 1, 4-butanediol ditosylate to yield 80.52 g of final product as white crystals. Yield: 72.86%.

1H-NMR (CDCl3, 300MHz) d: 1.7 to 1.5 (m, 4H), 2.45 (s, 6H),3.97 (s, 4H),7.36 (d, 4H),7.77 (d, 4H),

EXAMPLE-4
Preparation of 8-aza-5-azoniaspiro[4,5]decane-8-benzo[b]thiophene tosylate

1-benzo[b]-thiophene-4-yl-piperzine hydrochloride (3.5 g, 0.013 moles), potassium carbonate (4.17 g, 0.30 moles) and acetonitrile (10 ml) were charged into a round bottom flask at 25-30°C and stirred for 25-30 min. 1, 4-butanediol ditosylate (6.0 g, 0.015 moles) was added to the reaction mass and heated to reflux at 75 – 80oC for 4 hr. Reaction mass was cooled to 25-30°C and filtered. The filtrate was evaporated to obtain a solid mass. This solid mass was further crystallized using isopropyl alcohol (40 ml) to obtain pure 8-aza-5-azoniaspiro[4,5]decane-8-benzo[b]thiophene tosylate (3.46 g). Yield: 60%.
1H-NMR (DMSO-d6, 300MHz) d: 12.25 (brs, 4H), 2.38 (s, 3H), 3.45(brs, 4H), 3.66-3.68(m, 8H), 7.10 (d, 1H), 7.36 (d, 2H), 7.44(t, 1H), 7.48 (d, 1H), 7.65-7.75 (m, 2H), 7.80 (d, 1H). MS: molecular ion at m/z: 273.2 [(M+H)].

EXAMPLE-5
Preparation of Brexpiprazole:

8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene tosylate (2 g, 0.0045 moles),7-Hydroxy-2(1H)-quinolinone (1.1g, 0.0068 moles) and N,N-dimethyl acetamide (10 ml) were charged into a round bottom flask at 25-30°C and stirred for 10-15min. Potassium carbonate (0.62g, 0.0044 moles) was added to the reaction mass and heated at 140 – 145 oC for 1 hr. Reaction mass was cooled to 25-30°C.Methylene chloride (20 ml) was added to the reaction mass, followed by DM water (30 ml). This mass was stirred for 20-30 min. The layers were separated and the aqueous layer was extracted with methylene chloride (20 ml) at25-30°C. The combined organic layer was washed with water (20 ml) at 25-30°C. The organic layer was concentrated at 25-30°C under vacuum till no more solvent distills. Toluene (10ml) was added to the concentrated mass and the mixture was heated to 45°C and maintained at that temperature for 15-20 min. This reaction mass was further cooled to 0-5°C and maintained at that temperature for 1hr. The solid mass was filtered at 0-5°C and washed with Toluene (5 ml). Solid mass was dried at 60-65°C under vacuum to get Brexpiprazole.
1H-NMR (DMSO-d6, 300MHz) d: 1.64-1.66 (m, 2H), 1.77-1.82 (m, 2H), 2.42-2.44(m, 2H), 2.62 (m, 4H), 3.06(m, 4H), 4.03-4.07 (m, 2H), 6.28 (d, 1H), 6.78-6.81 (m, 2H), 6.88 (d, 1H), 7.24-7.29(m, 1H), 7.38-7.40 (m, 1H), 7.53-7.55 (m, 1H), 7.56-7.62 (m, 2H), 7.68-7.69(d, 1H), 7.78-7.81 (d, 1H), 11.56(br, 1H), ,CLAIMS:We Claim:

1) A process for preparing Brexpiprazole of formula (I) comprising the steps of:

(a) Reacting piperazine-1-benzo[b]thien-4-yl or its acid addition salt (III) with a compound of formula (VII) in a solvent in the presence of a base to give salt of 8-aza-5-azoniaspiro[4.5]decane-8-benzo[b]thiophene having general formula (VI)

(b) Reacting tosyl salt of 8-aza-5-azoniaspiro [4.5]decane-8-benzo[b]thiophene of formula (VI) with 7-hydroxy-2-(1H)-quinolinone of formula (VIII) in a solvent and in presence of a base to obtain Brexpiprazole (I).

2) The process as claimed in claim 1, wherein base used in step a) and b) is same or different and can be selected from organic or inorganic base.

3) The process as claimed in claim 2, wherein the base is preferably an inorganic base selected from metal carbonate or bicarbonate preferably sodium carbonate or potassium carbonate.

4) The process as claimed in claim 1, wherein the solvent is selected from a group of polar aprotic solvents comprising of acetone, acetonitrile, DMF, DMSO or a mixture thereof.

5) A compound of formula VI: