WO2019073481A1 - Process for the preparation of brexpiprazole and its intermediates - Google Patents
Process for the preparation of brexpiprazole and its intermediates Download PDFInfo
- Publication number
- WO2019073481A1 WO2019073481A1 PCT/IN2018/050643 IN2018050643W WO2019073481A1 WO 2019073481 A1 WO2019073481 A1 WO 2019073481A1 IN 2018050643 W IN2018050643 W IN 2018050643W WO 2019073481 A1 WO2019073481 A1 WO 2019073481A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- acid
- group
- process according
- Prior art date
Links
- 0 *N(CC1)CCN1Oc1ccc(C=CC(N2)=O)c2c1 Chemical compound *N(CC1)CCN1Oc1ccc(C=CC(N2)=O)c2c1 0.000 description 4
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N O=C1Nc2cc(OCCCCN(CC3)CCN3c3c(cc[s]4)c4ccc3)ccc2C=C1 Chemical compound O=C1Nc2cc(OCCCCN(CC3)CCN3c3c(cc[s]4)c4ccc3)ccc2C=C1 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 2
- MGVMSYNDHUEBSB-UHFFFAOYSA-N O=C1Nc2cc(ON3CCNCC3)ccc2C=C1 Chemical compound O=C1Nc2cc(ON3CCNCC3)ccc2C=C1 MGVMSYNDHUEBSB-UHFFFAOYSA-N 0.000 description 1
- QGAXLPZEOROXNY-UHFFFAOYSA-N OCCCCOc1ccc(C=CC(N2)=O)c2c1 Chemical compound OCCCCOc1ccc(C=CC(N2)=O)c2c1 QGAXLPZEOROXNY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
Definitions
- the present invention relates to a process for the preparation of brexpiprazole and its pharmaceutically acceptable salt.
- the present invention further relates to novel intermediates and process for the preparation of the novel intermediates of brexpiprazole.
- the invention also relates to a process for purification of brexpiprazole to reduce or eliminate impurities.
- SD serotonin-dopamine activity modulator
- 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 the U.S. for the treatment of schizophrenia and as an adjunctive therapy to antidepressants for the treatment of major depressive disorder.
- hydrochloride salt of the compound of Formula II is reacted with 7-(4- chlorobutoxy)-lH-quinolin-2-one, the compound of Formula Ilia in the presence of a base such as potassium carbonate, a reagent such as sodium iodide in dimethylformamide solvent at 80°C to get crude 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy]-lH-quinolin-2-one (Brexpiprazole).
- a Chinese patent application, CN104844585 discloses a process for the synthesis of brexpiprazole of Formula I, wherein 7-hydroxy-3,4-dihydroquinolin-2(lH)-one of Formula B l is reacted with l-bromo-4-chlorobutane of Formula IVa in the presence of a base in a reaction solvent selected from ⁇ , ⁇ -dimethylacetamide, N,N- dimethylformamide, tetrahydrofuran and/or water to get 7-(4-chlorobutoxy)-3,4- dihydroquinolin-2(lH)-one of Formula B2.
- the compound of Formula B2 is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in tetrahydrofuran to give 7-(4- chlorobutoxy)quinolin-2(lH)-one of Formula Ilia.
- DDQ 2,3-dichloro-5,6-dicyanobenzoquinone
- the compound of Formula Ilia is reacted with hydrochloride salt of l-(benzo[b]thiophen-4-yl)piperazine, the compound of Formula II in the presence of sodium carbonate, sodium bromide in N-methylpyrrolidone to get crude brexpiprazole of Formula I.
- the crude brexpiprazole is purified via hydrochloride salt formation and neutralization.
- the reaction is represented in the following scheme II:
- Scheme II Another Chinese patent application CN104829602 discloses a process for preparation of brexpiprazole of Formula I, which involves condensing 7-(4- chlorobutoxy)-3,4-dihydroquinolin-2(lH)-one of Formula B2 with hydrochloride salt of l-(benzo[b]thiophen-4-yl)piperazine, the compound of Formula II in a solvent selected from acetonitrile, ethanol, n-butanol, dioxane, N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, N-methylpyrrolidone or a mixture thereof, to give 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)-3,4- dihydroquinolin-2(lH)-one, a compound of Formula CI .
- PCT patent publication WO2017078621 discloses a process for preparation of brexpiprazole of Formula I involving the following steps. l,l-dialkoxy-4- chlorobutane of Formula Dl is reacted with 7-hydroxyquinolin-2(lH)-one of Formula V in the presence of a base and a phase transfer catalyst in an organic solvent to form 7-(4,4-dialkoxybutyloxy)quinolin-2(lH)-one of Formula D2. The compound of Formula D2 is treated with an acid in an organic solvent to form 4- ((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butanal hydrate of Formula D3.
- brexpiprazole Reductive amination of the aldehyde of Formula D3 with hydrochloride salt of 1- (benzo[b]thiophen-4-yl)piperazine of Formula II in the presence of a reducing agent in an organic solvent to form brexpiprazole, the compound of Formula I.
- the crude brexpiprazole is purified via hydrochloride formation and neutralization.
- Ri is Ci-Cis alkyl, or both Ri moieties in combination with oxygen group to which they are attached may form a 5-8 membered heterocycloalkyl ring).
- WO2017025987 discloses a process for the synthesis of brexpiprazole comprising the following steps. 7-hydroxyquinolin-2(lH)-one of Formula V is reacted with a protected alcohol compound of Formula El in the presence of a base and a solvent to form a compound of Formula E2. Deprotection via hydrolysis of the compound of Formula E2 in the presence of a solvent to give 7-(4-hydroxybutoxy)quinolin-2(lH)-one of Formula E3. The hydroxy group of the compound of Formula E3 is converted to a leaving group in the presence of a base and a solvent to get a compound of Formula E4.
- the compound of Formula E4 is reacted with protected piperazine compound of Formula E5 in the presence of a base to obtain a compound of Formula E6.
- Deprotection of the compound of Formula E6 is carried out to get 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one of Formula E7.
- the amine compound E7 is condensed with 4-halobenzo[b]thiophene of Formula E8 to give brexpiprazole of Formula I.
- the reaction is represented in the following scheme V:
- R is hydroxyl protecting group
- X and Y are the same or different and are halogen
- LG is leaving group
- PG is amine protecting group
- the inventors of the present invention ameliorate the problems of the prior art processes by employing novel intermediate compounds as described herein that avoids the formation of major impurities, thereby eliminating the use of column chromatography for the purification of the intermediates, and the final product brexpiprazole, the compound of Formula I.
- the objective of the present invention is to prepare brexpiprazole, the compound of Formula I with an industrially viable and cost effective process.
- Another objective of the present invention is to provide a process for the preparation of brexpiprazole, the compound of Formula I with controlled formation of impurities.
- Yet another objective of the present invention is to provide novel intermediate compounds and an efficient process for the preparation of the novel intermediate compounds useful for the preparation of brexpiprazole, the compound of Formula I.
- the present invention provides a process for preparing brexpiprazole, the compound of Formula I or its pharmaceutically acceptable salts using readily available, cost effective, and industrially safe starting materials.
- X is fluorine, chlorine, bromine or iodine
- Y is selected from fluorine, chlorine, bromine or iodine; or -OR; wherein R is hydrogen, a hydroxyl protecting group, or a leaving group selected from alkyl sulfonate, aryl sulfonate and perfluoroalkyl sulfonate;
- step (c) hydrolyzing the compound of Formula VIII or its salt using a suitable reagent to isolate salt of brexpiprazole, the compound of Formula I; d) treating the compound obtained in step (c) with a base in presence of solvent to isolate brexpiprazole, the compound of Formula I; and e) purifying the isolated compound of step (d) to obtain pure crystalline brexpiprazole, the compound of Formula I.
- the present invention provides a process for purification of brexpiprazole, the compound of Formula I comprising;
- step (v) filtering the solid obtained in step (v) to isolate pure crystalline brexpiprazole, the compound of Formula I.
- the present invention provides a novel compound of Formula VII or a salt thereof,
- X is fluorine, chlorine, bromine or iodine
- Y is selected from fluorine, chlorine, bromine, iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group, or a leaving group selected from alkyl sulfonate, arylsulfonate and perfluoroalkylsulfonate.
- the present invention provides a novel compound of Formula VIII or a salt thereof,
- X is fluorine, chlorine, bromine or iodine.
- the present invention relates to a process for preparing brexpiprazole, the compound of Formula I or its pharmaceutically acceptable salt.
- the present invention discloses novel synthetic route for the preparation of brexpiprazole.
- novel intermediates that are formed provide an improved and efficient method for the synthesis of brexpiprazole, the compound of Formula I.
- the present invention provides a process for the preparation of brexpiprazole, the compound of Formula I, which comprises the steps of;
- Formula VI Formula IV Formula VII wherein X is fluorine, chlorine, bromine or iodine; Y is selected from fluorine, chlorine, bromine, iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group, or a leaving group selected from alkyl sulfonate, aryl sulfonate and perfluoroalkyl sulfonate; b) reacting the compound of Formula VII with l-(benzo[b]thiophen-4- yl)piperazine of Formula II or its salt in the presence of a base and a solvent
- step (c) treating the compound obtained in step (c) with a base in presence of solvent to isolate brexpiprazole, the compound of Formula I;
- step (d) purifying the isolated compound of step (d) to obtain pure crystalline brexpiprazole, the compound of Formula I.
- the suitable base used in step (a) of the process is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, ⁇ , ⁇ -diisopropylethylamine, diisopropylamine, pyridine, sodium tert-butoxide, potassium tert-butoxide, triethylamine or a mixture thereof.
- the preferred base used in step (a) of the process is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and triethyl amine, wherein the most preferred base used is potassium carbonate.
- the solvent used in step (a) of the process is selected from the group consisting of ethyl acetate, acetone, methyl isobutyl ketone, methanol, ethanol, isopropanol, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, toluene, xylene, heptane, cyclohexane, hexane, 2- methyltetrahydrofuran or a mixture thereof.
- the preferred solvent used in step (a) of the process is selected from ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, methyl isobutyl ketone, methanol and 2-methyltetrahydrofuran, wherein the most preferred solvent used is N,N-dimethylacetamide.
- the hydroxyl protecting group recited in the definition of R group is selected from acetyl, benzoyl, 2- methoxyethoxymethyl ether, methoxymethylether, pivaloyl and trityl.
- the leaving group recited in the definition of R group is selected from methanesulfonate ion (mesylate), trifluoromethanesulfonate ion (triflate) and 4-methylbenzenesulfonate ion (tosylate).
- the base used in step (b) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, N,N- diisopropylethylamine, diisopropylamine, pyridine, sodium tert-butoxide, potassium tert-butoxide and triethylamine or a mixture thereof.
- the preferred base used for the reaction is potassium carbonate.
- the preferred base used in step (b) is selected from potassium bicarbonate, sodium bicarbonate, potassium tert-butoxide and triethylamine, wherein most preferred base used is sodium bicarbonate.
- the solvent used in step (b) is selected from the group consisting of ethyl acetate, acetone, methyl isobutyl ketone, methanol, ethanol, isopropanol, ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, toluene, xylene, heptane, cyclohexane, hexane and 2-methyltetrahydrofuran or a mixture thereof.
- the preferred solvent used in step (b) of the process is selected from N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide and 2-methyltetrahydrofuran, wherein the most preferred solvent used is N,N- dimethylformamide.
- the reaction in step (b) is carried out in presence of a catalyst selected from the group consisting of sodium iodide, potassium iodide, potassium bromide, sodium bromide, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide and tetrabutyl phosphonium bromide or a mixture thereof.
- a catalyst selected from the group consisting of sodium iodide, potassium iodide, potassium bromide, sodium bromide, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide and tetrabutyl phosphonium bromide or a mixture thereof.
- the preferred catalyst used in step (b) reaction is selected from sodium iodide and potassium iodide.
- the compound of Formula VIII is isolated from the reaction as a free base or its salt.
- the preferred salt of the compound of Formula VIII is hydrochloride salt, hydrobromide salt or acetate salt.
- the suitable reagent used for the hydrolysis reaction in step (c) is an acidic reagent selected from the group of organic acids or mineral acids.
- the organic acid used for hydrolysis is selected from the group consisting of formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfomc acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid and para- toluenesulfonic acid.
- the mineral acid used for the hydrolysis is selected from the group consisting of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, perchloric acid, hydrofluoric acid and hydrobromic acid.
- the preferred acidic reagent used for the hydrolysis reaction is hydrochloric acid or acetic acid.
- the hydrolysis reaction of step (c) is carried out optionally in the presence of a solvent selected form the group consisting of toluene, xylene, chlorobenzene, dichloromethane, tetrahydrofuran, ethyl acetate, ethyl benzene, methyl isobutyl ketone, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, and water or a mixture thereof.
- a solvent selected form the group consisting of toluene, xylene, chlorobenzene, dichloromethane, tetrahydrofuran, ethyl acetate, ethyl benzene, methyl isobutyl ketone, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, and water or a mixture thereof.
- the salt isolated in step (c) is hydrochloride salt, hydrobromide salt or acetate salt of brexpiprazole, the compound of Formula I.
- the base used in step (d) for treating the compound as obtained in step (c) above is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.
- the preferred base used in step (d) is selected from, sodium carbonate, potassium carbonate and sodium hydroxide.
- the solvent used in step (d) is selected from the group consisting of ethyl acetate, methyl isobutyl ketone, toluene, xylene, n-propanol, water and chlorobenzene or a mixture thereof.
- the preferred solvent used is toluene, xylene and methyl isobutyl ketone and water, wherein the most preferred solvent used is mixture of toluene and water.
- the reaction in step (d) is carried out at a temperature in the range of 60°C to 80°C.
- the preferred temperature for treating the compound of step (c) is in the range of 60°C to 65°C.
- the process for obtaining pure crystalline brexpiprazole, the compound of Formula I, in step (e) as above comprises the steps of;
- step (i) treating the solution of step (i) with activated charcoal and filtering it hot;
- the first solvent used in step (i) of the process is selected from the group consisting of toluene, xylene, chlorobenzene, heptane, cyclohexane, hexane, tetrahydrofuran, 2-methyltetrahydrofuran, n- propanol, n-butanol, ethyl acetate, methyl isobutyl ketone, N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulfoxide, dichloromethane and ethylbenzene or a mixture thereof.
- the hot condition required for complete dissolution of crude brexpiprazole in step (i) is a temperature in the range of 80°C to 150°C.
- the preferred temperature for the dissolution is in the range of 100°C to 120°C.
- the most preferred temperature range for the dissolution is 107°C to 112°C.
- the solution obtained in step (i) is charcoalised and filtered hot through a hyflobed. The filtrate is cooled gradually to 25°C to 30°C and maintained. Filtered the solid to get the crystalline solid mass.
- the second solvent used in step (iv) of the process is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, methyl isobutyl ketone, dimethyl sulfoxide, toluene and water or a mixture thereof.
- the hot condition required for complete dissolution of crude brexpiprazole in step (iv) is a temperature in the range of 60°C to 110°C.
- the preferred temperature for the dissolution is in the range of 70°C to 110°C.
- the most preferred temperature range for the dissolution is 90°C to 100°C.
- the compound of Formula I is converted to its pharmaceutically acceptable salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate or salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, p- toluenesulfonate and glutamate.
- inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate or salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, p- toluenesulfonate and glutamate.
- the present invention provides a novel compound of Formula VII or its salt thereof.
- X is fluorine, chlorine, bromine or iodine
- Y is selected from fluorine, chlorine, bromine or iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group; or a leaving group selected from alkyl sulfonate, arylsulfonate and perfluoroalkylsulfonate.
- the "X" is -CI or -Br; and the “Y” is CI, Br or -OR wherein R is selected from H, acetyl, benzoyl, 2-methoxyethoxymethyl ether, methoxymethyl ether, pivaloyl, trityl, methanesulfonate ion (mesylate), trifluoromethanesulfonate ion (triflate) and 4- methylbenzenesulfonate ion (tosylate).
- the compound of Formula VII or a salt thereof according to the invention are selected from the following;
- the present invention provides the compound of formula VII (as described above) or its salt for use in the process for the manufacture of brexpiprazole, the compound of formula I.
- the present invention provides a novel compound of Formula VIII or its salt thereof.
- X is fluorine, chlorine, bromine or iodine.
- the salts of compound of formula VIII are preferably selected from hydrochloride salt or acetate salt.
- the present invention provides the compound of formula VIII (as described above) for use in the process for the manufacture of brexpiprazole, the compound of formula I.
- the advantage of the present invention over the existing prior art is that, it controls the formation of the impurities at the intermediate as well as the final stage.
- the present invention provides the final compound, brexpiprazole with increased yield, and avoids cumbersome purification process involved in the removal of the impurities, which makes the process industrially viable and overcome the problems associated with the processes known in the art.
- the present invention results in an industrially beneficial process and meets the ICH guidelines on the impurities to prepare pure brexpiprazole, the compound of Formula I.
- reaction mass was cooled to 25°C to 30°C and quenched with water (150 ml).
- water 150 ml
- Example 9 Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline acetate.
- reaction mass was cooled to 25-30°C and quenched with water (1.50 liters) and adjusted pH between 3 - 4 using acetic acid.
- the reaction mass was cooled to 0°C to 5°Cand stirred. Filtered the solid to isolate the product 7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-l-yl)butoxy)-2-chloroquinoline acetate (180 gm, 95.23%).
- Example 10 Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline acetate.
- reaction mass was cooled to 25-30°C and quenched with water (2.0 liters). Adjusted pH between 3 - 4 using acetic acid and cooled the reaction mass to 0 to 5°C. Filtered the solid mass to isolate the product, 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline acetate (180 gm, 95.23%).
- Example 11 Preparation of 7-(4-(4-(Benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one.
- Example 12 Purification of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one (Brexpiprazole).
- Example 15 Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-bromoquinoline acetate.
- reaction mass was cooled to 25-30°C, then quenched with water (54 ml) and adjusted the pH 3 - 4 using acetic acid. Cooled the reaction mass to 0 to 5°C and filtered the solid to obtain 7-(4-(4- (benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)-2-bromoquinoline acetate (2.8 gm, 88.05%).
- Example 16 Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one.
- Example 17 Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one.
- Example 18 Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline.
- reaction mass was cooled to 25°C - 30°C and quenched with water (600ml) and extracted with toluene (2 x 600ml), stirred and separated the layer. Distilled out toluene layer under vacuum at 50-55°C to obtain 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1- yl)butoxy)-2-chloroquinoline (175 gm 98.64%).
- Example 19 Preparation of 7-(4-(4-(Benzo[b]thiophen-4-yl) piperazin-1- yl)butoxy)quinolin-2(lH)-one.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention discloses to a process for the preparation of brexpiprazole and its pharmaceutically acceptable salt. The present invention further discloses novel intermediates and process for the preparation of the novel intermediates of brexpiprazole. The invention also discloses a process for purification of brexpiprazole to reduce or eliminate impurities.
Description
PROCESS FOR THE PREPARATION OF BREXPIPRAZOLE AND ITS
INTERMEDIATES"
FIELD OF INVENTION:
The present invention relates to a process for the preparation of brexpiprazole and its pharmaceutically acceptable salt.
The present invention further relates to novel intermediates and process for the preparation of the novel intermediates of brexpiprazole. The invention also relates to a process for purification of brexpiprazole to reduce or eliminate impurities.
BACKGROUND OF THE INVENTION:
The compound 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinolin- 2(lH)-one commonly known as brexpiprazole represented below as the compound of Formula I, is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SD
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 the U.S. for the treatment of schizophrenia and as an adjunctive therapy to antidepressants for the treatment of major depressive disorder.
Brexpiprazole and its pharmaceutical acceptable salts, and process for their preparation are described in US 7,888,362 ("US'362 Patent). The process described in the US'362 patent involves reaction of 4-bromobenzo[b]thiophene of Formula Al with anhydrous piperazine of Formula A2 in the presence of reagents such as
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 of Formula II, which is treated with concentrated hydrochloric acid in methanol to isolate the hydrochloride salt of 1- (benzo[b]thiophen-4-yl)piperazine, the compound of Formula II. The hydrochloride salt of the compound of Formula II is reacted with 7-(4- chlorobutoxy)-lH-quinolin-2-one, the compound of Formula Ilia in the presence of a base such as potassium carbonate, a reagent such as sodium iodide in dimethylformamide solvent at 80°C to get crude 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy]-lH-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 brexpiprazole, the compound of Formula I. The reaction is schematically represented in the following scheme I:
Formula I
Scheme I
The drawback of the process described in the US'362 patent involves in the formation of impurities during the reaction and purging of these impurities, which affects the yield and purity of the compound of Formula I. Moreover, to eliminate the impurities formed during the process, column chromatographic purification is
carried out at the intermediate stage as well as in the final stage, followed by recrystallization of the crude compound from ethanol to get pure brexpiprazole. It is not possible to carry out column chromatographic purification on industrial scale production of brexpiprazole and therefore, it is desirable to have a process which involves chemical purification, especially for large scale production of brexpiprazole having higher purity.
A Chinese patent application, CN104844585 discloses a process for the synthesis of brexpiprazole of Formula I, wherein 7-hydroxy-3,4-dihydroquinolin-2(lH)-one of Formula B l is reacted with l-bromo-4-chlorobutane of Formula IVa in the presence of a base in a reaction solvent selected from Ν,Ν-dimethylacetamide, N,N- dimethylformamide, tetrahydrofuran and/or water to get 7-(4-chlorobutoxy)-3,4- dihydroquinolin-2(lH)-one of Formula B2. The compound of Formula B2 is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in tetrahydrofuran to give 7-(4- chlorobutoxy)quinolin-2(lH)-one of Formula Ilia. The compound of Formula Ilia is reacted with hydrochloride salt of l-(benzo[b]thiophen-4-yl)piperazine, the compound of Formula II in the presence of sodium carbonate, sodium bromide in N-methylpyrrolidone to get crude brexpiprazole of Formula I. The crude brexpiprazole is purified via hydrochloride salt formation and neutralization. The reaction is represented in the following scheme II:
Formula I
Scheme II
Another Chinese patent application CN104829602 discloses a process for preparation of brexpiprazole of Formula I, which involves condensing 7-(4- chlorobutoxy)-3,4-dihydroquinolin-2(lH)-one of Formula B2 with hydrochloride salt of l-(benzo[b]thiophen-4-yl)piperazine, the compound of Formula II in a solvent selected from acetonitrile, ethanol, n-butanol, dioxane, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidone or a mixture thereof, to give 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)-3,4- dihydroquinolin-2(lH)-one, a compound of Formula CI . Dehydrogenation of the compound of Formula CI with 2,3-dichloro-5,6-dicyanobenzoquinone in a solvent selected from acetonitrile, ethanol, n-butanol, dioxane, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidone or a mixture thereof, to get brexpiprazole of Formula I. The reaction is schematically represented in the following scheme III:
Formula I
Scheme III
PCT patent publication WO2017078621 discloses a process for preparation of brexpiprazole of Formula I involving the following steps. l,l-dialkoxy-4- chlorobutane of Formula Dl is reacted with 7-hydroxyquinolin-2(lH)-one of Formula V in the presence of a base and a phase transfer catalyst in an organic solvent to form 7-(4,4-dialkoxybutyloxy)quinolin-2(lH)-one of Formula D2. The compound of Formula D2 is treated with an acid in an organic solvent to form 4- ((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butanal hydrate of Formula D3. Reductive
amination of the aldehyde of Formula D3 with hydrochloride salt of 1- (benzo[b]thiophen-4-yl)piperazine of Formula II in the presence of a reducing agent in an organic solvent to form brexpiprazole, the compound of Formula I. The crude brexpiprazole is purified via hydrochloride formation and neutralization. The
Scheme IV
(wherein Ri is Ci-Cis alkyl, or both Ri moieties in combination with oxygen group to which they are attached may form a 5-8 membered heterocycloalkyl ring).
Another PCT publication WO2017025987 discloses a process for the synthesis of brexpiprazole comprising the following steps. 7-hydroxyquinolin-2(lH)-one of Formula V is reacted with a protected alcohol compound of Formula El in the presence of a base and a solvent to form a compound of Formula E2. Deprotection via hydrolysis of the compound of Formula E2 in the presence of a solvent to give 7-(4-hydroxybutoxy)quinolin-2(lH)-one of Formula E3. The hydroxy group of the compound of Formula E3 is converted to a leaving group in the presence of a base and a solvent to get a compound of Formula E4. The compound of Formula E4 is reacted with protected piperazine compound of Formula E5 in the presence of a base to obtain a compound of Formula E6. Deprotection of the compound of Formula E6 is carried out to get 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one of Formula E7. The amine compound E7 is condensed with 4-halobenzo[b]thiophene
of Formula E8 to give brexpiprazole of Formula I. The reaction is represented in the following scheme V:
Scheme V
wherein R is hydroxyl protecting group; X and Y are the same or different and are halogen; LG is leaving group; and PG is amine protecting group.
There is always a need to develop a safe and cost effective process for the preparation of brexpiprazole, the 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 inventors of the present invention ameliorate the problems of the prior art processes by employing novel intermediate compounds as described herein that avoids the formation of major impurities, thereby eliminating the use of column chromatography for the purification of the intermediates, and the final product brexpiprazole, the compound of Formula I.
OBJECTIVES OF THE INVENTION:
The objective of the present invention is to prepare brexpiprazole, the compound of Formula I with an industrially viable and cost effective process.
Another objective of the present invention is to provide a process for the preparation of brexpiprazole, the compound of Formula I with controlled formation of impurities.
Yet another objective of the present invention is to provide novel intermediate compounds and an efficient process for the preparation of the novel intermediate compounds useful for the preparation of brexpiprazole, the compound of Formula I.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for preparing brexpiprazole, the compound of Formula I or its pharmaceutically acceptable salts using readily available, cost effective, and industrially safe starting materials.
According to primary object of the present invention, there is provided a novel, simple, cost effective and industrially safe process for the preparation of brexpiprazole, the compound of Formula I,
Formula I
which comprises the steps of :
a) reacting a compound of Formula VI with a compound of Formula IV in the presence of a suitable base and a solvent to obtain a compound of Formula VII
Formula VI Formula IV Formula VII wherein,
X is fluorine, chlorine, bromine or iodine; and
Y is selected from fluorine, chlorine, bromine or iodine; or -OR; wherein R is hydrogen, a hydroxyl protecting group, or a leaving group selected from alkyl sulfonate, aryl sulfonate and perfluoroalkyl sulfonate;
b) reacting the compound of Formula VII with l-(benzo[b]thiophen-4- yl)piperazine of Formula II or its salt in the presence of a base and a solvent to obtain a compound of Formula VIII or its salt,
Formula VTI Formula IT Formula VIII wherein, X and Y are as defined above;
c) hydrolyzing the compound of Formula VIII or its salt using a suitable reagent to isolate salt of brexpiprazole, the compound of Formula I; d) treating the compound obtained in step (c) with a base in presence of solvent to isolate brexpiprazole, the compound of Formula I; and
e) purifying the isolated compound of step (d) to obtain pure crystalline brexpiprazole, the compound of Formula I.
Yet, in another aspect, the present invention provides a process for purification of brexpiprazole, the compound of Formula I comprising;
i. suspending crude brexpiprazole, the compound of Formula I in a first solvent sufficient to achieve complete dissolution to get clear solution in hot condition;
ii. treating the solution with activated charcoal and filtering it hot;
iii. stirring and cooling the filtrate gradually to crystallise out solid mass and filtering ;
iv. suspending the wet solid mass in second solvent sufficient to achieve complete dissolution in hot condition;
v. cooling the solution to crystallize out solid mass; and
vi. filtering the solid obtained in step (v) to isolate pure crystalline brexpiprazole, the compound of Formula I.
In another aspect, the present invention provides a novel compound of Formula VII or a salt thereof,
Formula VII
wherein X is fluorine, chlorine, bromine or iodine; and
Y is selected from fluorine, chlorine, bromine, iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group, or a leaving group selected from alkyl sulfonate, arylsulfonate and perfluoroalkylsulfonate.
In another aspect, the present invention provides a novel compound of Formula VIII or a salt thereof,
Formula VIII
wherein, X is fluorine, chlorine, bromine or iodine.
DETAILED DESCRITION OF THE INVENTION:
The present invention relates to a process for preparing brexpiprazole, the compound of Formula I or its pharmaceutically acceptable salt.
The present invention discloses novel synthetic route for the preparation of brexpiprazole. Within the context of the present disclosure, the novel intermediates that are formed, provide an improved and efficient method for the synthesis of brexpiprazole, the compound of Formula I.
In an aspect, the present invention provides a process for the preparation of brexpiprazole, the compound of Formula I, which comprises the steps of;
a) reacting a compound of Formula VI with a compound of Formula IV in the presence of a suitable base and a solvent to obtain a compound of Formula
Formula VI Formula IV Formula VII wherein X is fluorine, chlorine, bromine or iodine;
Y is selected from fluorine, chlorine, bromine, iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group, or a leaving group selected from alkyl sulfonate, aryl sulfonate and perfluoroalkyl sulfonate; b) reacting the compound of Formula VII with l-(benzo[b]thiophen-4- yl)piperazine of Formula II or its salt in the presence of a base and a solvent
Formula VI I Formula I I Formula VIII wherein, X and Y is as defined above;
c) hydrolyzing the compound of Formula VIII or its salt using a suitable reagent to isolate salt of brexpiprazole, the compound of Formula I;
d) treating the compound obtained in step (c) with a base in presence of solvent to isolate brexpiprazole, the compound of Formula I; and
e) purifying the isolated compound of step (d) to obtain pure crystalline brexpiprazole, the compound of Formula I.
In an embodiment of the present invention, the suitable base used in step (a) of the process is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, Ν,Ν-diisopropylethylamine, diisopropylamine, pyridine, sodium tert-butoxide, potassium tert-butoxide, triethylamine or a mixture thereof. In an embodiment of the present invention, the preferred base used in step (a) of the process is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and triethyl amine, wherein the most preferred base used is potassium carbonate.
In an embodiment of the present invention, the solvent used in step (a) of the process is selected from the group consisting of ethyl acetate, acetone, methyl isobutyl
ketone, methanol, ethanol, isopropanol, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, toluene, xylene, heptane, cyclohexane, hexane, 2- methyltetrahydrofuran or a mixture thereof.
In an embodiment of the present invention, the preferred solvent used in step (a) of the process is selected from Ν,Ν-dimethylformamide, N,N-dimethylacetamide, methyl isobutyl ketone, methanol and 2-methyltetrahydrofuran, wherein the most preferred solvent used is N,N-dimethylacetamide.
In an embodiment of the present invention, the hydroxyl protecting group recited in the definition of R group is selected from acetyl, benzoyl, 2- methoxyethoxymethyl ether, methoxymethylether, pivaloyl and trityl.
In an embodiment of the present invention, the leaving group recited in the definition of R group is selected from methanesulfonate ion (mesylate), trifluoromethanesulfonate ion (triflate) and 4-methylbenzenesulfonate ion (tosylate).
In an embodiment of the present invention, the base used in step (b) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, N,N- diisopropylethylamine, diisopropylamine, pyridine, sodium tert-butoxide, potassium tert-butoxide and triethylamine or a mixture thereof. The preferred base used for the reaction is potassium carbonate.
In an embodiment of the present invention, the preferred base used in step (b) is selected from potassium bicarbonate, sodium bicarbonate, potassium tert-butoxide and triethylamine, wherein most preferred base used is sodium bicarbonate.
In an embodiment of the present invention, the solvent used in step (b) is selected from the group consisting of ethyl acetate, acetone, methyl isobutyl ketone, methanol, ethanol, isopropanol, Ν,Ν-dimethylformamide, N,N-dimethylacetamide,
toluene, xylene, heptane, cyclohexane, hexane and 2-methyltetrahydrofuran or a mixture thereof.
In an embodiment of the present invention, the preferred solvent used in step (b) of the process is selected from N,N-dimethylformamide, Ν,Ν-dimethylacetamide and 2-methyltetrahydrofuran, wherein the most preferred solvent used is N,N- dimethylformamide.
In an embodiment of the present invention, the reaction in step (b) is carried out in presence of a catalyst selected from the group consisting of sodium iodide, potassium iodide, potassium bromide, sodium bromide, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide and tetrabutyl phosphonium bromide or a mixture thereof.
In an embodiment of the present invention, the preferred catalyst used in step (b) reaction is selected from sodium iodide and potassium iodide.
In an embodiment of the present invention, the compound of Formula VIII is isolated from the reaction as a free base or its salt. The preferred salt of the compound of Formula VIII is hydrochloride salt, hydrobromide salt or acetate salt.
In an embodiment of the present invention, the suitable reagent used for the hydrolysis reaction in step (c) is an acidic reagent selected from the group of organic acids or mineral acids.
In an embodiment of the present invention, the organic acid used for hydrolysis is selected from the group consisting of formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfomc acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid and para- toluenesulfonic acid.
In an embodiment of the present invention, the mineral acid used for the hydrolysis is selected from the group consisting of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, perchloric acid, hydrofluoric acid and hydrobromic acid. The preferred acidic reagent used for the hydrolysis reaction is hydrochloric acid or acetic acid.
In an embodiment of the present invention the hydrolysis reaction of step (c) is carried out optionally in the presence of a solvent selected form the group consisting of toluene, xylene, chlorobenzene, dichloromethane, tetrahydrofuran, ethyl acetate, ethyl benzene, methyl isobutyl ketone, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, and water or a mixture thereof.
In an embodiment of the present invention, the salt isolated in step (c) is hydrochloride salt, hydrobromide salt or acetate salt of brexpiprazole, the compound of Formula I.
In an embodiment of the present invention, the base used in step (d) for treating the compound as obtained in step (c) above is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.
In an embodiment of the present invention, the preferred base used in step (d) is selected from, sodium carbonate, potassium carbonate and sodium hydroxide.
In an embodiment of the present invention, the solvent used in step (d) is selected from the group consisting of ethyl acetate, methyl isobutyl ketone, toluene, xylene, n-propanol, water and chlorobenzene or a mixture thereof. The preferred solvent used is toluene, xylene and methyl isobutyl ketone and water, wherein the most preferred solvent used is mixture of toluene and water.
In an embodiment of the present invention, the reaction in step (d) is carried out at a temperature in the range of 60°C to 80°C. The preferred temperature for treating the compound of step (c) is in the range of 60°C to 65°C.
In another embodiment of the present invention, the process for obtaining pure crystalline brexpiprazole, the compound of Formula I, in step (e) as above, comprises the steps of;
i. suspending crude brexpiprazole, the compound of Formula I in a first solvent sufficient to achieve complete dissolution to get a clear solution in hot condition;
ii. treating the solution of step (i) with activated charcoal and filtering it hot;
iii. stirring and cooling the filtrate gradually to crystallise out solid mass and filtering ;
iv. suspending the wet solid mass in second solvent sufficient to achieve complete dissolution in hot condition;
v. cooling the solution to crystallize out solid mass; and
vi. filtering the solid to isolate pure crystalline brexpiprazole, the compound of Formula I.
In an embodiment of the present invention, the first solvent used in step (i) of the process is selected from the group consisting of toluene, xylene, chlorobenzene, heptane, cyclohexane, hexane, tetrahydrofuran, 2-methyltetrahydrofuran, n- propanol, n-butanol, ethyl acetate, methyl isobutyl ketone, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane and ethylbenzene or a mixture thereof.
In an embodiment of the present invention the hot condition required for complete dissolution of crude brexpiprazole in step (i) is a temperature in the range of 80°C to 150°C. The preferred temperature for the dissolution is in the range of 100°C to 120°C. The most preferred temperature range for the dissolution is 107°C to 112°C.
In an embodiment of the present invention, the solution obtained in step (i) is charcoalised and filtered hot through a hyflobed. The filtrate is cooled gradually to 25°C to 30°C and maintained. Filtered the solid to get the crystalline solid mass.
In an embodiment of the present invention, the second solvent used in step (iv) of the process is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, methyl isobutyl ketone, dimethyl sulfoxide, toluene and water or a mixture thereof.
In an embodiment of the present invention, the hot condition required for complete dissolution of crude brexpiprazole in step (iv) is a temperature in the range of 60°C to 110°C. The preferred temperature for the dissolution is in the range of 70°C to 110°C. The most preferred temperature range for the dissolution is 90°C to 100°C.
In an aspect of the present invention brexpiprazole base, the compound of Formula I is converted to its pharmaceutically acceptable salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate or salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, p- toluenesulfonate and glutamate.
In an additional aspect, the present invention provides a novel compound of Formula VII or its salt thereof.
Formula VII
wherein,
X is fluorine, chlorine, bromine or iodine; and
Y is selected from fluorine, chlorine, bromine or iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group; or a leaving group selected from alkyl sulfonate, arylsulfonate and perfluoroalkylsulfonate.
In a preferred aspect of the present invention, in the compound of Formula VII, the "X" is -CI or -Br; and the "Y" is CI, Br or -OR wherein R is selected from H, acetyl, benzoyl, 2-methoxyethoxymethyl ether, methoxymethyl ether, pivaloyl, trityl, methanesulfonate ion (mesylate), trifluoromethanesulfonate ion (triflate) and 4- methylbenzenesulfonate ion (tosylate).
Still more preferably, the compound of Formula VII or a salt thereof according to the invention are selected from the following;
In an embodiment, the present invention provides the compound of formula VII (as described above) or its salt for use in the process for the manufacture of brexpiprazole, the compound of formula I.
In a further aspect, the present invention provides a novel compound of Formula VIII or its salt thereof.
Formula VIII
wherein, X is fluorine, chlorine, bromine or iodine.
The salts of compound of formula VIII are preferably selected from hydrochloride salt or acetate salt.
In an embodiment, the present invention provides the compound of formula VIII (as described above) for use in the process for the manufacture of brexpiprazole, the compound of formula I.
The advantage of the present invention over the existing prior art is that, it controls the formation of the impurities at the intermediate as well as the final stage. The present invention provides the final compound, brexpiprazole with increased yield, and avoids cumbersome purification process involved in the removal of the impurities, which makes the process industrially viable and overcome the problems associated with the processes known in the art. Thus, the present invention results in an industrially beneficial process and meets the ICH guidelines on the impurities to prepare pure brexpiprazole, the compound of Formula I.
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: Preparation of l-(benzo[b]thiophen-4-yl)piperazine
hydrochloride.
In a flask charged 4-bromobenzo[b]thiophene (50 gm, 0.235 mole), anhydrous piperazine (101.09 gm, 1.173 mole), sodium tert-butoxide (31.82 gm, 0.3309 mole), (2,2'-bis(diphenylphosphino)-l, l'-binaphthyl) (1.0 gm, 0.0016 mole), dipalladium tris(dibenzylideneacetone) (1.0 gm, 0.00109 mole) and toluene (500 ml) and refluxed for 1 hour under nitrogen atmosphere. The reaction completion was monitored on HPLC. After completion, the reaction mass was cooled to 25°C to 30°C and quenched with water (150 ml). Charged ethyl acetate, and extracted the aqueous layer. Separated the organic layer and concentrated the solvent under reduced pressure to get the residual mass. Charged solution of methanolic hydrochloride to the residual mass and stirred. Filtered the solid to isolate the product l-(benzo[b]thiophen-4-yl) piperazine hydrochloride (54.5 gm, 79.79%).
Example 2: Preparation of 7-hydroxyquinolin-2(lH)-one.
In a flask charged dichloromethane (1.0 liter), 7-hydroxy-3, 4-dihydroquinolin- 2(lH)-one (200 gm, 1.2257 mole) and acetic acid (73.5 gm, 1.225 mole) and stirred to form a solution. Charged 2,3-dichloro-5,6-dicyanobenzoquinone (334 gm, 1.47 mole) and continue stirring for 18 hrs at 25°C to 30°C. Monitored the completion of reaction on HPLC. After completion of reaction, the reaction mass was quenched with water and stirred. Filtered the solid mass and wet cake was leached in methanol to isolate pure 7-hydroxyquinolin-2(lH)-one (173 gm, 87.58%).
Example 3: Preparation of 2-Chloroquinolin-7-ol.
In a flask charged 7-hydroxyquinolin-2(lH)-one (100 gm, 0.6205 mol), N,N- dimethylformamide (200 ml), stirred and then charged phosphorus oxychloride (189.25 gm, 1.241 mol). The reaction mass was heated for to 70°C to 75°C, and monitored the completion of reaction on HPLC. After the reaction was completed, quenched the reaction mass with ice chilled water (600 ml) stirred for 1 hour and
adjusted pH between 7.0 - 7.5 using 40% sodium hydroxide solution. Raised the temperature to 25°C to 30°C. Filtered the solid to isolate the product, 2- chloroquinolin-7-ol (105 gm, 94.0%).
7.16-7.21 (2H m), 7.29-7.31QH, d), 7.85 - 7.87QH, d), 8.25-8.27 (lH,d), 10.4 (1H, bs).
IR(KBr): 1622cm"1, 1431cm"1, 1234cm"1, 1219cm"1, 1126cm"1, 1099cm"1, 950cm" 833cm"1, 748cm"1, 632cm"1.
Mass: 180.17 [M+H]+.
Example 4: Preparation of 2-chloroquinolin-7-ol.
In a flask charged N,N-dimethylformamide (20 ml), 7-hydroxyquinolin-2(lH)-one (10 gm, 0.06205 mole) and thionyl chloride (44.1gm, 0.370 mole). Raised the temperature of the reaction mass to 70°C to 75°C, and maintained. Monitored the completion of the reaction on HPLC. After the reaction was completed, quenched the reaction mass with ice chilled water (60 ml). Stirred for 1 hour and adjusted the pH in between 7.0 - 7.5 using 40% sodium hydroxide solution. Raised the temperature to 25°C to 30°C and maintained. Filtered the solid to isolate the product 2-chloroquinolin-7-ol (10.3gm, 92.45%).
Example 5: Preparation of 2-chloro-7-(4-chlorobutoxy)quinoline.
In a flask 2-chloroquinolin-7-ol (100 gm, 0.5535 mole) was dissolved in N,N- dimethylacetamide (400 ml). Charged water (15 ml) and potassium carbonate (152.99 gm, 1.1070 moles) at 25°C to 30°C and stirred for 15 minutes. Added 1- bromo-4-chlorobutane (379.6 gm, 2.214 mol) to the reaction mass and stirred at 25°C to 30°C for 5 to 6 hours. The completion of reaction was monitored by HPLC. After completion of the reaction, quenched the reaction mass with water (1.2 liters) and cyclohexane (200 ml). Stirred and filtered the solid mass to isolate the product 2-chloro-7-(4-chlorobutoxy)quinoline (125 gm, 83.11%).
1H- MR (CDC13) 5 ppm: 2.0 (4H, m), 3.60-3.64 (2H, t), 4.09-4.12 (2H, t), 7.15- 7.18 (1H, dd), 7.21-7.26 (lH,dd), 7.30 (lH,d), 7.65-7.68 (1H, d), 7.97-7.99 (1H, d).
JR (KBr): 2953 cm"1, 2873 cm"1, 1618 cm"1, 1496 cm"1, 1340 cm"1, 1213 cm"1, 1193 cm"1, 1130 cm"1, 835 cm"1, 719 cm"1. Mass: 270.16 [M+H]+.
Example 6: Preparation of 2-chloro-7-(4-chlorobutoxy)quinoline.
In a flask 2-chloroquinolin-7-ol (10.0 gm, 0.05535 mole) was dissolved in N,N- dimethylacetamide (40 ml). Charged water (1.5 ml) and potassium hydroxide (4.33 gm, 0.0774 mole) at 25°C to 30°C and stirred for 15 minutes. Added l-bromo-4- chlorobutane (37.96 gm, 0.2214 mol) to the reaction mass and stirred at 25°C to 30°C for 5 to 6 hours. The completion of reaction was monitored by HPLC. After completion of the reaction, quenched the reaction mass with water (120 ml) and cyclohexane (30 ml). Stirred and filtered the solid mass to isolate the product 2- chloro-7-(4-chlorobutoxy)quinoline (11.3 gm, 75.13%%).
Example 7: Preparation of 7-(4-chlorobutoxy)quinolin-2(lH)-one.
7-Hydroxyquinolin-2(lH)-one (100 gm, 0.6205 mole) was dissolved in N,N- dimethylacetamide (1.0 liter), 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(lH)-one (122.6 gm, 78.37%).
Example 8: Preparation of 2-chloro-7-(4-chlorobutoxy)quinoline.
In a flask charged 7-(4-chlorobutoxy)quinolin-2(lH)-one (20 gm, 0.0794 mole), toluene (100 ml), stirred and then charged phosphorus oxy chloride (24.3 gm, 0.1589 mole). The reaction mass was heated to 110-115°C, and monitored the completion of reaction on HPLC. After the reaction was completed, quenched the reaction mass with ice chilled water (100 ml), stirred, layers were separated and aqueous layer was again extracted with toluene (100 ml). Combined organic layer was washed with 100 ml 10% sodium bicarbonate solution. Toluene layer was distilled out at reduced pressure to obtain 2-chloro-7-(4-chlorobutoxy)quinoline (21 gm, 97.86%).
Example 9: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline acetate.
In a flask charged N,N-dimethylformamide (500 ml), 2-chloro-7-(4- chlorobutoxy)quinoline (100 gm, 0.369 mole), (l-benzo[b]thiophen-4-ylpiperazine hydrochloride (107.5 gm, 0.369 mole), sodium bicarbonate (124.12 gm, 1.477 mole), sodium iodide (60.8 gm, 0.406 mole), and stirred. Raised the temperature to 85°C to 90°C and maintained for 4-5 hours at the same temperature. The reaction completion was monitored on HPLC. After the reaction was completed, the reaction mass was cooled to 25-30°C and quenched with water (1.50 liters) and adjusted pH between 3 - 4 using acetic acid. The reaction mass was cooled to 0°C to 5°Cand stirred. Filtered the solid to isolate the product 7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-l-yl)butoxy)-2-chloroquinoline acetate (180 gm, 95.23%).
¾- MR (DMSO-de) δ ppm: 1.90-1.95 (2H, m), 1.97-1.99 (2H, m), 3.24-3.72 (6H, m), 3.52-3.55 (2H, d), 3.60-3.63 (2H, d), 4.20-4.22 (2H, t), 6.96 (1H, d), 7.29-7.33
(2H, m), 7.39 (1H, d), 7.41 (1H, dd), 7.50 (1H, d), 7.68 (1H, d), 7.77 (1H, d), 7.95 (1H, d), 8.35 (1H, d), 11.11 (1H, bs) .
JR (KBr): 2941 cm"1, 2814 cm"1, 1618 cm"1, 1497 cm"1, 1213 cm"1, 1128 cm"1, 837 cm"1, 748 cm"1.
Mass: 452.16 [M+H].+
Example 10: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline acetate.
In a flask charged N,N-dimethylformamide (1000 ml), 2-chloro-7-(4- chlorobutoxy)quinoline (100 gm, 0.369 mole), (l-benzo[b]thiophen-4- yl)piperazine hydrochloride (107.5 gm, 0.369 mole), potassium carbonate (102 gm, 0.738 mole), sodium iodide (60.8 gm, 0.406 mole), tetrabutyl ammonium bromide (1.0% w/w, 1.0 gm) and stirred. Raised the temperature of the reaction mass to 85°C to 90°C and maintained for 7 - 8 hours at the same temperature. The reaction was monitored on HPLC. After the reaction was completed, the reaction mass was cooled to 25-30°C and quenched with water (2.0 liters). Adjusted pH between 3 - 4 using acetic acid and cooled the reaction mass to 0 to 5°C. Filtered the solid mass to isolate the product, 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline acetate (180 gm, 95.23%).
Example 11: Preparation of 7-(4-(4-(Benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one.
In a flask charged toluene (700 ml), acetic acid (700 ml) and 7-(4-(4- (benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)-2-chloroquinoline acetate (180 gm, 0.351 mole) and stirred. Raised the temperature to 110°C to 115°C and maintained for 22 - 24 hours. The completion of the reaction was monitored by HPLC. After completion of the reaction, cooled the reaction mass to 0°C to 5°C temperature and filtered the solid mass. Charged the wet solid mass in purified water (600 ml) and adjusted the pH to 9 - 10 using 20% sodium carbonate solution. Charged toluene (600 ml) and heated the reaction mass to 60°C - 65°C, maintained for 2 hours, stopped heating and cooled the reaction mass to 25°C to 30°C and stirred. Filtered
the solid to isolate the product by filtration to obtain crude 7-(4-(4- (benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinolin-2(lH)-one (brexpiprazole) (120 gm, 78.72%).
1H- MR(DMSO-d6) δ ppm: 1.74-1.80 (2H, m), 1.87-1.90 (2H, m), 2.51-2.55 (2H, t) 2.72 (4H, m), 3.19(4H, m), 4.09-4.12(2H, t), 6.54-6.56 (1H, d), 6.80-6.82 (1H, dd), 6.88-6.90 (2H, m), 7.24-7.28 (1H, dd), 7.37-7.44 (3H, dd), 7.53-7.55 (1H, d), 7.77 (1H, d), 12.70 (1H, bs).
IR (KBr): 2941 cm"1, 2816 cm"1, 1647 cm"1, 1554 cm"1, 1219 cm"1, 1132 cm"1, 964 cm"l, 831 cm"1, 767cm"1.
Mass: 434.21 [M+H]+.
Example 12: Purification of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one (Brexpiprazole).
In a flask charged toluene (1.0 liter) and 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin- l-yl)butoxy)quinolin-2(lH)-one (100 gm, 0.2306 mole). Raised the temperature to reflux temperature and maintained to get a clear solution. Charged activated charcoal slurry and maintained for 30 minutes at reflux. Filtered hot solution through hyflo bed. Cooled the reaction mass gradually to 25°C to 30°C and stirred. Filtered the solid mass. The wet solid mass was suspended in n-propanol (2.0 litres) and recrystallised to isolate pure crystalline brexpiprazole (75 gm, 75.0%).
Example 13: Preparation of 2-bromoquinolin-7-ol.
In a flask charged N,N-dimethylformamide (10 ml), 7-hydroxyquinolin-2(lH)-one (5 gm, 0.031mole) and stirred. Charged phosphorus tribromide (16.7 gm, 0.0618 moles) and raised the temperature of the reaction mass to 70°C to 75°C. Maintained the reaction mass for 3 - 4 hours at 70°C to 75°C. The reaction was monitored on HPLC. After reaction was completed, then quenched reaction mass with ice chilled water (30 ml) and stirred for 1 hour. Adjusted the pH to 7.0 - 7.5 using 40% sodium hydroxide solution and raised the temperature to 25°C to 30°C. Filtered the solid to obtain 2-bromoquinolin-7-ol (5.5 gm, 79 %).
δ ρριη: 6.76-6.77 (1H, s), 6.97-7.00 (1H, d), 7.03-7.06, (1H, d), 7.56-7.58 (1H, d), 7.87-7.89 (1H, d).
IR(KBr): 2800-3600 cm"1 (bs), 1600 cm"1, 1479 cm"1, 1427 cm"1, 1359 cm"1, 1230 cm-1, 1118 cm-1, 937 cm-1, 835cm-1, 740cm-1, 648cm-1.
Mass: 224 [M+H]+.
Example 14: Preparation of 2-bromo-7-(4-chlorobutoxy)quinoline.
In a flask 2-bromoquinolin-7-ol (3 gm, 0.0134 mole) was dissolved in N,N- dimethylacetamide (12 ml), then added water (0.45 ml, 15% w/v) and potassium carbonate (3.7 gm, 0.0267 moles) at 25°C to 30°C. Stirred for 15 minutes and added l-bromo-4-chlorobutane (9.13 gm, 0.0532 moles) to the reaction mass and stirred for 5 - 6 hours at 25°C to 30°C. The reaction was monitored on HPLC, after the reaction was completed, quenched with water (36 ml) and cyclohexane (3 ml). The solid was isolated by filtration to obtain 2-bromo-7-(4-chlorobutoxy)quinoline (3.0 gm, 71.25%).
5 ppm: 1.90-1.91 (4H, m), 3.75 (2H, t), 4.16(2H, t), 7.27- 7.30 (1H, dd), 7.35-7.36 (1H, d), 7.49-7.51 (1H, d), 7.89-7.92 (1H, d), 8.20-8.22 (1H, d).
IR (KBr): 2951 cm-1, 2873 cm-1, 1614 cm-1, 1494 cm-1, 1338 cm-1, 1211cm-1, 1190cm-1, 1124cm-1, 835cm-1, 717 cm-1.
Mass: 313.60[M+H]+.
Example 15: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-bromoquinoline acetate.
In a flask charged Ν,Ν-dimethylformamide (18ml), 2-bromo-7-(4- chlorobutoxy)quinoline (1.8 gm, 0.0057 mole), (l-benzo[b]thiophen-4- yl)piperazine hydrochloride (1.38 gm, 0.0054 mole), sodium bicarbonate (1.91 gm, 0.023 mole), sodium iodide (0.93 gm, 0.0062 mole), tetrabutylammonium bromide (0.018 gm, 1.0% w/w) and stirred. Raised the temperature to 85°C - 90°C and maintained for 4-5 hours at the same temperature. The reaction was monitored on HPLC. After the reaction was completed, the reaction mass was cooled to 25-30°C,
then quenched with water (54 ml) and adjusted the pH 3 - 4 using acetic acid. Cooled the reaction mass to 0 to 5°C and filtered the solid to obtain 7-(4-(4- (benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)-2-bromoquinoline acetate (2.8 gm, 88.05%).
!H- MR MSO-de) 5 ppm: 1.92 (4H, m), 2.9-3.7 (10H, m), 4.22 (2H, t), 6.94- 6.96 (1H, d), 7.29-7.33 (2H, m), 7.41 (1H, d), 7.47-7.48 (1H, dd), 7.53-7.55 (1H, d), 7.67-7.69 (1H, d), 7.75-7.76 (1H, d), 7.95 (1H, d), 8.24-8.26 (1H, d).
IR (KBr): 3057 cm"1, 2953 cm"1, 2831 cm"1, 1622 cm"1, 1219 cm"1, 1122 cm"1, 956 cm-1, 835 cm-1, 746 cm-1.
Mass- 497.75 [M+H]+.
Example 16: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one.
In a flask charged 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)-2- bromoquinoline acetate (2.0 gm, 0.0035 mole) in acetic acid (9 ml) and toluene (9 ml) and stirred. Raised the temperature to 110°C to 115°C and maintained for 22 - 24 hours. Cooled the reaction mass to 0°C to 5°C, the product was isolated by filtration, wet cake was charged in purified water (12 ml) and adjusted the pH 9 - 10 using 20%) sodium carbonate solution. After adjustment of pH added toluene (12 ml) and heated reaction mass to 60-65°C for 2 hours, then cooled to 25-30°C and the solid was isolated by filtration to obtain crude 7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-l-yl)butoxy)quinolin-2(lH)-one (brexpiprazole) (1.3 gm, 83.70%>).
Example 17: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one.
In a flask charged 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)-2- chloroquinoline acetate (5.0 gm, 0.0035 mole) in dilute 10%> hydrochloric acid (50 ml) and stirred. Raised the temperature to 110°C to 115°C and maintained for 22 - 24 hours. Cooled the reaction mass to 0°C to 5°C, the product was isolated by filtration, wet cake was charged in purified water (30 ml) and adjusted the pH 9 -
10 using 20% sodium carbonate solution, after adjustment of pH added toluene (30 ml) and heated reaction mass to 60-65°C for 2 hours, then cooled to 25-30°C and the solid was isolated by filtration to obtain crude 7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-l-yl)butoxy)quinolin-2(lH)-one (brexpiprazole) (3.2 gm, 75.82%).
Example 18: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)-2-chloroquinoline.
In a flask charged N, N-dimethylformamide (500 ml), 2-chloro-7-(4-chlorobutoxy) quinoline (100 gm, 0.369 mole), (l-benzo[b]thiophen-4-ylpiperazine hydrochloride (89.41 gm, 0.350 mole), sodium bicarbonate (124.12 gm, 1.477 mole), sodium iodide (41.50 gm, 0.277 mole), and stirred. Raised the temperature to 80°C - 85°C and maintained for 4-5 hours at the same temperature. The reaction completion was monitored on HPLC. After the reaction was completed, the reaction mass was cooled to 25°C - 30°C and quenched with water (600ml) and extracted with toluene (2 x 600ml), stirred and separated the layer. Distilled out toluene layer under vacuum at 50-55°C to obtain 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1- yl)butoxy)-2-chloroquinoline (175 gm 98.64%).
Example 19: Preparation of 7-(4-(4-(Benzo[b]thiophen-4-yl) piperazin-1- yl)butoxy)quinolin-2(lH)-one.
In a flask charged toluene (640 ml), acetic acid (640 ml), 7-(4-(4- (benzo[b]thiophen-4-yl) piperazin-l-yl)butoxy)-2-chloroquinoline (175gm, 0.387 mole) and stirred. Raised the temperature to 110°C - 115°C and maintained for 16 - 20 hours. The completion of the reaction was monitored by HPLC. After completion of the reaction, cooled the reaction mass to 25°C - 35°C and quenched reaction mass with 960ml water, stirred and filtered the solid mass. Charged the wet solid mass in solution of sodium carbonate (150gm in 1280ml purified water). Charged toluene (960 ml) and heated the reaction mass to 60°C - 65 °C, maintained for 2 hours, stopped heating and cooled the reaction mass to 25°C - 30°C and stirred. The solid was isolated by filtration to obtain crude 7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-l-yl)butoxy)quinolin-2(lH)-one (brexpiprazole) (lOlgm, 60.16%).
Example 20: Purification of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one (Brexpiprazole).
In a flask charged n- propanol (500ml), 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin- l-yl)butoxy)quinolin-2(lH)-one (100 gm, 0.2306 mole) and DMSO(200ml). Raised the temperature to reflux temperature and maintained to get a clear solution. Charged activated charcoal slurry and maintained for 30 minutes at reflux. Filtered hot solution through hyflo bed. Cooled the reaction mass gradually to 25°C to 30°C and stirred. Filtered the solid mass. The wet solid mass was washed with methanol 100ml) to obtained pure crystalline brexpiprazole (90 gm, 90.0%).
Claims
1. A process for preparation of brexpiprazole, the compound of Formula I,
which comprises the steps of:
a) reacting a compound of Formula VI with a compound of Formula IV
Formula VI Formula IV Formula VII wherein,
X is fluorine, chlorine, bromine or iodine; and
Y is selected from fluorine, chlorine, bromine or iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group; or a leaving group;
b) reacting the compound of Formula VII with l-(benzo[b]thiophen-4- yl)piperazine, the compound of Formula II or its salt, in the presence of a base and a solvent to form a compound of Formula VIII or its salt;
Formula VII Formula II Formula VIII wherein, X and Y are as defined above;
c) hydrolysing the compound of Formula VIII or its salt using a suitable reagent to isolate salt of brexpiprazole, the compound of Formula I; d) treating the compound obtained in step (c) with a base in presence of solvent to isolate brexpiprazole, the compound of Formula I; and e) purifying the isolated compound of step (d) to obtain pure crystalline brexpiprazole, the compound of Formula I.
2. The process according to claim 1, wherein the suitable base used in step (a) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, N,N-diisopropylethylamine, diisopropylamine, pyridine, sodium tert-butoxide, potassium tert- butoxide and triethylamine or a mixture thereof.
3. The process according to claim 1, wherein the solvent used in step (a) is selected from the group consisting of ethyl acetate, acetone, methyl isobutyl ketone, methanol, ethanol, isopropanol, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, toluene, xylene, heptane, cyclohexane, hexane and 2-methyltetrahydrofuran or a mixture thereof.
4. The process according to claim 1, wherein the base used in step (b) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, N,N-diisopropylethylamine, diisopropylamine, pyridine, sodium tert-butoxide, potassium tert- butoxide and triethylamine or a mixture thereof.
5. The process according to claim 1, wherein the solvent used in step (b) is selected from the group consisting of ethyl acetate, acetone, methyl isobutyl ketone, methanol, ethanol, isopropanol, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, toluene, xylene, heptane, cyclohexane, hexane and 2-methyltetrahydrofuran or a mixture thereof.
6. The process according to claim 1, wherein the reaction of step (b) is carried out in the presence of a catalyst selected from the group consisting of sodium iodide, potassium iodide, potassium bromide,
sodium bromide, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide and tetrabutyl phosphonium bromide or a mixture thereof.
7. The process according to claim 1, wherein the suitable reagent used for hydrolysis in step (c) is an acid selected from an organic acid or a mineral acid.
8. The process according to claim 7, wherein the reagent used for hydrolysis is an organic acid selected from the group consisting of formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid and para-toluenesulfonic acid.
9. The process according to claim 7, wherein the reagent used for hydrolysis is mineral acid selected from the group consisting of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, perchloric acid, hydrofluoric acid and hydrobromic acid.
10. The process according to claim 1, wherein the hydrolysis in step (c) is optionally carried out in presence of a solvent selected from the group consisting of toluene, xylene, chlorobenzene, dichloromethane, tetrahydrofuran, ethyl acetate, ethyl benzene, methyl isobutyl ketone, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, and water or a mixture thereof.
11. The process according to claim 1, wherein the base used for treating in step (d) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.
12. The process according to claim 1, wherein the solvent used in step (d) is selected from the group consisting of ethyl acetate, methyl isobutyl ketone, toluene, xylene, n-propanol, water and chlorobenzene or a mixture thereof.
13. The process according to claim 1, wherein the reaction in step (d) is carried out at a temperature in the range of 60°C to 80°C.
14. The process according to claim 1, wherein the hydroxyl protecting group recited in the definition of R group is selected from the group consisting of acetyl, benzoyl, 2-methoxyethoxymethyl ether, methoxymethylether, pivaloyl and trityl.
15. The process according to claim 1, wherein the leaving group recited in the definition of R group is selected from the group consisting of alkyl sulfonate, arylsulfonate and perfluoroalkylsulfonate.
16. The process according to claim 15, wherein the leaving group is selected from the group consisting of methanesulfonate ion (mesylate), trifluoromethanesulfonate ion (triflate) and 4-methylbenzenesulfonate ion (tosylate).
17. The process according to claim 1, wherein the salt of the compound of Formula VIII is hydrochloride salt, hydrobromide salt or acetate salt.
18. The process according to claim 1, wherein the purification process of step (e) comprises the following steps;
i. suspending crude brexpiprazole, the compound of Formula I in a first solvent sufficient to achieve complete dissolution to get clear solution in hot condition;
ii. treating the solution with activated charcoal and filtering it hot;
iii. stirring and cooling the filtrate gradually to crystallise out solid mass and filtering it ;
iv. suspending the wet solid mass in second solvent sufficient to achieve complete dissolution in hot condition;
v. cooling the solution to crystallize out solid mass; and vi. filtering the solid to isolate pure crystalline brexpiprazole, the compound of Formula I.
19. The process according to claim 18, wherein, the first solvent used in step (i) of the process is selected from the group consisting of toluene, xylene, chlorobenzene, heptane, cyclohexane, hexane, tetrahydrofuran, 2-methyltetrahydrofuran, n-propanol, n-butanol, ethyl acetate, methyl
isobutyl ketone, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane and ethylbenzene or a mixture thereof.
20. The process according to claim 18, wherein, the dissolution in step (i) is carried out at a temperature in the range of 80°C to 150°C to obtain a clear solution.
21. The process according to claim 18, wherein, the second solvent used in step (iv) of the process is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, methyl isobutyl ketone, dimethylsulfoxide and toluene; or a mixture thereof.
22. The process according to claim 18, wherein, the dissolution in step (iv) is carried out at a temperature in the range of 60°C to 110°C.
Formula VII
wherein, X is fluorine, chlorine, bromine or iodine; and
Y is selected from fluorine, chlorine, bromine or iodine, or -OR; wherein R is hydrogen, a hydroxyl protecting group; or a leaving group selected from alkyl sulfonate, arylsulfonate and perfluoroalkylsulfonate.
24. The compound of Formula VII or a salt thereof as claimed in claim 23, are
b)
Formula VIII
wherein, X is fluorine, chlorine, bromine or iodine.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN201721036332 | 2017-10-12 | ||
IN201721036332 | 2017-10-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019073481A1 true WO2019073481A1 (en) | 2019-04-18 |
Family
ID=66101306
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2018/050643 WO2019073481A1 (en) | 2017-10-12 | 2018-10-10 | Process for the preparation of brexpiprazole and its intermediates |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2019073481A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7888362B2 (en) * | 2005-04-14 | 2011-02-15 | Otsuka Pharmaceutical Co., Ltd. | Piperazine-substituted benzothiophenes for treatment of mental disorders |
WO2017078621A1 (en) * | 2015-11-03 | 2017-05-11 | Scinopharm Taiwan, Ltd. | Processes for preparing brexpiprazole |
WO2017115287A1 (en) * | 2015-12-28 | 2017-07-06 | Honour (R&D) | Process for the preparation of quinoline-2(1h)-one derivatives |
-
2018
- 2018-10-10 WO PCT/IN2018/050643 patent/WO2019073481A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7888362B2 (en) * | 2005-04-14 | 2011-02-15 | Otsuka Pharmaceutical Co., Ltd. | Piperazine-substituted benzothiophenes for treatment of mental disorders |
WO2017078621A1 (en) * | 2015-11-03 | 2017-05-11 | Scinopharm Taiwan, Ltd. | Processes for preparing brexpiprazole |
WO2017115287A1 (en) * | 2015-12-28 | 2017-07-06 | Honour (R&D) | Process for the preparation of quinoline-2(1h)-one derivatives |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8324244B2 (en) | Process and intermediates for preparing integrase inhibitors | |
US7799916B2 (en) | Process for the preparation of 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide | |
CN102770420B (en) | Novel process for the manufacture of dronedarone | |
US8334381B2 (en) | Process for the preparation of intermediates useful in the synthesis of imatinib | |
EP0235762A1 (en) | 8-Position substituted quinolone-carboxylic acid derivatives and process for their preparation | |
AU2005273430B2 (en) | Methods for producing isoindole derivatives | |
US6653307B2 (en) | 1-aryl-4-oxo-1,4-dihydro-3-quinolinecarboxamides as antiviral agents | |
WO2018172463A1 (en) | Process for the preparation of brexpiprazole | |
WO2020108522A1 (en) | Preparation method for deuterated macrocyclic compound | |
JP4953822B2 (en) | Method for producing muscarinic receptor antagonist and intermediate thereof | |
US20090198059A1 (en) | Process for the preparation of polymorphs, solvates of aripiprazole using aripirazole acid salts | |
EP2608791B1 (en) | A process for the preparation of imatinib base | |
IL182439A (en) | Intermediates useful for the preparation of aripiprazole and methods for the preparation of the intermediates and aripiprazole | |
WO2011070588A1 (en) | Process for the preparation of imatinib and salts thereof | |
WO2019073481A1 (en) | Process for the preparation of brexpiprazole and its intermediates | |
US5914401A (en) | Methods for the manufacture of quinolone carboxylic acids derivatives and intermediates thereof | |
KR20170013800A (en) | Process of Preparing a Quinazoline Derivative | |
WO2007148191A2 (en) | An improved process for the preparation of aripiprazole | |
JPH10109982A (en) | Flavone derivative and medicine containing the same | |
JPH06100540A (en) | 5-isoquinolinesulfonic acid amide derivative | |
KR20060113792A (en) | An improved process for preparing pure ondansetron hydrochloride dihydrate | |
JP3234627B2 (en) | Pyrano [2,3-f] quinoline derivative | |
EP3609875B1 (en) | An improved process for the preparation of n-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin -4-amine dihydrochloride | |
TWI545120B (en) | Process for producing 3,4-dihydroisoquinoline derivatives and intermediates for the production of such derivatives | |
JP2002519424A (en) | 3-alkylpyrrolo [3,2-c] quinoline derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18866412 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 18866412 Country of ref document: EP Kind code of ref document: A1 |