WO2014037886A1 - Process for the preparation of lurasidone hydrochloride - Google Patents

Process for the preparation of lurasidone hydrochloride Download PDF

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Publication number
WO2014037886A1
WO2014037886A1 PCT/IB2013/058288 IB2013058288W WO2014037886A1 WO 2014037886 A1 WO2014037886 A1 WO 2014037886A1 IB 2013058288 W IB2013058288 W IB 2013058288W WO 2014037886 A1 WO2014037886 A1 WO 2014037886A1
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formula
trans
dicarboxylic acid
lurasidone
isomer
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PCT/IB2013/058288
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French (fr)
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Suresh Babu Jayachandra
Udaibhan Singh Gahlot
Tarun Kumar Singh
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • an antipsychotic agent useful for the treatment of schizophrenia.
  • Lurasidone hydrochloride is chemically (3aR,4S,7R,7aS)-2- ⁇ (lR,2R)-2-[4- (l,2-benzisothiazol-3-yl)piperazin-l-ylmethyl]cyclohexylmethyl ⁇ hexahydro-4,7-methano- 2H-isoindole-l,3-dione hydrochloride, having the structure represented by Formula I.
  • the present inventors have developed an improved process that involves separating the racemic trans- 1 ,2-cyclohexane dicarboxylic acid of Formula III into its (R,R)-trans- and (S,S)-?ra «s-isomers, and then using the desired (R,R)-?ra «s-isomer for the preparation of lurasidone hydrochloride. Since the process of the present invention involves the separation of the undesired (S,S)-?ra «s-isomer in the initial stages of the manufacturing process, it overcomes the difficulty associated with the formation of the undesired isomers of the intermediates formed in the subsequent steps.
  • the present inventors have found that when a co-base is added to the reaction mixture along with the chiral amine, the quantity of the chiral amine required for carrying out the chiral resolution is significantly reduced. Additionally, the use of a co-base also results in the use of a less solvent, reduced reaction time, no need for carrying out multiple crystallizations, better chiral purity and increased yield. Thus, the use of a co-base in chiral resolution process is industrially advantageous.
  • the present inventors have developed an improved, eco-friendly, industrially advantageous, and cost-effective process for the chiral resolution of the racemic trans- 1 ,2- cyclohexane dicarboxylic acid of Formula III using a co-base along with a chiral amine.
  • the use of the co-base at the chiral resolution step is industrially advantageous as it reduces the amount of the costly chiral amine required for the chiral resolution and provides the ?ra «s-(R,R)- l,2-cyclohexane dicarboxylic acid of better chiral purity.
  • trans-(R,R)- 1 ,2-cyclohexane dicarboxylic acid obtained by the process of the present invention, provides highly pure lurasidone hydrochloride.
  • the process of the present invention can be carried out in-situ without isolating one or more of the intermediates.
  • a first aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
  • a second aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
  • R is a C 1 -C4 alkyl group or a benzyl group
  • R' is a leaving group
  • a third aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
  • R is a C1-C4 alkyl group or a benzyl group
  • R' is a leaving group
  • a fourth aspect of the present invention provides the use of the trans (R,R)- 1 ,2- cyclohexane dicarboxylate having chiral purity greater than 99.5% for the preparation of lurasidone hydrochloride.
  • a fifth aspect of the present invention provides lurasidone hydrochloride having less than 0.05% of the isomer of Formula XIV
  • a sixth aspect of the present invention provides lurasidone hydrochloride having less than 0.05% of the isomer of Formula XV
  • a seventh aspect of the present invention provides lurasidone hydrochloride having less than 0.05% of the bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
  • An eighth aspect of the present invention provides lurasidone hydrochloride free of the lurasidone oxide impurity of Formula XVI
  • a ninth aspect of the present invention provides lurasidone hydrochloride having less than 0.15% of total impurities, as determined by HPLC.
  • a tenth aspect of the present invention provides lurasidone hydrochloride having less 0.05% of any single impurity, as determined by HPLC.
  • ambient temperature refers to a temperature in the range of about 20°C to about 35°C.
  • contacting refers to dissolving, slurrying, stirring, or combinations thereof.
  • total impurities refers to the sum of known and unknown impurities in lurasidone hydrochloride.
  • any single impurity refers to the bicyclo[2.2. l]heptane- 2-exo-3-exo-dicarboximide of Formula VIII, the isomer of Formula XIV, the isomer of Formula XV, or the lurasidone oxide impurity of Formula XVI.
  • Racemic trans- 1 ,2-cyclohexane dicarboxylic acid of Formula III to be used for the preparation of lurasidone hydrochloride of Formula I of the present invention, may be obtained by the methods known in the literature such as that disclosed in U.S. Patent No. 5,532,372. It may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation or it may be isolated, and then used for the synthesis of lurasidone hydrochloride.
  • the chiral amine is selected from the group comprising of (R)- 1 -phenylethyl amine, alpha-methylbenzylamine, l-(l -naphthyl)-ethylamine, sec-butylamine l -amino-2- methylbutane, ⁇ , ⁇ -dimethyl- 1 -phenylethylamine, 1 -cyclohexylethylamine, 2- (methoxymethyl)-pyrrolidine, l -(4-nitrophenyl)-ethylamine, 2-amino- l-butanol, 1 -amino- 2-propanol, cinchonidine, brucine, strychnine, cinchonine, N-methyl-ephedrine, and alpha- phenyl-glycinol.
  • the chiral amine used is (R)- 1 -phenylethyl amine.
  • the co-base is selected from the group comprising of trimethylamine,
  • the co-base used is triethylamine or diisopropylamine.
  • Resolution may be carried out using solvent(s) selected from the group comprising of alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles,
  • hydrocarbons or mixtures thereof.
  • alcohols include methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol.
  • ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • alkyl acetates include ethyl acetate and isopropyl acetate.
  • chlorinated hydrocarbons include dichloromethane and chloroform.
  • ethers include diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
  • nitriles include acetonitrile and propionitrile.
  • hydrocarbons include benzene, xylene, toluene, hexanes, heptanes, and pentane.
  • Addition of the chiral amine and the co-base into the reaction mixture containing the racemic trans- 1 ,2-cyclohexane dicarboxylic acid is carried out slowly at a temperature of about 0°C to about - 100°C.
  • the reaction mixture is stirred for about 10 minutes to about 2 hours, warmed to ambient temperature, further stirred for about 2 hours to about 10 hours, optionally cooled to about - 10°C to aboutl 0°C, and stirred for about 10 minutes to about 1 hour.
  • Isolation of the resolved salt of the (R,R)-?ra «s- l ,2-cyclohexane dicarboxylic acid with the chiral amine is accomplished by filtration and drying. Drying may be carried out using any suitable method such as drying under reduced pressure, drying under atmospheric pressure, air drying, or drying with aeration of inert gas such as nitrogen, at a temperature of about 40°C to about 80°C for about 2 hours to about 10 hours.
  • the resolved salt of the (R,R)-?ra «s-l,2-cyclohexane dicarboxylic acid with the chiral amine is further purified by crystallization using solvent(s) selected from the group comprising of alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles, or mixtures thereof.
  • solvents selected from the group comprising of alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles, or mixtures thereof.
  • alcohols include methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol.
  • hydrocarbons examples include benzene, xylene, toluene, hexane, heptanes, and pentane.
  • ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • alkyl acetates examples include ethyl acetate and isopropyl acetate.
  • chlorinated hydrocarbons include dichloromethane and chloroform.
  • ethers examples include diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
  • nitriles examples include acetonitrile and propionitrile.
  • the resolved salt of the (R,R)- trans- 1 ,2-cyclohexane dicarboxylic acid with the chiral amine is purified by techniques known in the art, such as crystallization. Crystallization is carried out by dissolving the resolved salt of trans- 1 ,2-cyclohexane dicarboxylic acid formed with the chiral amine in a solvent mixture comprising an alcohol and a hydrocarbon at a temperature of about 50°C to about 100°C, cooling the solution to about - 10°C to ambient temperature, stirring for about 30 minutes to about 2 hours, then isolating the product. In a preferred embodiment of the present invention, the crystallization is carried out using a mixture of ethanol and toluene.
  • the conversion of the (R,R)-?ra «s-l,2-cyclohexane dicarboxylic acid into the dicarboxylate intermediate of Formula X is carried out by contacting the (R,R)-trans- ⁇ ,2- cyclohexane dicarboxylic acid with a mixture of a C1-C4 alcohol and a hydrocarbon solvent at a temperature of about 5°C to ambient temperature.
  • C1-C4 alcohols include methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, and sec- butanol.
  • hydrocarbons examples include benzene, xylene, toluene, hexane, heptanes, and pentane.
  • the conversion of the (R,R)-?ra «s-l,2-cyclohexane dicarboxylic acid into the dicarboxylate intermediate of Formula X is carried out in the presence of concentrated sulphuric acid.
  • the reaction mixture is stirred at about 25°C to about 60°C for about 1 hour to about 24 hours, and concentrated. Isolation of the dicarboxylate intermediate of Formula X is accomplished by the addition deionized water, solvent extraction, and concentration.
  • the dicarboxylate intermediate of Formula X may be isolated from the reaction mixture and then used in the next stage, or the reaction mixture containing the dicarboxylate intermediate of Formula X is concentrated, and the concentrated organic layer is used as such in the next stage.
  • the trans (R,R)- ⁇ ,2- cyclohexane dicarboxylic acid is converted into the trans (R,R)- 1 ,2-dimethyl cyclohexane dicarboxylate of Formula X by contacting with methanol at about 10°C to about 15°C, adding concentrated sulphuric acid, stirring the reaction mixture at about 50°C for about 20 hours, followed by concentrating the reaction mixture under reduced pressure at about 50°C, and isolation.
  • the trans (R,R)- ⁇ ,2- cyclohexane dicarboxylic acid is converted into the trans (R,R)- l,2-dimethyl cyclohexane dicarboxylate of Formula X by contacting with a mixture of methanol and toluene at ambient temperature, adding concentrated sulphuric acid, stirring the reaction mixture at about 50°C to about 60°C for about 20 hours, followed by concentrating the reaction mixture under reduced pressure.
  • the conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2-bis(hydroxymethyl)cyclohexane of Formula XI is carried out in an inert atmosphere by slowly adding a reducing agent at a temperature of about - 10°C to ambient temperature in a hydrocarbon or ether solvent.
  • the reaction mixture is warmed to ambient temperature, and stirred for about 2 hours to about 10 hours.
  • About 2N hydrochloric acid solution is added to the reaction mixture at about -5°C to about 60°C.
  • the reaction mixture is stirred for about 10 hours to 20 hours, filtered, and concentrated.
  • Examples of reducing agents for the conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane of Formula XI include diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, calcium borohydride, and lithium triethylborohydride.
  • Examples of hydrocarbon solvents include benzene, xylene, toluene, hexane, heptanes, and pentane.
  • Examples of ethers include diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme, and dioxane.
  • the conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane of Formula XI is carried out using diisobutyl aluminum hydride in a hydrocarbon solvent.
  • the conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2- bis(hydroxymethyl) cyclohexane of Formula XI is carried out using diisobutyl aluminum hydride in toluene.
  • Formula XI is converted into a leaving group by reaction with a halide or a sulphonyl compound to obtain an intermediate of Formula XII.
  • halide compounds include thionyl chloride and thionyl bromide.
  • sulphonyl compounds include alkyl- or aryl-sulphonyl halides selected from the group comprising of methane sulphonyl chloride, ethane sulphonyl chloride, p-toluene sulphonyl chloride, or benzene sulphonyl chloride.
  • An organic or inorganic base is added at about -5°C to ambient temperature.
  • Examples of organic bases include triethylamine, ammonia, and pyridine.
  • Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the conversion is carried out in the presence of hydrocarbon or chlorinated hydrocarbon solvents such as dichloromethane, chloroform, toluene, or pyridine at a temperature of about - 10°C to about 10°C.
  • the reaction mixture is stirred at ambient temperature for about 1 hour to about 8 hours. De- ionized water is added.
  • the reaction mixture is further stirred, and the aqueous layer is extracted with a hydrocarbon solvent.
  • the organic layers are combined and concentrated.
  • the trans (R,R)- ⁇ ,2- Z «s(hydroxymethyl)cyclohexane is converted into the trans (R,R)- 1 ,2- Z «s(methanesulfonylmethyi)cyclohexane using methane sulphonyl chloride in the presence of triethylamine at a temperature of about 0°C to about 15°C in toluene.
  • the reaction mixture is stirred at ambient temperature for about 2 hours. Deionized water is added. The reaction mixture is further stirred, and the aqueous layer is extracted with toluene. The organic layers are combined and concentrated.
  • trans (R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane is converted into the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'-(l,2-benzoisothiazole-3- yl)]piperazine methane sulfonate of Formula Vila by contacting with 3-(l-piperazinyl-l,2- benzisothiazole) of Formula VI in a nitrile or amide solvent in the presence of a base.
  • nitrile solvents include acetonitrile and propionitrile.
  • amide solvents include N, N-dimethylformamide or ⁇ , ⁇ -diethylformamide.
  • bases include carbonates, bicarbonates, and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the reaction mixture is refluxed for about 15 hours to 2 days, filtered, and concentrated at about 40°C to 80°C under reduced pressure to obtain a residue.
  • a ketone solvent such as acetone, methyl ethyl ketone, or methyl isobutyl ketone is added, and the reaction mixture is stirred at ambient temperature to about 60°C.
  • a hydrocarbon solvent such as benzene, xylene, toluene, hexane, heptanes, or pentane is added.
  • the reaction mixture is again stirred for about 10 minutes to about 2 hours at ambient temperature, filtered, washed with a mixture of ketone and hydrocarbon solvent, and dried at about 40°C to about70°C under reduced pressure for about 10 hours to about 20 hours to obtain the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'- (l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila.
  • the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2-benzoisothiazole- 3-yl)]piperazine methane sulfonate is reacted with bicyclo[2.2.1 ]heptane-2-exo-3-exo- dicarboximide of Formula VIII in the presence of a base.
  • bases include carbonates, bicarbonates, and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, or potassium hydroxide. Hydrides of alkali metals such as sodium hydride and potassium hydride may also act as base.
  • the reaction is carried out in a hydrocarbon solvent selected from the group comprising of benzene, xylene, toluene, hexane, heptanes, and pentane.
  • a hydrocarbon solvent selected from the group comprising of benzene, xylene, toluene, hexane, heptanes, and pentane.
  • the reaction mixture is refluxed for about 1 hour to about 20 hours, filtered, treated with activated carbon, and concentrated at about 40°C to about 100°C under reduced pressure.
  • a solvent mixture of 2-propanol and acetone is added to the residue. Contents are stirred for about 30 minutes to about 5 hours, filtered, washed with a 2- propanokacetone solvent mixture, and dried under reduced pressure at ambient temperature for about 1 hour.
  • Lurasidone is converted into lurasidone hydrochloride by the drop-wise addition of aqueous hydrochloric acid to a solution of lurasidone in a solvent at ambient temperature to reflux temperature of the solvent, preferably at about 40°C to about 65°C.
  • the reaction mixture is cooled to ambient temperature, stirred for about 1 hour to about 5 hours, further cooled to about 5°C to about 15°C, stirred again for about 10 minutes to about 1 hour, and then isolated.
  • solvents include alcohols, alkyl acetates, ketones, or hydrocarbons.
  • Examples of alcohols include methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol.
  • Examples of alkyl acetates include ethyl acetate and isopropyl acetate.
  • Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • Examples of hydrocarbons include benzene, xylene, toluene, hexane, heptanes, and pentane.
  • lurasidone is converted into lurasidone hydrochloride by adding 15% aqueous hydrochloric acid to a solution of lurasidone in acetone.
  • Lurasidone hydrochloride of the present invention has a chiral purity greater than 99.5%.
  • Lurasidone hydrochloride of the present invention contains less than 0.05% of the isomer of Formula XIV. In a preferred embodiment of the present invention, lurasidone hydrochloride contains less than 0.03% w/w of the isomer of Formula XIV.
  • Lurasidone hydrochloride of the present invention contains less than 0.05% of the isomer of Formula XV. In a preferred embodiment of the present invention, lurasidone hydrochloride contains less than 0.03% of isomer of Formula XV.
  • Lurasidone hydrochloride of the present invention contains less than 0.05% of the bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII. In a preferred embodiment of the present invention, lurasidone hydrochloride contains less than 0.02% of the bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII.
  • Lurasidone hydrochloride of the present invention contains no detectable amount of the lurasidone oxide impurity of Formula XVI.
  • Lurasidone hydrochloride of the present invention contains less than 0.15% of total impurities as determined by HPLC.
  • Lurasidone hydrochloride of the present invention contains less 0.05% of any single impurity as determined by HPLC.
  • Lurasidone hydrochloride prepared by the process of the present invention is an easy to filter, free-flowing solid, having a small average particle size.
  • HPLC purity was determined using a Water Alliance, Model 2695 instrument.
  • the chiral purity was determined using an Agilent, Model 6890 series instrument.
  • the reaction mixture was stirred for 30 minutes, warmed to ambient temperature, stirred for 2.5 hours, further cooled to 0°C to -5°C, and stirred for 30 minutes.
  • the trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (Formula X; 810 mL) obtained above as the organic layer was added slowly to diisobutyl aluminum hydride (1200 g, 25% solution in toluene) at 0°C to 20°C in an inert atmosphere.
  • the reaction mixture was warmed to ambient temperature, stirred for 4 hours, and then quenched by drop-wise addition of about 2N HC1 (420 mL) at 0°C to 40°C.
  • the reaction mixture was further stirred for 18 hours and filtered.
  • the filtrate was concentrated under reduced pressure to obtain the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane (Formula XI; 915 mL) as the organic layer.
  • Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (Formula VIII; 38.16 g) and potassium carbonate (43.5 g) were added to a solution of trans (R,R)-3a,7a- octahydroisoindolium-2-spiro- 1 '-[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (Formula Vila; 90 g) in toluene (900 mL). The reaction mixture was refluxed for 10 hours. The inorganic salts were filtered through a celite bed and washed with toluene (180 mL).
  • Aqueous hydrochloric acid (15%; 90 g) was slowly added to a clear solution of lurasidone (Formula XIII; 91 g; wet) in acetone (1350 mL) at 55°C.
  • the reaction mixture was allowed to cool to about 26°C, stirred for 3 hours, further cooled to 1 1°C, stirred again for 30 minutes, and filtered.
  • the wet solid was again stirred with acetone (135 mL) at 13°C, filtered, washed with acetone (135 mL), and dried at 60°C under reduced pressure to obtain lurasidone hydrochloride (Formula I; 89.6 g).

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Abstract

Provided herein is a process for the preparation of the antipsychotic agent lurasidone hydrochloride useful for the treatment of schizophrenia.

Description

PROCESS FOR THE PREPARATION OF LURASIDONE HYDROCHLORIDE
Field of the Invention
Provided herein is a process for the preparation of an antipsychotic agent useful for the treatment of schizophrenia.
Background of the Invention
The present invention provides a process for the preparation of lurasidone hydrochloride. Lurasidone hydrochloride is chemically (3aR,4S,7R,7aS)-2- {(lR,2R)-2-[4- (l,2-benzisothiazol-3-yl)piperazin-l-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano- 2H-isoindole-l,3-dione hydrochloride, having the structure represented by Formula I.
Figure imgf000002_0001
Formula I
U.S. Patent No. 5,532,372 discloses the preparation of lurasidone hydrochloride by the process as depicted in Scheme I:
Scheme I
Figure imgf000003_0001
Formula IX
The process disclosed in U.S. Patent No. 5,532,372 involves the use of the racemic trans- 1 ,2-cyclohexane dicarboxylic acid of Formula III as an intermediate. The trans- \,2- cyclohexane dicarboxylic acid of Formula III further exists as (R,R)-trans and (S,S)-trans isomers. Out of the (R,R)-trans and (S,S)-trans isomers of the ?ra«s- l,2-cyclohexane dicarboxylic acid of Formula III, only the (R,R)-?ra«sisomer is required for the preparation of lurasidone.
Since the process disclosed in U.S. Patent No. 5,532,372 involves the use of racemic trans- 1 ,2-cyclohexane dicarboxylic acid, the undesired (S,S)-trans isomer is carried through the subsequent steps. Thus, in the process disclosed in U.S. Patent No. 5,532,372, a chiral resolution step (i.e., chiral resolution of the free base of Formula IX) was carried out in the last stages of the synthetic process to obtain lurasidone free base. The lurasidone free base, thus obtained, was then converted into lurasidone hydrochloride.
However, carrying out the chiral resolution of the intermediate of Formula IX is difficult, costly, and not suitable for an industrial scale preparation due to the presence of six chiral centers in the free base of Formula IX. Further, carrying out the chiral resolution of the intermediate of Formula IX affects the overall yield and cost of the manufacturing process.
Thus, there exists a need in the art for the development of an easy, cost-effective, and industrially advantageous process for the preparation of lurasidone hydrochloride which overcomes the difficulties of the prior art process.
The present inventors have developed an improved process that involves separating the racemic trans- 1 ,2-cyclohexane dicarboxylic acid of Formula III into its (R,R)-trans- and (S,S)-?ra«s-isomers, and then using the desired (R,R)-?ra«s-isomer for the preparation of lurasidone hydrochloride. Since the process of the present invention involves the separation of the undesired (S,S)-?ra«s-isomer in the initial stages of the manufacturing process, it overcomes the difficulty associated with the formation of the undesired isomers of the intermediates formed in the subsequent steps.
Processes for the chiral resolution of the trans- 1 ,2-cyclohexane dicarboxylic acid of Formula III using (R)- 1 -phenylethyl amine are disclosed in the European Journal of Organic Chemistry, 2002 (17) 2948-2952, and Analytical Sciences, 15(6) 609-610 (1999). The disclosed processes are time consuming and costly, and involve the use of an equimolar ratio of the racemic trans- 1 ,2-cyclohexane dicarboxylic acid and the chiral amine, large amounts of the solvent, long reaction time, and multiple crystallizations for obtaining the desired (R,R)-trans-isomer.
Since chiral amines are costly reagents, there exists a need in the art for a chiral resolution process that requires a lesser amount of the chiral amine.
The present inventors have found that when a co-base is added to the reaction mixture along with the chiral amine, the quantity of the chiral amine required for carrying out the chiral resolution is significantly reduced. Additionally, the use of a co-base also results in the use of a less solvent, reduced reaction time, no need for carrying out multiple crystallizations, better chiral purity and increased yield. Thus, the use of a co-base in chiral resolution process is industrially advantageous.
Summary of the Invention
The present inventors have developed an improved, eco-friendly, industrially advantageous, and cost-effective process for the chiral resolution of the racemic trans- 1 ,2- cyclohexane dicarboxylic acid of Formula III using a co-base along with a chiral amine. The use of the co-base at the chiral resolution step is industrially advantageous as it reduces the amount of the costly chiral amine required for the chiral resolution and provides the ?ra«s-(R,R)- l,2-cyclohexane dicarboxylic acid of better chiral purity.
Additional advantages offered by the use of the co-base during the chiral resolution step include better yield, shorter reaction time, less solvent, and the elimination of the need for carrying out multiple crystallizations for obtaining the desired purity. The trans-(R,R)- 1 ,2-cyclohexane dicarboxylic acid, obtained by the process of the present invention, provides highly pure lurasidone hydrochloride. The process of the present invention can be carried out in-situ without isolating one or more of the intermediates.
A first aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
Figure imgf000005_0001
Formula I
comprising the steps of:
i) resolving a trans (racemic)- 1,2-cyclohexane dicarboxylic acid of Formula III
Figure imgf000005_0002
Formula III
trans (racemic) into a trans (R,R)-l,2-cyclohexane dicarboxylic acid using a chiral amine in the presence of a co-base; and
ii) converting the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid into lurasidone hydrochloride of Formula I.
A second aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
Figure imgf000006_0001
Formula I
comprising the steps of:
i) resolving a trans (racemic)- l,2-cyclohexane dicarboxylic acid of Formula III
Figure imgf000006_0002
Formula III
trans (racemic)
into a trans (R,R)-l,2-cyclohexane dicarboxylic acid by reacting with a chiral amine in the presence of a co-base;
ii) converting the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid into a trans (R,R)-dicarboxylate intermediate of Formula X,
Figure imgf000006_0003
Formula X
trans(R,R)-isomer
wherein R is a C1-C4 alkyl group or a benzyl group;
iii) converting the trans (R,R)-dicarboxylate intermediate of Formula X into a trans (R,R)- l,2-bis(hydroxymethyl) cyclohexane of Formula XI;
Figure imgf000007_0001
Formula XI
trans(R,R)-isomer
converting the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane of Formula XI into an intermediate of Formula XII,
Figure imgf000007_0002
Formula XII
fra/7s(R,R)-isomer
wherein R' is a leaving group;
reacting the intermediate of Formula XII with 3 -( 1 -piperazinyl)- 1 ,2- benzisothiazole of Formula VI
Figure imgf000007_0003
Formula VI
to obtain a trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- l '-[4'-(l ,2- benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
Figure imgf000008_0001
Formula Vila
frans(R,R)-isomer
reacting the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'-(l,2- benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila with bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
Figure imgf000008_0002
Formula VIII
to obtain lurasidone of Formula XIII; and
Figure imgf000008_0003
Formula XIII
vii) treating the lurasidone of Formula XIII with hydrogen chloride to obtain lurasidone hydrochloride of Formula I.
A third aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
Figure imgf000009_0001
Formula I
comprising the steps of:
i) resolving a trans (racemic)- l,2-cyclohexane dicarboxylic acid of Formula III
Figure imgf000009_0002
Formula III
trans (racemic)
into trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid by reacting with a chiral amine in the presence of a co-base;
converting the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid into a trans (R,R)-dicarboxylate intermediate of Formula X,
Figure imgf000009_0003
Formula X
frans(R,R)-isomer
wherein R is a C1-C4 alkyl group or a benzyl group;
converting the trans (R,R)-dicarboxylate intermediate of Formula X into a trans (R,R)- l,2-bis(hydroxymethyl)cyclohexane of Formula XI;
Figure imgf000010_0001
Formula XI
frans(R,R)-isomer
converting the trans (R,R)- 1 ,2-bis(hydroxymethyl)cyclohexane of Formula XI into an intermediate of Formula XII,
Figure imgf000010_0002
Formula XII
fra/7s(R,R)-isomer
wherein R' is a leaving group;
reacting the intermediate of Formula XII with 3 -( 1 -piperazinyl)- 1 ,2- benzisothiazole of Formula VI
Figure imgf000010_0003
Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- l '-[4'-(l ,2- benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
Figure imgf000011_0001
Formula Vila
frans(R,R)-isomer
reacting the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'-(l,2- benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila with bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
Figure imgf000011_0002
Formula VIII
to obtain lurasidone of Formula XIII; and
Figure imgf000011_0003
Formula XIII
vii) treating the lurasidone of Formula XIII with hydrogen chloride to obtain lurasidone hydrochloride of Formula I, wherein the process is carried out without the isolation of the intermediates of Formulae X, XI, and XII.
A fourth aspect of the present invention provides the use of the trans (R,R)- 1 ,2- cyclohexane dicarboxylate having chiral purity greater than 99.5% for the preparation of lurasidone hydrochloride.
A fifth aspect of the present invention provides lurasidone hydrochloride having less than 0.05% of the isomer of Formula XIV
Figure imgf000012_0001
Formula XIV
as determined by HPLC.
A sixth aspect of the present invention provides lurasidone hydrochloride having less than 0.05% of the isomer of Formula XV
Figure imgf000012_0002
Formula XV
as determined by HPLC.
A seventh aspect of the present invention provides lurasidone hydrochloride having less than 0.05% of the bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
Figure imgf000012_0003
Formula VIII
as determined by HPLC.
An eighth aspect of the present invention provides lurasidone hydrochloride free of the lurasidone oxide impurity of Formula XVI
Figure imgf000013_0001
Formula XVII
as determined by HPLC.
A ninth aspect of the present invention provides lurasidone hydrochloride having less than 0.15% of total impurities, as determined by HPLC.
A tenth aspect of the present invention provides lurasidone hydrochloride having less 0.05% of any single impurity, as determined by HPLC.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term "ambient temperature", as used herein, refers to a temperature in the range of about 20°C to about 35°C.
The term "contacting", as used herein, refers to dissolving, slurrying, stirring, or combinations thereof.
The term "total impurities", as used herein, refers to the sum of known and unknown impurities in lurasidone hydrochloride.
The term "any single impurity", as used herein, refers to the bicyclo[2.2. l]heptane- 2-exo-3-exo-dicarboximide of Formula VIII, the isomer of Formula XIV, the isomer of Formula XV, or the lurasidone oxide impurity of Formula XVI.
Racemic trans- 1 ,2-cyclohexane dicarboxylic acid of Formula III, to be used for the preparation of lurasidone hydrochloride of Formula I of the present invention, may be obtained by the methods known in the literature such as that disclosed in U.S. Patent No. 5,532,372. It may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation or it may be isolated, and then used for the synthesis of lurasidone hydrochloride. The chiral amine is selected from the group comprising of (R)- 1 -phenylethyl amine, alpha-methylbenzylamine, l-(l -naphthyl)-ethylamine, sec-butylamine l -amino-2- methylbutane, Ν,Ν-dimethyl- 1 -phenylethylamine, 1 -cyclohexylethylamine, 2- (methoxymethyl)-pyrrolidine, l -(4-nitrophenyl)-ethylamine, 2-amino- l-butanol, 1 -amino- 2-propanol, cinchonidine, brucine, strychnine, cinchonine, N-methyl-ephedrine, and alpha- phenyl-glycinol. In a preferred embodiment of the present invention, the chiral amine used is (R)- 1 -phenylethyl amine.
The co-base is selected from the group comprising of trimethylamine,
triethylamine, diisopropylamine, Ν,Ν-diisopropylethylamine, N-methylmorpholine, and pyridine. In the preferred embodiments of the present invention, the co-base used is triethylamine or diisopropylamine.
Resolution may be carried out using solvent(s) selected from the group comprising of alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles,
hydrocarbons, or mixtures thereof. Examples of alcohols include methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol. Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of alkyl acetates include ethyl acetate and isopropyl acetate. Examples of chlorinated hydrocarbons include dichloromethane and chloroform. Examples of ethers include diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
Examples of nitriles include acetonitrile and propionitrile. Examples of hydrocarbons include benzene, xylene, toluene, hexanes, heptanes, and pentane.
Addition of the chiral amine and the co-base into the reaction mixture containing the racemic trans- 1 ,2-cyclohexane dicarboxylic acid is carried out slowly at a temperature of about 0°C to about - 100°C. The reaction mixture is stirred for about 10 minutes to about 2 hours, warmed to ambient temperature, further stirred for about 2 hours to about 10 hours, optionally cooled to about - 10°C to aboutl 0°C, and stirred for about 10 minutes to about 1 hour.
Isolation of the resolved salt of the (R,R)-?ra«s- l ,2-cyclohexane dicarboxylic acid with the chiral amine is accomplished by filtration and drying. Drying may be carried out using any suitable method such as drying under reduced pressure, drying under atmospheric pressure, air drying, or drying with aeration of inert gas such as nitrogen, at a temperature of about 40°C to about 80°C for about 2 hours to about 10 hours.
The resolved salt of the (R,R)-?ra«s-l,2-cyclohexane dicarboxylic acid with the chiral amine is further purified by crystallization using solvent(s) selected from the group comprising of alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles, or mixtures thereof. Examples of alcohols include methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol. Examples of hydrocarbons include benzene, xylene, toluene, hexane, heptanes, and pentane. Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of alkyl acetates include ethyl acetate and isopropyl acetate. Examples of chlorinated hydrocarbons include dichloromethane and chloroform. Examples of ethers include diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
Examples of nitriles include acetonitrile and propionitrile.
In a preferred embodiment of the present invention, the resolved salt of the (R,R)- trans- 1 ,2-cyclohexane dicarboxylic acid with the chiral amine is purified by techniques known in the art, such as crystallization. Crystallization is carried out by dissolving the resolved salt of trans- 1 ,2-cyclohexane dicarboxylic acid formed with the chiral amine in a solvent mixture comprising an alcohol and a hydrocarbon at a temperature of about 50°C to about 100°C, cooling the solution to about - 10°C to ambient temperature, stirring for about 30 minutes to about 2 hours, then isolating the product. In a preferred embodiment of the present invention, the crystallization is carried out using a mixture of ethanol and toluene.
The conversion of the (R,R)-?ra«s-l,2-cyclohexane dicarboxylic acid into the dicarboxylate intermediate of Formula X is carried out by contacting the (R,R)-trans- \,2- cyclohexane dicarboxylic acid with a mixture of a C1-C4 alcohol and a hydrocarbon solvent at a temperature of about 5°C to ambient temperature. Examples of C1-C4 alcohols include methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, and sec- butanol. Examples of hydrocarbons include benzene, xylene, toluene, hexane, heptanes, and pentane. The conversion of the (R,R)-?ra«s-l,2-cyclohexane dicarboxylic acid into the dicarboxylate intermediate of Formula X is carried out in the presence of concentrated sulphuric acid. The reaction mixture is stirred at about 25°C to about 60°C for about 1 hour to about 24 hours, and concentrated. Isolation of the dicarboxylate intermediate of Formula X is accomplished by the addition deionized water, solvent extraction, and concentration.
In the process of the present invention, the dicarboxylate intermediate of Formula X may be isolated from the reaction mixture and then used in the next stage, or the reaction mixture containing the dicarboxylate intermediate of Formula X is concentrated, and the concentrated organic layer is used as such in the next stage.
In a preferred embodiment of the present invention, the trans (R,R)- \,2- cyclohexane dicarboxylic acid is converted into the trans (R,R)- 1 ,2-dimethyl cyclohexane dicarboxylate of Formula X by contacting with methanol at about 10°C to about 15°C, adding concentrated sulphuric acid, stirring the reaction mixture at about 50°C for about 20 hours, followed by concentrating the reaction mixture under reduced pressure at about 50°C, and isolation.
In another preferred embodiment of the present invention, the trans (R,R)-\,2- cyclohexane dicarboxylic acid is converted into the trans (R,R)- l,2-dimethyl cyclohexane dicarboxylate of Formula X by contacting with a mixture of methanol and toluene at ambient temperature, adding concentrated sulphuric acid, stirring the reaction mixture at about 50°C to about 60°C for about 20 hours, followed by concentrating the reaction mixture under reduced pressure.
The conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2-bis(hydroxymethyl)cyclohexane of Formula XI is carried out in an inert atmosphere by slowly adding a reducing agent at a temperature of about - 10°C to ambient temperature in a hydrocarbon or ether solvent. The reaction mixture is warmed to ambient temperature, and stirred for about 2 hours to about 10 hours. About 2N hydrochloric acid solution is added to the reaction mixture at about -5°C to about 60°C. The reaction mixture is stirred for about 10 hours to 20 hours, filtered, and concentrated. Examples of reducing agents for the conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane of Formula XI include diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, calcium borohydride, and lithium triethylborohydride. Examples of hydrocarbon solvents include benzene, xylene, toluene, hexane, heptanes, and pentane. Examples of ethers include diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme, and dioxane.
In a preferred embodiment of the present invention, the conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane of Formula XI is carried out using diisobutyl aluminum hydride in a hydrocarbon solvent. In a more preferred embodiment of the present invention, the conversion of the dicarboxylate intermediate of Formula X into the trans (R,R)- 1 ,2- bis(hydroxymethyl) cyclohexane of Formula XI is carried out using diisobutyl aluminum hydride in toluene.
The hydroxyl group of the trans (R,R)-l,2-bis(hydroxymethyl) cyclohexane of
Formula XI is converted into a leaving group by reaction with a halide or a sulphonyl compound to obtain an intermediate of Formula XII. Examples of halide compounds include thionyl chloride and thionyl bromide. Examples of sulphonyl compounds include alkyl- or aryl-sulphonyl halides selected from the group comprising of methane sulphonyl chloride, ethane sulphonyl chloride, p-toluene sulphonyl chloride, or benzene sulphonyl chloride. An organic or inorganic base is added at about -5°C to ambient temperature. Examples of organic bases include triethylamine, ammonia, and pyridine. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. The conversion is carried out in the presence of hydrocarbon or chlorinated hydrocarbon solvents such as dichloromethane, chloroform, toluene, or pyridine at a temperature of about - 10°C to about 10°C. The reaction mixture is stirred at ambient temperature for about 1 hour to about 8 hours. De- ionized water is added. The reaction mixture is further stirred, and the aqueous layer is extracted with a hydrocarbon solvent. The organic layers are combined and concentrated.
In a preferred embodiment of the present invention, the trans (R,R)- \,2- Z«s(hydroxymethyl)cyclohexane is converted into the trans (R,R)- 1 ,2- Z«s(methanesulfonylmethyi)cyclohexane using methane sulphonyl chloride in the presence of triethylamine at a temperature of about 0°C to about 15°C in toluene. The reaction mixture is stirred at ambient temperature for about 2 hours. Deionized water is added. The reaction mixture is further stirred, and the aqueous layer is extracted with toluene. The organic layers are combined and concentrated. The trans (R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane is converted into the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'-(l,2-benzoisothiazole-3- yl)]piperazine methane sulfonate of Formula Vila by contacting with 3-(l-piperazinyl-l,2- benzisothiazole) of Formula VI in a nitrile or amide solvent in the presence of a base. Examples of nitrile solvents include acetonitrile and propionitrile. Examples of amide solvents include N, N-dimethylformamide or Ν,Ν-diethylformamide. Examples of bases include carbonates, bicarbonates, and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. The reaction mixture is refluxed for about 15 hours to 2 days, filtered, and concentrated at about 40°C to 80°C under reduced pressure to obtain a residue. A ketone solvent such as acetone, methyl ethyl ketone, or methyl isobutyl ketone is added, and the reaction mixture is stirred at ambient temperature to about 60°C. A hydrocarbon solvent such as benzene, xylene, toluene, hexane, heptanes, or pentane is added. The reaction mixture is again stirred for about 10 minutes to about 2 hours at ambient temperature, filtered, washed with a mixture of ketone and hydrocarbon solvent, and dried at about 40°C to about70°C under reduced pressure for about 10 hours to about 20 hours to obtain the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'- (l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila.
The trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2-benzoisothiazole- 3-yl)]piperazine methane sulfonate is reacted with bicyclo[2.2.1 ]heptane-2-exo-3-exo- dicarboximide of Formula VIII in the presence of a base. Examples of bases include carbonates, bicarbonates, and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, or potassium hydroxide. Hydrides of alkali metals such as sodium hydride and potassium hydride may also act as base. The reaction is carried out in a hydrocarbon solvent selected from the group comprising of benzene, xylene, toluene, hexane, heptanes, and pentane. The reaction mixture is refluxed for about 1 hour to about 20 hours, filtered, treated with activated carbon, and concentrated at about 40°C to about 100°C under reduced pressure. A solvent mixture of 2-propanol and acetone is added to the residue. Contents are stirred for about 30 minutes to about 5 hours, filtered, washed with a 2- propanokacetone solvent mixture, and dried under reduced pressure at ambient temperature for about 1 hour. Lurasidone is converted into lurasidone hydrochloride by the drop-wise addition of aqueous hydrochloric acid to a solution of lurasidone in a solvent at ambient temperature to reflux temperature of the solvent, preferably at about 40°C to about 65°C. The reaction mixture is cooled to ambient temperature, stirred for about 1 hour to about 5 hours, further cooled to about 5°C to about 15°C, stirred again for about 10 minutes to about 1 hour, and then isolated. Examples of solvents include alcohols, alkyl acetates, ketones, or hydrocarbons. Examples of alcohols include methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol. Examples of alkyl acetates include ethyl acetate and isopropyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of hydrocarbons include benzene, xylene, toluene, hexane, heptanes, and pentane. In a preferred embodiment of the present invention, lurasidone is converted into lurasidone hydrochloride by adding 15% aqueous hydrochloric acid to a solution of lurasidone in acetone.
Lurasidone hydrochloride of the present invention has a chiral purity greater than 99.5%.
Lurasidone hydrochloride of the present invention contains less than 0.05% of the isomer of Formula XIV. In a preferred embodiment of the present invention, lurasidone hydrochloride contains less than 0.03% w/w of the isomer of Formula XIV.
Lurasidone hydrochloride of the present invention contains less than 0.05% of the isomer of Formula XV. In a preferred embodiment of the present invention, lurasidone hydrochloride contains less than 0.03% of isomer of Formula XV.
Lurasidone hydrochloride of the present invention contains less than 0.05% of the bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII. In a preferred embodiment of the present invention, lurasidone hydrochloride contains less than 0.02% of the bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII.
Lurasidone hydrochloride of the present invention contains no detectable amount of the lurasidone oxide impurity of Formula XVI.
Lurasidone hydrochloride of the present invention contains less than 0.15% of total impurities as determined by HPLC.
Lurasidone hydrochloride of the present invention contains less 0.05% of any single impurity as determined by HPLC.
Lurasidone hydrochloride prepared by the process of the present invention is an easy to filter, free-flowing solid, having a small average particle size.
In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. The examples are not intended in any way to limit the scope of the present invention, and variants within the scope of the invention would be evident to persons ordinarily skilled in the art.
Methods
The HPLC purity was determined using a Water Alliance, Model 2695 instrument. The chiral purity was determined using an Agilent, Model 6890 series instrument.
EXAMPLES
Example 1 : Preparation of the Trans L2-dimethyl cyclohexane dicarboxylate (Formula X)
A reaction mixture containing racemic trans- 1 ,2-cyclohexane dicarboxylic acid (Formula III; 15 g; 0.0871 mole) in ethanol (1 12 mL) was cooled to -72°C. (R)- l- phenylethyl amine (5.3 g; 0.0435 mole) and diisopropylamine (4.4 g; 0.0435 mole) were added slowly to the reaction mixture. The reaction mixture was stirred for 30 minutes, warmed to ambient temperature, stirred for 2.5 hours, further cooled to 0°C to -5°C, and stirred for 30 minutes. The reaction mixture was filtered, washed with chilled ethanol (10 mL), and dried under reduced pressure at 40°C to 45°C to obtain the crude salt of trans (R,R)-l,2-cyclohexane dicarboxylic acid with (R)- 1 -phenylethyl amine (9.5 g).
5 g of the crude salt was dissolved in an ethanol:toluene mixture (180 mL; 1 : 1 mixture) at 70°C to 80°C. The solution was cooled to 0°C to 5°C, stirred for 2 hours, filtered, and dried under reduced pressure to obtain the purified salt of the trans (R,R)-l,2- cyclohexane dicarboxylic acid with (R)- 1 -phenylethyl amine (4.2 g).
A solution of the purified salt of trans (R,R)- l,2-cyclohexane dicarboxylic acid with (R)-l -phenylethyl amine (4.2 g) in methanol (40 mL) was cooled to 10°C to 15°C. Sulphuric acid (4 mL) was added. The reaction mixture was stirred at 50°C for 20 hours, and then concentrated under reduced pressure at 50°C. Deionized water (15 mL) was added. The reaction mixture was extracted with ethyl acetate (2x35 mL). The organic layer was washed with 5% sodium bicarbonate solution (15 mL) and brine (15 mL), and concentrated at 55°C under reduced pressure to obtain the trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (Formula X; 2.6 g).
Chiral Purity: 99.87%
Example 2: Preparation of the Trans (R.R -3a,7a-octahydroisoindolium-2-spiro- -r4'-(l,2- benzoisothiazole-3-yl)lpiperazine methane sulfonate (Formula Vila)
A reaction mixture containing the trans- 1 ,2-cyclohexane dicarboxylic acid (Formula III; 200 g; 1.16 mole) in iso-propanol (2000 mL) was cooled to below -5°C. (R)-l -phenyl ethylamine (84.5g; 0.696 mole) and diisopropyl amine (47g; 0.464 mole) were added slowly to the reaction mixture. The reaction mixture was warmed to ambient temperature, stirred for 5 hours to 6 hours, filtered, washed with 2-propanol (200mL), and dried at ambient temperature under reduced pressure to obtain a crude salt of the trans (R,R)-l,2-cyclohexane dicarboxylic acid with (R)- 1 -phenylethyl amine (228.4 g).
219 g of the crude salt was stirred in a toluene:ethanol mixture (2000 mL; 1 : 1 mixture) at 70°C to 80°C for 1 hour to 2 hours. The reaction mixture was cooled to 10°C to 15°C, stirred fori hour to 2 hours, filtered, washed with a toluene:ethanol mixture (200 mL; 1 : 1 mixture), and dried under reduced pressure to obtain the purified salt of the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid with (R)- 1 -phenylethyl amine (124.5 g, wet; S- isomer: 0.26%).
The purified salt of the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid with (R)- 1 - phenylethyl amine (123.5 g wet) was added to a mixture of methanol (410 mL) and toluene (950 mL) followed by the addition of sulphuric acid (73.9 mL) at ambient temperature. The reaction mixture was stirred at 55°C for 20 hours. Deionized water (680 mL) was added to the reaction mixture, and the layers were separated. The aqueous layer was further extracted with toluene (410 mL). The organic layers were combined, washed with brine, and concentrated at about 60°C under reduced pressure to obtain the trans (R,R)- 1 ,2-dimethyl cyclohexane dicarboxylate (Formula X; 810 mL).
The trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (Formula X; 810 mL) obtained above as the organic layer was added slowly to diisobutyl aluminum hydride (1200 g, 25% solution in toluene) at 0°C to 20°C in an inert atmosphere. The reaction mixture was warmed to ambient temperature, stirred for 4 hours, and then quenched by drop-wise addition of about 2N HC1 (420 mL) at 0°C to 40°C. The reaction mixture was further stirred for 18 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane (Formula XI; 915 mL) as the organic layer.
The trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane (Formula XI; 810 mL;
obtained above as the organic layer) was taken, and methane sulfonyl chloride (154.2 g) and triethylamine (182 g) were added to it at 0°C to 15°C. The reaction mixture was stirred at ambient temperature for 2 hours. Deionized water (120 mL) was added, the reaction mixture was stirred at 40°C to 45°C for 30 minutes, and the layers were separated. The aqueous layer was further extracted with toluene (200 mL). The organic layers were combined, washed with about 5% brine solution (130 mL), and the trans (R,R)- 1 ,2-bis (methanesulfonylmethyl)cyclohexane was separated as the organic layer (Formula XII; l lOO mL).
The trans (R,R)-\,2-bis (methanesulfonylmethyl)cyclohexane (Formula XII; 1 100 mL; obtained above as organic layer) was concentrated completely under reduced pressure at 60°C. Acetonitrile (1300 mL), 3-(l-piperazinyl-l,2-benzisothiazole) (Formula VI; 94.5 g), and sodium carbonate (91.3 g) were added at 30°C. The reaction mixture was refluxed for 20 hours, and then filtered at 70°C. The inorganic salts were further stirred with acetonitrile (325 mL) at 70°C, filtered, and washed with acetonitrile (65 mL). The combined filtrates and washings were concentrated at 60°C under reduced pressure to obtain a residue.
Acetone (325 mL) was added to the residue, and the reaction mixture was stirred at 40°C till the product precipitated out. Hexane (325 mL) was added. The reaction mixture was stirred for 30 minutes at 30°C, filtered, washed with a mixture of acetone and hexane (130 mL, 1 : 1 mixture), and dried under reduced pressure at 60°C for 15 hours to obtain the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2-benzoisothiazole-3- yl)]piperazine methane sulfonate (Formula Vila; HPLC purity: 99.35%).
Example 3 : Preparation of lurasidone hydrochloride (Formula I)
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (Formula VIII; 38.16 g) and potassium carbonate (43.5 g) were added to a solution of trans (R,R)-3a,7a- octahydroisoindolium-2-spiro- 1 '-[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (Formula Vila; 90 g) in toluene (900 mL). The reaction mixture was refluxed for 10 hours. The inorganic salts were filtered through a celite bed and washed with toluene (180 mL). The filtrate and washing were combined, stirred with activated carbon (2.7 g) at 40°C to 45°C for 15 minutes, filtered, and washed with toluene (180 mL). The filtrate and washing were combined, and concentrated at 60°C under reduced pressure. The residue obtained was stirred with a 2-propanol:acetone mixture (250 mL; 3: 1 mixture) at ambient temperature for 2 hours. The solid was filtered, washed with a mixture of 2- propanol:acetone (90 mL; 3: 1 mixture), and dried at ambient temperature for 1 hour under reduced pressure to obtain lurasidone (Formula XIII; 93.3 g, wet; HPLC purity: 99.11%).
Aqueous hydrochloric acid (15%; 90 g) was slowly added to a clear solution of lurasidone (Formula XIII; 91 g; wet) in acetone (1350 mL) at 55°C. The reaction mixture was allowed to cool to about 26°C, stirred for 3 hours, further cooled to 1 1°C, stirred again for 30 minutes, and filtered. The wet solid was again stirred with acetone (135 mL) at 13°C, filtered, washed with acetone (135 mL), and dried at 60°C under reduced pressure to obtain lurasidone hydrochloride (Formula I; 89.6 g).
Chiral Purity: 99.99%
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (Formula VIII): 0.02%
Isomer of Formula XIV: 0.02%
Isomer of Formula XV: 0.01%
Impurity of Formula VIII: 0.01 %
Impurity of Formula XVI: Not detectable

Claims

We Claim:
1. A process for the preparation of lurasidone hydrochloride of Formula I
Figure imgf000024_0001
Formula I
comprising the steps of:
i) resolving a trans (racemic)- l,2-cyclohexane dicarboxylic acid of Formula III
Figure imgf000024_0002
Formula III
trans (racemic)
into a trans (R,R)-l,2-cyclohexane dicarboxylic acid using a chiral amine in the presence of a co-base; and
ii) converting the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid into the
lurasidone hydrochloride of Formula I.
2. A process for the preparation of lurasidone hydrochloride of Formula I
Figure imgf000024_0003
Formula I
comprising the steps of:
i) resolving a trans (racemic)- 1,2-cyclohexane dicarboxylic acid of Formula III
Figure imgf000025_0001
Formula III
trans (racemic)
into a trans (R,R)- l ,2-cyclohexane dicarboxylic acid by reacting with a chiral amine in the presence of a co-base;
converting the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid into a trans (R,R)-dicarboxylate intermediate of Formula X,
Figure imgf000025_0002
Formula X
trans(R,R)-isomer
wherein R is a C1-C4 alkyl group or a benzyl group;
converting the trans (R,R)-dicarboxylate intermediate of Formula X into a trans (R,R)- l,2-bis(hydroxymethyl)cyclohexane of Formula XI;
Figure imgf000025_0003
Formula XI
trans(R,R)-isomer
converting the trans (R,R)- 1 ,2-bis(hydroxymethyl)cyclohexane of Formula XI into an intermediate of Formula XII,
Figure imgf000025_0004
Formula XII
fra/is(R,R)-isomer wherein R' is a leaving group;
v) reacting the intermediate of Formula XII with 3 -( 1 -piperazinyl)- 1 ,2- benzisothiazole of Formula VI
Figure imgf000026_0001
Formula VI
to obtain a trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2- benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
Figure imgf000026_0002
Formula Vila
fra/7s(R,R)-isomer
vi) reacting the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2- benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila with bicyclo[2.2.1 ]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
= H 0 NH
= " O
H υ
Formula VIII
to obtain lurasidone of Formula XIII; and
Figure imgf000027_0001
Formula XIII
vii) treating the lurasidone of Formula XIII with hydrogen chloride to obtain the lurasidone hydrochloride of Formula I.
3. A process for the preparation of lurasidone hydrochloride of Formula I
Figure imgf000027_0002
Formula I
comprising the steps of:
i) resolving a trans (racemic)- l,2-cyclohexane dicarboxylic acid of Formula III
Figure imgf000027_0003
Formula III
trans (racemic)
into trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid by reacting with a chiral amine in the presence of a co-base;
ii) converting the trans (R,R)- 1 ,2-cyclohexane dicarboxylic acid into a trans (R,R)-dicarboxylate intermediate of Formula X,
Figure imgf000027_0004
Formula X
frans(R,R)-isomer wherein R is a C1-C4 alkyl group or a benzyl group;
iii) converting the trans (R,R)-dicarboxylate intermediate of Formula X into a trans (R,R)- l,2-bis(hydroxymethyl)cyclohexane of Formula XI;
Figure imgf000028_0001
Formula XI
frans(R,R)-isomer
iv) converting the trans (R,R)- 1 ,2-bis(hydroxymethyl)cyclohexane of Formula XI into an intermediate of Formula XII,
Figure imgf000028_0002
Formula XII
fra/7s(R,R)-isomer
wherein R' is a leaving group;
reacting the intermediate of Formula XII with 3-(l-piperazinyl)-l,2- benzisothiazole of Formula VI
Figure imgf000028_0003
Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2- benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
Figure imgf000029_0001
Formula Vila
frans(R,R)-isomer
vi) reacting the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'-(l,2- benzoisothiazole-3-yl)] piperazine methane sulfonate of Formula Vila with bicyclo[2.2.1 ]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
Figure imgf000029_0002
Formula XIII
vii) treating the lurasidone of Formula XIII with hydrogen chloride to obtain the lurasidone hydrochloride of Formula I, wherein the process is carried out without the isolation of the intermediates of Formulae X, XI, and XII.
4. The process according to any of claims 1, 2, or 3, wherein the chiral amine is selected from the group consisting of (R)- l-phenylethyl amine, alpha-methylbenzylamine, 1 -(1 -naphthyl)-ethylamine, sec-butylamine 1 -amino-2-methylbutane, N, N-dimethyl- 1 - phenylethylamine, 1 -cyclohexylethylamine, 2-(methoxymethyl)-pyrrolidine, l-(4- nitrophenyl)-ethylamine, 2-amino- 1 -butanol, 1 -amino-2-propanol, cinchonidine, brucine, strychnine, cinchonine, N-methyl-ephedrine, and alpha-phenyl-glycinol.
5. The process according to any of claims 1, 2, or 3, wherein the co-base is selected from the group consisting of trimethylamine, triethylamine, diisopropylamine, N,N- diisopropylethylamine, N-methylmorpholine, and pyridine.
6. The process according to any of claims 1, 2, or 3, wherein the resolution of the trans (racemic)- l,2-cyclohexane dicarboxylic acid of Formula III is carried out using solvent(s) selected from the group consisting of alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles, hydrocarbons, or mixtures thereof.
7. The process according to claim 6, wherein the solvent is ethanol.
8. The process according to claim 6, wherein the solvent is iso-propanol.
9. The process according to any of claims 1, 2, or 3, wherein the resolution of the trans (racemic)- l,2-cyclohexane dicarboxylic acid of Formula III is carried out at a temperature of about 0°C to - 100°C.
10. The process according to claims 1, 2 or 3, wherein the trans (R,R)- 1 ,2-cyclohexane dicarboxylate has a chiral purity greater than 99.5%.
1 1. Lurasidone hydrochloride having less than 0.05% of the isomer of Formula XIV
Figure imgf000030_0001
Formula XIV
as determined by HPLC.
12. Lurasidone hydrochloride having less than 0.05% of the isomer of Formula XV
Figure imgf000030_0002
Formula XV as determined by HPLC.
13. Lurasidone hydrochloride having less than 0.05% of the bicyclo[2.2.1]heptane-2- exo-3-exo-dicarboximide intermediate of Formula VIII
Figure imgf000031_0001
Formula VIII
as determined by HPLC.
14. Lurasidone hydrochloride free of the lurasidone oxide impurity of Formula XVI
Figure imgf000031_0002
Formula XVI
as determined by HPLC.
15. Lurasidone hydrochloride having less than 0.15% of total impurities, as determined by HPLC.
PCT/IB2013/058288 2012-09-04 2013-09-04 Process for the preparation of lurasidone hydrochloride WO2014037886A1 (en)

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CN105985222A (en) * 2015-01-29 2016-10-05 上海彩迩文生化科技有限公司 Chiral diol preparation method
CN106916151A (en) * 2015-12-28 2017-07-04 苏州二叶制药有限公司 A kind of preparation method of Lurasidone HCl
US10426770B2 (en) 2014-10-14 2019-10-01 Jubilant Generics Limited Process for the preparation of Lurasidone hydrochloride
CN112716946A (en) * 2021-01-22 2021-04-30 中国人民解放军陆军军医大学 Application of sultam-cyclohexanone spiro derivative 1-3-51 in preparation of medicine for treating gastric cancer
CN115950695A (en) * 2021-10-09 2023-04-11 北京阳光诺和药物研究股份有限公司 Method for preparing lurasidone toxic impurities

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
US10426770B2 (en) 2014-10-14 2019-10-01 Jubilant Generics Limited Process for the preparation of Lurasidone hydrochloride
CN105985222A (en) * 2015-01-29 2016-10-05 上海彩迩文生化科技有限公司 Chiral diol preparation method
CN106916151A (en) * 2015-12-28 2017-07-04 苏州二叶制药有限公司 A kind of preparation method of Lurasidone HCl
CN112716946A (en) * 2021-01-22 2021-04-30 中国人民解放军陆军军医大学 Application of sultam-cyclohexanone spiro derivative 1-3-51 in preparation of medicine for treating gastric cancer
CN112716946B (en) * 2021-01-22 2022-02-08 中国人民解放军陆军军医大学 Application of sultam-cyclohexanone spiro derivative 1-3-51 in preparation of medicine for treating gastric cancer
CN115950695A (en) * 2021-10-09 2023-04-11 北京阳光诺和药物研究股份有限公司 Method for preparing lurasidone toxic impurities
CN115950695B (en) * 2021-10-09 2023-07-28 北京阳光诺和药物研究股份有限公司 Method for preparing lurasidone-based toxic impurities

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