CA2831703A1 - Process for the preparation of an antipsychotic agent - Google Patents
Process for the preparation of an antipsychotic agent Download PDFInfo
- Publication number
- CA2831703A1 CA2831703A1 CA2831703A CA2831703A CA2831703A1 CA 2831703 A1 CA2831703 A1 CA 2831703A1 CA 2831703 A CA2831703 A CA 2831703A CA 2831703 A CA2831703 A CA 2831703A CA 2831703 A1 CA2831703 A1 CA 2831703A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- trans
- cyclohexane
- process according
- dicarboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a process for the preparation of an antipsychotic agent useful for the treatment of schizophrenia.
Description
I
PROCESS FOR THE PREPARATION OF AN ANTIPSYCHOTIC AGENT
Field of the Invention A process for the preparation of an antipsychotic agent useful for the treatment of schizophrenia is provided.
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-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yppiperazin-1-y1methy1]cyc1ohexy1methy1}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride having the structure as represented by Formula I.
.,,r...H= H 0 . _ ,.. N
H H N/ \ ----s N /
r.
: --"N--___...
4, .HCI
i H 0 A
Formula I
Lurasidone hydrochloride is marketed in the United States under the brand name Latuda for the treatment of schizophrenia.
U.S. Patent No. 5,532,372 describes preparation of lurasidone hydrochloride using racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III as intermediate as depicted in Scheme I.
PROCESS FOR THE PREPARATION OF AN ANTIPSYCHOTIC AGENT
Field of the Invention A process for the preparation of an antipsychotic agent useful for the treatment of schizophrenia is provided.
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-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yppiperazin-1-y1methy1]cyc1ohexy1methy1}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride having the structure as represented by Formula I.
.,,r...H= H 0 . _ ,.. N
H H N/ \ ----s N /
r.
: --"N--___...
4, .HCI
i H 0 A
Formula I
Lurasidone hydrochloride is marketed in the United States under the brand name Latuda for the treatment of schizophrenia.
U.S. Patent No. 5,532,372 describes preparation of lurasidone hydrochloride using racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III as intermediate as depicted in Scheme I.
Scheme I
H H
Formula!!
[C77.0 H 0Ms -a-OR 0 H 0Ms H H
cr.COOH / N ..õ-S
Formula IV Formula V
N =COOH
Formula III 1 N H j Formula VI
trans (racemic) H
N
cc:4 >1 / ----s Cp 4lOt .-OMs Formula V11 r Formula VIII
Chiral Resolution /
Formula 1 -.., ___________________ N H H N N /
Sodium bicarbonate \ __ / .HCI
E ---: ---H 7 Fi 0 411k Formula IX
The process described in U.S. Patent No. 5,532,372 involves use of racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III as an intermediate. The trans intermediate of Formula III may further exist as (R,R) trans and (S,S) trans isomers. In the process described in U.S. Patent No. 5,532,372, resolution of free base of Formula IX
was carried out using a chiral resolving agent in the last step to obtain lurasidone followed by subsequent conversion of lurasidone into lurasidone hydrochloride.
H H
Formula!!
[C77.0 H 0Ms -a-OR 0 H 0Ms H H
cr.COOH / N ..õ-S
Formula IV Formula V
N =COOH
Formula III 1 N H j Formula VI
trans (racemic) H
N
cc:4 >1 / ----s Cp 4lOt .-OMs Formula V11 r Formula VIII
Chiral Resolution /
Formula 1 -.., ___________________ N H H N N /
Sodium bicarbonate \ __ / .HCI
E ---: ---H 7 Fi 0 411k Formula IX
The process described in U.S. Patent No. 5,532,372 involves use of racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III as an intermediate. The trans intermediate of Formula III may further exist as (R,R) trans and (S,S) trans isomers. In the process described in U.S. Patent No. 5,532,372, resolution of free base of Formula IX
was carried out using a chiral resolving agent in the last step to obtain lurasidone followed by subsequent conversion of lurasidone into lurasidone hydrochloride.
The present inventors have observed that chiral resolution of free base of an intermediate of Formula IX is difficult due to the presence of six chiral centers. This affects the overall yield and the cost of manufacturing. Thus, there exists a need for the development of a simple, cost-effective, and industrially advantageous process for the preparation of lurasidone hydrochloride which overcomes the difficulties of the prior art process.
Summary of the Invention The present invention provides an easy, cost-effective and industrially advantageous process for the preparation of highly pure lurasidone hydrochloride which involves separating the racemic trans 1, 2-cyclohexane dicarboxylic acid of Formula III
into its R,R trans and S,S trans isomers and then using the desired trans R,R
isomer for the preparation of lurasidone hydrochloride. Since the process of the present invention involves separating the undesired S,S trans isomer in the initial stages of the manufacturing process, no undesired isomers due to reaction with trans (S,S)-isomer are formed in the subsequent steps.
Lurasidone hydrochloride prepared by the process of the present invention is a highly pure, easy to filter, free-flowing solid having small average particle size.
A first aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
= H
. -N
H H
E .HCI
H
Formula l comprising the steps of:
i) Resolving trans (racemic)-1,2-cyclohexane dicarboxylic acid of Formula :COOH
'COON
Formula III
trans (racemic) into trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ma COON
'COON
Formula Illa trans (R,R)-isomer ii) Converting trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ina into trans (R,R)-dicarboxylate intermediate of Formula X, wherein R is C 1 -C4 alkyl or benzyl;
0"0,,COOR
'COOR
Formula X
trans(R,R)-isomer iii) Converting trans (R,R)-dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI;
OH
OH
Formula XI
trans(R,R)-isomer iv) Converting trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI
into an intermediate of Formula XII
H
H
Formula XII
trans(R,R)-isomer wherein R' is a leaving group;
v) Reacting intermediate of Formula XII with 3-(1-piperaziny1-1,2-benzisothiazole) of Formula VI
HN
N.....__N\
S
=
Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4' -(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
H
CpN ____________________________ N 9's . -OMs \ ______________________________ /
H
Formula Vila trans(R,R)-isomer vi) Reacting trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'44'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
lzg- H
: ,...-. .
7_, H NH
Formula VIII
to obtain lurasidone of Formula XIII; and = H
\
x,µ
_ . \ / N
N
41#i Formula XIII
vii) Treating lurasidone of Formula XIII with hydrogen chloride to obtain lurasidone hydrochloride of Formula I.
A second aspect of the present invention provides use of trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ma COON
"C
"COOH
Formula Illa trans (R,R)-isomer for the preparation of lurasidone hydrochloride of Formula I.
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, stiffing or a combination thereof.
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 methods known in the literature such as the one disclosed in U.S.
Patent No.
Summary of the Invention The present invention provides an easy, cost-effective and industrially advantageous process for the preparation of highly pure lurasidone hydrochloride which involves separating the racemic trans 1, 2-cyclohexane dicarboxylic acid of Formula III
into its R,R trans and S,S trans isomers and then using the desired trans R,R
isomer for the preparation of lurasidone hydrochloride. Since the process of the present invention involves separating the undesired S,S trans isomer in the initial stages of the manufacturing process, no undesired isomers due to reaction with trans (S,S)-isomer are formed in the subsequent steps.
Lurasidone hydrochloride prepared by the process of the present invention is a highly pure, easy to filter, free-flowing solid having small average particle size.
A first aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
= H
. -N
H H
E .HCI
H
Formula l comprising the steps of:
i) Resolving trans (racemic)-1,2-cyclohexane dicarboxylic acid of Formula :COOH
'COON
Formula III
trans (racemic) into trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ma COON
'COON
Formula Illa trans (R,R)-isomer ii) Converting trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ina into trans (R,R)-dicarboxylate intermediate of Formula X, wherein R is C 1 -C4 alkyl or benzyl;
0"0,,COOR
'COOR
Formula X
trans(R,R)-isomer iii) Converting trans (R,R)-dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI;
OH
OH
Formula XI
trans(R,R)-isomer iv) Converting trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI
into an intermediate of Formula XII
H
H
Formula XII
trans(R,R)-isomer wherein R' is a leaving group;
v) Reacting intermediate of Formula XII with 3-(1-piperaziny1-1,2-benzisothiazole) of Formula VI
HN
N.....__N\
S
=
Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4' -(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
H
CpN ____________________________ N 9's . -OMs \ ______________________________ /
H
Formula Vila trans(R,R)-isomer vi) Reacting trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'44'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
lzg- H
: ,...-. .
7_, H NH
Formula VIII
to obtain lurasidone of Formula XIII; and = H
\
x,µ
_ . \ / N
N
41#i Formula XIII
vii) Treating lurasidone of Formula XIII with hydrogen chloride to obtain lurasidone hydrochloride of Formula I.
A second aspect of the present invention provides use of trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ma COON
"C
"COOH
Formula Illa trans (R,R)-isomer for the preparation of lurasidone hydrochloride of Formula I.
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, stiffing or a combination thereof.
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 methods known in the literature such as the one disclosed in U.S.
Patent No.
5,532,372, which is incorporated herein by reference. 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 in the next step.
Racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III may be resolved into (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ma and (S,S) trans 1,2-cyclohexane dicarboxylic acid using a chiral resolving agent selected from the group comprising (R)-1-phenylethyl amine, alpha-methylbenzylamine, 1-(1-naphthyl)-ethylamine, sec-butylamine 1-amino-2-methylbutane, N,N-dimethyl-l-phenylethylamine, 1-cyclohexylethylamine, 2-(methoxymethyl)-pyrrolidine, 1-(4-nitropheny1)-ethylamine, 2-amino-1-butanol, 1-amino-2-propanol, cinchonidine, brucine, strychnine, cinchonine, N-methyl-ephedrine or alpha-phenyl-glycinol. In a preferred embodiment, the resolving agent used is (R)-1-phenylethyl amine.
Resolution may be carried out using a solvent selected from the group comprising alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles or hydrocarbons. Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol or n-pentanol. Examples of ketones are acetone, methyl ethyl ketone or methyl isobutyl ketone. Examples of alkyl acetates are ethyl acetate or isopropyl acetate. Examples of chlorinated hydrocarbons are dichloromethane or chloroform. Examples of ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran or dioxane. Examples of nitriles are acetonitrile or propionitrile.
Examples of hydrocarbons are benzene, xylene, toluene, hexanes, heptane or pentane.
Resolving agent may be added at a temperature of about 0 C to -100 C. The reaction mixture may be stirred for about 30 minutes to about 2 hours, warmed to ambient temperature and stirred for about 2 hours to about 10 hours followed by isolation.
Racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III may be resolved into (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ma and (S,S) trans 1,2-cyclohexane dicarboxylic acid using a chiral resolving agent selected from the group comprising (R)-1-phenylethyl amine, alpha-methylbenzylamine, 1-(1-naphthyl)-ethylamine, sec-butylamine 1-amino-2-methylbutane, N,N-dimethyl-l-phenylethylamine, 1-cyclohexylethylamine, 2-(methoxymethyl)-pyrrolidine, 1-(4-nitropheny1)-ethylamine, 2-amino-1-butanol, 1-amino-2-propanol, cinchonidine, brucine, strychnine, cinchonine, N-methyl-ephedrine or alpha-phenyl-glycinol. In a preferred embodiment, the resolving agent used is (R)-1-phenylethyl amine.
Resolution may be carried out using a solvent selected from the group comprising alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles or hydrocarbons. Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol or n-pentanol. Examples of ketones are acetone, methyl ethyl ketone or methyl isobutyl ketone. Examples of alkyl acetates are ethyl acetate or isopropyl acetate. Examples of chlorinated hydrocarbons are dichloromethane or chloroform. Examples of ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran or dioxane. Examples of nitriles are acetonitrile or propionitrile.
Examples of hydrocarbons are benzene, xylene, toluene, hexanes, heptane or pentane.
Resolving agent may be added at a temperature of about 0 C to -100 C. The reaction mixture may be stirred for about 30 minutes to about 2 hours, warmed to ambient temperature and stirred for about 2 hours to about 10 hours followed by isolation.
Isolation may be 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.
Drying may be carried out at a temperature of about 40 C to about 80 C for about 2 hours to about 10 hours.
The salt of trans 1,2-cyclohexane dicarboxylic acid of Formula III with the resolving agent may be further purified by crystallization from the solvent selected from the group consisting of alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles and mixtures thereof. Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol.
Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
Examples of alkyl acetates are ethyl acetate, and isopropyl acetate. Examples of chlorinated hydrocarbons are dichloromethane and chloroform. Examples of ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
Examples of nitriles are acetonitrile and propionitrile. In a preferred embodiment, salt of (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia with the resolving agent is purified by crystallization from a solvent mixture comprising an alcohol and a hydrocarbon.
Crystallization may be carried out by dissolving the salt of trans 1,2-cyclohexane dicarboxylic acid of Formula III with the resolving agent at a temperature of about 60 C to about 100 C. The solution may be cooled to about -10 C to an ambient temperature, stirred for about 30 minutes to about 2 hours, filtered and dried. The crystallization step may be repeated if required. The solid material thus obtained may be dissolved in about IN hydrochloric acid solution, extracted with a solvent and isolated to obtain trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ma. In a preferred embodiment, purification is carried out by crystallization from ethanol:toluene mixture.
In another preferred embodiment, purification is carried out by crystallization from ethanol:toluene mixture (1:1) mixture.
Conversion of (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ma into dicarboxylate intermediate of Formula X may be carried out by contacting with a C1-C4 alcohol or benzyl alcohol in the presence of sulphuric acid. Examples of C1-C4 alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, and sec-butanol.
The reaction mixture may be stirred at about 25 C to 60 C for about 1 hour to 24 hours and concentrated. Isolation may be accomplished by adding de-ionized water, solvent extraction and concentration.
In a particular embodiment, trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Illa may be converted into trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate of Formula X by contacting with methanol in the presence of sulphuric acid.
The reaction mixture may be stirred at about 40 C for about 18 hours. The reaction mixture may be concentrated under reduced pressure at about 50 C. De-ionized water may be added.
Isolation of trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate may be accomplished by solvent extraction and concentration.
Conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out by adding a reducing agent selected from the group comprising diisobutyl aluminum hydride, lithium aluminium hydride, lithium borohydride, sodium borohydride, calcium borohydride, and lithium triethylborohydride, in an inert atmosphere. A solvent selected from the group comprising hydrocarbons or ethers may be added. Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes or pentane. Examples of ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane. The reducing agent may be added drop-wise at a temperature of about -10 C to 10 C.
The reaction mixture may be warmed to an ambient temperature and stirred for about 2 hours to 10 hours. About 1N hydrochloric acid solution may be added at about -5 C to 40 C.
The reaction mixture may be stirred for about 10 hours to 15 hours. Isolation may be accomplished by filtration and concentration.
In a preferred embodiment, conversion of dicarboxylate intermediate of Formula X
into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out using diisobutyl aluminum hydride in a hydrocarbon solvent. In a more preferred embodiment, conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out using diisobutyl aluminum hydride in toluene.
The hydroxyl group of trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be converted into a leaving group by reaction with a halide or a sulphonyl compound to obtain a intermediate of Formula XII. Examples of halides are thionyl chloride and thionyl bromide. Examples of sulphonyl compounds are alkyl- or aryl-sulphonyl halides selected from the group comprising of methane sulphonyl chloride, ethane sulphonyl chloride, p-toluene sulphonyl chloride, and benzene sulphonyl chloride.
An organic or inorganic base may be added. Examples of organic bases are triethylamine, ammonia, and pyridine. Examples of inorganic bases are 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. Conversion may be carried out in the presence of a solvent selected from the group comprising of chlorinated hydrocarbons such as dichloromethane or chloroform or in pyridine at a temperature of about -10 C to about 10 C. The reaction mixture may be further stirred at ambient temperature for about 1 hour to 8 hours. De-ionized water may be added. Organic layer may be concentrated at a temperature of about 35 C to 60 C.
Precipitation of the hydroxyl protected intermediate may be achieved by adding an ether solvent such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane, stirring for about 30 minutes to 2 hours followed by isolation.
In a preferred embodiment, trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane may be converted into trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane using methane sulphonyl chloride in the presence of triethylamine. Addition of methane sulphonyl chloride may be carried out at a temperature of about -10 C to 10 C in a chlorinated solvent. Reaction mixture may be stirred at ambient temperature for about 1 hour to 8 hours. De-ionized water may be added. Organic layer may be concentrated at about 45 C
under reduced pressure. Precipitation of trans (R, R)-1,2-bis(methanesulfonylmethyl)cyclohexane may be achieved using di-isopropyl ether. The reaction mixture may be stirred at an ambient temperature for about 30 minutes to 2 hours followed by isolation.
trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane may be converted to trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yp]piperazine methane sulfonate of Formula VIIa by contacting with 3-(1-piperaziny1-1,2-benzisothiazole) of Formula VI in a nitrile or amide solvent in the presence of a base.
Examples of nitriles are acetonitrile and propionitrile. Examples of amide solvents are N,N-dimethyl formamide and N,N-diethylformamide. Examples of bases are 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 may be refluxed for about 15 hours to 2 days, filtered and concentrated at about 40 C to 80 C under reduced pressure.
Precipitation may be achieved by adding a ketone solvent, a hydrocarbon solvent or mixtures thereof.
Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
The reaction mixture may be stirred for about 10 minutes to 1 hour followed by isolation.
trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1 ' - [4 ' -(1,2 -benzo isothiazo le-3 -yl)]piperazine methane sulfonate of Formula VIIa may be reacted with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide of Formula VIII in the presence of a catalyst and a base. The catalyst may be selected from crown ethers such as dibenzo-18-crown-6 or 18-crown-6. Examples of bases are 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.
Hydrides of alkali metals such as sodium hydride and potassium hydride may also act as base. The reaction may be carried out in a hydrocarbon solvent selected from the group comprising benzene, xylene, toluene, hexane, heptanes, and pentane. The reaction mixture may be refluxed for about 1 hour to 2 days, filtered and concentrated at about 40 C
to 100 C
under reduced pressure. Precipitation of lurasidone may be carried out by adding an alcohol selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol or n-pentanol followed by isolation.
Lurasidone may be converted into lurasidone hydrochloride by drop-wise addition of hydrogen chloride to a solution of lurasidone in a solvent. The solvent may be selected from the group comprising alcohols, alkyl acetates, ketones, and hydrocarbons.
Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol. Examples of alkyl acetates are ethyl acetate and isopropyl acetate. Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane. Conversion of lurasidone into lurasidone hydrochloride may be carried out by purging hydrogen chloride gas or by adding aqueous hydrochloric acid in a solvent selected from iso-propanol, ethyl acetate, toluene, and water at ambient temperature to about 80 C. The reaction mixture may be stirred at ambient temperature to the reflux temperature of the solvent for about 10 minutes to 1 hour followed by isolation.
When aqueous hydrogen chloride is used for the conversion of lurasidone into lurasidone hydrochloride, the concentration of aqueous hydrogen chloride may vary from 0.1% to 36%.
In a preferred embodiment, lurasidone may be converted to lurasidone hydrochloride by contacting a solution of lurasidone in ethyl acetate with 6%
to 8%
aqueous hydrogen chloride at about 40 C, stirring at ambient temperature for about 30 minutes to 5 hours followed by isolation.
Lurasidone hydrochloride prepared by the process of the present invention is a highly pure, easy to filter, free-flowing solid having small average particle size.
In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Methods HPLC purity was determined using Water alliances, Model 2695 instrument.
EXAMPLES
Example 1: Preparation of trans (R,R)-1,2-Cyclohexane Dicarboxylic Acid To a suspension of racemic trans 1,2-cyclohexane dicarboxylic acid (65 g) in ethanol (650 mL) was added (R)-1-phenylethyl amine (50.7 mL) at about -70 C.
The reaction mixture was stirred for about 90 minutes, warmed to ambient temperature and stirred for about 5 hours. Precipitates were filtered, washed with ethanol (25 mL) and dried under reduced pressure at about 40 C to obtain crude salt of trans (R,R)-1,2-cyclohexane dicarboxylic acid (96.5 g).
The salt of trans (R,R)-1,2-cyclohexane dicarboxylic acid, obtained above, was dissolved in ethanol:toluene (1:1) mixture (1.4 L) at about 80 C. The solution was cooled to about 0 C to about 5 C over a period of about 60 minutes to about 90 minutes, filtered and dried under reduced pressure at about 45 C. Crystallization was repeated twice. Solid material, thus obtained, was dissolved in about 1N hydrogen chloride (250 mL) and extracted two times with ethyl acetate (600+300 mL). Organic layers were combined, washed with brine and concentrated at about 45 C under reduced pressure to obtain trans (R,R)-1,2-cyclohexane dicarboxylic acid as colorless crystals.
Yield: 30%
Example 2: Preparation of trans (R,R)-1,2-Dimethyl Cyclohexane Dicarboxylate Sulphuric acid (9 mL) was added to a solution of trans (R,R)-1,2-cyclohexane dicarboxylic acid (18 g) in methanol (180 mL). The reaction mixture was stirred at about 40 C for about 18 hours. The reaction mixture was concentrated at about 50 C
under reduced pressure. De-ionized water (150 mL) was added. The reaction mixture was extracted twice with ethyl acetate (150 + 100 mL). The organic layers were combined, washed with brine and concentrated under reduced pressure at about 50 C to obtain trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate as an oil.
Yield: 97%
Example 3: Preparation of trans (R,R)-1,2-Bis(Hydroxymethyl)Cyclohexane trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate (20 g) was dissolved in toluene (200 mL) at about 0 C to about -5 C in an inert atmosphere. Diisobutyl aluminum hydride (248.5 ml, 20% solution in toluene) was added drop-wise into the above solution.
The reaction mixture was warmed to an ambient temperature and stirred for about 6 hours.
The reaction was quenched by drop-wise addition of about 1N HC1 (125 mL) at about -5 C to about 40 C. The reaction mixture was further stirred for about 13 hours to get freely filterable inorganic solids. The solids were filtered out and the filtrate was concentrated under reduced pressure to obtain trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane as an oil.
Yield: 74%
Example 4: Preparation of trans (R,R)-1,2-Bis(Methanesulfonylmethyl)Cyclohexane Methane sulfonyl chloride (23.85 g) was added to a solution of (R,R) trans 1,2-bis(hydroxymethyl)cyclohexane (10.0 g) and triethylamine (15.45 g) in chloroform (100 mL) at about 0 C to about 5 C. The reaction mixture was stirred at an ambient temperature for about 5 hours. De-ionized water (120 mL) was added. The organic layer was separated and concentrated under reduced pressure at about 45 C.
Diisopropyl ether (120 mL) was added. The reaction mixture was stirred at ambient temperature for about 60 minutes, filtered and dried under reduced pressure at about 40 C to obtain trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane.
Yield: 90.8%
Example 5: Preparation of trans (R,R)-3a,7a-Octahydroisoindolium-2-Spiro-1'44'-(1,2-Benzoisothiazole-3-Y1)]Piperazine Methane Sulfonate 3-(1-Piperaziny1-1,2-benzisothiazole) (13.2 g) and sodium carbonate (6.5 g) were added to a solution of trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane (18 g) in acetonitrile (180 mL) at ambient temperature. The reaction mixture was refluxed for about 30 hours, filtered and washed with acetonitrile (2x25 mL). The combined filtrate was concentrated at about 60 C under reduced pressure. Acetone (40 mL) was added to the residue and the reaction mixture was stirred at about 40 C until the product precipitated out. Hexane (50 mL) was added. The reaction mixture was stirred for about 30 minutes at ambient temperature, filtered and dried under reduced pressure at about 45 C for about 8 hours to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'44'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate.
Yield: 88%
Example 6: Preparation of Lurasidone Method A:
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate (7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (15 g) in xylene (150 mL). The reaction mixture was refluxed for about 25 hours, filtered and concentrated at about 70 C under reduced pressure. Sticky residue was obtained. Isopropanol (30 mL) was added. The reaction mixture was cooled to ambient temperature, stirred for about 5 hours, filtered, washed with isopropanol (15 mL) and dried at about 45 C under reduced pressure for about 15 hours to obtain lurasidone.
Yield: 76.8%
Method B:
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate (7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (15 g) in toluene (150 mL). The reaction mixture was refluxed for about 12 hours, filtered and concentrated at about 55 C to 60 C under reduced pressure.
Sticky residue was obtained. Denatured spirit (75 mL) was added. The reaction mixture was heated to about 40 C, maintained for about 1 hour, cooled to ambient temperature and stirred for about 6 hours. The solid was filtered, washed with denatured spirit (20 mL) and dried at about 45 C under reduced pressure for about 15 hours to obtain lurasidone free base.
Yield: 86.35%
HPLC Purity: 98.41%
Example 7: Preparation of Lurasidone Hydrochloride About 7% aqueous hydrochloric acid (5 mL) was slowly added to a reaction mixture containing lurasidone (1.0 g) in ethyl acetate (25 mL) at about 40 C.
The reaction mixture was stirred at ambient temperature for about 2 hours, filtered and dried at about 45 C under reduced pressure to obtain lurasidone hydrochloride.
Yield: 93%
HPLC Purity: 98.98%
Drying may be carried out at a temperature of about 40 C to about 80 C for about 2 hours to about 10 hours.
The salt of trans 1,2-cyclohexane dicarboxylic acid of Formula III with the resolving agent may be further purified by crystallization from the solvent selected from the group consisting of alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles and mixtures thereof. Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol.
Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
Examples of alkyl acetates are ethyl acetate, and isopropyl acetate. Examples of chlorinated hydrocarbons are dichloromethane and chloroform. Examples of ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
Examples of nitriles are acetonitrile and propionitrile. In a preferred embodiment, salt of (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia with the resolving agent is purified by crystallization from a solvent mixture comprising an alcohol and a hydrocarbon.
Crystallization may be carried out by dissolving the salt of trans 1,2-cyclohexane dicarboxylic acid of Formula III with the resolving agent at a temperature of about 60 C to about 100 C. The solution may be cooled to about -10 C to an ambient temperature, stirred for about 30 minutes to about 2 hours, filtered and dried. The crystallization step may be repeated if required. The solid material thus obtained may be dissolved in about IN hydrochloric acid solution, extracted with a solvent and isolated to obtain trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ma. In a preferred embodiment, purification is carried out by crystallization from ethanol:toluene mixture.
In another preferred embodiment, purification is carried out by crystallization from ethanol:toluene mixture (1:1) mixture.
Conversion of (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ma into dicarboxylate intermediate of Formula X may be carried out by contacting with a C1-C4 alcohol or benzyl alcohol in the presence of sulphuric acid. Examples of C1-C4 alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, and sec-butanol.
The reaction mixture may be stirred at about 25 C to 60 C for about 1 hour to 24 hours and concentrated. Isolation may be accomplished by adding de-ionized water, solvent extraction and concentration.
In a particular embodiment, trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Illa may be converted into trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate of Formula X by contacting with methanol in the presence of sulphuric acid.
The reaction mixture may be stirred at about 40 C for about 18 hours. The reaction mixture may be concentrated under reduced pressure at about 50 C. De-ionized water may be added.
Isolation of trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate may be accomplished by solvent extraction and concentration.
Conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out by adding a reducing agent selected from the group comprising diisobutyl aluminum hydride, lithium aluminium hydride, lithium borohydride, sodium borohydride, calcium borohydride, and lithium triethylborohydride, in an inert atmosphere. A solvent selected from the group comprising hydrocarbons or ethers may be added. Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes or pentane. Examples of ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane. The reducing agent may be added drop-wise at a temperature of about -10 C to 10 C.
The reaction mixture may be warmed to an ambient temperature and stirred for about 2 hours to 10 hours. About 1N hydrochloric acid solution may be added at about -5 C to 40 C.
The reaction mixture may be stirred for about 10 hours to 15 hours. Isolation may be accomplished by filtration and concentration.
In a preferred embodiment, conversion of dicarboxylate intermediate of Formula X
into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out using diisobutyl aluminum hydride in a hydrocarbon solvent. In a more preferred embodiment, conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out using diisobutyl aluminum hydride in toluene.
The hydroxyl group of trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI may be converted into a leaving group by reaction with a halide or a sulphonyl compound to obtain a intermediate of Formula XII. Examples of halides are thionyl chloride and thionyl bromide. Examples of sulphonyl compounds are alkyl- or aryl-sulphonyl halides selected from the group comprising of methane sulphonyl chloride, ethane sulphonyl chloride, p-toluene sulphonyl chloride, and benzene sulphonyl chloride.
An organic or inorganic base may be added. Examples of organic bases are triethylamine, ammonia, and pyridine. Examples of inorganic bases are 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. Conversion may be carried out in the presence of a solvent selected from the group comprising of chlorinated hydrocarbons such as dichloromethane or chloroform or in pyridine at a temperature of about -10 C to about 10 C. The reaction mixture may be further stirred at ambient temperature for about 1 hour to 8 hours. De-ionized water may be added. Organic layer may be concentrated at a temperature of about 35 C to 60 C.
Precipitation of the hydroxyl protected intermediate may be achieved by adding an ether solvent such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane, stirring for about 30 minutes to 2 hours followed by isolation.
In a preferred embodiment, trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane may be converted into trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane using methane sulphonyl chloride in the presence of triethylamine. Addition of methane sulphonyl chloride may be carried out at a temperature of about -10 C to 10 C in a chlorinated solvent. Reaction mixture may be stirred at ambient temperature for about 1 hour to 8 hours. De-ionized water may be added. Organic layer may be concentrated at about 45 C
under reduced pressure. Precipitation of trans (R, R)-1,2-bis(methanesulfonylmethyl)cyclohexane may be achieved using di-isopropyl ether. The reaction mixture may be stirred at an ambient temperature for about 30 minutes to 2 hours followed by isolation.
trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane may be converted to trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yp]piperazine methane sulfonate of Formula VIIa by contacting with 3-(1-piperaziny1-1,2-benzisothiazole) of Formula VI in a nitrile or amide solvent in the presence of a base.
Examples of nitriles are acetonitrile and propionitrile. Examples of amide solvents are N,N-dimethyl formamide and N,N-diethylformamide. Examples of bases are 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 may be refluxed for about 15 hours to 2 days, filtered and concentrated at about 40 C to 80 C under reduced pressure.
Precipitation may be achieved by adding a ketone solvent, a hydrocarbon solvent or mixtures thereof.
Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
The reaction mixture may be stirred for about 10 minutes to 1 hour followed by isolation.
trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1 ' - [4 ' -(1,2 -benzo isothiazo le-3 -yl)]piperazine methane sulfonate of Formula VIIa may be reacted with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide of Formula VIII in the presence of a catalyst and a base. The catalyst may be selected from crown ethers such as dibenzo-18-crown-6 or 18-crown-6. Examples of bases are 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.
Hydrides of alkali metals such as sodium hydride and potassium hydride may also act as base. The reaction may be carried out in a hydrocarbon solvent selected from the group comprising benzene, xylene, toluene, hexane, heptanes, and pentane. The reaction mixture may be refluxed for about 1 hour to 2 days, filtered and concentrated at about 40 C
to 100 C
under reduced pressure. Precipitation of lurasidone may be carried out by adding an alcohol selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol or n-pentanol followed by isolation.
Lurasidone may be converted into lurasidone hydrochloride by drop-wise addition of hydrogen chloride to a solution of lurasidone in a solvent. The solvent may be selected from the group comprising alcohols, alkyl acetates, ketones, and hydrocarbons.
Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol. Examples of alkyl acetates are ethyl acetate and isopropyl acetate. Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane. Conversion of lurasidone into lurasidone hydrochloride may be carried out by purging hydrogen chloride gas or by adding aqueous hydrochloric acid in a solvent selected from iso-propanol, ethyl acetate, toluene, and water at ambient temperature to about 80 C. The reaction mixture may be stirred at ambient temperature to the reflux temperature of the solvent for about 10 minutes to 1 hour followed by isolation.
When aqueous hydrogen chloride is used for the conversion of lurasidone into lurasidone hydrochloride, the concentration of aqueous hydrogen chloride may vary from 0.1% to 36%.
In a preferred embodiment, lurasidone may be converted to lurasidone hydrochloride by contacting a solution of lurasidone in ethyl acetate with 6%
to 8%
aqueous hydrogen chloride at about 40 C, stirring at ambient temperature for about 30 minutes to 5 hours followed by isolation.
Lurasidone hydrochloride prepared by the process of the present invention is a highly pure, easy to filter, free-flowing solid having small average particle size.
In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Methods HPLC purity was determined using Water alliances, Model 2695 instrument.
EXAMPLES
Example 1: Preparation of trans (R,R)-1,2-Cyclohexane Dicarboxylic Acid To a suspension of racemic trans 1,2-cyclohexane dicarboxylic acid (65 g) in ethanol (650 mL) was added (R)-1-phenylethyl amine (50.7 mL) at about -70 C.
The reaction mixture was stirred for about 90 minutes, warmed to ambient temperature and stirred for about 5 hours. Precipitates were filtered, washed with ethanol (25 mL) and dried under reduced pressure at about 40 C to obtain crude salt of trans (R,R)-1,2-cyclohexane dicarboxylic acid (96.5 g).
The salt of trans (R,R)-1,2-cyclohexane dicarboxylic acid, obtained above, was dissolved in ethanol:toluene (1:1) mixture (1.4 L) at about 80 C. The solution was cooled to about 0 C to about 5 C over a period of about 60 minutes to about 90 minutes, filtered and dried under reduced pressure at about 45 C. Crystallization was repeated twice. Solid material, thus obtained, was dissolved in about 1N hydrogen chloride (250 mL) and extracted two times with ethyl acetate (600+300 mL). Organic layers were combined, washed with brine and concentrated at about 45 C under reduced pressure to obtain trans (R,R)-1,2-cyclohexane dicarboxylic acid as colorless crystals.
Yield: 30%
Example 2: Preparation of trans (R,R)-1,2-Dimethyl Cyclohexane Dicarboxylate Sulphuric acid (9 mL) was added to a solution of trans (R,R)-1,2-cyclohexane dicarboxylic acid (18 g) in methanol (180 mL). The reaction mixture was stirred at about 40 C for about 18 hours. The reaction mixture was concentrated at about 50 C
under reduced pressure. De-ionized water (150 mL) was added. The reaction mixture was extracted twice with ethyl acetate (150 + 100 mL). The organic layers were combined, washed with brine and concentrated under reduced pressure at about 50 C to obtain trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate as an oil.
Yield: 97%
Example 3: Preparation of trans (R,R)-1,2-Bis(Hydroxymethyl)Cyclohexane trans (R,R)-1,2-dimethyl cyclohexane dicarboxylate (20 g) was dissolved in toluene (200 mL) at about 0 C to about -5 C in an inert atmosphere. Diisobutyl aluminum hydride (248.5 ml, 20% solution in toluene) was added drop-wise into the above solution.
The reaction mixture was warmed to an ambient temperature and stirred for about 6 hours.
The reaction was quenched by drop-wise addition of about 1N HC1 (125 mL) at about -5 C to about 40 C. The reaction mixture was further stirred for about 13 hours to get freely filterable inorganic solids. The solids were filtered out and the filtrate was concentrated under reduced pressure to obtain trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane as an oil.
Yield: 74%
Example 4: Preparation of trans (R,R)-1,2-Bis(Methanesulfonylmethyl)Cyclohexane Methane sulfonyl chloride (23.85 g) was added to a solution of (R,R) trans 1,2-bis(hydroxymethyl)cyclohexane (10.0 g) and triethylamine (15.45 g) in chloroform (100 mL) at about 0 C to about 5 C. The reaction mixture was stirred at an ambient temperature for about 5 hours. De-ionized water (120 mL) was added. The organic layer was separated and concentrated under reduced pressure at about 45 C.
Diisopropyl ether (120 mL) was added. The reaction mixture was stirred at ambient temperature for about 60 minutes, filtered and dried under reduced pressure at about 40 C to obtain trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane.
Yield: 90.8%
Example 5: Preparation of trans (R,R)-3a,7a-Octahydroisoindolium-2-Spiro-1'44'-(1,2-Benzoisothiazole-3-Y1)]Piperazine Methane Sulfonate 3-(1-Piperaziny1-1,2-benzisothiazole) (13.2 g) and sodium carbonate (6.5 g) were added to a solution of trans (R,R)-1,2-bis(methanesulfonylmethyl)cyclohexane (18 g) in acetonitrile (180 mL) at ambient temperature. The reaction mixture was refluxed for about 30 hours, filtered and washed with acetonitrile (2x25 mL). The combined filtrate was concentrated at about 60 C under reduced pressure. Acetone (40 mL) was added to the residue and the reaction mixture was stirred at about 40 C until the product precipitated out. Hexane (50 mL) was added. The reaction mixture was stirred for about 30 minutes at ambient temperature, filtered and dried under reduced pressure at about 45 C for about 8 hours to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'44'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate.
Yield: 88%
Example 6: Preparation of Lurasidone Method A:
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate (7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (15 g) in xylene (150 mL). The reaction mixture was refluxed for about 25 hours, filtered and concentrated at about 70 C under reduced pressure. Sticky residue was obtained. Isopropanol (30 mL) was added. The reaction mixture was cooled to ambient temperature, stirred for about 5 hours, filtered, washed with isopropanol (15 mL) and dried at about 45 C under reduced pressure for about 15 hours to obtain lurasidone.
Yield: 76.8%
Method B:
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate (7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (15 g) in toluene (150 mL). The reaction mixture was refluxed for about 12 hours, filtered and concentrated at about 55 C to 60 C under reduced pressure.
Sticky residue was obtained. Denatured spirit (75 mL) was added. The reaction mixture was heated to about 40 C, maintained for about 1 hour, cooled to ambient temperature and stirred for about 6 hours. The solid was filtered, washed with denatured spirit (20 mL) and dried at about 45 C under reduced pressure for about 15 hours to obtain lurasidone free base.
Yield: 86.35%
HPLC Purity: 98.41%
Example 7: Preparation of Lurasidone Hydrochloride About 7% aqueous hydrochloric acid (5 mL) was slowly added to a reaction mixture containing lurasidone (1.0 g) in ethyl acetate (25 mL) at about 40 C.
The reaction mixture was stirred at ambient temperature for about 2 hours, filtered and dried at about 45 C under reduced pressure to obtain lurasidone hydrochloride.
Yield: 93%
HPLC Purity: 98.98%
Claims (12)
1. A process for the preparation of lurasidone hydrochloride of Formula I
comprising the steps of:
i) Resolving trans (racemic)-1,2-cyclohexane dicarboxylic acid of Formula III
into trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula lila;
ii) Converting trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ilia into trans (R,R)-dicarboxylate intermediate of Formula X, wherein R is C1-C4 alkyl or benzyl;
iii) Converting trans (R,R)-dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI;
iv) Converting trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI
into an intermediate of Formula XII
wherein R' is a leaving group;
v) Reacting intermediate of Formula XII with 3-(1-piperazinyl-1,2-benzisothiazole) of Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1 ' -[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula VIIa;
vi) Reacting trans (R, R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula VIIa with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
to obtain lurasidone of Formula XIII; and vii) Treating lurasidone of Formula XIII with hydrogen chloride to obtain lurasidone hydrochloride of Formula I.
comprising the steps of:
i) Resolving trans (racemic)-1,2-cyclohexane dicarboxylic acid of Formula III
into trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula lila;
ii) Converting trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ilia into trans (R,R)-dicarboxylate intermediate of Formula X, wherein R is C1-C4 alkyl or benzyl;
iii) Converting trans (R,R)-dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI;
iv) Converting trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI
into an intermediate of Formula XII
wherein R' is a leaving group;
v) Reacting intermediate of Formula XII with 3-(1-piperazinyl-1,2-benzisothiazole) of Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1 ' -[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula VIIa;
vi) Reacting trans (R, R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula VIIa with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII
to obtain lurasidone of Formula XIII; and vii) Treating lurasidone of Formula XIII with hydrogen chloride to obtain lurasidone hydrochloride of Formula I.
2. The process according to claim 1, wherein resolution is carried out using a chiral resolving agent.
3. The process according to claim 1, wherein the resolution is carried out at a temperature of about 0°C to -100°C.
4. The process according to claim 1, wherein the salt of trans 1,2-cyclohexane dicarboxylic acid of Formula III with the resolving agent is further purified by crystallization from a solvent selected from alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles, or mixtures thereof.
5. The process according to claim 1, wherein conversion of trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula IIIa into trans (R,R)-dicarboxylate intermediate of Formula X is carried out in a C1-C4 alcohol or benzyl alcohol.
6. The process according to claim 1, wherein conversion of trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula Ma into trans (R,R)-dicarboxylate intermediate of Formula X is carried out at about 40°C.
7. The process according to claim 1, wherein conversion of trans (R,R)-dicarboxylate intermediate of Formula X into trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI is carried out by adding a reducing agent in a hydrocarbon or ether solvent.
8. The process according to claim 1, wherein conversion of trans (R,R)-1,2-bis(hydroxymethyl)cyclohexane of Formula XI into trans R,R intermediate of Formula XII by reaction with a halide or sulphonyl compound in the presence of a base in a chlorinated hydrocarbon or pyridine.
9. The process according to claim 1, wherein trans R,R intermediate of Formula XII
is reacted with 3-(1-piperazinyl-1,2-benzisothiazole) of Formula VI in the presence of a base in a nitrile or amide solvent to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula VIIa.
is reacted with 3-(1-piperazinyl-1,2-benzisothiazole) of Formula VI in the presence of a base in a nitrile or amide solvent to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula VIIa.
10. The process according to claim 1, wherein the reaction of trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula VIIa with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide intermediate of Formula VIII is carried out in the presence of a base in a hydrocarbon solvent.
11. The process according to claim 1, wherein a solution of lurasidone in ethyl acetate is treated with 7% aqueous hydrochloric acid.
12. Use of trans (R,R)-1,2-cyclohexane dicarboxylic acid of Formula IIIa for the preparation of lurasidone hydrochloride.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN943/DEL/2011 | 2011-04-01 | ||
| IN943DE2011 | 2011-04-01 | ||
| PCT/IB2012/051500 WO2012131606A1 (en) | 2011-04-01 | 2012-03-28 | Process for the preparation of an antipsychotic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2831703A1 true CA2831703A1 (en) | 2012-10-04 |
Family
ID=45937504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2831703A Abandoned CA2831703A1 (en) | 2011-04-01 | 2012-03-28 | Process for the preparation of an antipsychotic agent |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2694499A1 (en) |
| AU (1) | AU2012235724A1 (en) |
| CA (1) | CA2831703A1 (en) |
| WO (1) | WO2012131606A1 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9409899B2 (en) | 2012-02-13 | 2016-08-09 | Cadila Healthcare Limited | Process for preparing benzisothiazol-3-yl-piperazin-1-yl-methyl-cyclo hexylmethanisoindol-1,3-dione and its intermediates |
| WO2014037886A1 (en) * | 2012-09-04 | 2014-03-13 | Ranbaxy Laboratories Limited | Process for the preparation of lurasidone hydrochloride |
| CN102911170A (en) * | 2012-11-15 | 2013-02-06 | 苏州第壹制药有限公司 | Method for preparing imide compound hydrochloride |
| CN102936243B (en) * | 2012-11-16 | 2015-08-05 | 上海伯倚化工科技有限公司 | A kind of synthetic method of Lurasidone |
| CN103864774B (en) * | 2012-12-14 | 2016-09-28 | 成都弘达药业有限公司 | A kind of preparation method of Lurasidone |
| WO2014102808A1 (en) | 2012-12-25 | 2014-07-03 | Lee Pharma Limited | A process for preparation of trans (lr,2r)-cyclo hexane 1, 2-dicarboxylic acid |
| ITMI20130262A1 (en) * | 2013-02-22 | 2014-08-23 | Edmond Pharma Srl | PROCEDURE FOR THE PREPARATION OF CHLORIDATED LURASIDONE |
| ITMI20131245A1 (en) * | 2013-07-24 | 2015-01-25 | Olon Spa | PROCEDURE FOR THE PRODUCTION OF LURASIDONE WITH HIGH PURITY |
| CN104513182A (en) * | 2013-10-08 | 2015-04-15 | 无锡万全医药技术有限公司 | Method for preparing (1R,2R)-1,2-cyclohexanedimethanol disulfonate |
| ITMI20131737A1 (en) | 2013-10-17 | 2015-04-18 | Procos Spa | PROCESS FOR THE INDUSTRIAL SYNTHESIS OF LURASIDONE |
| CN103724238A (en) * | 2013-12-31 | 2014-04-16 | 无锡万全医药技术有限公司 | Preparation method of (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate |
| ES2826603T3 (en) | 2014-06-16 | 2021-05-18 | Johnson Matthey Plc | Processes for the preparation of alkylated arylpiperazine and alkylated arylpiperidine compounds including novel intermediates |
| EP3207041B1 (en) | 2014-10-14 | 2019-12-04 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | An improved process for the preparation of lurasidone hydrochloride |
| US10196400B2 (en) | 2015-01-08 | 2019-02-05 | Piramal Enterprises Limited | Process for the preparation of lurasidone and its intermediate |
| 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 |
| CN106518729A (en) * | 2016-09-21 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | Lurasidone hydrochloride intermediate preparation method |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2800953B2 (en) | 1990-07-06 | 1998-09-21 | 住友製薬株式会社 | New imide derivatives |
| JP4219696B2 (en) | 2003-01-27 | 2009-02-04 | 大日本住友製薬株式会社 | Process for producing optically active trans-1,2-cyclohexanedicarboxylic acid derivative |
| US20110003994A1 (en) | 2009-07-02 | 2011-01-06 | Dainippon Sumitomo Pharma Co., Ltd. | Cycloalkane derivative |
-
2012
- 2012-03-28 CA CA2831703A patent/CA2831703A1/en not_active Abandoned
- 2012-03-28 WO PCT/IB2012/051500 patent/WO2012131606A1/en active Application Filing
- 2012-03-28 EP EP12713375.9A patent/EP2694499A1/en not_active Withdrawn
- 2012-03-28 AU AU2012235724A patent/AU2012235724A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012131606A1 (en) | 2012-10-04 |
| EP2694499A1 (en) | 2014-02-12 |
| AU2012235724A1 (en) | 2013-10-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2831703A1 (en) | Process for the preparation of an antipsychotic agent | |
| JP5410578B2 (en) | Improved process for producing cilastatin acid | |
| CA2578409A1 (en) | A method for preparing irbesartan and intermediates thereof | |
| US11472770B2 (en) | Process for the preparation of enantiomerically enriched 3-aminopiperidine | |
| WO2014037886A1 (en) | Process for the preparation of lurasidone hydrochloride | |
| US10426770B2 (en) | Process for the preparation of Lurasidone hydrochloride | |
| US7470816B2 (en) | Tramadol recovery process | |
| JPH0859517A (en) | Optical resolution agent and production of optically active tetrahydrofuran-carboxylic acid using the same | |
| US8129536B2 (en) | Method for the purification of lansoprazole | |
| CA2570415C (en) | An improved process for the preparation of 5,6 -dihydro -4h-4(s)-ethylamino-6(s)-methylthieno[2,3-b] thiopyran-2-sulfonamide- 7,7 -dioxide and its salt | |
| US20120035374A1 (en) | Process for the preparation of fluvastatin and salts thereof | |
| US9828334B2 (en) | Process for preparing levomilnacipran | |
| JP4126921B2 (en) | Process for producing optically active β-phenylalanine derivative | |
| JP4752285B2 (en) | Efficient optical resolution of trifluorolactic acid | |
| KR100503639B1 (en) | A purification process of Tamsulosin | |
| US20180029993A1 (en) | Method for producing optically active valeric acid derivative | |
| JPWO2010079605A1 (en) | Method for producing high purity 1-benzyl-3-aminopyrrolidine | |
| JP5704182B2 (en) | Process for producing optically active tetrahydrofuran-2-carboxylic acid | |
| WO2003068728A1 (en) | PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE β-PHENYLALANINE | |
| JP3694923B2 (en) | Process for producing optically active 1- (2,4-dichlorophenyl) ethylamine | |
| JP5176452B2 (en) | Process for producing optically active tetrahydropyranylglycine compound | |
| JPWO2004046075A1 (en) | Crystallization solvent containing cycloalkyl ether compound and crystallization method using the solvent | |
| JPH10101629A (en) | Production of optically active butyric acid derivative | |
| JPH10195015A (en) | Optical resolution of 2-benzylsuccin acid compound | |
| JP2003238513A (en) | Method for producing optically active 2- aminopentanenitrile salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |
Effective date: 20150330 |