WO2010082110A2 - Novel process for preparing pure 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride and its conversion to paliperidone - Google Patents
Novel process for preparing pure 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride and its conversion to paliperidone Download PDFInfo
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- WO2010082110A2 WO2010082110A2 PCT/IB2010/000041 IB2010000041W WO2010082110A2 WO 2010082110 A2 WO2010082110 A2 WO 2010082110A2 IB 2010000041 W IB2010000041 W IB 2010000041W WO 2010082110 A2 WO2010082110 A2 WO 2010082110A2
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- NJUUUSVHPZXOAO-UHFFFAOYSA-N CC(N=C1N2CCCC1O)=C(CCN(CC1)CCC1c1n[o]c3c1ccc(N(CC1)CCC1c1n[o]c4cc(F)ccc14)c3)C2=O Chemical compound CC(N=C1N2CCCC1O)=C(CCN(CC1)CCC1c1n[o]c3c1ccc(N(CC1)CCC1c1n[o]c4cc(F)ccc14)c3)C2=O NJUUUSVHPZXOAO-UHFFFAOYSA-N 0.000 description 1
- LLIWRHGEHGEQJI-UHFFFAOYSA-N Fc(cc1)cc2c1c(C(CC1)CCN1c1ccc(c(C3CCNCC3)n[o]3)c3c1)n[o]2 Chemical compound Fc(cc1)cc2c1c(C(CC1)CCN1c1ccc(c(C3CCNCC3)n[o]3)c3c1)n[o]2 LLIWRHGEHGEQJI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention relates to neve! process for providing substantially pure 6-Fluoro-3- piperidin-4-yl-1 ,2-benzisoxazole hydrochloride and its conversion to Paliperidone having dimer compound of structural formuIa-1A is less than 0.2 % and HPLC purity > 99.7%.
- Paliperidone chemically known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1- yl]-ethyl]- 9-hydroxy -2-methyl-6,7,8,94etrahydro-4H-pyrido-[1 ,2-a]-pyrimidin-4-one is a benz- isoxazole derivative having the structural formula 1.
- Paliperidone is known as 9-hydroxy risperidone and useful for the treatment of schizophrenia.
- 9-hydr ⁇ xy risperidone is a metabolite of risperidon.
- Paliperidone was first disclosed in US Patent No(s). 5,158,952, and 5,254,556 (herein after designated as US '952 & US '556 patents respectively).
- US '952 Patent describe process for the synthesis of paliperidone by condensation of 6-fluoro-3-piperidin-4-yl-1 ,2- benzisoxazole hydrochloride (formuIa-2) and 3-(2-chIoroethyl)-9-hydroxy-2-methyl-6,7,8,9- tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-3) in presence of organic base.
- Both compounds of formula 2 and formula 3 are key intermediates useful in synthesis of Paliperidone.
- the benzisoxazole hydrochloride intermediate of formula-2 is commonly used for the preparation of Risperidone and Paliperidone.
- WO 2008/140641 provides pure Paliperidone comprising less than about 0.1%, preferably less than about 0.05% and more preferably less than about 0.02% impurity X as well as purification processes to obtain thereof.
- WO2008/021346 provides pure Paliperidone as well as purification processes to obtain thereof.
- WO 2008/021345 described a process for preparing paliperidone from its intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one.
- the object of the present invention is to provide industrially scalable process for the preparation of Paliperidone having dimer compound of structural formula-1A less than 0.2 %.
- Another object of the present invention is to provide novel process for purification of 6- fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole or its acid addition salt.
- Yet another object of the present invention is to provide Paliperidone having HPLC purity >99.7 %; having dimmer impurity of formula 1a ⁇ 0.2% w/w, preferably ⁇ 0.1 % w/w and more preferably less than 0.05% w/w.
- Yet another object of the present invention is to provide novel organic acid addition salt of 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole.
- Yet another object of the present invention is to provide, a novel compound of formula 1a, present in paliperidone as an impurity.
- the present invention relates to an industrially scalable process for the preparation of Paliperidone having dimer compound of structural forrnula-1A less than 0.2 %.
- the invention also relates to provide novel process for purifying 6-fluoro-3- piperidin-4-yl-1 , 2-benzisoxazole or its acid addition salt.
- the commercially available 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole hydrochloride contains hydrochloride salt of formula-2a as an impurity.
- the compound of formula-2a reacts with 3-(2-chloroethyl)-9-hydroxy-2-methyI-6,7,8,9-tetrahydro-4H-pyrido[1 ,2- a]-pyrimidin-4-one to give compound of formu!a-1 a, herein referred to as "Dimer compound". If compound of formula-2a is present in compound of formula-2, it is observed that the removal of dimer compound is difficult during purification of paliperidone.
- 6-fluoro-3-piperidin-4-yl-1 2-benzisoxazole of formula-2 is converted to corresponding organic acid addition salt to remove compound of formula 2a.
- An organic acid for preparing acid addition salt of 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole having formula-2 is selected from mono basic acid such as acetic acid, formic acid, propionic acid; dibasic acid such as oxalic acid, fumaric acid, succinic acid, glutaric acid, tartaric acid, malonic acid, maleic acid; tribasic acid such as citric acid, benzene sulfonic acid.
- the inorganic acids such as sulfate, nitric acid, phosphoric acid can also be use for the preparing an acid addition salt.
- the tartaric acid is preferred for preparing an acid addition salt of 6-fluoro-3-piperidin-4-yl-1 ,2- benzisoxazole having formula 2.
- 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole of formula-2 formula-2 is dissolved in water, followed by addition of dichloromethane.
- the reaction mixture is treated with a base.
- the base is preferable selected from primary amine wherein ammonia is preferred.
- Dichloromethane layer from reaction mixture is separated and dried over anhydrous sodium sulfate.
- Tartaric acid in methanol is added to prepare tartarate salt of 6-fluoro-3-piperidin-4-yl-1 ,2- benzisoxazole in dried organic layer and separated by filtration.
- Free base is prepared by treatment with suitable base like sodium hydroxide, ammonia, sodium carbonate.
- 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole is converted to its hydrochloride salt.
- the pure 6-Fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole obtained via acid salt formation is reacting with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4/-/-pyrido[1 ,2-a]- pyrimidin-4-one to give Paliperidone.
- the purified 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole or its hydrochloride salt (formula-2), is reacted with compound of formula-3 using a base optionally in presence of metal halide catalysts such as NaI, Kl, LiI, CsI, NaBr 1 KBr, preferably an iodide source compounds like sodium iodide or potassium iodide.
- the crude paliperidone is purified using a base in an organic solvent to give pure paliperidone.
- the base is selected from carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkoxides of C 1 to C 4 alcohols; or organic tertiary amine bases such as C 1 to C 4 trialkyl amines, N-methyl morpholine, N-methyl pyrrolidine, N-methyl piperidine, Diaza(1,3)bicyclo[5.4.0]undecane [DBU], 1,5-Diazabicyc!o[4.3.0]non-5-ene [ DBN ] and 1 ,4-diazabicyclo[2.2.2]octane [DABCO].
- the solvent is selected from water, methanol, benzotrifluoride, sulfolane, isoamyl alcohol, amyl alcohol, isopropyl alcohol, acetone or mixtures thereof. •
- Paliperidone obtained by the process is having HPLC purity >99.7%; having dimmer impurity of formula 1a ⁇ 0.2% w/w, preferably ⁇ 0.1% w/w and more preferably less than 0.05% w/w.
- Example-1 Purification of 6-Fiuoro-3-piperidin-4-yI-1, 2-benzisoxazole HC! 50 gm of 6-Fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole HCI with 250 ml DM water and 300 ml MDC was stirred at ambient temperature. 20 ml of aqueous ammonia was added at 25-30 0 C and stirred for 50 min. MDC layer was separated. The MDC layer was washed with. DM water twice and dried over anhydrous sodium sulfate. MDC was completely distilled off under vaccum.
Abstract
The invention relates to novel process for providing substantially pure 6-Fluoro-3- piperidin-4-yl-1,2-benzisoxazole hydrochloride and its conversion to Paliperidone having dimer compound of structural formula-1 A is less than 0.2 % and HPLC purity > 99.7%.
Description
Novel process for preparing pure 6~Fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride and its conversion to Paliperidone
FIELD OF THE INVENTION
The invention relates to neve! process for providing substantially pure 6-Fluoro-3- piperidin-4-yl-1 ,2-benzisoxazole hydrochloride and its conversion to Paliperidone having dimer compound of structural formuIa-1A is less than 0.2 % and HPLC purity > 99.7%.
Formula 1a [Dimer impurity]
BACKGROUND OF THE INVENTION
Paliperidone, chemically known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1- yl]-ethyl]- 9-hydroxy -2-methyl-6,7,8,94etrahydro-4H-pyrido-[1 ,2-a]-pyrimidin-4-one is a benz- isoxazole derivative having the structural formula 1.
Paliperidone is known as 9-hydroxy risperidone and useful for the treatment of schizophrenia. 9-hydrόxy risperidone is a metabolite of risperidon.
US Patent No. 4,804,663 and 5,158,952 describe variety of processes for the preparation of 3-piperidinyl-1 ,2-benzisoxazole derivatives along with their pharmaceutical compositions and methods of use. The processes for synthesizing paliperidone and related compounds are disclosed in U.S. Patent No. 5,158,952; 5,254,556 and 5,688,799.
Paliperidone was first disclosed in US Patent No(s). 5,158,952, and 5,254,556 (herein after designated as US '952 & US '556 patents respectively). US '952 Patent describe process for the synthesis of paliperidone by condensation of 6-fluoro-3-piperidin-4-yl-1 ,2-
benzisoxazole hydrochloride (formuIa-2) and 3-(2-chIoroethyl)-9-hydroxy-2-methyl-6,7,8,9- tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-3) in presence of organic base. Both compounds of formula 2 and formula 3 are key intermediates useful in synthesis of Paliperidone. The benzisoxazole hydrochloride intermediate of formula-2 is commonly used for the preparation of Risperidone and Paliperidone.
WO 2008/140641 provides pure Paliperidone comprising less than about 0.1%, preferably less than about 0.05% and more preferably less than about 0.02% impurity X as well as purification processes to obtain thereof.
WO2008/021346 provides pure Paliperidone as well as purification processes to obtain thereof.
WO 2008/021345 described a process for preparing paliperidone from its intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one.
The prior art processes as disclosed above for the preparation of Paliperidone involving the reaction of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H- pyrrido[1 ,2-a]-pyrimidin-4-one (formula-3) with 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole hydrochloride (formula-2), result in the formation of impurities that are difficult to remove.
There is a need in the art for a novel process for preparing substantially pure Paliperidone having dimer compound of structural formula-1 A is less than 0.2 %.
SUMMARY OF THE INVENTION
The object of the present invention is to provide industrially scalable process for the preparation of Paliperidone having dimer compound of structural formula-1A less than 0.2 %.
Another object of the present invention is to provide novel process for purification of 6- fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole or its acid addition salt.
Yet another object of the present invention is to provide Paliperidone having HPLC purity >99.7 %; having dimmer impurity of formula 1a <0.2% w/w, preferably <0.1 % w/w and more preferably less than 0.05% w/w.
Yet another object of the present invention is to provide novel organic acid addition salt of 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole.
Yet another object of the present invention is to provide, a novel compound of formula 1a, present in paliperidone as an impurity.
Formula 1a (Dimer impurity) Formula 2a
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an industrially scalable process for the preparation of Paliperidone having dimer compound of structural forrnula-1A less than 0.2 %. In accordance with the same the invention also relates to provide novel process for purifying 6-fluoro-3- piperidin-4-yl-1 , 2-benzisoxazole or its acid addition salt.
The commercially available 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole hydrochloride (formula-2) contains hydrochloride salt of formula-2a as an impurity. The compound of formula-2a reacts with 3-(2-chloroethyl)-9-hydroxy-2-methyI-6,7,8,9-tetrahydro-4H-pyrido[1 ,2- a]-pyrimidin-4-one to give compound of formu!a-1 a, herein referred to as "Dimer compound". If compound of formula-2a is present in compound of formula-2, it is observed that the removal of dimer compound is difficult during purification of paliperidone.
6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole of formula-2 is converted to corresponding organic acid addition salt to remove compound of formula 2a. An organic acid for preparing acid addition salt of 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole having formula-2 is selected from mono basic acid such as acetic acid, formic acid, propionic acid; dibasic acid such as oxalic acid, fumaric acid, succinic acid, glutaric acid, tartaric acid, malonic acid, maleic acid; tribasic acid such as citric acid, benzene sulfonic acid. The inorganic acids such as sulfate, nitric acid, phosphoric acid can also be use for the preparing an acid addition salt. The tartaric acid is preferred for preparing an acid addition salt of 6-fluoro-3-piperidin-4-yl-1 ,2- benzisoxazole having formula 2.
6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole of formula-2 formula-2 is dissolved in water, followed by addition of dichloromethane. The reaction mixture is treated with a base. The base is preferable selected from primary amine wherein ammonia is preferred. Dichloromethane layer from reaction mixture is separated and dried over anhydrous sodium sulfate. Tartaric acid in methanol is added to prepare tartarate salt of 6-fluoro-3-piperidin-4-yl-1 ,2- benzisoxazole in dried organic layer and separated by filtration. Free base is prepared by treatment with suitable base like sodium hydroxide, ammonia, sodium carbonate. The purification is optionally repeated to improve the purity of 6-fluoro-3-piperidin-4-yl-1 ,2- benzisoxazole. 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole, is converted to its hydrochloride
salt. The pure 6-Fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole obtained via acid salt formation is reacting with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4/-/-pyrido[1 ,2-a]- pyrimidin-4-one to give Paliperidone.
In the N- alkylation step, the purified 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole or its hydrochloride salt (formula-2), is reacted with compound of formula-3 using a base optionally in presence of metal halide catalysts such as NaI, Kl, LiI, CsI, NaBr1 KBr, preferably an iodide source compounds like sodium iodide or potassium iodide. The crude paliperidone is purified using a base in an organic solvent to give pure paliperidone. The base is selected from carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkoxides of C1 to C4 alcohols; or organic tertiary amine bases such as C1 to C4 trialkyl amines, N-methyl morpholine, N-methyl pyrrolidine, N-methyl piperidine, Diaza(1,3)bicyclo[5.4.0]undecane [DBU], 1,5-Diazabicyc!o[4.3.0]non-5-ene [ DBN ] and 1 ,4-diazabicyclo[2.2.2]octane [DABCO]. The solvent is selected from water, methanol, benzotrifluoride, sulfolane, isoamyl alcohol, amyl alcohol, isopropyl alcohol, acetone or mixtures thereof. •
Paliperidone obtained by the process is having HPLC purity >99.7%; having dimmer impurity of formula 1a <0.2% w/w, preferably <0.1% w/w and more preferably less than 0.05% w/w.
The co-formation of impurity of Formula-1a, in paliperidone is depicted in scheme as follows.
The invention is further illustrated by following non-limiting examples.
Example-1 Purification of 6-Fiuoro-3-piperidin-4-yI-1, 2-benzisoxazole HC!
50 gm of 6-Fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole HCI with 250 ml DM water and 300 ml MDC was stirred at ambient temperature. 20 ml of aqueous ammonia was added at 25-300C and stirred for 50 min. MDC layer was separated. The MDC layer was washed with. DM water twice and dried over anhydrous sodium sulfate. MDC was completely distilled off under vaccum.
To the residual mass, 250 ml Methyl Ethyl Ketone was added and stirred at 55-600C for 30 mins and cooled up to 300C. 30 ml IPA-HCI was added to it at 25-300C in 15 mins, stirred for 1 hr, filtered and washed with 25 ml MEK and then dried in oven at 50-550C for 12 hrs to give 22.0 gm (77.5% w/w) 6-Fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole HCI (HPLC purity 98.92%; compound of formula-2a is 0.53%).
Exampϊe-2 Purification of 6-FIυoro-3-piperidin-4-y!-1 ,2-benzisoxazole HCI
200 gm of 6-Fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole HCI with water and DCM was stirred at ambient temperature. 200 ml of aqueous ammonia was added and stirred further till dichloromethane iayer was separaled. The organic layer was washed with water and dried over anhydrous sodium sulfate. A solution of tartaric acid in methanol was added and stirred. The tartrate salt was filtered, washed with methanol and dried. If required, the process is repeated optionally to get pure 6-Fluoro-3-piperidin-4-yl-1, 2-benzisoxazole HCI.
255 gm of tartrate salt of 6-Fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole obtained by above process was stirred with water and dichloromethane and treated with aqueous ammonia. Dichloromethane layer was separated, dried over sodium sulfate and treated with 2-propanolic HCI and stirred for 30-45 minutes. The solid was filtered, washed with methanol and dried to give 155 gm (77.5% w/w) 6-Fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole HCI (HPLC purity 99.93%; compound of formula-2a is 0.05%).
Example-3 Purification of 6-Fluoro-3-piperJdin-4-yI-1, 2-benzisoxazole HCi
100 gm of 6-Fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole HCI with water and DCM was stirred at ambient temperature. 100 ml of aqueous ammonia was added and stirred further till dichloromethane layer was separated. The organic layer was washed with water and dried over anhydrous sodium sulfate. A solution of tartaric acid in methanol was added and stirred. The tartrate salt was filtered, washed with methanol and dried. If required, the process is repeated optionally to get pure 6-FlL.oro-3-piperidin-4-yl-1 , 2-benzisoxazoie HCI.
109 gm of tartrate salt of 6-Fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole obtained by above process was stirred with water and dichloromethane and treated with aqueous ammonia. Dichloromethane layer was separated, dried over sodium sulfate and treated with 2-propanolic HC! and stirred for 25-35 minutes. The solid was filtered, washed with methanol
and dried to give 65 gm (65.0% w/w) 6-Fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole HCI (HPLC purity 99.94%; compound of formula-2a is 0.04%).
Example- 4 Preparation of 3-[2-[4-(6-FIuOrO-I,, 2-benzϊsoxazoI-3-yl) piperidin-1-yl] ethyl]-9-hydroxy -a-methyl-ΘJ.β.θ-tetrahydro^H-pyrido [1,2-a] -pyrϊmidin- 4-one (Formula-1)
100 gm of purified . 6-Fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole hydrochloride (Formula-2), and 143.4 gm potassium carbonate, 6.5 gm potassium iodide in 900 ml of acetonitrile was charged at 300C. The mixture was heated upto 55-600C and stirred for 1 hr. The previously prepared solution of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro- 4H-pyrido[1 ,2-a]pyrimidin-4-one (Formula-3) dissolved into 600 ml acetonitrile and charged drop wise into the reaction mass at about 600C followed by stirring for 46 h. The acetonitrile was distilled at 500C- 550C under reduced pressure. The crude product was obtained and ϊ slurried in water with stirring for 1 hr at 250C-SO0C. If required water wash is repeated. The solid product was dried in vacuum oven at 60 - 650C to provide crude Paliperidone (purity >98%, dimer compound <0.1 %)
Purification of 3-[2-[4-(6-Fluoro 1,2-benzisoxazol-3-yl)piperidin-1-yl ]ethyl ]-9-hydroxy -2-methyl-6,7,8s9-tetrahydro-4H-pyrido [1,2-a] -pyrϊmidin-4-one (Formula-1)
14O g of Crude paliperidone obtained in previous step was dissolved in hot lsopropyl alcohol and activated charcoal was charged. The content was stirred for 30 min and filtered through hyflow in hot condition and washed with previously heated lsopropyl alcohol. The filtered mass was gradually cooled up to 0-5 0C and stirred for 2 hr. The solid product was filtered and washed with IPA. The purification is repeated if required and the obtained product was dried in vacuum oven at 65-70 0C to give product with >99% [should be > 99.7 %] purity.
Claims
1. A process for the preparation of 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole hydrochloride (formula-2) substantially free from compound of formula-2a,
Formula 2a comprising steps: a. crude 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole hydrochloride of formula-2 is treated with a base in an organic solvent to give 6-fluoro-3-piperidin-4-yl-1 ,2- benzisoxazole. b. filtering reaction mixture, c. treating the filtrate as obtained in step-(b) with an organic acid for saltification, d. treating the salt as obtained in step-(c) with a base to give pure 6-fluoro-3- piperidin-4-yl-1 ,2-benzisoxazole, e. treating the product obtained in step-(d) with hydrochloric acid to give 6-fluoro- 3-piperidin-4-yl-1 ,2-benzisoxazole HCI.
2. A process of preparing paliperidone having dimer compound of structural formula^ A less than 0.2%
Formula 1a [Dimer impurity]
comprising steps: a. reacting 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole or its acid addition salt prepared as obtained in claim 1, with 3-(2-chloroethyl)-9-hydroxy-2-methyl- 6,7,8,9-tetrahydro-4/i'-pyrido[1,2-a]pyrimidin-4-one (Formula-3) in solvent(s), in presence of base, optionally using a halide catalyst or using a phase transfer catalyst to provide paliperidone or its salt, b. separating paliperidone from the reaction mixture, c. purifying paliperidone to provide substantially pure paliperidone.
3. The process according to c!aim-(2), wherein, substantially pure paliperidone having dimer compound of structural formula-1A is less than 0.2%, preferably less than 0.1% and, more preferably less than 0.05%
4. The process according to claim-(1), wherein the base is selected from hydroxides, carbonates of alkali or alkaline earth metal NaOH, KOH, Ca(OH)2, Ba(OH)2, Na2CO3, K2CO3, LiOH, Li2CO3, CsOH, Cs2CO3; or ammonia or substituted amines, such as (R1)(R2)(R3)N wherein Ri,R2,R3, is C1-C10 alkyl or aralkyl or heteroaryl groups;
5. The process according to c!aim-(4), wherein the base used in step (a) is preferably aqueous ammonia.
6 The process according to claim-(4), wherein the base used in step [d] is preferably potassium carbonates.
7 The process according to claim-(1), wherein the acid used in step [c] or step [e] is selected from organic mono basic acids such as acetic acid, formic acid, propionic acid; dibasic acid such as oxalic acid, fumaric acid, succinic acid, glutaric acid, tartaric acid, malonic acid, maleic acid; tribasic acid such as citric acid; benzene sulfonic acid; inorganic mineral acids such as sulfuric, hydrochloric acid, nitric acid, phosphoric acid.
8 The process according to claim-(7), wherein the acid used in step [c] is preferably tartaric acid.
9 The process according to claim-(7), wherein the acid used in step je] is preferably hydrogen chloride.
10 The process according to claim-(2), wherein the solvent used in step-[a] is selected from ethers such as tetrahydro furan, dioxane, methyl tert. butyl ether, di-n- propyl ether; nitriles such as acetonitrile, propionitrile; aliphatic and alicyclic solvents such as hexane, heptane, cyclohexane, methyl cyclohexane ; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, alcohols such as C1 to C5; benzotrifluoride; sulfolane; DMSO; N,N-dimethyl formamide; N1N- dimethyl acetamide; N-methyl 2-pyrrolidone; 1 ,3-dimethyl imidazolidin-2-one; 1,3 dimethyl propylene urea; tetramethy! urea or mixtures of solvents mentioned here in above.
11 The process according to c!aim-(10), wherein the preferable solvent used in step-[a] is acetonitrile.
12 The process according to claim-(2), wherein the reaction in step-[a] is optionally carried out in presence of metal halide catalysts such as NaI, Kl, Li!, CsI, NaBr, KBr, preferably iodide source compounds like sodium iodide or potassium iodide.
13 The process according to claim-(2), wherein the reaction in step-[a] is optionally carried out using phase transfer catalysts, such as quaternary ammonium salts, or quaternary phosphonium salts, poly ethylene glycol ethers such as PEG 400, PEG- 600.
14. Paliperidone having less than 0.1% wt/wt compound of structural formula-1 A
Formula 1a [Dimer impurity].
15. 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole hydrochloride (formula-2), obtained from tartrate salt of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole, a key intermediate for the preparation of Paiiperidone; substantially free from compound of formula-2a,
Formula 2
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---|---|---|---|---|
WO2011015936A2 (en) * | 2009-08-04 | 2011-02-10 | Orchid Chemicals And Pharmaceuticals Ltd | An improved process for the preparation of pure paliperidone |
CN111087204A (en) * | 2019-12-31 | 2020-05-01 | 山西凯迪建材有限公司 | Mineral admixture ternary cementing material and preparation method thereof |
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US4458076A (en) * | 1983-05-31 | 1984-07-03 | Hoechst-Roussel Pharmaceuticals | 3-(4-Piperidinyl)-1,2-benzisothiazoles |
US5783705A (en) * | 1997-04-28 | 1998-07-21 | Texas Biotechnology Corporation | Process of preparing alkali metal salys of hydrophobic sulfonamides |
US20080171875A1 (en) * | 2006-08-14 | 2008-07-17 | Santiago Ini | Process for the synthesis of 9-hydroxy risperidone (paliperidone) |
-
2010
- 2010-01-12 WO PCT/IB2010/000041 patent/WO2010082110A2/en active Application Filing
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US4458076A (en) * | 1983-05-31 | 1984-07-03 | Hoechst-Roussel Pharmaceuticals | 3-(4-Piperidinyl)-1,2-benzisothiazoles |
US5783705A (en) * | 1997-04-28 | 1998-07-21 | Texas Biotechnology Corporation | Process of preparing alkali metal salys of hydrophobic sulfonamides |
US20080171875A1 (en) * | 2006-08-14 | 2008-07-17 | Santiago Ini | Process for the synthesis of 9-hydroxy risperidone (paliperidone) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011015936A2 (en) * | 2009-08-04 | 2011-02-10 | Orchid Chemicals And Pharmaceuticals Ltd | An improved process for the preparation of pure paliperidone |
WO2011015936A3 (en) * | 2009-08-04 | 2011-04-14 | Orchid Chemicals And Pharmaceuticals Ltd | An improved process for the preparation of pure paliperidone |
CN111087204A (en) * | 2019-12-31 | 2020-05-01 | 山西凯迪建材有限公司 | Mineral admixture ternary cementing material and preparation method thereof |
Also Published As
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WO2010082110A3 (en) | 2010-09-10 |
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