WO2013080220A2 - An improved process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydio-9-hydroxy-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one. - Google Patents
An improved process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydio-9-hydroxy-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one. Download PDFInfo
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- WO2013080220A2 WO2013080220A2 PCT/IN2012/000771 IN2012000771W WO2013080220A2 WO 2013080220 A2 WO2013080220 A2 WO 2013080220A2 IN 2012000771 W IN2012000771 W IN 2012000771W WO 2013080220 A2 WO2013080220 A2 WO 2013080220A2
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- Prior art keywords
- acid
- paliperidone
- preparation
- solvent
- group
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention provides an improved process for the preparation of Paliperidone from Paliperidone Palmitate.
Abstract
A process for the preparation of paliperidone from the hydrolysis of paliperidone palmitate in the presence of an acid in a solvent.
Description
Title of the invention:
An improved process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol- 3- yl)- 1 -piperidinyl] ethyl]-6,7,8,9-tetrahydro-9-hydroxy -2-methyl-4H-pyrido[1,2-a] pyrimidin -4-one.
Cross reference to related application:
[0001 ] -This-' application claims priority from the provisional . specification No. 4104/CHE/2011 filed on 28.11.2011
Field of the invention:
[0002] The present invention provides an improved process for the preparation of Paliperidone from Paliperidone Palmitate.
Background of the invention:
[0003] Paliperidone chemically known as 3-[2-[4-(6-fluoro-l, 2-benzisoxazol-3-yl)- 1 -piperidinyl] ethyl] -6. 7, 8, 9-tetrahydro-9-hydroxy-2-methyI-4H-pyrido [1, 2-a-| pyrimidin-4-one, is a 5-HT antagonist, belonging to the chemical class of benzisoxazole derivatives and having the following structural formula:
[0004] Paliperidone ("PLP") is a metabolite of Risperidone marketed under the trade
name Invega(R). Pal i peridone is an anti-psychotropic agent developed by Janssen Pharmaceuticals which is approved in the United States for the treatment of schizophrenia.
[ 0005 ] The pal m itate ester of pal iperidone chemical ly known as 3-[2-[4-(6-fluoro- l , 2-benzoisoxazol-3-yl)- l -piperidyl] ethyl]-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl- 4H-pyrido [ 1 , 2-a] pyrimid in-4-one palmitate ester is a valuable prodrug of paliperidone useful in depot formulations and has the following formula:
[0006] Paliperidone is first described in the patent US5 1 58952 which discloses a process for the preparation of paliperidone, wherein 3-(2-chloroethyl)-6,7,8,9- tetra.hyclro4)-hycliO.xy-4H-pyrid.o[ l ,2-a]pyrimi.din-4-one is condensed with 6-fluoro- 3-(4-pi peric! iny 1)- 1 ,2-benzisoxazole monohydrochloride in the presence of a base in an solvent to obtain paliperidone. The paliperidone obtained by this process is subjected to column chromatography to get pure paliperidone. This process results in low yield of the product as it involves the purification of the residue using column chromatography.
[0007] Paliperidone Palmitate (PLP-P) is described in US5158952 and US5254556 (herein re ferred as US'556). The patent US ' 556 discloses process for preparation of both the decanoyl and the acetyl esters of paliperidone. Other processes for the preparation of PLP- P are described in US Patent No. 6077843 and US Application No. US20080214808.
[0008] WO20 1 10740 1 7 discloses a process for the preparation of paliperidone, wherei n 9-O-acylated paliperidone (wherein R = C 1 -C 1 0 alkyl chain) undergoes hydrolysis in presence o f base in a solvent to obtain Paliperidone with improved yield wi thout usi ng a column chromatography and repeated recrystallization techniciues.
[0009] In order to avoid column chromatography and. to get better product quality, the present inventors have developed an improved process for the preparation of Paliperidone.
Summary of the invention :
[00 1 0] The main objective o f the present invention is to provide an improved process for the preparation of Pal i peridone comprising the steps of:
i) hydrolyzing Paliperidone Palmitate in the presence of an acid in a solvent and ii) mai ntai ni ng it for sufficient time to obtain Paliperidone
wherein the acid is organic or inorganic acid.
Detailed description of the invention:
[001 1 ] The present invention involves a process for the preparation of Paliperidone
from Paliperidone Palmitale which is depicted in following scheme -J.
[0012] Starting material of the present invention that is Paliperidone- palmitate is prepared by the following process which is depicted in following scheme -II.
Paliperidone palmitate
[001 3] The present invention involves a process for preparing Paliperidone comprising the steps of:
(i) hydrolyzing Paliperidone Pahnitate in the presence of an acid in a solvent and
(i i) mai ntai ning it for sufficient time to obtain Paliperidone
wherein the acid is organ ic or inorganic acid. The inorganic acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifl uoroacetic acid, p-tol uene sulfonic acid and methane sulfon ic acid .
[001 4] The organic acid is selected from the group comprising of C2 - C6 carbons containing al kyl acid such as acetic acid, propanoic acid and aryl acids such as benzoic acid, chloro benzoic acid.
[001 5] The sol vent is selected from the group comprising df water, alcohols such as methanol, ethanol, propanol. isopropanol, butanol; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,2-dichloroethane; ethers such as diethylether, diisopropylether, tetrahyd.ro furan, methyl tetrahydrofuran, 1 ,4-dioxane; aromatic hydrocarbons such as benzene, nitrobenzene, methyl-benzene, dimethylbenzene, chlorobenzene, methoxy-benzene; ketones such as -2-propanone, 4-methyl-2- pentanone; aprotic sol vents such as N,N-dimethylformamicle, N,N- dimethylacetamide, climethylsulfoxide; pyridine, nitriles such as acetonitrile, propionitri le and mixtures thereof. The solvent .preferably used in the process is water, methanol, ethanol, propanol, isopropanol, butanol, . dichloromethane, chloroform, 1 ,2-d.ichloroethane or mixtures thereof. ·
Examples
Example 1 : Preparation of Paliperidone
|Ό01 6 | To a m i xture of puri fied water and hydrochloric acid. Paliperidone Palmitate was added and heated to a temperature of 75-80°C, then stirred for 2 hrs at the same temperature. The progress of the reaction was monitored by TLC. A fter completion of the reaction, the contents' were cooled to 25-30°C and washed with methylene chloride. The separated aqueous layer was added to methylene chloride and methanol (8 :2) mixture and ad justed the pH o f the reaction mass to 10.0- 12.0 with 20% sodium hydrox ide sol ution . The organic layer was separated, washed with water followed by treatment wi th activated carbon, then fi ltered. The filtrate was concentrated; isopropyl alcohol was added and the contents were heated to reflux at 80-85°C. The reaction mass was cooled slowly to 25-30°C, fi ltered, washed with isopropyl alcohol and dried at 60-65°C under vacuum until the loss of drying reaches to less than 0.5%.
Yield: 95%. HPLC purity : More than 99%
Example 2: P reparation of Pa liperidone
[001 7] To a mi xture of methanol and hydrochloric acid, Paliperidone Palmitate was added and heated to a temperature of 75-80°C, then stirred for 2 hrs at 75-80°C. The' progress o f the reaction was monitored by TLC. The contents were cooled to 25- 30°C and disti l led off methanol. The reaction mass then washed with methylene chloride. The separated aqueous layer was added to methylene chloride and methanol
(8 :2) mix ture and ad j usted the pH of the reaction mass to 10.0- 12.0 with 20% sodium hydroxide sol ution. The organic layer was separated, washed with water fol lowed by treatment with acti vated carbon, then filtered. The filtrate was concentrated; isopropyl alcohol was added and. heated the contents to reflux at 80- 85°C. The reaction mass was slowly cooled to 25-30°C, fi ltered, washed with isopropyl alcohol and dried at 60-65 °C under vacuum unti l the loss of drying reaches to less than 0.5%.
Yield : 90%. fl P LC purity : More than 99%
Example 3: Preparation of Paliperidone
[001 8] To a m ixture of methylene chloride and hydrochloric acid, Paliperidone Palmilate was added and heated to a temperature of 45-50°C, then stirred for 2 hrs at 45-50°C. The progress o f the reaction was monitored by TLC. The contents were cooled to 25-30' C. The aqueous layer was separated, and was added to methylene chloride and methanol (8 :2) mixture, then adjusted the pH of the reaction mass, to 10.0- 1 2.0 with 20% sodium hydroxide solution. The organic layer was separated, washed with water followed by treatment of activated carbon, and filtered. The filtrate was concentrated ; isopropyl alcohol was added to the residue, heated the contents to re fl ux at 8Q-85°C. The contents were slowly cooled to 25-30°C, filtered, washed with isopropyl alcohol and dried at 60-65°C under vacuum until the loss of drying reaches to less than 0.5%.
Yield : 90% I I P! C purity : More than 99%
Claims
1. A process for the preparation of paliperidone comprising the steps of:
i) hydrolyzing pal iperidone palmitate in the presence of an acid in a solvent and ii) mai ntaining it for sufficient time to obtain paliperidone
wherein the acid is organic or inorganic acid.
2. The process according to claim 1 , wherein the inorganic acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid,' acetic acid, tritiuoroacctic acid, p-toluene sulfonic acid and methane sul fonic acid.
3. The process according to claim 1 wherein the organic acid is selected from the group comprising of C2 - C6 carbons containing alkyl acid such as acetic acid, propanoic acid and aryl acids such as benzoic acid, chloro benzoic acid. ■
4. The process according to claim 1 , wherein the solvent is selected from the group comprising of water, alcohols halogenated hydrocarbons, ethers, aromatic hydrocarbons, ketones aprotic solvents, pyridine, nitriles and mixtures thereof.
5. The solvent according to claim 4 is water, methanol, ethanol, propanol, isopropanol, butanol, dichloromethane, chloroform, 1 ,2-dichloroethane or mixtures thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN4104/CHE/2011 | 2011-11-28 | ||
IN4104CH2011 | 2011-11-28 |
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WO2013080220A2 true WO2013080220A2 (en) | 2013-06-06 |
WO2013080220A3 WO2013080220A3 (en) | 2013-07-25 |
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PCT/IN2012/000771 WO2013080220A2 (en) | 2011-11-28 | 2012-11-26 | An improved process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydio-9-hydroxy-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one. |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111440168A (en) * | 2020-05-22 | 2020-07-24 | 烟台大学 | Preparation method and application of 6-methoxy paliperidone palmitate |
CN111533737A (en) * | 2020-05-22 | 2020-08-14 | 烟台大学 | 4-fluorophlipiperidone palmitate and preparation method and application thereof |
CN112110914A (en) * | 2019-06-19 | 2020-12-22 | 上海天慈中商药业有限公司 | Preparation method of paliperidone palmitate |
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US20090048272A1 (en) * | 2007-08-16 | 2009-02-19 | Pratap Reddy Padi | Preparation of paliperidone |
WO2009089076A2 (en) * | 2008-01-10 | 2009-07-16 | Teva Pharmaceutical Industries Ltd. | Processes for the preparation and purification of paliperidone palmitate |
WO2011067220A1 (en) * | 2009-12-01 | 2011-06-09 | Chemo Ibérica, S.A. | A process for the purification of paliperidone |
WO2011074017A1 (en) * | 2009-12-17 | 2011-06-23 | Alkem Laboratories Ltd. | A novel process for the preparation of paliperidone |
WO2012164582A1 (en) * | 2011-05-31 | 2012-12-06 | Ramamohan Rao Davuluri | Preparation of 3-[2-[4-((6-fluoro-1, 2-benzisoxazol-3-yl)-l-piperidinyl)-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-4h-pyrido[ 1, 2-a]-pyrimidin-4-one (paliperidone) and paliperidone palmitate. |
-
2012
- 2012-11-26 WO PCT/IN2012/000771 patent/WO2013080220A2/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090048272A1 (en) * | 2007-08-16 | 2009-02-19 | Pratap Reddy Padi | Preparation of paliperidone |
WO2009089076A2 (en) * | 2008-01-10 | 2009-07-16 | Teva Pharmaceutical Industries Ltd. | Processes for the preparation and purification of paliperidone palmitate |
WO2011067220A1 (en) * | 2009-12-01 | 2011-06-09 | Chemo Ibérica, S.A. | A process for the purification of paliperidone |
WO2011074017A1 (en) * | 2009-12-17 | 2011-06-23 | Alkem Laboratories Ltd. | A novel process for the preparation of paliperidone |
WO2012164582A1 (en) * | 2011-05-31 | 2012-12-06 | Ramamohan Rao Davuluri | Preparation of 3-[2-[4-((6-fluoro-1, 2-benzisoxazol-3-yl)-l-piperidinyl)-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-4h-pyrido[ 1, 2-a]-pyrimidin-4-one (paliperidone) and paliperidone palmitate. |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112110914A (en) * | 2019-06-19 | 2020-12-22 | 上海天慈中商药业有限公司 | Preparation method of paliperidone palmitate |
CN111440168A (en) * | 2020-05-22 | 2020-07-24 | 烟台大学 | Preparation method and application of 6-methoxy paliperidone palmitate |
CN111533737A (en) * | 2020-05-22 | 2020-08-14 | 烟台大学 | 4-fluorophlipiperidone palmitate and preparation method and application thereof |
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