WO2010064134A2 - Procédé de synthèse de la palipéridone - Google Patents

Procédé de synthèse de la palipéridone Download PDF

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Publication number
WO2010064134A2
WO2010064134A2 PCT/IB2009/007652 IB2009007652W WO2010064134A2 WO 2010064134 A2 WO2010064134 A2 WO 2010064134A2 IB 2009007652 W IB2009007652 W IB 2009007652W WO 2010064134 A2 WO2010064134 A2 WO 2010064134A2
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WO
WIPO (PCT)
Prior art keywords
methyl
pyrimidin
hydroxy
pyrido
chloroethyl
Prior art date
Application number
PCT/IB2009/007652
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English (en)
Other versions
WO2010064134A3 (fr
Inventor
Indravadan Ambalal Modi
Keval Rameshchandra Sodagar
Malik Vineet
Sudhir Hukamchand Jain
Sanjay Natvarlal Parikh
Arun Omprakash Sharma
Uday Rajaram Bapat
Bakulesh Mafatlal Khamar
Original Assignee
Cadila Pharmaceuticals Ltd.
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Publication date
Application filed by Cadila Pharmaceuticals Ltd. filed Critical Cadila Pharmaceuticals Ltd.
Publication of WO2010064134A2 publication Critical patent/WO2010064134A2/fr
Publication of WO2010064134A3 publication Critical patent/WO2010064134A3/fr

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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 invention relates to an improved process for preparation of 3-(2-chloroethyl)-9-hydroxy- 2-methyl-6,7,8 l 9-tetrahydro-4/-/-pyrido[1,2-a]pyrimidin-4-one, an intermediate used in the synthesis of Paliperidone and process for its conversion in to Paliperidone.
  • Paliperidone chemically known as 3-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidin-1-yl ]ethyl ]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one is a ⁇ benzisoxazole derivative having the structural of compound 1.
  • Paliperidone also known as a 9-hydroxyrisperidone is a metabolite of risperidon. It .is marketed in USA under the brand name "Invega ® " for the treatment of schizophrenia.
  • Paliperidone was first disclosed in US patent No. 5,158,952, and 5,254,556 (herein after designated as '952 & '556 patents respectively).
  • '952 patent describes process for synthesis of paliperidone by condensation of 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole hydrochloride (compound-2) and 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin- 4-one (compound-3) in presence of organic base (scheme-1).
  • Compound 6 can react further in the synthetic path way of Paliperidone and give corresponding Paliperidone analogue as impurity in the final product.
  • the OPRD process mentions hydrogenation at low pressure. Failure to meet stringent requirement of low pressure leads to formation of impurities.
  • the process of '415 application is fraught with problems like corrosion of plant equipment due to use of hydrochloric acid in the reduction step.
  • the object of present invention is to provide an improved and industrially scalable process for the preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6 l 7 l 8,9-tetrahydro-4/-/-pyrido[1 ,2-a]pyrimidin- 4-one (compound-3).
  • Another object of present invention is to provide a process for the preparation of 3-(?- chloroethyl)-9-hydroxy-2-methyl-6J ⁇ 9-tetrahydro ⁇ H-pyrido[1,2-a]pyrimidin-4-Qne (compound-3) or its benzyl derivatives or their acid addition salts by catalytic hydrogenation using an organic acid as solvent.
  • Yet another object of present invention is to provide a process for purification of 3-(2- chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4/-/-pyrido[1 l 2-a]pyrimidin-4-one (compound-3) by formation of corresponding acid addition salt.
  • Yet another object of the invention is to provide a process for conversion of hydrochloride salt of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7 l 8,9-tetrahydro-4/-/-pyrido[1 ,2-a]pyrimidin-4-one (compound-3) to Paliperidone.
  • 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9- tetrahydro ⁇ 4H-pyrido[1,2-a]pyrimidin-4-one (compound-3) is obtained by catalytic hydrogenation of hydrochloride salt of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one (compound-4) using an organic acid as solvent which is further optionally purified by forming an acid addition salt in presence of an organic solvent. The acid addition salt is filtered and base is added to filtrate to form the free base. The free base is further reacted with compound 2 to give Paliperidone.
  • the process of the invention is depicted in scheme-3 SCHEME: 03
  • the compound of formula 4a is obtained by the known process in art.
  • Compound 10 is treated with chlorinating agent in presence of organic solvent to give hydrochloride salt of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one (compound-4).
  • the strong acid provides a proton source in instant reaction, which is used from sulfuric acid, hydrochloric acid, aryl sulfonic acid, p-toluene sulfonic acid, methane sulfonic acid, strong cation exchange resins, solid acids, super acids and like.
  • the solvent for the reaction is selected from aromatic hydrocarbon solvents such as benzene, toluene, xylene, decalin; alicyclic hydrocarbons such as cyclohexane, methyl cyclohexane; chlorinated solvents such as chlorobenzene, carbon tetrachloride.
  • aromatic hydrocarbon solvents such as benzene, toluene, xylene, decalin
  • alicyclic hydrocarbons such as cyclohexane, methyl cyclohexane
  • chlorinated solvents such as chlorobenzene, carbon tetrachloride.
  • the chlorinating agents are selected from thionyl chloride, sulfuryl chloride.oxalyl chloride, phosphorus trichloride, phosphorus oxychloride and cyanuril chloride.
  • the solvent used for the chlorination reaction is selected from halogenated solvents such as chloroform, dichloromethane, ethylene dichloride, aromatic hydrocarbon solvents such as benzene, toluene, xylene; aprotic polar solvents such as , N 1 N dimethyl formamide, N 1 N dimethyl acetamide, N-methyl 2-pyrrolidone, 1 ,3- dimethyl imidazolidin-2-one, 1,3 dimethyl propylene urea, tetramethyl urea; sulfolane; alicyclic hydrocarbons such as cyclohexane, methyl cyclohexane.
  • the catalytic hydrogenation of hydrochloride salt of 3-(2- chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one is carried out in presence of raney nickel or other precious metal catalysts such as palladium, rhodium, ruthenium, platinum, iridium, palladium on charcoal and the like in an organic acid as a solvent.
  • the organic acid is selected from formic acid, acetic acid, propanoic acid and the like.
  • the organic acid is optionally being used in aqueous condition wherein the amount of water is ranging from 0% to 99%.
  • the reaction is carried out at temperature ranging from 40 to 14O 0 C under hydrogen pressure after completion of reaction, pH of the reaction mixture is adjusted.
  • pH of the reaction mixture is adjusted.
  • both the steps hydrogenation of ring double bonds and debenzylation take place simultaneously to give Compound 3.
  • the crude is purified by the formation of organic acid addition salt in organic solvent.
  • the acid addition salt is filtered and further converted in to free base by treatment with base.
  • the organic acid used for the purification of Compound 3 is oxalic acid, tartaric acid and like.
  • the organic acid addition salt is converted to free base using the base which is selected from potassium acetate, sodium acetate and like.
  • the aqueous acetic acid is preferred as solvent for catalytic hydrogenation of hydrochloride salt of 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4/-/-pyrido[1 ,2-a]pyrimidin-4- one (compound-4a) or 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one (compound-4) using metal catalyst to give 3-(2-chloroethyl)-9-hydroxy-2-methyl-6, 7,8,9- tetrahydro-4/7-pyrido[1 ,2-a]pyrimidin-4-one (compound-3).
  • N-alkylation reaction of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H- pyrido[1 ,2-a]pyrimidin-4-one (compound-3) with (6-fluoro-3-piperidine-4-yl-1 ,2-benzisoxazole is carried out using a base in organic solvent to give Paliperidone.
  • the organic solvent is selected from ethers such as tetrahydro furan (THF) 1 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 1 N,N-dimethyl formamide [DMF] N 1 N- dimethyl acetamide [DMA], N-methyl 2-pyrrolidone, 1,3-dimethyl imidazolidin- 2-one, 1,3 dimethyl propylene urea, tetramethyl urea; sulfolane.
  • nitriles such as acetonitrile, propionitrile
  • aliphatic and alicyclic solvents such as
  • the base used in this reaction 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-Diazabicyclo[4.3.0]non-5-ene [ DBN ] and 1,4-diazabicyclo[2.2.2]octane [DABCO].
  • the reaction is carried out at 0 to 150 0 C, preferably at 10 to 100 0 C.
  • N-alkylation can also be carried out using a phase transfer catalyst.
  • the obtained Paliperidone is purified from solvent selected from acetonitrile, C1 to C5 alcohols, amides such as DMF, DMA, ethers such as 2-methyl THF, THF 1 dioxanes, esters such as alkyl acetates, water, benzotrifluoride, methyl cellosolve, or mixtures thereof.
  • solvent selected from acetonitrile, C1 to C5 alcohols, amides such as DMF, DMA, ethers such as 2-methyl THF, THF 1 dioxanes, esters such as alkyl acetates, water, benzotrifluoride, methyl cellosolve, or mixtures thereof.
  • solvent selected from acetonitrile, C1 to C5 alcohols, amides such as DMF, DMA, ethers such as 2-methyl THF, THF 1 dioxanes, esters such as alkyl acetates, water, benzotrifluoride, methyl cellosolve, or
  • Hydrochloride salt of Compound-4 (100 g) was dissolved in 1:1 aqueous acetic acid (800 mL) and heated up to 50 - 55 0 C followed by the addition of charcoal (10 g) at 50 - 55 0 C. The content was stirred for 30 min at 50 - 55 0 C. The mass was filtered through hyflow and washed with 1:1 aqueous acetic acid (100 mL). This filtered mass was charged into a 2 L hydrogenator at 25 - 35 0 C followed by the addition of Pd-C (10%, 10 g) and the pressure of hydrogen gas was maintained in the range of 4.0 -4.5 kg/cm 2 at 40-45 0 C. The reaction progress was monitored by HPLC.
  • reaction rate comes down, then again slurry of Pd/C (10 %, 5 g) in 1:1 aqueous acetic acid (50 mL) was charged and the reaction continued. After completion of the reaction, catalyst is filtered and filtrate distilled off completely to afford 100-105 g crude product in the form of oily mass which is used in the next step.
  • Hydrochloride salt of CompouncMa (125 g) was dissolved in aqueous acetic acid (800 mL) and heated up to 50 - 55 0 C followed by the addition of charcoal to reaction mixture. The content was stirred for 30 min. The mass was filtered through hyflow and washed with aqueous acetic acid (100 mL). This filtered mass was charged into a 2 L hydrogenator at 25 - 35 0 C followed by the addition of 10% Pd-C and the pressure of hydrogen gas was maintained in the range of 4.0 -4.5 kg/cm 2 at 40- 45 0 C. On completion of the reaction, catalyst is filtered and filtrate was distilled off to afford 100-105 g crude product in the form of oily mass which is used in the next step.
  • the obtained distilled crude product was slurried in DM water (1500 mL) and stirred for 1 h at 25°C-30 0 C.
  • the solid Product was filtered and washed with DM water.
  • the solid product was dried in vacuum oven at 60 - 65 0 C for 10-12h to afford 140 - 145 g of crude Paliperidone (purity >95%) was obtained.
  • Example- 7 Purification of 3-[2-[4-(6-FIuoro-1,2-benzisoxazol-3-yl)piperidin-1-yl ]ethyl ]-9- hydroxy -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -pyrimidin-4-one (Compound-1)
  • Crude paliperidone (140 g) obtained in previous step was dissolved in of lsopropyl alcohol (4200 mL) at 80 ⁇ 2 0 C and charged activated charcoal (8.8 g). The content was stirred at 80 ⁇ 2 0 C for 30 min and filtered through hyflow in hot condition.
  • the hyflo bed was washed with hot lsopropyl alcohol (140 mL).
  • the filtered mass was gradually cooled up to 0 0 C and stirred it for 2 h at 0-5 0 C.
  • the solid product was filtered and washed twice with chilled IPA (70 mL).
  • the product was dried in vacuum oven at 65-70 0 C for 24 h. 85-90 g product (purity >99%) was obtained. Repeated purification was also made to afford adequate quality and color of the compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L’invention concerne un procédé amélioré de préparation de 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, un intermédiaire utilisé dans la synthèse de la palipéridone et un procédé pour transformer ce dernier en palipéridone.
PCT/IB2009/007652 2008-12-05 2009-12-04 Procédé de synthèse de la palipéridone WO2010064134A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2544/MUM/2008 2008-12-05
IN2544MU2008 2008-12-05

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WO2010064134A2 true WO2010064134A2 (fr) 2010-06-10
WO2010064134A3 WO2010064134A3 (fr) 2010-08-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073997A3 (fr) * 2009-12-14 2011-12-22 Cadila Healthcare Limited Procédé de préparation de palipéridone et de ses sels pharmaceutiquement acceptables de ces derniers
WO2012042368A1 (fr) * 2010-09-30 2012-04-05 Aurobindo Pharma Limited Procédé de préparation de palipéridone

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688799A (en) * 1993-11-23 1997-11-18 Janssen Pharmaceutica N.V. 9-Hydroxy-pyrido 1,2-a!pyrimidin-4-one ether derivatives
US6320048B1 (en) * 1988-11-07 2001-11-20 Janssen Pharmaceutica, N.V. 3-piperidinyl-1,2-benzisoxazoles
US20050222228A1 (en) * 2004-04-02 2005-10-06 Birgit Bossenmaier Novel diazine derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6320048B1 (en) * 1988-11-07 2001-11-20 Janssen Pharmaceutica, N.V. 3-piperidinyl-1,2-benzisoxazoles
US5688799A (en) * 1993-11-23 1997-11-18 Janssen Pharmaceutica N.V. 9-Hydroxy-pyrido 1,2-a!pyrimidin-4-one ether derivatives
US20050222228A1 (en) * 2004-04-02 2005-10-06 Birgit Bossenmaier Novel diazine derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073997A3 (fr) * 2009-12-14 2011-12-22 Cadila Healthcare Limited Procédé de préparation de palipéridone et de ses sels pharmaceutiquement acceptables de ces derniers
WO2012042368A1 (fr) * 2010-09-30 2012-04-05 Aurobindo Pharma Limited Procédé de préparation de palipéridone

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