WO2009044413A2 - Improved process for preparing paliperidone, novel polymorphic forms of the same and process thereof - Google Patents
Improved process for preparing paliperidone, novel polymorphic forms of the same and process thereof Download PDFInfo
- Publication number
- WO2009044413A2 WO2009044413A2 PCT/IN2008/000642 IN2008000642W WO2009044413A2 WO 2009044413 A2 WO2009044413 A2 WO 2009044413A2 IN 2008000642 W IN2008000642 W IN 2008000642W WO 2009044413 A2 WO2009044413 A2 WO 2009044413A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- paliperidone
- crystalline form
- solvent
- process according
- vii
- Prior art date
Links
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 title claims abstract description 186
- 229960001057 paliperidone Drugs 0.000 title claims abstract description 170
- 238000000034 method Methods 0.000 title claims abstract description 96
- 230000008569 process Effects 0.000 title claims abstract description 95
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000002904 solvent Substances 0.000 claims abstract description 55
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- MRMGJMGHPJZSAE-UHFFFAOYSA-N 6-fluoro-3-piperidin-4-yl-1,2-benzoxazole Chemical compound N=1OC2=CC(F)=CC=C2C=1C1CCNCC1 MRMGJMGHPJZSAE-UHFFFAOYSA-N 0.000 claims abstract description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 27
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 17
- 238000002411 thermogravimetry Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 230000009466 transformation Effects 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000012296 anti-solvent Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 150000004679 hydroxides Chemical class 0.000 claims description 3
- 229910000510 noble metal Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- JKVUGXRJSYRXFN-UHFFFAOYSA-N 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound OC1CCCN2C(=O)C(CCCl)=C(C)N=C21 JKVUGXRJSYRXFN-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000010899 nucleation Methods 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 14
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- -1 Form I Chemical compound 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000000561 anti-psychotic effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000013265 extended release Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 229960001534 risperidone Drugs 0.000 description 2
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 1
- PMXMIIMHBWHSKN-LJQANCHMSA-N (R)-paliperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCC[C@@H](O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-LJQANCHMSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- DFZLZGAIWJGCIJ-UHFFFAOYSA-N 3-(2-chloroethyl)-2-methyl-9-phenylmethoxypyrido[1,2-a]pyrimidin-4-one Chemical compound C=1C=CN2C(=O)C(CCCl)=C(C)N=C2C=1OCC1=CC=CC=C1 DFZLZGAIWJGCIJ-UHFFFAOYSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
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- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- This invention in general relates to a process for preparing paliperidone. More particularly, the present invention provides an improved process for preparing paliperidone, its novel polymorphic forms and process thereof.
- the primary active metabolite of the existing antipsychotic risperidone is 9-hydroxyrisperidone, i.e., risperidone with an extra hydroxyl group.
- Paliperidone (Invega), known as second generation antipsychotic drug developed by Janssen Pharmaceuticals is an extended release formulation of paliperidone that employs an oral osmotic extended release delivery system for once- daily dosing. Paliperidone was approved by FDA for the treatment of schizophrenia on December 20, 2006. It was initially marketed for the treatment of schizophrenia and then for bipolar mania.
- US 5,158,952 discloses paliperidone and a process for the preparation of paliperidone, wherein 3-(2-chloroethyl)-2-methyl-9- (phenylmethoxy)-4H-pyrido[1.2-a] pyrimidin-4-one is hydrogenated to obtain 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one which is subsequently condensed with 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride in presence of a base in a solvent, preferably methanol to obtain paliperidone.
- the isolation of desired product is very difficult and requires purification techniques like column chromatography and repeated crystallization in different solvents.
- the impurities formed in the hydrogenation reaction are carried forward as such and interfere with the condensation step thereby resulting in the formation of corresponding impurities.
- the formation of these impurities in the reaction mass makes it very difficult to isolate the final product without subjecting the reaction mass to column purifications and repeated crystallization steps.
- a number of purification and crystallization steps increase the operational cost of the entire process, thereby making it uneconomical for large-scale production.
- It is an object of the present invention is to provide an improved process for the preparation of paliperidone.
- an improved process for producing paliperidone comprising of hydrogenating 3-(2-chloroethyl)-2-methyl-9- (hydroxyprotected)-4H- pyrido[l,2-a] pyrimidin-4-one in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido
- an improved process for producing crystalline Form VI of paliperidone wherein the process comprises of dissolving paliperidone in a solvent and isolating said crystalline Form VI of paliperidone.
- an improved process for producing crystalline form VII of paliperidone comprising of dissolving said paliperidone in a solvent or mixture of solvents followed by cooling an antisolvent, adding said solvent mixture of paliperidone to the anti-solvent and isolating crystalline Form VII of paliperidone.
- a crystalline Form VI of paliperidone characterized by an X-Ray powder diffraction pattern having peaks at 5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42 ⁇ 0.2 2 ⁇ values.
- a crystalline Form VII of paliperidone characterized by an X-Ray Powder diffraction pattern having peaks at 5.48, 6.04, 9.51, 9.88, 12.46, 14.29, 14.93, 15.43, 15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ⁇ 0.2 2 ⁇ values.
- a process for producing polymorphic Form I of paliperidone comprising of dissolving paliperidone in a solvent, preferably ethyl acetate, at reflux temperature followed by cooling and isolating said Form I.
- a process for producing polymorphic Form I of paliperidone comprising of dissolving paliperidone in a chlorinated solvent or alcohol or mixture thereof followed by isolating resultant solid employing ether, preferably isopropyl ether.
- a process for producing polymorphic Form-I of paliperidone comprising of heating Form VI of paliperidone for a time sufficient to induce transformation of Form VI of paliperidone to Form I of paliperidone and isolating Form
- a process for producing polymorphic Form I of paliperidone comprising of subjecting paliperidone Form VI to relative humidity >90% for a time sufficient to induce the transformation of polymorphic Form VI of paliperidone to said polymorphic Form I and isolating said polymorphic Form I.
- Figure 1 shows the X-ray powder diffraction pattern of crystalline paliperidone Form I.
- Figure 2 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
- Figure 3 shows the X-ray powder diffraction pattern of crystalline paliperidone Form III.
- Figure 4 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
- FIG. 5 shows the Differential Scanning Calorimetry (DSC) thermogram of paliperidone Form IV.
- Figure 6 shows the Thermo Gravimetric Analysis (TGA) of paliperidone Form IV.
- Figure 7 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
- Figure 8 shows the DSC thermogram of paliperidone Form V.
- Figure 9 shows the X-ray powder diffraction pattern of crystalline paliperidone Form VI.
- Figure 10 shows the DSC thermogram of paliperidone Form VI.
- Figure 11 shows the TGA of paliperidone Form VI.
- Figure 12 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
- Figure 13 shows the DSC thermogram of paliperidone Form VII.
- Figure 14 shows the TGA of paliperidone Form VII.
- Figure 15 shows the X-ray powder diffraction pattern of amorphous paliperidone.
- the present invention discloses an improved high yielding and economical process for the preparation of paliperidone.
- the present invention provides crystalline Form VI and Form VII and process for preparing thereof employing the improved process.
- the present invention discloses method for producing polymorphic forms Form I, II, III, IV, V and amorphous form of paliperidone.
- the present invention in general relates to an improved process for the preparation of paliperidone, wherein 3-(2-chloroethyl)-2-methyl-9-( hydroxyprotected)- 4H-pyrido[l,2-a] pyrimidin-4-one of Formula (I) is subjected to hydrogenation reaction in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a] -pyrimidin-4-one of Formula (II) which is further condensed with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula (III) followed by workup to give Paliperidone with improved yield as depicted in Scheme-I. '
- the hydroxyprotected group of 3-(2-chloroethyl)-2-methyl-9-(hydroxyprotected)-4H-pyrido[l ,2-a]-pyrimidin- 4-one of Formula (I) is selected from benzyl or methyl.
- hydrogenation reaction is carried out in the presence of catalyst selected from noble metal catalyst such as Palladium, Rhodium and Ruthenium; or Raney nickel, under hydrogen pressure.
- noble metal catalyst such as Palladium, Rhodium and Ruthenium; or Raney nickel
- the hydrogenation reaction is carried out in presence of a solvent selected from methanol, ethanol or isopropyl alcohol.
- a solvent selected from methanol, ethanol or isopropyl alcohol.
- the hydrogenation reaction carried out in the presence of the acid results in formation of fewer impurities compared to prior art process.
- the yield of desired product is more than 90%. Due to formation of minimal impurities during the hydrogenation step, isolation of desired product is simple and does not require column purification and crystallization in different solvents, thereby leading to improvement in yield.
- the acid employed in the hydrogenation reaction is selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, para-toluene sulphonic acid or methane sulphonic acid or mixtures thereof.
- the reaction mass was filtered and concentrated under reduced pressure to give residue.
- the residue was isolated in distilled mineral (DM) water to yield 3-(2-chloroethyl)-6,7,8,9,-tetrahydro-9-hydroxy-2-methyl-4Hpyrido[l,2- a]-pyrimidin-4-one of formula (H).
- the 3-(2-chloroethyl)-6,7,8,9, -tetrahydro-9- hydroxy-2-methyl-4Hpyrido[l,2-a]-pyrimidin-4-one is condensed with 6-fluoro-3-(4- piperidinyl)-l-benzisoxazole in the presence of a base and solvent to give paliperidone.
- the base is selected from alkali, alkaline earth carbonates, bicarbonates or hydroxides such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, preferably sodium carbonate.
- the solvent employed in the condensation step is selected from alcohol, ketone, nitrile, ester or ether.
- the alcohol solvent is selected form methanol, ethanol, isopropyl alcohol and n-butanol.
- the ketone solvent is selected form acetone, methyl ethyl ketone and the nitrile solvent is acetonitrile.
- the ester solvent is ethyl acetate and the ether used is preferably tetrahydrofuran.
- the reaction mass is cooled to low temperature, separated solid filtered and washed with solvent such as alcohol, water or mixture thereof to give paliperidone.
- the said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
- the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
- the Cu-anode X-ray tube was operated at 4OkV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
- DSC Differential Scanning Calorimetry
- the DSC measurements were carried out on Mettler Toledo 822 star e and TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.
- TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 l e and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25 ml/min.
- Another alternate embodiment of the present invention relates to a process for producing polymorphic forms of paliperidone. Paliperidone is subjected to
- the crystalline paliperidone polymorphic Form I is having a substantially similar powder X-ray diffraction pattern shown in Fig. 1 with peaks at about 14.58, 22.04 , 24.65 and 25.05 ° ( ⁇ ) 0.2 ⁇ .
- the process for producing paliperidone polymorphic Form-I includes: a) condensing 3-(2-chloroethyl)-6,7,8,9-teterahyro-9-hydroxy-4H-pyrido[l ,2- a] pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazolemonohydro chloride in the presence of organic base such as diisopropyl amine in an alcoholic solvent such as methanol. b) removing the solvent and treating with acetone and c) isolating polymorphic Form I in alcohol such as isopropyl alcohol.
- the polymorphic Form I of paliperidone is prepared by dissolving paliperidone in a solvent such as ethyl acetate at reflux temperature followed by cooling of the resulting solution and isolating the Form I of paliperidone.
- Form I of paliperidone is alternatively prepared by treating the Form VI or the Form
- the paliperidone polymorphic Form I is prepared by dissolving paliperidone in chlorinated solvent or alcohol or mixture thereof and isolating the solid in ethers such as isopropyl ether to give the polymorphic Form-I.
- the paliperidone polymorphic Form I is alternatively prepared by heating Form VI for a time sufficient to transform the Form VI to the Form I of paliperidone, at 40-60°C preferably at 45-50°C.
- the Form VI of paliperidone is subjected to heating for at least 6- 1 ldays, preferably about 7-9 days to convert to paliperidone Form I.
- Form I of paliperidone is prepared by exposing Form VI to relative humidity >90%. The reaction is carried out for a time sufficient to convert the Form VI to Form I. According to an exemplary process the Form VI of paliperidone is exposed to relative humidity >90% for at least 1-4 days, preferably about 2-3 days to convert to paliperidone Form I.
- paliperidone polymorphic Form I is alternatively prepared by exposing Form VII to relative humidity >90%. The reaction is carried out for a time sufficient to convert the Form VII to Form I preferably for 8-12 days, more preferably about 9-10 days to convert to the Form I of paliperidone.
- polymorphic Form II of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 2, with peaks at about 17.02, 18.90 and 26.11 ° ( ⁇ ) 0.2 ⁇ .
- the process for producing polymorphic Form II of paliperidone includes condensing 3-(2-chloroethyl)-6,7,8,9-teterahyro-9- hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole monohydrochloride in the presence inorganic base such as sodium carbonate in solvent medium preferably acetonitrile at 60-65° C, subsequently cooling the reaction product to room temperature, filtering the solid and isolating the separated solid using mixture of water and alcoholic solvents preferably isopropyl alcohol to give polymorphic Form II of paliperidone.
- inorganic base such as sodium carbonate
- solvent medium preferably acetonitrile at 60-65° C
- the crystalline polymorphic Form III of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 3, with peaks at about 9.65, 15.70, 21.04, 21.43 and 25.81° ( ⁇ ) 0.2 ⁇ .
- the paliperidone polymorphic Form II is dissolved in an alcoholic solvent such as methanol, ethanol, isopropyl alcohol, n- butanol mixtures thereof, followed by gradual cooling and filtration to give crystalline polymorphic Form III of paliperidone.
- the crystalline polymorphic Form IV of paliperidone is having a substantially similar powder X-ray diffraction pattern as shown in Fig. 4, with peaks at about 10.25, 23.79 and 25.99° ( ⁇ ) 0.2 ⁇ .
- the crystalline polymorphic Form IV of paliperidone is further characterized by differential scanning calorimetry (DSC) as shown in Fig. 5, and thermogravemetric analysis (TGA) as shown in Fig. 6.
- the crystalline polymorphic Form IV of paliperidone contains water around 8.7%, which is equivalent to around 2.0 moles of water with respect to the paliperidone.
- crystalline polymorphic Form IV of paliperidone is prepared by dissolving the crystalline polymorphic Form II in a mixture of water and water miscible organic solvents, subjecting resulting clear solution to cooling, filtering separated solid and washing the solid to give crystalline paliperidone polymorphic Form IV.
- the water miscible organic solvent used is selected from alcohol or ketone.
- the alcohol used is selected from methanol, ethanol, isopropyl alcohol or n- butanol or mixtures thereof and the ketone solvent is selected from acetone or methyl ethyl ketone.
- crystalline polymorphic Form V of paliperidone is having a substantially similar powder X-ray diffraction pattern as shown in Fig. 7, with peaks at about 9.68, 21.09, 21.47 and 25.86°
- the crystalline polymorphic Form V of paliperidone is further characterized by DSC as shown in Fig. 8.
- the crystalline Form V of paliperidone is prepared by suspending crystalline polymorphic Form II in water, followed by slow addition of acid to give clear solution, adjustment of pH of resulting acid solution between 7.0- 10.0 preferably 8.0-9.0 by using a base and subsequent precipitation, filteration and washing with water to give the crystalline paliperidone Form V.
- the acid used is selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid or sulfuric acid, preferably hydrochloric acid.
- the base used is selected from alkali, alkaline earth carbonates, bicarbonates or hydroxides such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide peferably sodium carbonate.
- the crystalline polymorphic Form VI of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 9, with peaks at about 5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42° ( ⁇ ) 0.2 ⁇ .
- the crystalline paliperidone polymorphic Form VI is further characterized by DSC as shown in Fig. 10 and TGA as shown in Fig. 11.
- crystalline polymorphic Form VI of paliperidone contains moisture content less than 1.0%.
- the polymorphic Form VI of paliperidone is prepared by dissolving paliperidone in a solvent selected from chlorinated solvent or mixture thereof followed by removal of the solvent.
- the chlorinated solvent is selected from chloroform, dichloromethane, dichloroethane or mixture thereof.
- crystalline paliperidone polymorphic Form VII having substantially similar powder X-ray diffraction pattern as shown in Figure-12, with peaks at about 5.48, 6.04, 9.51, 9.88, 12.46, 14.29, 14.93, 15.43, 15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ⁇ 0.2 0°.
- the crystalline paliperidone polymorphic Form- VI is further characterized by DSC as shown in Fig. 13 and TGA as shown in Fig. 14.
- process for the preparation of polymorphic Form VII of paliperidone comprises a) dissolving the paliperidone in a solvent or mixture of solvents b) cooling the anti-solvent to -30 to -35°C c) slowly adding solution mixture of step a) to step b); and d) isolating crystalline polymorphic Form VII of paliperidone.
- Solvent is selected from alcohol such as isopropyl alcohol, chlorinated hydrocarbon such as chloroform or ether such as isopropyl ether.
- the process includes optionally seeding the solvent mixture with polymorphic Form VII.
- amorphous paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 15.
- process for the preparation of amorphous paliperidone comprises melting the crystalline paliperidone and isolating amorphous paliperidone.
- reaction mass was further cooled and Pd/C was filtered over celite and washed with methanol.
- the solution was cooled to 10-15°C, pH adjusted to 8.0 with sodium carbonate at 10-15°C and the solution stirred for 1 hr at 25-35°C. Resulting salts were filtered and washed with methanol (50.0 ml).
- the solvent was distilled off completely under vacuum at below 40°C.
- DM Water 150 ml was charged to the residue at 25-35°C and cooled to 10- 15°C. Contents were stirred for 1 hr at 10-15°C.
- Example-3 The temperature was slowly raised to 60- 65°Cand maintained at 60-65°C for 30-45 hrs. Subsequently, mass was cooled and maintained at 25-35°C for 1 hr. The solid is filtered and treated with water (600 ml) for 1 hr. The solid was again filtered, washed with water and IPA and dried at 40-45°C to give 85 gm of paliperidone.
- Example-3
- reaction mass was then maintained at 60-65°C for 30-45 hrs, slowly cooled and maintained at 25-35°C for 1 hr.
- the resultant solid was filtered and treated with water (600 ml) for 1 hr.
- the solid was again filtered, washed with water and IPA and dried at 40-45°C to give 85 gm of Form II of paliperidone.
- Example-7 Process for the preparation of crystalline polymorphic Form III of paliperidone
- Paliperidone (7.2 gm) was added to isopropyl alcohol (220 ml) at 25-35°C and stirred for 15 min. Slowly the temperature was raised to reflux temperature to obtain a clear solution.
- Activated carbon (1.5 gm) was charged to the reaction mass at reflux temperature and maintained at reflux for 60 min. The carbon was then filtered over celite bed at reflux and washed with hot isopropyl alcohol. The filtrate was cooled to 0-
- Example-9 Process for the preparation of crystalline polymorphic Form IV of paliperidone
- Example- 11 Process for the preparation of crystalline polymorphic Form V of paliperidone
- Paliperidone (1 gm) was added to 0.5N Hydrochloric acid solution (10 ml) at 25-35°C and stirred for 15 min. The solution was then heated to 60-65°C and pH adjusted to 8.0 with sodium carbonate solution at 60-65°C. Further, the suspension was cooled slowly and stirred at 25-35°C for 2 hrs. The solid was filtered and washed with chilled water ( 5 ml), dried under vacuum below 40-45°C to give 0.90 gm of Form V of paliperidone.
- Example- 12 Process for the preparation of crystalline polymorphic Form VI of paliperidone
- Example-14 Process for the preparation of crystalline polymorphic Form VII of Paliperidone
- Paliperidone was heated at about 17O 0 C and maintained for about 5 minutes to form a melt followed by cooling the melt to obtain amorphous paliperidone.
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Abstract
Disclosed herein is an improved process for producing paliperidone, wherein the process includes hydrogenating 3-(2-chloroethyl)-2-methyl-9-(hydroxyprotected)-4H- pyrido[1.2-a] pyrimidin-4-one in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido[l,2-a]-pyrimidin-4-one and condensing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-2-methyl-4H-pyrido[l,2-a] -pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)- 1,2-benzisoxazole in presence of a base and a solvent to give paliperidone. In addition, the invention discloses novel polymorphic Forms VI and VII of paliperidone. Furthermore the invention discloses processes for producing the novel polymorphic forms and Form I from the novel polymorphic forms thereof.
Description
IMPROVED PROCESS FOR PREPARING PALIPERIDONE, NOVEL POLYMORPHIC FORMS OF THE SAME AND PROCESS THEREOF
Field of the Invention This invention, in general relates to a process for preparing paliperidone. More particularly, the present invention provides an improved process for preparing paliperidone, its novel polymorphic forms and process thereof.
Background of the Invention
Paliperidone, the primary active metabolite of the existing antipsychotic risperidone is 9-hydroxyrisperidone, i.e., risperidone with an extra hydroxyl group.
Paliperidone, chemically known as 3-[2-[4-(6-fluoro-l, 2-benzisoxozol-3-yl)-l- piperidinyl]-ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a] pyrimidin-
4-one, is represented by Formula-A:
Formula-A
Paliperidone (Invega), known as second generation antipsychotic drug developed by Janssen Pharmaceuticals is an extended release formulation of paliperidone that employs an oral osmotic extended release delivery system for once- daily dosing. Paliperidone was approved by FDA for the treatment of schizophrenia on December 20, 2006. It was initially marketed for the treatment of schizophrenia and then for bipolar mania.
US 5,158,952 discloses paliperidone and a process for the preparation of paliperidone, wherein 3-(2-chloroethyl)-2-methyl-9- (phenylmethoxy)-4H-pyrido[1.2-a] pyrimidin-4-one is hydrogenated to obtain 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one which is subsequently condensed with 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride in presence of a base in a solvent, preferably methanol to obtain paliperidone. Following alkylation reaction, methanol is removed by reduced pressure to give oily residue followed by dissolving the residue in chloroform and washing with water. The organic layer is dried, concentrated under reduced pressure to obtain residue, subjected to column
chromatographic purification using a mixture of chloroform and methanol, followed by evaporation of eluents to give residue. The residue so obtained is subjected to repeated crystallizations in different solvents like acetone and isopropyl alcohol to give paliperidone having the melting point 179.8° C. According to the prior art process, the step of hydrogenation of 3-(2- chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2-a] pyrimidin-4-one in the presence of 10% Palladium on charcoal catalyst in methanol under hydrogen pressure to obtain 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[l ,2-a] pyrimidin-4- one results in formation of large amount of side products and low yield of around 50% of the desired product. In addition, due to formation of large amount of side products, the isolation of desired product is very difficult and requires purification techniques like column chromatography and repeated crystallization in different solvents.
Moreover, the impurities formed in the hydrogenation reaction are carried forward as such and interfere with the condensation step thereby resulting in the formation of corresponding impurities. The formation of these impurities in the reaction mass makes it very difficult to isolate the final product without subjecting the reaction mass to column purifications and repeated crystallization steps. A number of purification and crystallization steps increase the operational cost of the entire process, thereby making it uneconomical for large-scale production. To overcome the drawback associated with the prior art processes, it is desirable to provide an improved process for the preparation of paliperidone with high purity and yield. Further, the process requires fewer purification steps to obtain the desired product, thereby making the process economical for industrial use.
Object and Summary of the Invention
It is an object of the present invention is to provide an improved process for the preparation of paliperidone.
It is another object of the present invention to provide an economical method for large scale production of paliperidone.
It is yet another object of the present invention to provide an improved process for the preparation of paliperidone, wherein the process results in formation of less impurity, thereby requiring fewer purification steps to obtain the desired product.
It is still another object of the present invention to provide novel polymorphic forms VI and VII of paliperidone and process for producing the same thereof.
It is yet another object of the present invention to provide a process for producing crystalline polymorphic forms of paliperidone i.e. Form I, Form II, Form III, Form IV, Form V, Form VI, and Form VII.
It is still another object of the present invention to provide a process for the preparation of the amorphous paliperidone.
The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with one preferred embodiment of the present invention there is provided an improved process for producing paliperidone, wherein the process comprises of hydrogenating 3-(2-chloroethyl)-2-methyl-9- (hydroxyprotected)-4H- pyrido[l,2-a] pyrimidin-4-one in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido
[1,2-a] -pyrimidin-4-one and subsequently condensing 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one with 6-fluoro-3-(4- piperidinyl)-l,2-benzisoxazole in presence of a base and a solvent to give said paliperidone.
In accordance with yet another embodiment of the present invention there is provided an improved process for producing crystalline Form VI of paliperidone, wherein the process comprises of dissolving paliperidone in a solvent and isolating said crystalline Form VI of paliperidone.
In accordance with still another embodiment of the present invention there is provided an improved process for producing crystalline form VII of paliperidone, wherein the process comprises of dissolving said paliperidone in a solvent or mixture of solvents followed by cooling an antisolvent, adding said solvent mixture of paliperidone to the anti-solvent and isolating crystalline Form VII of paliperidone.
In accordance with still another embodiment of the present invention there is provided a crystalline Form VI of paliperidone characterized by an X-Ray powder diffraction pattern having peaks at 5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42 ± 0.2 2Θ values.
In accordance with yet another embodiment of the present invention there is provided a crystalline Form VII of paliperidone characterized by an X-Ray Powder diffraction pattern having peaks at 5.48, 6.04, 9.51, 9.88, 12.46, 14.29, 14.93, 15.43,
15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ± 0.2 2Θ values.
In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of dissolving paliperidone in a solvent, preferably ethyl acetate, at reflux temperature followed by cooling and isolating said Form I.
In accordance with yet another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of dissolving paliperidone in a chlorinated solvent or alcohol or mixture thereof followed by isolating resultant solid employing ether, preferably isopropyl ether.
In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form-I of paliperidone, wherein the process comprises of heating Form VI of paliperidone for a time sufficient to induce transformation of Form VI of paliperidone to Form I of paliperidone and isolating Form
I of paliperidone.
In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of subjecting paliperidone Form VI to relative humidity >90% for a time sufficient to induce the transformation of polymorphic Form VI of paliperidone to said polymorphic Form I and isolating said polymorphic Form I.
In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of subjecting polymorphic Form VII of paliperidone to relative humidity >90% for a time sufficient to induce the transformation of polymorphic Form
VII to said polymorphic Form I and isolating said polymorphic Form I.
Brief Description of the Drawings
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:
Figure 1 shows the X-ray powder diffraction pattern of crystalline paliperidone Form I.
Figure 2 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
II.
Figure 3 shows the X-ray powder diffraction pattern of crystalline paliperidone Form III.
Figure 4 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
IV.
Figure 5 shows the Differential Scanning Calorimetry (DSC) thermogram of paliperidone Form IV. Figure 6 shows the Thermo Gravimetric Analysis (TGA) of paliperidone Form IV.
Figure 7 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
V.
Figure 8 shows the DSC thermogram of paliperidone Form V.
Figure 9 shows the X-ray powder diffraction pattern of crystalline paliperidone Form VI.
Figure 10 shows the DSC thermogram of paliperidone Form VI.
Figure 11 shows the TGA of paliperidone Form VI.
Figure 12 shows the X-ray powder diffraction pattern of crystalline paliperidone Form
VII. Figure 13 shows the DSC thermogram of paliperidone Form VII.
Figure 14 shows the TGA of paliperidone Form VII.
Figure 15 shows the X-ray powder diffraction pattern of amorphous paliperidone.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The present invention discloses an improved high yielding and economical process for the preparation of paliperidone. In addition, the present invention provides crystalline Form VI and Form VII and process for preparing thereof employing the improved process.
In addition, the present invention discloses method for producing polymorphic forms Form I, II, III, IV, V and amorphous form of paliperidone.
The present invention in general relates to an improved process for the preparation of paliperidone, wherein 3-(2-chloroethyl)-2-methyl-9-( hydroxyprotected)- 4H-pyrido[l,2-a] pyrimidin-4-one of Formula (I) is subjected to hydrogenation reaction in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a] -pyrimidin-4-one of Formula (II) which is further condensed with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula (III) followed by workup to give Paliperidone with improved yield as depicted in Scheme-I. '
(i) (H)
R = Benzyl Methyl
Formula-(III)
Scheme I
According to an embodiment of the present invention, the hydroxyprotected group of 3-(2-chloroethyl)-2-methyl-9-(hydroxyprotected)-4H-pyrido[l ,2-a]-pyrimidin- 4-one of Formula (I) is selected from benzyl or methyl.
According to a preferred embodiment of the present invention, hydrogenation reaction is carried out in the presence of catalyst selected from noble metal catalyst such as Palladium, Rhodium and Ruthenium; or Raney nickel, under hydrogen pressure.
According to an alternate embodiment of the invention, the hydrogenation reaction is carried out in presence of a solvent selected from methanol, ethanol or isopropyl alcohol. The hydrogenation reaction carried out in the presence of the acid results in formation of fewer impurities compared to prior art process. The yield of desired product is more than 90%. Due to formation of minimal impurities during the hydrogenation step, isolation of desired product is simple and does not require column purification and crystallization in different solvents, thereby leading to improvement in yield.
According to the present invention, the acid employed in the hydrogenation reaction is selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, para-toluene sulphonic acid or methane sulphonic acid or mixtures thereof. According to an exemplary embodiment of the present invention, after completion of the hydrogenation, the reaction mass was filtered and concentrated under reduced pressure to give residue. The residue was isolated in distilled mineral (DM) water to yield 3-(2-chloroethyl)-6,7,8,9,-tetrahydro-9-hydroxy-2-methyl-4Hpyrido[l,2- a]-pyrimidin-4-one of formula (H). According to the present invention, the 3-(2-chloroethyl)-6,7,8,9, -tetrahydro-9- hydroxy-2-methyl-4Hpyrido[l,2-a]-pyrimidin-4-one is condensed with 6-fluoro-3-(4- piperidinyl)-l-benzisoxazole in the presence of a base and solvent to give paliperidone. The base is selected from alkali, alkaline earth carbonates, bicarbonates or hydroxides such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, preferably sodium carbonate.
The solvent employed in the condensation step is selected from alcohol, ketone, nitrile, ester or ether. The alcohol solvent is selected form methanol, ethanol, isopropyl alcohol and n-butanol. The ketone solvent is selected form acetone, methyl ethyl ketone
and the nitrile solvent is acetonitrile. The ester solvent is ethyl acetate and the ether used is preferably tetrahydrofuran.
According to the present invention, after completion of the condensation reaction, the reaction mass is cooled to low temperature, separated solid filtered and washed with solvent such as alcohol, water or mixture thereof to give paliperidone.
Powder X-ray Diffraction (PXRD)
The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time. Differential Scanning Calorimetry (DSC)
The DSC measurements were carried out on Mettler Toledo 822 stare and TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.
Thermo Gravimetric Analysis (TGA)
TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 le and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25 ml/min.
Another alternate embodiment of the present invention relates to a process for producing polymorphic forms of paliperidone. Paliperidone is subjected to
J crystallization in different solvents and applying different cooling patterns to yield various polymorphic forms, designated as paliperidone crystalline Forms I, II, III, IV, V, VI, VII and an amorphous form.
According to an embodiment of the present invention the crystalline paliperidone polymorphic Form I is having a substantially similar powder X-ray diffraction pattern shown in Fig. 1 with peaks at about 14.58, 22.04 , 24.65 and 25.05 ° (±) 0.2Θ.
According to the present invention, the process for producing paliperidone polymorphic Form-I includes:
a) condensing 3-(2-chloroethyl)-6,7,8,9-teterahyro-9-hydroxy-4H-pyrido[l ,2- a] pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazolemonohydro chloride in the presence of organic base such as diisopropyl amine in an alcoholic solvent such as methanol. b) removing the solvent and treating with acetone and c) isolating polymorphic Form I in alcohol such as isopropyl alcohol.
According to an alternate process of the present invention, the polymorphic Form I of paliperidone is prepared by dissolving paliperidone in a solvent such as ethyl acetate at reflux temperature followed by cooling of the resulting solution and isolating the Form I of paliperidone.
According to another alternate process of the present invention the polymorphic
Form I of paliperidone is alternatively prepared by treating the Form VI or the Form
VII or mixtures thereof in a solvent such as isopropyl alcohol, acetonitrile, heptane, methanol or mixtures thereof to form a slurry followed by filtration to yield the Form I of paliperidone.
According to yet another alternate process of the present invention, the paliperidone polymorphic Form I is prepared by dissolving paliperidone in chlorinated solvent or alcohol or mixture thereof and isolating the solid in ethers such as isopropyl ether to give the polymorphic Form-I. According to the present invention, the paliperidone polymorphic Form I is alternatively prepared by heating Form VI for a time sufficient to transform the Form VI to the Form I of paliperidone, at 40-60°C preferably at 45-50°C. According to an exemplary process the Form VI of paliperidone is subjected to heating for at least 6- 1 ldays, preferably about 7-9 days to convert to paliperidone Form I. According to an alternate embodiment of the present invention, the polymorphic
Form I of paliperidone is prepared by exposing Form VI to relative humidity >90%. The reaction is carried out for a time sufficient to convert the Form VI to Form I. According to an exemplary process the Form VI of paliperidone is exposed to relative humidity >90% for at least 1-4 days, preferably about 2-3 days to convert to paliperidone Form I.
According to the present invention, paliperidone polymorphic Form I is alternatively prepared by exposing Form VII to relative humidity >90%. The reaction is carried out for a time sufficient to convert the Form VII to Form I preferably for 8-12 days, more preferably about 9-10 days to convert to the Form I of paliperidone.
According to another embodiment of the present invention, polymorphic Form II of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 2, with peaks at about 17.02, 18.90 and 26.11 ° (±) 0.2Θ.
According to the present invention, the process for producing polymorphic Form II of paliperidone includes condensing 3-(2-chloroethyl)-6,7,8,9-teterahyro-9- hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole monohydrochloride in the presence inorganic base such as sodium carbonate in solvent medium preferably acetonitrile at 60-65° C, subsequently cooling the reaction product to room temperature, filtering the solid and isolating the separated solid using mixture of water and alcoholic solvents preferably isopropyl alcohol to give polymorphic Form II of paliperidone.
According to still another embodiment of the present invention, the crystalline polymorphic Form III of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 3, with peaks at about 9.65, 15.70, 21.04, 21.43 and 25.81° (±) 0.2θ.
According to the present invention, the paliperidone polymorphic Form II is dissolved in an alcoholic solvent such as methanol, ethanol, isopropyl alcohol, n- butanol mixtures thereof, followed by gradual cooling and filtration to give crystalline polymorphic Form III of paliperidone. According to still another embodiment of the present invention, the crystalline polymorphic Form IV of paliperidone is having a substantially similar powder X-ray diffraction pattern as shown in Fig. 4, with peaks at about 10.25, 23.79 and 25.99° (±) 0.2Θ. The crystalline polymorphic Form IV of paliperidone is further characterized by differential scanning calorimetry (DSC) as shown in Fig. 5, and thermogravemetric analysis (TGA) as shown in Fig. 6.
According to the present invention, the crystalline polymorphic Form IV of paliperidone contains water around 8.7%, which is equivalent to around 2.0 moles of water with respect to the paliperidone.
According to the present invention, crystalline polymorphic Form IV of paliperidone is prepared by dissolving the crystalline polymorphic Form II in a mixture of water and water miscible organic solvents, subjecting resulting clear solution to cooling, filtering separated solid and washing the solid to give crystalline paliperidone polymorphic Form IV. The water miscible organic solvent used is selected from alcohol or ketone. The alcohol used is selected from methanol, ethanol, isopropyl alcohol or n-
butanol or mixtures thereof and the ketone solvent is selected from acetone or methyl ethyl ketone.
According to another embodiment of the present invention, crystalline polymorphic Form V of paliperidone is having a substantially similar powder X-ray diffraction pattern as shown in Fig. 7, with peaks at about 9.68, 21.09, 21.47 and 25.86°
(±) 0.2Θ. The crystalline polymorphic Form V of paliperidone is further characterized by DSC as shown in Fig. 8.
According to the present invention, the crystalline Form V of paliperidone is prepared by suspending crystalline polymorphic Form II in water, followed by slow addition of acid to give clear solution, adjustment of pH of resulting acid solution between 7.0- 10.0 preferably 8.0-9.0 by using a base and subsequent precipitation, filteration and washing with water to give the crystalline paliperidone Form V. The acid used is selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid or sulfuric acid, preferably hydrochloric acid. The base used is selected from alkali, alkaline earth carbonates, bicarbonates or hydroxides such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide peferably sodium carbonate.
According to another embodiment of the present invention, the crystalline polymorphic Form VI of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 9, with peaks at about 5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42° (±) 0.2Θ. The crystalline paliperidone polymorphic Form VI is further characterized by DSC as shown in Fig. 10 and TGA as shown in Fig. 11. According to the present invention, crystalline polymorphic Form VI of paliperidone contains moisture content less than 1.0%. According to the present invention, the polymorphic Form VI of paliperidone is prepared by dissolving paliperidone in a solvent selected from chlorinated solvent or mixture thereof followed by removal of the solvent. The chlorinated solvent is selected from chloroform, dichloromethane, dichloroethane or mixture thereof.
According to another embodiment of the present invention, crystalline paliperidone polymorphic Form VII having substantially similar powder X-ray diffraction pattern as shown in Figure-12, with peaks at about 5.48, 6.04, 9.51, 9.88, 12.46, 14.29, 14.93, 15.43, 15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ± 0.2 0°. The crystalline paliperidone polymorphic Form- VI is further characterized by DSC as shown in Fig. 13 and TGA as shown in Fig. 14.
According to the present invention, process for the preparation of polymorphic Form VII of paliperidone comprises a) dissolving the paliperidone in a solvent or mixture of solvents b) cooling the anti-solvent to -30 to -35°C c) slowly adding solution mixture of step a) to step b); and d) isolating crystalline polymorphic Form VII of paliperidone. Solvent is selected from alcohol such as isopropyl alcohol, chlorinated hydrocarbon such as chloroform or ether such as isopropyl ether. The process includes optionally seeding the solvent mixture with polymorphic Form VII.
According to another embodiment of the present invention, amorphous paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 15. According to the present invention, process for the preparation of amorphous paliperidone comprises melting the crystalline paliperidone and isolating amorphous paliperidone.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.
Example- 1 Preparation of 3-r2-Chloro-ethvn-9-hvdroxy-2-methyl-6.7.8.9-tetrahvdro-pyrido[1.2- a]pyrimidin-4-one
9-Benzyloxy-3-(2-chloro-ethyl)-2-methyl-pyrido[l,2-a]pyrimidin- 4-one, prepared as per US 5,158,952 (100 g,0.305 mole) was added to methanol (500 ml) at
25-35°C. The suspension was maintained for 15 minutes at 25-35°C and acetic acid
(25g, 0.416 moles) was added to the above suspension at 25-35°C followed by drop wise addition of cone.
H2SO4 (30g, 0.306mole) at 25-35° C to get a clear solution. The solution was treated with activated carbon 10.0 gm for 1 hr. Reaction mass was then filtered over celite bed and washed with methanol (50.0 ml). The filtrate was charged into autoclave at 25-35°C along with 10% Pd Carbon [10 g (50% wet)] at 25-35°C. Hydrogenation was continued at 4-5 kg/cm2 at 60-65°C until 9-hydroxy-3-(2-chloro- ethyl)-2-methyl-pyrido[l,2-a] pyrimidin- 4-one <1.0%. The reaction mass was further cooled and Pd/C was filtered over celite and washed with methanol. The solution was cooled to 10-15°C, pH adjusted to 8.0 with sodium carbonate at 10-15°C and the solution stirred for 1 hr at 25-35°C. Resulting salts were filtered and washed with methanol (50.0 ml). The solvent was distilled off completely under vacuum at below 40°C. DM Water (150 ml) was charged to the residue at 25-35°C and cooled to 10-
15°C. Contents were stirred for 1 hr at 10-15°C. Resultant solid was filtered, washed with water and dried at 40-45°C to give 50 g of 3-(2-Chloro-ethyl)-9-hydroxy-2- methyl-6,7,8,9-tetrahydro-pyrido [ 1 ,2-a]pyrimidin-4-one.
Example-2 Preparation of Paliperidone
3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (60 gm, 0.165 mole) was added to acetonitrile (300 ml) at 25-35°C and stirred for 10 mins at 25-35°C. 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole.HCl (55.9 gm,0.218 mole) and sodium carbonate anhydrous (78.8 gm, 0.743 mole) was added. Resultant mass was stirred for 10 min at 25-35°C. The temperature was slowly raised to 60- 65°Cand maintained at 60-65°C for 30-45 hrs. Subsequently, mass was cooled and maintained at 25-35°C for 1 hr. The solid is filtered and treated with water (600 ml) for 1 hr. The solid was again filtered, washed with water and IPA and dried at 40-45°C to give 85 gm of paliperidone. Example-3
Process for the preparation of crystalline Form I of paliperidone 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2- a]pyrimidine-4-one (5.0 gm,0.021 moles), 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride (4 gm,0.018 molar), diisopropylamine (4 gms,0.039 moles) and methanol (48 ml) were stirred overnight at 60°C. The reaction mass was evaporated and the residue was suspended in dichloromethane (50 ml) and washed with water. The solvent was evaporated and the residue treated with acetone to get paliperidone crude (5.0 gms). The crude paliperidone (4 gm) was charcoalised in isopropyl alcohol at 75- 80° C, the filtrate cooled and stirred for 1 hr. The reaction mass was again cooled to 0- 5°C and stirred for 2 hrs. Slurry was filtered and washed with chilled isopropyl alcohol. The wet cake was dried at 35-40°C under vacuum (3.3 gm) to obtain polymorphic Form I of paliperidone
Example-4
Transformation of Form VI to Form I of paliperidone by Slurry, Relative Humidity (RTO and Heating
Ig of Form VI of paliperidone is subjected to different crystallization processes. The results are tabulated as follows.
Example-5
Transformation of Form VII to Form I of paliperidone by Slurry and Relative Humidity
Ig of paliperidone Form VII was subjected to different crystallization processes. The results are tabulated as follows.
Process for the preparation of crystalline polymorphic Form II of paliperidone
3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (60 gm, 0.165 mole) was added to acetonitrile (300 ml) at 25-350C and stirred for 10 mins at 25-35°C. 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole.HCl (55.9 gm,0.218 mole) and sodium carbonate anhydrous (78.8 gm, 0.743 mole) was added to the reaction mass. The reaction mass was then stirred for 10 min at 25-35°C and temperature was raised to 60-65°C. The reaction mass was then maintained at 60-65°C for 30-45 hrs, slowly cooled and maintained at 25-35°C for 1 hr. The resultant solid was filtered and treated with water (600 ml) for 1 hr. The solid was again filtered, washed with water and IPA and dried at 40-45°C to give 85 gm of Form II of paliperidone.
Example-7 Process for the preparation of crystalline polymorphic Form III of paliperidone
Paliperidone (7.2 gm) was added to isopropyl alcohol (220 ml) at 25-35°C and stirred for 15 min. Slowly the temperature was raised to reflux temperature to obtain a clear solution. Activated carbon (1.5 gm) was charged to the reaction mass at reflux temperature and maintained at reflux for 60 min. The carbon was then filtered over celite bed at reflux and washed with hot isopropyl alcohol. The filtrate was cooled to 0-
5°C and maintained for 2 hrs. The solid was then filtered, washed with chilled isopropyl alcohol and dried under vacuum below 40-45°C to give 4.5 gm of Form III of paliperidone.
ExampIe-8 Process for the preparation of crystalline polymorphic Form III of Paliperidone
1 gm of polymorphic Form IV of paliperidone was dried in a static dryer and heated at 40-60° C under vacuum to give polymorphic Form III of paliperidone.
Example-9 Process for the preparation of crystalline polymorphic Form IV of paliperidone
Paliperidone (2 gm) was added to ethanol (20 ml) and water (2ml) at 25-35°C and stirred for 15 min. Slowly the temperature was raised to reflux under nitrogen to obtain a clear solution. The solution was slowly cooled to 25-35°C in 1.5hours and further cooled to 0-50C in 30 minutes and maintained for 1.0 hour. Solid was then filtered and washed with chilled ethanol, dried under vacuum below 40-450C to give 1.0 gm of Form IV of paliperidone.
Example-10
Process for the preparation of crystalline polymorphic Form IV of paliperidone
3 gm of Paliperidone was dissolved in 1:1 mixture of acetonitrile and water ( v/v 350 ml), resulting solution was then subjected to freeze drying at -104° C and below 200 Torr vacuum to give polymorphic Form IV of paliperidone.
Example- 11 Process for the preparation of crystalline polymorphic Form V of paliperidone
Paliperidone (1 gm) was added to 0.5N Hydrochloric acid solution (10 ml) at 25-35°C and stirred for 15 min. The solution was then heated to 60-65°C and pH adjusted to 8.0 with sodium carbonate solution at 60-65°C. Further, the suspension was cooled slowly and stirred at 25-35°C for 2 hrs. The solid was filtered and washed with chilled water ( 5 ml), dried under vacuum below 40-45°C to give 0.90 gm of Form V of paliperidone.
Example- 12 Process for the preparation of crystalline polymorphic Form VI of paliperidone
5 gm of Paliperidone was dissloved in 65 ml chloroform under stiring at 55-60° C for 10 minutes. The resulting solution was filtered through celite to remove undissloved particulate. The filtrate was subjected to spray drying at temperature 100- 105°C using nitrogen gas to give crystalline polymorphic Form- VI of paliperidone. Example- 13
Process for the preparation of crystalline polymorphic Form VII of paliperidone
5g of Paliperidone was suspended in 1 : 1 mixture of chloroform and isopropyl alcohol (v/v 80ml) at room temperature and heated to about 4O0C to obtain a clear solution. The resulting solution was filtered through hyflo bed to remove the particulate and added to isopropyl ether (420 ml) maintained at -3O0C for 15 min with agitation.
The precipitated solid was then filtered to give Form VII of paliperidone.
Example-14 Process for the preparation of crystalline polymorphic Form VII of Paliperidone
5g of Paliperidone was suspended in 1 :1 mixture of chloroform and isopropyl alcohol (v/v 80ml) at room temperature and heated to about 4O0C to obtain a clear solution. The resulting solution was filtered through celite bed to remove the particulate and added to isopropyl ether (420 ml) maintained at -3O0C with seeds of Form VII for 15 min with agitation. The precipitated solid was filtered to give Form VII of paliperidone.
Example- 15
Process for the preparation of amorphous paliperidone
5g of Paliperidone was heated at about 17O0C and maintained for about 5 minutes to form a melt followed by cooling the melt to obtain amorphous paliperidone.
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.
Claims
1. An improved process for preparing paliperidone, the process comprising: a) hydrogenating 3 -(2-chloroethyl)-2-methyl-9-(hydroxyprotected)- 4H-pyrido[1.2-a] pyrimidin-4-one in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrido[l ,2-a]-pyrimidin-4-one; and b) condensing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrido [ 1 ,2-a] -pyrimidin-4-one with 6-fluoro-3 -(4-piperidinyl)- 1,2- benzisoxazole in presence of a base and a solvent to give paliperidone.
2. The process according to claim 1, wherein the hydroxyprotected group is selected from benzyl or methyl.
3. The process according to claim 1, wherein the acid used is selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, para-toluene sulphonic acid and methane sulphonic acid.
4. The process according to claim 1, wherein the catalyst used is a noble metal catalyst.
5. The process according to claim 4, wherein the noble metal catalyst is selected from Palladium, Rhodium and Ruthenium.
6. The process according to claim 1, wherein the step of hydrogenation is carried out in presence of a solvent selected from alcoholic solvent, preferably methanol, ethanol and isopropyl alcohol.
7. The process according to claim 1, wherein the base used is selected from a group consisting of alkali, alkaline earth carbonates, bicarbonates or hydroxides, preferably sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, more preferably sodium carbonate.
8. The process according to claim 1, wherein the solvent used in the condensation step is selected from methanol, ethanol, isopropyl alcohol, n-butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate and tetrahydrofuran.
9. The process according to claim 1, wherein the process comprising dissolving said paliperidone in a solvent and isolating crystalline Form VI of paliperidone.
10. The process according to claim 9, wherein the solvent used is a chlorinated solvent, preferably chloroform, dichloromethane or dichloroethane or mixture thereof.
11. The process according to claim 9, wherein said crystalline Form VI of paliperidone is having an X-ray powder diffraction pattern characterized by peaks at
5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42 ± 0.2 2Θ values.
12. The process according to claim 9, wherein said crystalline Form VI is characterized by differential scanning calorimetry (DSC) as depicted in Figure 10 and Thermo Gravimetric Analysis (TGA) as depicted in Figure 11.
13. The process according to claim 1 , wherein the process comprising a) dissolving said paliperidone in a solvent or mixture of solvents; b) cooling anti-solvent to -30 to -35°C; c) adding slowly the solution mixture of step a) to step b); and d) isolating crystalline Form VII of paliperidone.
14. The process according to claim 13, wherein the process comprising optionally seeding with crystalline Form VII.
15. The process according to claim 13, wherein the solvent used is selected from a group consisting of alcohol, chlorinated hydrocarbon, ester and ether.
16. The process according to claim 15, wherein the solvent used is preferably methanol, ethanol, propanol, isopropyl alcohol, dichloromethane, trichloromethane, ethyl acetate and isopropyl ether.
17. The process according to claim 13, wherein said crystalline Form VII of paliperidone is having an X-ray powder diffraction pattern characterized by peaks at about 5.48, 6.04, 9.51, 9.88, 12.46, 14.29, 14.93, 15.43, 15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ± 0.2 2Θ values.
18. The process according to claim 13, wherein said crystalline Form VII is characterized by DSC as depicted in Figure 13 and TGA as depicted in Figure 14.
19. A crystalline Form VI of paliperidone, wherein said crystalline form VI is having an X-ray powder diffraction pattern characterized by peaks at 5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42 ± 0.2 2Θ values.
20. The crystalline Form VI of paliperidone according to claim 19, wherein said crystalline Form VI is having a substantially similar X-ray powder diffraction pattern as depicted in Figure 9.
21. • The crystalline form VI according to claim 19, wherein said crystalline Form VI is characterized by DSC as depicted in Figure 10 and TGA as depicted in Figure 11.
22. A crystalline Form VII of paliperidone, wherein said crystalline Form VII is having an X-ray powder diffraction pattern characterized by peaks at 5.48, 6.04,
9.51, 9.88, 12.46, 14.29, 14.93, 15.43, 15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ± 0.2 2Θ values.
23. The crystalline Form VII according to claim 22, wherein said crystalline Form VII is having a substantially similar powder X-ray diffraction pattern as depicted in Figure 12.
24. The crystalline Form VII according to claim 22, wherein said crystalline Form VII is characterized by DSC as depicted in Figure 13 and TGA as depicted in Figure 14.
25. A process for the preparing crystalline Form VI of paliperidone, wherein paliperidone is dissolved in a solvent selected from chlorinated solvent or mixture thereof followed by removal of solvent.
26. A process for preparing crystalline Form VII of paliperidone, wherein the process comprising: a) dissolving said paliperidone in a solvent or mixture of solvents; b) cooling anti-solvent to -30 to -35°C; c) adding slowly the solution mixture of step a) to step b);-and d) isolating crystalline Form VII of paliperidone.
27. A process for preparing crystalline Form I of paliperidone, wherein the process comprising dissolving paliperidone in a solvent, preferably ethyl acetate, at reflux temperature followed by cooling and isolating said crystalline Form I.
28. A process for producing crystalline Form I of paliperidone, wherein the process comprising dissolving paliperidone in a chlorinated solvent or alcohol or mixture thereof followed by isolating resultant solid employing an ether, preferably isopropyl ether to obtain said crystalline Form I.
29. A process for producing crystalline Form I of paliperidone, wherein the process comprising:
a) heating crystalline Form VI of paliperidone as claimed in claim 19 for a time sufficient to induce transformation of crystalline Form VI to crystalline Form-I; and b) isolating crystalline Form-I.
30. A process for producing crystalline Form I of paliperidone, wherein the process comprising: a) subjecting crystalline Form VI of paliperidone as claimed in claim 19 to relative humidity >90% for a time sufficient to induce the transformation of polymorphic Form VI of paliperidone to said polymorphic Form I; and b) isolating said crystalline Form I.
31. A process for producing crystalline Form I of paliperidone, wherein the process comprising: a) subjecting crystalline Form VII of paliperidone as claimed in claim 22 to relative humidity >90% for a time sufficient to induce the transformation of polymorphic Form VII to said polymorphic Form I; and b) isolating said crystalline Form I.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009144288A1 (en) * | 2008-05-29 | 2009-12-03 | Inke, S.A. | Process to prepare paliperidone and intermediates thereof |
WO2009130710A3 (en) * | 2008-04-21 | 2009-12-17 | Glenmark Generics Limited | A process for the preparation of paliperidone intermediates |
ITMI20090663A1 (en) * | 2009-04-21 | 2010-10-22 | Dipharma Francis Srl | PROCEDURE FOR THE PURIFICATION OF PALIPERIDONE |
WO2010122575A3 (en) * | 2009-04-20 | 2011-01-06 | Matrix Laboratories Ltd | Process for the preparation of pure paliperidone |
WO2011015936A2 (en) * | 2009-08-04 | 2011-02-10 | Orchid Chemicals And Pharmaceuticals Ltd | An improved process for the preparation of pure paliperidone |
CN104140423A (en) * | 2013-05-10 | 2014-11-12 | 江苏豪森药业股份有限公司 | Refining method for paliperidone |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009130710A3 (en) * | 2008-04-21 | 2009-12-17 | Glenmark Generics Limited | A process for the preparation of paliperidone intermediates |
WO2009144288A1 (en) * | 2008-05-29 | 2009-12-03 | Inke, S.A. | Process to prepare paliperidone and intermediates thereof |
US8309717B2 (en) | 2008-05-29 | 2012-11-13 | Inke, S.A. | Process to prepare paliperidone and intermediates thereof |
WO2010122575A3 (en) * | 2009-04-20 | 2011-01-06 | Matrix Laboratories Ltd | Process for the preparation of pure paliperidone |
ITMI20090663A1 (en) * | 2009-04-21 | 2010-10-22 | Dipharma Francis Srl | PROCEDURE FOR THE PURIFICATION OF PALIPERIDONE |
EP2243780A3 (en) * | 2009-04-21 | 2010-12-29 | Dipharma Francis S.r.l. | Process for the purification of paliperidone |
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 |
CN104140423A (en) * | 2013-05-10 | 2014-11-12 | 江苏豪森药业股份有限公司 | Refining method for paliperidone |
Also Published As
Publication number | Publication date |
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WO2009044413A8 (en) | 2009-07-30 |
WO2009044413A3 (en) | 2009-10-29 |
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