WO2004009591A1 - Procede de preparation de risperidone antipsychotique - Google Patents
Procede de preparation de risperidone antipsychotique Download PDFInfo
- Publication number
- WO2004009591A1 WO2004009591A1 PCT/IN2003/000207 IN0300207W WO2004009591A1 WO 2004009591 A1 WO2004009591 A1 WO 2004009591A1 IN 0300207 W IN0300207 W IN 0300207W WO 2004009591 A1 WO2004009591 A1 WO 2004009591A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- risperidone
- methyl
- oxime
- pyrido
- Prior art date
Links
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229960001534 risperidone Drugs 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 230000000561 anti-psychotic effect Effects 0.000 title abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000002923 oximes Chemical class 0.000 claims abstract description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims abstract description 3
- DAQWROFRHWHKFE-UHFFFAOYSA-N n-[(2,4-difluorophenyl)-piperidin-4-ylmethylidene]hydroxylamine Chemical compound C=1C=C(F)C=C(F)C=1C(=NO)C1CCNCC1 DAQWROFRHWHKFE-UHFFFAOYSA-N 0.000 claims abstract description 3
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims abstract 2
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 1
- CMWCQQUYLPYOMY-UHFFFAOYSA-N 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound C1CCCN2C(=O)C(CCCl)=C(C)N=C21 CMWCQQUYLPYOMY-UHFFFAOYSA-N 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- CPVWKXXFKMUDPA-UHFFFAOYSA-N n-[(2,4-difluorophenyl)-piperidin-4-ylmethylidene]hydroxylamine;hydrochloride Chemical compound Cl.C=1C=C(F)C=C(F)C=1C(=NO)C1CCNCC1 CPVWKXXFKMUDPA-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- YAYOVHRLVOHYMW-UHFFFAOYSA-N 1h-pyrimidin-6-one;hydrochloride Chemical compound Cl.O=C1C=CN=CN1 YAYOVHRLVOHYMW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- -1 oxime compound Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QPJONRGTWKXJLG-UHFFFAOYSA-N (2,4-difluorophenyl)-piperidin-4-ylmethanone;hydrochloride Chemical compound Cl.FC1=CC(F)=CC=C1C(=O)C1CCNCC1 QPJONRGTWKXJLG-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- ZLMJMSJWJFRBEC-OUBTZVSYSA-N potassium-40 Chemical compound [40K] ZLMJMSJWJFRBEC-OUBTZVSYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 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
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- AYOOGWWGECJQPI-NSHDSACASA-N n-[(1s)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(3-propan-2-yloxy-1h-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine Chemical compound N1C(OC(C)C)=CC(N2C3=NC(N[C@@H](C)C=4N=CC(F)=CN=4)=CC=C3N=C2)=N1 AYOOGWWGECJQPI-NSHDSACASA-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
- 238000011112 process operation 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
- Risperidone (Compound I) is an antipsychotic agent belonging to 3-piperidinyl-l-,2- benzisoxazole derivative reported by Janssen Pharmaceutica in US Patent 4,804,663.
- COMPOUND I The benzisoxazole intermediate (Compound V) required in this route of risperidone synthesis has been prepared in US Patent 4,804,663 and US Patent 5,134,147 by cyclization of 4-(2,4- difluorobenzoyl)piperidine oxime (Compound III) in aqueous sodium hydroxide solution.
- This approach of preparing risperidone involves number of chemical steps and results in an overall yield of 40%.
- the aim of the present invention is to provide a method to obtain highly pure risperidone in high yield.
- the instant invention relates to an industrially advantageous, economic and efficient method for the preparation of highly pure risperidone.
- the process comprises reacting 4-(2,4-difluorobenzoyl)piperidine oxime hydrochloride (Compound III) with 3-(2-chlbroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one monochloride (Compound II) in a solvent such as acetonitrile, methyl isobutyl ketone, NN-Dimethylformamide using potassium carbonate or sodium carbonate base in presence of catalytic amount of potassium iodide to obtain an intermediate oxime (Compound IV) that cyclizes in situ to produce risperidone.
- the product thus produced is crystallized from ethyl acetate to obtain highly pure risperidone in 81% yield.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
L'invention porte sur un procédé de préparation de risperidone antipsychotique (Formule I); qui consiste à faire réagir 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one (Formule II); avec 4-(2,4-difluorobenzoyl)piperidine oxime (Formule III); afin de former de l'oxime (Formule IV); et comprend la cyclisation in situ d'oxime (Formule IV) afin de former du risperidone (Formule I) dans un solvant choisi dans le groupe acétonitrile,N, N dimetylformamide et méthyle isobutyle cétone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003237597A AU2003237597A1 (en) | 2002-07-22 | 2003-06-02 | A process for the preparation of antipsychotic risperidone |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN545/MAS/2002 | 2002-07-22 | ||
| IN545CH2002 | 2002-07-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004009591A1 true WO2004009591A1 (fr) | 2004-01-29 |
Family
ID=30471464
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2003/000207 WO2004009591A1 (fr) | 2002-07-22 | 2003-06-02 | Procede de preparation de risperidone antipsychotique |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2004009591A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030772A1 (fr) * | 2003-09-26 | 2005-04-07 | Jubilant Organosys Ltd. | Procede de preparation de risperidone |
| WO2009077551A1 (fr) * | 2007-12-18 | 2009-06-25 | Janssen Pharmaceutica Nv | Procédé de préparation de la rispéridone |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4804663A (en) * | 1985-03-27 | 1989-02-14 | Janssen Pharmaceutica N.V. | 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles |
| EP0453042A1 (fr) * | 1990-04-19 | 1991-10-23 | Janssen Pharmaceutica N.V. | 4H-pyrido-(1,2-a)pyrimidin-4-ones substituées sur les positiones 2 et 9 |
| US5134147A (en) * | 1989-11-07 | 1992-07-28 | Adir Et Compagnie | 1,2-benzisoxazole compounds |
| ES2050069A1 (es) * | 1992-07-10 | 1994-05-01 | Vita Invest Sa | Procedimiento para la obtencion de 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino)etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido(1,2-a) pirimidin-4-ona. |
| WO1995014691A1 (fr) * | 1993-11-23 | 1995-06-01 | Janssen Pharmaceutica N.V. | NOUVEAUX DERIVES DU 9-HYDROXY-PYRIDO[1,2-a]PYRIMIDINE-4-ONE ETHER |
| WO2003042212A1 (fr) * | 2001-11-13 | 2003-05-22 | EGIS Gyógyszergyár Rt. | Procede ameliore de preparation de 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one |
-
2003
- 2003-06-02 WO PCT/IN2003/000207 patent/WO2004009591A1/fr not_active Application Discontinuation
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4804663A (en) * | 1985-03-27 | 1989-02-14 | Janssen Pharmaceutica N.V. | 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles |
| US5134147A (en) * | 1989-11-07 | 1992-07-28 | Adir Et Compagnie | 1,2-benzisoxazole compounds |
| EP0453042A1 (fr) * | 1990-04-19 | 1991-10-23 | Janssen Pharmaceutica N.V. | 4H-pyrido-(1,2-a)pyrimidin-4-ones substituées sur les positiones 2 et 9 |
| ES2050069A1 (es) * | 1992-07-10 | 1994-05-01 | Vita Invest Sa | Procedimiento para la obtencion de 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino)etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido(1,2-a) pirimidin-4-ona. |
| WO1995014691A1 (fr) * | 1993-11-23 | 1995-06-01 | Janssen Pharmaceutica N.V. | NOUVEAUX DERIVES DU 9-HYDROXY-PYRIDO[1,2-a]PYRIMIDINE-4-ONE ETHER |
| WO2003042212A1 (fr) * | 2001-11-13 | 2003-05-22 | EGIS Gyógyszergyár Rt. | Procede ameliore de preparation de 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one |
Non-Patent Citations (1)
| Title |
|---|
| "RISPERIDONE", DRUGS OF THE FUTURE, BARCELONA, ES, vol. 13, no. 12, 1 December 1988 (1988-12-01), pages 1052 - 1055, XP002046839, ISSN: 0377-8282 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030772A1 (fr) * | 2003-09-26 | 2005-04-07 | Jubilant Organosys Ltd. | Procede de preparation de risperidone |
| WO2009077551A1 (fr) * | 2007-12-18 | 2009-06-25 | Janssen Pharmaceutica Nv | Procédé de préparation de la rispéridone |
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