Patent EA-003774-B1 (EA)
Title: Process for preparation of pyrazolo [4,3-d] pyrimidin-7-ones and intermediates thereof
Inventor: DUNN PETER JAMES
IPC: C07D487/04
Filed: 1999-10-11
Abstract: 1. A process for the preparation of a compound of formulae (IA) and (IB): comprising reacting a compound of formula (IIA) and (IIB) respectively in the presence of <->OR, wherein R in the case of formation of compound (IA) is CH2CH3 and R in the case of formation of compound (IB) is CH2CH2CH3, where X is a leaving group, provided that X is not ethoxy: 2. A process as claimed in claim 1 wherein X is selected from the group consisting of arylsulphonyloxy, C1-C4 alkylsulphonyloxy, nitro or halo substituted benzenesulphonyloxy, C1-C4 perfluoroalkylsulphonyloxy, aroyloxy, C1-C4 perfluoroalkanoyloxy, C1-C4 alkanoyloxy; halo; diazonium; C1-C4 primary and secondary alkoxy (excluding etoxy), oxonium, perchloryloxy, quatenaryammonium C1-C4 alkylsulphonuloxy, halosulphonyloxy, halonium and diarylsulphonylamino. 3. A process as claimed in claim 2 wherein X is a halo or methoxy. 4. A process as claimed in claim 3 wherein X is fluoro, chloro or methoxy. 5. A process as claimed in claim 4 wherein X is fluoro or chloro. 6. A process as claimed in any one of the preceeding claims wherein OR is present with an auxiliary base. 7. A process as claimed in claim 6 wherein the auxiliary base is selected from the group consisting of sterically hindered base, metal salts of 1-methyl piperazine (especially for compound IA), 1-ethylpiperazine (especially for compound IB), morpholine, a metal hydride, metal oxide, metal carbonate and metal bicarbonate. 8. A process as claimed in claim 7 wherein the sterically hindered base is a metal salt of a sterically hindered alcohol or amine. 9. A process as claimed in claim 8 wherein the metal salt of a sterically hindered alcohol or amine is selected from the group consisting of a secondary or tertiary C4-C12 alkanol, a C3-C12 cycloalkanol and a secondary or tertiary (C3-C8 cycloalkyl)C1-C6 alkanol, a N-(secondary or tertiary C3-C6 alkyl)-N-(primary, secondary or tertiary C3-C6 alkyl)amine, a N-(C3-C8 cycloalkyl)-N-(primary, secondary or tertiary C3-C6 alkyl)amine, a di(C3-C8 cycloalkyl)amine or hexamethyldisilazane 1,5-diazabicyclo[4,3,0]non-5-ene 1,8-diazabicyclo[5,4,0]undec-7-ene and tertiary amines such as triethylamine. 10. A process as claimed in claims 9 wherein the auxiliary base is a metal salt of a tertiary alkanol. 11. A process as claimed in any one of the preceding claims wherein the reaction is carried out in an inert solvent or ROH or a mixture of both. 12. A process as claimed in claim 11 wherein the solvent is selected from the group consisting of ethanol (for IA), n-propanol (for IB), a secondary or tertiary C4-C12 alkanol, a C3-C12 cycloalkanol, a tertiary C4-C12 cycloalkanol, a secondary or tertiary (C3-C7 cycloalkyl)C2-C6 alkanol, a C3-C9 alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixtures thereof. 13. A process as claimed in claim 12 wherein the solvent is selected from the group consisting of ethanol (for IA), n-propanol (for IB), a tertiary C4-C12 alkanol, a tertiary C4-C12 cycloalkanol, a tertiary (C3-C7 cycloalkyl)C2-C6 alkanol, a C3-C9 alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixtures thereof. 14. A process as claimed in claim 13 wherein the solvent is ethanol (for IA) or propanol (for IB). 15. A process for the preparation of a compound of formula (IA) and (IB) according to any one of the preceding claims comprising reacting a compound of formula (IIA) and (IIB) respectively with ZOR, or with ROH and an auxiliary base as defined hereinbefore or with ZOR and an auxiliary base, wherein ZOR is a salt of OR and Z is a cation. 16. A process as claimed in claim 15 wherein compound (IA) is formed by reaction of compound (IIA): a) with ethanol and auxiliary base, optionally in an inert solvent; or b) with ZOEt and an auxiliary base in ethanol or an inert solvent or both; or c) with ZOEt and ethanol or an inert solvent or both. 17. A process as claimed in claim 15 wherein compound (IB) is formed by reaction of compound (IIB): d) with propanol and auxiliary base, optionally in an inert solvent (as defined herebefore); or e) with ZOPr and an auxiliary base, in propanol or an inert solvent or both; or f) with ZOPr, and propanol or an inert solvent or both. 18. A process as claimed in any one of the preceding claims wherein the compound of formula (IIA) is prepared by coupling a compound of formula (VIIA): with a compound of formula (IXA): and a compound of formula (IIB) is prepared by coupling a compound of formula (VIIB): with a compound of formula (IXB): 19. A process as claimed in claim 18 wherein a compound of the formula (VIIA) is formed by coupling a compound of formula (VIA) with N-methylpiperazine and a compound of formula (VIIB) is formed by coupling a compound of formula (VIA) with N-ethylpiperazine. 20. A compound of formula (IIA) and (IIB): wherein X is selected from halogen or methoxy. 21. A compound of formula (IIIA) and (IIIB): wherein X is selected from halogen or methoxy. 22. A compound of formula (VIIA) and (VIIB) wherein X is selected from halogen or methoxy. 23. A compound as claimed in any of claims 20 to 22 wherein X is selected from the group consisting of fluoro, chloro and methoxy. 24. A compound as claimed in claim 22 wherein X is selected from fluoro or chloro