Patent EA-003145-B1 (EA)
Title: Process for the preparation of pyrazolo [4,3-d] pyrimidin-7-ones-3-pyridylsulphonyl compounds and intermediates thereof
Inventor: DEVRIES KEITH M
IPC: C07D401/14
Filed: 2000-10-10
Abstract: 1. A process for the preparation of a compound of formula (I) wherein R is C1 to C6 alkyl optionally substituted with one or two substituents selected from C3 to C5 cycloalkyl, OH, C1 to C4 alkoxy, benzyloxy, NR<5>R<8>, phenyl, furanyl and pyridinyl; C3 to C6 cycloalkyl; 1-(C1 to C4 alkyl)piperidinyl; tetrahydrofuranyl or tetrahydropyranyl and wherein said C1 to C6 alkyl or said C1 to C4 alkoxy groups are optionally substituted by haloalkyl; R<1> (which can be linked to either nitrogen of the pyrazole ring) is C1 to C3 alkyl, optionally substituted with phenyl, Het or a N linked heterocyclic group selected from piperidinyl and morpholinyl and wherein said phenyl group is optionally substituted by: C1 to C4 alkyl which is optionally substituted by haloalkyl or haloalkoxy; or C1 to C4 alkoxy; or halo or CN; R<2> is C1 to C6 alkyl; and Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5membered heterocyclic group containing two or three nitrogen atoms, wherein any of heterocyclic groups is optionally substituted with C1 to C4 alkyl or C1 to C4 alkoxy NHR<7>, wherein R<7> is H, C1 to C4 alkyl or C1 to C4 alkanoil. R<3> and R<4> constitute with linked nitrogen atom 4-R<8>- piperazinilic group, optionally substituted with one or two C1 to C4 alkylic groups, and optionally as its 4-N-oxide; R<5> and R<6> are separately selected from H and C1 to C4 alkyl, optionally substituted with C3 to C5 cycloalkyl, or C1 to C4 alkoxy, or constitute with linked nitrogen atom azetidinylic, pyrrolidinylic, piperidinylic, and morpholinyl groups; R<8> is H; C1 to C4 alkyl, optionally substituted with one or two substituents selected from OH, NR<5>R<6>, CONR<5>R<6>, phenyl, optionally substituted with C1 to C4 alkoxy, benzodioxolyl and benzodioxanyl; C3 to C6 alkenyl, pyridinyl or pyrimidinyl; wherein said process comprise reacting of a compound of formula (II), (III), or (IV) over((OR and hydroxide trapping agent, or in case of compound of formula (IV), reacting over a auxiliary base and hydroxide trapping agent (OR is substituted with auxiliary base), wherein X is leaving group R<1>-R<4> as specified above. 2. A process for the preparation of a compound of formula (IA) and (IB) comprising reacting a compound of formula (IIA), (IIIA) or (IVA), and (IIB), (IIIB) or (IVB) respectively in the presence of OR and a hydroxide trapping agent, or alternatively in the case of compounds of formula (IVA) and (IVB) reacting in the presence of ( OR and an auxiliary base wherein OR in the case of formation of compound (IA) is CH3O(CH2)2O-, and OR in the case of formation of compound (IB) is (R)-CH3OCH2CH(CH3)O-and wherein X in formulae (IIA) to (IVA) and formula (IIB) to (IVB) is a leaving group. 3. A process as claimed in claims 1 or 2 wherein the hydroxide trapping agent is an ester. 4. A process as claimed in any of claims 1- 3 wherein the hydroxide trapping agent is an ester of the formula: TOC(O)W wherein OT is OR or the residue of a bulky alcohol or a non-nucleophilic alcohol or TOH is an alcohol which can be azeotropically removed during the reaction; and C(O)W is the residue of a carboxylic acid. 5. A process as claimed in any one of claims 1 to 4 wherein X is selected from the group consisting of arylsulphonyloxy, C1-C4 alkylsulphonyloxy, nitro or halo substituted benzenesulphonyloxy, C1-C4 perfluoroalkylsulphonyloxy, optionally substituted aroyloxy, C1-C4 perfluoroalkanoyloxy, C1-C4 alkanoyloxy, halo; diazonium; C1-C4 primary and secondary alkoxy, oxonium, perchloryloxy, quatenaryammonium C1-C4 alkylsulphonuloxy, halosulphonyloxy, halonium and diarylsulphonylamino. 6. A process as claimed in claim 5 wherein X is a C1-C6 alkoxy. 7. A process as claimed in any one of claims 1 to 6 wherein -OR is present with an auxiliary base. 8. A process as claimed in claim 7 wherein the auxiliary base is selected from the group consisting of sterically hindered base, a metal hydride, metal oxide, metal carbonate and metal bicarbonate. 9. A process as claimed in claim 8 wherein the sterically hindered base is a metal salt of a sterically hindered alcohol or amine. 10. A process as claimed in claim 9 wherein the reaction is carried out in an inert solvent or ROH or a mixture of both. 11. A process as claimed in claim 10 wherein the solvent is selected from the group consisting of ROH, a secondary or tertiary C4-C12 alkanol, a C3-C12 cycloalkanol, a tertiary C4-C12 cycloalkanol, a secondary or tertiary (C3-C7 cycloalkyl)C2C8 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. 12. A process as claimed in claim 11 wherein the solvent is ROH. 13. A process as claimed in any one of claims 2 to 12 wherein compound (1A) is formed by reaction of compound (IIA) or (IIIA): a) with 2-methoxyethanol and auxiliary base, optionally in an inert solvent and in the presence of said trapping agent; or b) with ZO(CH2)2OCH3 and an auxiliary base in 2-methoxyethanol or an inert solvent or both, in the presence of said trapping agent; or c) with ZO(CH2)2OCH3 and 2-methoxyethanol or an inert solvent or both, in the presence of said trapping agent, and wherein Z is a metal. 14. A process as claimed in any one of claims 2 to 12 wherein compound (IB) is formed by reaction of compound (IIB) or (IIIB): a) with (R)-CH3OCH2CH(CH3)OH and auxiliary base, optionally in an inert solvent and in the presence of said trapping agent; or b) with (R)-CH3OCH2CH(CH3)OZ and an auxiliary base in (R)-CH3OCH2CH(CH3)OH or an inert solvent or both, in the presence of said trapping agent; or c) with (R)-CH3OCH2CH(CH3)OZ and (R)-CH3OCH2CH(CH3)OH or an inert solvent or both, in the presence of said trapping agent, and wherein Z is a metal. 15. A process as claimed in any one of claims 1 to 14 wherein a compound of formula (III) is formed by coupling a compound of formula (V) with a compound of formula (VI) or a salt thereof. 16. A process according to claim 15 wherein a compound of formula (VI) or a salt thereof is formed from a compound of formula (VII) (a) for a compound formula (VI) wherein X is arylsulfonyloxy, C1-C4 alkylsulfonyloxy, C1-C4 pertluoroalkylsulfonyloxy, aryloxy, C1-C4 perfluoroalkanoyloxy, C1-C4 alkanoyloxy, quarternaryammonium C1-C4 alkylsulfonyloxy or halosulfonyloxy, comprising reacting a compound of formula (VII) wherein Y and V are OH in the presence of an appropriate sulphonylating, arylating or acylating agent of X; (b) for a compound of formula (VI) wherein X is Cl, comprising reaction of a compound of formula (VII) wherein Y is Cl and V is P and P is a protecting group, with a deprotecting agent; (c) for a compound of formula (VI) wherein X is diazonium, comprising reacting a compound of formula (VII) wherein Y is NH2, V is OH with nitrous acid; (d) for a compound of formula (VI) wherein X is (diarylsulfonyl)amino comprising reacting a compound of formula (VII) wherein Y=NH2 and V=OH in the presence of an appropriate sulphonylating agent; (e) for a compound of formula (VI) wherein X is OR which is C1-6 alkoxy, comprising reacting a compound of formula (VII) wherein V is P where P is a protecting group and Y is a C1-6 primary or secondary alkoxy with a deprotecting agent. 17. A process for the preparation of compounds of formula (VII) as shown in claim 16 from compounds of formula (VIII) wherein D is Cl or Br and P is a protecting group, (a) wherein for compounds of compound (VII) wherein Y is OH and V is OH, comprising reacting a compound of formula (VIII) with a hydrolising agent and optionally a further deprotecting agent where P is not deprotected by the hydrolysing agent; (b) wherein for compounds of formula (VII) wherein Y is NH2 and V is OH, comprising reacting a compound of formula (VIII) with an ammoniating agent to form an intermediate compound of formula (VII) wherein Y is NH2 and V is P (a protecting group) and the reacting said intermediate (VII) with a deprotecting agent; and (c) wherein for compounds of compound (VII) wherein Y is OR which is a C1-6 alkoxy and V is P, comprising reacting a compound of formula (VIII) in the presence of -OR; 18. A process for the preparation of a compound of formula (VIII) according to claim 17 comprising reaction of compounds of formula (IX) in the presence of an amine NH(R3)(R4) wherein R3 and R4 are as defined in claim 1, wherein D and P are as defined in claim 17. 19. A process for the preparation of a compound of formula (IX) according to claim 18 comprising reacting a compound of formula (X) with a chlorinating or brominating agent wherein P is as defined in claim 17. 20. A process according to claim 19 for preparation of a compound of formula (X) comprising reacting a compound of formula (XI) in the presence of an agent which will form a protecting group (P) on the carboxylic acid 21. A process according to claim 20 for the preparation of a compound of formula (XI) comprising reacting 2-hydroxynicotinic acid or a salt thereof in the presence of SO3 in a solvent. 22. A process according to claim 21 wherein the SO3 is in an aprotic solvent, a mineral acid, or a liquid carboxylic acid. 23. A process according to any one of claims 16 to 22 wherein the compounds of formula (VI), (VII) and (VIII) are (VIA), (VIIA) and (VIIIA) respectively wherein X is a C1-6 alkoxy, D and P are as defined in claims 16 and 17, and the compounds (VIA) and (VIIA) are formed according to claim 16(e) and claim 17(c) respectively and compound (VIIIA) is formed according to claim 18 by reacting compound (IX) with N-ethyl piperazine or a salt thereof. 24. A process according to claim 23 wherein X is OEt and the compound (VIA) is formed by reaction of compound (VIIA) with a deprotecting agent, and compound (VIIA) is formed by reaction of c