Patent ID: 6593471
Filing Date: 2003-07-15
Classification: C07D

Abstract:
A process of making a compound of the formula(A) wherein:W is CR3 or N, wherein R3 is chosen from hydrogen, C1-5alkyl, C1-5alkoxy, and arylC0-5alkyl; Ar is chosen from: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl and indolyl each being optionally substituted by one or more R1 or R2; Y is chosen from a bond, C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; wherein when Y is the carbon chain, the terminal atom of Y is carbon which is covalently attached to the heterocycle possessing W and; Z is chosen from: aryl, heteroaryl chosen from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl and pyranyl, heterocycle chosen from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, C1-3acyl, oxo, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, halogen or mono- or di-(C1-3 alkyl)amino; or Z is optionally substituted with one to three amino or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)mâ€”or arylC0-3alkyl-S(O)mâ€” each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy; or Z is nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl or C1-3alkoxyC1-3alkyl, C1-6alkyl branched or unbranched, C1-6alkoxy, nitrileC1-4alkyl, C1-6 alkyl-S(O)m, aryl chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each aryl being optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m or nitrile; R1 and R2 are independently chosen from: a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1-3 alkyl-S(O)m optionally partially or fully halogenated or phenylsulfonyl; m=0, 1 or 2; said process comprising: i) in a one pot process, reacting a compound of the formula(C) with a Grignard reagent Râ€”Mgâ€”Xb followed by the addition of an E-Y-Z compound wherein the E-Y moiety of E-Y-Z is an electrophilic derivative of Y as defined above, said reaction taking place in a suitable aprotic solvent at âˆ’78Â° C. to RT, for a reaction time of Â½ hour to 2 hours, and isolating the compound of the formula (D); â€ƒwherein: Xa is chosen from Br and Cl, and attached to the ring at the 4 or 5 position; Xb is chosen from Br, Cl and I; Xc is chosen from I and Br; wherein Xa and Xc are not the same R is chosen from aryl, C1-6alkyl and C5-7cycloalkyl; ii) reacting the compound of the formula(D) from step a) with an aryl boronic acid of the formula (E) in the presence of a catalyst chosen from nickel, palladium and a combination of a palladium source and an appropriate ligand, in a suitable solvent at 0Â° C. to 150Â° C., for about 1 to 24 hours: â€ƒwherein the group H2Nâ€”Arâ€” in the formula(A) is attached to the ring via the 4 or 5 position and wherein P in the formula(E) is an amino protecting group, and subsequently removing said protecting group under suitable conditions to produce a compound of the formula(A).