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US 8,557,991 B2Granted
Process for preparing enantiomerically pure indolopyridines
Assignee4Sc AG
InventorsBernd Muller, Helmut Schlemper
Life of this patent
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Abstract
Disclosed is a novel process for the preparation of pharmacologically interesting indolopyridine derivatives containing tetracyclic tetrahydro-11-carboline-hydantoines linked to a basic side chain and the corresponding salts, which can be used as Eg5 inhibitors, with very high overall chemical yield and enantiomeric purity.
Claims20
A process for preparing an enantiomerically pure (stereomerically pure) compound of formula
- in which
- R1 is 2-7C-alkyl substituted by —N(R111)R112,
- R111 is 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkinyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, 1N-(1-4C-alkyl)-pyrazolyl, 1N—(H)-pyrazolyl, isoxazolyl, or completely or partially fluorine-substituted 1-4C-alkyl,
- R112 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, or 3-7C-cycloalkyl-1-4C-alkyl,
- or
- R111 and R112 together and with inclusion of the nitrogen atom, to which they are bonded, form a ring Het,
- Het is piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, S-oxo-thiomorpholin-4-yl, S,S-dioxo-thiomorpholin-4-yl, pyrrolidin-1-yl, azetidin-1-yl, homopiperidin-1-yl, 4N—(R113)-piperazin-1-yl, 4N—(R113)-homopiperazin-1-yl, 2,5-dihydro-pyrrol-1-yl, 1,2,3,6-tetra-hydropyridin-1-yl, pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, triazol-1-yl, or tetrazol-1-yl, wherein said Het may be optionally substituted by one or two substituents independently selected from fluorine and 1-4C-alkyl,
- R113 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkylcarbonyl, amidino, or completely or partially fluorine-substituted 1-4C-alkyl,
- R2 is hydrogen, 1-4C-alkyl, halogen trifluoromethyl, 1-4C-alkoxy or hydroxyl,
- R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl or 1-4C-alkoxy,
- R4 is 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,
- R5 is 1-4C-alkyl, halogen, 1-4C-alkoxy, trifluoromethyl, cyano, hydroxyl, phenyl-1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, hydroxy-2-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy, and
- R6 is hydrogen, 1-4C-alkyl or halogen,
- or a salt thereof
- which process comprises
- c) optionally protecting the compound of formula IIa
- wherein R, R2, R3, R4, R5, and R6 are as defined above,
- at the 3-hydroxyphenyl moiety to obtain a compound of formula IIa*,
- wherein R, R2, R3, R4, R5, and R6 are as defined above and Z is a protective group,
- d) heterocyclizing the compound of formula IIa* or the compound of formula IIa by in situ prepared isocyanate R1-N═C═O by adding a reaction mixture of carbonyldiimidazole and an amine R1NH2 in a solvent selected from the group consisting of toluene, xylene, a mixture of toluene and acetonitrile and a mixture of toluene and benzonitrile to obtain a compound of formula Ia,
- wherein R1-R6 and Z are as defined above,
- or to obtain the compound of formula I, and
- e) deprotecting the 3-hydroxyphenyl moiety of the compound of formula Ia to obtain the compound of formula I, provided that the compound of formula IIa have been protected at the 3-hydroxyphenyl moiety in c).
20 more elements
A process for preparing an enantiomerically pure (stereomerically pure) compound of formula Ia
- wherein
- R1 is 2-7C-alkyl substituted by —N(R111)R112,
- R111 is 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkinyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, 1N-(1-4C-alkyl)-pyrazolyl, 1N—(H)-pyrazolyl, isoxazolyl, or completely or partially fluorine-substituted 1-4C-alkyl,
- R112 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, or 3-7C-cycloalkyl-1-4C-alkyl,
- or
- R111 and R112 together and with inclusion of the nitrogen atom, to which they are bonded, form a ring Het,
- Het is piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, S-oxo-thiomorpholin-4-yl, S,S-dioxo-thiomorpholin-4-yl, pyrrolidin-1-yl, azetidin-1-yl, homopiperidin-1-yl, 4N—(R113)-piperazin-1-yl, 4N—(R113)-homopiperazin-1-yl, 2,5-dihydro-pyrrol-1-yl, 1,2,3,6-tetra-hydropyridin-1-yl, pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, triazol-1-yl, or tetrazol-1-yl, wherein said Het may be optionally substituted by one or two substituents independently selected from fluorine and 1-4C-alkyl,
- R113 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkylcarbonyl, amidino, or completely or partially fluorine-substituted 1-4C-alkyl,
- R2 is hydrogen, 1-4C-alkyl, halogen trifluoromethyl, 1-4C-alkoxy or hydroxyl,
- R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl or 1-4C-alkoxy,
- R4 is 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,
- R5 is 1-4C-alkyl, halogen, 1-4C-alkoxy, trifluoromethyl, cyano, hydroxyl, phenyl-1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, hydroxy-2-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,
- R6 is hydrogen, 1-4C-alkyl or halogen, and
- Z is a protective group,
- which process comprises
- c) optionally protecting the compound of formula IIa
- wherein R, R2, R3, R4, R5, and R6 are as defined above,
- at the 3-hydroxyphenyl moiety to obtain a compound of formula IIa*,
- wherein R, R2, R3, R4, R5, and R6 are as defined above and Z is a protective group, and
- d) heterocyclizing the compound of formula IIa* or the compound of formula IIa by in situ prepared isocyanate R1-N═C═O by adding a reaction mixture of carbonyldiimidazole and an amine R1NH2 in a solvent selected from the group consisting of toluene, xylene, a mixture of toluene and acetonitrile and a mixture of toluene and benzonitrile to obtain a compound of formula Ia.
17 more elements
Dependencies are inferred from the claim text.