Patent NZ-503307-A (NZ)
Title: Method for the synthesis of quinoline derivatives
Inventor: SISKO JOSEPH
IPC: A61P11/06
Filed: 1998-09-17
Abstract: A method for preparing a compound of formula (I) wherein: Ar is an optionally substituted phenyl group, or a naphthyl or C5-7 cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 hetero-atoms in the or each ring selected from S, O, N; R is linear or branched C1-8 alkyl, C3-7 cycloalkyl, C4-7 cycloalkylalkyl, an optionally substituted phenyl group or a phenyl C1-6 alkyl group, an optionally substituted 5-membered heteroaromatic ring comprising up to 4 heteroatom selected from 0 and N, hydroxy C1-6 alkyl, di C1-6 alkylaminoalkyl, C1-6 acylaminoalkyl, C1-6 alkoxyalkyl, C1-6 alkylcarbonyl, carboxy, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl C1-6 alkyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di C1-6 alkylaminocarbonyl; or is a group -(CH2)p- when cyclized onto Ar, where p is 2 or 3; R1 and R2, which may be the same or different, are independently H or C1-6 linear or branched alkyl, or together form a -(CH2)n- group in which n represents 3, 4, or 5; or R1 together with R forms a group -(CH2)q-, in which q is 2, 3,4 or 5; R3 and R4, which may be the same or different, are independently H, C1-6 linear or branched alkyl, C1-6 alkenyl, aryl, C1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, trifluoromethyl, amino, mono and di-C1-6 alkylamino, -O(CH2)rNT2, in which r is 2, 3, or 4 and T is C1-6 alkyl or both T together with the N from a heterocyclic group (A) or (B) in which u is 0, 1 or 2; -O(CH2)s-OW2 in which s is 2, 3, or 4 and W is C1-6 alkyl; hydroxyalkyl, mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with up to 4 R3 substituents being present in the quinoline nucleus; or R4 is a group -(CH2)t- when cyclized onto R5 as aryl, in which t is 1, 2, or 3; and R5 is branched or linear C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkylalkyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen, C1-6 alkoxy or C1-6 alkyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N; comprising: 1) adding a compound of formula (III) to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula (II) to form a second reaction mixture, and heating the second reaction mixture to form a compound of formula (IV); 2) isolating the compound of formula (IV) and then reacting the compound of formula (IV), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture, and adding carbonyl-activating agent to form a fourth reaction mixture; 3) adding a compound of formula (V) to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof, wherein Ar, R, R1, R2, R3, R4, and R5 as used in a compound of formulae (II) through (VI) are as defined for a compound of formula (I).