Method for the synthesis of quinoline derivatives

A method for preparing (−)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide comprising:

• 1) reacting 3-hydroxy-2-phenylquinoline-4-carboxylic acid, in a suitable solvent, with triethyl amine to form a first reaction mixture, cooling the first reaction mixture, and adding thionyl chloride to form a second ion mixture comprising 6,14,22,30Tetraphenyl-[1,5,9,13]tetraoxahexadecino[2,3-c:6,7-c′:10,11-c″:14,15-c′″]tetraquinoline-8,16,24,32-tetrone and Ethyl 3-acetoxy-2-phenylquinoline-4-carboxylate;
• 2) adding (S)-1-phenyl propylamine to the second reaction mixture to form a third reaction mixture comprising (−)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide and (S)-2-Phenyl-4-[[(1-phenylpropyl)amino]carbonyl]-3-quinolinyl-3-hydroxy-2-phenyl-4-quinoline-carboxylate;
• 3) heating the third reaction mixture;
• and
• 4) optionally converting (−)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide to a pharmaceutically acceptable salt.

A compound of formula (VII):

• 42
• 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 four hetero-atoms in the or each ring selected from S, O, N;
• and
• R3 is hydrogen, 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)r—NT2, in which r is 2, 3, or 4 and T is C1-6 alkyl or it forms a heterocyclic group
• 43
• in which V and V1 are hydrogen and 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 four R3 substituents being present in the quinoline nucleus;
• and
• R′4 is OH or OAc.

A method for preparing a compound of formula (Ia):

• 46
• 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 four 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 five-membered heteroaromatic ring comprising up to four heteroatom selected from O and N, hydroxy C1-6 alkyl, di C1-6 alkylaminoalkyl, C1-6 acylaminoalkyl, 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;
• R2 is hydrogen or C1-6 linear or branched alkyl;
• and
• R3 and R4, which may be the same or different, are independently hydrogen, 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 it forms a heterocyclic group
• 47
• in which V and V1 are hydrogen and u is 0, 1 or 2;
• —O(CH2)s-OW2 in which s is 2, 3, or 4 and W is C1-4 alkyl;
• hydroxyalkyl, mono- or di-alkylaminoalkyl acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino;
• with up to four R3 substituents being present in the quinoline nucleus;
• comprising:
• 1) adding a compound of formula (III):
• 48
• to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula (IIa):
• 49
• to form a second reaction mixture, and heating the second reaction mixture to form a compound of formula (IVa):
• 50
• 2) isolating the compound of formula (IVa) and then reacting the compound of formula (IVa), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture, and adding a carbonyl-activating agent to form a fourth reaction mixture;
• 3) adding a compound of formula (Va):
• 51
• to the fourth reaction mixture to form a fifth reaction mixture;
• 4) beating 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 (IIa), and (IVa) through (VIa) are as defined for a compound of formula (Ia).