Ethyl 5-chloroquinoline-6-carboxylate synthesis

Yield:-

Reaction Conditions:

Stage #1: 4-amino-2-chlorobenzoic acid;glycerolwith sulfuric acid;sodium 3-nitrobenzenesulfonate in water at 100 - 140; for 4 h;
Stage #2: ethanol in water at 60;
Stage #3: with ammonia in water;

Steps:

8.a

Ethyl 7-chloro-6-quinolinecarboxylate and ethyl 5-chloro-6-quinolinecarboxylate.A solution of 4-amino-2-chlorobenzoic acid (17.1 g; 0.1 mol.), glycerol (41.4 g; 0.45 mol.), sodium 3-nitrobenzenesulfonate (45.0 g; 0.2 mol.) and 75% aq. sulfuric acid (250 mL) was stirred and heated at 100 ⁰C for 3 h then at 140⁰C for 1 h. The mixture was allowed to cool to 60 ° then ethanol was added and the EPO solution stirred and heated at 60 ° overnight. The solution was evaporated and the residue poured into a ice-water mixture then basified with sat. aq. ammonium hydroxide. The mixture was then diluted with ethyl acetate (1 L), filtered to remove charred material, then the organic layer separated, dried and evaporated. The residue was purified by chromatography (silica gel, 40% ethyl acetate in hexanes) to give a mixture of the two isomeric title compounds as an orange oil (12.6 g; 53%). Ethyl δ-chloro-δ-quinolinecarboxylate: 1 H NMR (400 MHz, DMSO-CZ₆) D 1.37 (t, J=7.07 Hz, 3 H) 4.42 (q, J=7.24 Hz, 2 H) 7.79 (dd, J=8.59, 4.29 Hz, 1 H) 8.04 (d, J=8.59 Hz, 1 H) 8.11 (d, J=8.84 Hz, 1 H) 8.74 (m, 1 H) 9.09 (dd, J=4.29, 1.52 Hz, 1 H). Ethyl 7-chloro-6-quinolinecarboxylate: 1 HNMR (400 MHz, DMSOd₆) δ ppm 1.37 (t, J=7.20 Hz, 3 H) 4.40 (q, J=7.07 Hz, 2 H) 7.66 (dd, J=8.34, 4.29 Hz, 1 H) 8.19 (s, 1 H) 8.53 - 8.58 (m, 2 H) 9.04 (dd, J=4.17, 1.64 Hz, 1 H).

References:

WO2006/132739,2006,A2 Location in patent:Page/Page column 37-38