To 2,4-Cl2C6H3NH2 (81 g.) and 81 g. Na2CO3 in 500 cc. acetone was added slowly 52.3 g. MeCH:CHCOCl at 15-25°, the mixture kept 15 min. at 30-5°, poured into 1000 cc. cold H2O, acidified to Congo red with HCl, and the precipitate washed with H2O until neutral and dried at 40-50° in vacuo yielding 105 g. croton-2,4-dichloroanilide (I), m. 154-5° (from EtOH).The following RCOCH:CR'R'' were similarly prepared (R, R', R'' m.p., % yield, and recrystallization solvent given): Ph, H, Et, 69°, 60, C6H6-petr. ether; PhNH, H, Pr, 102-3°, 95, EtOH-H2O; PhNH, Me, Me, 129-30°, 66, EtOH; p-ClC6H4NH, H, Me, 171-2°, 84, EtOH; o-ClC6H4NH, H, Me, 107-8°, 87, EtOH; m-ClC6H4NH, H, Me, 94-5°, 73, C6H6; 2,4-Cl2C6H3NH, Pr, 98°, 89, MeOH; 2,5-Cl2C6H3NH, H, Me, 153°, 35, EtOH; 2,6-Cl2C6H3NH, H, Me, 199°, 36, acetone; p-BrC6H4NH, H, Me, 168°, 83, EtOH-H2O; p-EtOC6H4NH, H, Pr, 95°, 72, EtOH-H2O; cyclohexylamino, H, Me, 133-4°, 84, EtOH; piperidino, H, Me, -, b0.6 93°, 61, -; 2-chloro-4-quinolylamino, H, Me, 171-3°, 38, EtOH.I (100 g.) and 17 cc. piperidine (II) refluxed 2 hrs., the excess II distilled in vacuo, the residue poured into 500 cc. H2O and 40 cc. 10N HCl, the mixture filtered, 50 cc. "concentrated NaOH" added, and the 2,4-Cl2C6H3NHCOCH2CHMeR (R = piperidino) (III) precipitate dried in vacuo at 40-50° yielded 120 g. m. 85-7° (from petr. ether).III (120 g.) in 500 cc. EtOAc and an equivalent amount 8N alc. HCl cooled at 0° gave a good yield of III.HCl (IV), m. 165-6°.MeCHRCH2CONHPh.HCl (R = 2-methylpiperidino) (V), m. 202° (from MeOH-H2O) was similarly prepared in 35% yield.The following RCOCH2CR'R''R''' were similarly prepared (R, R', R'', R''', m.p., % yield, and recrystallization solvent given): PhNH, H, Pr, piperidino, 106-7° 26, EtOH-H2O; PhNH, Me, Me, piperidino, 108-9°, 13, EtOH-H2O; p-ClC6H4NH, H, Me, piperidino, 105-7°, 71, EtOH; o-ClC6H4NH, H, Me, piperidino, 85-6°, 71, EtOH; m-ClC5H4NH, H, Me, piperidino, 115-16°, 49, acetone; 2,4-Cl2C6H3NH, H, Me, Et2N, 70-2°, 50, petr. ether; 2,5-Cl2C6H3NH, H, Me, Et2N, 70-2°, 50, petr. ether; 2,5-Cl2C6H3NH, H, Me, piperidino, 111-12°, 46, acetone; 2,6-Cl2C6H3NH, H, Me, piperidino, 92° 57, Et2O-petr. ether; p-BrC6H4NH, H,Me, piperidino, 122°, 80, EtOH-H2O; cyclohexylamino, H, Me, piperidino, 86-8°, 63, petr. ether; 2-piperidino-4-quinolylamino, H, Me, piperidino, 149-50°, 59, acetone.The HCl salts of the following oily RCOCH2CR'R''R''' were prepared (R, R', R'', R''', m.p. of the salt, % yield, and recrystallization solvent given): PhNH, H,Me, piperidino, 212-13°, 40, EtOH-EtOAc; PhNH, H, Et, piperidino, 185°, 67, acetone-EtOAc; PhNH, H, Me, morpholino, 127°, 84, EtOH-Et2O; p-ClC6H4NH, H, Me, Et2N, 133-7°, 23, EtOH-EtOAc; p-ClC6H4NH, H, Me, 2-methylpiperidino, 211°, 9, EtOH-Et2O; 2,4-Cl2C6H3NH, H, Me, morpholino, 169°, 73, EtOH-Et2O; 2,4-ClC6H3NH, H, Pr, piperidino, 166°, 34, MeOH-Et2O; p-BrC6H4NH, H, Me, Et2N, 147°, 19, EtOH-Et2O; p-EtOC6H4NH, H, Pr, piperidino, 166°, 13, EtOH-Et2O; piperidino, H, Me, piperidino, 210-15°, 63, EtOH-EtOAc.Ph2NH (17 g.) 11 g. MeCH:CHCOCl, and 70 cc. Et2O kept 4 hrs. at 100-20° in an autoclave gave 18.2 g. MeCHClCH2CONPh2 (VI), m. 127-8° (from EtOH).2,4-Cl2C6H3COCH2Cl (VII), m. 102° (80% yield) was similarly preparedVI (12 g.) in 50 cc. II refluxed overnight, the excess of II distilled in vacuo, the residue poured into dilute HCl, the mixture filtered, the solution made alk. and extracted with ether, and the extract washed with H2O, dried, and treated with 3 cc. 8N HCl gave 7.5 g. 3-piperidino analog, m. 187-8° (from EtOH-Et2O), of VI.VII (12 g.), 50 cc. EtOH, and 10 g. 2-methylpiperidine refluxed overnight, poured into H2O, the oil taken up in ether, and the solution washed with H2O, dried, and treated with alc. HCl to give 15 g. 2,4-Cl2C6H8NHCOCH2R.HCl (R = 2-methylpiperidino), m. 185° (from MeOH). p-ClC6H4NHCOCH2Z (66%), m. 213° (from MeOH-Et2O), and PhCOCH2Z (88%) (Z = 2-methylpiperidino), m. 183° (from MeOH-Et2O), were similarly prepared IV and V showed relatively low toxicity and very high anesthetic activity, while a number of the other anilides were also very active, but had undesirable properties such as tissue irritation.
