化药合成,抗肿瘤新药(16)

treated in a manner similar to that described for5a to af-ford white crystals7a(2.0g,70%),mp235–238°C(from ethyl ether);FAB-MS m/e283(M+1);UV k max358,343, 305,272,236,219nm;IR(KBr):3402,2956,2869,1726, 1625,1333,1238cmÀ1;1H NMR(500MHz,CDCl3): 8.94(1H,s,H-4),8.83(1H,s,H-1),8.18–8.20(1H,d, J=7.5Hz,H-8),7.63–7.66(1H,m,H-5),7.48–7.50 (1H,d,J=8.5Hz,H-6),7.34–7.37(1H,m,H-7),4.46–4.49(2H,m,OC H2CH2CH2CH3),3.97(3H,s,NC H3), 1.84–1.90(2H,m,J=7.0Hz,OCH2C H2CH2CH3), 1.48–1.56(2H,m,OCH2CH2C H2CH3),0.99–1.02(3H, m,OCH2CH2CH2C H3).Anal.Calcd for C17H18N2O2: C,72.34;H,6.38;N,9.93.Found:C,72.25;H,6.58; N,9.85.

4.1.23.Butyl9-ethyl-b-carboline-3-carboxylate(7b).A mixture of6(2.4g,10mmol)and anhydrous DMF (60mL)was stirred at rt for10min,then60%NaH (0.6g,15mmol)and iodoethane(2.5mL,30mmol)were ter the mixture was treated in a manner simi-lar to that described for5a to a?ord white crystals6b (2.0g,65%),mp76–77°C(from ethyl ether);FAB-MS m/e297(M+1);UV k max360,345,306,273,240, 220nm;IR(KBr):3053,2963,2401,1999,1722,1627, 1337,1269cmÀ1;1H NMR(500MHz,CDCl3):9.02 (1H,s,H-4),8.86(1H,s,H-1),8.20–8.22(1H,d, J=8Hz,H-8),7.63–7.67(1H,m,H-5),7.51–7.53(1H, d,J=7.5Hz,H-6),7.35–7.38(1H,m,H-7),4.47–4.51 (4H,m,OC H2CH2CH2CH3,NC H2CH3), 1.84–1.90 (2H,m,OCH2C H2CH2CH3),1.49–1.56(2H,m,OCH2-CH2C H2CH3),0.99–1.02(3H,m,OCH2CH2CH2C H3). Anal.Calcd for C18H20N2O2:C,72.97;H, 6.76;N, 9.46.Found:C,72.83;H,6.97;N,9.39.

4.1.24.Butyl9-butyl-b-carboline-3-carboxylate(7c).A mixture of6(2.4g,10mmol)and anhydrous DMF (60mL)was stirred at rt for10min,then60%NaH (0.6g,15mmol)and n-butyl iodide(6mL,50mmol)were added and re?uxed ter the mixture was trea-ted in a manner similar to that described for5a to a?ord white crystals6c(2.2g,74%),mp94–95°C(from petro-leum ether–ethyl ether1:2);FAB-MS m/e325(M+1); UV k max359,344,307,274,238,221nm;IR(KBr): 3061,2956,2866,1728,1624,1358,1247cmÀ1;1H NMR(500MHz,CDCl3):8.95(1H,s,H-4),8.85(1H, s,H-1),8.19–8.20(1H,d,J=7Hz,H-8),7.60–7.64 (1H,m,H-5),7.49–7.50(1H,d,J=8.5Hz,H-6),7.32–7.36(1H,m,H-7),4.47–4.49(2H,m,OC H2CH2CH2-CH3), 4.37–4.42(2H,m,NC H2CH2CH2CH3), 1.84–1.92(4H,m,OCH2C H2CH2CH3,NCH2C H2CH2CH3), 1.49–1.56(2H,m,OCH2CH2C H2CH3),1.34–1.40(2H, m,NCH2CH2C H2CH3),0.99–1.02(3H,m,OCH2CH2-CH2C H3),0.92–0.95(3H,m,NCH2CH2CH2C H3). Anal.Calcd for C20H24N2O2:C,74.07;H,7.41;N, 8.64.Found:C,73.88;H,7.65;N,8.57.

4.1.2

5.Butyl9-benzyl-b-carboline-3-carboxylate(7d).A mixture of5(2.4g,10mmol)and anhydrous DMF (60mL)was stirred at rt for10min,then60%NaH (0.6g,15mmol)and benzyl bromide(5mL,40mmol) were added and re?uxed ter the mixture was treated in a manner similar to that described for5a to a?ord white crystals7d(2.4g,67%),mp105–106°C (from ethyl ether);FAB-MS m/e359(M+1);UV k max 356,342,305,273,235,205nm;IR(KBr):3051,2959, 2930,2869,1700,1620,1362,1246cmÀ1;1H NMR (500MHz,CDCl3):8.89(1H,s,H-4),8.85(1H,s,H-1),8.19–8.20(1H,d,J=8Hz,H-8),7.56–7.59(1H,m, H-5),7.45–7.46(1H,d,J=8.5Hz,H-6),7.33–7.36(1H, m,H-7),7.22–7.26(3H,m,ArH),7.11–7.13(2H,m, ArH), 5.56(2H,s,C H2Ar), 4.45–4.48(2H,m, OC H2CH2CH2CH3), 1.82–1.88(2H,m,OCH2-

C H2CH2CH3),1.47–1.54(2H,m,OCH2CH2C H2CH3),

0.98–1.01(3H,m,OCH2CH2CH2C H3).Anal.Calcd for C23H22N2O2:C,77.09;H,6.15;N,7.82.Found:C, 76.89;H,6.35;N,7.75.

4.1.26.General procedure for the preparation of b-carb-oline-3-carboxylic acids8a–e.A mixture of the corre-sponding b-carboline-3-carboxylate(6a–f,10mmol), NaOH(50mmol),ethanol(50mL),and H2O(100mL) was re?uxed for1h,and the ethanol was removed on the rotary evaporator.The mixture was neutralized (pH5)with5M HCl and cooled.The precipitate was collected,washed well with H2O,and dried in vacuo.

4.1.27.9-Methyl-b-carboline-3-carboxylic acid(8a).Yel-low solid was obtained(2.32g,99%).Mp267–269°C; FAB-MS m/e227(M+1);UV k max384,360,273,241, 217nm;IR(KBr):3250–2100,1716,1630,1405, 1200cmÀ1;1H NMR(500MHz,DMSO-d6)d12.15 (1H,s,COO H),9.19(1H,s,H-4),9.12(1H,s,H-1), 8.42–8.44(1H,d,J=8.0Hz,H-8),7.81–7.88(2H,m,H-5,H-6),7.50–7.53(1H,m,H-7),4.16(1H,s,NC H3). Anal.Calcd for C13H10N2O2:C,69.03;H, 4.42;N, 12.39.Found:C,68.96;H,4.57;N,12.31.

4.1.28.9-Ethyl-b-carboline-3-carboxylic acid(8b).Yel-low solid was obtained(2.41g,98%).Mp201–202°C; FAB-MS m/e241(M+1);UV k max387,359,273,239, 220nm;IR(KBr):3250–2250,1713,1630,1407,1336, 1198cmÀ1;1H NMR(500MHz,DMSO-d6)d12.10 (1H,s,COO H),9.16(1H,s,H-4),8.97(1H,s,H-1), 8.31–8.33(1H,d,J=8.0Hz,H-8),7.75–7.81(2H,m,H-5,H-6),7.43–7.46(1H,m,H-7), 4.63–4.67(2H,s, NC H2CH3),1.46–1.52(3H,s,NCH2C H3).Anal.Calcd for C14H12N2O2:C,70.00;H,