CN102391285A - 一种苯并[f]噻吩并[3,2-b]喹啉衍生物的合成方法 - Google Patents
一种苯并[f]噻吩并[3,2-b]喹啉衍生物的合成方法 Download PDFInfo
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Abstract
本发明涉及苯并[f]噻吩并[3,2-b]喹啉衍生物的合成,具体是涉及11-芳基-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物衍生物的合成,是以芳醛、乙萘胺和3-氧代环丁砜为原料,在无溶剂条件下经三组分一锅法一步反应生成。合成工艺路线简捷,条件温和,总收率达到70%以上。
Description
技术领域
本发明属于有机合成技术领域,涉及苯并[f]噻吩并[3,2-b]喹啉衍生物的合成方法。
背景技术
噻吩并吡啶衍生物能抗疟疾(Goerlitzer,K.;Meyer,H.;Walter,R.D.;Jomaa,H.;Wiesner,J.Pharmazie 2004,59,506-512.),也能用作钾离子通道开放剂(Lynch,J.J.;Brune,M.E.;Lubbers,N.L.;Coghlan,M.J.;Cox,B.F.;Polakowski,J.S.;King,L.L.;Sullivan,J.P.;Brioni,J.D.Life Sciences 2003,72,1931-1941;Brune,M.E.;Fey,T.A.;Brioni,J.D.;Sullivan,J.P.;Williams,M.;Carroll,W.A.;Coghlan,M.J.;Gopalakrishnan,M.J.Pharmacol.Exp.Therap.2002,303,387-394.c)Fryer,R.M.;Preusser,L.C.;Calzadilla,S.V.;Hu,Y.H.;Xu,H.Y.;Marsh,K.C.;Cox,B.F.;Lin,C.T.;Gopalakrishnan,M.;Reinhart,G.A.J.Cardiov.Pharm.2004,44,137-147.)。因此此类化合物的合成及生物活性研究已经成为化学工作者和药物科学工作者关注的一个热点。文献已经报道了两步法合成这类化合物,但产率低,反应复杂(Kamel,M.M.;El-Deen,E.M.M.;Abdou,W.A.M.Bullet.Fac.Pharm.2003,41,197-206.),亟待改进。
发明内容
本发明的目的在于提供一种合成苯并[f]噻吩并[3,2-b]喹啉衍生物的方法:芳醛、乙萘胺和3-氧代环丁砜为原料,按摩尔比1∶1∶1在无溶剂条件下经三组分一锅法一步生成(如附图所示)。
本发明通过下述方法实现的:在研钵中加入1毫摩尔的芳醛,1毫摩尔的乙萘胺和1毫摩尔的3-氧代环丁砜,在85℃反应9-13小时,即得到相应的苯并[f]噻吩并[3,2-b]喹啉衍生物。
所述的芳醛为苯甲醛或带有氟、氯等卤素原子、甲氧基或硝基的苯甲醛,其所带的取代基的数量不超过2,其取代基的位置在醛基的邻、间、对位。
具体实施方式
下面结合附图1及实施例1对本发明作进一步描述。
实施例1:
11-苯基-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物的制备:在研钵中加入1毫摩尔的苯甲醛(0.11g),1毫摩尔的乙萘胺(0.14g)和1毫摩尔的3-氧代环丁砜(0.13g),在85℃下反应11小时(TLC跟踪监测)。反应结束后,反应物用乙醇及N,N-二甲基甲酰胺混合液重结晶即得到相应的11-苯基-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(0.30g,产率86%)。本品为无色粉末,熔点:250-252℃。
实施例1-13的反应原料,反应条件及产率见表1。
表1实施例1-21的反应原料,反应条件及产率
由表可知,本发明的方法原料易得,操作简单安全,反应条件温和、收率高,后处理简单,原子经济性高。
所得化合物的的表征数据如下。
11-苯基-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4a)
m.p.250-252℃;IR(KBr,ν,cm-1):3281,3017,1662,1533,1506,1473,1397,1264,1234,1125,1099,1082,810,744,699,594;1H NMR(CDCl3,400MHz)(δ,ppm):9.81(s,1H,NH),7.89-7.80(m,3H,ArH),7.38(t,J=7.2Hz,1H,ArH),7.32-7.23(m,4H,ArH),7.18(t,J=7.2Hz,2H,ArH),7.07(t,J=7.2Hz,1H,ArH),5.81(s,1H,CH),3.44-3.34(m,2H,CH2),3.11-3.03(m,1H,CH2),2.95-2.89(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+ C21H17NO2SNa:370.0872;found:370.0865.
11-(2-氟苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4b)
m.p.273-275℃;IR(KBr,ν,cm-1):3295,1667,1624,1587,1532,1506,1486,1456,1403,1374,1282, 1262,1233,1169,1136,1106,818,746,616;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.88(s,1H,NH),7.85-7.82(m,2H,ArH),7.72(d,J=8.8Hz,1H,ArH),7.43(t,J=7.6Hz,1H,ArH),7.34-7.26(m,2H,ArH),7.16-7.03(m,3H,ArH),6.98(t,J=7.2Hz,1H,ArH),6.03(s,1H,CH),3.41-3.29(m,2H,CH2),3.12-3.03(m,1H,CH2),2.98-2.91(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+C21H16FNO2SNa:388.0778;found:388.0774.
11-(3-氟苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4c)
m.p.254-256℃;IR(KBr,ν,cm-1):3299,1665,1614,1589,1559,1531,1506,1487,1473,1448,1401,1281,1259,1236,1136,1100,1085,816,747,687;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.87(s,1H,NH),7.91(d,J=8.4Hz,1H,ArH),7.83(t,J=8.4Hz,2H,ArH),7.40(t,J=7.2Hz,1H,ArH),7.33-7.20(m,3H,ArH),7.06(d,J=7.6Hz,2H,ArH),6.93-6.89(m,1H,ArH),5.88(s,1H,CH),3.44-3.31(m,2H,CH2),3.12-3.05(m,1H,CH2),2.97-2.89(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+C21H16FNO2SNa:388.0783;found:388.0774.
11-(4-氟苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4d)
m.p.260-262℃;IR(KBr,ν,cm-1):3353,1667,1624,1602,1586,1528,1471,1397,1271,1246,1216,1158,1128,1096,843,813,744;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.83(s,1H,NH),7.89-7.80(m,3H,ArH),7.38(t,J=7.2Hz,1H,ArH),7.33-7.25(m,4H,ArH),7.01(t,J=8.8Hz,2H,ArH),5.86(s,1H,CH),3.41-3.31(m,2H,CH2),3.11-3.04(m,1H,CH2),2.97-2.88(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M-H]-C21H15FNO2S:364.0807;found:364.0810.
11-(3-氯苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4e)
m.p.262-264℃;IR(KBr,ν,cm-1):3280,1666,1584,1532,1504,1470,1432,1399,1273,1238,1185,1125,1106,887,814,780,750,687,671,647,622,510;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.86(s,1H,NH),7.91-7.81(m,3H,ArH),7.40(t,J=8.0Hz,1H,ArH),7.34-7.27(m,3H,ArH),7.23-7.14(m,3H,ArH),5.89(s,1H,CH),3.45-3.32(m,2H,CH2),3.14-3.06(m,1H,CH2),2.98-2.88(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+C21H16ClNO2SNa:404.0482;found:404.0440.
11-(4-氯苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4f)
m.p.260-262℃;IR(KBr,ν,cm-1):3353,1667,1585,1528,1488,1470,1398,1269,1245,1201,1132,1102,1016,878,830,809,740,660,598,501;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.84(s,1H,NH),7.87-7.81(m,3H,ArH),7.38(t,J=7.6Hz,1H,ArH),7.32(d,J=7.6Hz,1H,ArH),7.29(s,1H,ArH),7.26(s,4H,ArH),5.86(s,1H,CH),3.41-3.30(m,2H,CH2),3.11-3.03(m,1H,CH2),2.97-2.89(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+C21H16ClNO2SNa:404.0488;found:404.0455.
11-(3,4-二氯苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4g)
m.p.261-263℃;IR(KBr,ν,cm-1):3280,1665,1625,1588,1531,1506,1469,1400,1256,1134,1103, 1086,1030,886,816,746,671,623,608,566,515;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.90(s,1H,NH),7.92-7.82(m,3H,ArH),7.52-7.39(m,3H,ArH),7.35-7.27(m,2H,ArH),7.21-7.19(m,1H,ArH),5.93(s,1H,CH),3.43-3.32(m,2H,CH2),3.13-3.05(m,1H,CH2),2.98-2.91(m,1H,CH2);13C NMR(100MHz,DMSO-d6)(δ,ppm):146.8,143.6,135.3,131.0,130.7,130.5,129.4,129.0,128.5,128.0,127.1,123.8,122.7,117.4,112.7,107.8,49.0,35.7,23.0;HRMS(ESI)m/z:calcd.for[M+Na]+C21H15Cl2NO2SNa:438.0098;found:438.0076.
11-(2,3-二氯苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4h)
m.p.284-286℃;IR(KBr,ν,cm-1):3312,1660,1624,1586,1533,1506,1471,1417,1401,1265,1134,1106,1084,1045,812,748,647,598;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.97(s,1H,NH),7.86(t,J=9.2Hz,2H,ArH),7.59(d,J=7.6Hz,1H,ArH),7.44(t,J=8.0Hz,1H,ArH),7.39-7.28(m,3H,ArH),7.16-7.00(m,2H,ArH),6.26(s,1H,CH),3.42-3.28(m,2H,CH2),3.10-3.03(m,1H,CH2),3.00-2.93(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+C21H15Cl2NO2SNa:438.0098;found:438.0076.
11-(2,6-二氯苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4i)
m.p.256-258℃;IR(KBr,ν,cm-1):3309,1667,1588,1532,1507,1472,1435,1398,1266,1242,1194,1132,1106,1088,814,767,653,601,507;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.98(s,1H,NH),7.80(d,J=8.4Hz,2H,ArH),7.59-7.50(m,2H,ArH),7.35(t,J=7.2Hz,1H,ArH),7.27(t,J=7.2Hz,1H,ArH),7.20(d,J=4.8Hz,2H,ArH),7.13(d,J=8.8Hz,1H,ArH),6.71(s,1H,CH),3.46-3.27(m,2H,CH2),3.02-2.93(m,2H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+C21H15Cl2NO2SNa:438.0098;found:438.0066.
11-(3-硝基苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4j)
m.p.248-250℃;IR(KBr,ν,cm-1):3305,1705,1668,1586,1528,1471,1398,1349,1268,1230,1133,1110,826,754,715,681,616,505;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.97(s,1H,NH),8.08(s,1H,ArH),7.98-7.91(m,2H,ArH),7.88-7.82(m,2H,ArH),7.76(d,J=7.6Hz,1H,ArH),7.52(t,J=8.0Hz,1H,ArH),7.41-7.30(m,3H,ArH),6.10(s,1H,CH),3.43-3.31(m,2H,CH2),3.13-3.06(m,1H,CH2),3.00-2.93(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M+Na]+C21H16N2O4SNa:415.0728;found:415.0731.
11-(4-甲基苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4k)
m.p.232-234℃;IR(KBr,ν,cm-1):3301,1665,1590,1515,1471,1401,1250,1206,1123,1101,1082,835,812,747,651,609,558,506;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.78(s,1H,NH),7.88-7.80(m,3H,ArH),7.37(t,J=7.6Hz,1H,ArH),7.31-7.26(m,2H,ArH),7.12(d,J=8.0Hz,2H,ArH),6.98(d,J=7.6Hz,2H,ArH),5.76(s,1H,CH),3.45-3.29(m,2H,CH2),3.09-3.02(m,1H,CH2),2.95-2.88(m,1H,CH2),2.16(s,3H,CH3);HRMS(ESI)m/z:calcd.for[M-H]-C22H18NO2S:360.1057;found:360.1058.
11-(2-甲氧基苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4I)
m.p.233-235℃;IR(KBr,ν,cm-1):3357,1661,1621,1599,1584,1528,1490,1470,1395,1370,1269, 1162,1127,1099,1050,1020,808,769,757,620,511;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.72(s,1H,NH),7.81-7.72(m,3H,ArH),7.40-7.25(m,3H,ArH),7.07-6.95(m,2H,ArH),6.80-6.66(m,2H,ArH),6.17(s,1H,CH),3.95(s,3H,CH3),3.35-3.26(m,2H,CH2),3.07-3.00(m,1H,CH2),2.93-2.89(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M-H]-C22H18NO3S:376.1007;found:376.1006.
11-(3-甲氧基苯基)-7,8,9,11-四氢苯并[f]噻吩并[3,2-b]喹喏啉-10,10-二氧化物(4m)
m.p.233-235℃;3284,1664,1607,1584,1535,1487,1454,1429,1400,1316,1262,1148,1130,1091,1043,812,749,694,599,566;1H NMR(400MHz,DMSO-d6)(δ,ppm):9.80(s,1H,NH),7.92-7.82(m,3H,ArH),7.39-7.27(m,3H,ArH),7.09(t,J=7.2Hz,1H,ArH),6.81-6.65(m,3H,ArH),5.79(s,1H,CH),3.65(s,3H,CH3),3.40-3.28(m,2H,CH2),3.09-3.06(m,1H,CH2),2.94-2.91(m,1H,CH2);HRMS(ESI)m/z:calcd.for[M-H]-C22H18NO3S:376.1007;found:376.1010.
Claims (3)
1.本发明涉及苯并[f]噻吩并[3,2-b]喹啉衍生物的合成,是以芳醛、乙萘胺和3-氧代环丁砜为原料,一锅法一步反应生成。
2.按照权利要求(1)所述的苯并[f]噻吩并[3,2-b]喹啉衍生物的合成方法,其特征是合成的反应条件是芳醛、乙萘胺和3-氧代环丁砜无溶剂条件下反应,适宜的条件是常压、85℃和反应9~13小时,原料的摩尔比为芳醛∶乙萘胺∶3-氧代环丁砜=1∶1∶1。
3.按照权利要求(1)所述的苯并[f]噻吩并[3,2-b]喹啉衍生物的合成方法,其特征在于所述的芳醛为苯甲醛或带有氟、氯等卤素原子、甲氧基或硝基的苯甲醛,其所带的取代基的数量不超过2,其取代基的位置在醛基的邻、间、对位。
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