CN1431206A - 11-羧丙基取代的苯并[a]呫吨酮类化合物及其光化学合成法 - Google Patents
11-羧丙基取代的苯并[a]呫吨酮类化合物及其光化学合成法 Download PDFInfo
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- 125000005605 benzo group Chemical group 0.000 claims abstract description 11
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Abstract
本发明涉及式I的11-丙酸基取代的苯并[a]呫吨酮类化合物及其制备方法。式I化合物可以从取代联萘酚出发在水存在的条件下,经铜胺络合物催化合成1-氧代-13c-羟基-1,13c-二氢-二苯并[a,k1]呫吨类化合物,继而进一步分别在含水、醇、氨(或胺)体系中经光照开环合成。式I中的Nu,R1,R2,R3和R4的定义如说明书所述。
Description
技术领域
本发明涉及11-丙酸基取代的苯并[a]呫吨酮类化合物及其制备方法。
背景技术
呫吨酮类化合物是部分高等植物,真菌或地衣类的二级代谢产物。近年来,各种结构的呫吨酮类化合物被不断从植物中分离出来(Peres,V.;Nagem,T.J..Phytochemistry 1997,44:191;(b)Petres,V.;Nagerm,T.J.;de Oliveira,F. F.;Phytochemistry 2000,55:683)。由于这类化合物和黄酮化合物在结构上的相似性,使其具有很好的生理活性如:抗微生物作用、对生物体的调节作用、抗病毒、抗肿瘤作用等。因此,在药物化学中占据了比较重要的位置,也引起了人们较大的研究兴趣,从而发展了多种合成呫吨酮的方法,但能用于合成苯并呫吨酮的方法主要是两种:
1.利用酚类和水杨酸在多聚磷酸的催化下,脱水生成各种取代的呫吨酮和苯并呫吨酮,条件温和,但在酸催化下易生成酯化产物,产率不高,一般为35-45%。通过缩合反应制备呫吨酮和苯并呫吨酮(Patel,G.N.;Trivedi,K.N.IndianJournal of Chemistry:B 1991,30:437)(见式A)。式A
发明内容
本发明的目的是提供11-丙酸基取代的苯并[a]呫吨酮类化合物及其光化学合成方法,以克服现有技术所存在的上述问题。
式I中:
R2或R4是H,卤素,NO2,CN,COOR,CONR’R’,CH2OR,OR,NR’R”,N=NR中的任一种;R,R’,R”是1-12碳数的烷基中的任一种,或者是H,苯基或苄基;R,R’与R”可以相同也可以不同;R2和R4可以相同,也可以不同;
R1或R3为COOR,CONR’R”,CH2OR中的任一种;R,R’,R”是1-12碳数的烷基中的任一种,或者是H,苯基或苄基;R,R’与R”可以相同也可以不同;R1和R3可以相同,也可以不同;
本发明的式I化合物可通过以下方法制备:从取代联萘酚出发在水存在下,铜胺络合物催化合成1-氧代-13c-羟基-1,13c-二氢-二苯并[a,kl]呫吨类化合物,并进一步光照开环合成式I化合物。反应过程如式C所示。式C
上述式I化合物的制备方法的具体步骤为:
以对称取代或不对称取代的联萘酚(化合物3)为原料,在含水的非质子性极性溶剂中,在空气或氧气氛围以及≤60℃温度条件下,经过铜胺络合物作用,反应至原料转化完全,减压蒸去溶剂,残留物加入与水不互溶的常用有机溶剂重新溶解,分别以5%的氨水洗涤和水洗涤;所得有机相用无水硫酸纳干燥,浓缩后以硅胶柱层析分离,得到羟基取代的二苯并呫吨化合物2;继而将化合物2在溶液中,在≤60℃温度下,加入大于leq.的水或其它亲核试剂,光照下开环生成相应的新的11-丙酸基、丙酸酯基或丙酰胺基取代的苯并[a]呫吨酮I,TLC跟踪至反应完全;反应混合物浓缩后进行硅胶柱层析分离得纯的式I化合物。
上述方法中所说的含水的非质子性极性溶剂可以是:卤代烃类、酰胺类、酯类、二甲基亚砜或乙腈;铜胺络合物中的铜盐可以是:氯化铜、氯化亚铜、溴化铜、硝酸铜、醋酸铜或高氯酸铜,胺可以是:十个碳以内的乙醇胺类,脂肪族和芳香族伯胺、仲胺或叔胺类;反应物萘酚与试剂铜、胺的摩尔比一般为1∶(1-4)∶1,最好是1∶2∶1。
上述方法中的化合物2转化为11-丙酸基取代的苯并[a]呫吨酮I所用的溶剂可以是常用的酮类、酯类或酰胺类溶剂,或二甲基亚砜,或乙腈。所说的其它亲核试剂与前面所述的Nu相对应。
本发明的式I化合物具有与黄酮化合物相似的结构部分,提示其可能具有抗微生物作用、对生物体的调节作用、抗病毒、抗肿瘤作用等生理活性。因此,本发明的式I化合物具有潜在的药用价值。
本发明的式I化合物制备方法的合成产率可达54-75%。
具体实施方式
实施例一:3-(12-氧代-12H-苯并[a]呫吨-11-基)丙酸(Ia)的制备
于30mL乙腈中,滴加入1mmol吡啶和加入2mmol CuCl,振摇得到一棕色溶液,再加入1mmol 1,1’-联-2-萘酚(3a)。常压下通氧搅拌,室温下反应60小时。减压蒸去溶剂,残留物加入乙酸乙酯50mL重新溶解,5%的氨水洗涤(3×30mL),继而水洗至中性。分出有机相,用无水硫酸纳干燥。最后以硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶6洗脱)。产物为1-氧代-13c-羟基-1,13c-二氢-二苯并[a,kl]呫吨(2a),黄色粉末。产率60%。m.p.>250℃(dec.)。1HNMR(DMSO-d6,500MHz)δH:6.28(d,J=10.0Hz,1H),7.17(d,J=8.5Hz,1H),7.19(s,1H,OH,氘代后消失),7.22(d,J=7.0Hz,1H),7.36(d,J=10.0Hz,1H),7.37~7.42(m,3H),7.44(t,J=7.0Hz,8.5Hz,1H),7.87(d,J=7.0Hz,1H),7.97(d,J=9.0Hz,1H),8.01(d,J=8.5Hz,1H);13CNMR(DMSO-d6,125MHz)δC:68.29(C-OH),116.35,117.17,124.01,124.88,125.81(信号重叠),127.83,128.47,130.38,130.82,138.89(1CH);112.29,120.21,130.60,132.51,133.14,148.51,149.29(C);199.61(C=O);IR(KBr)ν:3473.1,3066.3,1691.9,1593.3,1265.4,1228.9,978.7,748.0cm-1;MS-FABm/z(%):301(M++1,17),300(M+,15),283(M+-OH,64),272(M+-CO,38);Anal.calcd for C20H12O3:H4.03,C79.99;Found:H4.24,C79.70。
将2a(1mmol)溶解于20mLDMSO中,加入约2mmol的水作为亲核试剂,于目光下照射,TLC跟踪至反应完全。反应混合物浓缩后进行硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶4洗脱)得Ia的白色针状晶体。产率62%,m.p.194~195℃。1HNMR(DMSO-d6,500MHz)δH:2.66(t,J=7.5Hz,2H),3.57(t,J=7.5Hz,2H),7.33(d,J=7.5Hz,1H),7.58(d,J=8.5Hz,1H),7.65(t,J=6.5Hz.,8.0Hz,1H),7.70(d,J=8.5Hz,1H),7.74(t,J=8.0Hz,1H),7.80(t,J=7.5Hz,1H),8.09(d,J=7.5Hz,1H),8.35(d,J=9.0Hz,1H),9.85(d,J=8.5Hz,1H,),12.05(s,1H,OH,氘代后消失);13CNMR(DMSO-d6,125MHz)δC:30.16(CH2),35.11(CH2),116.36,117.62,125.73,125.93,126.92,128.71,129.23,133.64,136.77(9CH);114.45,120.77,129.86,130.30,143.18,155.52,155.98(7C);173.71(C=O),179.28(C=O);IR(KBr)ν:3434.2,3028.0,1691.8,1639.9,1606.6,1255.1,821.6,750.6cm-1;FAB-MS m/z(%):319(M++1,52),318(M+,18),301(M+-OH,36),273(M+-CO,30),259(M+-OH-CO-CH2,7),245(M+-OH-CO-CH2-CH2,6);Anal.calcd for C20H14O4,H4.43,C75.46;Found H4.46,C75.35。
实施例二:3-(3,9-二溴-12-氧代-12H-苯并[a]呫吨-11-基)丙酸(Ib)的制备
于30mL乙腈中,滴加入1mmol乙醇胺和加入2mmol CuCl2·2H2O,振摇得到一棕色溶液,再加入1mmol 6,6’-二溴代-1,1’-联-2-萘酚(3b)。常压下通氧搅拌,室温下反应77小时。减压蒸去溶剂,残留物加入乙酸乙酯50mL重新溶解,5%的氨水洗涤(3×30mL),继而水洗至中性。分出有机相,用无水硫酸纳干燥。最后以硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶6洗脱)。产物为5,11-二溴-1-氧代-13c-羟基-1,13c-二氢-二苯并[a,kl]呫吨(2b),为黄色粉末。产率62%,m.p.>250℃(dec.)。1HNMR(DMSO-d6,500MHz)δH:6.36(d,J=10.0Hz,1H),7.38(d,J=10.0Hz,1H),7.44(d,J=9.0Hz,1H),7.45(s,1H,OH,氘代后消失),7.50(d,J=2.0Hz,1H),7 52(d,J=2.0Hz,1H),7.53(dd,J=2.0Hz,9.0Hz,1H),7.90(d,J=9.0Hz,1H),8.01(d,J=9.0Hz,1H),8.20(d,J=2.0Hz,1H);13CNMR(DMSO-d6,125MHz)δc:67.94(C-OH),112.50,117.46,118.43,118.73,119.34,122.87,126.80,126.90,128.05,129.68,130.40,130.56,131.11,132.18,134.92,137.97,148.69,149.82(9CH,9C),198.81(C=O);IR(KBr)ν:3510.8,3073.9,1709.1,1593.0,1498.5,1258.8,815.6,782.2cm-1。MS-FAB m/z(%):459(M++1,6),458(M+,6),441(M+-OH,12),440(M+-CO,10);Anal.calcd for C20H10Br2O3:H 2.20,C52.44;Found H2.37,C52.59。
将2b(1mmol)溶解于20mL乙酸乙酯中,加入约3mmol的水作为亲核试剂,于日光下照射,TLC跟踪至反应完全。反应混合物浓缩后进行硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶4洗脱)得Ib的白色针状晶体。产率60%。m.p.228~229℃。1HNMR(DMSO-d6,500MHz,)δH:2.65(t,J=7.5Hz,2H),3.53(t,J=7.5Hz,2H),7.55(d,J=2.5Hz,1H),7.77(d,J=9.0Hz,1H),7.92(d,J=2.5Hz,1H),7.94(dd,J=9.0,2.5Hz,1H),8.38(d,J=9.0Hz,1H),8.41(d,J=2.5Hz,1H)9.76(d,J=9.0Hz,1H);IR(KBr)ν:3414.6,3069.0,1707.2,1593.5,1573.8,1272.0,834.9,773.6cm-1;FAB-MS m/z(%):477(M++1,3),460(M++1-OH,5);Anal.calcd for C20H12O4Br2:H2.54,C50.45;Found H2.52 C50.72。
实施例三:3-(12-氧代-12H-苯并[a]呫吨-11-基)丙酸甲酯(Ic)的制备
将实施例一的2a(1mmol)溶解于20mL乙酸乙酯中,加入约1mmol的甲醇作为亲核试剂,于日光下照射,TLC跟踪至反应完全。反应混合物浓缩后进行硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶4洗脱)得Ic的白色针状晶体。产率75%。m.p.116~117℃。1HNMR(CDCl3,500MHz)δH:2.87(t,J=7.5Hz,2H),3.68(s,3H,OCH3),3.72(t,J=7.5Hz,2H),7.24(d,J=7.5Hz,1H),7.44(d,J=7.5Hz,1H),7.52(d,J=9.0Hz,1H),7.57-7.60(m,2H),7.76(t,J=7.5Hz,1H),7.90(d,J=7.5Hz,1H),8.10(d,J=9.0Hz,1H),8.97(d,J=8.5Hz,1H);13CNMR(CDCl3,125MHz)δC:30.98(CH2),35.51(CH2),51.47(OCH3),108.89,115.53,116.62,117.60,121.69,125.99,126.70 ,127.12,128.45,129.41,130.22,131.05,133.07,136.33,143.57,156.25,173.82,180.10;IR(KBr)ν:3433.9,3067.0,1725.5,1644.2,1610.3,1581.7,1261.6,827.7,756.2cm-1;FAB-MS m/z(%):333(M++1,100),332(M+,30),301(M+-OCH3,60),273(M+-OCH3-CO,90),259(M+-OCH3-CO-CH2,20),245(M+-OCH3-CO-CH2-CH2,10);Anal.calcd.for C21H16O4,H4.85,C75.89;Found H4.92,C75.75。实施例四:3-(12-氧代-12H-苯并[a]呫吨-11-基)丙酸异丙酯(Id)的制备
将实施例一的2a(1mmol)溶解于20mL乙酸乙酯中,加入约1mmol的异丙醇作为亲核试剂,于日光下照射,TLC跟踪至反应完全。反应混合物浓缩后进行硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶4洗脱)得Id的白色针状晶体。产率57%。m.p.86~87℃。1HNMR(CDCl3,500MHz)δH:1.21(d,J=6.5Hz,6H),2.82(t,J=7.5Hz,2H),3.71(t,J=7.5Hz,2H),5.00~5.04(m,1H),7.24(d,J=7.5Hz,1H),7.43(dd,J=7.5Hz,1.0Hz,1H),7.51(d,J=9.0Hz,1H),7.56~7.60(m,2H),7.74~7.78(m,1H),7.89(d,J=2.5Hz,1H),8.09(d,J=9.0Hz,1H),9.97(d,J=8.0Hz,1H);13CNMR(CDCl3,125MHz)δC:21.87,30.98,35.94,67.47,96.12,115.50,116.51,117.58,121.66,125.94,126.67,127.17,128.43,129.36,130.19,131.03,132.95,136.26,143.72,156.20,156.43,172.93,180.08;IR(KBr)ν:3063.1,2974.5,1727.1,1641.6,1582.7,1514.0,1254,824.6,763.1cm-1;FAB-MS m/z(%):361(M++1,20),301(M+-OCH(CH3)2,100),273(M+-OCH(CH3)2-CO,60),259(M+-OCH(CH3)2-CO-CH2,10),245[M+-OCH(CH3)2-CO-CH2,10];Anal.calcd.for C23H20O4,H5.59,C76.65;Found H5.74,C75.92。实施例五:N,N-二乙基-3-(12-氧代-12H-苯并[a]呫吨-11-基)丙酰胺(Ie)的制备
将实施例一的2a(1mmol)溶解于20mL乙酸乙酯中,加入约1mmol的二乙胺作为亲核试剂,于日光下照射,TLC跟踪至反应完全。反应混合物浓缩后进行硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶4洗脱)得Ie的黄色针状晶体。产率62%。m.p.108~110℃。1HNMR(CDCl3,500MHz)δH:1.18(t,J=7.5Hz,6H),2.92(t,J=7.5Hz,2H),3.46-3.47(m,4H),3.72(t,J=7.5Hz,2H),7.39(d,J=7.5Hz,1H),7.43(d,J=7.5Hz,1H),7.55(d,J=9.0Hz,1H),7.57~7.612(m,2H),7.75(t,J=7.5Hz,1H),7.90(d,J=8.0Hz,1H),8.10(d,J=9.0Hz,1H),9.93(d,J=8.5Hz,1H);IR(KBr)ν:3056.0,2972.6,1636.7,1607,6,1582.5,1257.6,820.8,761.2cm-1;FAB-MS m/z(%):374(M++1,100),301,273,259,245;Anal.calcd.for C24H23NO3:H6.21,C77.19,N3.75;Found H6.30,C77.31,N3.54。实施例六:11-[3-(4-吗啡啉基)-3-氧代丙基]苯并[a]呫吨-12-酮(If)的制备
将实施例一的2a(1mmol)溶解于20mL乙酸乙酯中,加入约1mmol的吗啡啉作为亲核试剂,于日光下照射,TLC跟踪至反应完全。反应混合物浓缩后进行硅胶柱层析分离(硅胶100-200目,以乙酸乙酯∶石油醚=1∶15-1∶4洗脱)得If的黄色针状晶体。产率71%。m.p.190~192℃。1HNMR(CDCl3,500MHz)δH:2.86(t,J=7.5Hz,2H),3.62~3.69(m,10H.),7.30(d,J=7.5Hz,1H),7.43(d,J=7.5Hz,1H),7.50(d,J=9.0Hz,1H),7.57~7.60(m,2H),7.75(t,J=7.5 Hz,1H),7.89(d,J=8.0Hz,1H),8.09(d,J=8.5Hz,1H),9.90(d,J=8.5Hz,1H);13CNMR(CDCl3,125MHz)δC:31.85,34.95,42.00,46.18,66.85,66.93(6CH2),115.35,116.50,117.59,121.70,125.99,126.40, 127.61,128.53,129.38,130.20 ,130.93,133.21,136.38,143.90,156.11,156.47,171.57,180.18;IR(KBr)ν:3437.2,3259.0,3067.0,1638.6,1612,1579,1245,829.9,756.9cm-1;FAB-MS m/z(%):388(M++1,55),387(M+,7),301,273,259,245Anal.calcd.for C24H21NO4:H5.46,C74.40,N3.62;Found H5.40,C74.59,N3.54。
Claims (6)
1.一种如结构通式I所示的11-丙酸基取代的苯并[a]呫吨酮类化合物,
式I中:
R2和R4分别是H,卤素,NO2,CN,COOR,CON R’R’,CH2OR,OR,NR’R”,N=NR中的任一种;R,R’,R”是1-12碳数的烷基中的任一种,或者是H,苯基或苄基;R,R’与R”可以相同也可以不同;R2与R4可以相同,也可以不同;
R1和R3分别为COOR,CON R’R”,CH2OR中的任一种;R,R’和R”分别是1-12碳数的烷基中的任一种,或者是H,苯基或苄基;R,R’与R”可以相同也可以不同;R1与R3可以相同,也可以不同。
2.权利要求1所述的式I化合物的制备方法,从取代联萘酚出发在水存在下,铜胺络合物催化合成1-氧代-13c-羟基-1,13c-二氢-二苯并[a,kl]呫吨类化合物,并进一步光照开环合成式I化合物。
3.按照权利要求2所述的方法,其特征是具体步骤为:
以对称取代或不对称取代的联萘酚为原料,在含水的非质子性极性溶剂中,在空气或氧气氛围以及≤60℃温度条件下,经过铜胺络合物作用,反应至原料转化完全,减压蒸去溶剂,残留物加入与水不互溶的常用有机溶剂重新溶解,分别以5%的氨水洗涤和水洗涤;所得有机相用无水硫酸纳干燥,浓缩后以硅胶柱层析分离,得到羟基取代的二苯并呫吨化合物2;继而将化合物2在溶液中,在≤60℃温度下,加入大于1eq.的水或其它亲核试剂,光照下开环生成相应的新的11-丙酸基、丙酸酯基或丙酰胺基取代的苯并[a]呫吨酮I,TLC跟踪至反应完全;反应混合物浓缩后进行硅胶柱层析分离得纯的式I化合物。
4.按照权利要求3所述的方法,其特征是其中所说的含水的非质子性极性溶剂是:卤代烃类、酰胺类、酯类、二甲基亚砜或乙腈;铜胺络合物中的铜盐是:氯化铜、氯化亚铜、溴化铜、硝酸铜、醋酸铜或高氯酸铜,胺是:十个碳以内的乙醇胺类,脂肪族和芳香族伯胺、仲胺或叔胺类;反应物萘酚与试剂铜、胺的摩尔比为1∶(1-4)∶1;所说的其它亲核试剂与权利要求1的Nu相对应。
5.按照权利要求4所述的方法,其特征是其中所说的反应物萘酚与试剂铜、胺的摩尔比是1∶2∶1。
6.按照权利要求3,4或5所述的方法,其特征是其中的化合物2转化为11-丙酸基取代的苯并[a]呫吨酮I所用的溶剂是常用的酮类、酯类或酰胺类溶剂,或二甲基亚砜,或乙腈。
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CN104610219A (zh) * | 2015-01-14 | 2015-05-13 | 云南民族大学 | 一种具有氧化异戊烯基的呫吨酮类化合物及其制备方法和应用 |
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US8323750B2 (en) | 2007-08-21 | 2012-12-04 | Beijing Wanhexinyuan Biotechnology Co., Ltd. | Method of ultraviolet light assisted surface modification and product having a surface formed by this method |
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CN104610219B (zh) * | 2015-01-14 | 2016-08-24 | 云南民族大学 | 一种具有氧化异戊烯基的呫吨酮类化合物及其制备方法和应用 |
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