CN115028581A - 氢化菲啶类衍生物的制备方法以及在制备抗肿瘤药物中的应用 - Google Patents
氢化菲啶类衍生物的制备方法以及在制备抗肿瘤药物中的应用 Download PDFInfo
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- CN115028581A CN115028581A CN202210481449.9A CN202210481449A CN115028581A CN 115028581 A CN115028581 A CN 115028581A CN 202210481449 A CN202210481449 A CN 202210481449A CN 115028581 A CN115028581 A CN 115028581A
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
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Abstract
本发明涉及医药、有机化工及精细化工领域,具体涉及氢化菲啶类衍生物的制备方法以及在制备抗肿瘤药物中的应用。以2‑氨基苯乙炔或2‑氨基苯乙烯类化合物和4,4‑二乙烯基碳酸亚乙酯为原料,金属钯为催化剂,在磷配体的参与下,氯代烃做溶剂,50‑100℃的加热反应条件下,历时20‑30小时合成产物。反应经过简单后处理即可以高产率得到一系列氢化菲啶类化合物。并抗肿瘤活性测试表明所制备的氢化菲啶类衍生物具有潜在的抗肿瘤生物活性。
Description
技术领域
本发明涉及医药、有机化工及精细化工领域,具体涉及一种四氢菲啶和六氢菲啶类化合物的合成方法。其中以2-氨基苯乙炔或2-氨基苯乙烯类化合物和4,4-二乙烯基碳酸亚乙酯为原料,金属钯为催化剂,在磷配体的参与下,50-100℃下简单高效的合成氢化菲啶类衍生物的方法。
背景技术
氢化菲啶是常见的多元含氮杂环化合物,广泛存在于天然化合物以及生物活性的药物中,作为关键分子骨架,含有氢化菲啶结构的常见分子包括左南曲朵、CB2受体激动剂、BKCa激动剂等。其中左南曲朵的精神活性是大麻中主要活性成分四氢大麻酚的30倍以上,并且左南曲朵还具有镇痛和止吐特性,其效力也是吗啡的9-14倍。因此具有氢化菲啶结构类化合物的多样性合成具有积极的研究价值。
目前多氢菲啶化合物的合成路线主要是通过催化烯烃加成的基础上实现。2013年JaredT.Shaw等人发现了一种钪催化的烯烃环化反应(式1),顺利的由双烯基化合物催化环化生成了八氢菲啶化合物,具有高的非对映选择性和区域选择性。(参见:JamesC.Fettinger andJaredT.Shaw.Chem.Sci.,2013,4,292.)
2014年,Asieh Otaredi-Kashani等人开发了一种以六羰基钼作为羰基源,钯催化的邻碘苯胺与降冰片烯的环化反应(式2),成功实现了六氢菲啶酮类衍生物的合成,并避免了气态一氧化碳的使用,该反应与各种未受保护的苯胺相容,大大的拓宽了菲啶酮类衍生物的合成路线。(参见:Farnaz Jafarpour;AsiehOtaredi-Kashani.Carbonylativeannulation of unsaturated compounds using molybdenum hexacarbonyl:anefficient synthesis of2(1H)-quinolones.Volume 2014,Issue 4,pp.193-203.)
2018年,Xianxiu Xu课题组通过连续的迈克尔加成以及分子内的阿扎-亨利反应开发了一种新的反应策略(式3),成功的实现了无金属催化下六氢菲啶酮衍生物的合成,在这个过程中硝基甲烷作为三亲核试剂,对其反应位点高度利用,无金属催化且条件温和。(参见:Qun Liu,andXianxiu Xu.J.Org.Chem.2018,83,3,1232–1240.)
尽管目前合成多氢菲啶骨架的方法已取得一定的进展,但底物的限制仍是影响此类结构合成的主要因素,因此拓展多氢菲啶的合成路径仍是十分必要的。
钯催化在过渡金属催化环化反应中起至关重要的作用,尤其是钯催化的两性离子-π-烯丙基钯,在过去引起了广泛的关注和研究,各种烯丙基供体产生的反应性偶极物种可作为一种多功能合成子,成功应用于不同不饱和亲电试剂的钯催化环化反应,其中包括用于构建制药工业的结构支架和具有潜在生物吸引力的新型杂环骨架。
乙烯基碳酸酯作为常用的偶极子,大多数是以1,3-偶极子的案例出现,其作为1,5-偶极子的反应相对较少。2017年,YuZhao课题组在钯催化下实现了第一次对映选择性形式[5+4]环加成反应(式4),以实现苯并呋喃稠合的八元环的构建。(参见:YuZhao.,J.Am.Chem.Soc.2017,139,15304-15307.)
2018年,Frank Glorius等人报道了N-杂环卡宾(NHC)/Pd催化体系与乙烯基碳酸亚乙酯的高度对映选择性[5+2]环化(式5)。双齿膦配体的使用在与防止NHC有机催化剂与活性Pd催化剂的配位,且与NHC结合提高了反应性和对映选择性。(参见:Frank Glorius.,J.Am.Chem.Soc.2018,140,3551-3554)
2020年,Han及其同事开发了一种碳酸乙烯酯和烯丙基甲基丙烯腈的区域聚合环化反应,用于合成中型杂环化合物(式6)。[5+4]环化反应在较低温度下在MeCN中顺利进行,以高产率提供九元氧杂环。将溶剂改为四氢呋喃并升高温度完全逆转了闭环步骤的区域选择性,从而产生七元杂环的[5+2]环化。通过这种方式,他们的策略允许通过简单的反应条件操作,从同一组底物选择性组装两种杂环大小。(参见:Bo Han.Chem.Sci.,2020,11,2888.)
由上所述,乙烯基碳酸酯作为偶极子完成的直接环加成反应在杂环化合物的构建中已有很多案例报道。但是,利用乙烯基碳酸酯作为偶极子实现的连续胺化/环加成反应却少有报道,能够为更复杂的多环化合物的合成提供全新的思路。
发明内容
鉴于背景技术中的不足,作为氢化菲啶类化合物合成的一项持续工作和新方法,本发明使用乙烯基碳酸酯作为偶极子,利用钯催化剂和磷配体共同作用,在温和条件下实现了氢化菲啶类骨架的合成。是首次利用偶极子进行的连续胺化/环化反应,实现氢化菲啶类多环化合物的合成。为氢化菲啶和氢化异喹啉类的构建提供了一种全新的连续反应机理,作为氢化菲啶类化合物的合成策略,丰富了氢化菲啶骨架衍生物的合成。并且研究了新结构氢化菲啶类化合物在抗肿瘤中的生物活性,为其后续用于抗肿瘤药物中提供积极意义。
本发明提供了一种四氢菲啶和六氢菲啶类化合物的合成方法:以2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)和4,4-二乙烯基碳酸亚乙酯(式II)为原料,金属钯为催化剂,在磷配体的参与下,在有机溶剂,在50-100℃的加热条件下反应,历时20-30小时得到一系列四氢菲啶和六氢菲啶类类化合物(式III)。该反应的具体工艺过程如下所示:
进一步,其中2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)中R1选自氢、酯基、硝基、氰基、醛基、羰基、酰胺基、磷酸酯基、烷基、芳基、取代的芳基、杂芳基中的任意一种;
烷基选自甲基、乙基、丙基、异丙基、丁基、叔丁基和苄基中的一种;
芳基选自苯基、萘基、菲基、蒽基基中的一种;
取代的芳基中的取代基分别独立选自氟、氯、溴、碘、氰基、羟基、氨基、烷基、烷氧基、烯基、炔基、硝基、巯基、羟基烷氧基、烷基酯基、芳基、芳基烷基、杂环基、杂环基烷基、环烷基、芳氧基和杂芳氧基中的一种;
杂芳基选自吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吲哚基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噻唑基、喹啉基、异喹啉基和嘌呤基中的一种;
进一步,2-氨基苯乙炔类化合物或2-氨基苯乙烯类化合物(式I)中R2选自氟、氯、溴、碘、氰基、羟基、氨基、烷基、烷氧基、烯基、炔基、硝基、巯基、羟基烷氧基、烷基酯基、芳基、芳基烷基、杂环基、杂环基烷基、环烷基、芳氧基和杂芳氧基中的一种;
进一步,2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)中R3选自氢、磺酰基、酰基、磷酰基、烷基和芳基中的一种;
烷基选自甲基、乙基、丙基、异丙基、丁基、叔丁基和苄基中的一种;芳基选自苯基、萘基、菲基、蒽基、苊烯基、苊基、芴基、芘基和荧蒽基中的一种;
式I化合物结构优选为:
进一步,4,4-二乙烯基碳酸亚乙酯(式II)中n为1、2或3。
进一步,4,4-二乙烯基碳酸亚乙酯(式II)中R4选自氢、烷基和芳基中的一种;所述烷基选自甲基、乙基、丙基、异丙基、丁基、叔丁基和苄基中的一种;所述芳基选自苯基、萘基、菲基、蒽基、苊烯基、苊基、芴基、芘基和荧蒽基中的一种;
式II化合物结构优选为:
进一步,磷配体选自PPh3(三苯基膦),PEt3(三乙基膦),PCy3(三环己基膦),Xantphos(4,5-双(二苯基膦)-9,9-二甲基氧杂蒽),Aphos([4-(N,N-二甲基氨基)苯基]-二叔丁基膦),HPCy2(二环己基膦),TPPO(三苯基氧膦),DPEPhos(双(2-二苯基膦)苯醚),dppb(1,4-双(二苯膦)丁烷),dppp(1,3-双(二苯膦)丙烷),dppe(1,2-双(二苯膦)乙烷)或dcpe(2-(二环己基膦基)联苯)。其用量为2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)原料摩尔数的5-10mol%,进一步优选为6mol%。
金属钯催化剂为Pd(PPh3)4(四(三苯基膦)钯),Pd2(dba)3(三(二亚苄基丙酮)二钯),Pd(dppf)Cl2(1,1'-双(二苯基膦基)二茂铁]二氯化钯),Pd(cod)Cl2(1,5-环辛二烯)二氯化钯),PdCl2或Pd(PPh3)2Cl2。其用量为2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)原料摩尔数的5~10mol%,进一步优选为3mol%。
进一步,优选有机溶剂为:二氯乙烷(DCE)、氯苯(PhCl)。
作为优选,本发明在Pd(PPh3)4为催化剂,Xantphos为配体的条件下,反应效果最佳。所述的反应后处理简便,只需要简单的柱色谱分离方法,以石油醚与乙酸乙酯的混合溶剂为洗脱剂就可以得到纯净的化合物。
氢化菲啶类化合物结构为:
相应地,制备的氢化菲啶类衍生物对肿瘤有抑制效果,可制备抑制肿瘤药物。
一种肿瘤抑制剂,所述肿瘤抑制剂包含有上述方法制备的抗肿瘤氢化菲啶类衍生物。
优选地,该肿瘤包括:人体宫颈癌细胞系、肺癌细胞系、卵巢癌细胞系中的一种或几种。
优选地,肿瘤抑制剂还包括:甘油、聚山梨酯、聚乙二醇、高酰基结冷胶、黄原胶、卡拉胶、海藻酸钠、羧甲基纤维素钠、微晶纤维素、羟丙基甲基纤维素、交联聚维酮、聚丙烯酸树脂类聚合物、红花籽油、软磷脂和蜂蜡中的至少一种医药学上可接受的辅料;和/或,所述肿瘤抑制剂的剂型包括:口服液、胶囊剂、片剂、膏剂、粉剂、颗粒剂、丸剂、栓剂、植入型制剂、定位靶向制剂、缓释制剂和控释制剂中的至少一种医药学上可接受的剂型。
与现有技术相比,本发明的有益效果为:开发了一种用于氢化菲啶类衍生物合成的连续性胺化/环化反应。该方法提供了从简单的起始材料2-氨基苯乙炔或2-氨基苯乙烯类化合物和4,4-二乙烯基碳酸亚乙酯合成各种四氢菲啶和六氢菲啶骨架的途径。在该反应中,金属钯催化剂促进1,5-偶极子的形成,随后发生连续的胺化和D-A环合反应得到四氢菲啶和六氢菲啶类化合物,为氢化菲啶的构建提供了一种全新的策略,丰富了氢化菲啶骨架衍生物的合成。本发明通过肿瘤活性实验,证实了本发明提供的肿瘤抑制剂具有显著地抗肿瘤活性,对多类癌细胞能够高效的杀灭;并且对于正常人体细胞损伤较小,毒副作用小,具有良好的抗肿瘤选择性。
具体实施方式
实施案例中的对甲苯磺酰基保护的邻氨基苯丁烯酸乙酯可通已知文献合成得到(参照:DavidW.Lupton.,Org.Lett.2021,23,24,9413–9418.).实施案例中的双乙烯基碳酸酯可通过已知文献合成得到(参照:Hongchao Guo.,Org.Lett.2020,22,18,7158–7163.)
其中(E)-3-(4-氟-2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯的合成路径如下:
(实施例中与式I化合物与此反应条件相同,仅原料的选择不同)
合成步骤:
步骤一:在室温,氮气保护下,向5-氟-2-碘苯胺和丙烯酸乙酯的DMF溶液中加入Pd(OAc)2(5mol%),PPh3(10mol%),K2CO3(2eq)和TBAB(5mol%),在80℃下搅拌4小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,产率为95%。
步骤二:将步骤一所得产物溶于DCM中,后加入TsCl(1.1eq),吡啶(1.0eq),在室温下搅拌2小时,反应混合物用DCM稀释并浓缩,然后在DCM与PE混合液中重结晶,产率为61%。
核磁数据:1HNMR(300MHz,CDCl3)δ7.62(d,J=8.34MHz,2H),7.50-7.36(m,2H),7.28-7.19(m,3H),7.14(s,1H),6.90(td,J1=2.52MHz,J2=8.16MHz,1H),6.09(d,J=15.69MHz,1H),4.24(q,J=7.14MHz,2H),2.37(s,3H),1.33(t,J=7.11MHz,3H)ppm.13C NMR(300MHz,CDCl3)δ166.57,165.33,162.00,144.17,137.96,136.65,136.51,135.66,129.74,128.72,128.60,127.16,125.47,125.43,120.43,120.41,114.17,113.88,113.45,113.13,60.91,21.46,14.19ppm.19F NMR(300MHz,CDCl3)δ-107.58ppm.
下面结合实施例对本发明进行详细的说明,本发明各实施例反应如下:
实施例1,(6aS,10S,10aS)-7-(羟甲基)-5-甲苯磺酰基-5,6,6a,9,10,10a-六氢菲啶-10-羧酸乙酯
(6aS,10S,10aS)-ethyl-7-(hydroxymethyl)-5-tosyl-5,6,6a,9,10,10a-hexahydrophe nanthridine-10-carboxylate
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率80%(105mg),,该化合物为黄色固体(1a)。
核磁数据:1H NMR(300MHz,CDCl3)δ7.74(dd,J1=1.08MHz,J2=8.07MHz,1H),7.46(d,J=8.31MHz,2H),7.28-7.25(m,1H),7.21(d,J=8.13MHz,2H),7.10(td,J1=1.14MHz,J2=7.62MHz,1H),6.91(d,J=7.68MHz,1H),5.75(d,J=5.79MHz,1H),4.15-4.01(m,5H),3.42(t,J=12.18MHz,1H),2.62(td,J1=5.22MHz,J2=11.49MHz,1H),2.49-2.34(m,4H),2.28-2.13(m,1H),2.07-1.86(m,2H),1.18(t,J=7.11MHz,3H)ppm.13C NMR(400MHz,CDCl3)δ175.0,143.6,137.1,136.0,135.8,135.4,129.6,126.9,126.8,126.5,125.5,122.4,122.1,64.1,60.5,50.4,40.7,40.5,38.9,28.9,21.5,14.0ppm.
质谱数据:HRMS(CI+)calculated for C24H27NO5S[M-H]+:441.1610,Found:441.1613.
对比例1
与实施例1相比,反应中未加入Pd(PPh3)4,其它操作与实施例1相同。
在室温下,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入Xantphos(0.018mmol,6mol%)。将反应混合物在室温下搅拌28小时。反应无法得到目标产物。
对比例2
与实施例1相比,反应中未加入Xantphos,其它操作与实施例1相同。
在室温下,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%)。将反应混合物在室温下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有43%(56mg)。
对比例3
与实施例1相比,反应中加入Pd2(dba)3催化剂,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入Pd2(dba)3(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有63%(82mg)。
对比例4
与实施例1相比,反应中加入Pd(dppf)Cl2催化剂,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入Pd(dppf)Cl2(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有23%(30mg)。
对比例6
与实施例1相比,反应中加入Pd(cod)Cl2催化剂,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入Pd(cod)Cl2(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有33%(43mg)。
对比例7
与实施例1相比,反应中加入PdCl2催化剂,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入PdCl2(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有55%(72mg)。
对比例8
与实施例1相比,反应中加入Pd(PPh3)2Cl2催化剂,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入Pd(PPh3)2Cl2(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有60%(79mg)。
对比例9
与实施例1相比,反应中加入磷配体PPh3,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体PPh3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有72%(95mg)。
对比例10
与实施例1相比,反应中加入磷配体PCy3,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体PCy3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有68%(89mg)。
对比例11
与实施例1相比,反应中加入磷配体PEt3,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体PEt3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有65%(85mg)。
对比例12
与实施例1相比,反应中加入磷配体Aphos,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体Aphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有55%(72mg)。
对比例13
与实施例1相比,反应中加入磷配体HPCy2,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体HPCy2(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有45%(59mg)。
对比例14
与实施例1相比,反应中加入磷配体TPPO,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体TPPO(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有58%(76mg)。
对比例15
与实施例1相比,反应中加入磷配体DPEPhos,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体DPEPhos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有48%(63mg)。
对比例16
与实施例1相比,反应中加入磷配体dppb,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体dppb(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有63%(83mg)。
对比例17
与实施例1相比,反应中加入磷配体dppp,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体dppp(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有69%(90mg)。
对比例18
与实施例1相比,反应中加入磷配体dppe,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体dppe(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有60%(79mg)。
对比例19
与实施例1相比,反应中加入磷配体dcpe,其它操作与实施例1相同。
在室温,氮气保护下,向(E)-3-(2-(4-甲基苯基磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入磷配体dcpe(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化,收率仅有53%(70mg)。
实施例2(6aS,10S,10aS)-7-(羟甲基)-3-甲基-5-甲苯磺酰基-5,6,6a,9,10,10a-六氢菲啶-10-羧酸乙酯
(6aS,10S,10aS)-ethyl-7-(hydroxymethyl)-3-methyl-5-tosyl-5,6,6a,9,10,10a-hexa hydrophenanthridine-10-carboxylate
在室温,氮气保护下,向(E)-3-(4-甲基-2-(4-甲苯磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率86%(117.1mg)该化合物为无色固体(1b)。
核磁数据:1H NMR(300MHz,CDCl3)δ7.55(s,1H),7.45(d,J=8.28MHz,2H),7.20(d,J=8.01MHz,2H),6.90(d,J=7.86MHz,1H),6.77(d,J=7.83MHz,1H),5.72(d,J=5.67MHz,1H),4.15-3.96(m,5H),3.38(t,J=12.6MHz,1H),2.45-2.34(m,4H),2.33(s,3H),2.24-2.08(m,1H),2.04-1.79(m,2H),1.74(s,1H),1.17(t,J=7.11MHz,3H)ppm.13C NMR(300MHz,CDCl3)δ175.1,143.5,136.8,136.1,135.6,135.5,134.1,129.5,127.2,126.9,126.3,122.2,122.1,64.2,60.5,50.4,40.9,40.7,38.6,28.9,21.5,21.1,14.1ppm.
质谱数据:HRMS(CI+)calculated for C25H29NO5S[M-H]+:455.1766,Found:455.1768.
实施例3:(6aS,10S,10aS)-7-(羟甲基)-3-甲氧基-5-甲苯磺酰基-5,6,6a,9,10,10a-六氢菲啶-10-羧酸乙酯
(6aS,10S,10aS)-ethyl7-(hydroxymethyl)-3-methoxy-5-tosyl-5,6,6a,9,10,10a-hex ahydrophenanthridine-10-carboxylate
在室温,氮气保护下,向(E)-3-(4-甲氧基-2-(4-甲苯磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率87%(122.5mg)该化合物为无色固体(1c)。
核磁数据:1H NMR(300MHz,CDCl3)δ7.46(d,J=8.25MHz,2H),7.32(d,J=.58MHz,1H),7.20(d,J=8.16MHz,2H),6.78(d,J=8.52MHz,1H),6.63(dd,J1=2.58MHz,J2=8.52MHz,1H),5.71(d,J=5.55MHz,1H),4.15-3.99(m,5H),3.79(s,3H),3.37(t,J=12.06MHz,1H),2.56(td,J1=5.22MHz,J2=11.46MHz,1H),2.46-2.32(m,4H),2.24-2.08(m,1H),2.05-1.79(m,3H),1.17(t,J=7.11MHz,3H)ppm.13C NMR(300MHz,CDCl3)δ175.17,158.34,143.61,136.67,135.95,135.37,129.57,129.08,126.87,122.96,122.18,111.97,111.27,64.19,60.54,55.38,50.44,40.77,40.72,38.36,28.92,21.47,14.04ppm
质谱数据:HRMS(CI+)calculated for C25H29NO6S[M-H]+:471.1716,Found:471.1719.
实施例4:(6aS,10S,10aS)-7-(羟甲基)-3-氯-5-甲苯磺酰基-5,6,6a,9,10,10a-六氢菲啶-10-羧酸乙酯
(6aS,10S,10aS)-ethyl3-chloro-7-(hydroxymethyl)-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine-10-car boxylate
在室温,氮气保护下,向(E)-3-(4-氯-2-(4-甲苯磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率86%(122.9mg),该化合物为黄色固体(1d)。
核磁数据:1H NMR(300MHz,CDCl3)δ7.75(d,J=2.1MHz,1H),7.48(d,J=8.31MHz,2H),7.22(d,J=7.98MHz,2H),7.06(dd,J1=2.13MHz,J2=8.28MHz,1H),6.81(dd,J1=0.72MHz,J2=8.28MHz,1H),5.74(d,J=5.67MHz,1H),4.17-3.97(m,5H),3.39(dd,J1=11.28MHz,J2=12.18MHz,1H),2.59(td,J1=5.25MHz,J2=11.43MHz,1H),2.49-2.33(m,4H),2.25-2.10(m,1H),2.07-1.83(m,2H),1.17(t,J=7.11MHz,3H)ppm.13C NMR(300MHz,CDCl3)δ174.80,143.95,137.04,135.74,135.36,135.20,132.42,129.73,126.88,126.27,125.42,123.47,122.44,64.25,60.70,50.38,40.49,40.45,38.70,28.81,21.51,14.05ppm
质谱数据:HRMS(CI+)calculated for C24H26ClNO6S[M-H]+:475.9849,Found:475.9853.
实施例5:(6aS,10S,10aS)-7-(羟甲基)-3-氟-5-甲苯磺酰基-5,6,6a,9,10,10a-六氢菲啶-10-羧酸乙酯
(6aS,10S,10aS)-ethyl3-fluoro-7-(hydroxymethyl)-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine-10-car boxylate
在室温,氮气保护下,向(E)-3-(4-氟-2-(4-甲苯磺酰胺基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率80%(109.7mg),该化合物为白色固体(1e)。
核磁数据:1H NMR(300MHz,CDCl3)δ7.55-7.45(m,3H),7.22(d,J=5.07MHz,2H),6.88-6.74(m,2H),5.75(d,J=5.67MHz,1H),4.18-3.98(m,5H),3.39(t,J=12.15MHz),2.60(td,J1=5.28MHz,J2=11.46MHz,1H),2.50-2.32(m,4H),2.28-2.11(m,1H),2.09-1.87(m,2H),1.17(t,J=7.11MHz,3H)ppm.13C NMR(300MHz,CDCl3)δ174.95,162.90,159.67,143.93,137.22,137.07,135.73,135.24,132.44,132.39,129.71,127.20,126.87,123.41,123.29,122.47,113.72,113.39,112.10,111.82,64.27,60.69,50.42,40.61,40.48,38.61,28.85,21.50,14.04ppm
质谱数据:HRMS(CI+)calculated for C24H26FNO6S[M-H]+:459.1516,Found:459.1517.
实施例6:1-((6aS,10S,10aS)-7-(羟甲基)-5-甲苯磺酰基-5,6,6a,9,10,10a-六氢菲啶-10-基)乙酮
1-((6aS,10S,10aS)-7-(hydroxymethyl)-5-tosyl-5,6,6a,9,10,10a-hexahydrophenan thridin-10-yl)ethanone
在室温,氮气保护下,向(E)-4-甲基-N-(2-(3-氧代丁-1-烯-1-基)苯基)苯磺酰胺(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率82%(100.9mg),该化合物为白色固体(1f)。
核磁数据:1H NMR(400MHz,CDCl3)δ7.72(d,J=7.96MHz,1H),7.41(d,J=8.16MHz,2H),7.29-7.15(m,3H),7.08(t,J=7.44MHz,1H),6.65(d,J=7.6MHz,1H),5.74(d,J=5.04MHz,1H),4.12-3.97(m,3H),3.45(t,J=11.84MHz,1H),2.69(td,J1=5.28MHz,J2=11.64MHz,1H),2.40-2.23(m,4H),2.23-2.11(m,1H),1.97-1.84(m,5H),1.84-1.73(m,2H)ppm.13C NMR(400MHz,CDCl3)δ210.99,143.75,137.11,136.28,135.77,135.33,129.61,127.22,126.85,125.92,122.89,121.85,64.14,50.51,48.11,41.03,38.90,28.04,26.34,21.40ppm
质谱数据:HRMS(CI+)calculated for C23H25NO4S[M-H]+:411.1504,Found:411.1509.
实施例7:(6aS,10S,10aS)-5-叔丁基10-乙基7-(羟甲基)-6,6a,10,10a-四氢菲啶-5,10(9H)-二羧酸酯
(6aS,10S,10aS)-5-tert-butyl 10-ethyl 7-(hydroxymethyl)-6,6a,10,10a-tetrahydrophenanthridine-5,10(9H)-dicarboxylate
在室温,氮气保护下,向(E)-3-(2-((叔丁氧基羰基)氨基)苯基)丙烯酸乙酯(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.36mmol),在DCE(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入Xantphos(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率84%(98mg),该化合物为白色固体。
核磁数据:1H NMR(300MHz,CDCl3)δ7.52(s,1H),7.23-7.10(m,1H),6.99(d,J=4.17MHz,2H),5.82(d,J=5.61MHz,1H),4.34-4.00(m,4H),3.84(dd,J1=6.93MHz,J2=11.34MHz,1H),3.48(t,J=12.24MHz,1H),2.93-2.74(m,2H),2.63-2.49(m,1H),2.41-2.10(m,2H),1.80(s,1H),1.51(s,9H),1.28(t,J=7.11MHz,3H)ppm.
13C NMR(400MHz,CDCl3)δ175.9,154.0,137.4,136.7,135.2,126.2,124.6,123.6,122.0,121.7,80.9,64.3,60.9,49.2,40.8,39.8,39.4,29.2,28.3,14.1ppm.
质谱数据:HRMS(CI+)calculated for C22H29NO5[M-H]+:387.2046,Found:387.2048.
实施例8:(2-甲苯磺酰基-2,3,3a,6-四氢-1H-异吲哚-4-基)甲醇
(2-tosyl-2,3,3a,6-tetrahydro-1H-isoindol-4-yl)methanol
在室温,氮气保护下,向N-炔丙基-4-甲基苯磺酰胺(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.45mmol),在PhCl(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入PPh3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率76%(69.6mg),该化合物为白色固体。
核磁数据:1H NMR(400MHz,D-Acetone)δ7.82(d,J=8.20MHz,2H),7.50(d,J=8.04MHz,2H),5.75(s,1H),5.67(s,1H),4.17-4.00(m,4H),3.95(t,J=5.52MHz,1H),3.81(d,J=13.32MHz,1H),3.18-3.07(m,1H),2.80(dd,J1=9.20MHz,J2=11.16MHz,1H),2.76-2.68(m,2H),2.49(s,3H)ppm.13C NMR(400MHz,D-Acetone)δ144.12,136.04,135.70,134.62,130.32,128.17,121.38,117.45,64.96,52.80,50.89,39.25,27.60,21.15ppm
质谱数据:HRMS(CI+)calculated for C16H19NO3S[M-H]+:305.1086,Found:305.1089.
实施例9:(7-(4-氯苯基)-2-甲苯磺酰基-2,3,3a,6-四氢-1H-异吲哚-4-基)甲醇
(7-(4-chlorophenyl)-2-tosyl-2,3,3a,6-tetrahydro-1H-isoindol-4-yl)methanol
在室温,氮气保护下,向N-对氯苯基炔丙基-4-甲基苯磺酰胺(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.45mmol),在PhCl(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入PPh3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率90%(112mg),该化合物为黄色固体。
核磁数据:1H NMR(300MHz,D-Acetone)δ7.66(d,J=8.10MHz,2H),7.38(t,J=8.16MHz,4H),7.24(d,J=8.4MHz,2H),5.78,(s,1H),4.21(d,J=13.95MHz,1H),4.14-3.88(m,4H),3.60(d,J=13.95MHz,1H),3.39-3.05(m,2H),2.98-2.85(m,2H),2.39(s,3H)ppm.13C NMR(300MHz,D-Acetone)δ144.1,139.3,135.7,134.7,133.3,132.2,130.3,129.7,129.0,128.7,128.1,121.3,64.7,52.0,50.1,41.0,32.2,21.1ppm.
质谱数据:HRMS(CI+)calculated for C22H22ClNO3S[M-H]+:415.1009,Found:415.1013.
实施例10:(7-(4-氟苯基)-2-甲苯磺酰基-2,3,3a,6-四氢-1H-异吲哚-4-基)甲醇
(7-(4-fluorophenyl)-2-tosyl-2,3,3a,6-tetrahydro-1H-isoindol-4-yl)methanol
在室温,氮气保护下,向N-对氟苯基炔丙基-4-甲基苯磺酰胺(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.45mmol),在PhCl(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入PPh3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率86%(102.3mg),该化合物为白色固体。
核磁数据:1H NMR(300MHz,CDCl3)δ7.64(d,J=8.25MHz,2H),7.26(d,J=7.98MHz,2H),7.10-6.95(m,4H),5.81(s,1H),4.17-4.05(m,3H),3.99(t,J=8.76MHz,1H),3.62(d,J=13.74MHz,1H),3.38-3.20(m,1H),3.18-2.68(m,3H),2.39(s,3H),1.89(s,1H)ppm.13CNMR(300MHz,CDCl3)δ163.58,160.31,143.49,135.66,135.61,134.13,133.69,130.58,129.83,129.68,128.98,128.87,128.43,127.52,127.35,122.43,115.42,115.14,65.10,51.29,49.58,40.43,32.29,21.44ppm.19F NMR(300MHz,CDCl3)δ-114.17ppm
质谱数据:HRMS(CI+)calculated for C22H22FNO3S[M-H]+:399.1304,Found:399.1308.
实施例11:(7-(4-甲基苯基)-2-甲苯磺酰基-2,3,3a,6-四氢-1H-异吲哚-4-基)甲醇
(7-(p-tolyl)-2-tosyl-2,3,3a,6-tetrahydro-1H-isoindol-4-yl)methanol:
在室温,氮气保护下,向N-对甲基苯基炔丙基-4-甲基苯磺酰胺(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.45mmol),在PhCl(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入PPh3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率96%(112.2mg),该化合物为白色固体。
核磁数据:1H NMR(300MHz,CDCl3)δ7.64(d,J=8.25MHz,2H),7.25(d,J=7.95MHz,2H),7.13(d,J=7.89MHz,2H),6.99(d,J=8.1MHz,2H),5.81(s,1H),4.16(dt,J1=1.41MHz,J2=3.8MHz,1H),4.08(s,2H),3.99(dd,J1=7.71MHz,J2=8.76MHz,1H),3.69(d,J=13.77MHz,1H),3.38-3.20(m,1H),3.19-3.03(m,1H),2.97-2.81(m,1H),2.76(dd,J1=8.91MHz,J2=11.25MHz,1H),2.38(s,3H),2.35(s,3H)ppm.13C NMR(300MHz,CDCl3)δ143.32,137.20,136.65,134.10,133.78,129.73,129.61,129.15,128.96,127.31,127.10,122.51,65.06,51.27,49.71,40.40,32.10,21.39,21.05ppm
质谱数据:HRMS(CI+)calculated for C23H25NO3S[M-H]+:395.1555Found:395.1558.
实施例12:(7-(4-甲氧基苯基)-2-甲苯磺酰基-2,3,3a,6-四氢-1H-异吲哚-4-基)甲醇
(7-(4-methoxyphenyl)-2-tosyl-2,3,3a,6-tetrahydro-1H-isoindol-4-yl)methanol
在室温,氮气保护下,向N-对甲氧基苯基炔丙基-4-甲基苯磺酰胺(0.30mmol)和4,4-二乙烯基碳酸亚乙酯(0.45mmol),在PhCl(3.0mL)中的溶液中加入催化剂Pd(PPh3)4(0.009mmol,3mol%),然后加入PPh3(0.018mmol,6mol%)。将反应混合物在80℃下搅拌28小时。反应混合物用乙酸乙酯稀释并浓缩,然后将残留物直接通过硅胶柱层析纯化(洗脱液:石油醚/乙酸乙酯=3:1),收率96%(117.9mg),该化合物为白色固体。
核磁数据:1H NMR(300MHz,CDCl3)δ7.64(d,J=8.25MHz,2H),7.26(d,J=8.04MHz,2H),7.05(d,J=8.73MHz,2H),6.86(d,J=8.76MHz,2H),5.82(s,1H),4.17(dt,J1=1.38MHz,J2=13.77MHz,1H),4.09(s,2H),3.99(dd,J1=7.77MHz,J2=8.67MHz,1H),3.82(s,3H),3.69(d,J=13.68MHz,1H),3.37-3.21(m,1H),3.19-3.03(m,1H),2.97-2.80(m,1H),2.75(dd,J1=8.88MHz,J2=11.22MHz,1H),2.39(s,3H)ppm.13C NMR(300MHz,CDCl3)δ158.84,143.36,134.16,133.86,131.94,129.65,129.36,128.79,128.43,127.36,122.62,113.68,65.20,55.23,51.29,49.79,40.47,32.11,21.44ppm
质谱数据:HRMS(CI+)calculated for C23H25NO4S[M-H]+:411.1504,Found:41.
为了进一步验证本发明实施例制备的氢化菲啶类衍生物对肿瘤细胞的抑制性,对于本发明实施例1~6制备的化合物1a~1f进行了肿瘤细胞抑制试验。此外,由实施例7-12制备的化合物与化合物1a~1f属于相似衍生物,尽管没做活性测试,但是可以类推其具有相似的肿瘤抑制活性。
本发明实施例以商品化药物阿霉素(Doxorubicin)为对照组,以化合物1a~1f为实验组,以人体宫颈癌细胞系(HeLa)、肺癌细胞系(A549)、卵巢癌细胞系(A2780)为肿瘤细胞测试对象,以肺成纤维细胞系(MRC-5)作为正常细胞检测以上化合物对于正常细胞的毒副作用。采用MTT法检测细胞活性:取对数生长期细胞,消化、计数,并转移至96孔培养板,培养24小时后,将化合物1a~1f的不同浓度溶液与肿瘤细胞共孵育72小时后,除去上清液,加入100微升的MTT溶液(5mg/mL),继续孵育4小时,去上清液,每孔加入150微升DMSO,振荡混匀,然后用酶标仪测量在550nm和700nm的吸收。计算化合物对肿瘤细胞的抑制率。计算公式:抑制率(%)=(对照组吸光度值-给药组吸光度值)/(对照组吸光度值-空白组吸光度值)×100%。并通过IC50计算软件(中国药科大学)求出半数抑制浓度(IC50)。化合物1a~1f对不同肿瘤细胞的半数抑制浓度(IC50)如下表1所示:
表1
由上述测试结果可知,本发明实施例1~6制备的化合物1a~1f对于人体宫颈癌细胞系(HeLa)、肺癌细胞系(A549)、卵巢癌细胞系(A2780)等多种肿瘤细胞中均有一定的抑制效果;另一方面,在正常人类细胞如肺成纤维细胞系(MRC-5)中,与药物阿霉素相比,显示出更低的毒副作用,因此本发明合成的氢化菲啶类化合物展现出了一定的潜在应用价值。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (11)
2.根据权利要求1所述的氢化菲啶类衍生物的制备方法,其特征在于:所述2-氨基苯乙炔类化合物或2-氨基苯乙烯类化合物(式I)中R1选自氢、酯基、硝基、氰基、醛基、羰基、酰胺基、磷酸酯基、烷基、芳基、取代的芳基、杂芳基中的任意一种;
所述烷基选自甲基、乙基、丙基、异丙基、丁基、叔丁基和苄基中的一种;
所述芳基选自苯基、萘基、菲基、蒽基基中的一种;
所述取代的芳基中的取代基分别独立选自氟、氯、溴、碘、氰基、羟基、氨基、烷基、烷氧基、烯基、炔基、硝基、巯基、羟基烷氧基、烷基酯基、芳基、芳基烷基、杂环基、杂环基烷基、环烷基、芳氧基和杂芳氧基中的一种;
所述杂芳基选自吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吲哚基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噻唑基、喹啉基、异喹啉基和嘌呤基中的一种。
3.根据权利要求1所述的氢化菲啶类衍生物的制备方法,其特征在于:所述2-氨基苯乙炔类化合物或2-氨基苯乙烯类化合物(式I)中R2选自氟、氯、溴、碘、氰基、羟基、氨基、烷基、烷氧基、烯基、炔基、硝基、巯基、羟基烷氧基、烷基酯基、芳基、芳基烷基、杂环基、杂环基烷基、环烷基、芳氧基和杂芳氧基中的一种。
4.根据权利要求1所述的氢化菲啶类衍生物的制备方法,其特征在于:所述2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)中R3选自氢、磺酰基、酰基、磷酰基、烷基和芳基中的一种;
所述烷基选自甲基、乙基、丙基、异丙基、丁基、叔丁基和苄基中的一种;
所述芳基选自苯基、萘基、菲基、蒽基、苊烯基、苊基、芴基、芘基和荧蒽基中的一种。
5.根据权利要求1所述的氢化菲啶类衍生物的制备方法,其特征在于:所述4,4-二乙烯基碳酸亚乙酯(式II)中n为1、2或3;
所述4,4-二乙烯基碳酸亚乙酯(式II)中R4选自氢、烷基和芳基中的一种;
所述烷基选自甲基、乙基、丙基、异丙基、丁基、叔丁基和苄基中的一种;
所述芳基选自苯基、萘基、菲基、蒽基、苊烯基、苊基、芴基、芘基和荧蒽基中的一种。
6.根据权利要求1所述的氢化菲啶类衍生物的制备方法,其特征在于:所述磷配体选自PPh3,PEt3,PCy3,Xantphos,Aphos,HPCy2,TPPO,DPEPhos,dppb,dppp,dppe或dcpe;磷配体用量为2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)原料摩尔数的5-10mol%。
7.根据权利要求1所述的氢化菲啶类衍生物的制备方法,其特征在于:金属钯催化剂为Pd(PPh3)4,Pd2(dba)3,Pd(dppf)Cl2,Pd(cod)Cl2,PdCl2或Pd(PPh3)2Cl2,其用量为2-氨基苯乙炔或2-氨基苯乙烯类化合物(式I)原料摩尔数的5~10mol%。
9.一种肿瘤抑制剂,其特征在于,所述肿瘤抑制剂包含如权利要求1-7任一项所述的方法制备的氢化菲啶类衍生物。
10.如权利要求9所述的肿瘤抑制剂,其特征在于,所述肿瘤包括:人体宫颈癌细胞系、肺癌细胞系、卵巢癌细胞系中的一种或几种。
11.如权利要求10所述的肿瘤抑制剂,其特征在于,所述肿瘤抑制剂还包括口服液、胶囊剂、片剂、膏剂、粉剂、颗粒剂、丸剂、栓剂、定位靶向制剂、缓释制剂和控释制剂中的至少一种医药学上可接受的剂型。
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