CN112898285B - 含三氟甲基双噁唑类化合物及其合成方法和在抗癌药物中的应用 - Google Patents
含三氟甲基双噁唑类化合物及其合成方法和在抗癌药物中的应用 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 description 1
- 229960005498 telotristat ethyl Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
本发明公开了含三氟甲基双噁唑类化合物及其合成方法和在抗癌药物中的应用,属于有机化学领域。采用4‑取代‑2‑三氟甲基噁唑酮(1)与芳烯基噁唑(2)在硫脲催化剂催化下,高立体和高对映选择性反应得到含三氟甲基双噁唑类化合物(3)。该类化合物对肝癌、肺癌、胃癌、食管癌、乳腺癌和卵巢癌均具有一定的抑制作用。本发明方法中,原料易得,条件温和,反应效率高,反应路径短,得到的含三氟甲基双噁唑类化合物产物,具有高立体选择性和高光学纯度。
Description
技术领域
本发明属于有机化学中的不对称合成技术领域,具体涉及含三氟甲基双噁唑类化合物及其合成方法和在抗癌药物中的应用。
背景技术
有机氟化合物在新材料、诊断工具、生物研究、药物和农用化学品的发展中已变得至关重要。在这些领域中,F原子或CF3基团的引入对pKa、亲脂性、分子识别、构象和代谢氧化电位有重要影响,并进一步提高母核分子的效能、选择性、吸收和代谢。
含有手性三氟甲基的候选药物具有重要的药用价值:依法韦伦(Efavirenz)是HIV1型逆转录酶(HIV-1)的非核苷抑制剂;贝氟沙通(Befloxatone)可作为可逆选择性单胺氧化酶抑制剂使用;Telotristat ethyl是一种口服小分子色氨酸羟化酶抑制剂,有治疗类癌综合征的潜力;奥当卡替(Odanacatib)被报道为绝经后妇女骨质疏松症的潜在治疗药物,作为一种选择性的组织蛋白酶K抑制剂可导致骨密度的增加;Bitopertin是一种潜在的治疗精神分裂症和口服小分子甘氨酸转运蛋白-1抑制剂。因此,将三氟甲基引入有机手性分子已成为研究热点课题。
构建含手性三氟甲基化合物有两类策略:一是通过亲核、亲电或自由基直接不对称三氟甲基化反应;二是利用已含有三氟甲基基团的砌块作为亲核或亲电试剂参与的不对称催化反应。目前,含三氟甲基砌块作为亲电试剂参与的不对称反应已取得巨大的进展。
然而,α-CF3化合物型亲核试剂的种类以及作为亲核试剂直接参与的不对称催化反应还很有限,主要原因在于:α-CF3碳负离子和相应的有机金属物种通过β-氟消除生成二氟烯烃化合物;α-CF3基团强的吸电子效应降低α-CF3负碳离子的亲核性。因此,发展α-CF3化合物作为亲核试剂直接构建高对映选择性和非对映体选择性碳-碳(硫)键形成的反应具有挑战性。
发明内容
为了克服上述技术缺陷,本发明公开了含三氟甲基双噁唑类化合物及合成方法和抗癌药物应用。采用4-取代-2-三氟甲基噁唑酮(1)与芳烯基噁唑(2)在硫脲催化剂催化下,高立体和高对映选择性反应得到含三氟甲基双噁唑类化合物(3)。该类化合物对肝癌、肺癌、胃癌、食管癌、乳腺癌和卵巢癌均具有一定的抑制作用。本发明方法原料易得,条件温和,反应效率高,反应路径短,后处理简单,得到的含三氟甲基双噁唑类化合物产物,具有高立体选择性和高光学纯度。
本发明所述一种含三氟甲基双噁唑类化合物(3),其结构通式为:
其中,Ar为苯基、卤代苯基、三氟甲基苯基、硝基苯基、C1-C3取代苯基、C1-C3烷氧基苯基、噻吩基、呋喃基或喹啉基;R为C1-C6烷基、苯基或苄基。
进一步地,在上述技术方案中,Ar为C6H5、4-CF3C6H5、4-FC6H5、4-ClC6H5、4-MeOC6H5、4-MeC6H5、3-CF3C6F5、3-FC6F5、3-ClC6F5、3-MeOC6H5、3-MeC6H5、2-FC6H5、2-ClC6H5、2-BrC6H5、2-NO2C6H5、2,4-Cl2C6H5、3,5-F2C6H5、2-噻吩基、2-呋喃基或2-喹啉基;R为CH3、C2H4、C4H9、C6H5、CH2C6H5或C6H11。
本发明还提供了如上所述含三氟甲基双噁唑类化合物的制备方法,合成路线如下:
包括如下步骤:
将4-取代-2-三氟甲基噁唑酮(1)与芳烯基噁唑(2)在硫脲催化剂存在下,有机溶剂中反应得到含三氟甲基双噁唑类化合物(3)。
进一步地,在上述技术方案中,所述硫脲催化剂选自如下结构:
进一步地,在上述技术方案中,所述4-取代-2-三氟甲基噁唑酮(1)、芳烯基噁唑(2)与硫脲催化剂摩尔比为1.2-1.5:1.0:0.05-0.10。
进一步地,在上述技术方案中,所述有机溶剂选自甲苯、二氯甲烷、叔丁基甲基醚、五氟苯、氯苯、溴苯、三氟甲基苯、间二甲苯、3-溴甲苯或均三甲苯。
进一步地,在上述技术方案中,反应温度为20-30℃,反应时间为72-96小时。
本发明还提供了所述含三氟甲基双噁唑类化合物(3)或其消旋体在抗癌药物中的应用。
进一步地,在上述技术方案中,所述抗癌药物为肝癌、肺癌、胃癌、食管癌、乳腺癌或卵巢癌药物。
进一步地,在上述技术方案中,所述抗癌药物为PC-9和A549肺癌、MGC-803和SGC-7901胃癌、EC-9706和EC1食管癌、HepG2和Hep3B肝癌、MCF-7乳腺癌及A2780卵巢癌药物。
发明有益效果:
本发明高效制备含三氟甲基双噁唑类化合物,该方法具有如下优势:原料易得,条件温和,反应效率高,后处理简单,产物具有高立体选择性和高光学纯度。该类化合物应用于肝癌、肺癌、胃癌、食管癌、乳腺癌和卵巢癌药物中,具有良好的效果。
具体实施方式
以下结合具体实施例对本发明的技术方案作进一步详细说明,但本发明的保护范围并不局限于此。所有实施例中,除有特殊说明之外,d.r.值均为>20:1。
仪器与主要化学试剂
Bruker AVANCE NEO型核磁共振仪(瑞士)和Bruker AVANCE III HD 600MHZ型核磁共振仪(瑞士);UltiMate3000赛默飞高效液相色谱仪(美国)。
本发明实施过程中所用的原料、溶剂均为商业途径购进。
实施例1:
消旋化合物3合成步骤如下:
将化合物1(1.5eq,0.15mmol)、催化剂(0.1eq,0.01mmol)、1mL溶剂和化合物2(1.0eq,0.1mmol)加入到反应瓶中,在25℃反应72-96h,通过薄层板(TLC)监测反应进程,待反应结束后,旋干溶剂,通过柱层析(洗脱剂为PE:EA=400:1-200:1配置后,再与DCM按照4:1混合)分离得到消旋化合物3。催化剂选自三乙胺、四甲基胍、DBU、氢氧化钠等有机碱或无机碱。溶剂选自卤代烷烃、腈类、醚类、苯类等溶剂,溶剂的量只会影响反应速率,无其他影响,另外此反应不仅能够在常温下进行反应,在低温和高温下均能进行。
实施例2:
a除非另有说明,1a(0.075mmol),Cat.(0.005mmol),2a(0.05mmol),solvent(0.5mL).b分离产率.c dr值通过粗产品的氢谱分析得到.d ee值通过手性柱HPLC手性分析得到.
在反应条件的筛选过程中,首先考察了不同手性催化剂对反应的影响(entries1-13),发现C10为最佳手性催化剂,另外,除了上述表中所列催化剂,还有很多催化剂的使用也能够得到不同ee值的产物,如氨基酸衍生物、奎宁类、奎尼丁类等各类生物碱类催化剂。随后,考察了不同溶剂对反应的影响(entries 14-25),最终确定了五氟苯为最佳溶剂,随后采用C10对映异构体构型C11做催化剂,得到的产物为原产物的对映异构体。除上述所列溶剂,实验发现此反应在各类卤代烷烃、醚类、苯类等溶剂中均能够得到不同ee值的产物。另外此反应不仅能够在常温下进行反应,在低温和稍高温下均能进行,如-10℃和35℃。
反应条件的考察(以entry 24为例),化合物3a合成步骤如下:
将化合物1a(0.075mmol,1.5eq)、催化剂C10(0.005mmol,0.1eq)、0.5mL五氟苯和化合物2a(0.05mmol,1.0eq)加入到反应瓶中,25℃反应72h,通过薄层板(TLC)监测反应进程,待反应结束后,旋干溶剂,通过柱层析(洗脱剂为PE:EA=400:1-200:1配置后,再与DCM按照4:1混合)分离得到白色固体3a,收率为89%,96%ee。1H NMR(600MHz,CDCl3)δ7.24-7.18(m,3H),7.13-7.08(m,2H),4.41(dd,J=12.0,4.7Hz,1H),4.10-4.01(m,1H),3.84(dd,J=15.4,4.7Hz,1H),2.41(s,3H),0.99(s,9H).
实施例3:
化合物3b合成步骤如下:
将化合物1a(0.15mmol,1.5eq)、催化剂C10(0.01mmol,0.1eq)、1mL五氟苯和化合物2b(0.1mmol,1.0eq)加入到反应瓶中,25℃反应96h,通过薄层板(TLC)监测反应进程,待反应结束后,旋干溶剂,通过柱层析(洗脱剂为PE:EA=400:1-200:1配置后,再与DCM按照4:1混合)分离得到白色固体3b,收率为89%,94%ee。1H NMR(600MHz,CDCl3)δ7.53(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),4.50(dd,J=11.7,4.8Hz,1H),4.03(dd,J=15.5,11.7Hz,1H),3.87(dd,J=15.5,4.8Hz,1H),2.44(s,3H),1.03(s,9H).
实施例4:
化合物3c合成步骤如下:
将实施例3中化合物2b换成2c,反应72h,其它实验步骤及提纯方式参照实施例3进行,得到白色固体3c,收率为74%,96%ee。1H NMR(600MHz,CDCl3)δ7.15-7.09(m,2H),6.96-6.89(m,2H),4.41(dd,J=11.9,4.8Hz,1H),3.98(dd,J=15.3,11.9Hz,1H),3.81(dd,J=15.3,4.8Hz,1H),2.43(s,3H),1.05(s,9H).
实施例5:
化合物3d合成步骤如下:
将实施例3中化合物2b换成2d,反应72h,其它实验步骤及提纯方式参照实施例3进行,得到白色固体3d,收率为87%,96%ee。1H NMR(600MHz,CDCl3)δ7.22(d,J=8.1Hz,2H),7.08(d,J=8.1Hz,2H),4.39(dd,J=11.8,4.8Hz,1H),3.98(dd,J=15.4,11.8Hz,1H),3.80(dd,J=15.4,4.8Hz,1H),2.43(s,3H),1.05(s,9H).
实施例6:
化合物3e合成步骤如下:
将实施例3中化合物2b换成2e,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到白色固体3e,收率为52%,96%ee。1H NMR(600MHz,CDCl3)δ7.02(d,J=8.3Hz,2H),6.73(d,J=8.3Hz,2H),4.36(dd,J=12.4,4.7Hz,1H),4.09-3.93(m,1H),3.80(dd,J=15.3,4.7Hz,1H),3.71(s,3H),2.42(s,3H),1.03(s,9H).
实施例7:
化合物3f合成步骤如下:
将实施例3中化合物2b换成2f,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到白色固体3f,收率为58%,94%ee。1H NMR(600MHz,CDCl3)δ7.01(d,J=7.9Hz,2H),6.98(d,J=7.9Hz,2H),4.37(dd,J=12.0,4.7Hz,1H),4.03(dd,J=15.3,12.0Hz,1H),3.82(dd,J=15.3,4.7Hz,1H),2.42(s,3H),2.23(s,3H),1.00(s,9H).
实施例8:
化合物3g合成步骤如下:
将实施例3中化合物2b换成2g,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到无色油状3g,收率为72%,93%ee。1H NMR(600MHz,CDCl3)δ7.54-7.50(m,1H),7.45-7.37(m,3H),4.49(dd,J=11.7,4.8Hz,1H),4.02(dd,J=15.4,11.7Hz,1H),3.88(dd,J=15.4,4.8Hz,1H),2.44(s,3H),1.02(s,9H).
实施例9:
化合物3h合成步骤如下:
将实施例3中化合物2b换成2h,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到无色油状3h,收率为81%,91%ee。1H NMR(600MHz,CDCl3)δ7.25-7.19(m,1H),6.98-6.89(m,2H),6.89-6.82(m,1H),4.40(dd,J=11.7,4.7Hz,1H),3.96(dd,J=15.4,11.7Hz,1H),3.83(dd,J=15.4,4.7Hz,1H),2.44(s,3H),1.05(s,9H).
实施例10:
化合物3i合成步骤如下:
将实施例3中化合物2b换成2i,反应72h,其它实验步骤及提纯方式参照实施例3进行,得到白色固体3i,收率为94%,95%ee。1H NMR(600MHz,CDCl3)δ7.24-7.16(m,2H),7.13(s,1H),7.06(d,J=7.4Hz,1H),4.38(dd,J=11.7,4.7Hz,1H),3.98(dd,J=15.5,11.7Hz,1H),3.84(dd,J=15.5,4.7Hz,1H),2.44(s,3H),1.05(s,9H).
实施例11:
化合物3j合成步骤如下:
将实施例3中化合物2b换成2j,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到黄色油状3j,收率为72%,95%ee。1H NMR(600MHz,CDCl3)δ7.10(t,J=7.9Hz,1H),6.76-6.71(m,1H),6.69-6.64(m,1H),6.64-6.58(m,1H),4.38(dd,J=12.0,4.7Hz,1H),4.06(dd,J=15.3,12.0Hz,1H),3.82(dd,J=15.3,4.7Hz,1H),3.72(s,3H),2.42(s,3H),1.01(s,9H).
实施例12:
化合物3k合成步骤如下:
将实施例3中化合物2b换成2k,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到白色固体3k,收率为63%,95%ee。1H NMR(600MHz,CDCl3)δ7.08(t,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.94-6.81(m,2H),4.36(dd,J=12.0,4.6Hz,1H),4.06(dd,J=15.4,12.0Hz,1H),3.84(dd,J=15.4,4.6Hz,1H),2.42(s,3H),2.24(s,3H),0.98(s,9H).
实施例13:
化合物3l合成步骤如下:
将实施例3中化合物2b换成2l,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到白色晶体3l,收率为80%,93%ee。1H NMR(600MHz,CDCl3)δ7.25-7.18(m,2H),7.05-7.02(m,1H),6.99-6.94(m,1H),4.96-4.80(m,1H),4.00(dd,J=15.5,11.8Hz,1H),3.89(dd,J=15.5,4.8Hz,1H),2.43(s,3H),1.03(s,9H).
实施例14:
化合物3m合成步骤如下:
将实施例3中化合物2b换成2m,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到无色油状3m,收率为63%,96%ee。1H NMR(600MHz,CDCl3)δ7.31-7.24(m,2H),7.20-7.12(m,2H),5.25(dd,J=11.5,5.0Hz,1H),4.00-3.90(m,2H),2.43(s,3H),1.00(s,9H).
实施例15:
化合物3n合成步骤如下:
将实施例3中化合物2b换成2n,反应72h,其它实验步骤及提纯方式参照实施例3进行,得到无色油状3n,收率为90%,90%ee。1H NMR(600MHz,CDCl3)δ7.46(d,J=8.0Hz,1H),7.29-7.25(m,1H),7.24-7.20(m,1H),7.16-6.96(m,1H),5.26(dd,J=10.6,6.0Hz,1H),4.00-3.90(m,2H),2.44(s,3H),1.01(s,9H).
实施例16:
化合物3o合成步骤如下:
将实施例3中化合物2b换成2o,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到棕色油状3o,收率为76%,92%ee。1H NMR(400MHz,CDCl3)δ7.76-7.68(m,1H),7.59-7.47(m,2H),7.47-7.38(m,1H),5.50(dd,J=12.0,4.4Hz,1H),4.13(dd,J=15.0,4.4Hz,1H),3.97(dd,J=15.0,12.0Hz,1H),2.46(s,3H),0.99(s,9H).
实施例17:
化合物3p合成步骤如下:
将实施例3中化合物2b换成2p,反应72h,其它实验步骤及提纯方式参照实施例3进行,得到淡黄色固体3p,收率为76%,96%ee。1H NMR(600MHz,CDCl3)δ7.33(d,J=2.2Hz,1H),7.24(d,J=8.5Hz,1H),7.18(dd,J=8.5,2.2Hz,1H),5.19(dd,J=10.0,6.6Hz,1H),3.95-3.85(m,2H),2.46(s,3H),1.07(s,9H).
实施例18:
化合物3q合成步骤如下:
将实施例3中化合物2b换成2q,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到白色固体3q,收率为80%,88%ee。1H NMR(400MHz,CDCl3)δ6.74(m,3H),4.38(dd,J=10.7,5.5Hz,1H),3.94-3.75(m,2H),2.48(s,3H),1.14(s,9H).
实施例19:
化合物3r合成步骤如下:
将实施例3中化合物2b换成2r,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到黄色固体3r,收率为67%,82%ee。1H NMR(600MHz,CDCl3)δ7.27-7.25(m,1H),6.22-6.17(m,1H),6.16-6.11(m,1H),4.50(dd,J=11.7,4.7Hz,1H),3.94-3.83(m,2H),2.48(s,3H),1.16(s,9H).
实施例20:
化合物3s合成步骤如下:
将实施例3中化合物2b换成2s,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到黄色固体3s,收率为70%,93%ee。1H NMR(600MHz,CDCl3)δ7.17-7.11(m,1H),6.92-6.76(m,2H),4.72(dd,J=11.7,4.7Hz,1H),4.11-3.71(m,2H),2.45(s,3H),1.07(s,9H).
实施例21:
化合物3t合成步骤如下:
将实施例3中化合物2b换成2t,反应96h,其它实验步骤及提纯方式参照实施例3进行,得到黄色固体3t,收率为62%,85%ee。1H NMR(400MHz,CDCl3)δ8.03(d,J=8.4Hz,1H),7.98-7.93(m,1H),7.76-7.71(m,1H),7.71-7.65(m,1H),7.55-7.48(m,1H),7.21(d,J=8.4Hz,1H),4.63(dd,J=11.5,3.3Hz,1H),4.48(dd,J=15.8,11.5Hz,1H),4.07(dd,J=15.8,3.3Hz,1H),2.41(s,3H),0.78(s,9H).
实施例22:
活性测试实验
(1)以MTT法测定化合物Racemic-3i和高光学纯度化合物3i分别对PC-9、A549肺癌细胞,MGC-803、SGC-7901胃癌细胞,EC-9706、EC1食管癌细胞,HepG2、Hep3B肝癌细胞,MCF-7乳腺癌细胞以及A2780卵巢癌细胞的毒性作用,并分别计算两种化合物的半数抑制浓度(IC50)。
(2)以MTT法测定高光学纯度化合物3b、3c、3d、3h、3n和3s分别对HepG2肝癌细胞、MGC-803胃癌细胞和PC-9肺癌细胞的毒性作用,计算每种化合物的半数抑制浓度(IC50)。
测定方法的具体步骤为:
将肿瘤细胞系维持在含有质量百分比10%胎牛血清和2mM谷氨酰胺的RPMI1640中。使细胞在体积百分比5%CO2的加湿培养箱中于37℃生长。将40uL细胞播种(10000细胞/孔)于Corning黑色透明底384孔板中的生长培养基中,于37℃下在体积百分比5%CO2中培养过夜。使用Echo555声波定剂量(Cacoustically dosed),将质量百分比100%DMSO连续稀释的本发明化合物加至细胞。将培养板再培养2小时,轻柔混合培养基之后,将40uL裂解缓冲液添加到各孔中。将Greiner黑色高结合力384孔板用捕捉抗体覆盖,然后用质量百分比3%BAS进行封闭。接着去除封闭液,将15uL裂解液转移到Greiner黑色高结合力384孔板中,培养2小时。轻柔混合和用PBS清洗培养板之后,添加20uL检测抗体,培养2小时。轻柔混合和用PBS清洗培养板之后,添加20uL QuantaBlu荧光过氧化物酶底物,培养1小时。将20uLQuantaBlu终止溶液添加到培养板中,采用352nm激发波长和460nm发射波长的Envision微孔板检测仪读出荧光。将各化合物获得的数据输入合适的软件包以执行曲线拟合分析。基于此数据并通过计算获得50%效果所需的化合物浓度来确定IC50的值。结果如下两个表所示:
表1
表2:
racemic-3i对PC-9、A549肺癌细胞,MGC-803、SGC-7901胃癌细胞,EC-9706、EC1食管癌细胞,HepG2、Hep3B肝癌细胞,MCF-7乳腺癌细胞以及A2780卵巢癌细胞的IC50分别为6.29、>100、5.73、23.72、>100、11.54、3.24、>100、7.23和12.04μM。
高光学纯度化合物3i对PC-9、A549肺癌细胞,MGC-803、SGC-7901胃癌细胞,EC-9706、EC1食管癌细胞,HepG2、Hep3B肝癌细胞,MCF-7乳腺癌细胞以及A2780卵巢癌细胞的IC50分别为6.26、>100、4.18、6.53、>100、6.54、2.14、>100、9.53和6.50μM。
3b、3c、3d、3h、3n和3s对HepG2肝癌细胞的IC50值分别为6.10、12.8、12.49、12.13、12.41和25.33。
3b、3c、3d、3h、3n和3s对MGC-803胃癌细胞的IC50值分别为6.06、13.21、12.58、7.67、12.43和27.95。
3b、3c、3d、3h、3n和3s对Pc-9肺癌细胞的IC50值分别为3.76、12.51、6.77、6.03、12.02和24.82。
上述实验结果表明:Racemic-3i和高光学纯度化合物3i分别对Pc-9、A549肺癌细胞,MGC-803、SGC-7901胃癌细胞,EC-9706、EC1食管癌细胞,HepG2、Hep3B肝癌细胞,MCF-7乳腺癌细胞以及A2780卵巢癌细胞均具有一定的抑制作用,其中对HepG2肝癌细胞尤为明显。
另外3b、3c、3d、3h、3n和3s对HepG2肝癌细胞、MGC-803胃癌细胞和Pc-9肺癌细胞均具有一定的抑制作用,其中3b的作用最为显著,具有成药的潜力,因此,按照药物开发的一般途径(先进行常规的抗肿瘤体外筛选,然后进行针对性的研究),本发明化合物可以通过与人体可接受的酸成盐或与药用载体混合制备新的抗肿瘤药。
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,本发明还会有各种变化和改进,这些变化和改进均落入本发明保护的范围内。
Claims (10)
2.根据权利要求1所述含三氟甲基双噁唑类化合物,其特征在于:Ar为C6H5、4-CF3C6H5、4-FC6H5、4-ClC6H5、4-MeOC6H5、4-MeC6H5、3-CF3C6H5、3-FC6H5、3-ClC6H5、3-MeOC6H5、3-MeC6H5、2-FC6H5、2-ClC6H5、2-BrC6H5、2-NO2C6H5、3,4-Cl2C6H5、3,5-F2C6H5、2-噻吩基、2-呋喃基或2-喹啉基;R为CH3、C2H5、C4H9、C6H5、CH2C6H5或C6H11。
5.根据权利要求3或4所述含三氟甲基双噁唑类化合物的制备方法,其特征在于:所述4-取代-2-三氟甲基噁唑酮1、芳烯基噁唑2与硫脲催化剂摩尔比为1.2-1.5:1.0:0.05-0.10。
6.根据权利要求3所述含三氟甲基双噁唑类化合物的制备方法,其特征在于:所述有机溶剂选自有机溶剂选自甲苯、二氯甲烷、叔丁基甲基醚、五氟苯、氯苯、溴苯、三氟甲基苯、间二甲苯、3-溴甲苯或均三甲苯。
7.根据权利要求3所述含三氟甲基双噁唑类化合物的制备方法,其特征在于:反应温度为20-30℃,反应时间为72-96小时。
8.如权利要求1所述含三氟甲基双噁唑类化合物或其消旋体在制备抗癌药物中的应用。
9.根据权利要求8所述含三氟甲基双噁唑类化合物或其消旋体在制备抗癌药物中的应用,其特征在于:所述抗癌药物为PC-9和A549肺癌、MGC-803和SGC-7901胃癌、EC-9706和EC1食管癌、HepG2和Hep3B肝癌、MCF-7乳腺癌或A2780卵巢癌药物。
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