CN106946781B - 一种吡唑二苯基脲类衍生物及其制备方法和用途 - Google Patents
一种吡唑二苯基脲类衍生物及其制备方法和用途 Download PDFInfo
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- C07D231/16—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种吡唑二苯基脲类衍生物及其制备方法和用途,其中吡唑二苯基脲类衍生物的结构式为:式中:R=H、4‑CH3、3‑CH3、4‑Cl、3‑Cl、4‑F、3‑F、4‑Br、3‑Br、4‑CF3、3‑CF3、4‑OCF3或3‑OCF3。本发明依据药物的拼合原理和基于结构的药物分子设计理念,基于吡唑和脲的活性,对同时具有吡唑和脲的先导化合物进行结构修饰和先导优化,设计出一种新型的吡唑二苯基脲类衍生物。生物活性测试结果表明此系列化合物对黑色素瘤有较好的抑制活性。
Description
技术领域
本发明涉及一种吡唑二苯基脲类衍生物及其制备方法和用途。
背景技术
吡唑是一类含有两个处于相邻位置氮原子的五元杂环,因结构的可塑性较高且具有高效广谱的生物活性:抗菌、抗肿瘤、抗惊厥、抗炎等。自从对阿霉素改造后的蒽吡唑类络索蒽醌对乳腺癌和转移性乳腺癌有良好的治疗效果(Semin Oncol.(1992).19(6):687-94)。研究人员设计了大量的吡唑衍生物,且从中筛选出许多高抑肿瘤活性化合物。吡唑肽类化合物对肺癌细胞A549的抑制活性较好(Bioorg.Med.Chem.Lett.,2012,22,6882-6887)。4-吡唑-1,8-萘酰亚胺衍生物对人乳腺癌细胞、人宫颈癌细胞、和肺癌细胞都表现出了良好的抑制活性。
脲衍生物如芳香脲,杂环脲,和硫脲通常是一种最有效的抗癌剂,对多种白血病和实体瘤都具有活性(Cancer Res.2002,62(21),6080-6088)。含有1H--吡咯并[3,2-c]吡啶的二芳基脲类衍生物对(A375P)人黑素瘤细胞系和(NCI-9)人黑素瘤细胞系细胞系的体外抗增殖活性,表现出了比索拉菲尼更好的抗A375P活性(European Journal of MedicinalChemistry 45(2010)2928-2937)。杂环脲衍生物通过对受体酪氨酸激酶(RTK),RAF激酶,蛋白质酪氨酸激酶(PTK)和NADH氧化酶(在肿瘤产生的许多方面中起关键作用)有抑制作用(Anti-Cancer Agents in Medicinal Chemistry,2009,9,471-480)。含吡唑基的酰基硫脲类化合物对白血病细胞、结肠癌细胞、肝癌细胞三种癌细胞都有较好的抑制活性(Bioorg.Med.Chem.,2013,21,3859-3865.)。
发明内容
本发明旨在提供一种吡唑二苯基脲类衍生物及其制备方法和用途。本发明依据药物的拼合原理和基于结构的药物分子设计理念,基于吡唑和脲的活性,对同时具有吡唑和脲的先导化合物进行结构修饰和先导优化,设计出一种新型的吡唑二苯基脲类衍生物。生物活性测试结果表明此系列化合物对黑色素瘤有较好的抑制活性。
本发明吡唑二苯基脲类衍生物,其结构式为:
式中:
R=H、4-CH3、3-CH3、4-Cl、3-Cl、4-F、3-F、4-Br、3-Br、4-CF3、3-CF3、4-OCF3或3-OCF3。
本发明吡唑二苯基脲类衍生物的制备方法,包括如下步骤:
步骤1:向0℃的N,N-二甲基甲酰胺(冰水浴中冷却)中滴加三氯氧磷,约20分钟滴完,滴完后将圆底烧瓶转移至油浴锅中,向体系中加入3-甲基-1-苯基-1H-吡唑,升温至100℃回流反应1小时,反应结束后冷却,将反应液在搅拌下慢慢倒入120ml冰水混合物中(调pH值至中性),静置2小时,抽虑,干燥,得化合物A—5-Cl-3-甲基-1-苯基-1H-吡唑-4-甲醛,为灰白色固体;
步骤1中,3-甲基-1-苯基-1H-吡唑、N,N-二甲基甲酰胺与三氯氧磷的摩尔比为1:5:9。
步骤2:向无水乙醇中加入步骤1所得化合物A和苯胺衍生物,TLC检测,直至沉淀产生完全后停止反应,抽滤,干燥,得化合物B—吡唑-4-希夫碱衍生物;
步骤2中,化合物A与苯胺衍生物的摩尔比为1:1.2。
步骤2中,无水乙醇的用量为每毫摩尔化合物A加10ml。
所述苯胺衍生物为苯胺、4-甲基苯胺、3-甲基苯胺、4-氯苯胺、3-氯苯胺、4-氟苯胺、3-氟苯胺、4-溴苯胺、3-溴苯胺、4-三氟甲基苯胺、3-三氟甲基苯胺、4-三氟甲氧基苯胺、或3-三氟甲氧基苯胺。
步骤3:向步骤2的反应体系中缓慢滴加硼氢化钠,常温下搅拌2小时至反应液彻底澄清,向反应体系中加水,用二氯甲烷萃取2-3次,合并有机相后减压浓缩,薄层色谱法(洗脱液为乙酸乙酯/石油醚=1/10,v/v)进行分离纯化得到化合物C—1-苯基-4-甲基苯胺结构的吡唑衍生物;
步骤3中,化合物A与硼氢化钠的摩尔比为1:4。
步骤4:将步骤3所得化合物C溶于氯仿中,再向其中滴加异氰酸苯酯,常温反应1小时后TLC分离得到目标产物。
步骤4中,化合物C与异氰酸苯酯的摩尔比为1:1.2。
步骤4中,氯仿的用量为每毫摩尔化合物C加1ml。
本发明吡唑二苯基脲类衍生物的用途,是在制备BRAFV600E抑制剂中的应用。
本发明的有益效果体现在:
本发明的的吡唑二苯基脲类衍生物对小鼠黑色素瘤细胞株(B16-F10)有明显的抗增殖作用,因此本发明的吡唑二苯基脲类衍生物可以在制备抗肿瘤药物中应用。
具体实施方式
通过以下实施例进一步详细说明本发明,但应注意本发明的范围并不受这些实施例的任何限制。
实施例1:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-1,3-二苯基脲(化合物1)
制备过程如下:
步骤1:在常温搅拌台上的50ml三口瓶中放入一颗磁力搅拌子并加入2.3ml(0.05mol)DMF,冰水浴冷却至0℃左右滴加8.2ml(0.09mol)POCl3,约20分钟滴完,滴完后将三口瓶转移至油浴锅中,向体系中加入3-甲基-1-苯基-1H-吡唑1.75g(0.01mol),升温至100℃回流反应1小时,反应结束后冷却,将反应液在搅拌下慢慢倒入盛有120ml冰水混合物的大烧杯中(调pH值至中性),静置2小时,抽虑,干燥,得到化合物A—5-Cl-3-甲基-1-苯基-1H-吡唑-4-甲醛,为灰白色固体。
步骤2:向100ml单口圆底烧瓶中加入10mL无水乙醇和磁力搅拌子,然后加入化合物A(1mmol)和苯胺(1.2mmol),TLC检测,直至沉淀产生完全后停止反应,抽滤,干燥,得化合物B—吡唑-4-希夫碱衍生物;
步骤3:向圆底烧瓶中缓慢向反应体系中滴加硼氢化钠(38mg,4mmol),为保证实验完全可加入稍微过量硼氢化钠,在常温下搅拌反应2小时,至反应液彻底澄清;向反应体系中加水,转移出至150ml的分液漏斗中,每次加50ml二氯甲烷萃取2-3次,将萃取液收集到锥形瓶中,然后用100ml圆底烧瓶将萃取液用旋转蒸发仪减压蒸去二氯甲烷后得到仲胺产物并浓缩转移到5ml的圆底烧瓶中,最后将仲胺产物溶于少量二氯甲烷中,采用制备型薄层色谱法(洗脱液为乙酸乙酯/石油醚=1/10,v/v)进行分离纯化得到化合物C—1-苯基-4-甲基苯胺结构的吡唑衍生物;
步骤4:将步骤3所得化合物C(1mmol)溶于1mL氯仿中,再向其中滴加异氰酸苯酯(1.2mmol),常温反应1小时后TLC分离得到目标产物,为淡黄色粉末,收率80%,熔点135-136℃。1H NMR(600MHz,DMSO)δ7.71(s,1H),7.48(t,J=7.7Hz,2H),7.40(dt,J=13.4,7.9Hz,7H),7.29(t,J=7.2Hz,1H),7.19(dt,J=7.8,3.7Hz,4H),6.92(t,J=7.0Hz,1H),4.81(s,2H),2.10(s,3H).13C NMR(151MHz,CDCl3)δ156.62,152.33,142.58,141.39,140.74,132.89,132.00,131.57,131.47,131.34,130.67,127.42,125.71,122.11,116.58,43.85,15.16.
实施例2:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-(对甲苯基)脲(化合物2)
制备方法同实施例1,不同的是以4-甲基苯胺代替苯胺,得到黄色固体粉末目标化合物,收率63%,熔点127-128℃。
1H NMR(600MHz,CDCl3)δ7.47-7.40(m,4H),7.37(d,J=4.6Hz,1H),7.28(t,J=7.4Hz,2H),7.25-7.20(m,4H),7.05(d,J=7.7Hz,2H),6.99(t,J=7.3Hz,1H),4.91(d,J=12.0Hz,2H),2.38(s,3H),2.27(d,J=11.1Hz,3H).13C NMR(151MHz,DMSO)δ157.42,152.01,150.06,143.00,142.95,140.84,133.72,132.23,131.29,129.23,127.71,125.40(s),125.05(s),124.02–123.99,123.53,122.32-122.28,121.29-121.24,116.79,44.63,15.37.
实施例3:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-(间甲苯基)脲(化合物3)
制备方法同实施例1,不同的是以3-甲基苯胺代替苯胺,得到黄色固体粉末目标化合物,收率60%,熔点109-110℃。
1H NMR(600MHz,DMSO)δ7.64(s,1H),7.49(t,J=7.7Hz,2H),7.44-7.34(m,5H),7.25(t,J=7.7Hz,1H),7.19(t,J=7.8Hz,2H),7.09(t,J=13.2Hz,1H),7.01(s,1H),6.98-6.89(m,2H),4.78(s,2H),2.27(s,3H),2.10(s,3H).13C NMR(151MHz,DMSO)δ157.41,152.07,143.57,142.94,141.92,140.88,132.32,132.08,131.26,131.07,129.17,128.61,127.65,125.23,123.15,117.12,58.00,44.39,24.00,15.37.
实施例4:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-(对氯苯基)脲(化合物4)
制备方法同实施例1,不同的是以4-氯苯胺代替苯胺,得到白色固体粉末目标化合物,收率65%,熔点158-159℃。
1H NMR(600MHz,DMSO)δ8.10(s,1H),7.52-7.45(m,3H),7.41(t,J=8.1Hz,3H),7.37(d,J=7.6Hz,2H),7.32-7.12(m,5H),6.95(t,J=7.3Hz,1H),4.85(s,2H),2.20-2.07(m,3H).13C NMR(151MHz,DMSO)δ151.81,149.69,140.97,140.70,132.28,131.17,128.28-128.15,127.73,124.10,119.29,118.19,117.58-117.33,113.02,112.67,58.50,39.60,15.55.
实施例5:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-(间氯苯基)脲(化合物5)
制备方法同实施例1,不同的是以3-氯苯胺代替苯胺,得到白色固体粉末目标化合物,收率63%,熔点96-98℃。
1H NMR(600MHz,DMSO)δ8.04(s,1H),7.49(t,J=7.3Hz,2H),7.46-7.32(m,7H),7.29(d,J=1.4Hz,1H),7.21(t,J=7.4Hz,2H),7.15-7.11(m,1H),6.94(t,J=7.2Hz,1H),4.82(s,2H),2.14(s,3H).13C NMR(151MHz,DMSO)δ157.29,152.04,145.36,142.94,140.83,136.36,133.94,132.28,131.61,131.29,130.44,130.17,129.21,127.69,125.40,123.45,116.81,44.45,15.42.
实施例6:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-(对氟苯基)脲(化合物6)
制备方法同实施例1,不同的是以4-氟苯胺代替苯胺,得到白色固体粉末目标化合物,收率65%,熔点136-137℃。
1H NMR(600MHz,DMSO)δ7.74(s,1H),7.49(t,J=7.7Hz,2H),7.45-7.36(m,5H),7.28-7.15(m,6H),6.97-6.89(m,1H),4.78(s,2H),2.12(s,3H).13C NMR(151MHz,DMSO)δ157.26,152.05,145.62,142.91,140.84,133.89,132.27,131.27,129.14,127.81-127.56,125.40,123.43,118.79,117.18,116.88,44.50,15.43.
实施例7:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-(间氟苯基)脲(化合物7)
制备方法同实施例1,不同的是以3-氟苯胺代替苯胺,得到白色固体粉末目标化合物,收率70%,熔点140-141℃。
1H NMR(600MHz,DMSO)δ7.99(s,1H),7.54-7.45(m,2H),7.45-7.35(m,6H),7.21(t,J=7.9Hz,2H),7.12(t,J=7.8Hz,2H),7.02(d,J=7.6Hz,1H),6.93(dd,J=16.9,9.6Hz,1H),4.83(s,2H),2.15(s,3H).13C NMR(151MHz,CDCl3)δ156.28,152.26,144.31,141.11,140.81,134.00,131.55,130.70,129.92,127.72,127.43,126.02,122.33,119.30,119.16,118.48,116.19,43.99,15.26.
实施例8:1-(4-溴苯基)-1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-基)甲基)-3-苯基脲(化合物8)
制备方法同实施例1,不同的是以4-溴苯胺代替苯胺,得到白色固体粉末目标化合物,收率61%,熔点164-165℃。
1H NMR(600MHz,DMSO)δ7.94(s,1H),7.55(d,J=8.6Hz,2H),7.49(t,J=7.7Hz,2H),7.45-7.35(m,5H),7.20(t,J=7.9Hz,2H),7.15(d,J=8.6Hz,2H),6.93(t,J=7.3Hz,1H),4.80(s,2H),2.13(s,3H).13C NMR(151MHz DMSO)δ157.32,152.02,143.20,142.94,140.83,135.47133.82,132.28,131.27,129.11,127.70,125.37,123.47,123.14,116.89,44.43,15.44.
实施例9:1-(3-溴苯基)-1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-基)甲基)-3-苯基脲(化合物9)
制备方法同实施例1,不同的是以3-溴苯胺代替苯胺,得到白色固体粉末目标化合物,收率40%,熔点112-113℃。
1H NMR(600MHz,DMSO)δ8.17(s,1H),7.62(d,J=7.8Hz,1H),7.57(dd,J=15.0,7.2Hz,1H),7.48(dd,J=15.8,7.9Hz,4H),7.41(t,J=7.5Hz,3H),7.35(d,J=7.5Hz,2H),7.22(q,J=8.3Hz,2H),6.95(t,J=7.3Hz,1H),4.87(s,2H),2.15(d,J=14.1Hz,3H).13CNMR(151MHz,CDCl3)δ156.24,152.27,144.07,141.07,140.78,135.17,134.47,134.00,131.56,130.72,130.04,127.53,126.05,126.01,122.37,116.09,43.99,32.33,15.27.
实施例10:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-((对三氟甲基)苯基)脲(化合物10)
制备方法同实施例1,不同的是以4-三氟甲基苯胺代替苯胺,得到白色固体粉末目标化合物,收率42%,熔点104-105℃。
1H NMR(600MHz,CDCl3)δ7.71(d,J=7.9Hz,1H),7.46-7.34(m,1H),7.28(dd,J=17.3,8.7Hz,4H),7.04(t,J=6.9Hz,6H),6.05(s,2H),5.01-4.90(m,2H),2.36-2.25(m,3H).13C NMR(151MHz,CDCl3)δ156.34,152.15,140.74,132.17,131.91,131.68,130.95,130.03,128.73,127.46,126.41,122.66,121.42,121.35,116.10,44.24,32.33,15.26.
实施例11:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-((间三氟甲基)苯基)脲(化合物11)
制备方法同实施例1,不同的是以3-三氟甲基苯胺代替苯胺,得到白色固体粉末目标化合物,收率50%,常温下液态。
1H NMR(600MHz,DMSO)δ7.68(s,1H),7.49(t,J=7.7Hz,2H),7.43-7.39(m,2H),7.38(d,J=8.3Hz,4H),7.29(t,J=7.4Hz,1H),7.19(dd,J=7.3,5.1Hz,4H),6.92(t,J=7.3Hz,1H),4.81(s,2H),2.10(s,3H).13C NMR(151MHz,DMSO)δ157.37,152.02,144.70,142.91,140.79,135.87,133.60,132.90,132.26,131.31,129.18,128.28,127.62,126.72,125.47,123.53,116.67,44.39,32.12,15.35.
实施例12:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-((对三氟甲氧基)苯基)脲(化合物12)
制备方法同实施例1,不同的是以4-三氟甲氧基苯胺代替苯胺,得到白色固体粉末目标化合物,收率54%,熔点97-98℃。
1H NMR(600MHz,CDCl3)δ7.71(d,J=7.7Hz,2H),7.45-7.39(m,5H),7.37(t,J=7.3Hz,3H),7.34-7.32(m,1H),7.29(t,J=7.8Hz,3H),4.96(s,2H),2.29(s,3H).13C NMR(151MHz,CDCl3)δ156.39,152.26,151.61,141.09,140.68,133.68,131.61,131.53,130.78,130.06,127.38,126.08,125.19,122.38,116.15,44.07,32.32,15.21.
实施例13:1-((5-氯-3-甲基-1-苯基-1H-吡唑-4-)甲基)-3-苯基-1-((间三氟甲氧基)苯基)脲(化合物13)
制备方法同实施例1,不同的是以3-三氟甲氧基苯胺代替苯胺,得到白色固体粉末目标化合物,收率54%,熔点69-70℃。
1H NMR(600MHz,CDCl3)δ7.53(d,J=8.4Hz,2H),7.43(d,J=5.8Hz,4H),7.37(d,J=7.0Hz,2H),7.30(dd,J=19.0,10.1Hz,4H),7.16(dd,J=14.1,7.7Hz,1H),7.02(dd,J=13.4,6.2Hz,1H),4.92(m,2H),2.32(m,2H).13C NMR(151MHz,CDCl3)δ156.22,152.90,152.21,144.22,140.96,140.55,134.09,131.61,130.86,130.57,129.06,127.60,126.18,124.77,123.79,122.46,116.11,44.24,32.32,27.37.
实施例14:吡唑二苯基脲类衍生物(化合物1-13)体外抗黑色素瘤活性评价
1、采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定化合物1-13对小鼠黑色素瘤细胞株(B16-F10)的抗增殖活性。
2、取事先培养好的对数期细胞,胰蛋白酶消化后收集细胞,用移液管吹打均匀,取两滴细胞悬液锥虫蓝(Trypan Blue)染色,于显微镜下计数活细胞数目(死细胞数目不得超过5%),用配得的10%胎牛血清RPMI1640培养液调整细胞数目至5×104个细胞/mL;
3、于96孔细胞培养板中每孔加入100μL细胞悬液(边缘孔使用无菌水填充),每组设置对照。将培养板置于37℃、5%CO2培养箱中培养至细胞单层铺满孔底;
4、取出培养板后于每孔中加1μL含不同浓度梯度的待测药品溶液,每个浓度设3个平行孔。加完药后培养板于微孔板振荡器上振荡混匀,置于37℃、5%CO2培养箱中继续孵育48小时;
5、取出培养板,每孔加入10μL 5mg/mL的MTT液(即5%MTT),振荡混匀,继续培养4小时;
6、终止培养,准备溶解结晶:加入每孔100μL SDS裂解液后培养6-8小时;
7、显微镜下观察结晶全部溶解后在570nm波长下测试吸光度;
8、结果统计
细胞50%生长抑制所需的药物浓度GI50由SPSS 13.0统计软件计算可得,计算公式如下:GI50:即[(T-T0)/(C-T0)]=50%
其中,T:加药组的细胞OD值,T0:表示加药时对照组细胞的OD值,C:对照组细胞OD值。测得的IC50见表1所示
表1化合物1-13对B16-F10细胞的抗增殖活性。
从表1中可以看出,本发明的的吡唑二苯基脲类衍生物对小鼠黑色素瘤细胞株(B16-F10)有明显的抗增殖作用,其中大部分化合物展示出了强于阳性对照5-Fu的抗增殖活性,化合物5具有最强的抗增殖活性(IC50=5.4μM)。因此本发明的吡唑二苯基脲类衍生物可以在制备抗肿瘤药物中应用。
Claims (9)
1.一种吡唑二苯基脲类衍生物,其特征在于其结构式为:
式中:
R=H、4-CH3、3-CH3、4-Cl、3-Cl、4-F、3-F、4-Br、3-Br、4-CF3、3-CF3、4-OCF3或3-OCF3。
2.一种权利要求1所述的吡唑二苯基脲类衍生物的制备方法,其特征在于包括如下步骤:
步骤1:向0℃的N,N-二甲基甲酰胺中滴加三氯氧磷,滴完后将圆底烧瓶转移至油浴锅中,向体系中加入3-甲基-1-苯基-1H-吡唑,升温至100℃回流反应1小时,反应结束后冷却,将反应液在搅拌下慢慢倒入pH值调至中性的冰水混合物中,静置2小时,抽滤,干燥,得化合物A—5-Cl-3-甲基-1-苯基-1H-吡唑-4-甲醛,为灰白色固体;
步骤2:向无水乙醇中加入步骤1所得化合物A和苯胺或苯胺衍生物,TLC检测,直至沉淀产生完全后停止反应,抽滤,干燥,得化合物B—吡唑-4-希夫碱衍生物;所述苯胺衍生物为4-甲基苯胺、3-甲基苯胺、4-氯苯胺、3-氯苯胺、4-氟苯胺、3-氟苯胺、4-溴苯胺、3-溴苯胺、4-三氟甲基苯胺、3-三氟甲基苯胺、4-三氟甲氧基苯胺、或3-三氟甲氧基苯胺;
步骤3:向步骤2的反应体系中缓慢滴加硼氢化钠,常温下搅拌2小时至反应液彻底澄清,向反应体系中加水,用二氯甲烷萃取2-3次,合并有机相后减压浓缩,薄层色谱法进行分离纯化得到化合物C—1-苯基-4-甲基苯胺结构的吡唑衍生物;
步骤4:将步骤3所得化合物C溶于氯仿中,再向其中滴加异氰酸苯酯,常温反应1小时后TLC分离得到目标产物。
3.根据权利要求2所述的制备方法,其特征在于:
步骤1中,3-甲基-1-苯基-1H-吡唑、N,N-二甲基甲酰胺与三氯氧磷的摩尔比为1:5:9。
4.根据权利要求2所述的制备方法,其特征在于:
步骤2中,化合物A与苯胺衍生物的摩尔比为1:1.2。
5.根据权利要求2所述的制备方法,其特征在于:
步骤2中,无水乙醇的用量为每毫摩尔化合物A加10ml。
6.根据权利要求2所述的制备方法,其特征在于:
步骤3中,化合物A与硼氢化钠的摩尔比为1:4。
7.根据权利要求2所述的制备方法,其特征在于:
步骤4中,化合物C与异氰酸苯酯的摩尔比为1:1.2。
8.根据权利要求2所述的制备方法,其特征在于:
步骤4中,氯仿的用量为每毫摩尔化合物C加1ml。
9.一种权利要求1所述的吡唑二苯基脲类衍生物的用途,其特征在于:
所述吡唑二苯基脲类衍生物在制备抗黑色素瘤药物中的应用。
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