CN106146362B - 一种合成c‑7280948的方法 - Google Patents
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Abstract
本发明公开了一种合成C‑7280948的方法。包括如下步骤：在反应容器中，加入4‑氨基苯磺酰胺、苯乙醇，铱络合物催化剂和碱，反应混合物在100‑120 oC下反应数小时后，冷却到室温，旋转蒸发除去溶剂，然后通过柱分离，得到目标化合物。本发明使用商品化的4‑氨基苯磺酰胺和近于无毒的醇为起始原料；反应只生成水为副产物，无环境危害；反应原子经济性。
Description
技术领域
本发明属有机合成化学技术领域，具体涉及一种合成C-7280948的方法。
背景技术
PRMT1属于Ⅰ型PRMT酶，分子大小约40kDa，常以大分子复合体形式发挥作用。其底物分子众多，酶活性受多因素调节。PRMT1参与了细胞信号转导、DNA损伤修复、转录调节、RNA代谢、蛋白质相互作用等多种细胞过程。PRMT1与多种癌性疾病及非癌性疾病有关。C-7280948(4-氨基-N-苯乙基苯磺酰胺)是一类非常有前景的PRMT1抑制剂，目前已经在疾病治疗中取得重要的进展。((a)Itoh Y et al.Small-molecular modulators of cancer-associated epigenetic mechanisms.Mol Biosyst 9:873-96(2013).(b)Bissinger EMet al.Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitorsof the arginine methyltransferase hPRMT1.Bioorg Med Chem 19:3717-31(2011).(c)Heinke R et al.Virtual screening and biological characterization of novelhistone arginine methyltransferase PRMT1inhibitors.ChemMedChem 4:69-77(2009).
C-7280948的合成方法目前有2种。一种方法是以4-硝基苯磺酰氯和苯丙胺为起始原料，在N-甲基吗啡啉参与下，发生亲核取代反应，得到4-硝基-N-苯乙基苯磺酰胺。4-硝基-N-苯乙基苯磺酰胺再经还原反应得到。(E.M.Bissinger,R.Heinke,A.Spannhoff,A.Eberlin,E.Metzger,V.Cura,P.Hassenboehler,J.Cavarelli,R.Schüle,M.T.Bedford,W.Sippl,M.Jung,Bioorg.Med.Chem.2011,19,3717-3731)
另一种方法是从4-乙酰氨基苯磺酰氯和苯丙胺为起始原料，发生亲核取代反应，得到4-乙酰氨基-N-苯乙基苯磺酰胺。4-乙酰氨基-N-苯乙基苯磺酰胺在碱性条件下脱乙酰基保护得到4-氨基-N-苯乙基苯磺酰胺。(Baraldi,Pier Giovanni；Borea,Pier Andrea；Geppetti,Pierangelo,WO 2006045498,2006).
这两种方法都需要多步反应，所使用的试剂苯磺酰氯衍生物都是高毒性物质，具有刺激性气味，稳定性差，在空气中与水容易转化为苯磺酸。反应过程中生成大量的副产物，也严重影响环境。反应的原子经济性低。
发明内容
本发明的目的在于提供一种合成C-7280948的新方法。
本发明通过下述技术方案实现：一种合成C-7280948(式Ⅰ)的新方法
其包含使4-氨基苯磺酰胺(式Ⅱ)
与苯乙醇(式Ⅲ)反应
反应是在铱络合物催化剂和碱存在下发生，其反应通式为
具体的，所述的目标产物通过下述步骤制备：
在反应容器中，加入4-氨基苯磺酰胺、苯乙醇，铱络合物催化剂和碱，反应混合物在100-120℃下反应数小时后，冷却到室温，旋转蒸发除去溶剂，然后通过柱分离，得到目标化合物。
其中，铱络合物催化剂为[Cp*IrCl2]2(Cp*＝pentamethylcyclopentadienyl)。
碱选自KOH、NaOH、KOtBu和NaOtBu中任意一种；铱络合物催化剂用量相对于4-氨基苯磺酰胺的摩尔比为1mol％；碱相对于4-氨基苯磺酰胺摩尔比为1equiv.；苯乙醇相对于4-氨基苯磺酰胺的摩尔比为4:1；反应温度为120℃；反应时间为12小时以上。
同现有技术相比，本发明从4-氨基苯磺酰胺出发，通过和醇发生反应，得到C-7280948，反应展现出三个显著的优点：1)使用商品化的4-氨基苯磺酰胺和近于无毒的醇为起始原料；2)反应只生成水为副产物，无环境危害；3)反应原子经济性高；因此，该反应符合绿色化学的要求，具有广阔的发展前景。
具体实施方式
下面从实施例进一步阐述本发明的技术方案。
实施例1:
氮气保护下，将4-氨基苯磺酰胺(172mg,1mmol)，[Cp*IrCl2]2(8mg,0.01mmol,1mol％)，氢氧化钾(56mg,1mmol)，苯乙醇(610mg,5equiv)依次加到25mLSchlenk反应瓶中。混合物在120℃下反应12小时后，冷却到室温，真空减压除去溶剂。然后通过柱层析(展开剂：乙酸乙酯/正己烷)得到纯净的目标化合物，产率：80％。
mp 133-134℃；1H NMR(500MHz,DMSO-d6)δ7.40(d,J＝8.3Hz,2H,ArH),7.26(t,J＝7.2Hz,2H,ArH),7.21-7.10(m,3H,ArH and 1H,NH),6.60(d,J＝8.3Hz,2H,ArH),5.90(s,2H,NH2),2.86(quart,J＝6.7Hz,2H,NCH2),2.64(t,J＝7.3Hz,2H,CH2)；13C NMR(125MHz,DMSO-d6)δ152.4,138.9,128.6,128.4,128.3,126.1,125.3,112.6,44.1,35.2.
实施例2:
除用氢氧化钠(40mg,1mmol,1equiv.)代替氢氧化钾，其它反应原料，条件和产物同实施例1，产率：75％
实施例3:
除用叔丁醇钾(42.4mg,0.2mmol,0.2equiv.)代替氢氧化钾，其它反应原料，条件和产物同实施例1，产率：79％
实施例4:
除用叔丁醇钠(40mg,1mmol,1equiv.)代替氢氧化钾，其它反应原料，条件和产物同实施例1，产率：77％
实施例5:
除反应温度为110℃,其它反应原料，条件和产物同实施例1，产率：68％.
实施例6:
除反应温度为100℃,其它反应原料，条件和产物同实施例1，产率：51％。
Claims (7)
1.一种合成4-氨基-N-苯乙基苯磺酰胺的方法，其特征在于，所述产物
是通过4-氨基苯磺酰胺Ⅱ
与苯乙醇Ⅲ
在铱络合物催化剂和碱的存在下发生反应，
其中，铱络合物催化剂为[Cp*IrCl2]2，Cp*＝五甲基环戊二烯基；
碱选自KOH、NaOH、KOtBu和NaOtBu中任意一种。
2.如权利要求1所述的合成4-氨基-N-苯乙基苯磺酰胺的方法，其特征在于，铱络合物催化剂用量相对于4-氨基苯磺酰胺的摩尔比为1mol％。
3.如权利要求1所述的合成4-氨基-N-苯乙基苯磺酰胺的方法，其特征在于，碱用量相对于4-氨基苯磺酰胺的摩尔比为1当量。
4.如权利要求1所述的合成4-氨基-N-苯乙基苯磺酰胺的方法，其特征在于，苯乙醇用量相对于4-氨基苯磺酰胺的摩尔比为4:1。
5.如权利要求1所述的合成4-氨基-N-苯乙基苯磺酰胺的方法，其特征在于，反应在100-120℃温度下进行。
6.如权利要求1所述的合成4-氨基-N-苯乙基苯磺酰胺的方法，其特征在于，反应在120℃温度下进行。
7.如权利要求1所述的合成4-氨基-N-苯乙基苯磺酰胺的方法，其特征在于，反应时间为12小时以上。
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