CN113387937B - 一种合成手性含吡唑三芳基甲烷化合物的方法 - Google Patents

一种合成手性含吡唑三芳基甲烷化合物的方法 Download PDF

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CN113387937B
CN113387937B CN202010172372.8A CN202010172372A CN113387937B CN 113387937 B CN113387937 B CN 113387937B CN 202010172372 A CN202010172372 A CN 202010172372A CN 113387937 B CN113387937 B CN 113387937B
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周永贵
谢焕平
孙蕾
余长斌
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Dalian Institute of Chemical Physics of CAS
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Abstract

本发明提供了一种手性含吡唑三芳基甲烷化合物及其制备方法：从氮杂二烯和吡唑啉‑5‑酮试剂出发，在有机催化剂的作用下反应可以得到含各种取代基的手性吡唑三芳基甲烷化合物。本发明操作简便实用，产率高，对映选择性高。

Description

一种合成手性含吡唑三芳基甲烷化合物的方法
技术领域
本发明涉及手性含吡唑三芳基甲烷化合物的合成，具体地说是一种应用有机催化体系高度对映选择性合成手性含吡唑三芳基甲烷化合物的方法。
背景技术
三芳基甲烷骨架广泛存在于天然产物、药物和材料分子中，杂环取代的三芳基甲烷具有抗炎、抗肿瘤等活性(.a))Parai,M.K.；Panda,G.；Chaturvedi,V.；Manju,Y.K.；Sinha,S.Bioorg.Med.Chem.Lett.,2008,18,289；b)Yin,L.；Hu,Q.；Hartmann,R.W.J.Med.Chem.,2013,56,460.)。吡唑基团作为一类非常重要的含氮杂环，具有很好的生物活性，存在于药物分子中。因此，将吡唑基团引入三芳基甲烷骨架，构建手性含吡唑三芳基甲烷化合物具有十分重要的意义。
在众多的合成吡唑类化合物的方法中，以吡唑啉-5-酮为原料实现该类化合物的合成，是近些年来发展的一种比较快速且直接的合成方法。吡唑啉-5-酮由于其较高的反应活性，可以作为一种亲核试剂与不同的迈克尔受体发生加成或串联反应，这些受体可以是硝基烯烃、不饱和腈和不饱和羰基化合物等(文献二：a)Liao,Y.-H.；Chen,W.-B.； Wu,Z.-J.；Du,X.-L.；Cun,L.-F.；Zhang,X.-M.；Yuan,W.-C.Adv.Synth.Catal.；2010,352, 827；b)Gogoi,S.；Zhao,C.-G.Tetrahedron Lett.,2009,50,2252；c)Yetra,S.R.；Mondal,S.；Suresh,E.；Biju,A.T.Org.Lett.,2015,17,1417.)。该策略有非常好的原子经济性。但是吡唑啉-5-酮对α,β-不饱和亚胺的迈克尔加成却未见报道。这可能是由于以下原因造成的：1)α,β-不饱和亚胺不够稳定，易水解为α,β-不饱和酮；2)低的反应活性、难以控制对映选择性和区域选择性。因此，发展一种简单、有效、成本低廉以及底物多样性的亲核试剂对α,β-不饱和亚胺的不对称迈克尔加成反应，从而得到一系列手性含吡唑三芳基甲烷化合物是非常必要的。
发明内容
本发明的目的是从化合物1和化合物2出发，经过一步反应可以高产率、高对映选择性地得到一系列含各种取代基的手性含吡唑三芳基甲烷化合物。
本发明的技术方案如下：
本发明提供手性含吡唑三芳基甲烷化合物的合成方法，采用化合物1(氮杂二烯)和化合物2(吡唑啉-5-酮)为反应物，采用双功能有机催化剂作为反应催化剂，所述方法的反应式和条件如下：
Figure BDA0002409645420000021
式中，Ar1为苯基、萘基或任选地被至少一个选自C1-6烷基、卤素或甲氧基的基团取代的苯基；
Ar2为苯基或被至少一个选自C1-6烷基、卤素或甲氧基的基团取代的苯基；
R1为对甲苯磺酰基、对硝基苯磺酰基、甲基苯磺酰基；
R2为烷基、苯基。
所述的双功能有机催化剂为奎宁，奎尼丁，辛可宁，辛可尼丁，硫脲，方酰胺中的一种；
优选所述化合物1与化合物2的摩尔比为1:1-1:1.5。
优选所述化合物1与有机催化剂的摩尔比为1:0.02-1:0.2。
上述方法优选包括以下步骤：
步骤一，在0-30℃下，将化合物1放入反应瓶中，得体系Ⅰ；
步骤二，向体系Ⅰ中加入化合物2，得体系Ⅱ；
步骤三，向体系Ⅱ中加入有机催化剂，得体系Ⅲ；
步骤四，向体系Ⅲ中加入有机溶剂1，得体系Ⅳ；
步骤五，将体系Ⅳ在30℃下反应2-4小时，反应结束后用硅胶柱层析得到中间体3。
步骤六，在室温下，将中间体3放入反应瓶中，得体系Ⅴ；
步骤七，向体系Ⅴ中加入酸酐、碱得体系Ⅵ；
步骤八，向体系Ⅵ中加入溶剂2，得体系Ⅶ；
步骤九，将体系Ⅶ在室温下反应2-5小时，反应结束后用硅胶柱层析得到所述的手性含吡唑三芳基甲烷化合物。
基于以上技术方案，优选的，所述体系Ⅳ中，化合物1的浓度为0.01-1.0mol/L；
所述体系Ⅶ中，中间体3的浓度为0.01-1.0mol/L；
所述体系Ⅶ中，酸酐的浓度为0.01-1.5mol/L，碱的浓度为0.004-0.4mol/L。
基于以上技术方案，优选的，所述步骤四中所述的溶剂1为二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、四氢呋喃、均三甲苯中的至少一种；
所述步骤八中所述的有机溶剂2为氯仿；
所述酸酐为醋酸；所述碱为三乙胺、三甲胺、1,3-丙二胺中的至少一种。
基于以上技术方案，优选的：所述方法的对映选择性为70-99％ee。
本发明从各种氮杂二烯1出发，与化合物2(吡唑啉-5酮)反应生成手性含吡唑三芳基甲烷化合物，该反应采用有机催化剂作为催化剂，反应产率高，对映选择性高，底物范围广。本发明原料廉价易得，操作简便，体系简单，为后处理提供了便利，大大提高了反应效率，反应能容忍各种不同的取代基和官能团。
本发明具有以下优点：
1.原料简单易得并且操作简单。
2.反应底物范围广。
3.反应活性高，能获得高纯度的产物。
4.能高对映选择性地得到含各种取代基的手性含吡唑三芳基甲烷化合物。
具体实施方式
本发明将化合物1，在有机溶剂中和化合物2反应，使用有机催化剂作为催化剂，其合成路线如下：
Figure BDA0002409645420000031
其中：
取代基Ar1为苯基、含取代基的苯基或萘基，所述取代基为C1-6烷基、卤素、甲氧基；
Ar2为苯基、含取代基的苯基或萘基，所述取代基为C1-6烷基、卤素、甲氧基；
R1为对甲苯磺酰基、对硝基苯磺酰基、甲基苯磺酰基；
R2为烷基、苯基或含取代基的苯基；所述取代基为C1-6烷基、卤素、三氟甲基，硝基、氰基或甲氧基中的至少一种。
下面通过实施例详述本发明；但本发明并不限于下述的实施例。
实施例1-12
条件优化
在20-30℃下，向4mL反应瓶中加入氮杂二烯1a(0.2毫摩尔)，吡唑啉-5-酮2a(0.22毫摩尔)，有机催化剂5(12.6毫克，0.02毫摩尔)和溶剂1(3.0毫升)。30℃下反应2小时，反应结束后用硅胶柱层析得到中间体化合物3。将化合物3aa溶于溶剂2(3.0毫升)，加入乙酸酐(22.5毫克，0.22毫摩尔)，三乙胺(6.1毫克，0.06毫摩尔)，室温下反应2小时，反应结束用硅胶柱层析得到最终产物4aa。反应结构式如下：
Figure BDA0002409645420000041
产物的产率为分离收率，ee值为产物的对映体过量百分率，见表1。
表1.合成手性含吡唑三芳基甲烷化合物4的条件优化a
Figure BDA0002409645420000042
a反应条件：氮杂二烯1a(0.1毫摩尔),吡唑啉5-酮2a(0.1毫摩尔),有机催化剂5(0.01 毫摩尔)，溶剂(1.5mL),30℃,2小时.b基于吡唑啉-5-酮的分离收率.c通过手性HPLC确定.d 2a的用量为0.11毫摩尔。
实施例13-26
氮杂二烯1和吡唑啉-5-酮2a的反应
在20-30℃下，向4mL反应瓶中加入氮杂二烯1(0.2毫摩尔)，吡唑啉-5-酮2a (0.22毫摩尔)有机催化剂5a(0.02毫摩尔)和溶剂1(3.0毫升)。30℃下反应2小时，反应结束用硅胶柱层析得到中间体化合物3。将化合物3溶于溶剂2(3.0毫升)，加入乙酸酐(22.5毫克，0.22毫摩尔)，三乙胺(6.1毫克，0.06毫摩尔)，室温下反应2小时，反应结束用硅胶柱层析得到相应的手性含吡唑三芳基甲烷化合物。改变反应中底物化合物1的种类得到14个不同的实施例，终产物具体见表2。
表2.氮杂二烯1和吡唑啉-5-酮2a的反应
Figure BDA0002409645420000051
实施例27-34
氮杂二烯1a和吡唑啉-5-酮2的反应
在20-30℃下，向4mL反应瓶中加入氮杂二烯1a(0.2毫摩尔)，吡唑啉-5-酮2 (0.22毫摩尔)有机催化剂5a(0.02毫摩尔)和溶剂1(3.0毫升)。30℃下反应2小时，反应结束用硅胶柱层析得到中间体化合物3。将化合物3溶于溶剂2(3.0毫升)，加入乙酸酐(22.5毫克，0.22毫摩尔)，三乙胺(6.1毫克，0.06毫摩尔)，室温下反应2小时，反应结束用硅胶柱层析得到相应的手性含吡唑三芳基甲烷化合物。改变反应中化合物2的种类得到8个不同的实施例，终产物具体见表3
表3.氮杂二烯1a和吡唑啉-5-酮2的反应
Figure BDA0002409645420000061
各个化合物的实验数据如下：
(-)-3-Methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-phenyl-1H- pyrazol-5-yl acetate(4aa):101mg,87％yield,viscous liquid,new compound,Rf＝0.30(hexanes/ethyl acetate＝5:1),98％ee,[α]20 D＝-80.16(c 0.60,CHCl3).1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.3 Hz,2H),7.51-7.43(m,2H),7.42-7.36(m,2H),7.35-7.26(m,5H),7.22-7.11(m,5H),7.09-7.00(m,2H), 6.47(s,1H),5.49(s,1H),2.35(s,3H),2.02(s,3H),1.75(s,3H)；13C NMR(100MHz,CDCl3)δ168.0,154.8,153.3,148.4,144.2,141.9,138.5,137.9,136.9,129.8,129.3,128.6,128.5,127.6,127.5,127.1, 125.9,124.7,123.3,122.9,119.3,113.6,111.6,107.7,37.2,21.7,20.0,13.7.HPLC:Chiralcel IA column, 254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 13.3min and 20.1min (major).HRMS Calculated ForC34H30N3O5S[M+H]+592.1901,found:592.1909.
(+)-3-Methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(o-tolyl)methyl)-1-phenyl-1H- pyrazol-5-yl acetate(4ba):84mg,70％yield,viscousliquid,new compound,Rf＝0.29(hexanes/ethyl acetate＝3:1),94％ee,[α]20 D＝+29.05(c 0.84,CHCl3).1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.3 Hz,2H),7.50-7.43(m,2H),7.42-7.32(m,3H),7.33-7.29(m,1H),7.23-7.04(m,9H),6.28-6.21(br,1H), 5.61(s,1H),2.34(s,3H),2.18(s,3H),1.99(s,3H),1.59(s,3H)；13C NMR(100MHz,CDCl3)δ167.5, 153.9,153.2,148.2,144.1,142.1,138.0,136.9,136.6,136.6,130.7,129.7,129.3,128.8,127.6,127.4, 127.4,126.2,126.1,124.6,123.3,123.0,119.4,113.7,111.7,106.6,35.3,21.7,19.8,19.6,13.2.HPLC: Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 11.6 min and 13.7min(major).HRMSCalculated For C35H32N3O5S[M+H]+606.2057,found:606.2054.
(-)-3-Methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(m-tolyl)methyl)-1-phenyl-1H- pyrazol-5-yl acetate(4ca):77mg,64％yield,viscousliquid,new compound,Rf＝0.19(hexanes/ethyl acetate＝2:1),93％ee,[α]20 D＝-120.72(c 0.77,CHCl3).1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.3 Hz,2H),7.49-7.44(m,2H),7.42-7.32(m,3H),7.31-7.27(m,1H),7.21-7.14(m,4H),7.10-7.03(m,3H), 6.89(d,J＝6.8Hz,2H),6.25(s,1H),5.39(s,1H),2.36(s,3H),2.31(s,3H),2.02(s,3H),1.73(s,3H)；13C NMR(100MHz,CDCl3)δ167.9,154.8,153.2,148.4,144.1,141.9,138.3,138.1,137.9,136.9, 129.8,129.3,129.2,128.4,127.9,127.7,127.4,126.0,125.7,124.6,123.3,122.9,119.3,113.5,111.7, 107.7,37.1,21.7,21.6,20.0,13.7.HPLC:ChiralcelIA column,254nm,30℃,n-Hexane/i-PrOH＝ 70/30,flow＝0.7mL/min,retention time11.3min and 15.2min(major).HRMS Calculated For C35H32N3O5S[M+H]+606.2057,found:606.2062.
(-)-3-Methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(p-tolyl)methyl)-1-phenyl-1H- pyrazol-5-yl acetate(4da):106mg,88％yield,viscousliquid,new compound,Rf＝0.31(hexanes/ethyl acetate＝3:1),75％ee,[α]20 D＝-82.82(c 1.06,CHCl3).1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.3 Hz,2H),7.49-7.42(m,2H),7.41-7.26(m,4H),7.22-7.13(m,3H),7.11-7.03(m,4H),6.99(d,J＝8.0Hz, 2H),6.43-6.35(br,1H),5.41(s,1H),2.36(s,3H),2.33(s,3H),2.02(s,3H),1.74(s,3H)；13C NMR(100 MHz,CDCl3)δ168.0,155.0,153.2,148.4,144.1,141.9,137.9,136.9,136.7,135.4,129.8,129.3,129.2, 128.5,127.7,127.4,125.6,124.6,123.3,122.9,119.3,113.5,111.6,107.8,36.8,21.7,21.2,20.0,13.7. HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 11.8min and 17.4min(major).HRMSCalculated For C35H32N3O5S[M+H]+606.2057,found: 606.2060.
(-)-4-((4-Isopropylphenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)-3-methyl-1- phenyl-1H-pyrazol-5-yl acetate(4ea):100mg,79％yield,viscous liquid,new compound,Rf＝0.22 (hexanes/ethyl acetate＝3:1),75％ee,[α]20 D＝-61.60(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ 7.70-7.64(m,2H),7.48-7.43(m,2H),7.42-7.32(m,3H),7.31-7.27(m,1H),7.22-7.16(m,3H), 7.15-7.11(m,2H),7.09-6.99(m,4H),6.22(s,1H),5.40(s,1H),2.89(hept,J＝6.9Hz,1H),2.37(s,3H), 2.02(s,3H),1.75(s,3H),1.24(d,J＝6.9Hz,6H)；13C NMR(100MHz,CDCl3)δ168.0,155.0,153.2, 148.4,147.6,144.1,141.9,138.0,136.9,135.6,129.8,129.3,128.5,127.7,127.4,126.6,126.0,124.6, 123.3,123.0,119.3,113.5,111.7,107.8,36.9,33.8,24.1,21.7,20.0,13.8.HPLC:Chiralcel IA column, 254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 11.4min and 12.8min (major).HRMS Calculated For C37H36N3O5S[M+H]+634.2370,found:634.2369.
(-)-4-((4-Methoxyphenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)-3-methyl-1-p henyl-1H-pyrazol-5-yl acetate(4fa):117mg,94％yield,viscous liquid,new compound,Rf＝0.17 (hexanes/ethyl acetate＝3:1),73％ee,[α]20 D＝-74.95(c 1.17,CHCl3).1H NMR(400MHz,CDCl3)δ 7.68(d,J＝8.3Hz,2H),7.47-7.42(m,2H),7.41-7.35(m,2H),7.33(d,J＝8.3Hz,1H),7.31-7.27(m, 1H),7.22-7.15(m,3H),7.09-7.00(m,4H),6.85-6.77(d,J＝8.8Hz,2H),6.29-6.20(br,1H),5.40(s,1H), 3.79(s,3H),2.37(s,3H),2.02(s,3H),1.74(s,3H)；13C NMR(100MHz,CDCl3)δ168.0,158.7,155.2,153.2,148.4,144.2,141.8,138.0,136.9,130.5,129.8,129.7,129.3,127.7,127.5,126.0,124.6,123.4, 123.0,119.3,113.9,113.3,111.7,107.9,55.4,36.5,21.7,20.0,13.8.HPLC:Chiralcel IA column,254 nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time13.9min and24.2min(major). HRMS Calculated For C35H32N3O6S[M+H]+622.2006,found:622.2009.
(-)-3-Methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(naphthalen-1-yl)methyl)-1-ph enyl-1H-pyrazol-5-yl acetate(4ga):111mg,87％yield,viscous liquid,new compound,Rf＝0.34 (hexanes/ethyl acetate＝3:1),92％ee,[α]20 D＝-7.21(c 1.11,CHCl3).1H NMR(400MHz,CDCl3) δ7.92-7.85(m,2H),7.80(d,J＝8.2Hz,1H),7.68(d,J＝8.3Hz,2H),7.50-7.44(m,4H),7.40-7.34(m, 3H),7.30-7.26(m,3H),7.21-7.14(m,2H),7.12-7.03(m,3H),6.46(s,1H),6.21(s,1H),2.27(s,3H), 1.96(s,3H),1.51(s,3H)；13C NMR(100MHz,CDCl3)δ167.6,154.2,153.2,148.2,144.1,142.2,138.0, 137.0,134.1,133.9,131.5,129.7,129.3,128.9,128.3,127.6,127.4,126.7,126.7,126.1,125.9,125.4, 124.6,123.4,123.3,123.0,119.5,113.7,111.7,107.3,34.8,21.6,19.7,13.3.HPLC:Chiralcel IA column, 254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝1.0mL/min,retention time 10.9min and 22.9min (major).HRMS CalculatedFor C38H32N3O5S[M+H]+642.2057,found:642.2051.
(-)-4-((4-Chlorophenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)-3-methyl-1-ph enyl-1H-pyrazol-5-yl acetate(4ha):101mg,81％yield,viscous liquid,new compound,Rf＝0.38 (hexanes/ethyl acetate＝3:1),80％ee,[α]20 D＝-87.12(c 1.01,CHCl3).1H NMR(400MHz,CDCl3)δ 7.66(d,J＝8.3Hz,2H),7.47-7.42(m,2H),7.41-7.35(m,2H),7.33(d,J＝8.3Hz,1H),7.30-7.27(m, 1H),7.25-7.23(m,1H),7.21-7.14(m,3H),7.11-7.02(m,3H),6.96(d,J＝7.8Hz,1H),6.49(s,1H),5.51 (s,1H),2.35(s,3H),2.03(s,3H),1.79(s,3H)；13C NMR(100MHz,CDCl3)δ167.9,154.5,153.2,148.2, 144.3,141.9,137.8,137.2,136.7,132.9,130.0,129.8,129.3,128.6,127.6,127.5,125.7,124.8,123.4, 122.9,119.2,113.7,111.6,107.4,36.5,21.6,20.0,13.8..HPLC:Chiralcel IA column,254nm,30℃, n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 11.4min and 22.0min(major).HRMS Calculated ForC34H29ClN3O5S[M+H]+626.1511,found:626.1518.
(-)-4-((3-Chlorophenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)-3-methyl-1-ph enyl-1H-pyrazol-5-yl acetate(4ia):82mg,65％yield,viscous liquid,new compound,Rf＝0.36 (hexanes/ethyl acetate＝3:1),99％ee,[α]20 D＝-107.43(c 0.82,CHCl3).1H NMR(400MHz,CDCl3)δ 7.67(d,J＝8.3Hz,2H),7.47-7.42(m,2H),7.41-7.32(m,3H),7.31-7.27(m,1H),7.24-7.14(m,5H), 7.10-7.02(m,4H),6.54(s,1H),5.46(s,1H),2.36(s,3H),2.04(s,3H),1.79(s,3H)；13C NMR(100MHz, CDCl3)δ167.9,154.2,153.3,148.2,144.3,142.0,140.6,137.8,136.7,134.3,129.9,129.8,129.3,128.6, 127.6,127.6,127.4,126.9,125.8,124.9,123.5,123.0,119.3,113.9,111.7,107.2,36.8,21.7,20.0,13.8. HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 13.3min and 16.1min(major).HRMSCalculated For C34H29ClN3O5S[M+H]+626.1511,found: 626.1513.
(-)-4-((3-Bromophenyl)(3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)methyl)-3-methyl-1-phenyl- 1H-pyrazol-5-yl acetate(4ja):97mg,72％yield,viscous liquid,new compound,viscous liquid,Rf＝0.29 (hexanes/ethyl acetate＝3:1),99％ee,[α]20 D＝-114.84(c 0.97,CHCl3).1H NMR(400MHz,CDCl3)δ7.68(d, J＝8.1Hz,2H),7.45(d,J＝8.2Hz,2H),7.42-7.32(m,4H),7.32-7.27(m,1H),7.24-7.13(m,5H),7.13-7.02 (m,3H),6.66-6.41(br,1H),5.45(s,1H),2.36(s,3H),2.05(s,3H),1.79(s,3H)；13C NMR(100MHz,CDCl3) δ167.9,154.1,154.1,153.3,148.2,144.3,142.0,140.9,137.8,136.7,131.4,130.3,130.1,129.7,129.3,127.6, 127.6,127.3,125.8,124.9,123.5,123.0,122.6,119.3,113.9,111.7,107.2,36.7,21.7,20.0,13.8.HPLC: ChiralcelIA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time14.4min and 16.4min(major).HRMS Calculated For C34H29BrN3O5S[M+H]+670.1006,found:670.1011.
(-)-3-Methyl-4-((5-methyl-3-((toluyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-phenyl-1H- pyrazol-5-yl acetate(4ka):0.1mmol,42mg,69％yield,viscous liquid,new compound,Rf＝0.48 (hexanes/ethyl acetate＝3:1),76％ee,[α]20 D＝-75.71(c 0.42,CHCl3).1H NMR(400MHz,CDCl3)δ 7.68(d,J＝8.2Hz,2H),7.48-7.43(m,2H),7.42-7.34(m,2H),7.31-7.23(m,4H),7.22-7.10(m,5H), 7.02-6.94(m,1H),6.66(s,1H),6.35(s,1H),5.46(s,1H),2.37(s,3H),2.25(s,3H),2.01(s,3H),1.76(s,3H)；13C NMR(100MHz,CDCl3)δ168.0,155.2,151.7,148.4,144.1,141.9,138.6,138.0,137.0,132.8, 129.8,129.3,128.6,128.5,127.8,127.4,127.1,126.0,125.9,122.9,119.0,113.3,111.2,107.7,37.1,21.6, 21.2,20.1,13.7.HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7 mL/min,retention time 10.2min and13.3min(major).HRMS Calculated For C35H32N3O5S[M+H]+ 606.2057,found:606.2066.
(-)-3-Methyl-4-((6-methyl-3-((toulyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-phenyl-1H- pyrazol-5-yl ace-tate(4la):105mg,89％yield,yellow solid,new compound,m.p.＝110-111℃,Rf＝ 0.23(hexanes/ethyl acetate＝3:1),81％ee,[α]20 D＝-85.44(c 2.04,CHCl3).1H NMR(400MHz,CDCl3) δ7.65(d,J＝8.2Hz,2H),7.44(d,J＝7.6Hz,2H),7.40-7.32(m,2H),7.30-7.20(m,4H),7.17-7.06(m, 5H),6.96-6.84(m,2H),6.59(s,1H),5.45(s,1H),2.37(s,3H),2.33(s,3H),1.99(s,3H),1.77(s,3H). 13C NMR(100MHz,CDCl3)δ167.9,153.8,153.7,148.4,144.0,141.9,138.7,137.9,136.8,134.9, 129.7,129.2,128.5,128.4,127.6,127.4,127.0,124.7,123.4,122.9,118.8,113.5,111.8,107.8,37.1,21.7, 21.6,20.0,13.7.HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7 mL/min,retention time 11.9min and14.4min(major).HRMS Calculated For C35H32N3O5S[M+H]+ 606.2057,found:606.2058.
(-)-3-Methyl-4-((3-((4-nitrophenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-phenyl-1H-py razol-5-yl acetate(4ma):69mg,56％yield,yellowsolid,new compound,m.p.＝115-116℃,Rf＝0.17 (hexanes/ethyl acetate＝3:1),81％ee,[α]20 D＝-68.43(c 1.02,CHCl3).1H NMR(400MHz,CDCl3)δ 8.09(d,J＝8.8Hz,2H),7.87(d,J＝8.8Hz,2H),7.41(d,J＝7.6Hz,2H),7.38-7.31(m,3H),7.28-7.17 (m,6H),7.15-7.11(m,2H),7.07-6.99(m,1H),6.91-6.86(m,1H),5.53(s,1H),2.01(s,3H),1.78(s,3H).13C NMR(100MHz,CDCl3)δ168.0,155.1,153.2,150.2,148.4,145.4,141.9,138.3,137.7,129.3, 128.8,128.6,128.4,127.6,127.3,125.3,125.1,124.3,123.6,123.0,118.7,112.9,111.9,107.6,37.2,20.1, 13.6.HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min, retention time 13.4min and 18.6min(major).HRMS Calculated For C33H27N4O7S[M+H]+623.1595, found:623.1590.
(-)-4-((3-(Mesitylamino)benzofuran-2-yl)(phenyl)methyl)-3-methyl-1-phenyl-1H-pyrazol-5-yl acetate(4na):111mg,90％yield,yellow solid,newcompound,m.p.＝92-93℃,Rf＝0.43 (hexanes/ethyl acetate＝3:1),90％ee,[α]20 D＝-109.72(c 2.20,CHCl3).1H NMR(400MHz,CDCl3)δ 7.46-7.41(m,2H),7.39-7.28(m,3H),7.28-7.16(m,5H),7.14-7.03(m,4H),6.84(s,2H),6.45(s,1H), 5.37(s,1H),2.51(s,6H),2.22(s,3H),2.00(s,3H),1.67(s,3H).13C NMR(100MHz,CDCl3)δ168.0, 155.4,153.3,148.2,142.9,141.8,139.6,138.4,137.9,134.1,132.1,129.3,128.6,128.4,127.4,127.1, 126.4,124.6,123.5,122.8,119.5,113.4,111.6,107.6,37.3,23.3,21.0,20.0,13.6.HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 8.4min and 10.9 min.(major)HRMS Calculated For C36H34N3O5S[M+H]+620.2214,found:620.2211.
(-)-3-Ethyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-phenyl-1H-p yrazol-5-yl acetate(4ab):100mg,83％yield,viscous liquid,new compound,Rf＝0.35(hexanes/ethyl acetate＝5:1),96％ee,[α]20 D＝-115.99(c 1.30,CHCl3).1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.3 Hz,2H),7.49-7.44(m,2H),7.42-7.35(m,2H),7.34-7.23(m,5H),7.22-7.16(m,3H),7.15-7.02(m,4H), 6.17(s,1H),5.46(s,1H),2.47-2.37(m,2H),2.37(s,3H),1.67(s,3H),1.09(t,J＝7.5Hz,3H)；13CNMR(100MHz,CDCl3)δ167.9,154.9,153.3,153.0,144.2,141.8,138.7,138.1,136.9,129.8,129.3, 128.7,128.5,127.7,127.4,127.2,126.0,124.7,123.4,123.0,119.3,113.5,111.6,107.0,37.1,21.7,21.1, 19.9,12.6.HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min, retention time 10.1min and 23.0min(major).HRMS Calculated For C35H32N3O5S[M+H]+606.2057, found:606.2060.
(-)-4-((3-((4-Methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-phenyl-3-propyl-1H- pyrazol-5-yl acetate(4ac):119mg,96％yield,viscous liquid,new compound,Rf＝0.40(hexanes/ethyl acetate＝5:1),84％ee,[α]20 D＝-79.03(c 2.08,CHCl3)..1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.3 Hz,2H),7.49-7.42(m,2H),7.42-7.35(m,2H),7.35-7.23(m,5H),7.23-7.15(m,3H),7.14-7.02(m,4H), 6.27(s,1H),5.46(s,1H),2.37(s,3H),2.41-2.25(m,2H),1.65(s,3H),1.59-1.39(m,2H),0.86(t,J＝ 7.4Hz,3H)；13C NMR(100MHz,CDCl3)δ167.8,154.7,153.2,151.9,144.1,141.6,138.6,138.0,136.8, 129.7,129.2,128.6,128.4,127.6,127.3,127.0,125.9,124.5,123.3,122.9,119.2,113.4,111.5,107.2, 37.1,29.7,21.8,21.6,19.8,14.2.HPLC:ChiralcelIA column,254nm,30℃,n-Hexane/i-PrOH＝70/30, flow＝0.7mL/min,retention time10.8min and 35.3min(major).HRMS Calculated For C36H34N3O5S [M+H]+620.2214,found:620.2217.
(-)-4-((3-((4-Methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-phenyl-3-(m-tolyl)-1 H-pyrazol-5-yl acetate(4ad):95mg,71％yield,yellow solid,new compound,m.p.＝186-187℃,Rf＝ 0.21(heanes/dichloromethane/ethyl acetate＝2:2:0.1),49％ee,[α]20 D＝-77.67(c 1.76,CHCl3).1H NMR(400MHz,CDCl3)δ7.57-7.47(m,3H),7.44-7.37(m,4H),7.32-7.13(m,11H),6.92(d,J＝8.2Hz, 4H),5.89-5.79(br,1H),5.19(s,1H),2.32(s,3H),2.24(s,3H),1.54(s,3H).13C NMR(100MHz,CDCl3) δ167.0,153.6,153.3,151.0,143.9,142.5,138.5,138.3,137.9,136.2,132.8,129.6,129.5,129.4,129.3, 128.7,128.5,128.4,127.9,127.5,127.0,126.3,125.7,124.7,123.5,123.2,120.2,113.8,111.4,107.5, 37.6,21.6,21.5,20.0.HPLC:ChiralcelIA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7 mL/min,retention time9.6min(minor)and 22.9(major)min.HRMS Calculated For C40H34N3O5S [M+H]+668.2214,found:668.2210.
(-)-3-Methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-(p-tolyl)-1H -pyrazol-5-yl acetate(4ae):111mg,92％yield,viscous liquid,new compound,Rf＝0.40(hexanes/ethyl acetate＝5:1),80％ee,[α]20 D＝-89.99(c 2.02,CHCl3).1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.3 Hz,2H),7.37-7.32(m,3H),7.31-7.25(m,3H),7.24-7.17(m,5H),7.15-7.11(m,2H),7.11-7.06(m,2H), 6.50(s,1H),5.48(s,1H),2.38(s,3H),2.36(s,3H),2.03(s,3H),1.76(s,3H)；13C NMR(100MHz,CDCl3)δ168.0,154.9,153.2,148.0,144.1,141.9,138.5,137.4,136.9,135.5,129.8,129.8,128.6,128.5, 127.6,127.1,126.0,124.6,123.3,122.9,119.3,113.6,111.6,107.4,37.2,21.7,21.2,20.0,13.7.HPLC: Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 16.1 min and 23.5min(major).HRMSCalculated For C35H32N3O5S[M+H]+606.2057,found:606.2053.
(-)-1-(4-Methoxyphenyl)-3-methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl) methyl)-1H-pyrazol-5-yl acetate(4af):113mg,91％yield,viscous liquid,new compound,Rf＝0.30 (hexanes/ethyl acetate＝5:1),82％ee,[α]20 D＝-88.33(c 2.34,CHCl3).1H NMR(400MHz,CDCl3)δ 7.67(d,J＝8.2Hz,2H),7.36-7.31(m,3H),7.31-7.26(m,3H),7.21-7.14(m,3H),7.12-7.01(m,4H), 6.96-6.78(m,2H),6.26(s,1H),5.43(s,1H),3.80(s,3H),2.37(s,3H),2.00(s,3H),1.71(s,3H).13C NMR(100MHz,CDCl3)δ168.1,159.0,155.0,153.3,147.9,144.2,141.9,138.5,136.9,131.0,129.8, 128.6,128.5,127.7,127.1,126.0,124.9,124.7,123.4,119.3,114.4,113.6,111.7,107.1,55.6,37.2,21.7, 20.0,13.7.HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min, retention time 20.2min(minor)and32.8min(major).HRMS Calculated For C35H32N3O6S[M+H]+ 622.2006,found:622.2008.
(-)-1-(4-Chlorophenyl)-3-methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)m ethyl)-1H-pyrazol-5-yl acetate(4ag):113mg,90％yield,viscous liquid,new compound,Rf＝0.40 (hexanes/ethyl acetate＝5:1),78％ee,[α]20 D＝-78.70(c 1.70,CHCl3).1H NMR(400MHz,CDCl3)δ 7.67(d,J＝8.3Hz,2H),7.44-7.37(m,2H),7.37-7.31(m,3H),7.31-7.25(m,3H),7.23-7.10(m,5H), 7.08-7.03(m,1H),7.01-6.95(m,1H),6.42(s,1H),5.51(s,1H),2.36(s,3H),2.02(s,3H),1.77(s,3H)；13C NMR(100MHz,CDCl3)δ167.8,154.8,153.2,148.8,144.2,142.0,138.4,136.9,136.5,133.0,129.8,129.5,128.6,127.6,127.2,125.9,124.7,124.0,123.4,119.2,113.6,111.7,108.1,37.1,21.7,20.0, 13.7.HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min, retention time 15.2min and 22.9min(major).HRMSCalculated For C34H29ClN3O5S[M+H]+626.1511, found:626.1512.
(-)-3-Methyl-4-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1-(m-tolyl)-1H-pyr azol-5-yl acetate(4ah):85 mg,70％yield,pale yellow solid,new compound,m.p.＝86-87℃,Rf＝0.40 (hexanes/ethyl acetate＝5:1),99％ee,[α]20 D＝-86.89(c 1.04,CHCl3).1H NMR(400MHz,CDCl3)δ7.68(d, J＝8.3Hz,2H),7.37-7.27(m,4H),7.26-7.14(m,6H),7.14-7.02(m,5H),6.38(s,1H),5.46(s,1H),2.36(s, 3H),2.35(s,3H),2.01(s,3H),1.75(s,3H)；13C NMR(100MHz,CDCl3)δ168.0,154.9,153.3,148.2,144.2, 141.9,139.5,138.5,137.8,136.7,129.8,129.0,128.6,128.5,128.3,127.7,127.1,126.0,124.7,123.8,123.3, 119.7,119.3,113.6,111.7,107.6,37.2,21.7,21.5,20.0,13.7.HPLC:Chiralcel IA column,254nm,30℃, n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 12.6min and 20.2min(major).HRMSCalculated For C35H32N3O5S[M+H]+606.2057,found:606.2060.。

Claims (7)

1.一种合成手性含吡唑三芳基甲烷化合物的方法，其特征在于，反应式和条件如下：
Figure FDA0003740193350000011
式中，Ar1为苯基、萘基或含取代基的苯基；所述取代基为C1-6烷基、卤素、三氟甲基，硝基、氰基或甲氧基中的至少一种；
Ar2为苯基或含取代基的苯基；所述取代基为C1-6烷基、卤素或甲氧基中的至少一种；
R1为对甲苯磺酰基、对硝基苯磺酰基；
R2为烷基、苯基或含取代基的苯基；所述取代基为C1-6烷基、卤素、三氟甲基，硝基、氰基或甲氧基中的至少一种；
所述催化剂5为双功能有机催化剂；所述双功能有机催化剂为奎宁，奎尼丁，辛可宁，辛可尼丁，硫脲或方酰胺中的一种；
所述的溶剂1为二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、四氢呋喃、均三甲苯中的至少一种；
所述的溶剂2为氯仿。
2.如权利要求1所述的方法，其特征在于：
所述化合物1与化合物2的摩尔比为1:1-1:1.5。
3.如权利要求1所述的方法，其特征在于：
所述化合物1与催化剂5的摩尔比为1:0.02-1:0.2。
4.如权利要求1所述的方法，其特征在于：所述方法包括以下步骤：
步骤一，在0-30℃下，将化合物1放入反应瓶中，得体系Ⅰ；
步骤二，向体系Ⅰ中加入化合物2，得体系Ⅱ；
步骤三，向体系Ⅱ中加入有机催化剂5，得体系Ⅲ；
步骤四，向体系Ⅲ中加入溶剂1，得体系Ⅳ；
步骤五，将体系Ⅳ在30℃下反应2-4小时，反应结束后用硅胶柱层析得到中间体3；
步骤六，在20-30℃下，将中间体3放入反应瓶中，得体系Ⅴ；
步骤七，向体系Ⅴ中加入酸酐和碱得体系Ⅵ；
步骤八，向体系Ⅵ中加入溶剂2，得体系Ⅶ；
步骤九，将体系Ⅶ在室温下反应2-4小时，反应结束后用硅胶柱层析得到所述的手性含吡唑三芳基甲烷化合物。
5.如权利要求4所述的方法，其特征在于：
所述体系Ⅳ中，化合物1的浓度为0.01-1.0mol/L；
所述体系Ⅶ中，中间体3的浓度为0.01-1.0mol/L；
所述体系Ⅶ中，酸酐的浓度为0.01-1.5mol/L，碱的浓度为0.004-0.4mol/L。
6.如权利要求4所述的方法，其特征在于：
所述酸酐为醋酸酐；所述碱为三乙胺、三甲胺、1,3-丙二胺中的至少一种。
7.如权利要求4所述的方法，其特征在于：所述方法的对映选择性为70-99％ee。
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