CN102558057A - 多取代吡唑制备方法 - Google Patents
多取代吡唑制备方法 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及多取代吡唑的制备方法。本发明所述的多取代吡唑具有式1所示的结构特点。其中,R1可为烷基、烯丙基、炔丙基、苄基、苯甲酰基或取代苯甲酰基的任一种;R3、R4、R5可分别为烷基、氢原子、芳基或取代芳基和任一种,且3-位取代基的体积R3大于等于5-位取代基R5的体积,即R3≥R5。
背景技术
近年来,大量研究和实践表明吡唑类化合物具有广泛的生物活性,无论在医药领域还是在农药领域吡唑类化合物都得到了广泛的应用,而且吡唑环上取代位点和取代基的多样性变化使市场化的吡唑类化合物日益丰富。目前,吡唑的工业合成常用的方法是:通过1,3-二羰基化合物和肼在缩和反应条件下制得(von Auwers,K.;Schmidt,W. Chem.Ber.1925,58,528.),反应式如式2所示。该反应最终产物中5-位取代基(R5)的体积大于等于3-位取代基(R3)的体积即R5≥R3,且反应中肼的种类限制了产物中吡唑1-位取代基(R1)的类型,不利于实现其多样性变化。
1963年,Closs等人报道了α,β-不饱和苯磺酰腙在醇钠作用下可环化生成吡唑,反应式如式3所示。(a:Closs,G. L.;W.A.Angew.Chem.Int.Ed.Engl.1963,2,399.;b:Closs,G.L.;Closs,L.E.;W.A.J.Am.Chem.Soc.1963,85,3796.)。但是由于该方法中,所生成的两种产物在碱性条件下可相互转化,且不易分离鉴定,至今该方法在吡唑的合成中没有得到很好的应用。
发明内容
本发明的目的在于为多取代吡唑提供一条简捷高效、可工业化的合成路线,同时克服和弥补现有多取代吡唑制备技术的不足。
本发明制备方法的反应通式如式4所示,即以α,β-不饱和醛或α,β-不饱和酮、对甲苯磺酰肼和R1-X为原料,按式4进行反应,得到多取代吡唑,式中:R1可为烷基、烯丙基、炔丙基、苄基、苯甲酰基或取代苯甲酰基;R3、R4、R5可分别为烷基、氢原子、芳基或取代芳基,且R3≥R5;对甲苯磺酰肼与α,β-不饱和醛或酮的物质量之比为1.05-1.5;R1-X为各种卤代物或酰氯,如碘甲烷、碘乙烷、烯丙基溴、炔丙基溴、溴苄或苯甲酰氯中的任一种,R1-X与α,β-不饱和醛或酮的物质的量之比为1.1-1.5;所用的碱为NaOH、KOH、K2CO3、Na2CO3、甲醇钠、乙醇钠或叔丁醇钾中的任一种,碱与α,β-不饱和化合物物质的量之比为2.2-3;反应所采用的溶剂为乙腈或乙醇。
本发明的多取代吡唑最佳制备方法是:将1.0mmol α,β-不饱和醛或α,β-不饱和酮和1.05-1.5mmol对甲苯磺酰肼溶于2mL乙腈或乙醇中,室温搅拌反应2-48h,补加2mL乙腈或乙醇,加1.1mmol碱,于80-100℃油浴中反应15-48h。冷却至室温(如前步用乙醇做溶剂,此时应减压蒸除乙醇并补加4mL乙腈),依次加入1.1-1.5mmol碱和1.1-1.5mmol卤代物或酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)可得所需产物。
本发明使用对甲苯磺酰肼和卤代物代替传统吡唑合成中常用的取代肼,更有利于吡唑1-位取代基的多样性变化。在没有使用配体和其他添加剂的条件下,通过一锅反应实现了多取代吡唑的高效合成。整个反应过程中没有使用惰性气体保护,实验所用溶剂和其他试剂均为市售而且没有经过任何前期处理,该方法在吡唑类药物和农药的合成中有广阔的应用前景。
具体实施方式
下列实施例将有助于理解本发明,但本发明的内容并不局限于此。
以下实施例中使用的α,β-不饱和醛或α,β-不饱和酮均为市售化合物,当然也可根据文献经Aldol反应制备(A.;Pihko,P. M.J. Org.Chem.2006,71,2538.);所使用的TsNHNH2为工业用对甲苯磺酰肼;R1-X采用了多种卤代物或酰氯;碱采用了NaOH和甲醇钠,而在实际的制备中也可使用KOH、K2CO3、Na2CO3、乙醇钠或叔丁醇钾;所用的溶剂为乙腈或乙醇。
实施例1:1-苄基-3-苯基吡唑的合成
将132mg(1.0mmol)肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和257mg(1.5mmol)溴苄,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得213mg白色固体,产率91%。
产物检测数据如下:
熔点:60-62℃;1H NMR(400MHz,CDCl3)δ=5.32(s,2H),6.55(d,J=2.4Hz,1H),7.20-7.23(m,2H),7.25-7.33(m,5H),7.35-7.39(m,2H),7.81-7.82(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=56.0,103.2,125.6,127.5,127.6,127.9,128.5,128.7,130.5,133.5,136.6,151.5ppm;HRMS(ESI):Calcd for C16H15N2[M+H]+:235.1230,found:235.1232;IR(film):ν=3126.64,3107.90,3062.80,3033.08,2936.71,1498.93,1455.79,1078.97cm-1.
实施例2:1-苯甲酰基-3-苯基吡唑的合成
将132mg(1.0mmol)肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于9O℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和210mg(1.5mmol)苯甲酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得221mg无色油状液体,产率89%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=6.84(d,J=2.8Hz,1H),7.35-7.44(m,3H),7.49-7.53(m,2H),7.59-7.63(m,1H),7.85-7.88(m,2H),8.24-8.27(m,2H),8.45(d,J=2.8Hz,1H)ppm;13C NMR(100MHz,CDCl3)δ=107.1,126.4,128.0,128.7,129.1,131.5,131.7,131.78,131.84,132.9,155.9,166.0ppm;HRMS(ESI):Calcdfor C16H12N2ONa[M+Na]+:271.0842,found:271.0838;IR(film):ν=3150.06,3125.58,3062.28,1697.70,1541.33,1451.57,1403.49,1351.62,1275.65cm-1.
实施例3:1-乙基-3-苯基吡唑的合成
将132mg(1.0mmol)肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于9O℃油浴中回流反应15h。冷却至室温,依次加入44mg(1.1mmol)NaOH和172mg(1.1mmol)碘乙烷,室温反应1h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得150mg无色油状液体,产率87%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=1.48(t,J=7.6Hz,3H),4.17(q,J=7.6Hz,2H),6.51(d,J=2.0Hz,1H),7.26(t,J=7.2Hz,1H),7.36-7.39(m,3H),7.80(d,J=7.2Hz,2H)ppm;13C NMR(100MHz,CDCl3)δ=15.6,47.0,102.5,125.5,127.3,128.5,129.4,133.7,151.1ppm;HRMS(ESI):Calcd for C11H13N2[M+H]+:173.1073,found:173.1070;IR(film):ν=3063.51,3035.92,2982.01,2939.24,1605.19,1500.64,1457.92,1352.44,1225.98cm-1.
实施例4:1-烯丙基-3-苯基吡唑的合成
将132mg(1.0mmol)肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和180mg(1.5mmol)烯丙基溴,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得158mg无色油状液体,产率86%。
产物检测数据如下:
1H NMR (400MHz,CDCl3)δ=4.75(dt,J=5.6,1.2Hz,2H),5.17-5.26(m,2H),5.99-6.08(m,1H),6.55(d,J=2.4Hz,1H),7.25-7.29(m,1H),7.35-7.39(m,3H),7.79-7.81(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=54.7,102.9,118.4,125.5,127.4,128.5,130.1,132.9,133.5,151.4ppm;HRMS(ESI):Calcd forC12H13N2[M+H]+:185.1073,found:185.1070;IR(film):ν=3066.41,3035.37,2985.99,2925.00,1500.30,1458.58,1355.43,1327.89,1226.96,1074.65cm-1.
实施例5:1-炔丙基-3-苯基吡唑的合成
将132mg(1.0mmol)肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和177mg(1.5mmol)炔丙基溴,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得129mg无色油状液体,产率71%。
产物检测数据如下:
1H NMR (400MHz,CDCl3)δ=2.49(t,J=2.8Hz,1H),4.95(d,J=2.8Hz,2H),6.57(d,J=2.4Hz,1H),7.26-7.30(m,1H),7.36-7.39(m,2H),7.60(d,J=2.4Hz,1H),7.78(dd,J=8.0,1.2Hz,2H)ppm;13C NMR(100MHz,CDCl3)δ=41.5,74.7,76.7,103.3,125.6,127.7,128.5,130.0,133.2,152.0ppm;HRMS(ESI):Calcdfor C12H11N2[M+H]+:183.0917,found:183.0919;IR(film):ν=3290.58,3063.88,3037.04,2925.89,2127.20,1500.22,1459.51,1337.64,1227.66cm-1.
实施例6:1-苄基-4-苄基吡唑的合成
将146mg(1.0mmol)2-苄基丙烯醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应2h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和257mg(1.5mmol)溴苄,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得218mg无色油状液体,产率88%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=3.79(s,2H),5.21(s,2H),7.11(s,1H),7.17-7.21(m,5H),7.24-7.33(m,5H),7.37(s,1H)ppm;13C NMR(100MHz,CDCl3)δ=30.6,55.9,121.0,126.0,127.5,127.9,128.0,128.36,128.39,128.7,136.7,139.3,141.0ppm;HRMS(ESI):Calcd for C17H17N2[M+H]+:249.1386,found:249.1381;IR(film):ν=3061.56,3028.51,2922.10,2848.94,1494.32,1450.02,1396.02,1152.51cm-1.
实施例7:1-苯甲酰基-4-苄基吡唑的合成
将146mg(1.0mmol)2-苄基丙烯醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应2h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和210mg(1.5mmol)苯甲酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得233mg无色油状液体,产率89%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=3.88(s,2H),7.22-7.26(m,3H),7.31-7.34(m,2H),7.45-7.50(m,2H),7.56-7.61(m,1H),7.63(s,1H),8.06-8.08(m,2H),8.16(d,J=0.4Hz,1H)ppm;13C NMR(100MHz,CDCl3)δ=30.5,124.8,126.6,128.0,128.3,128.5,128.7,131.3,131.6,132.8,139.3,145.2,166.3ppm;HRMS(ESI):Calcd for C17H14N2Na[M+Na]+:285.0998,found:285.1002;IR(film):ν=3062.32,3028.81,2919.26,2850.34,1697.33,1365.23,1244.00cm-1.
实施例8:1-乙基-4-苄基吡唑的合成
将146mg(1.0mmol)2-苄基丙烯醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应2h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入44mg(1.1mmol)NaOH和172mg(1.1mmol)碘乙烷,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得173mg无色油状液体,产率93%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=1.44(t,J=7.2Hz,3H),3.81(s,2H),4.09(q,J=7.2Hz,2H),7.12(s,1H),7.17-7.21(m,3H),7.24-7.30(m,2H),7.33(s,1H)ppm;13C NMR(100MHz,CDCl3)δ=15.5,30.6,46.8,120.4,126.0,127.0,128.37,128.43,138.7,141.2ppm;HRMS(ESI):Calcd for C12H15N2[M+H]+:187.1230,found:187.1237;IR(film):ν=3082.92,3061.58,3026.96,2981.41,2934.82,1494.27,1449.28,1397.39,1356.83,1157.63cm-1.
实施例9:1-烯丙基-4-苄基吡唑的合成
将146mg(1.0mmol)2-苄基丙烯醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应2h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和180mg(1.5mmol)烯丙基溴,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得176mg无色油状液体,产率89%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=3.81(s,2H),4.66(dt,J=6.0,1.2Hz,2H),5.15-5.24(m,2H),5.94-6.04(m,1H),7.13(s,1H),7.17-7.20(m,3H),7.24-7.29(m,2H),7.35(s,1H)ppm;13C NMR(100MHz,CDCl3)δ=30.6,54.6,118.3,120.8,126.0,127.7,128.37,128.39,133.0,139.1,141.1ppm;HRMS(ESI):Calcd forC13H15N2[M+H]+:199.1230,found:199.1232;IR(film):ν=3083.15,3026.23,2919.15,2849.93,1494.21,1446.44,1397.73,1328.65,1152.35cm-1.
实施例10:1-炔丙基-4-苄基吡唑的合成
将146mg(1.0mmol)2-苄基丙烯醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应2h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和177mg(1.5mmol)炔丙基溴,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得161mg无色油状液体,产率82%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=2.45(t,J=2.4Hz,1H),3.81(s,2H),4.85(d,J=2.4Hz,2H),7.18-7.21(m,3H),7.24-7.30(m,2H),7.33-7.35(m,2H)ppm;13CNMR(100MHz,CDCl3)δ=30.5,41.4,74.4,76.9,121.3,126.1,127.5,128.4,139.8,140.8ppm;HRMS(ESI):Calcd for C13H13N2[M+H]+:197.1073,found:197.1074;IR(film):ν=3289.02,3084.55,3061.47,3027.50,2916.93,2126.07,1602.27,1494.03,1446.93,1395.93,1349.20,1152.30cm-1.
实施例11:1-苄基-3-苯基-4-甲基吡唑的合成
将146mg(1.0mmol)α-甲基肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和257mg(1.5mmol)溴苄,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得233mg无色油状液体,产率94%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=2.20(s,3H),5.27(s,2H),7.15(s,1H),7.21-7.35(m,6H),7.38-7.42(m,2H),7.69-7.71(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=10.1,55.9,114.2,127.1,127.4,127.7,127.9,128.3,128.7,129.7,134.1,136.8,149.7ppm;HRMS(ESI):Calcd for C17H17N2[M+H]+:249.1386,found:249.1380;IR (film):ν=3061.57,3030.89,2926.21,2867.94,1603.95,1552.37,1496.07,1444.57,1343.86,1162.54cm-1.
实施例12:1-苯甲酰基-3-苯基-4-甲基吡唑的合成
将146mg(1.0mmol)α-甲基肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和210mg(1.5mmol)苯甲酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得250mg无色油状液体,产率95%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=2.31(s,3H),7.37-7.51(m,5H),7.58(t,J=7.2Hz,1H),7.75(d,J=7.2Hz,2H),8.21-8.25(m,3H)ppm;13C NMR(100MHz,CDCl3)δ=10.4,118.8,127.8,128.0,128.5,128.6,130.0,131.67,131.72,132.5,132.7,155.5,165.9ppm;HRMS(ESI):Calcd for C17H14N2ONa[M+Na]+:285.0998,found:285.0997;IR(film):ν=3061.55,3030.80,2925.61,2867.91,1603.99,1552.39,1495.76,1447.29,1343.97,1162.34cm-1.
实施例13:1-烯丙基-3-苯基-4-甲基吡唑的合成
将146mg(1.0mmol)α-甲基肉桂醛,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,依次加入60mg(1.5mmol)NaOH和180mg(1.5mmol)烯丙基溴,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得154mg无色油状液体,产率78%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=2.22(d,J=0.8Hz,3H),4.71(dt,J=4.4,1.2Hz,2H),5.20-5.25(m,2H),5.99-6.09(m,1H),7.21(s,1H),7.27-7.31(m,1H),7.37-7.41(m,2H),7.67-7.69(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=10.0,54.5,113.9,118.3,127.0,127.4,128.3,129.4,133.1,134.1,149.7ppm;HRMS(ESI):Calcd for C13H15N2[M+H]+:199.1230,found:199.1232;IR(film):ν=3062.76,3024.61,2922.05,2868.37,1604.55,1552.41,1438.60,1340.63,1165.52cm-1.
实施例14:1-苄基-3-苯基-5-苯基吡唑的合成
将208mg(1.0mmol)查耳酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙醇中,室温搅拌反应48h,补加2mL乙醇,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,减压蒸除溶剂。依次加入4mL乙腈,60mg(1.5mmol)NaOH和257mg(1.5mmol)溴苄,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得276mg白色固体,产率89%。
产物检测数据如下:
熔点:114-117℃;1H NMR(400MHz,CDCl3)δ=5.38(s,2H),6.66(s,1H),7.09(d,J=7.2Hz,2H),7.21-7.30(m,4H),7.32-7.42(m,7H),7.87(d,J=7.2Hz,2H)ppm;13C NMR(100MHz,CDCl3)δ=53.2,103.7,125.6,126.7,127.4,127.6,128.55,128.56,128.6,128.8,130.6,133.4,137.7,145.4,150.9ppm;HRMS (ESI):Calcd for C22H19N2[M+H]+:311.1543,found:311.1536;IR(film):ν=3060.37,2955.52,2924.66,2853.97,1452.94,1361.89,1307.61cm-1.
实施例15:1-苯甲酰基-3-苯基-5-苯基吡唑的合成
将208mg(1.0mmol)查耳酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙醇中,室温搅拌反应48h,补加2mL乙醇,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,减压蒸除溶剂。依次加入4mL乙腈,60mg(1.5mmol)NaOH和210mg(1.5mmol)苯甲酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得275mg无色油状液体,产率85%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=6.86(s,1H),7.35-7.44(m,6H),7.47-7.51(m,4H),7.59-7.63(m,1H),7.86(dd,J=8.0,1.2Hz,2H),8.11-8.13(m,2H)ppm;13CNMR(100MHz,CDCl3)δ=108.9,126.3,128.0,128.2,128.5,128.7,129.1,130.8,131.8,131.9,132.5,133.1,148.6,153.5,167.4ppm;HRMS(ESI):Calcd forC22H16N2ONa[M+Na]+:347.1155,found:347.1158;IR(film):ν=3061.19,2924.95,2856.66,1709.82,1560.35,1488.33,1453.89,1331.06,1305.77cm-1.
实施例16:1-乙基-3-苯基-5-苯基吡唑的合成
将208mg(1.0mmol)查耳酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙醇中,室温搅拌反应48h,补加2mL乙醇,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,减压蒸除溶剂。依次加入4mL乙腈,44mg(1.1mmol)NaOH和172mg(1.1mmol)碘乙烷,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得243mg无色油状液体,产率98%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=1.44(t,J=7.2Hz,3H),4.20(q,J=7.2Hz,2H),6.57(s,1H),7.29(t,J=7.6Hz,1H),7.38-7.48(m,7H),7.84-7.86(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=15.9,44.6,103.3,125.6,127.5,128.48,128.54,128.7,128.8,130.9,133.6,144.4,150.5ppm;HRMS(ESI):Calcd for C17H17N2[M+H]+:249.1386,found:249.1384;IR(film):ν=3060.40,2976.71,2937.62,1605.66,1548.94,1481.20,1460.17,1373.56,1304.19cm-1.
实施例17:1-烯丙基-3-苯基-5-苯基吡唑的合成
将208mg(1.0mmol)查耳酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙醇中,室温搅拌反应48h,补加2mL乙醇,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,减压蒸除溶剂。依次加入4mL乙腈,60mg(1.5mmol)NaOH和180mg(1.5mmol)烯丙基溴,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得250mg无色油状液体,产率96%。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ=4.77(dd,J=3.2,1.6Hz,2H),5.03(dd,J=16.8,1.2Hz,1H),5.20(dd,J=10.4,1.2Hz,1H),6.00-6.09(m,1H),6.61(s,1H),7.29(t,J=7.6Hz,1H),7.37-7.46(m,7H),7.84-7.86(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=52.0,103.3,117.2,125.6,127.6,128.52,128.56,128.59,128.7,130.6,133.4,133.8,145.1,150.9ppm;HRMS(ESI):Calcd for C18H17N2[M+H]+:261.1386,found:261.1385;IR(film):ν=3062.80,2986.49,2928.08,1605.22,1549.01,1483.54,1459.99,1438.44,1367.22,1304.64cm-1.
实施例18:1-炔丙基-3-苯基-5-苯基吡唑的合成
将208mg (1.0mmol)查耳酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙醇中,室温搅拌反应48h,补加2mL乙醇,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,减压蒸除溶剂。依次加入4mL乙腈,60mg(1.5mmol)NaOH和177mg(1.5mmol)炔丙基溴,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得191mg白色固体,产率74%。
产物检测数据如下:
熔点:93-95℃;1H NMR(400MHz,CDCl3)δ=2.42(t,J=2.4Hz,1H),4.90(d,J=2.4Hz,2H),6.62(s,1H),7.28-7.32(m,1H),7.38-7.50(m,5H),7.55-7.58(m,2H),7.84-7.86(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=39.7,73.6,78.4,103.7,125.7,127.8,128.5,128.7,128.8,130.1,133.1,145.0,151.4ppm;HRMS(ESI):Calcd for C18H15N2[M+H]+:259.1230,found:259.1223;IR(film):ν=3294.31,3063.68,2963.18,2932.77,1482.75,1458.06,1432.01cm-1.
实施例19:1-苄基-3-苯基-5-甲基吡唑的合成
将146mg(1.0mmol)苄叉丙酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应17h。冷却至室温,依次加入60mg(1.5mmol)NaOH和257mg(1.5mmol)溴苄,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得194mg白色固体,产率78%。
产物检测数据如下:
熔点:86-87℃;1H NMR(400MHz,CDCl3)δ=2.18(s,3H),5.32(s,2H),6.37(s,1H),7.11(d,J=6.8Hz,2H),7.22-7.31(m,4H),7.36-7.39(m,2H),7.80-7.82(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=11.2,53.1,103.2,125.5,126.6,127.4,127.5,128.5,128.6,133.7,137.0,139.8,150.3ppm;HRMS(ESI):Calcd for C17H17N2[M+H]+:249.1386,found:249.1385;IR(film):ν=3063.11,3027.38,2914.79,1547.20,1480.24,1451.67,1427.88,1310.54cm-1.
实施例20:1-苯甲酰基-3-苯基-5-甲基吡唑的合成
将146mg(1.0mmol)苄叉丙酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应3h,补加2mL乙腈,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应17h。冷却至室温,依次加入60mg(1.5mmol)NaOH和210mg(1.5mmol)苯甲酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得199mg白色固体,产率76%。
使用(E)-1-苯基-2-丁烯-1-酮代替苄叉丙酮可得相同的产物。
将146mg(1.0mmol)(E)-1-苯基-2-丁烯-1-酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙醇中,室温搅拌反应48h,补加2mL乙醇,加44mg(1.1mmol)NaOH,于90℃油浴中回流反应15h。冷却至室温,减压蒸除溶剂。依次加入4mL乙腈,60mg(1.5mmol)NaOH和210mg(1.5mmol)苯甲酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得191mg白色固体,产率73%。
产物检测数据如下:
熔点:81-83℃;1H NMR(400MHz,CDCl3)δ=2.72(d,J=0.8Hz,3H),6.57(d,J=0.8Hz,1H),7.23-7.41(m,3H),7.46-7.50(m,2H),7.56-7.60(m,1H),7.78-7.81(m,2H)ppm;13C NMR(100MHz,CDCl3)δ=14.5,107.9,126.2,127.8,128.6,128.9,131.7,132.0,132.5,133.1,145.7,153.4,168.5ppm;HRMS (ESI):Calcd for C17H14N2ONa[M+Na]+:285.0998,found:285.0991;IR(film):ν=3112.93,3061.00,3031.92,2970.04,2925.69,1690.93,1597.05,1577.75,1469.47,1446.11,1349.43cm-1.
实施例21:1-苯甲酰基-3-苯基-4-甲基-5-甲基吡唑的合成
将160mg(1.0mmol)(E)-3-甲基-4-苯基-3-丁烯-2-酮,205mg(1.1mmol)对甲苯磺酰肼溶于2mL乙腈中,室温搅拌反应24h,补加2mL乙腈,加62mg(1.1mmol)NaOMe,于90℃油浴中回流反应20h。冷却至室温,依次加入84mg(1.5mmol)NaOMe和210mg(1.5mmol)苯甲酰氯,室温反应2h。加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离(乙酸乙酯/石油醚作洗脱剂)得207mg白色固体,产率75%。
产物检测数据如下:
熔点:143-146℃;1H NMR(400MHz,CDCl3)δ=2.17(s,3H),2.63(s,3H),7.33-7.46(m,5H),7.52-7.68(m,1H),7.67(d,J=7.2Hz,2H),8.06(d,J=7.2Hz,2H)ppm;13C NMR(100MHz,CDCl3)δ=9.2,12.4,116.5,127.7,128.1,128.4,131.5,132.3,132.9,133.4,141.5,153.8,168.5ppm;HRMS(ESI):Calcd forC18H16N2ONa[M+Na]+:299.1155,found:299.1146;IR(film):ν=3061.23,2960.11,2925.15,1694.79,1450.32,1338.28cm-1。
Claims (3)
1.多取代吡唑制备方法,其特征在于以α,β-不饱和醛或α,β-不饱和酮、对甲苯磺酰肼和R1-X为原料,按式1进行反应,
得到多取化吡唑,式1中:R1可为烷基、烯丙基、炔丙基、苄基、苯甲酰基或取代苯甲酰基;R3、R4、R5可分别为烷基、氢原子、芳基或取代芳基,且3-位取代基的体积R3大于等于5-位取代基R5的体积,即R3≥R5;对甲苯磺酰肼与α,β-不饱和醛或酮的物质量之比为1.05-1.5;R1-X为各种卤代物或酰氯,R1-X与α,β-不饱和醛或酮的物质的量之比为1.1-1.5;所用的碱为NaOH、KOH、K2CO3、Na2CO3、甲醇钠、乙醇钠或叔丁醇钾中的任一种,碱与α,β-不饱和化合物物质的量之比为2.2-3;反应所采用的溶剂为乙腈或乙醇。
2.根据权利要求1所述的多取代吡唑制备方法,其特征在于R1-X为碘甲烷、碘乙烷、烯丙基溴、炔丙基溴、溴苄或苯甲酰氯中的任一种。
3.根据权利要求2所述的多取代吡唑制备方法,其特征在于将1.0mmol α,β-不饱和醛或α,β-不饱和酮和1.05-1.5mmol对甲苯磺酰肼溶于2mL乙腈或乙醇中,室温搅拌反应2-48h,补加2mL乙腈或乙醇,加1.1mmol碱,于80-100℃油浴中反应15-48h,冷却至室温,如前步用乙醇做溶剂,此时应减压蒸除乙醇并补加4mL乙腈,再依次加入1.1-1.5mmol碱和1.1-1.5mmol卤代物或酰氯,室温反应2h,加入10mL水,50mL乙醚萃取,饱和食盐水洗涤,有机相用无水MgSO4干燥,过滤,滤液减压浓缩经硅胶柱层析分离后得产物。
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CN106916106A (zh) * | 2015-12-28 | 2017-07-04 | 兰州大学 | 一种吡唑的制备方法 |
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CN103980201A (zh) * | 2014-05-23 | 2014-08-13 | 苏州大学 | 一种含砜基的全取代吡唑的制备方法 |
CN103980201B (zh) * | 2014-05-23 | 2016-02-10 | 苏州大学 | 一种含砜基的全取代吡唑的制备方法 |
CN106916106A (zh) * | 2015-12-28 | 2017-07-04 | 兰州大学 | 一种吡唑的制备方法 |
CN106916106B (zh) * | 2015-12-28 | 2019-08-27 | 兰州大学 | 一种吡唑的制备方法 |
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