CN103275008B - 3,4,5-三取代吡唑类化合物及其制备方法 - Google Patents
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Abstract
本发明公开了一种3,4,5-三取代吡唑类化合物,其特征是结构通式为:
Description
技术领域
本发明属化合物的合成方法,主要涉及吡唑类化合物及其制备方法。
背景技术
吡唑类化合物是一类重要的杂环化合物,在医药、农药中有广泛的开发和应用前景。吡唑类化合物具有抗肿瘤、抗菌、抗炎和降血糖等生物活性。并且,吡唑的衍生物吡唑啉是医药和染料的重要中间体。所以,吡唑类化合物在有机化学和药物化学中都起着举足轻重的作用。
目前,吡唑类化合物最重要的合成方法为:
以1,3-二酮和肼为原料,环合得到吡唑类化合物(式1)。但由于1,3-二酮容易缩合,所以,1,3-二酮的制备存在一些困难。并且,含有醛基、氰基、卤素、酯基等官能团的1,3-二酮并不适用于该方法来合成吡唑类化合物。
发明内容
本发明要解决的技术问题是提供一种3,4,5-三取代吡唑类化合物及其制备方法。
为了解决上述技术问题,本发明提供一种3,4,5-三取代吡唑类化合物,其结构通式为:
所述R1、 R2和R3均为单取代的芳环、单取代的芳杂环、多取代的芳环或多取代的芳杂环。
作为本发明的3,4,5-三取代吡唑类化合物的改进,其结构式为以下任意一种:
本发明还同时提供了上述3,4,5-三取代吡唑类化合物的制备方法,依次包括以下步骤:
1)、将烯烃叠氮类化合物、醛和对甲苯磺酰肼在溶剂和碱存在的条件下三组分(即烯烃叠氮类化合物、醛和对甲苯磺酰肼)一锅法于60~80℃反应(属于环合反应)1~2小时;所述烯烃叠氮类化合物、醛和对甲苯磺酰肼的摩尔比为1:1:1,所述碱与烯烃叠氮类化合物的摩尔比为5~7:1;
所述烯烃叠氮类化合物的结构通式为:
2)、将步骤1)所得物进行抽滤或柱层析,得3,4,5-三取代吡唑类化合物。
作为本发明的3,4,5-三取代吡唑类化合物的制备方法的改进:
烯烃叠氮类化合物为1,3-二苯基-2-叠氮-2-丙烯-1-酮、1-对氯苯基-2-叠氮-3-苯基-2-丙烯-1-酮或1-对甲基苯基-2-叠氮-3-苯基-2-丙烯-1-酮;
醛为苯甲醛、对溴苯甲醛、间溴苯甲醛、对硝基苯甲醛、4-吡啶甲醛或对甲基苯甲醛。
作为本发明的3,4,5-三取代吡唑类化合物的制备方法的进一步改进:碱为碳酸铯、氢氧化钠或甲醇钠。
作为本发明的3,4,5-三取代吡唑类化合物的制备方法的进一步改进:溶剂为极性溶剂或非极性溶剂;
极性溶剂为甲醇、乙醇、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、乙腈或氯仿;非极性溶剂为苯、甲苯。
在本发明中,一般每0.4mmol烯烃叠氮类化合物配用1.5~3 ml的溶剂。
分子多样性是发现创新药物的物质基础,为此,发明人设计合成了结构新颖的3,4,5-三取代吡唑类化合物(式2),以发现具有抗肿瘤活性的先导化合物。
本发明为3,4,5-三取代吡唑类化合物的合成提供一种新的方法,即将对甲苯磺酰肼、醛、烯烃叠氮类化合物三组分一锅法进行环合反应,从而高产率得到目标化合物3,4,5-三取代吡唑类化合物。
本发明所提供的3,4,5-三取代吡唑类化合物的合成路线如式3所示:
烯烃叠氮类化合物(Ⅰ)、醛(Ⅱ)和对甲苯磺酰肼(Ⅲ)在溶剂存在下进行环合反应,得到目标物(Ⅳ),所用溶剂选用极性溶剂或非极性溶剂,所得产物通过抽滤或柱层析到纯化合物。
本发明提供的3,4,5-三取代吡唑类化合物的合成新方法具有以下特点:(1)三组分一锅法于50~70℃(较佳为60℃)环合反应,不需要高温回流。(2)产率高,大部分产物产率在80%以上。(3)产物结构单一,无异构体生成。
烯烃叠氮类化合物是一类重要的合成子,在杂环化合物的合成中应用广泛,具有反应活性高,反应速度快的特点,并且烯烃叠氮类化合物参与的反应一般比较温和。因此,本发明以对甲苯磺酰肼、醛、烯烃叠氮类化合物为原料,在温和条件下合成3,4,5-三取代吡唑类化合物。此合成方法在50~70℃(较佳为60℃)下进行,合成方法新颖,未见文献报道;合成的化合物结构新颖,未见文献报道;合成的化合物具有一定的抗肿瘤活性,为理想的抗肿瘤先导化合物。本发明所得的3,4,5-三取代吡唑类化合物的用途是抗肿瘤先导化合物。
具体实施方式
下面将通过实施例对本发明作进一步的说明。
实施例1、3-苯甲酰基-4,5-二苯基-1H-吡唑 (m1)
将苯甲醛42.4mg (0.4mmol),对甲苯磺酰肼74.4mg (0.4mmol),1,3-二苯基-2-叠氮-2-丙烯-1-酮99.6mg (0.4mmol)加至反应瓶中,后加入DMF(N,N-二甲基甲酰胺) 2.0 ml,氢氧化钠0.08克(2.0mmol),加料完毕后,60℃搅拌反应2小时,TLC检测反应(PE:EA=4:1,即石油醚:乙酸乙酯=4:1的体积比)。确认反应结束后,反应液用20*3mL乙酸乙酯萃取三次,有机层(位于上层)合并后用30*3 mL饱和食盐水洗涤三次,然后用无水硫酸钠(约2.0g)干燥30分钟,浓缩(用旋转蒸发仪浓缩),柱层析(PE:AE=6:1),所述柱层析的具体工艺参数如下:
选有硅胶柱作为层析柱;
以PE:AE=6:1作为洗液;流速为1 mL/min;收集第90min~第110min的洗脱液;然后经旋转蒸发仪干燥处理后,得到产物3-苯甲酰基-4,5-二苯基-1H-吡唑107.6 mg,收率83%。
该3-苯甲酰基-4,5-二苯基-1H-吡唑的结构式为:
White solid; mp: 175.8 – 176.9 °C; 1H NMR (500 MHz, CDCl3): 1H NMR (500 MHz, CDCl3) δ 10.97 (br s, 1H), 7.87 –7.85 (d, J = 7.5 Hz, 2H), 7.47-7.44(t, J = 7.4 Hz, 1H), 7.35 – 7.29 (m, 7H), 7.21– 7.17 (m, 5H); 13C NMR (126 MHz, CDCl3) δ 188.71, 137.16, 132.88, 131.89, 130.60, 130.20, 128.79, 128.60, 128.28, 128.12, 128.03, 127.37, 122.41; HRMS (ESI): m/z calcd for C22H16N2O [M+H]+: 325.1335, found: 325.1336.
以下为不同温度的对照实验:
对比例1-1、将60℃搅拌反应2小时改成40℃搅拌反应5小时,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑90.7mg,收率71%。
对比例1-2、将60℃搅拌反应2小时改成80℃搅拌反应1小时,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑110.2mg,收率85%。
对比例1-3、将氢氧化钠由5.0当量改成1.5当量,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑63.5mg,收率49%。
对比例1-4、将氢氧化钠由5.0当量改成3当量,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑95.9mg,收率74%。
对比例1-5、将氢氧化钠由5.0当量改成7当量,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑114.0mg,收率88%。
对比例1-3~对比例1-5显示碱加入的多少对反应很重要。
对比例1-6、用二氧六环代替DMF,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑59.6mg,收率46%。
对比例1-7、用甲苯代替DMF,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑95.9mg,收率74%。
对比例1-8、用乙醇代替DMF,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑32.4mg,收率25%。
对比例1-9、用乙腈代替DMF,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑111.5mg,收率86%。
对比例1-10、用碳酸铯代替氢氧化钠,摩尔量不变,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑97.2mg,收率75%。
对比例1-11、用甲醇钠代替氢氧化钠,摩尔量不变,其余同实施例1。得到白色固体状产物3-苯甲酰基-4,5-二苯基-1H-吡唑63.5mg,收率49%。
对比例1-12、用DABCO(1,4-二氮杂二环[2.2.2]辛烷)代替氢氧化钠,摩尔量不变,其余同实施例1。无产物生成。
实施例2、3-苯甲酰基-4-苯基-5-(4-溴苯基)-1H-吡唑 (m2)
以对溴苯甲醛代替苯甲醛,摩尔量不变,其余等同于实施例1。得到白色固体状产物3-苯甲酰基-4-苯基-5-(4-溴苯基)-1H-吡唑143.5mg,收率89%。
其结构式为:
White solid; mp: 217.0 – 217.7 °C; 1H NMR (500 MHz, CDCl3) δ 11.08 (br s, 1H), 7.74 (d, J = 7.0Hz, 2H), 7.43 – 7.41 (m, 3H), 7.25 – 7.21 (m, 4H), 7.18 – 7.17 (m, 3H), 7.10 (d, J = 6.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 188.12, 136.75, 135.08, 132.97, 131.91 131.56, 130.60, 129.98, 129.69, 128.42, 128.12, 127.61, 122.77; HRMS (ESI): m/z calcdfor C22H15BrN2O [M+H]+: 403.0441, found: 403.0438.
实施例3、3-苯甲酰基-4-苯基-5-(3-溴苯基)-1H-吡唑 (m3)
以间溴苯甲醛代替苯甲醛,摩尔量不变,其余等同于实施例1。得到白色固体状产物3-苯甲酰基-4-苯基-5-(3-溴苯基)-1H-吡唑137.7mg,收率85%。
其结构式为:
White solid; mp: 155.5 – 156.5 °C; 1H NMR (500 MHz, CDCl3) δ 11.81 (br s, 1H), 7.73 (d, J = 6.4Hz, 2H), 7.60 (s, 1H), 7.43 – 7.37 (m, 6H), 7.25– 7.13 (m, 2H), 7.11 – 7.08 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 188.11, 136.64, 132.98, 131.41, 131.39, 131.03, 130.59, 130.09, 129.98, 128.39, 128.10,127.63, 126.81, 123.02, 122.70; HRMS (ESI): m/z calcdfor C22H15BrN2O [M+H]+: 403.0441, found: 403.0442.
实施例4、3-苯甲酰基-4-苯基-5-(4-硝基苯基)-1H-吡唑 (m4)
以对硝基苯甲醛代替苯甲醛,摩尔量不变,其余等同于实施例1。得到白色固体状产物3-苯甲酰基-4-苯基-5-(4-硝基苯基)-1H-吡唑137.7mg,收率92%。
其结构式为:
Pale yellow solid; mp: 206.7 – 207.7 °C; 1H NMR(500 MHz, DMSO-d6) δ 14.24 (s, 1H), 8.21 (s, 2H),8.01 (s, 1H), 7.72 – 7.42 (m, 5H), 7.40 – 7.15(d, 6H); 13C NMR (125 MHz, CDCl3) δ 187.26, 147.46,136.14, 133.14, 131.10, 130.61, 129.68, 128.86, 128.66, 128.15, 128.06, 123.87, 123.83; HRMS (ESI): m/zcalcd for C22H15N3O3 [M+H]+: 370.1186, found: 370.1190.
实施例5、3-苯甲酰基-4-苯基-5-(4-吡啶基)-1H-吡唑 (m5)
以4-吡啶甲醛代替苯甲醛,摩尔量不变,其余等同于实施例1。得到淡黄色固体状产物3-苯甲酰基-4-苯基-5-(4-吡啶基)-1H-吡唑140.9mg,收率82%。
White solid; mp: 308.1 – 308.9 °C; 1H NMR (500 MHz, DMSO-d6) δ 14.28 (br s, 1H), 8.53 (d, J = 5.3 Hz, 2H), 7.89 (s, 2H), 7.59 (t, J = 7.1 Hz, 1H)., 7.45 (t, J = 7.3 Hz, 2H), 7.32 – 7.29 (m, 5H), 7.20 (d, J = 4.8 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 188.03, 149.98, 137.22, 132.91, 132.03, 130.13, 129.93, 128.30, 128.22, 127.37, 122.69, 121.59;HRMS (ESI): m/z calcd for C21H15N3O [M+H]+: 326.1288,found: 326.1286.
实施例6、3-(4-氯苯甲酰基)-4,5-二苯基-1H-吡唑 (m6)
以1-对氯苯基-2-叠氮-3-苯基-2-丙烯-1-酮113.2mg (0.4mmol)代替1,3-二苯基-2-叠氮-2-丙烯-1-酮,其余等同于实施例1。得到白色固体状产物3-(4-氯苯甲酰基)-4,5-二苯基-1H-吡唑124.6mg,收率87%。
White solid; mp: 240.9 – 241.8 °C; 1H NMR (500 MHz, DMSO-d6) δ 14.04 (s, 1H), 8.02 (s, 2H), 7.56(s, 2H), 7.35 – 7.19 (m, 10H); 13C NMR (125 MHz,DMSO-d6) δ 187.20, 137.56, 136.17, 132.37, 131.80, 130.17, 128.54, 128.39, 128.20, 127.96, 127.68, 126.87,121.18; HRMS (ESI): m/z calcd for C22H15ClN2O [M+H]+:359.0946, found: 359.0948.
实施例7、3-(4-甲基苯甲酰基)-4,5-二苯基-1H-吡唑 (m7)
以1-对甲基苯基-2-叠氮-3-苯基-2-丙烯-1-酮105.2mg (0.4mmol)代替1,3-二苯基-2-叠氮-2-丙烯-1-酮,其余等同于实施例1。得到白色固体状产物3-(4-甲基苯甲酰基)-4,5-二苯基-1H-吡唑100.0mg,收率74%。
White solid; mp: 238.3 – 238.8 °C; 1H NMR (500 MHz, CDCl3) δ 10.72 (br s, 1H), 7.78 (d, J = 7.6Hz, 1H), 7.40 – 7.28 (m, 5H), 7.23 – 7.15 (m, 5H), 7.11 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 188.17, 143.18, 134.90, 132.68, 130.25, 130.18, 129.39, 128.77, 128.60, 128.31,128.05, 127.73, 126.82, 120.85, 21.19; HRMS (ESI): m/z calcd for C23H18N2O [M+H]+: 339.1492, found: 339.1495.
实施例8、3-(4-甲基苯甲酰基)-4-苯基-5-(3-溴苯基)-1H-吡唑 (m8)
以间溴苯甲醛代替了苯甲醛,摩尔量不变,其余等同于实施例7。得到白色固体状产物3-(4-甲基苯甲酰基)-4-苯基-5-(3-溴苯基)-1H-吡唑148.2mg,收率85%。
White solid; mp: 157.5 – 158.4 °C; 1H NMR (500 MHz, CDCl3) δ 11.72 (br s, 1H), 7.73 (s, 3H), 7.57(s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.25 – 7.15(m, 6H), 7.11 (t, J = 7.8 Hz, 3H); 13C NMR (125MHz, CDCl3): δ 186.93, 139.41, 135.08, 131.60, 131.47, 131.23, 130.93, 130.54, 130.20, 128.52, 128.43, 127.83, 126.75, 123.01, 122.79; LC-MS (ESI): m/z calcdfor C22H14BrClN2O [M+H]+: 437.0051, found: 437.0052.
实施例9、3-(4-甲基苯甲酰基)-4-苯基-5-(3-溴苯基)-1H-吡唑 (m9)
以对甲基苯甲醛代替了苯甲醛,摩尔量不变,其余同实施例6。得到白色固体状产物3-(4-氯苯甲酰基)-4-苯基-5-(4-甲基苯基)-1H-吡唑133.9mg,收率90%。
White solid; mp: 215.7 – 216.5 °C; 1H NMR (500 MHz, DMSO-d6) δ 13.91 (s, 1H), 8.05 (s, 2H), 7.57(s, 2H), 7.34 – 7.06 (m, 6H), 2.29 (s, 3H); 13CNMR (125 MHz, DMSO-d6): δ 187.30, 140.88, 138.02, 137.54, 136.21, 132.47, 131.84, 130.16, 129.14, 128.19,127.93, 127.54, 126.80, 125.59 120.81, 20.68; LC-MS(ESI): m/z calcd for C23H17ClN2O [M+H]+: 373.1102, found: 373.1104.
实施例10、3-(4-甲基苯甲酰基)-4-苯基-5-(4-甲基苯基)-1H-吡唑(m10)
以对甲基苯甲醛代替了苯甲醛,摩尔量不变,其余同实施例7。得到淡黄色固体状产物3-(4-甲基苯甲酰基)-4-苯基-5-(4-甲基苯基)-1H-吡唑104.2mg,收率74%。
Pale yellow solid; mp: 189.5 – 190.4 °C; 1H NMR(500 MHz, CDCl3) δ 10.95 (br s, 1H), 7.81 (s, 2H), 7.21 – 7.20 (m, 7H), 7.13 – 7.09 (m, 4H), 2.35 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3):δ 188.61, 143.67, 138.46, 134.72, 132.15, 130.56, 130.49, 129.47, 128.84, 128.23, 127.79, 127.18, 121.79,21.77, 21.40; LC-MS (ESI): m/z calcd for C24H20N2O [M+H]+: 353.1648, found: 353.1642.
体外抗肿瘤活性实验
以K562(人慢性髓源白血病细胞)为测试细胞株,以临床使用抗肿瘤药物达沙替尼为阳性对照,采用MTT法对目标化合物进行抗肿瘤活性评价。将受试药物配制为一定浓度与肿瘤细胞株作用24小时后,进行抑制率检测。(结果见表1)
检测方法具体如下:
1、收集对数期生长细胞,调节细胞悬液浓度为5000/孔;
2、加入待测化合物,使之终浓度达到10umol/L;
3、37摄氏度,5% CO2孵育24小时;
4、每孔加入20uL,5mg/mLMTT溶液,继续培养4h;
5、700r/min离心5min,小心除去上清液,每孔加入150uL DMSO,摇床低速震动15min充分溶解,在酶联免疫检测仪OD570nm测试各孔吸光度。
表1 化合物对K562肿瘤细胞的抑制率
化合物 | 抑制率(%) |
m1 | 87.56 |
m2 | 90.80 |
m3 | 88.89 |
m4 | 82.93 |
m5 | 14.84 |
m6 | 87.10 |
m7 | 91.45 |
m8 | 95.19 |
m9 | 82.15 |
m10 | 91.55 |
达沙替尼 | 93.09 |
从表1可以看出,大部分化合物抑制肿瘤细胞的活性与达沙替尼相当,甚至化合物m8抑制肿瘤细胞的活性大于达沙替尼,显示该类化合物为理想的抗肿瘤先导化合物,对其进一步进行结构修饰,有望发现结构新颖的抗肿瘤药物。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (5)
1.3,4,5-三取代吡唑类化合物,其特征是结构式为:
2.如权利要求1所述的3,4,5-三取代吡唑类化合物的制备方法,其特征是依次包括以下步骤:
1)、将烯烃叠氮类化合物、醛和对甲苯磺酰肼在溶剂和碱存在的条件下三组分一锅法于60~80℃反应1~2小时;所述烯烃叠氮类化合物、醛和对甲苯磺酰肼的摩尔比为1:1:1,所述碱与烯烃叠氮类化合物的摩尔比为5~7:1;
所述烯烃叠氮类化合物为1-对甲基苯基-2-叠氮-3-苯基-2-丙烯-1-酮;
所述醛为间溴苯甲醛;
2)、将步骤1)所得物进行抽滤或柱层析,得3,4,5-三取代吡唑类化合物。
3.根据权利要求2所述的3,4,5-三取代吡唑类化合物的制备方法,其特征是:所述碱为碳酸铯、氢氧化钠或甲醇钠。
4.根据权利要求3所述的3,4,5-三取代吡唑类化合物的制备方法,其特征是:所述溶剂为极性溶剂或非极性溶剂。
5.根据权利要求4所述的3,4,5-三取代吡唑类化合物的制备方法,其特征是:所述极性溶剂为甲醇、乙醇、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、乙腈或氯仿;所述非极性溶剂为苯、甲苯。
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