CN103373987A - 一类含吡嗪环的三氮唑衍生物及其制法与用途 - Google Patents
一类含吡嗪环的三氮唑衍生物及其制法与用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一类含吡嗪环的三氮唑衍生物及其制法与用途。
吡嗪类化合物于1888年首次被人们合成,许多含吡嗪环的化合物具有重要的生理活性,吡嗪类化合物在药物上主要起抗结核、驱饶虫、抗惊厥、抗菌、清除自由基等重要作用。其衍生物有较多应用,如二苯并吡嗪是重要的染料,吩嗪以具有抗肿瘤、抗菌和利尿的性质而著称。而四甲基吡嗪被报道可以捕捉超氧阴离子,并减少人体有粒细胞的氮氧化物产生。
三氮唑是生产酮康唑、伊曲康唑、氟康唑、伏立康唑、沙排康唑等抗真菌药物的重要中间体,由于该类药物具有抗菌谱广、抗真菌活性好、吸收好,尤其适于口服吸收等特点,因此在临床上被广泛使用。很多吡嗪的衍生物也被报道具有抗菌活性。因此,本发明将吡嗪环引入1,2,4-三氮唑,制备含有吡嗪环的1,2,4-三氮唑衍生物。
1,2,4-三氮唑衍生物作为很有潜力的抗真菌药物的前景十分值得关注。随着1,2,4-三氮唑类药物研究的不断深入,在对其抗真菌作用机制不断了解的基础上进行有效的结构改造与修饰和分子设计,将会有越来越多的高效、低毒的1,2,4-三氮唑类抗真菌药物用于临床,造福人类。此类含吡嗪的三氮唑衍生物可能成为潜在的抗真菌药物。
发明内容
本发明的目的在于提供一类含吡嗪换的三氮唑衍生物以及它们的制备方法与用途。
本发明的技术方案如下:
一类含吡嗪环的三氮唑衍生物,其特征是它有如下通式:
式中R为:
一种制备上述的含吡嗪环的三氮唑衍生物的方法,其特征是它由下列步骤组成:
步骤1.将10mmol 2-吡嗪羧酸,15mL乙醇置于带有回流装置的圆底烧瓶中,搅拌下缓慢滴加40μL浓硫酸,油浴加热,在90℃下回流反应10-12h,将反应体系减压浓缩除去乙醇后加适量水。再用乙酸乙酯10mL萃取三次,合并有机相,并用饱和食盐水10mL洗涤三次。最后将有机相减压浓缩即可得到油状液体产物。
步骤2.将步骤1所得的酯溶于15mL乙醇,搅拌下逐渐滴加85%水合肼0.6mL,升温至90℃搅拌回流4-6h,减压蒸去溶剂乙醇,然后加水,待固体析出后,过滤并用水洗。滤饼用乙醇重结晶后烘干。
步骤3.将步骤2所得的酰肼,10mmol异硫氰酸苯酯,15mL无水乙醇置于带有回流装置的圆底烧瓶中,油浴加热,在85℃下回流反应4h。冷却至室温。将冷却产物后的圆底烧瓶中析出的固体滤出烘干,称取20mmol的氢氧化钠,溶于10mL水中,加入过滤所得的已干燥固体。在90℃下回流反应0.5h,放置冷 却。
步骤4.用10%的盐酸溶液将步骤3反应完的溶液调至pH=5,析出白色固体。真空抽滤后将白色滤饼用乙醇重结晶,干燥后得产物。
步骤5.将步骤4中得到的白色产物溶于无水乙腈,然后加入各种取代的溴化苄、氢氧化钠,90℃回流反应5h。其中反应物白色固体与各种取代的溴化苄的摩尔比是1∶1,与氢氧化钠的摩尔比是1∶2。
步骤6.反应完全后,将溶剂乙腈蒸干,加入适量水,再用适量乙酸乙酯萃取三次,合并有机相,然后用无水Na2SO4干燥有机相,将有机相减压蒸干,得到的粗产物用无水乙醇重结晶得到本发明的含吡嗪的三氮唑衍生物。
本发明的含吡嗪环的三氮唑衍生物可能成为潜在的抗真菌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例一:2-(5-((2-氟苄基)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物1)的制备。
将10mmol 2-吡嗪羧酸,15mL乙醇置于带有回流装置的圆底烧瓶中,搅拌下缓慢滴加40μL浓硫酸,油浴加热,在90℃下回流反应10-12h,将反应体系减压浓缩除去乙醇后加适量水。再用乙酸乙酯10mL萃取三次,合并有机相,并用饱和食盐水10mL洗涤三次。最后将有机相减压浓缩所得的酯溶于15mL乙醇,搅拌下逐渐滴加85%水合肼0.6mL,升温至90℃搅拌回流4-6h,减压蒸去溶剂 乙醇,然后加水,待固体析出后,过滤并用水洗。滤饼用乙醇重结晶后烘干,然后和10mmol异硫氰酸苯酯,15mL无水乙醇一起置于带有回流装置的圆底烧瓶中,油浴加热,在85℃下回流反应4h。将冷却产物后的圆底烧瓶中析出的固体滤出烘干,称取20mmol的氢氧化钠,溶于10mL水中,加入过滤所得的已干燥固体。在90℃下回流反应0.5h,放置冷却。用10%的盐酸溶液将溶液调至pH=5,析出白色固体。真空抽滤后将白色滤饼用乙醇重结晶,干燥后溶于无水乙腈,然后加入2-氟溴化苄、氢氧化钠,90℃回流反应5h。其中反应物白色固体与2-氟溴化苄的摩尔比是1∶1,与氢氧化钠的摩尔比是1∶2。反应完全后,将溶剂乙腈蒸干,加入适量水,再用适量乙酸乙酯萃取三次,合并有机相,然后用无水Na2SO4干燥有机相,将有机相减压蒸干,得到的粗产物用无水乙醇重结晶得到目标产物。黄色固体,产率74c/o,mp:131-132℃.1H NMR(500MHz,CDCl3):4.64(s,2H);7.01-7.10(m,2H);7.16(d,J=7.35Hz,2H);7.24-7.30(m,1H);7.43-7.50(m,3H);7.54(t,J=7.60Hz,1H);8.24(s,1H);8.49(s,1H);9.39(s,1H).ESI-MS:364.1(C19H15FN5S,[M+H]+).Anal.Calcd for C19H14FN5S:C,62.79;H,3.88;N,19.27.Found:C,62.61;H,3.89;N,19.33.
实施例二:2-(5-((2-氯苯)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物2)的制备。
制备方法同实施例一。以2-氯溴化苄代替2-氟溴化苄,得目标化合物。黄色固体,产率74c/o,mp:144-145℃.1H NMR(500MHz,CDCl3):4.69(s,2H);7.13-7.16(m,2H);7.19-7.26(m,2H);7.35-7.38(m,1H);7.41-7.49(m,3H);7.61-7.64(m,1H);8.24(s,1H);8.49(s,1H);9.38(s,1H).ESI-MS:380.1 (C19H15ClN5S,[M+H]+).Anal.Calcd for C19H14ClN5S:C,60.07;H,3.71;N,18.44.Found:C,60.21;H,3.70;N,18.40.
实施例三:2-(5-((2-溴甲基)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物3)的制备。
制备方法同实施例一。以2-溴溴化苄代替2-氟溴化苄,得目标化合物。黄色固体,产率75c/o,mp:160-162℃.1H NMR(500MHz,CDCl3):4.70(s,2H);7.12-7.17(m,3H);7.24-7.28(m,1H);7.42-7.51(m,3H);7.55(d,J=7.50Hz,1H);7.64(d,J=7.50Hz,1H);8.24(s,1H);8.49(s,1H);9.38(s,1H).ESI-MS:424.0(C19H15BrN5S,[M+H]+).Anal.Calcd for C19H14BrN5S:C,53.78;H,3.33;N,16.50.Found:C,53.60;H,3.34;N,16.44.
实施例四:2-(5-((3-氯苯)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物4)的制备。
制备方法同实施例一。以3-氯溴化苄代替2-氟溴化苄,得目标化合物。黄 色固体,产率78c/o,mp:117-118℃.1H NMR(500MHz,CDCl3):4.55(s,2H);7.15-7.17(m,2H);7.23-7.27(m,2H);7.38(s,1H);7.45-7.51(m,4H);8.25(s,1H);8.50(s,1H);9.39(s,1H).ESI-MS:380.1(C19H15ClN5S,[M+H]+).Anal.Calcd for C19H14ClN5S:C,60.07;H,3.71;N,18.44.Found:C,59.92;H,3.70;N,18.49.
实施例五:2-(5-((3-溴甲基)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物5)的制备。
制备方法同实施例一。以3-溴溴化苄代替2-氟溴化苄,得目标化合物。白色粉末,产率60c/o,mp:135-136℃.1H NMR(500MHz,CDCl3):4.50(s,2H);7.14-7.18(m,3H);7.34(d,J=7.60Hz,1H);7.39(d,J=7.90Hz,1H);7.44-7.51(m,3H);7.52(s,1H);8.24(s,1H);8.49(s,1H);9.38(s,1H).ESI-MS:424.0(C19H15BrN5S,[M+H]+).Anal.Calcd for C19H14BrN5S:C,53.78;H,3.33;N,16.50.Found:C,53.89;H,3.34;N,16.45.
实施例六:2-(5-((4-氟苄基)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物6)的制备。
制备方法同实施例一。以4-氟溴化苄代替2-氟溴化苄,得目标化合物。黄色固体,产率66c/o,mp:144-145℃.1H NMR(500MHz,CDCl3):4.59(s,2H);7.10-7.16(m,4H);7.28(s,2H);7.37-7.49(m,3H);8.24(s,1H);8.49(s,1H);9.38(s,1H).ESI-MS:364.1(C19H15FN5S,[M+H]+).Anal.Calcd for C19H14FN5S:C,62.79;H,3.88;N,19.27.Found:C,62.62;H,3.89;N,19.34.
实施例七:2-(5-((4-氯苯)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物7)的制备。
制备方法同实施例一。以4-氯溴化苄代替2-氟溴化苄,得目标化合物。黄色固体,产率77c/o,mp:169-170℃.1H NMR(500MHz,CDCl3):4.52(s,2H);7.14(d,J=6.78Hz,1H);7.24(s,1H);7.27(s,1H);7.34(d,J=8.43Hz,2H);7.44-7.48(m,4H);8.23(s,1H);8.49(s,1H);9.37(s,1H).ESI-MS:380.1(C19H15ClN5S,[M+H]+).Anal.Calcd for C19H14ClN5S:C,60.07;H,3.71;N,18.44.Found:C,60.18;H,3.70;N,18.39.
实施例八:2-(5-((2,4-二氟)硫基)-4-苯基-4H-1,2,4-三氮唑-3-基)吡嗪(化合物8)的制备。
制备方法同实施例一。以2,4-二氟溴化苄代替2-氟溴化苄,得目标化合物。黄色固体,产率80c/o,mp:156-157℃.1H NMR(500MHz,CDCl3):4.56(s,2H);6.77-6.84(m,2H);7.17-7.21(m,2H);7.44-7.51(m,3H);7.57(dd,J1=8.40Hz,J2=14.95Hz,1H);8.24(s,1H);8.49(s,1H);9.39(s,1H).ESI-MS:382.1(C19H14F2N5S,[M+H]+).Anal.Calcd for C19H13F2N5S:C,59.83;H,3.44;N,18.36.Found:C,59.67;H,3.45;N,18.42。
Claims (3)
2.一种制备权利要求1所述的含吡嗪环的三氮唑衍生物的方法,其特征是它由下列步骤组成:
步骤1.将10mmol 2-吡嗪羧酸,15mL乙醇置于带有回流装置的圆底烧瓶中,搅拌下缓慢滴加40μL浓硫酸,油浴加热,在90℃下回流反应10-12h,将反应体系减压浓缩除去乙醇后加适量水。再用乙酸乙酯10mL萃取三次,合并有机相,并用饱和食盐水10mL洗涤三次。最后将有机相减压浓缩即可得到油状液体产物。
步骤2.将步骤1所得的酯溶于15mL乙醇,搅拌下逐渐滴加85%水合肼0.6mL,升温至90℃搅拌回流4-6h,减压蒸去溶剂乙醇,然后加水,待固体析出后,过滤并用水洗。滤饼用乙醇重结晶后烘干。
步骤3.将步骤2所得的酰肼,10mmol异硫氰酸苯酯,15mL无水乙醇置于带有回流装置的圆底烧瓶中,油浴加热,在85℃下回流反应4h。冷却至室温。将冷却产物后的圆底烧瓶中析出的固体滤出烘干,称取20mmol的氢氧化钠,溶于10mL水中,加入过滤所得的已干燥固体。在90℃下回流反应0.5h,放置冷却。
步骤4.用10%的盐酸溶液将步骤3反应完的溶液调至pH=5,析出白色固体。真空抽滤后将白色滤饼用乙醇重结晶,干燥后得产物。
步骤5.将步骤4中得到的白色产物溶于无水乙腈,然后加入各种取代的溴化苄、氢氧化钠,90℃回流反应5h。其中反应物白色固体与各种取代的溴化苄的摩尔比是1∶1,与氢氧化钠的摩尔比是1∶2。
步骤6.反应完全后,将溶剂乙腈蒸干,加入适量水,再用适量乙酸乙酯萃取三次,合并有机相,然后用无水Na2SO4干燥有机相,将有机相减压蒸干,得到的粗产物用无水乙醇重结晶得到本发明的含吡嗪环的三氮唑衍生物。
3.权利要求1所述的含吡嗪环的三氮唑衍生物在制备抗真菌药物中的应用。
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EP3210469A1 (de) | 2016-02-23 | 2017-08-30 | Bayer Cropscience AG | Verwendung von substituierten thio-1,2,4-triazolen zur steigerung der stresstoleranz in pflanzen |
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CN107082774A (zh) * | 2017-06-09 | 2017-08-22 | 南京大学 | 一类含1,2,4‑氮三唑类骨架的衍生物及其制备方法和应用 |
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