CN107325080B - 含三嗪或氨基胍结构的咔唑类衍生物的制备方法及其抗菌应用 - Google Patents
含三嗪或氨基胍结构的咔唑类衍生物的制备方法及其抗菌应用 Download PDFInfo
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明涉及药物化学技术领域,尤其是咔唑类衍生物的制备方法及其抗菌应用。
背景技术
细菌感染在人们的生活中非常常见。世界卫生组织估计2011年全球死亡总人数为5500万人,其中感染性疾病占了三分之一。因为抗生素的滥用以及针对不同细菌感染没有正确选择药物等原因,药物的耐药性快速增长,产生了大量的多重耐药细菌,更有超级细菌的报道,耐药性感染和相关的发病率和死亡率呈上升趋势。过去的十年中,细菌的耐药性一直被视为最常见和最具有挑战性的问题之一。
20世纪40年代以来,抗生素数量几乎成指数级上升,自60年代以来,新的抗生素的发现速度大幅度减慢。目前临床上应用的抗菌药物包括:各种抗生素、磺胺类、噁唑烷酮类、硝基咪唑类、喹诺酮类、抗菌肽等。但分别存在耐药、化学性质不稳定、口服给药难被吸收、肾毒性、生产成本较高等缺点。
叶酸参与核酸和蛋白质的合成,还有各种氨基酸的代谢过程,是抗菌药物的一个重要靶点。DHFR(二氢叶酸还原酶)是生物体内一种重要的酶,可催化二氢叶酸还原成四氢叶酸。不同来源的DHFR,其蛋白质一级结构不同。DHFR抑制剂能特异性地与DHFR结合,抑制其活性,使二氢叶酸不能转变成四氢叶酸,阻碍叶酸代谢,产生抗菌、抗癌等作用。将叶酸的嘧啶环上一个碳原子换成其等电原子氮,即得到三嗪类化合物,许多研究表明,该类化合物对DHFR有抑制作用。有必要深入研究可与该靶点特异性结合的化合物,以寻找体内活性更好、靶点明确、毒副作用小的抗菌药物。
因此,如何研发出一类靶点明确的新型药效好、活性更高和低毒副作用的药物来克服目前抗菌药物存在的如上所述的缺点成为全社会关注的问题。所以新型抗菌药物的设计研发具有十分重要的意义。
发明内容
为解决上述问题,本发明提供了一类新型的含三嗪结构的咔唑类抗菌衍生物及其合成方法。其中一些化合物的抗菌效果优于目前临床上常用的抗菌药物莫西沙星(moxifloxacin)和加替沙星(gatifloxacin),且对大多数细菌不易产生耐药性。
本发明的技术方案如下:
一类新型的含三嗪结构的咔唑类衍生物,其结构通式如下:
其中,Y为H,Br;
R1分别是乙基、苄基、对甲基苄基、邻氟苄基、2,4-二氯苄基、对氯苄基、间氯苄基、对溴苄基、对氰基苄基、苯基、低级烷基、卤素、氨基、低级链烯基、羟基、烷氧基、硝基、羧基、羧基烷基中的任意一种。
该类化合物合成方法简单,合理,生产成本低。
式(E)化合物的合成通法如下:
(a)NaH,DMF,rt,16h;(b)POCl3DMF,90℃,8-18h;(c)AcOH,120℃,4-8h/CH2CH3OH,HCl,40℃,6h
如式(E)的含三嗪结构的咔唑类衍生物的合成方法,包括以下步骤:
(1)取100mL的圆底烧瓶,向其中加入咔唑,溶解于50mL DMF中,置于冰浴条件下,逐渐慢慢加入NaH,搅拌3-8min,得到墨绿色液体,滴加对甲基溴苄,搅拌3-8min,得到棕色液体,室温条件下反应12-24h,TLC跟踪反应至结束,加入冰水淬灭反应,析出固体,抽滤并干燥,用水洗涤固体,干燥得到灰白色粗产物,用无水乙醇重结晶,得到化合物C;
(2)取100mL两口瓶,氮气保护,加入DMF,置于冰浴条件下,冷却至零度,慢慢滴入三氯氧磷,室温搅拌45-75min,冰浴下滴加化合物B或者化合物C的二氯乙烷溶液,室温反应45-75min,在油浴锅中加热至85-95℃回流18h,TLC跟踪反应至结束,加冰水淬灭,用饱和碳酸钠溶液调节pH至中性,二氯甲烷萃取反应液三次,有机层用无水硫酸镁干燥过夜,抽滤,减压干燥滤液,得到的粗产品经柱层析(石油醚∶乙酸乙酯=40∶1)分离的到黄色至绿色固体纯品,得到化合物D;
(3)将盐酸二甲双胍与化合物D溶解于醋酸溶液中,氮气保护的情况下在油浴锅中加热至110-130℃反应4-8h,或者将氨基胍碳酸氢盐与化合物D共同置于50mL圆底烧瓶中,氮气保护,溶于无水乙醇溶液中,加入浓盐酸,在油浴锅中加热至30-50℃反应4-7h;TLC监测至反应结束,停止反应,减压蒸去溶剂得到白色固体;柱层析(二氯甲烷:甲醇=20:1)分离后,得到目标化合物E。
优选的,所述的步骤(1)中,咔唑、NaH和对甲基溴苄的摩尔比为1:(1-2):(0.8-1.5),进一步优选为1:1.5:1。
优选的,所述的步骤(2)中,DMF、三氯氧磷和中间体的摩尔比为(3-6):(1-1.2):1,进一步优选为60:17.25:15;所述的中间体为化合物B或者化合物C。
优选的,所述的步骤(2)中,盐酸二甲双胍与化合物D的摩尔比为1:1。
优选的,所述的步骤(2)中,氨基胍碳酸氢盐与化合物D的摩尔比为1:1。
优选的,如式(E)的含三嗪结构的咔唑类衍生物的合成方法,包括以下步骤:
(1)取100mL的圆底烧瓶,向其中加入咔唑(20mmol,3.34g),溶解于50mL DMF中,置于冰浴条件下,逐渐慢慢加入NaH(30mmol,1.20g),搅拌5min,得到墨绿色液体,滴加20mmol对甲基溴苄,搅拌5min,得到棕色液体,室温条件下反应16h,TLC跟踪反应至结束,加入冰水淬灭反应,析出固体,抽滤并干燥,用水洗涤固体,干燥得到灰白色粗产物,用无水乙醇重结晶,得到化合物C;
(2)取100mL两口瓶,氮气保护,加入60mmol DMF,置于冰浴条件下,冷却至零度,慢慢滴入三氯氧磷17.25mmol,室温搅拌1h,冰浴下滴加15mmol化合物B或者化合物C的二氯乙烷溶液,室温反应1h,在油浴锅中加热至90℃回流18h,TLC跟踪反应至结束,加冰水淬灭,用饱和碳酸钠溶液调节pH至中性,二氯甲烷萃取反应液三次,有机层用无水硫酸镁干燥过夜,抽滤,减压干燥滤液,得到的粗产品经柱层析(石油醚:乙酸乙酯=40:1)分离的到黄色至绿色固体纯品,得到化合物D;
(3)将2mmol盐酸二甲双胍与2mmol的化合物D溶解于醋酸溶液中,氮气保护的情况下在油浴锅中加热至120℃反应4-8h,或者将2.3mmol氨基胍碳酸氢盐与2mmol的化合物D共同置于50mL圆底烧瓶中,氮气保护,溶于无水乙醇溶液中,加入5滴浓盐酸,在油浴锅中加热至40℃反应6h;TLC监测至反应结束,停止反应,减压蒸去溶剂得到白色固体;柱层析(二氯甲烷:甲醇=20:1)分离后,得到目标化合物E。
本发明的有益之处在于:本发明的含三嗪结构的咔唑类衍生物的抗菌效果显著,比目前临床上常用的抗菌药物加替沙星和莫西沙星均具有更好的抗菌抑制效果,而且具有低细胞毒特性。
附图说明
图1为实施例1中目标化合物3的谱图,其中图1a为氢谱图,图1b为碳谱图,1c为高分辨质谱图。
图2为实施例2中目标化合物14的谱图,其中图2a为氢谱图,图2b为碳谱图,2c为高分辨质谱图。
具体实施方式
以下通过对若干具体化合物合成实例的实施方式再对本发明的上述内容作进一步的详细说明,但不应将此理解为本发明上述主题的范围仅限于下述的实例。
实施例1:
以4-氨基-3,6-二氢-2-二甲氨基-6-(9-(4-甲基苄基)-9H-咔唑-3-)1,3,5-三嗪(3)为例介绍式(E)化合物的合成通法。
化合物4-氨基-3,6-二氢-2-二甲氨基-6-(9-(4-甲基苄基)-9H-咔唑-3-)1,3,5-三嗪(3)的化学式如下:
化合物4-氨基-3,6-二氢-2-二甲氨基-6-(9-(4-甲基苄基)-9H-咔唑-3-)1,3,5-三嗪(3)的合成方法,包括以下步骤:
(1)取100mL的圆底烧瓶,向其中加入咔唑(20mmol,3.34g),溶解于50mL DMF中,置于冰浴条件下,逐渐慢慢加入NaH(30mmol,1.20g),搅拌5min,得到墨绿色液体,滴加20mmol对甲基溴苄,搅拌5min,得到棕色液体,室温条件下反应16h,TLC跟踪反应至结束,加入冰水淬灭反应,析出固体,抽滤并干燥,用水洗涤固体,干燥得到灰白色粗产物,用无水乙醇重结晶,得到化合物9-(4-甲基苄基)-9H-咔唑。
(2)取100mL两口瓶,氮气保护,加入60mmol DMF,置于冰浴条件下,冷却至零度,慢慢滴入三氯氧磷17.25mmol,室温搅拌1h,冰浴下滴加15mmol 9-(4-甲基苄基)-9H-咔唑的二氯乙烷溶液,室温反应1h,在油浴锅中加热至90℃回流18h,TLC跟踪反应至结束,加冰水淬灭,用饱和碳酸钠溶液调节pH至中性,二氯甲烷萃取反应液三次,有机层用无水硫酸镁干燥过夜,抽滤,减压干燥滤液,得到的粗产品经柱层析(石油醚:乙酸乙酯=40:1)分离的到黄色至绿色固体纯品,为化合物3-甲酰基-9-(4-甲基苄基)-9H-咔唑。
(3)将2mmol盐酸二甲双胍与2mmol的3-甲酰基-9-(4-甲基苄基)-9H-咔唑溶解于醋酸溶液中,氮气保护的情况下在油浴锅中加热至120℃反应4-8h。TLC监测至反应结束,停止反应,减压蒸去溶剂得到白色固体。柱层析(二氯甲烷:甲醇=20:1)分离后,得到目标化合物4-氨基-3,6-二氢-2-二甲氨基-6-(9-(4-甲基苄基)-9H-咔唑-3-)1,3,5-三嗪(3)。
目标化合物3的产率、谱图数据如下所示:产率58.8%;m.p.237.2-239.8℃.IR(KBr)cm-1:3350,3037(NH2,NH),1609(C=N).1H NMR(300MHz,DMSO-d6,ppm)δ8.88(s,1H,NH2),8.82(s,1H,NH2),8.32-8.14(m,2H,Ar-H),7.69(dd,2H,J=12.8,8.2Hz,Ar-H),7.49(dd,2H,J=19.7,8.4Hz,Ar-H),7.25(t,1H,J=7.4Hz,Ar-H),7.07(d,4H,J=4.7Hz,Ar-H),5.97(s,1H,CH),5.77(s,1H,NH),5.65(s,2H,CH2),3.07(s,6H,CH3),2.22(s,3H,CH3).13CNMR(75MHz,DMSO-d6,ppm)δ158.06,156.35,141.06,140.77,136.92,135.05,131.69,129.58(2C),127.20(2C),126.63,124.63,122.47,122.40,120.75,119.77,118.79,110.33(2C),63.34,55.44,45.95,37.41,21.09.HRMS(MALDI)calcd for C25H26N6:411.2292,found:411.2299(M+1).
实施例2:
以9-(3-氯苯甲基)-9H-咔唑-3-甲醛缩氨基胍(14)为例介绍式(E)化合物的合成通法
化合物9-(3-氯苯甲基)-9H-咔唑-3-甲醛缩氨基胍(14)的化学式如下:
化合物9-(3-氯苯甲基)-9H-咔唑-3-甲醛缩氨基胍(14)的合成方法,包括以下步骤:
(1)取100mL的圆底烧瓶,向其中加入咔唑(20mmol,3.34g),溶解于50mL DMF中,置于冰浴条件下,逐渐慢慢加入NaH(30mmol,1.20g),搅拌5min,得到墨绿色液体,滴加20mmol间氯溴苄,搅拌5min,得到棕色液体,室温条件下反应16h,TLC跟踪反应至结束,加入冰水淬灭反应,析出固体,抽滤并干燥,用水洗涤固体,干燥得到灰白色粗产物,用无水乙醇重结晶,得到化合物9-(3-氯苯甲基)-9H-咔唑。
(2)取100mL两口瓶,氮气保护,加入60mmol DMF,置于冰浴条件下,冷却至零度,慢慢滴入三氯氧磷17.25mmol,室温搅拌1h,冰浴下滴加15mmol 9-(3-氯苯甲基)-9H-咔唑的二氯乙烷溶液,室温反应1h,在油浴锅中加热至90℃回流18h,TLC跟踪反应至结束,加冰水淬灭,用饱和碳酸钠溶液调节pH至中性,二氯甲烷萃取反应液三次,有机层用无水硫酸镁干燥过夜,抽滤,减压干燥滤液,得到棕色粗产品,柱层析(石油醚:乙酸乙酯=40:1)分离的到黄色至绿色固体纯品,为化合物3-甲酰基-9-(3-氯苯甲基)-9H-咔唑。
(3)将2.3mmol氨基胍碳酸氢盐与2mmol的3-甲酰基-9-(3-氯苯甲基)-9H-咔唑共同置于50mL圆底烧瓶中,氮气保护,溶于无水乙醇溶液中,加入5滴浓盐酸,在油浴锅中加热至40℃反应6h。TLC监测反应结束,停止反应,减压蒸去溶剂。柱层析(二氯甲烷:甲醇=15:1)分离得到白色固体,为目标化合物9-(3-氯苯甲基)-9H-咔唑-3-甲醛缩氨基胍(14)。
目标化合物14的产率、谱图数据如下所示:产率41.5%;m.p.256.1-257.5℃.IR(KBr)cm-1:3389,3137(NH2,NH),1634(C=N).1H NMR(300MHz,DMSO-d6,ppm)δ11.93(s,1H,NH),8.68(s,1H,CH=N),8.33(s,1H,Ar-H),8.22(d,1H,J=7.7Hz,Ar-H),8.09-7.58(m,6H,Ar-H and NH),7.49(t,1H,J=7.7Hz,Ar-H),7.29(t,4H,J=6.0Hz,Ar-H),7.08(dd,1H,J=6.6,3.1Hz,Ar-H),5.75(s,2H,CH2).13C NMR(75MHz,DMSO-d6,ppm)δ155.89,148.00,141.82,140.97,140.57,133.66,131.02,127.81,127.07,126.96,125.94,125.83,125.46,122.91,122.77,121.19,121.07,120.38,110.43,110.28,45.59.HRMS(MALDI)calcd forC21H18ClN5:376.1326,found:376.1319(M+1).
以下利用二倍连续稀释法测定抗菌活性实验
化合物的体外抗菌活性实验采用二倍连续稀释法测定,通过测定最低抑菌浓度(Minimal inhibitory concentration,MIC)及最低杀菌浓度(Minimum bactericidalconcentration,MBC)初步评价抗菌活性。测试中所用到的革兰氏阳性菌包括:金黄色葡萄球菌(Staphylococcus aureus 4220)、耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus CCARM 3167)、变形链球菌(Streptococcus mutans3289)。革兰氏阴性菌包括:大肠杆菌(Escherichia coli 1924)。真菌包括:白色念珠菌(Candida albicans 7535)。对照药选取加替沙星(gatifloxacin)和莫西沙星(moxifloxacin)作为参考。
具体细筛操作过程:称量一定质量药品与DMSO配置成测定抗菌活性的起始浓度。测定抗菌活性前,将需要用到的耗材进行灭菌。在2mL的MHB(Mu eller-Hinton broth)培养基中将20μL待测菌种接种培养至对数期,在培养皿中用培养基将细菌稀释为105CFU/mL。首先取100μL的培养基于96孔板中,向首列孔内分别加入样品4μL。根据二倍稀释法原理,取100μL的培养基,采用连续稀释的方式,之后向每个微孔内加入100μL的待测菌稀释液,获得一系列成二倍递减的样品浓度,并做空白对照,只加细菌,对比细菌生长情况,每孔最终体积为200μL。然后将96孔板放入的酶标仪(650nm)中,测定其吸光度。37℃的培养箱内培养24h后,再将96孔板放入酶标仪(650nm)中,记录此时的吸光度。根据同一96孔板前后吸光度值的变化,运用公式,计算出抑菌率,抑菌率大于百分之九十的浓度即为相应的MIC值。实验平行进行3次为纠正误差。
计算公式:
A’培养24h后的吸光度值,A培养前的吸光度值,A0’空白对照培养24h后的吸光度值,A0空白对照培养24h前的吸光度值。
最低杀菌浓度(Minimum bactericidal concentration,MBC)是指能够杀灭培养基内细菌(即杀死99.9%供试微生物)的最低浓度,是判断药物耐药性的指标。具体细筛操作过程:取LB肉汤培养基(24g/L)和1.7%琼脂粉(每1000mL含17g)混合配成500mL的溶液,搅拌均匀,高压灭菌(60min),趁热倒入培养皿中,冷却凝固后倒置存放,制成固体培养基。从MIC测定实验的96孔板中,从高浓度向低浓度的每个孔依次取5μL澄清液体,涂布于固体培养基上,标记细菌和药品编号,以加替沙星和莫西沙星为阳性对照,DMSO为阴性对照,37℃培养24h,记录固体培养基上细菌的生长情况。无菌落生长或生长的菌落数少于5个,该浓度即为相应的MBC值。若MBC≥4MIC,说明该物易产生耐药性。目标化合物的抗菌活性结果(MIC/MBC)如图所示:
NT:没有测定
a金黄色葡萄球菌4220.b耐甲氧西林金黄色葡萄球菌3167.c变形链球菌3289.d大肠杆菌1924.e白色念珠菌7535。
体外细胞毒性评价实验
测试用细胞选用人胃癌细胞SGC-7901,人胃癌细胞AGS和人肝正常细胞L-02。将所需要测试的化合物配制成浓度分别为100,10,1,0.1mmol/L的DMSO储备液,用培养基稀释至所需浓度。细胞用含10%小牛血清和1%P/S的RPMI l640培养液于5%CO2及饱和湿度的培养箱中培养,恒为培养箱中相对湿度为95%,每隔1-2天换液一次,待测试。取对数生长期的人肠胃癌分化早期细胞SGC-7901、人胃癌细胞AGS、人正常肝细胞L-02,经胰蛋白酶消化后,每个微孔内计数以1×104个细胞接种于96孔细胞培养板中,每组3个平行孔。在5%CO2环境下恒温培养过夜,待细胞贴壁后,实验组中加入150μL/孔不同浓度(0.1、1、10、100μmol/L,由DMSO溶解配制成最终浓度1000倍的浓溶液,使用前用RPMI1640培养基稀释成所需浓度)的待测药物。培养48h后,取出培养板,弃去培养液,加入160μL培养基(1mL5mg/mL)的MTT溶液用15mL RPMI1640培养基稀释,继续培养4h,取出细胞培养板,底部出现蓝紫色结晶,小心弃去培养基,每孔加入150μL DMSO,摇床振荡10min,溶解产生的甲瓒结晶,酶标仪测光吸收值A492nm。
抑制率(%)=(1-A药/A对照)×100%
(A药为给药组吸光度值;A对照为空白对照组吸光度值)
最后曲线模拟计算半数抑制浓度IC50值如表所示:
aIC50为抑制50%细胞生长时的浓度,为3次独立的平行试验的平均值,变化在5–10%之间
b人体胃癌细胞
c人体胃癌细胞
d人体正常细胞。
以上所述的仅是本发明的几种实施方式,并不能因此而理解为对本发明专利范围的限制,应当指出,对于本领域的普通技术员来说,在不脱离本发明构思的前提下,还可以做出其它若干变形和改进,这些都属于本发明的保护范围。
Claims (10)
4.一种如式(E)的含三嗪结构的咔唑类衍生物的合成方法,其特征在于,包括以下步骤:
(1)取100mL的圆底烧瓶,向其中加入咔唑,溶解于50mL DMF中,置于冰浴条件下,逐渐慢慢加入NaH,搅拌3-8min,得到墨绿色液体,滴加对甲基溴苄,搅拌3-8min,得到棕色液体,室温条件下反应12-24h,TLC跟踪反应至结束,加入冰水淬灭反应,析出固体,抽滤并干燥,用水洗涤固体,干燥得到灰白色粗产物,用无水乙醇重结晶,得到化合物C;
(2)取100mL两口瓶,氮气保护,加入DMF,置于冰浴条件下,冷却至零度,慢慢滴入三氯氧磷,室温搅拌45-75min,冰浴下滴加化合物C的二氯乙烷溶液,室温反应45-75min,在油浴锅中加热至85-95℃回流18h,TLC跟踪反应至结束,加冰水淬灭,用饱和碳酸钠溶液调节pH至中性,二氯甲烷萃取反应液三次,有机层用无水硫酸镁干燥过夜,抽滤,减压干燥滤液,得到的粗产品经柱层析分离得到黄色至绿色固体纯品,得到化合物D;
(3)将盐酸二甲双胍与化合物D溶解于醋酸溶液中,氮气保护的情况下在油浴锅中加热至110-130℃反应4-8h,TLC监测至反应结束,停止反应,减压蒸去溶剂得到白色固体;柱层析分离后,得到目标化合物E;
所述的化学式E如下:
所述的化合物C的化学式如下:
所述的化合物D的化学式如下:
其中,Y为H;R1是对甲基苄基;
5.如权利要求4所述的如式(E)的含三嗪结构的咔唑类衍生物的合成方法,其特征在于,所述的步骤(1)中,咔唑、NaH和对甲基溴苄的摩尔比为1:(1-2):(0.8-1.5)。
6.如权利要求5所述的如式(E)的含三嗪结构的咔唑类衍生物的合成方法,其特征在于,所述的步骤(1)中,咔唑、NaH和对甲基溴苄的摩尔比为1:1.5:1。
7.如权利要求4所述的如式(E)的含三嗪结构的咔唑类衍生物的合成方法,其特征在于,所述的步骤(2)中,DMF、三氯氧磷和中间体的摩尔比为(3-6):(1-1.2):1;所述的中间体为化合物C。
8.如权利要求5所述的如式(E)的含三嗪结构的咔唑类衍生物的合成方法,其特征在于,所述的步骤(2)中,DMF、三氯氧磷和中间体的摩尔比为60:17.25:15;所述的中间体为化合物C。
9.如权利要求4所述的如式(E)的含三嗪结构的咔唑类衍生物的合成方法,其特征在于,所述的步骤(3)中,盐酸二甲双胍与化合物D的摩尔比为1:1。
10.如权利要求4所述的如式(E)的含三嗪结构的咔唑类衍生物的合成方法,其特征在于,包括以下步骤:
(1)取100mL的圆底烧瓶,向其中加入20mmol咔唑,溶解于50mL DMF中,置于冰浴条件下,逐渐慢慢加入30mmolNaH,搅拌5min,得到墨绿色液体,滴加20mmol对甲基溴苄,搅拌5min,得到棕色液体,室温条件下反应16h,TLC跟踪反应至结束,加入冰水淬灭反应,析出固体,抽滤并干燥,用水洗涤固体,干燥得到灰白色粗产物,用无水乙醇重结晶,得到化合物C;
(2)取100mL两口瓶,氮气保护,加入60mmolDMF,置于冰浴条件下,冷却至零度,慢慢滴入三氯氧磷17.25mmol,室温搅拌1h,冰浴下滴加15mmol化合物C的二氯乙烷溶液,室温反应1h,在油浴锅中加热至90℃回流18h,TLC跟踪反应至结束,加冰水淬灭,用饱和碳酸钠溶液调节pH至中性,二氯甲烷萃取反应液三次,有机层用无水硫酸镁干燥过夜,抽滤,减压干燥滤液,得到的粗产品经柱层析分离得到黄色至绿色固体纯品,得到化合物D;
(3)将2mmol盐酸二甲双胍与2mmol的化合物D溶解于醋酸溶液中,氮气保护的情况下在油浴锅中加热至120℃反应4-8h,TLC监测至反应结束,停止反应,减压蒸去溶剂得到白色固体;柱层析分离后,得到目标化合物E。
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