CN1331856C - 多羟基茋类化合物的制备和抑制sars病毒药物的用途 - Google Patents
多羟基茋类化合物的制备和抑制sars病毒药物的用途 Download PDFInfo
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- CN1331856C CN1331856C CNB2005100470239A CN200510047023A CN1331856C CN 1331856 C CN1331856 C CN 1331856C CN B2005100470239 A CNB2005100470239 A CN B2005100470239A CN 200510047023 A CN200510047023 A CN 200510047023A CN 1331856 C CN1331856 C CN 1331856C
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- phenyl
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- vinyl
- stilbene
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Abstract
本发明提供了一类药用多羟基芪类化合物及其制备方法和用于SARS冠状病毒的抑制与杀灭作用。多羟基芪类化合物是由多烷(氧)基取代氯(溴)甲基苯或吡淀化合物与亚磷酸三乙酯反应制得膦酸酯;然后,膦酸酯化合物再与多烷(氧)基苯(吡啶)甲醛反应生成多烷(氧)基芪类化合物;最后,在三溴化硼等脱烷氧基试剂作用下制得带有取代基的多羟基芪类化合物。含有多羟基芪活性成分可与一种或多种药物赋形剂或辅剂构成含多羟基芪0.001-50%(wt)的组合物,用于抑制和杀灭SARS冠状病毒。多羟基茋在浓度为2.0mg/ml时,无细胞毒作用;在药物浓度为0.5-2.0mg/ml时,可将Vero E6细胞中的SARS病毒杀灭、无法繁殖。
Description
技术领域
本发明涉及一类药用多羟基茋类新化合物及其制备方法和用途。该类新化合物用于抑制和杀灭SARS冠状病毒。
背景技术
茋类化合物为具有均二苯乙烯母核的一类化合物的总称。在自然界,多羟基茋类化合物存在藜芦、大黄、虎仗、首乌等许多中草药中和葡萄、花生、桑椹等食物中,具有抗菌、抗氧化、降血脂、抗血栓、抗肿瘤、杀虫、提高免疫能力等诸多生理活性。
在WO 02/057219专利中,公开了一类茋类化合物作为T细胞、嗜中性细胞、巨噬细胞以及相应的细胞因子的调节器,用于治疗免疫性、发炎及自身免疫的疾病。WO02/057219专利公开的结构中,只有一个苯环中有3,5位含有烷氧基或羟基取代基,另一苯环基本为烷烃和卤代烃取代,另外双键上一般有三取代或四取代。
在CN 200410022517.7专利公开中,发现姜黄素在1%-100%剂量范围内制备治疗或预防SARS的应用。
在CN200410022518.1专利公开中,发现黄烷醇多酚在1%-100%剂量范围内制备治疗或预防SARS的应用。
在Inhibition of SARS-coronavirus infection in vitro byS-nitroso-N-acetylpenicillamine,a nitric oxide donor compound文章中[Intrenational Journalof Infectious Diseases(2004)8,223-226(刊源)]
该文对S-亚硝基-N-乙酰基青霉胺(SANP)和硝普盐(SNP)两个NO供体化合物对SARS(Severe actute respiratory syndrome)的冠状病毒链Frankfurt-1在非洲绿猴上复制(Vero E6)细胞进行抑制活性实验和毒性实验,其中S-亚硝基-N-乙酰基青霉胺(SANP),其中SANP化合物50%抑制SARS-CoV浓度IC50为222.3±83.7μM,50%有毒浓度为587.7±22.5μM,选择系数为2.6。而SANP未检测到对SARS-CoV有作用。该研究的化合物与本发明申请的多羟基茋和多羟基氮杂茋化合物可抑制SARS-CoV无相关性。
本发明的目的是开发一类至今未见报导的多羟基茋类化合物及其制备方法和用于抗非典型肺炎SARS冠状病毒药物。
发明内容
本发明是一种带有取代基的多羟基茋类化合物,该类化合物具有下列结构通式(I):
通式(I)中:
当X=N原子时,
R1=0;
R2-R10=相同或不同的H、OH、OR1、C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C9环烷基、苯基、苄基或被1-3个由Y取代的苯基或苄基;
R1=C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、苯基、苄基或1-3个被Y取代的苯基或苄基;
Y=C1-C3烷基、C2-C4烯基、卤素、CN或NO2;
当X=C原子时,
R1-R10=相同或不同的H、OH、OR1、C1-C8烯基、C2-C8炔基、C3-C9环烷基、苯基、苄基或被1-3个由Y取代的苯基或苄基;
R1=C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、苯基、苄基或1-3个被Y取代的苯基或苄基;
Y=C1-C3烷基、C2-C4烯基、卤素、CN或NO2。
特别优选的化合物是:
1、(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶;
2、(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶;
3、(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶;(简称:R0303)
4、(E)-2-[2-(4-羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶;
5、(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶;
6、(E)-5-[2-(3,5-二羟基苯基)乙烯基]-1,3-苯二酚;
又名(E)-3,3’,5,5’-四羟基茋
7、(E)-4-[2-(3,5-二羟基苯基)乙烯基]-1,3-苯二酚;
又名(E)-2,3’,4,5’-四羟基茋
8、(E)-2-[2-(3,5-二羟基苯基)乙烯基]-1,3-苯二酚;(简称:R0305)
又名(E)-2,3’,5,5’-四羟基茋
9、(E)-4-[2-(4-羟基苯基)乙烯基]-1,3-苯二酚;
又名(E)-2,4,4’-三羟基茋
10、(E)-4-[2-(2,4-二羟基苯基)乙烯基]-1,3-苯二酚;
又名(E)-2,2’,4,4’-四羟基茋
11、(E)-4-[2-(2,5-二甲氧基苯基)乙烯基]-1,3-苯二酚;
又名(E)-2’,5’-二甲氧基-2,4-二羟基茋
12、(E)-5-[2-(4-甲氧基-3-((E)-3-甲基-1-丁烯基)苯基)乙烯基]-1,3-二甲氧基苯;
又名(E)-3-[(E)-3-甲基-1-丁烯基]-3’,4,5’-三甲氧基茋
13、(E)-4-[2-(4-羟基-苯基)乙烯基]-2((E)-3-甲基-丁烯基)苯酚;
又名:(E)-3-((E)-3-甲基-丁烯基)-4,4’-二羟基茋
14、(E)-2-[2-(4-甲氧基-3-((E)-3-甲基-1-丁烯基)苯基)乙烯基]-1,4-二甲氧基苯;
又名:(E)-3’-((E)-3-甲基-1-丁烯基)-2,4’,5-三甲氧基茋
其式I化合物的制备方法如反应式1-3所示,其中的取代基除特别指明外,均如前限定。
多羟基茋类化合物的制备路线可用下列反应式表示:
反应式1
将具有烷氧取代基的苄基氯或溴化物与亚磷酸三乙酯,按摩尔比1∶1.5-15的比例加到反应器中,在少量四丁基碘化铵存在下,于95-125℃,搅拌6-18h,然后,减压蒸馏,除去过量的亚磷酸三乙酯,得膦酸酯产物III。
反应式2
产物III膦酸酯溶于干燥四氢呋喃(THF)中,冷却至0℃以下,搅拌下迅速加入NaH,搅拌。搅拌下缓慢滴加取代的烷氧基苯甲醛的THF溶液,滴加完,将反应混合物升至室温,搅拌8-16h。冷至0℃,缓慢滴加水10mL,淬灭过量的NaH。将反应液用HCl溶液中和至pH4-6。用乙酸乙酯萃取、有机相以饱和NaCl水溶液洗涤,无水硫酸钠干燥,回收溶剂,残留物重结晶,得精制的烷氧基茋类化合物II。
反应式3
将精制烷氧基茋类化合物II用无水二氯甲烷溶解,冷却至0℃以下,充氮气保护。搅拌下缓慢滴加BBr3的无水二氯甲烷溶液20mL,滴加完毕,升至25-28℃,搅拌3-6h左右。将反应液倾入冰水中,搅拌,加NaHCO3饱和溶液调节到pH5-8,出现微乳黄色沉淀,直接抽滤即可得到产物I,可对溶剂进行对I重结晶。
在上述反应通式中:
当X=N原子时,
R’1=0;
R’2-R’10=相同或不同的H、OR1、C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C9环烷基、苯基、苄基或被1-3个由Y取代的苯基或苄基;
R1=C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、苯基、苄基或1-3个被Y取代的苯基或苄基;
Y=C1-C3烷基、C2-C4烯基、卤素、CN或NO2
当X=C原子时,
R’1-R’10=相同或不同的H、OR1、C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C9环烷基、苯基、苄基或被1-3个由Y取代的苯基或苄基;
R1=C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、苯基、苄基或1-3个被Y取代的苯基或苄基;
Y=C1-C3烷基、C2-C4烯基、卤素、CN或NO2。
本发明的多羟基茋类化合物由于含有活性成份,可与一种或多种药物赋形剂或辅剂构成的组合物,使这种药物组合物里的多羟基茋为0.001-50%重量百分含量,适用于抑制和杀死SARS冠状病毒。
抗SARS活性试验实例
细胞:Vero E6细胞,北京工业大学生命科学与生物工程学院培养保存。
病毒:BJ9-2b,北京工业大学生命科学与生物工程学院培养保存(中国军事医学科学院赠送)
药物:待测药物先测定最大无毒浓度,检测抗病毒活性时,以最大无毒浓度的药物2-4倍稀释4-5个浓度。
1.抗SARS活性的检测
将Vero E6细胞用含10%Hyclone胎牛血清Eagles’培养液稀释成细胞悬液,每毫升(ml)含1.2×105细胞,加入平底96孔细胞培养板内,每孔0.1ml,于37℃,5%CO2温箱培养24-48小时后细胞长成单层,每孔加入100TCID50BJ-2B病毒,吸附2小时,吸取上清(弃去未进入细胞之游离病毒),选用最大无毒浓度药物(TC0)R0303和R0305,2倍稀释3个浓度,每个浓度3复孔,每孔100μl,分别加入96孔板,于37℃,5%CO2温箱继续培养,72小时后,采用CPE法进行结果判定,即当病毒对照组的孔75%细胞出现病变时,观察药物组的病变,以75%细胞出现病变为“+++”,50%细胞出现病变为“++”,25%细胞出现病变为“+”,无病变出现为“-”,试验分别设置病毒对照组、药物对照组、细胞对照组。最后计算50%抑制病毒病变浓度(IC50)及治疗指数(TI)。
2.细胞毒的检测
方法基本同上,但细胞铺板后,24-48小时后细胞长成单层,不感染病毒,仅加不同浓度的药物,于37℃,5%CO2温箱继续培养,72小时后,采用CPE法判断结果,75%细胞出现病变为“+++”,50%细胞出现病变为“++”25%细胞出现病变为“+”,无病变出现为“-”,试验分别设置药物对照组、细胞对照组,最后测定出最大无毒浓度。
见下列结果表1:
表1 药物抗病毒作用结果表
样品 | 试验次数 | 细胞毒2mg/ml | 药物浓度(mg/ml) | 病毒对(100TCID50) | ||
2 | 1 | 0.5 | ||||
R0303 | 1 | - | - | - | - | +++ |
2 | - | - | - | - | +++ | |
3 | - | - | - | - | +++ | |
R0305 | 1 | - | - | - | - | +++ |
2 | - | - | - | - | +++ | |
3 | - | - | - | - | +++ |
化合物R0303与R0305在2.0mg/ml浓度时,无细胞毒作用;在2.0mg/ml、1.0mg/ml、0.5mg/ml浓度时,Vero E6细胞中SARS冠状病毒被杀灭,无法繁殖。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可分为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等,优选口服。
本发明化合物或含有它的药物组合物的给药途径可分为注射给药。注射包括静脉注射、肌肉注射、皮下注射和皮内注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂型、混悬剂型。其它剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉剂等。
本发明的化合物可以制成普通制剂,也可以是缓释剂、控释剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、白陶土、微晶纤维素、硅酸铝等;润湿剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钟、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸杞酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸、硼酸、液体石蜡、聚乙二醇等。其它载体如聚丙烯酸树脂、脂质体、水溶性载体如PEG4000和PEG6000、PVP等。还可以将片剂进一步制成包衣片、例如糖包衣片、薄膜包衣片、肠溶包衣片或双片层和多片层。
例如为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄耆胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊,将有效成份本发明化合物与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明化合物制成注射用制剂,如溶液剂、混悬溶液剂、乳剂、冻干粉剂,这种制剂可以是含水或非水的。可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯、Polyoxyl 35等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外,如需要,也可以向药物中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其他材料。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明提取物或化合物、药物组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数、治疗目的,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明药效学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明的化合物的用量,最优选为0.1-20mg/Kg体重。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药,这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。由此可见,含有本发明披露的通式化合物多会产生本发明治疗或者预防SARS的作用。
具体实施方式
实施例1
(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶;(又名:(E)-4,6-二甲基-3’,5,5’-三羟基茋-2-氮)
3,5-二甲基-4-甲氧基吡啶-2-甲基膦酸酯的合成:50mL三口烧瓶中加入2-氯甲基-3,5-二甲基-4-甲氧基吡啶(0.01mol)、亚磷酸三乙酯2.5g(0.016mol),四丁基碘化铵少量,搅拌,油浴加热至100-110℃,反应3-6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余浅橙红色粘稠物直接用于下一步反应。
(E)-2-[2-(3,5-二甲氧基苯基)乙烯基]-3,5-二甲基-4-甲氧基吡啶的合成:上步反应所得膦酸酯溶于50mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加3,5-二甲氧基苯甲醛(0.01mol)的THF溶液30mL。约1.5h滴加完毕,将反应混合物升至室温(14-25℃),搅拌8-16h。冷至0℃,缓慢滴加水10mL,淬灭过量的NaH。将反应液以1M HCl溶液中和至pH6,以乙酸乙酯萃取(4×50mL),有机相以饱和NaCl水溶液(30mL)洗涤,无水硫酸钠干燥。回收溶剂,残留物以乙醇进行重结晶,得白色针状晶体,产率:34.7%,mp:94-95℃。1HNMR(CDCl3)δ:2.27(s,3H,4-CH3),2.35(s,3H,6-CH3),3.77(s,3H,5-OCH3),3.83(s,6H,3,5-OCH3),6.42(t,1H,J=2.0Hz,4-H),6.75(d,2H,J=2.0Hz,2,6-H),8.26(s,1H,3-H),7.29,7.63(d,2H,J=15.6Hz,α,β-H)。
(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶的合成:100mL三口烧瓶中加入(E)-2-[2-(3,5-二甲氧基苯基)乙烯基]-3,5-二甲基-4-甲氧基吡啶(0.001mol),以40mL无水二氯甲烷溶解,冰盐水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加BBr3(3.4mL,36mmol)的无水二氯甲烷溶液20mL,约1h滴加完毕,升至25-28℃,搅拌3-6h左右。将反应液倾入200mL冰水中,搅拌,呈微黄色,加NaHCO3饱和溶液调节到pH7左右,出现微乳黄色沉淀,直接抽滤即可得到产物,浅黄色无定形粉末,产率:94.0%,1HNMR(DMSO-d6)δ:6.47(d,2H,J=2.2Hz,2,6-H),6.23(t,1H,J=2.2Hz,4-H),7.56(s,1H,3-H),7.05,7.11(d,2H,J=16.63Hz,α,β-H),1.91(s,3H,4-CH3),2.06(s,3H,6-CH3)。
实施例2
(E)-2-[2-(4-羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶(又名:(E)-4,6-二甲基-4,5’-二羟基茋-2-氮)
3,5-二甲基-4-甲氧基吡啶-2-甲基膦酸酯的合成:50mL三口烧瓶中加入2-氯甲基-3,5-二甲基-4-甲氧基吡啶(0.01mol),亚磷酸三乙酯2.5g(0.016mol),四丁基碘化铵少量,搅拌,油浴加热至100-110℃,反应3-6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余浅橙红色粘稠物直接用于下一步反应。
(E)-2-[2-(4-甲氧基苯基)乙烯基]-3,5-二甲基-4-甲氧基吡啶的合成:上步反应所得膦酸酯溶于50mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加4-甲氧基苯甲醛(0.01mol)的THF溶液30mL。约1.5h滴加完毕,将反应混合物升至室温(14-25℃),搅拌8-16h。冷至0℃,缓慢滴加水10mL,淬灭过量的NaH。将反应液以1M HCl溶液中和至偏酸性,以乙酸乙酯萃取(4×50mL),有机相以饱和NaCl水溶液(30mL)洗涤,无水硫酸钠干燥。回收溶剂,残留物以乙醇进行重结晶,得黄色极细针状晶体,产率:60.6%,mp:131-133℃。IR(KBr)cm-1:2983,2840,2672,2560,1687,1604,1515,1468,1428,1305,1264,1171,1089,1027,970,930,845,,824,773,634,616。
(E)-2-[2-(4-羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶的合成:100mL三口烧瓶中加入(E)-2-[2-(4-甲氧基苯基)乙烯基]-3,5-二甲基-4-甲氧基吡啶(0.001mol),以40mL无水二氯甲烷溶解,冰盐水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加BBr3(3.4mL,36mmol)的无水二氯甲烷溶液20mL,约1h滴加完毕,升至40-42℃,搅拌3-6h左右。将反应液倾入200mL冰水中,搅拌,呈微黄色,加NaHCO3饱和溶液调节到pH7左右,出现微乳黄色沉淀,直接抽滤即可得到产物,浅黄色无定形粉末,产率:50.2%,1HNMR(DMSO-d6)δ:6.81(d,2H,J=8.4Hz,2,6-H),7.47(d,2H,J=8.4Hz,3,5-H),7.51(s,1H,3-H),7.03,7.17(d,2H,J=16.4Hz,α,β-H),1.89(s,3H,4-CH3),2.05(s,3H,6-CH3)。
实施例3
(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶(又名:(E)-4,6-二甲基-2,5,5’-三羟基茋-2-氮)
3,5-二甲基-4-甲氧基吡啶-2-甲基膦酸酯的合成:50mL三口烧瓶中加入2-氯甲基-3,5-二甲基-4-甲氧基吡啶(0.01mol),亚磷酸三乙酯2.5g(0.016mol),四丁基碘化铵少量,搅拌,油浴加热至100-110℃,反应3-6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余浅橙红色粘稠物直接用于下一步反应。
(E)-2-[2-(2,5-二甲氧基苯基)乙烯基]-3,5-二甲基-4-甲氧基吡啶的合成:上步反应所得膦酸酯溶于50mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加2,5-二甲氧基苯甲醛(0.01mol)的THF溶液30mL。约1.5h滴加完毕,将反应混合物升至室温(14-25℃),搅拌8-16h。冷至0℃,缓慢滴加水10mL,淬灭过量的NaH。将反应液以1M HCl溶液中和至pH7,以乙酸乙酯萃取(4×50mL),有机相以饱和NaCl水溶液(30mL)洗涤,无水硫酸钠干燥。回收溶剂,残留物为浅金黄油状,不结晶。
(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶的合成:100mL三口烧瓶中加入(E)-2-[2-(2,5-二甲氧基苯基)乙烯基]-3,5-二甲基-4-甲氧基吡啶(0.001mol),以40mL无水二氯甲烷溶解,冰盐水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加BBr3(3.4mL,36mmol)的无水二氯甲烷溶液20mL,约1h滴加完毕,升至32℃,搅拌3-6h左右。将反应液倾入200mL冰水中,搅拌,呈微黄色,加NaHCO3饱和溶液调节到pH7左右,出现微乳黄色沉淀,直接抽滤即可得到产物,浅黄色无定形粉末,产率:62.8%。1HNMR(DMSO-d6)δ:6.719(d,1H,J=8.5Hz,3-H),6.950(d,1H,J=3.0Hz,6-H),6.608(dd,1H,J=3.0Hz,J=8.5Hz,4-H),7.473(s,1H,3-H),7.143,7.392(d,2H,J=16.6Hz,α,β-H),1.887(s,3H,4-CH3),2.031(s,3H,6-CH3)。
实施例4
(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶(又名:(E)-3’,5,5’,6-四羟基茋-2-氮)
3,4-二甲氧基吡啶-2-甲基膦酸酯的合成:50mL三口烧瓶中加入2-氯甲基-3,4二甲氧基吡啶(0.01mol),亚磷酸三乙酯2.5g(0.016mol),四丁基碘化铵少量,搅拌,油浴加热至100-110℃,反应3-6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余浅橙红色粘稠物直接用于下一步反应。
(E)-2-[2-(3,5-二甲氧基苯基)乙烯基]-3,4-二甲氧基吡啶的合成:上步反应所得膦酸酯溶于50mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加3,5-二甲氧基苯甲醛(0.01mol)的THF溶液30mL。约1.5h滴加完毕,将反应混合物升至室温(14-25℃),搅拌8-16h。冷至0℃,缓慢滴加水10mL,淬灭过量的NaH。将反应液以1M HCl溶液中和至pH6,以乙酸乙酯萃取(4×50mL),有机相以饱和NaCl水溶液(30mL)洗涤,无水硫酸钠干燥。回收溶剂,残留物以乙醇进行重结晶,得黄色极细针状晶体,产率:18.9%,mp:88-89.5℃。1HNMR(CDCl3)δ:3.83(s,6H,3,5-OCH3),3.88(s,3H,5-OCH3),3.93(s,3H,6-OCH3),6.43(t,1H,J=2.0Hz,4-H),6.78(d,2H,J=2.0Hz,2,6-H),6.75(d,1H,J=5.2Hz,4-H),8.27(d,1H,J=5.2Hz,3-H),7.47,7.71(d,2H,J=16.0Hz,α,β-H)。
(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶的合成:100mL三口烧瓶中加入(E)-2-[2-(3,5-二甲氧基苯基)乙烯基]-3,4-二甲氧基吡啶(0.001mol),以40mL无水二氯甲烷溶解,冰盐水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加BBr3(3.4mL,36mmol)的无水二氯甲烷溶液20mL,约1h滴加完毕,升至20-26℃,搅拌3-6h左右。将反应液倾入200mL冰水中,搅拌,呈微黄色,加NaHCO3饱和溶液调节到pH7左右,出现微乳黄色沉淀,直接抽滤即可得到产物,浅黄色无定形粉末,产率:98.9%,1HNMR(DMSO-d6)δ:6.17(d,2H,J=2.2Hz,2,6-H)6.22(t,1H,J=2.2Hz,4-H),7.51(d,1H,J=6.5Hz,3-H),6.18(d,1H,J=6.5Hz,4-H),6.99,7.54(d,2H,J=16.5Hz,α,β-H)。
实施例5
(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶(又名:(E)-2’,5,5’,6-四羟基茋-2-氮)
3,4-二甲氧基吡啶-2-甲基膦酸酯的合成:50mL三口烧瓶中加入2-氯甲基-3,4-二甲氧基吡啶(0.01mol),亚磷酸三乙酯2.5g(0.016mol),四丁基碘化铵少量,搅拌,油浴加热至100-110℃,反应3-6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余浅橙红色粘稠物直接用于下一步反应。
(E)-2-[2-(2,5-二甲氧基苯基)乙烯基]-3,4-二甲氧基吡啶的合成:上步反应所得膦酸酯溶于50mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加3,5-二甲氧基苯甲醛(0.01mol)的THF溶液30mL。约1.5h滴加完毕,将反应混合物升至室温(14-25℃),搅拌8-16h。冷至0℃,缓慢滴加水10mL,淬灭过量的NaH。将反应液以1M HCl溶液中和至pH6,以乙酸乙酯萃取(4×50mL),有机相以饱和NaCl水溶液(30mL)洗涤,无水硫酸钠干燥。回收溶剂,残留物以甲醇进行重结晶,得微黄色柱状晶体,产率:20.7%,mp:100-101℃。1HNMR(CDCl3)δ:3.82(s,1H,5-OCH3),3.85(s,1H,2-OCH3),3.87(s,1H,5-OCH3),3.92(s,1H,6-OCH3),6.73(d,1H,J=5.6Hz,4-H),7.23(d,1H,J=2.4Hz,6-H),6.83(m,1H,4-H),6.84(d,1H,J=2.8Hz,3-H),8.28(d,1H,J=5.6Hz,3-H),8.08,7.52(d,2H,J=16.4Hz,α,β-H)。
(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶的合成:100mL三口烧瓶中加入(E)-2-[2-(3,5-二甲氧基苯基)乙烯基]-3,4-二甲氧基吡啶(0.001mol),以40mL无水二氯甲烷溶解,冰盐水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加BBr3(3.4mL,36mmol)的无水二氯甲烷溶液20mL,约1h滴加完毕,升至25-35℃,搅拌3-6h左右。将反应液倾入200mL冰水中,搅拌,呈微黄色,加NaHCO3饱和溶液调节到pH7左右,出现微乳黄色沉淀,直接抽滤即可得到产物,浅黄色无定形粉末,产率:58.3%,1HNMR(DMSO-d6)δ:6.90(d,1H,J=8.8Hz,3-H),6.73(d,1H,J=3.0Hz,6-H),6.58(dd,1H,J=3.0Hz,J=8.8Hz,4-H),7.47(d,1H,J=6.7Hz,3-H),6.18(d,1H,J=6.7Hz,4-H),7.16,7.54(d,2H,J=16.9Hz,α,β-H)。
实施例6
(E)-2,3’,5,5’-四羟基茋
3,5-二甲氧基苄基膦酸酯的合成:100mL三口烧瓶中加入3,5-二甲氧基苄基溴(0.01mol),亚磷酸三乙酯(0.015mol),四丁基碘化铵少量,搅拌,油浴加热至110-115℃,反应6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余的浅金黄色油状物即为产物,直接用于下一步反应。
(E)-2,3’,5,5’-四甲氧基茋的合成:上步反应所得膦酸酯溶于25mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加3,5-二甲氧基苯甲醛(0.01mol)的THF溶液25mL。将反应物升至室温(14-25℃),搅拌6-8小时。将反应液倾入冰水中,将反应液以1M HCl溶液中和至偏酸性,以乙酸乙酯萃取,有机相以饱和NaCl水溶液洗涤,无水硫酸钠干燥。回收溶剂,残留物中加少量乙醇-正己烷重结晶,得乳白色粉末,酯化、缩合两步反应总收率72.6%,mp:54-55℃。1HNMR(CDCl3)δ:3.83(s,12H,OCH3),6.39(t,1H,J=2.0Hz,4-H),6.70(d,2H,J=2.0Hz,2,6-H),6.80(dd,1H,J=2.8Hz,J=8.4Hz,4-H),6.83(d,1H,J=8.4Hz,3-H),7.13(d,1H,J=2.8Hz,6-H),7.42,7.02(d,2H,J=16.4Hz,α,β-H)。
(E)-2,3’,5,5’-四羟基茋的合成:100mL三口烧瓶中加入(E)-2,3’,5,5’-四甲氧基茋(4mmol),以40mL无水二氯甲烷溶解,冰盐水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加2.7mL BBr3的无水二氯甲烷溶液20mL,约1h滴加完毕,升至25-30℃,搅拌6小时。将反应液倾入200mL冰水中,搅拌,产生白色沉淀。以乙酸乙酯萃取,无水硫酸钠干燥。减压蒸除溶剂,以丙酮-水精制,得浅粉色粉末,产率:91.9%,mp:212-214℃。1HNMR(DMSO-d6)δ:6.29(s,1H,4-H),6.53(d,2H,J=2.0Hz,2,6H),6.60(m,1H,4-H),6.71(d,1H,J=8.4Hz,3-H),6.99(d,1H,J=2.8Hz,6-H),7.34,6.87(d,2H,J=16.4Hz,α,β-H)。
实施例7
(E)-3,3’,5,5’-四羟基茋
3,5-二甲氧基苄基膦酸酯的合成:100mL三口烧瓶中加入3,5-二甲氧基苄基溴(0.01mol),亚磷酸三乙酯(0.015mol),四丁基碘化铵少量,搅拌,油浴加热至110-115℃,反应6小时。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余的浅金黄色油状物即为产物,直接用于下一步反应。
(E)-3,3’,5,5’-四甲氧基茋的合成:上步反应所得膦酸酯溶于25mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加3,5-二甲氧基苯甲醛(0.01mol)的THF溶液25mL。将反应物升至室温(14-25℃),搅拌6-8小时。将反应液倾入冰水中,将反应液以1M HCl溶液中和至偏酸性,以乙酸乙酯萃取,有机相以饱和NaCl水溶液洗涤,无水硫酸钠干燥。回收溶剂,残留物中加少量乙醇-二氯甲烷重结晶,得乳白色粉末,酯化、缩合两步反应总收率83.0%,mp:135-136℃。1HNMR(CDCl3)δ:3.84(s,12H,OCH3),6.40(t,2H,J=2.0Hz,,4,4-H),6.67(d,4H,J=2.0Hz,2,2,6,6-H),7.01(s,2H,α,β-H)。
(E)-3,3’,5,5’-四羟基茋的合成:100mL三口烧瓶中加入(E)-3,3’,5,5’-四甲氧基茋(4mmol),以40mL无水二氯甲烷溶解,冰水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加3.4mL BBr3的无水二氯甲烷溶液20mL,26-40℃搅拌6小时。将反应液倾入200mL冰水中,搅拌,产生白色沉淀。以乙酸乙酯萃取,无水硫酸钠干燥。减压蒸除溶剂,以丙酮水精制,得浅黄色小晶粒,产率:95%,mp>300℃。1HNMR(DMSO-d6)δ:6.11(t,2H,J=1.6Hz,4,4-H),6.36(d,4H,J=1.6Hz,2,2,6,6-H),6.79(s,2H,α,β-H)。
实施例8
(E)-2,2’,5,5’-四羟基茋
2,5-二甲氧基苄基膦酸酯的合成:100mL三口烧瓶中加入3,5-二甲氧基苄基氯(0.01mol),亚磷酸三乙酯(0.015mol),四丁基碘化铵少量,搅拌,油浴加热至100-115℃,反应6小时。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余的浅金黄色油状物即为产物,直接用于下一步反应。
(E)-2,2’,5,5’-四甲氧基茋的合成:上步反应所得膦酸酯溶于25mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加2,5-二甲氧基苯甲醛(0.01mol)的THF溶液25mL。将反应物升至室温(14-25℃),搅拌6-8小时。将反应液倾入冰水中,将反应液以1M HCl溶液中和至偏酸性,以乙酸乙酯萃取,有机相以饱和NaCl水溶液洗涤,无水硫酸钠干燥。回收溶剂,残留物中加少量乙醇-重结晶,得浅黄色针状晶体,酯化、缩合两步反应总收率87.0%,mp 94.5-96℃。1HNMR(CDCl3)δ:3.82(s,6H,2,2-OCH3),3.83(s,6H,5,5-OCH3),6.79(dd,2H,J=9.0Hz,J=2.4Hz,4,4-H),6.83(d,2H,J=9.0Hz,3,3-H),7.20(d,2H,J=2.4Hz,6,6-H),7.43(s,2H,α,β-H)。
(E)-2,2’,5,5’-四羟基茋的合成:100mL三口烧瓶中加入(E)-3,3’,5,5’-四甲氧基茋(2mmol),以40mL无水二氯甲烷溶解,冰盐水浴冷却至0℃以下,充氮气保护。搅拌下缓慢滴加3.0mL BBr3的无水二氯甲烷溶液20mL,26-30℃下搅拌3-6小时。将反应液倾入200mL冰水中,搅拌,产生白色沉淀。减压蒸除溶剂二氯甲烷,加压抽滤,得乳白色粉状固体,产率:40.2%。1HNMR(DMSO-d6)δ:6.49(dd,2H,J=8.4Hz,J=2.0Hz,4,4-H),6.65(d,2H,J=8.4Hz,3,3-H),6.91(d,2H,J=2.4Hz,6,6-H),7.20(s,2H,α,β-H)。
实施例9
(E)-4,4’-四羟基茋
4-甲氧基苄基膦酸酯的合成:100mL三口烧瓶中加入4-甲氧基苄基氯(0.01mol),亚磷酸三乙酯(0.015mol),四丁基碘化铵少量,搅拌,油浴加热至100-115℃,反应6小时。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余的浅金黄色油状物即为产物,直接用于下一步反应。
(E)-4,4’-二甲氧基茋的合成:上步反应所得膦酸酯溶于25mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加对甲氧基苯甲醛(0.01mol)的THF溶液25mL。将反应物升至室温(14-25℃),搅拌6-8小时。将反应液倾入冰水中,将反应液以1M HCl溶液中和至偏酸性,回收四氢呋喃后,有白色片状晶体析出,产率79.2%。1HNMR(CDCl3)δ:3.82(s,6H,4,4-OCH3),6.89(d,4H,J=8.8Hz,3,3’,5,5’-H),7.42(d,4H,J=8.8Hz,2,2’,6,6’-H),6.93(s,2H,α,β-H)。
(E)-4,4’-二羟基茋的合成:100mL三口烧瓶中加入1.8mL BBr3的无水二氯甲烷溶液20mL,充氮气保护,19-20℃下,以50mL无水二氯甲烷溶解(E)-4,4’-二甲氧基茋(2mmol),缓慢滴加入三溴化硼中。滴加完毕,反应升温30℃下搅拌3-6小时。将反应液倾入200mL冰水中,搅拌,产生白色沉淀。减压蒸除溶剂二氯甲烷,加压抽滤,得白色粉状固体。1HNMR(DMSO-d6)δ:6.74(d,4H,J=8.4Hz,3,3’,5,5’-H),7.35(d,4H,J=8.4Hz,2,2’,6,6’-H),6.89(s,2H,α,β-H)。
实施例10-12
(E)-3’-((E)-3-甲基-1-丁烯)-3,4’,5-三甲氧基茋
3-氯甲基-4-甲氧基苯甲醛的合成:50mL三口梨形瓶中加入5.0g 37-40%的甲醛水溶液和2.5g氯化锌,置于水溶中缓慢升温,同时向其中通HCl气体。上述反应液达到58-60℃时,对6.8g对甲氧基苯甲醛缓慢滴入,滴加完毕后,保持该温度反应3-8h。将反应液倾入分液漏斗中,加50mL乙酸乙酯及50mL水,充分振荡,分出水层,有机相再以50mL水及50mL饱和NaHCO3水溶液分别洗涤,最后以无水Na2SO4除水。回收乙酸乙酯后,残余物冷却,直接析出浅棕黄色粒状晶体,产率60.7%。1HNMR(CDCl3)δ:3.98(s,3H,4-OCH3),4.67(s,2H,3-CH2),7.02(d,1H,J=8.4Hz,5-H),7.86(dd,1H,J=8.4Hz,J=2.0Hz,6-H),7.92(d,1H,J=2.0Hz,2-H),9.90(s,1H,1-CHO)。
3,5-二甲氧基苄基膦酸酯的合成:50mL三口烧瓶中加入0.01mol的3,5-二甲氧基苄基溴,0.015mol亚磷酸三乙酯,四丁基碘化铵少量,搅拌,油浴加热至110-115℃,反应3-6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余的浅金黄色油状物即为产物,直接用于下一步反应。
3’-氯甲基-3,4’,5-三甲氧基茋的合成:上步反应所得膦酸酯油状物溶于25mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.025mol),搅拌30min。搅拌下缓慢滴加0.01mol的3-氯甲基-4-甲氧基苯甲醛的25 mLTHF溶液。将反应物升至室温(14-25℃),搅拌6-8h。将反应液倾入冰水中,将反应液以1M HCl溶液中和至偏酸性,以乙酸乙酯萃取,有机相以饱和NaCl水溶液洗涤,无水硫酸钠干燥。回收溶剂,残留物中加少量乙醇重结晶,酯化、缩合两步反应总收率59.7%。
1HNMR(CDCl3)δ:3.83(s,6H,3,5-OCH3),3.90(s,4H,4’-OCH3),4.67(s,2H,3’-CH2),6.38(t,1H,J=2.0Hz,4-H),6.65(d,2H,J=2.4Hz,2,6-H),6.69(d,1H,J=8.4Hz,5-H),6.92,7.02(d,2H,J=16.4Hz,α,β-H),7.43(dd,1H,J=8.4Hz,J=2.0Hz,6-H),7.53(d,2H,J=2.0Hz,2-H)。
3,4’,5-三甲氧基茋-3’-亚甲基膦酯的合成:50mL三口烧瓶中加入0.005mol的3’-氯甲基-3,4’,5-三甲氧基茋,0.0075mol亚磷酸三乙酯,四丁基碘化铵少量,搅拌,油浴加热至110-115℃,反应3-6h。将反应物90℃以下减压蒸馏,除去过量的亚磷酸三乙酯,瓶中剩余的浅金黄色油状物即为产物,直接用于下一步反应。
(E)-3’-((E)-3-甲基-1-丁烯)-3,4’,5-三甲氧基茋的合成:上步反应所得膦酸酯油状物溶于25mL干燥四氢呋喃(THF)中,冰盐浴冷却至0℃以下,搅拌下迅速加入NaH粉末(0.0125mol),搅拌30min。搅拌下缓慢滴加1mL的异丁醛的25mL THF溶液。将反应物升至室温(14-25℃),搅拌6-8h。将反应液倾入冰水中,将反应液以1M HCl溶液中和至偏酸性,以乙酸乙酯萃取,有机相以饱和NaCl水溶液洗涤,无水硫酸钠干燥。回收溶剂,残留物为金黄色油状、不结晶。经柱分离(Mercker 200-300目硅胶),洗脱液(正己烷∶乙酸乙酯=5∶1),得到金黄色油状产物,产率:65.0%。1HNMR(CDCl3)δ:1.11(s,3H,CH3),1.13(s,3H,CH3),2.51(m,1H,3″-CH),3,81(s,6H,3,5-OCH3),3.84(s,4H,4’-OCH3),6.25(dd,1H,J=16.4Hz,J=6.25Hz,2″-H),6.37(t,1H,J=2.0Hz,4-H),6.65(d,2H,J=2.0Hz,2,6-H),6.67(d,1H,J=16.4Hz,1″-H),6.82
(d,1H,J=8.4Hz,6-H),6.92,7.04(d,2H,J=16.4Hz,α,β-H),7.31(dd,1H,J=8.4Hz,J=2.0Hz,5′-H),7.58(d,2H,J=2.0Hz,2′-H)。
(E)-3’-((E)-3-甲基-1-丁烯)-2,4’,5-三甲氧基茋的合成条件基本同上,柱分离得金黄色油状物。1HNMR(CDCl3)δ:1.11(s,3H,CH3),1.13(s,3H,CH3),2.51(m,1H,3″-CH),3,81(s,3H,5-OCH3),3.84(s,3H,2-OCH3),3.85(s,3H,4-OCH3),6.26(dd,J=16.0Hz,J=6.8Hz,2″-H),6.67(d,1H,J=16.0Hz,1″-H),6.76(dd,1H,J=9.0Hz,J=2.8Hz,4-H),6.82(d,1H,J=9.0Hz,3-H),6.82(d,1H,J=8.4Hz,6-H),7.14(d,1H,J=2.8Hz,6-H),7.05,7.32(d,2H,J=16.4Hz,α,β-H),7.31(dd,1H,J=8.4Hz,J=2.0Hz,5-H),7.59(d,1H,J=2.0Hz,2-H)。
(E)-3’-((E)-3-甲基-1-丁烯)-4,4′-二甲氧基茋的合成条件基本同上,应用乙醇/CH2Cl2重结晶得乳黄色粉末。1HNMR(CDCl3)δ:1.11(s,3H,CH3),1.13(s,3H,CH3),2.51(m,1H,3″-CH),3,83(s,3H,4-OCH3),3.86(s,3H,4-OCH3),6.25(dd,J=16.0Hz,J=6.8Hz,2″-H),6.67(d,1H,J=16.0Hz,1″-H),6.89(d,2H,J=8.8Hz,3′,5′-H),7.44(d,2H,J=8.8Hz,2′,6′-H),6.83(d,1H,J=8.4Hz,6-H),6.92,6.97(d,2H,J=16.0Hz,α,β-H),7.31(dd,1H,J=8.4Hz,J=2.0Hz,5-H),7.57(d,2H,J=2.0Hz,2-H)。
Claims (3)
2、根据权利要求1所述的多羟基茋类化合物,其特征化合物是:
(1)(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶;
(2)(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,4-二羟基吡啶;
(3)(E)-2-[2-(2,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶;
(4)(E)-2-[2-(4-羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶;
(5)(E)-2-[2-(3,5-二羟基苯基)乙烯基]-3,5-二甲基-4-羟基吡啶。
3、按照权利要求1所述多羟基茋类化合物的制备方法,其特征在于该方法是:首先,将具有烷氧基取代基的苄基氯或溴化物与亚磷酸三乙酯,按摩尔比1∶1.5-15的比例加到反应器中,在少量四丁基碘化铵存在下,于95-125℃,搅拌6-18h,然后减压蒸馏,除去过量的亚磷酸三乙酯;得膦酸酯溶于干燥四氢呋喃中,冷却至0℃以下,搅拌下迅速加入60%NaH,搅拌,并在搅拌下缓慢滴加取代的烷氧基苯甲醛的THF溶液,滴加完,将反应混合物升至室温,搅拌6-18h;冷至0℃,缓慢滴加水10ml,淬灭过量的NaH,将反应液用HCl溶液中和至pH4-6,用乙酸乙酯萃取、有机相以饱和NaCl水溶液洗涤,无水硫酸钠干燥,回收溶剂,残留物重结晶,得精制的烷氧基茋类化合物;将精制烷氧基化合物用无水二氯甲烷溶解,冷却至0℃以下,充氮气保护,搅拌下缓慢滴加BBr3的无水二氯甲烷溶液20ml,滴加完毕,升至25-28℃,搅拌3-6h,将反应液倾入冰水中,搅拌,加NaHCO3饱和溶液调节到pH7左右,出现微乳黄色沉淀,直接抽滤即可得到产物,可用溶剂进行重结晶。
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