1,4-二氫吡啶化合物的合成研究進(jìn)展

1,4-二氫吡啶化合物的合成研究進(jìn)展

1.4-二羥基吡啶（1.4-dph）是一種重要的有機(jī)化合物，具有良好的生理活性，主要用于生物和藥物。臨床上，它不僅可以用來治療高血壓、心絞痛、充血性心力衰竭、局部缺血、動脈粥狀硬化和其他心腦血管疾病，還可以用作治療胃腸疾病、雷諾基菌病、動脈高壓和癲癇的輔助藥物。因此，國內(nèi)外對這種化合物的研究非?；钴S。近年來，對1.4-二羥基吡啶的研究主要集中在：（1）1.4-二羥基吡啶的合成方法；（2）通過芳構(gòu)化合成吡啶。（3）以作為緩沖模型的形式還原亞胺。（4）用1-4-dhp藥物治療心腦血管疾病，對其進(jìn)行殺菌和理氣活性研究。作為4-羥基丙烯酸酯的合成，通常使用文獻(xiàn)中報(bào)道的華茨肖法進(jìn)行合成，然后將芳胺、乙酰甲酸乙酯和濃氨酸銨與乙醇混合10小時(shí)。這種方法需要很長時(shí)間，但收率低，以及對人體刺激的過度操作造成的不便。陸軍和其他采用碳酸氫銨代替濃氨酸鈉的反應(yīng)方法。然而，為了提高整體效率，需要將乙酰甲酸乙酯和乙酸銨與乙酰甲酸乙酯、丙烯酸銨等摩爾結(jié)合，然后使用微波輻射技術(shù)合成2-6-4-芳基-3、5-羥色胺-1和4-二羥基丙烯酸酯。然而，首先，必須將乙酰甲酸乙酯和乙酸銨混合使用。作為目前文獻(xiàn)的報(bào)道，我們報(bào)告了一種基于微波輻射的漸進(jìn)合成方法，其中乙酰甲酸乙酯和乙酸銨。該方法具有時(shí)間短、產(chǎn)率好、反應(yīng)時(shí)間短的優(yōu)點(diǎn)。目前，關(guān)于最大限度的工業(yè)化生產(chǎn)并不是困難。據(jù)文獻(xiàn)報(bào)道，采用乙腈、乙酰甲酸乙酯和乙酸銨的根工具包裝劑。三甲基氯仿和碘化鈉在乙腈中的溫度下反應(yīng)為6.8小時(shí)，dph是通過緩慢釋放率獲得的。因此，尋求1-4-二羥基丙烯酸酯的方法已成為合成趨勢之一。隨著人們對人類生存環(huán)境的日益重視,越來越多的科學(xué)家將有機(jī)合成的研究重點(diǎn)放在對環(huán)境無污染的綠色合成上,綠色合成要求合成過程中采用無毒的試劑、溶劑或催化劑,其中水被認(rèn)為是最理想的溶劑.Breslow于20世紀(jì)80年代重新發(fā)現(xiàn)了水可以作為有機(jī)反應(yīng)的溶劑,最近一些以水作為有機(jī)反應(yīng)溶劑的綠色合成已有文獻(xiàn)報(bào)道,如Claisen重排、Aldol縮合、Diels-Alder反應(yīng)、Michael加成反應(yīng)等.近兩年來,我們對以水作為溶劑的有機(jī)反應(yīng)進(jìn)行了研究,研究了水溶劑中的Darzens反應(yīng)和Knoevenagel反應(yīng).最近我們發(fā)現(xiàn)將芳醛(1)、乙酰乙酸酯(2)、醋酸銨(3)在TEBA存在下在水中于90℃反應(yīng)4～8h,即可一步合成得到4-芳基-1,4-二氫吡啶衍生物4(Eq.1).1實(shí)驗(yàn)部分1.1紅外光譜分析熔點(diǎn)測定使用XT5顯微熔點(diǎn)測定儀;紅外光譜采用FTIR-8101型紅外光譜儀測定(KBr壓片);核磁共振氫譜在Inova-400MHz型核磁共振儀上測定,CDCl3為溶劑,TMS為內(nèi)標(biāo).芳醛、乙酰乙酸乙酯、乙酰乙酸甲酯、醋酸銨均為分析純試劑.1.24標(biāo)準(zhǔn)4:q,q,nh,3h,2h,2h,2h,2h,2ch3o,3h,3h,2h,3h,2h,2h,3h,2h,3h,3h,2h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3h,3將芳醛(2.0mmol),乙酰乙酸乙酯(或甲酯)(4.0mmol),醋酸銨(5.0mmol),TEBA(0.15g)和10mL水加入到50mL單頸燒瓶中,在90℃攪拌下反應(yīng)4～8h(薄層層析跟蹤反應(yīng)),冷卻,抽濾,用95%乙醇重結(jié)晶,得到產(chǎn)物4.4a:1HNMR(CDCl3)δ:1.22(t,J=7.2Hz,6H,2×CH3),2.37(s,6H,2×CH3),4.10(q,J=7.2Hz,4H,2×CH2O),5.09(s,1H,CH),5.77(brs,1H,NH),7.38(t,J=8.0Hz,1H,ArH),7.64(d,J=8.0Hz,1H,ArH),8.00(d,J=8.0Hz,1H,ArH),8.13(s,1H,ArH);IR(KBr)ν:3333,2990,1700,1633,1510,1475,1350,1200,1110,1010,800,750,700cm-1.4b:1HNMR(CDCl3)δ:1.23(t,J=7.2Hz,6H,2×CH3),2.27(s,3H,CH3),2.32(s,6H,2×CH3),4.09(q,J=7.2Hz,4H,2×CH2O),4.95(s,1H,CH),5.70(brs,1H,NH),7.01(d,J=7.2Hz,2H,ArH),7.17(d,J=7.2Hz,2H,ArH);IR(KBr)ν:3350,2990,1700,1650,1490,1390,1300,1200,1100,1090cm-1.Anal.calcdforC20H25-NO4:C69.95,H7.34,N4.08;foundC70.03,H7.06,N3.95.4c:1HNMR(CDCl3)δ:1.23(t,J=7.2Hz,6H,2×CH3),2.32(s,6H,2×CH3),3.75(s,3H,CH3O),4.10(q,J=7.2Hz,4H,2×CH2O),4.93(s,1H,CH),5.69(brs,1H,NH),6.75(d,J=8.0Hz,2H,ArH),7.20(d,J=8.0Hz,2H,ArH);IR(KBr)ν:3350,2990,1700,1650,1500,1380,1300,1210cm-1.4d:1HNMR(CDCl3)δ:1.23(t,J=7.2Hz,6H,2×CH3),2.32(s,6H,2×CH3),4.09(q,J=7.2Hz,4H,2×CH2O),4.95(s,1H,CH),5.63(brs,1H,NH),7.17(d,J=8.0Hz,2H,ArH),7.22(d,J=8.0Hz,2H,ArH);IR(KBr)ν:3335,2990,1675,1645,1510,1490,1200,1120,1020cm-1.4e:1HNMR(CDCl3)δ:1.22(t,J=7.2Hz,6H,2×CH3),2.33(s,6H,2×CH3),4.10(q,J=7.2Hz,4H,2×CH2O),4.99(s,1H,CH),5.60(brs,1H,NH),7.10～7.29(m,5H,ArH);IR(KBr)ν:3310,2970,1700,1650,1500,1370,1300,1200,1115,1070,1010,700cm-1.4f:1HNMR(CDCl3)δ:1.22(t,J=7.2Hz,6H,2×CH3),2.30(s,6H,2×CH3),4.10(q,J=7.2Hz,4H,2×CH2O),4.91(s,1H,CH),5.87(s,3H,NH+OCH2O),6.63～6.77(m,3H,ArH);IR(KBr)ν:3350,2990,1690,1650,1480,1380,1200,1120,1040cm-1.4g:1HNMR(CDCl3)δ:1.24(t,J=7.2Hz,6H,2×CH3),2.34(s,6H,2×CH3),3.82(s,3H,CH3O),3.84(s,3H,CH3O),4.11(q,J=7.2Hz,4H,2×CH2O),4.95(s,1H,CH),5.62(brs,1H,NH),6.72(d,J=8.0Hz,1H,ArH),6.80(d,J=8.0Hz,1H,ArH),6.88(s,1H,ArH);IR(KBr)ν:3340,1700,1650,1510,1470,1200,1130,1030,780cm-1.4h:1HNMR(CDCl3)δ:2.28(s,3H,CH3),2.34(s,6H,2×CH3),3.64(s,6H,2×CH3O),4.96(s,1H,CH),5.59(brs,1H,NH),7.03(d,J=8.0Hz,2H,ArH),7.16(d,J=8.0Hz,2H,ArH);IR(KBr)ν:3300,1710,1660,1500,1430,1320,1200,1133,1100,850cm-1;Anal.calcdforC18H21NO4:C68.55,H6.71,N4.44;foundC68.82,H6.57,N4.61.4i:1HNMR(CDCl3)δ:2.38(s,6H,2×CH3),3.65(s,6H,2×CH3O),5.11(s,1H,CH),5.75(brs,1H,NH),7.38(t,J=8.0Hz,1H,ArH),7.63(d,J=8.0Hz,1H,ArH),8.01(d,J=8.0Hz,1H,ArH),8.10(s,1H,ArH);IR(KBr)ν:3350,2955,1700,1650,1510,1490,1360,1230,1130,1010,700cm-1.Anal.calcdforC17H18N2O6:C58.96,H5.24,N8.09;foundC59.14,H5.09,N8.23.2teba重復(fù)使用的研究進(jìn)展該反應(yīng)是在溶劑水中進(jìn)行的,反應(yīng)時(shí)間較短,產(chǎn)率較高,后處理方便,污染少,是一種方便、有效、快速的合成1,4-DHPs的方法,實(shí)驗(yàn)結(jié)果見表1.反應(yīng)中催化劑TEBA是必不可少的,在沒有TEBA存在時(shí),反應(yīng)很難進(jìn)行,TEBA在反應(yīng)中起相轉(zhuǎn)