CN110105318A - 一种α-吡喃酮类化合物的绿色合成方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种α‑吡喃酮类化合物的绿色合成方法,以α‑碘代环戊烯酮类化合物为原料,以空气作为氧化剂,在溶剂中进行加热反应,能够高效构建多官能团化的α‑吡喃酮类化合物。整个反应具有操作简便、条件温和、底物官能团兼容性好、杂质少、产物易分离等优点。研发制得的一种α‑吡喃酮类化合物具有潜在的生物活性,可经过后续测试其药物活性,进行药物的筛选。也可以作为一类重要的有机中间体应用于医药、农药等领域。
Description
技术领域
本发明属于化学合成技术领域,具体涉及一种α-吡喃酮类化合物的绿色合成方法。
背景技术
α-吡喃酮是一种六元环状不饱和内酯,广泛存在于很多天然产物中,并且在医药、农药、香料、染料等领域具有极其广泛的应用,同时吡喃酮也是有机合成中重要的中间体。决明子内酯是由决明子中提取分离出萘并吡喃酮化合物,具有保肝、降血脂、抗氧化、降血压、预防糖尿病等作用;佛手柑内酯具有治疗白癜风和银屑病的作用;蛇床子素广泛应用医药领域中,具有增强免疫功能、抗心律失常、降血压等功效;杀鼠灵是我国主要使用的香豆素类杀鼠剂之一,具有高效、毒性相对较低,对人畜无害等特点;从锯缘青蟹叶中分离的杂色曲霉Y10菌株的提取物,主要用来治疗一种常见的痴呆症——阿尔茨海默病,对脑乙酰胆碱酯酶具有抑制活性,使大脑中的乙酰胆碱恢复正常水平。
由于α-吡喃酮类衍生物在医药、农药、香料、染料等领域具有极其广泛的应用,因此吸引了许多化学家的关注,发展了各种合成此类化合物的方法。现行的吡喃酮化合物的合成方法有很多,过渡金属催化的环加成和环化反应是α-吡喃酮的的通常方法,但大多数方法具有区域选择性差或反应条件苛刻等缺点((a)Angew.Chem.Int.Ed.2007,46:8250-8253;(b)Chem.Commun.,2000:1987-1988;(c)Org.Lett.2015,17:5706-5709;(d)Adv.Synth.Catal.2017,359:2729-2734;(e)Org.Chem.Front.,2018,5:3574)。本发明使用α-碘代环戊烯酮类化合物原料,以空气作为氧化剂的Baeyer-Villiger类型扩环内酯化的策略,高效构建多官能团化的α-吡喃酮类化合物。
发明内容
本部分的目的在于提供一种α-吡喃酮绿色合成方法。
为实现上述目的,本发明提供了如下技术方案:一种式(1)所示的α-吡喃酮类化合物的绿色合成方法,其特征在于:在空气氛围下,以式(2)所示的α-碘代环戊烯酮类化合物为原料,在溶剂中进行加热反应,薄板层析跟踪反应直至反应完全,得到反应混合物,所述反应混合物经后处理得到式(1)所示α-吡喃酮类化合物;其化学反应式如下所示
其中,R1为C1-C6烷基、环烷基、芳基、萘基、单或多取代芳基;
R2代表一个取代基,选自C1-C10烷基、环烷基、羰基、酯基、苯甲酰基、苯磺酰基、含氮杂环基团中的一种或者几种的组合。
进一步,所述溶剂为N,N-二甲基甲酰胺(DMF),N,N-二甲基乙酰胺(DMA),甲苯,四氢呋喃,乙腈,二甲基亚砜(DMSO)或N-甲基吡咯烷酮(NMP),优选为DMA。
进一步,所述反应温度为50-130℃,反应时间为3-12小时。
进一步,所述空气取自所处环境,不受任何其它因素影响。
进一步,其特征在于,所述反应后处理方法为:反应结束后,将反应混合物用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取,再用饱和氯化钠溶液洗涤有机相,无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析,以石油醚∶乙酸乙酯体积比10∶1-1∶1的混合溶液为洗脱剂进行梯度洗脱,得到式(1)所示α-吡喃酮类化合物。
与现有技术相比,本发明的有益效果主要体现在:
(1)本发明以空气作为氧化剂,无需任何催化剂,只需在溶剂中进行加热就能反应,且杂质较少,处理简单,反应高效。
(2)本发明以α-碘代环戊烯酮类化合物为原料,原料易得,各种官能团耐受性相对较好。
(3)本发明的提供的α-吡喃酮类化合物,可以作为一类重要的有机中间体应用于医药、农药等领域。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合具体实施例对本发明的具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是本发明还可以采用其他不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似推广,因此本发明不受下面公开的具体实施例的限制。
实施例1:
反应式为:
取25mL茄形瓶,依次加入2a(89.5mg,0.3mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶5)分离得到产物1a(42mg,0.23mmol),产率为75%。
1H NMR(600MHz,CDCl3):δ7.56-7.55(m,2H),7.47-7.45(m,3H),6.34(s,1H),6.30(s,1H),2.31(s,3H);13C NMR(150MHz,CDCl3):δ163.5,162.2,155.5,135.8,130.6,129.2,126.7,108.2,103.5,20.2;HRMS(ESI)calcd.for C12H11O2[M+H]+:187.0759,found187.0757.
实施例2:
反应式为:
取25mL茄形瓶,依次加入2b(99.8mg,0.3mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶5)分离得到产物1b(45mg,0.21mmol),产率为70%。
1H NMR(600MHz,CDCl3):δ7.49(d,J=8.6Hz,2H),7.42(d,J=8.5Hz,2H),6.30(s,1H),6.25(s,1H),2.31(s,3H);13C NMR(150MHz,CDCl3):δ163.2,162.5,154.2,136.9,134.2,129.4,128.0,108.2,103.1,20.2;HRMS(ESI)calcd.for C12H10O2 35Cl[M+H]+:221.0369,found 221.0371.
实施例3:
反应式为:
取25mL茄形瓶,依次加入2c(94mg,0.2mmol),2ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶3)分离得到产物1c(52mg,0.145mmol),产率为72%。
1H NMR(600MHz,CDCl3):δ7.84-7.82(m,2H),7.71-7.69(m,2H),7.57-7.56(m,2H),7.47-7.45(m,3H),6.39(d,J=0.5Hz,1H),6.31(d,J=1.4Hz,1H),3.80(t,J=6.8Hz,2H),2.63(t,J=7.5Hz,2H),2.16-2.11(m,2H);13C NMR(150MHz,CDCl3):δ168.3,164.0,163.2,155.3,135.7,134.1,132.0,130.7,129.2,126.7,123.3,108.5,103.3,37.0,31.4,25.8;HRMS(ESI)calcd.for C22H17NO4Na[M+Na]+:382.1050,found:382.1053.
实施例4:
反应式为:
取25mL茄形瓶,依次加入2d(115mg,0.3mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶3)分离得到产物1d(62mg,0.228mmol),产率为76%。
1H NMR(600MHz,CDCl3)δ7.56-7.55(m,2H),7.47-7.45(m,3H),6.35(s,1H),6.33(s,1H),4.13(t,J=6.2Hz,2H),2.64(t,J=7.7Hz,2H),2.08-2.03(m,5H);13C NMR(150MHz,CDCl3)δ171.0,164.3,163.3,155.4,135.7,130.7,129.2,126.7,108.6,103.2,63.16,30.78,26.04,20.88;HRMS(ESI)calcd.for C16H16O4Na[M+Na]+:295.0941,found:295.0943.
实施例5:
反应式为:
取25mL茄形瓶,依次加入2e(87mg,0.25mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶4)分离得到产物1e(38mg,0.16mmol),产率为65%。
1H NMR(600MHz,CDCl3):δ7.93-7.91(m,3H),7.56-7.50(m,3H),7.42(dd,J=7.1,1.0Hz,1H),6.31(s,1H),6.21(d,J=0.8Hz,1H),2.34(s,3H);13C NMR(150MHz,CDCl3):δ163.1,161.5,156.9,135.3,133.7,130.0,129.9,128.7,127.0,126.5,125.9,125.3,124.9,112.1,106.8,20.1;HRMS(ESI)calcd.for C16H12O2Na[M+Na]+:259.0730,found:259.0732.
实施例6:
反应式为:
取25mL茄形瓶,依次加入2f(115mg,0.33mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶4)分离得到产物1f(48mg,0.21mmol),产率为64%。
1H NMR(600MHz,CDCl3):δ7.29(t,J=7.4Hz,2H),7.21-7.15(m,3H),5.94(s,1H),5.83(s,1H),2.65(t,J=7.6Hz,2H),2.37(t,J=7.6Hz,2H),2.20(s,3H),1.91-1.86(m,2H);13C NMR(150MHz,CDCl3):δ163.3,161.5,160.0,141.2,128.5,128.4,126.2,109.8,105.5,35.1,34.6,29.6,19.9;HRMS(ESI)calcd.for C15H16O2Na[M+Na]+:251.1045,found:251.1043.
实施例7:
反应式为:
取50mL茄形瓶,依次加入2g(237mg,0.70mmol),7ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶4)分离得到产物1g(83mg,0.37mmol),产率为53%。
1H NMR(600MHz,CDCl3):δ7.41-7.38(m,3H),7.25-7.23(m,2H),6.04(s,1H),2.57(td,J=6.5,0.6Hz,2H),2.20(tt,J=6.1,1.6Hz,2H),1.82-1.78(m,2H),1.64-1.60(m,2H);13C NMR(150MHz,CDCl3):δ162.6,159.9,159.4,136.7,129.0,128.5,127.6,112.1,112.1,27.9,25.0,22.4,21.7;HRMS(ESI)calcd.for C15H14O2Na[M+Na]+:249.0886,found:249.0890.
实施例8:
反应式为:
取25mL茄形瓶,依次加入2h(121mg,0.3mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶5)分离得到产物1h(54mg,0.18mmol),产率为61%。
1H NMR(600MHz,CDCl3):δ7.49(d,J=8.6Hz,2H),7.42(d,J=8.5Hz,2H),6.30(s,1H),6.25(s,1H),2.31(s,3H);13C NMR(150MHz,CDCl3):δ163.2,162.5,154.2,136.9,134.2,129.4,128.0,108.2,103.1,20.2;HRMS(ESI)calcd.for C17H24O4Na[M+Na]+:315.1567,found:315.1569.
实施例9:
反应式为:
取25mL茄形瓶,依次加入2i(174mg,0.3mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶4)分离得到产物1i(84mg,0.18mmol),产率为60%。
1H NMR(600MHz,CDCl3)δ7.40(d,J=8.2Hz,2H),7.30-7.28(m,3H),7.21(d,J=8.2Hz,2H),7.02-7.01(m,2H),5.91(s,1H),5.88(s,1H),3.55(t,J=6.4Hz,2H),2.54(t,J=7.3Hz,2H),2.40(s,3H),2.33(t,J=7.7Hz,2H),1.78-1.74(m,2H),1.54-1.50(m,2H),1.32-1.27(m,6H),0.87(t,J=6.5Hz,3H);13C NMR(150MHz,CDCl3)δ163.4,163.2,160.6,143.6,138.9,134.9,129.4,129.2,128.6,128.1,127.7,110.0,105.9,49.3,35.3,31.5,30.4,28.7,28.0,25.3,22.5,21.5,14.0;HRMS(ESI)calcd.for C27H33NO4SNa[M+Na]+:490.2023,found:490.2025.
实施例10:
反应式为:
取25mL茄形瓶,依次加入2j(178mg,0.3mmol),3ml N,N-二甲基乙酰胺,在空气氛围下搅拌,反应温度为120℃。TLC监控反应,反应结束后,用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取(25mLx2),合并有机相,再用饱和氯化钠溶液洗涤(30mLx3),无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析(洗脱剂:乙酸乙酯/石油醚V/V=1∶2)分离得到产物1j(94mg,0.20mmol),产率为65%。
1H NMR(600MHz,CDCl3)δ7.53-7.44(m,5H),7.19(d,J=8.5Hz,1H),6.71-6.70(m,1H),6.63(s,1H),6.37(s,1H),6.33(s,1H),4.01(t,J=5.6Hz,2H),2.89-2.86(m,2H),2.78(t,J=7.4Hz,2H),2.52-2.48(m,1H),2.41-2.35(m,1H),2.26-1.94(m,8H),1.66-1.41(m,5H),0.9l(s,3H);13C NMR(150MHz,CDCl3)δ220.9,164.8,163.4,156.8,155.4,137.9,135.8,132.3,130.6,129.2,126.7,126.4,114.5,112.2,108.6,103.4,66.3,50.4,48.0,44.0,38.4,35.9,31.6,30.8,29.7,26.7,26.6,25.9,21.6,13.9;HRMS(ESI)calcd.forC32H34O4Na[M+Na]+:505.2349,found:505.2353.
由此可见,本发明所提供的一种以α-碘代环戊烯酮类化合物为原料,以空气作为氧化剂,高效构建多官能团化的α-吡喃酮类化合物的新方法。整个反应具有操作简便、条件温和、底物官能团兼容性好、杂质少、产物易分离等优点。研发制得的一种α-吡喃酮类化合物具有潜在的生物活性,可经过后续测试其药物活性,进行药物的筛选。也可以作为一类重要的有机中间体应用于医药、农药等领域。
应说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (5)
1.一种式(1)所示的α-吡喃酮类化合物的绿色合成方法,其特征在于:在空气氛围下,以式(2)所示的α-碘代环戊烯酮类化合物为原料,在溶剂中进行加热反应,薄板层析跟踪反应直至反应完全,得到反应混合物,所述反应混合物经后处理得到式(1)所示α-吡喃酮类化合物;其化学反应式如下所示:
式(2)或式(1)中,所述R1为C1-C6烷基、环烷基、芳基、萘基、单或多取代芳基;
R2代表一个取代基,选自C1-C10烷基、环烷基、羰基、酯基、苯甲酰基、苯磺酰基、含氮杂环基团中的一种或者几种的组合。
2.如权利要求1所述的绿色合成方法,其特征在于,所述溶剂为N,N-二甲基甲酰胺(DMF),N,N-二甲基乙酰胺(DMA),甲苯,四氢呋喃,乙腈,二甲基亚砜(DMSO)或N-甲基吡咯烷酮(NMP),优选为DMA。
3.如权利要求1所述的绿色合成方法,其特征在于,所述反应温度为50-130℃,反应时间为3-12小时。
4.如权利要求1所述的绿色合成方法,其特征在于,所述空气取自所处环境,不受任何其它因素影响。
5.如权利要求1所述的绿色合成方法,其特征在于,所述反应后处理方法为:反应结束后,将反应混合物用硫代硫酸钠饱和溶液洗涤,乙酸乙酯萃取,再用饱和氯化钠溶液洗涤有机相,无水硫酸镁干燥,过滤并旋转蒸发浓缩滤液得到粗品,硅胶柱层析,以石油醚∶乙酸乙酯体积比10∶1-1∶1的混合溶液为洗脱剂进行梯度洗脱,得到式(1)所示α-吡喃酮类化合物。
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