CN112939855A - 一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法 - Google Patents
一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法 Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
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Abstract
Description
技术领域
本发明属于医药化工技术领域,更具体地说,涉及一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法。
背景技术
吡啶及其衍生物是一类重要的杂环化合物,存在于许多天然产物中,具有广泛的应用价值,可用于医药、农药、橡胶、染料等领域。作为吡啶衍生物中的一种,1,4-二氢吡啶衍生物具有抗菌、抗癌、抗肿瘤、抗氧化、抑制糖尿病和钙拮抗剂等多种生理活性,可以用于心血管疾病的预防治疗,同时对脂肪肝、中毒性肝炎等有一定的疗效。
薁类化合物具有显著的芳香性,易于发生取代反应,并且具有广泛的生物活性,在医药和农药领域也得到了广泛应用。而同时含有薁环和1,4-二氢吡啶结构的化合物兼有上述两者的优点,具有更为广泛的应用。因此,含有薁环结构的1,4-二氢吡啶衍生物的制备受到药物合成者的广泛关注。
目前,关于含有薁环结构的1,4-二氢吡啶衍生物的制备通常采用多步合成法,具有反应时间长、产率低、副产物复杂、反应条件苛刻以及环境污染严重等问题。基于此,渤海大学的王道林等以对甲苯磺酸作为催化剂,无水乙醇作为反应溶剂,通过1-甲酰基薁-3-甲酸甲酯、乙酰乙酸酯、醋酸铵或3-氨基-2-丁烯酸酯的三组分一锅法的缩合反应,可以制备出一系列含有薁环结构的1,4-二氢吡啶衍生物。该方法具有收率良好、操作简单、条件温和等优点(含有薁类结构的1,4-二氢吡啶衍生物的合成[J],有机化学,2010,30(11):1774~1777)。但是,上述方法也存在以下缺点:(1)催化剂不能循环使用,经济效益和环境效益较差;(2)副产物复杂,导致产物的提纯过程复杂,需要经硅胶柱分离,不能工业化大规模连续生产;(3)反应时间较长且产物收率仍然较低,原子经济性较差。
发明内容
1.要解决的问题
针对现有技术中制备含有薁环结构的1,4-二氢吡啶衍生物的方法存在的催化剂不能循环使用、环境污染严重且催化活性相对较低,反应时间较长,产物提纯过程复杂,不能连续工业化大规模生产等问题,本发明提供一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法。该方法采用的催化剂的选择性及催化效率较高,降低了副产物的产生,提高了产物的纯度,且缩短了反应时间。同时,该催化剂可以循环使用,大大提高了经济效益和环境效益。
2.技术方案
为了解决上述问题,本发明所采用的技术方案如下:
本发明的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,包括以下步骤:首先,量取混合溶剂并加入到三口瓶中;然后,称取1-甲酰基薁-3-甲酸甲酯、乙酰乙酸酯、3-氨基-2-丁烯酸酯或乙酸铵,将上述物料加入到盛有混合溶剂的三口瓶中,室温下搅拌均匀,再加入酸性离子液体,混合均匀;最后,在加热条件下回流反应一定时间,生成含有薁环结构的1,4-二氢吡啶衍生物;所述酸性离子液体的结构式为:
更进一步的,所述1-甲酰基薁-3-甲酸甲酯、乙酰乙酸酯、3-氨基-2-丁烯酸酯或乙酸铵、酸性离子液体的摩尔比为1:(1.6~2.0):(1.3~2.1):(0.03~0.06)。
更进一步的,所述混合溶剂为叔丁醇和乙酸乙酯按照一定比例混合制备的混合溶剂。
更进一步的,所述的混合溶剂中叔丁醇和乙酸乙酯的体积比例为9:(1~1.5)。
更进一步的,所述的以毫升计的混合溶剂的体积量为以毫摩尔计的1-甲酰基薁-3-甲酸甲酯摩尔量的7~10倍。
更进一步的,所述回流反应时间为142~237min。
更进一步的,含有薁环结构的1,4-二氢吡啶衍生物的提纯过程具体如下:反应结束后,待反应液自然冷却至室温,将析出的固体碾碎,静置、抽滤;其中,滤渣经洗涤液洗涤、真空干燥后得到提纯后的含有薁环结构的1,4-二氢吡啶衍生物;由洗涤液补齐体积量的滤液中直接加入反应原料后即可进行下一次反应。
更进一步的,所述洗涤液采用反应用的混合溶剂,洗涤3~5次,然后于75℃下真空干燥48h。
更进一步的,所述的乙酰乙酸酯为乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸异丙酯和乙酰乙酸叔丁酯中的任意一种。
更进一步的,所述的3-氨基-2-丁烯酸酯为3-氨基-2-丁烯酸乙酯、3-氨基-2-丁烯酸异丙酯和3-氨基-2-丁烯酸叔丁酯中的任意一种。
更进一步的,采用酸性离子液体催化制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其化学反应式为:
3.有益效果
相比于现有技术,本发明的有益效果为:
(1)本发明的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,通过对反应原料的选择及其配比进行优化设计,尤其是使用含有两个-SO3H的酸性离子液体作为催化剂,一方面,有效提高了反应的产率;另一方面,采用的酸性离子液体的选择性较高,有利于减少副产物的含量,从而大幅度提高了产物的纯度。同时,酸性离子液体的催化效率较高,显著减少了反应时间和催化剂的使用量,且利用酸性离子液体不易挥发且热稳定性好的特点,实现了催化剂的循环使用,大大提高了经济效益和环境效益。
(2)本发明的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,采用酸性离子液体作为催化剂,利用其阴阳离子组成且含有两个强极性基团-SO3H的结构,使得其与脂溶性较强的含有薁环结构的1,4-二氢吡啶衍生物的互溶性较差,便于催化剂与产物的分离,为后续产物的提纯简化提供便利,环境效益好、成本低。
(3)本发明的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,通过选用酸性离子液体与混合溶剂组成的催化体系,可以做到该催化体系的循环使用,既减少了催化剂和溶剂的分离操作,又可以同步提高反应原料和溶剂的利用率。
(4)本发明的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,通过选用叔丁醇-乙酸乙酯按照一定的体积比例组成的混合溶剂作为反应溶剂兼重结晶溶剂,使得产物的提纯过程比较简单,只需要进行混合溶剂洗涤即可,简化了产物含有薁环结构的1,4-二氢吡啶衍生物的提纯过程。另外,由于反应中副产物量的减少,不仅可以获得较高纯度的粗产物,还使得部分洗涤剂随着催化体系从而实现了部分循环回用,提高有机溶剂的使用效率的同时又减少了对环境的污染。
附图说明
图1为实施例1中催化体系循环使用次数对产物纯度和收率的影响示意图;
图2为实施例5中催化体系循环使用次数对产物纯度和收率的影响示意图;
图3为实施例8中催化体系循环使用次数对产物纯度和收率的影响示意图。
具体实施方式
下面结合具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定,本领域的技术人员根据本发明的内容做出一些非本质的改进和调整,均属于本发明的保护范围。除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。
下面实施例中反应产物的氢谱核磁共振表征采用的是德国Bruker公司的型号为AVANCE400MHz的核磁共振仪;红外光谱测试表征使用的是德国Bruker公司的型号为EQUINOX 55红外光谱仪(KBr压片);高效液相色谱纯度测定使用的是日本岛津公司的型号为ESSENTIA LC-15C的高效液相色谱仪。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例1
向盛有7ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、1.6mmol乙酰乙酸甲酯、1.8mmol乙酸铵,室温搅拌,混合均匀,再加入0.03mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应142min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=93:7)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1)洗涤(洗涤体积4ml×3次)、75℃下真空干燥48h后得到0.35g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二甲氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为99.2%,计算收率为86%。洗涤液补齐7ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸甲酯和乙酸铵后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二甲氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=2.32(s,6H),3.47(s,6H),3.88(s,3H),5.52(s,1H),5.76(br s,1H),7.34~7.39(m,2H),7.68(dd,J=9.8,9.8Hz,1H),8.16(s,1H),8.87(d,J=9.8Hz,1H),9.49(d,J=9.8Hz,1H);IR(KBr):ν=3330,1681,1662cm-1。
实施例2
向盛有8ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.2)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、1.7mmol乙酰乙酸乙酯、2.0mmol乙酸铵,室温搅拌,混合均匀,再加入0.04mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应158min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=92:8)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.2)洗涤(洗涤体积4ml×3次)、75℃下真空干燥48h后得到0.36g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二乙氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为99.0%,计算收率为82%。洗涤液补齐8ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸乙酯和乙酸铵后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二乙氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.04(t,J=7.4Hz,6H),2.34(s,6H),3.89(s,6H),3.94(q,J=7.4Hz,4H),5.53(s,1H),5.78(br s,1H),7.39~7.41(m,2H),7.71(dd,J=9.6,9.6Hz,1H),8.18(s,1H),8.85(d,J=9.6Hz,1H),9.50(d,J=9.6Hz,1H);IR(KBr):ν=3334,1678,1660cm-1。
实施例3
向盛有8ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.3)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、1.8mmol乙酰乙酸异丙酯、2.0mmol乙酸铵,室温搅拌,混合均匀,再加入0.04mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应181min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=92:8)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.3)洗涤(洗涤体积5ml×3次)、75℃下真空干燥48h后得到0.37g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二异丙氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为98.8%,计算收率为79%。洗涤液补齐8ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸异丙酯和乙酸铵后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二异丙氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.23(d,J=4.6Hz,12H),2.41(s,6H),3.97(s,6H),4.01(s,3H),4.05~4.11(m,2H),5.62(s,1H),5.98(br s,1H),7.46~7.50(m,2H),7.79(dd,J=9.6,9.6Hz,1H),8.29(s,1H),8.97(d,J=9.6Hz,1H),9.58(d,J=9.6Hz,1H);IR(KBr):ν=3340,1679,1655cm-1。
实施例4
向盛有9ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.4)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、1.8mmol乙酰乙酸叔丁酯、2.1mmol乙酸铵,室温搅拌,混合均匀,再加入0.04mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应193min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=92:8)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.4)洗涤(洗涤体积5ml×3次)、75℃下真空干燥48h后得到0.38g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二叔丁氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为98.5%,计算收率为76%。洗涤液补齐9ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸叔丁酯和乙酸铵后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3,5-二叔丁氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.27(s,18H),2.41(s,6H),2.38(s,6H),3.55(s,6H),3.96(s,3H),5.59(s,1H),5.73(br s,1H),7.42~7.48(m,2H),7.74(dd,J=9.6,9.6Hz,1H),8.24(s,1H),8.92(d,J=9.6Hz,1H),9.51(d,J=9.6Hz,1H);IR(KBr):ν=3335,1676,1652cm-1。
实施例5
向盛有9ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.4)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、1.7mmol乙酰乙酸甲酯、1.4mmol 3-氨基-2-丁烯酸乙酯,室温搅拌,混合均匀,再加入0.05mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应174min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=90:10)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.4)洗涤(洗涤体积5ml×5次)、75℃下真空干燥48h后得到0.34g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-甲氧羰基-5-乙氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为98.7%,计算收率为79%。洗涤液补齐9ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸甲酯和3-氨基-2-丁烯酸乙酯后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-甲氧羰基-5-乙氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.05(t,J=7.4Hz,3H),2.37(s,6H),3.51(s,3H),3.92(s,3H),4.00(q,J=7.4Hz,2H),5.56(s,1H),5.97(br s,1H),7.42~7.46(m,2H),7.73(dd,J=9.6,9.6Hz,1H),8.21(s,1H),8.90(d,J=9.6Hz,1H),9.53(d,J=9.6Hz,1H);IR(KBr):ν=3346,1690,1665cm-1。
实施例6
向盛有9ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.4)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、1.6mmol乙酰乙酸甲酯、1.3mmol 3-氨基-2-丁烯酸异丙酯,室温搅拌,混合均匀,再加入0.04mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应168min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=90:10)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.4)洗涤(洗涤体积5ml×5次)、75℃下真空干燥48h后得到0.35g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-甲氧羰基-5-异丙氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为98.9%,计算收率为80%。洗涤液补齐9ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸甲酯和3-氨基-2-丁烯酸异丙酯后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-甲氧羰基-5-异丙氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.22(d,J=4.8Hz,6H),2.38(s,6H),3.54(s,3H),3.94(s,3H),4.01~4.04(m,1H),5.61(s,1H),5.94(br s,1H),7.45~7.51(m,2H),7.77(dd,J=9.8,9.8Hz,1H),8.23(s,1H),8.95(d,J=9.8Hz,1H),9.54(d,J=9.8Hz,1H);IR(KBr):ν=3342,1698,1651cm-1。
实施例7
向盛有9ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.5)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、1.6mmol乙酰乙酸甲酯、1.3mmol 3-氨基-2-丁烯酸叔丁酯,室温搅拌,混合均匀,再加入0.05mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应207min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=90:10)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.5)洗涤(洗涤体积5ml×5次)、75℃下真空干燥48h后得到0.33g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-甲氧羰基-5-叔丁氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为98.4%,计算收率为71%。洗涤液补齐9ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸甲酯和3-氨基-2-丁烯酸叔丁酯后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-甲氧羰基-5-叔丁氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.25(s,9H),2.35(s,6H),3.48(s,3H),3.92(s,3H),5.54(s,1H),5.88(br s,1H),7.40~7.46(m,2H),7.72(dd,J=9.8,9.8Hz,1H),8.19(s,1H),8.93(d,J=9.8Hz,1H),9.51(d,J=9.8Hz,1H);IR(KBr):ν=3344,1692,1664cm-1。
实施例8
向盛有10ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.5)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、2.0mmol乙酰乙酸乙酯、1.7mmol 3-氨基-2-丁烯酸异丙酯,室温搅拌,混合均匀,再加入0.06mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应223min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=89:11)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.5)洗涤(洗涤体积5ml×5次)、75℃下真空干燥48h后得到0.30g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-乙氧羰基-5-异丙氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为99.2%,计算收率为67%。洗涤液补齐10ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸乙酯和3-氨基-2-丁烯酸异丙酯后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-乙氧羰基-5-异丙氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.11(t,J=7.6Hz,3H),1.26(d,J=5.0Hz,6H),2.38(s,6H),3.97(s,3H),4.05(q,J=7.6Hz,2H),4.08~4.13(m,1H),5.62(s,1H),5.83(br s,1H),7.37~7.44(m,2H),7.69(dd,J=9.6,9.6Hz,1H),8.23(s,1H),8.90(d,J=9.8Hz,1H),9.54(d,J=9.8Hz,1H);IR(KBr):ν=3341,1690,1658cm-1。
实施例9
向盛有10ml混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.5)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、2.0mmol乙酰乙酸乙酯、2.1mmol 3-氨基-2-丁烯酸叔丁酯,室温搅拌,混合均匀,再加入0.06mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应237min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=89:11)监测,原料点消失,反应结束。关闭加热和搅拌,反应液自然冷却至室温,析出大量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.5)洗涤(洗涤体积5ml×5次)、75℃下真空干燥48h后得到0.30g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-乙氧羰基-5-叔丁氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为99.0%,计算收率为64%。洗涤液补齐10ml的滤液中直接加入1-甲酰基薁-3-甲酸甲酯、乙酰乙酸乙酯和3-氨基-2-丁烯酸叔丁酯后进行重复使用。
本实施例所得产物2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-乙氧羰基-5-叔丁氧羰基-1,4-二氢吡啶的表征数据如下:
1H NMR(400MHz,CDCl3):δ=1.06(t,J=7.4Hz,3H),1.23(s,9H),2.39(s,6H),3.94(s,3H),4.01(q,J=7.4Hz,2H),5.57(s,1H),5.77(br s,1H),7.42~7.47(m,2H),7.75(dd,J=9.6,9.6Hz,1H),8.24(s,1H),8.88(d,J=9.8Hz,1H),9.59(d,J=9.8Hz,1H);IR(KBr):ν=3338,1684,1657cm-1。
实施例10
采用实施例1的方法,考察混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1)和酸性离子液体所组成的催化体系使用次数对产物纯度和收率的影响,其结果见图1。
实施例11
采用实施例5的方法,考察混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.4)和酸性离子液体所组成的催化体系使用次数对产物纯度和收率的影响,其结果见图2。
实施例12
采用实施例8的方法,考察混合溶剂(叔丁醇-乙酸乙酯的体积比为9:1.5)和酸性离子液体所组成的催化体系使用次数对产物纯度和收率的影响,其结果见图3。
对比例1
向盛有7ml叔丁醇的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、2.0mmol乙酰乙酸乙酯、2.1mmol 3-氨基-2-丁烯酸叔丁酯,室温搅拌,混合均匀,再加入0.06mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应237min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=89:11)监测,发现仍有很多反应原料未能参与反应。关闭加热和搅拌,反应液自然冷却至室温,未有固体析出。反应液高效液相色谱测定产物纯度为53.1%,计算收率为23%。
对比例2
向盛有7ml乙酸乙酯的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol1-甲酰基薁-3-甲酸甲酯、2.0mmol乙酰乙酸乙酯、2.1mmol 3-氨基-2-丁烯酸叔丁酯,室温搅拌,混合均匀,再加入0.06mmol酸性离子液体,混合形成乳状液。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应237min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=89:11)监测,发现仍有很多反应原料未能参与反应。关闭加热和搅拌,反应液自然冷却至室温,未有固体析出。反应液高效液相色谱测定产物纯度为8.4%,计算收率为3%。
对比例3
向盛有10ml混合溶剂(叔丁醇-乙酸乙酯的体积比为5:5)的带有球形冷凝管、温度计和搅拌子的50ml三口瓶中加入1.0mmol 1-甲酰基薁-3-甲酸甲酯、2.0mmol乙酰乙酸乙酯、2.1mmol 3-氨基-2-丁烯酸叔丁酯,室温搅拌,混合均匀,再加入0.06mmol酸性离子液体,混合均匀。油浴加热,均匀升温至回流(蒸气不超过球形冷凝管的第二个球),保持回流反应237min,TLC(硅胶薄板层析,展开剂为V(苯):V(乙酸乙酯)=89:11)监测,发现原料点未完全消失。关闭加热和搅拌,反应液自然冷却至室温,析出少量的固体,碾碎固体,静置36h,减压抽滤,滤渣经混合溶剂(叔丁醇-乙酸乙酯的体积比为5:5)洗涤(洗涤体积5ml×5次)、75℃下真空干燥48h后得到0.19g 2,6-二甲基-4-(3-甲氧羰基-1-薁基)-3-乙氧羰基-5-叔丁氧羰基-1,4-二氢吡啶,高效液相色谱测定其纯度为95.2%,计算收率为38%。
结合对比例1-3及图1-3可知,当催化剂选用酸性离子液体催化剂,并且反应溶剂采用叔丁醇和乙酸乙酯时,能够进一步提高产物含有薁环结构的1,4-二氢吡啶衍生物的纯度和收率。同时,催化剂和反应溶剂的循环使用效果较好,重复使用6次以上,所得产物的纯度均在98%以上、收率高达86%,且重复多次使用后,产物的纯度和收率下降较低,变化较小。
Claims (9)
2.根据权利要求1所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:所述1-甲酰基薁-3-甲酸甲酯、乙酰乙酸酯、3-氨基-2-丁烯酸酯或乙酸铵、酸性离子液体的摩尔比为1:(1.6~2.0):(1.3~2.1):(0.03~0.06)。
3.根据权利要求1所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:所述混合溶剂为叔丁醇和乙酸乙酯,且叔丁醇和乙酸乙酯的体积比例为9:(1~1.5)。
4.根据权利要求1所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:所述的以毫升计的混合溶剂的体积量为以毫摩尔计的1-甲酰基薁-3-甲酸甲酯摩尔量的7~10倍。
5.根据权利要求1-4中任一项所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:所述回流反应时间为142~237min。
6.根据权利要求5所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:提纯过程具体如下:反应结束后,待反应液自然冷却至室温,将析出的固体碾碎,静置、抽滤;其中,滤渣经洗涤液洗涤、真空干燥后得到提纯后的含有薁环结构的1,4-二氢吡啶衍生物;由洗涤液补齐体积量的滤液中直接加入反应原料后即可进行下一次反应。
7.根据权利要求6所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:所述洗涤液采用反应用的混合溶剂,洗涤3~5次,然后于75℃下真空干燥48h。
8.根据权利要求7所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:所述的乙酰乙酸酯为乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸异丙酯和乙酰乙酸叔丁酯中的任意一种。
9.根据权利要求8所述的一种制备含有薁环结构的1,4-二氢吡啶衍生物的方法,其特征在于:所述的3-氨基-2-丁烯酸酯为3-氨基-2-丁烯酸乙酯、3-氨基-2-丁烯酸异丙酯和3-氨基-2-丁烯酸叔丁酯中的任意一种。
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