CN105566195A - 一种吡咯衍生物的制备方法 - Google Patents
一种吡咯衍生物的制备方法 Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims abstract description 7
- VPOGPNWJJGESPL-UHFFFAOYSA-N 2-methylideneaziridine Chemical class C=C1CN1 VPOGPNWJJGESPL-UHFFFAOYSA-N 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 150000001345 alkine derivatives Chemical class 0.000 claims description 22
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 150000004032 porphyrins Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
Abstract
本发明涉及一种高效构建吡咯环结构的方法，通过银偶氮类金属框架材料作为催化剂，亚甲基氮杂环丙烷I和炔基化合物II进行环加成反应，合成了一系列吡咯类化合物III，收率较高，反应迅速，条件温和，易于进行工业化。
Description
技术领域
本发明涉及一种制备吡咯衍生物的方法。具体方法是由亚甲基氮杂环丙烷与炔，以银-偶氮四唑金属有机框架材料为催化剂，发生[3+2]环加成反应制备取代的吡咯衍生物。
背景技术
吡咯及其衍生物是药物化学重要的杂环化合物之一，这类结构广泛存在于天然产物及一些人工合成的具有生物活性的化合物结构中，比如卟啉，维生素B12等。吡咯环的构建被用于众多活性药物分子的合成，例如抗真菌药吡咯尼群，抗菌药司他霉素，消炎药托美丁，抗肿瘤药长春新碱等。可见吡咯环的构建是有机合成中非常有用的一个模块，吡咯环的构建一直是有机合成中的重要研究方向。而环加成反应则是构建环结构，尤其是杂环化合物的一种重要途径，其原子利用率高、条件温和（(a)Katritzky，A.R.;Yao,J.;Bao,W.;Qi,M.;Steel,P.J.J.Org.Chem.1999,64,346;(b)Washizuka,K.I.;Minakata,S.;Ryu,I.；Komatsu,M.Tetrahedron1999,55,12969.）。如何经济高效的进行吡咯环的构建一直是有机合成领域的研究热点。Chem.Comm.,2013,49,5073报道了一种环加成构建吡咯结构的方法，但存在收率较低，反应时间过长等缺点，难以应用于工业化生产；CryEngComm,2014,16,10485报道了一种新型的有机金属框架材料，分子式为C3H8AgN7为银-偶氮四唑结构，并将其应用于降解有机染料，但并未进一步报道其其他领域的应用。
发明内容
本发明涉及一种制备吡咯衍生物的方法。具体方法是由亚甲基氮杂环丙烷与炔，以银-偶氮四唑金属有机框架材料为催化剂，发生[3+2]环加成反应制备取代的吡咯衍生物。本发明采用的技术方案为：
采用在银偶氮四唑的催化下进行如下的反应式进行环加成构建吡咯环：
IIIIII
其中R1为H、C1-C8烷基（如甲基和乙基）、C1-C8烷氧基（如甲氧基和乙氧基）、C3-C8环烷基（如环丙烷基、环己烷基）、苯基、取代的苯基、苄基、取代的苄基中的一种，苯基或苄基上的取代基为C1-C8烷基、C1-C8烷氧基、F、Cl、Br、I、NO2中的一种、二种或三种；R2、R3可以相同或不同的为氢、C1-C8烷基（如甲基和乙基）、C1-C8烷氧基（如甲氧基和乙氧基）、C3-C8环烷基（如环丙烷基、环己烷基）、苯基。
C1-C8烷基可为但不限于例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基，戊基，己基；
C1-C8烷氧基可以为但不限于例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基，戊氧基，己氧基；
C3-C8环烷基可以为但不限于例如环丙烷、环丁烷、环戊烷、环己烷、环庚烷；
其中催化剂银-偶氮四唑金属有机框架材料分子式为C3H8AgN7；红外光谱数据为IRspectrum(cm-1):3338w，3248w，3160w，1598m，1391w，1052w，1008w，970w，745w，570w；且该晶体属于单斜晶系，空间点阵群是P21/c，晶胞参数如下：a/?=4.5401，b/?=11.0469，c/?=14.585，α(°)＝90，β(°)＝93.647(2)，γ(°)＝90。
具体制备步骤为在反应器中加入催化剂、亚甲基氮杂环丙烷I、炔II和溶剂，室温下反应2h-8h；反应结束后，抽掉溶剂，固体纯化后得到吡咯衍生物III。
化合物I和化合物II的摩尔比例为2:1-1:1，例如可以是1.9:1、1.8:1、1.7:1、1.6:1、1.5:1、1.4:1、1.3:1、1.2:1。
溶剂为四氢呋喃、N,N-二甲基甲酰胺、苯、甲苯、乙醚、四氯化碳、1,4-二氧六环、乙腈中的一种或多种。
相对于化合物II的摩尔量，催化剂的用量为3mol%-5%mol。
相对于化合物II的摩尔量，溶剂的用量为5ml/mmol-20ml/mmol，例如10ml/mmol、15ml/mmol。
反应时间可以为3h、4h、5h、6h、7h或者进一步通过TLC等进行跟踪确定；
反应结束后，用旋转蒸发仪浓缩，固体溶于合适的溶剂，如二氯甲烷上样进行硅胶柱层析，得到目标产物化合物III。
亚甲基氮杂环丙烷是一种化学性质丰富，但是相对稳定存在的三元环状化合物，我们发现亚甲基氮杂环丙烷和炔基，利用银偶氮四唑为催化剂，在温和条件下可以和炔基发生[3+2]环加成反应，高收率快速的获得吡咯衍生物。该方法原料廉价易得，操作简便，条件温和，不使用配体，反应较快，收率较高且稳定。所获得的吡咯衍生物容易进一步衍生化。
具体实施方式
实施例1
于20ml烧瓶中依次加入5mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入20mmol亚甲基氮杂环丙烷和10mmol的炔，加入10ml甲苯，最后室温25℃下反应2h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为90%，纯度≥99％。
实施例2
于20ml烧瓶中加入4mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入20mmol亚甲基氮杂环丙烷和10mmol炔，加入10ml甲苯，最后室温25℃下反应5h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为92%，纯度≥99％。
实施例3
于20ml烧瓶中加入3mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入20mmol亚甲基氮杂环丙烷和15mmol的炔，加入15ml甲苯，最后室温25℃下反应6h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为92%，纯度≥99％。
实施例4
于20ml烧瓶中加入5mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入15mmol亚甲基氮杂环丙烷和10mmol的炔，加入10ml甲苯，最后室温25℃下反应2h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为90%，纯度≥99％。
实施例5
于20ml烧瓶中加入5mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入12mmol亚甲基氮杂环丙烷和10mmol的炔，加入10ml甲苯，最后室温25℃下反应2h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为91%，纯度≥99％。
实施例6
于20ml烧瓶中加入5mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入12mmol亚甲基氮杂环丙烷和10mmol的炔，加入10ml甲苯，最后室温25℃下反应2h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为88%，纯度≥99％。
实施例7
于20ml烧瓶中加入5mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入12mmol亚甲基氮杂环丙烷和10mmol的炔，加入10ml甲苯，最后室温25℃下反应2h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为94%，纯度≥99％。
实施例8
于20ml烧瓶中加入5mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入12mmol亚甲基氮杂环丙烷和10mmol的炔，加入10ml甲苯，最后室温25℃下反应2h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为91%，纯度≥99％。
实施例9
于20ml烧瓶中加入5mol％（相对于炔）的银偶氮四唑催化剂C3H8AgN7，然后加入12mmol亚甲基氮杂环丙烷和10mmol的炔，加入10ml甲苯，最后室温25℃下反应2h。反应结束后过滤，旋转蒸发仪浓缩蒸除溶剂，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到目标吡咯类化合物，收率为95%，纯度≥99％。
根据上述说明书的揭示和教导，本发明所属领域的技术人员还可以对上述实施方式进行适当的变更和修改。因此，本发明并不局限于上面揭示和描述的具体实施方式，对本发明的一些修改和变更也应当落入本发明的权利要求的保护范围内。此外，尽管本说明书中使用了一些特定的术语，但这些术语只是为了方便说明，并不对本发明构成任何限制。
Claims (6)
1.一种吡咯衍生物的制备方法，其特征在于通过如下反应进行：
以下式所示的取代亚甲基氮杂环丙烷I和炔II为原料合成吡咯类化合物III，反应式如下：
IIIIII
其中催化剂C3H8AgN7为银-偶氮四唑金属有机框架材料；红外光谱数据为IRspectrum(cm-1):3338w，3248w，3160w，1598m，1391w，1052w，1008w，970w，745w，570w；且该晶体属于单斜晶系，空间点阵群是P21/c，晶胞参数如下：a/?=4.5401，b/?=11.0469，c/?=14.585，α(°)＝90，β(°)＝93.647(2)，γ(°)＝90；
R1为H、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、苯基、取代的苯基、苄基、取代的苄基中的一种，苯基或苄基上的取代基为C1-C8烷基、C1-C8烷氧基、F、Cl、Br、I、NO2中的一种、二种或三种；R2、R3可以相同或不同的为氢、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、苯基。
2.按照权利要求1所述的方法，其特征在于：具体制备步骤为在反应器中加入催化剂、化合物I、化合物II和溶剂，室温下搅拌反应2h-8h，反应结束后，用旋转蒸发仪减压浓缩，固体溶于二氯甲烷上样进行硅胶柱层析，得到化合物III。
3.按照权利要求1或2所述的方法，其特征在于：化合物I和II的摩尔比例为2:1-1:1，优选1.2:1或1.5:1。
4.按照权利要求1或2所述的方法，其特征在于：溶剂为四氢呋喃、N,N-二甲基甲酰胺、苯、甲苯、乙醚、四氯化碳、1,4-二氧六环、乙腈中的一种或多种。
5.按照权利要求1或2所述的方法，其特征在于：相对于化合物II的摩尔量，催化剂的用量为3mol%-5mol%。
6.按照权利要求1或2所述的方法，其特征在于：相对于化合物II的摩尔量，溶剂的用量为5ml/mmol-20ml/mmol。
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