CN110963977A - 一种恶唑杂环化合物的合成方法 - Google Patents
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- -1 oxazole heterocyclic compound Chemical class 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
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- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims abstract description 26
- 238000010438 heat treatment Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 17
- 238000010898 silica gel chromatography Methods 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
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- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
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- GEEMIKSHBWESFK-UHFFFAOYSA-N 5-(1,3-benzodioxol-5-yl)-2-phenyl-1,3-oxazole Chemical compound C1=C2OCOC2=CC=C1C(O1)=CN=C1C1=CC=CC=C1 GEEMIKSHBWESFK-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
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- 229930014626 natural product Natural products 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- SDHIXARCLVIOJM-UHFFFAOYSA-N 5-(1,3-benzodioxol-5-yl)-2-pyridin-3-yl-1,3-oxazole Chemical compound C1=C2OCOC2=CC=C1C(O1)=CN=C1C1=CC=CN=C1 SDHIXARCLVIOJM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 238000005580 one pot reaction Methods 0.000 description 2
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- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
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- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 description 1
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 1
- OTXINXDGSUFPNU-UHFFFAOYSA-N 4-tert-butylbenzaldehyde Chemical compound CC(C)(C)C1=CC=C(C=O)C=C1 OTXINXDGSUFPNU-UHFFFAOYSA-N 0.000 description 1
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- 235000019270 ammonium chloride Nutrition 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
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- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明属于有机合成及药物技术领域。具体涉及一种恶唑杂环化合物的合成方法。本发明以芳基醛和三氮唑衍生物作为原料,在三氯甲烷和醋酸铑催化剂存在的条件下,加热发生反应,得到恶唑杂环化合物。使用本发明提出的方法,在加热搅拌条件下,反应3‑12小时,即可以较高产率得到恶唑杂环类衍生物。本发明方法用简单易得的原料,一步法简便高效地合成了恶唑杂环类衍生物,为合成恶唑杂环衍生物提供了一条简单高效,底物普适性广的合成新方法。
Description
技术领域
本发明属于有机合成及药物技术领域。具体涉及一种恶唑杂环化合物的合成方法。
背景技术
恶唑环是一类重要的杂环化合物,特别是2,5-二取代和2,4,5-三取代恶唑环,广泛存在于天然产物、荧光染料和药物活性分子中[(a)Yu,X.;Chen,K.;Wang,Q.;Zhang,W.;Zhu,J.Chem.Commun 2018,54,1197.(b)Chatterjee,T.;Cho,J.Y.;Cho,E.J.JOrg.Chem.2016,81,6995]。如抗真菌的天然产物texaline[Giddens,A.C.;Boshoff,H.I.M.;Franzblau,S.G.;Barry,C.E.,III;Copp,B.R.Tetrahedron Lett.2005,46,7355]抗胰癌药PC-046[Shaw,A.Y.;Henderson,M.C.;Flynn,G.;Samulitis,B.;Han,H.;Stratton,S.P.;Chow,H.-H.S.;Hurley,L.H.;Dorr,R.T.J.Pharmacol.Exp.Ther.2009,331,636],抗糖尿病药AD-50614[Momose,Y.;Maekawa,T.;Yamano,T.;Kawada,M.;Odaka,H.;Ikeda,H.;Sohda,T.J.Med.Chem.2002,45,1518]。
目前合成恶唑环的方法主要有TBHP/I2介导氧化环化串联的[Wan,C.;Gao,L.;Wang,Q.;Zhang,J.;Wang,Z.Org.Lett.,2010,12,3902],金催化下芳基炔与腈基化合物在氧原子(吡啶/喹啉氮氧化物)氧化下的环化反应[He,W.;Li,C.;Zhang,L.J.Am.Chem.Soc.,2011,133,8482],铜催化下芳基炔与芳基羰基叠氮化物的环化合成恶唑环[(a)Cano,I.;Alvarez,E.;Nicasio,M.C.;Pérez,P.J.J.Am.Chem.Soc.,2011,133,191;(b)Haldón,E.Besora,M.;Cano,I.;Cambeiro,X.C.;Pericás,M.A.;Maseras,F.;Nicasio,M.C.;Pérez,P.J.Chem.–Eur.J.,2014,20,3463],但是这些方法都存在缺陷,如需外部氧化剂,底物普适性不广或原料的合成需要分步反应才能得到等。因此开发一条简单高效的恶唑杂环衍生物的新方法具有重要意义。
发明内容
本发明解决的技术问题是:为了扩大底物普适性,减少反应步骤,提高反应产率,提供一种简单的,以芳基炔和三氮唑衍生物为原料,一步反应,操作简单、高效地合成恶唑杂环衍生物的方法。
本发明提供一种合成恶唑杂环化合物的方法,以芳基炔和三氮唑衍生物为原料,在醋酸铑催化下,加热反应,生成恶唑杂环衍生物。反应条件为:空气条件下,加热到80-120℃,反应时间为3-12小时。
所述的芳基醛和三氮唑衍生物的摩尔比为1:2-1:3之间。
醋酸铑催化剂的用量为芳基醛摩尔量的1-2%。
所述的原料芳基醛可以是苯甲醛,2-甲氧基苯甲醛,2-氰基苯甲醛,4-甲氧基苯甲醛,4-二甲胺基苯甲醛,4-硝基苯甲醛,4-氰基苯甲醛,2,4-二氯苯甲醛,2,6-二甲基苯甲醛,2,4,6-三甲基苯甲醛,1-萘醛,2-氧代-2苯乙醛都能顺利反应得到相应的恶唑杂环衍生物。
三氮唑的合成方法为:
在冰水浴中,将噻吩-2-羧酸亚铜(0.019g,0.1mmol),甲苯(5mL)和芳基末端炔(1.0mmol)加入到50mL圆底烧瓶中,在此温度下缓慢加入磺酸叠氮化物,升至室温搅拌,TLC点板检测反应,结束后将反应液倒入饱和氯化铵水溶液中,用乙酸乙酯萃取,有机层用无水Na2SO4干燥3小时,过滤,旋干滤液得目标产物1-磺酰基-1,2,3-三氮唑。
所述恶唑杂环化合物的结构如下:
本发明的优点:恶唑杂环化合物是一类重要的生物和药物活性分子,在医学和药物学领域具有广泛的用途。本发明首次使用芳基炔和三氮唑衍生物为原料,在醋酸铑催化下,一步法快速简便地构建得到恶唑杂环母核,产率达53~85%。通过一步反应,简便高效地得到了2个天然产物texamine(3o)和baisoxin(3p)。所述的反应后处理简便,只需要简单的柱色谱分离方法,以石油醚与乙酸乙酯的混合溶剂为洗脱剂就可以得到纯净的取代恶唑杂环衍生物。
具体实施方式
本发明反应过程及得到产物的结构式为
实施例1
将苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3a的产率为68%。1H NMR(400MHz,DMSO-d6)δ6.92-6.90(m,2H),6.66(br,3H),6.37-6.31(m,5H),6.23(t,J=6.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.7,151.2,131.1,129.6,129.1,127.8,127.3,126.4,124.6,124.5.
实施例2
将2-甲氧基苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应1小时,硅胶柱层析分离,得到目标化合物3b的产率为53%。1H NMR(400MHz,CDCl3)δ7.98(d,J=7.6Hz,1H),7.66(d,J=8.0Hz,2H),7.47(s,1H),7.39-7.36(m,3H),7.27(t,J=7.3Hz,1H),7.01(t,J=8.2Hz,2H),3.96(s,3H).13C NMR(100MHz,CDCl3)δ158.3,151.1,129.8,129.3,129.1,128.8,125.0,124.5,120.9,112.1,56.4
实施例3
将4-甲氧基苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应3小时,硅胶柱层析分离,得到目标化合物3c的产率为85%。1H NMR(400MHz,CDCl3)δ8.04(d,J=8.8Hz,2H),7.69(d,J=7.5Hz,2H),7.44-7.39(m,3H),7.31(t,J=7.4Hz,1H),6.98(d,J=8.8Hz,2H),3.86(s,3H).13C NMR(100MHz,CDCl3)δ161.4,150.7,128.9,128.3,128.2,127.9,124.1,123.3,120.3,114.3,56.4.
实施例4
将4-二甲氨基苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3d的产率为72%。1H NMR(400MHz,CDCl3)δ7.97(d,J=8.7Hz,2H),7,69(d,J=8.2Hz,2H),7.42(t,J=7.6Hz,2H),7.38(s,1H),7.30(t,J=7.2Hz,1H),6.75(d,J=8.7Hz,2H),3.04(s,6H).13C NMR(100MHz,CDCl3)δ162.3,151.7,150.1,128.9,128.6,127.9,127.7,123.9,123.2,115.3,111.8,40.3.
实施例5
将4-叔丁基基苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3e的产率为58%。
实施例6
将4-氰基苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,得到目标化合物3f的产率为76%。
实施例7
将2,4-二氯苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,得到目标化合物3g的产率为60%。
实施例8
将2,6-二氯苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,得到目标化合物3h的产率为58%。
实施例9
将1-萘醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应10小时,硅胶柱层析分离,得到目标化合物3i的产率为65%。
实施例10
将2,4,6-三甲基苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应10小时,硅胶柱层析分离,得到目标化合物3j的产率为68%。
实施例11
将2-氰基苯甲醛(1mmol)和4-(4-氯苯)-1-对甲苯磺酰基-1H-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3k的产率为83%。
实施例12
将2-氰基苯甲醛(1mmol)和4-(2-氯苯)-1-对甲苯磺酰基-1H-1,2,3-三氮唑(2mmol)加入、醋酸铑(1%mmol)和氯仿(2mL)到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3l的产率为85%。
实施例13
将2-氰基苯甲醛(1mmol)和甲基-4-(1-对甲苯磺酰基-1,2,3-三氮唑)-苯甲酸酯(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3m的产率为75%。
实施例14
将2-氰基苯甲醛(1mmol)和4-噻吩-1-对甲苯磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3n的产率为69%。
实施例15
将苯甲醛(1mmol)和4-(苯并1,3二氧五环)-1-对甲苯磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3o的产率为71%。
实施例16
将苯甲醛(1mmol)和4-(3,4二甲氧基苯)-1-对甲苯磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,硅胶柱层析分离,得到目标化合物3p的产率为73%。
实施例17
将苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到80℃,反应12小时,得到目标化合物3a的产率为43%。
实施例18
将苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(3mmol)、醋酸铑(2%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,得到目标化合物3a的产率为63%。
对比实施例1
通氮气保护条件下,苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铑(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,不能得到目标化合物。
对比实施例2
将苯甲醛(1mmol)、4-苯基-1-磺酰基-1,2,3-三氮唑(2mmol)、醋酸铜(1%mmol)和氯仿(2mL)加入到15mL耐压管中,加热到120℃,反应12小时,基本没有目标化合物生成。
Claims (8)
1.一种恶唑杂环化合物的合成方法,其特征在于,所述合成方法以芳基醛和三氮唑衍生物为原料,以醋酸铑作为催化剂,搅拌反应生成恶唑杂环化合物。
2.根据权利要求1所述的恶唑杂环化合物的合成方法,其特征在于,所述合成方法为:向耐压管中加入芳基醛、三氮唑衍生物以及醋酸铑催化剂,再加入氯仿作为溶剂,将耐压管加热到80-120℃,反应3-12小时,结束后,将反应液旋干,粗产品用硅胶柱层析分离提纯得到恶唑杂环衍生物。
3.根据权利要求1所述的恶唑杂环化合物的合成方法,其特征在于,所述芳基醛和三氮唑衍生物的摩尔比为1:2-1:3之间。
4.根据权利要求1所述的恶唑杂环化合物的合成方法,其特征在于,所述芳基醛为苯甲醛,2-甲氧基苯甲醛,4-甲氧基苯甲醛,4-二甲胺基苯甲醛,4-硝基苯甲醛,4-氰基苯甲醛,2,4-二氯苯甲醛,2,6-二甲基苯甲醛,2,4,6-三甲基苯甲醛,1-萘醛,2-氧代-2苯乙醛。
5.根据权利要求1所述的恶唑杂环化合物的合成方法,其特征在于,所述醋酸铑催化剂的用量为芳基醛摩尔量的1%-2%。
7.根据权利要求6所述的恶唑杂环化合物的合成方法,其特征在于,所述三氮唑的合成方法为:
在冰水浴中,将噻吩-2-羧酸亚铜,甲苯和芳基末端炔加入到50mL圆底烧瓶中,缓慢加入磺酸叠氮化物,升至室温搅拌,TLC点板检测反应,结束后将反应液倒入饱和氯化铵水溶液中,用乙酸乙酯萃取,有机层用无水Na2SO4干燥3小时,过滤,旋干滤液得目标产物1-磺酰基-1,2,3-三氮唑。
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