脲的合成方法总结

脲的合成方法随着药物化学的发展，脲结构越来越多的在药物中出现，以建立独特的药物-靶点相互作用模式和调节类药性质。本文主要总结含脲化合物的合成方法。通常含脲的分子可以分为对称性脲和非对称性脲两大类，对称性脲的合成相对简单，而非对称性脲的合成相对难一些。由于非对称性脲的合成大多适用于对称性脲的合成，所以我们着重介绍非对称脲合成的一些常用方法。1、使用光气或光气等价物合成脲衍生物经典的脲衍生物制备方法涉及到光气或光气衍生物（如三光气）等试剂。这类方法通常是伯胺与三光气在碱性条件下生成异氰酸酯中间体，异氰酸酯再与不同胺类亲核试剂反应生成N、N-二取代或N、N、N-三取代的脲衍生物。对于低沸点的异氰酸酯，第一步反最好将其蒸馏出来，这样下一步反应相对干净。如果异氰酸酯沸点很高，采用“一锅法”也可以，但必须严格控制三光气的用量（三光气的用量为底物胺的1/3）。Scheme1.通过三光气合成脲1.1三光气与胺生成脲实例将三光气0.011g（0.037mmol）溶解在3mL二氯甲烷中，N2保护，冰盐浴条件降温至0℃，滴加含有（S）-1-（吡啶-3-基）乙-1-胺盐酸盐0.030g（0.107mmol）及三乙胺0.086g（0.852mmol）的二氯甲烷溶液(2mL)。反应液在0℃温搅拌反应5min后。加入6-甲基-N-（5-甲基-1H-吡唑-3-基）-2-（哌啶-4-基）嘧啶-4-胺三氟乙酸盐0.05g（0.107mmol）和三乙胺0.086g（0.852mmol），室温搅拌20min。反应完毕后，向反应液中加入50mL的二氯甲烷稀释，用10mL饱和食盐水洗涤。收集有机相，无水硫酸钠干燥，过滤。浓缩滤液所得粗品，经柱层析纯化得到白色粉末状固体目标物32mg。1.2使用氯甲酰胺与胺反应生成脲对于仲胺由于无法形成异氰酸酯，可以通过其与三光气反应得到氯甲酰胺，然后再与另一个胺反应。一般仲胺的氯甲酰胺中间体对水是稳定的，可以分离纯化出来。Scheme2.通过氯甲酰胺合成脲1.3仲胺通过氯甲酰胺反应生成脲实例ADDINEN.CITEADDINEN.CITE.DATA[1,2]A100mLtwo-neckedflaskwithamagneticstirringbarwasevacuatedandbackfilledwithnitrogenthreetimes.Triphosgene(5.0mmol)andCH2Cl2(30mL)wereaddedtotheflask.Themixturewascooledat0°Canddehydratedpyridine(3.0mL)wasslowlyaddedtotheflask.Afterstirringfor15minat0°C,secondaryamine(10mmol)wasslowlyaddedtothemixture.Themixturewaswarmedtoroomtemperatureandstirredfor6hatroomtemperature.Thereactionmixturewascarefullyquenchedby1MHCl(10mL)andwasextractedwithCH2Cl2(10mLx3).Theorganiclayerwaswashedwithwaterandbrine,thendriedoverMgSO4.Afterthefiltration,thesolutionwasconcentratedunderreducedpressure.Thismaterialwasusedinthesubsequentstepwithoutfurtherpurification.4-Isopropylaniline(18.7mM)andtriethylamine(20mM)weredissolvedintetrahydrofuran(50ml)andpiperidine-1-carbonylchloride(18.7mM)wereaddedtothesolution.Thesolutionwasmaintainedat20-25°Cfor10h,andthereactionmixturewasfilteredtoseparatetriethylaminehydrochloride.Filtratewasdistilledundervacuo,residuewasdissolvedinethylacetateandwashedwithwater.Organicportionwascollected,driedoversodiumsulfateandconcentratedundervacuo.Crudeproductwasfurtherpurifiedbycolumnchromatography.Thecrudeproductwasrecrystallisedwithethanolfollowedbyfiltrationanddryingtoobtainproduct.N-(4-isopropylphenyl)piperidine-1-carboxamide:ThesilicageleluentwasDCM/ethylacetate70:30,yield:65%.2、通过更安全的光气替代物合成脲衍生物2.1N，N'-羰基二咪唑（CDI）CDI是一种广泛使用的光气替代物。胺先与CDI反应，形成一个中间体，然后与另一分子胺反应生成脲。该类反应的优点是CDI不产生氯或氯化副产物，但由于CDI不稳定，放置时间久，遇水会分解，造成加料不准确，容易生成较难分离的二聚体。因此反应前确定CDI的质量尤为关键。Scheme3.通过CDI合成脲2.1.1CDI与胺生成脲实例在一50ml的三口瓶中依次加入CDI0.104g(0.643mmol)、DCM5ml。氮气保护下冰盐浴降温至0℃。在一10ml试管加入（S）-1-（吡啶-3-基）乙-1-胺盐酸盐0.146g(0.707mmol)，三乙胺0.390g(3.86mmol)，DCM5ml，混合均匀后缓慢将该溶液加入反应体系中。低温反应约30min后，向反应体系中加入含有6-甲基-N-（5-甲基-1H-吡唑-3-基）-2-（哌啶-4-基）嘧啶-4-胺三氟乙酸盐0.35g(0.643mmol)，三乙胺0.390g(3.86mmol)的DCM溶液5ml。加毕后室温下反应。待反应完毕后，将反应液倒入100ml纯化水中，DCM萃取。合并有机相加入无水硫酸钠干燥。随后过滤、浓缩并经柱层析纯化得到白色固体167mg。2.21,1'-羰基双苯并三唑（CBT）CBT是一种安全，温和的光气替代品，适用于制备不对称脲衍生物。例如，CBT与仲胺（7）反应得到相应的氨基甲酰基苯并三唑衍生物（8）。（8）随后与另一种仲胺（9）反应，温和的生成了四取代的不对称脲衍生物（10）。对于环状和脂肪族胺衍生物，反应只需在室温下进行，并且产率较高，而对于芳香族胺可能需要更高的温度或者回流条件。Scheme4.通过CBT合成脲2.2.1CBT与胺生成脲实例ADDINEN.CITE<EndNote><Cite><Author>Katritzky</Author><Year>1997</Year><RecNum>9</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>9</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595126567">9</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Katritzky,AlanR.</author><author>Pleynet,DavidP.M.</author><author>Yang,Baozhen</author></authors></contributors><titles><title>AGeneralSynthesisofUnsymmetricalTetrasubstitutedUreas</title><secondary-title>TheJournalofOrganicChemistry</secondary-title></titles><periodical><full-title>TheJournalofOrganicChemistry</full-title></periodical><pages>4155-4158</pages><volume>62</volume><number>12</number><section>4155</section><dates><year>1997</year></dates><isbn>0022-3263 1520-6904</isbn><urls></urls><electronic-resource-num>10.1021/jo962245t</electronic-resource-num></record></Cite></EndNote>[3]CBT(1.06g,4mmol)wasdissolvedindryTHF(40mL)underadryatmosphereofnitrogen,andaniline(0.37mL,4mmol)wasadded.Thereactionmixturewasstirredatroomtemperaturefor27h,octylamine(0.65mL,4mmol)wasthenadded,andtheresultingreactionmixturewasstirredatroomtemperaturefor27hbeforebeingextractedwithdiethylether(3×40mL).Theetherealextractsweresuccessivelywashedwith2NHCl(2×20mL),2NNaOH(2×20mL),andsaturatedNaCl(30mL),driedwithMgSO4,andfiltered.Removalofthesolventunderreducedpressuregave4aasawhitepowder(840mg,85%).2.3荒酸二甲酯（DMDTC）DMDTC可以作为光气的有效替代品，该反应可以在水中进行，方便高效的生成单取代，二取代和三取代的脲衍生物。Scheme6.通过DMDTC合成脲2.23.1DMDTC与胺生成脲实例ADDINEN.CITE<EndNote><Cite><Author>Fochi</Author><Year>2007</Year><RecNum>10</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>10</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595127983">10</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Fochi,Rita</author><author>Artuso,Emma</author><author>Degani,Iacopo</author><author>Magistris,Claudio</author></authors></contributors><titles><title>PreparationofMono-,Di-,andTrisubstitutedUreasbyCarbonylationofAliphaticAmineswithS,S-DimethylDithiocarbonate</title><secondary-title>Synthesis</secondary-title></titles><periodical><full-title>Synthesis</full-title></periodical><pages>3497-3506</pages><volume>2007</volume><number>22</number><section>3497</section><dates><year>2007</year></dates><isbn>0039-7881 1437-210X</isbn><urls></urls><electronic-resource-num>10.1055/s-2007-990813</electronic-resource-num></record></Cite></EndNote>[4]Step1.hexylamine(2.02g,20mmol)wasaddeddropwiseoveraperiodof10mintoasuspensionofS,S-dimethyldithiocarbonate(1.22g,10mmol)inH2O(5mL),undervigorousstirring.Thereactionwasmildlyexothermic,andduringtheadditionthetemperatureofthemixturewasmaintainedat20–25°Cwithanice-waterbath.TheprogressofthereactionwasmonitoredbyGCandGC-MSanalyses.Duringthereactionanemulsionwasformed.Stirringatr.t.(20–25°C)wasmaintaineduntildisappearanceofS,S-dimethyldithiocarbonate(2h).ThemixturewasthentreatedwithcoldCH2Cl2/aq5%HCl(2:1,100mL).TheaqueoussolnwasseparatedandextractedwithCH2Cl2(30mL).ThecombinedorganicextractswerewashedwithH2O(30mL),dried(Na2SO4),andevaporatedunderreducedpressuretogivecrudeProduct;yield:1.75g(ca.100%);99.9%purity(GCanalysis);mp56.5–57.5°C(pentane).Step2.AsuspensionofcrudeS-methylN-hexylthiocarbamate(1.75g,10mmol),obtainedinthefirststepasdescribedabove,inH2O(5mL)washeatedto60°Cinanoil-bath,undervigorousstirring.Anaq40%solnofbenzylamine(1.07g,10mmol)inH2O(2.7mL)wasaddeddropwiseandthenN2wasflushedthroughthemixture.AtonceS-methylN-hexylthiocarbamatebecameanoilthatemulsifiedinthereactionmedium.ProgressofthereactionwasmonitoredbyGCandGC-MSanalyses.After1h,acolorlesssolidseparatedoutfromthemixture.Tomakethestirringeasier,anotherportionofH2O(5mL)wasadded.Thereactionwascompleteafter2hwhenS-methylN-hexylthiocarbamatedisappearedandTargetcompoundwastheonlyproduct.ThemixturewasextractedwithCH2Cl2(2×80mL);theorganiclayerswerecollectedandwashedwithaq5%HCl(50mL)andthenwithH2O(50mL),dried(Na2SO4),andevaporatedunderreducedpressure.Thecruderesiduewasthetitlecompound;overallyieldofthetwosteps,basedonthestartingDMDTC(1):2.32g(99%);99.5%purity(GCanalysis).2.4氨基甲酸酯衍生物氨基甲酸酯衍生物的氨解是合成脲的主要方法。胺先与氯甲酸酯反应得到相应的氧基碳酰胺，然后再与另一分子胺反应生成脲。氨基甲酸酯与胺反应的效率不同,取决于离去基团性质。常见的氨基甲酸酯有：氯甲酸对硝基苯酯、氯甲酸苯酯、氯甲酸2-异丙烯酯、氯甲酸2-三氟乙基酯或氯甲酸2-三氯乙基酯等。2.4.1氯甲酸对硝基苯酯氯甲酸对硝基苯酯主要用于伯胺的反应，其反应机理是中间体对硝基苯氧基碳酰胺在碱性条件下，脱去对硝基苯酚得到相应的异氰酸酯，然后再与另一分子胺反应得到脲。使用本方法一个主要的注意点是第一步对硝基苯氧基碳酰胺的制备，一定要选择好相应的碱。氯甲酸对硝基苯酯也可以与仲胺反应生成脲，一般在DMAP-CH3CN，加热体系进行胺交换。Scheme7.通过氯甲酸对硝基苯酯合成脲氯甲酸对硝基苯酯与胺生成脲实例ADDINEN.CITEADDINEN.CITE.DATA[5]Toasolutionof1-(2,6-dichloro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indazol-6-ylamine(374mg,1.0mmol)anddiisopropylethylamine(640mg,5.0mmol)in100mLofDCMwasaddedasolutionof4-nitrophenylchloroformate(220mg,1.1mmol)in10mLofDCMat–20℃underN2atmosphere.Theresultingmixturewasstirredfor30minandthenadded(S)-3-amino-4-(3,4-difluorophenyl)-1-phenylbutan-2-one(275mg,1.0mmol).Afterstirredat-20℃for30min,themixturewaswarmedtoroomtemperatureandthenstirredforanother6hbeforepouredintowater.ThereactionmixturewasextractedwithDCM(3x100mL).Thecombinedorganicphaseswerewashedwithbrine(3x50mL),driedoveranhydrousNa2SO4andfiltered.Thefiltratewasconcentratedtothecrudeproduct,whichwaspurifiedbycolumnchromatographytoafford175mgof(S)-1-(1-(2,6-dichlorobenzyl)-3-(pyrrolidin-1-ylmethyl)-1H-indazol-6-yl)-3-(1-(3,4-difluorophenyl)-3-oxo-4-phenylbutan-2-yl)urea(26%)2.4.2氯甲酸苯酯氯甲酸苯酯也是一般用于伯胺脲的合成，其首先与胺的反应生成苯氧基碳酰胺，在碱性条件下，高温条件下与另一分子胺反应生成脲。其特点是相应的中间体苯氧基碳酰胺，较为稳定，易于制备及纯化。若将氯甲酸苯酯用于仲胺的脲的合成，在第二步反应一般用第二个胺的负离子反应。氯甲酸苯酯与胺生成脲实例ADDINEN.CITEADDINEN.CITE.DATA[6]Toasolutionofpyridin-3-ylamine(940mg,10mmol)andtriethylamine(2.0.g,20mmol)in50mlofDMFwasadded2.94gof(2-tert-Butyl-5-cyano-phenyl)-carbamicacidphenylesteratroomtemperatureunderN2atmosphere.Theresultingmixturewasheatedto100oCfor5hbeforepouredinto200mLofwater.ThemixturewasextractedwithDCM(3x100mL).Thecombinedorganicphaseswerewashedwith0.5NofHClaqueoussolution(3x100mL)andbrine(3x100mL).AfterdriedoveranhydrousNa2SO4andfiltered,thefiltratewasconcentratedtothecrudeproduct,whichwaspurifiedbycolumntoafford1.9gof1-(2-(tert-butyl)-5-cyanophenyl)-3-(pyridin-3-yl)urea(64%).2.5咪唑鎓盐咪唑鎓盐常被用作稳定的氨基甲酰基转移试剂，用来合成不对称四取代的脲。最常用氨基甲酰咪唑鎓盐是由仲胺与CDI反应，并与碘甲烷连续烷基化形成盐。在三乙胺存在下，氨基甲酰咪唑鎓盐中添加伯胺或仲胺可以分别有效地生成双取代或四取代脲。所产生的副产物（N-甲基咪唑和三乙胺盐酸盐）可以用稀酸洗涤除去。氨基甲酰咪唑鎓盐与脂肪胺反应较好，但对于亲核性较差的芳香胺，需要先将芳香胺与KHMDS或者n-BuLi处理生成相应的负离子，再与咪唑鎓盐反应，才能得到相应的脲。Scheme8.通过咪唑鎓盐合成脲2.5.1咪唑鎓盐与胺生成脲实例ADDINEN.CITE<EndNote><Cite><Author>Batey</Author><Year>1998</Year><RecNum>13</RecNum><DisplayText><styleface="superscript">[7]</style></DisplayText><record><rec-number>13</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595133799">13</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Batey,RobertA.</author><author>Santhakumar,V.</author><author>Yoshina-Ishii,Chiaki</author><author>Taylor,ScottD.</author></authors></contributors><titles><title>Anefficientnewprotocolfortheformationofunsymmetricaltri-andtetrasubstitutedureas</title><secondary-title>TetrahedronLetters</secondary-title></titles><periodical><full-title>TetrahedronLetters</full-title></periodical><pages>6267-6270</pages><volume>39</volume><number>35</number><section>6267</section><dates><year>1998</year></dates><isbn>00404039</isbn><urls></urls><electronic-resource-num>10.1016/s0040-4039(98)01330-6</electronic-resource-num></record></Cite></EndNote>[7]Step1:ToasuspensionofCDI(9.73g,60mmol)inTHF(100ml)wasaddedN-methylaniline(5.96ml,55mmol).Themixturewasrefluxedfor24hbeforecoolingtoroomtemperature.RemovalofsolventundervacuumgaveaviscousorangeoilwhichwasdissolvedinCH2Cl2(100ml),andwashedtwicewith100mLportionsofwater.TheorganiclayerwasdriedoveranhydrousMgSO4,filteredandconcentratedinvacuotoyieldalightyellowsolid(9.62g,87%).Step2:ToasolutionofN-methyl-N-phenyl-1H-imidazole-1-carboxamide(1.60g,8.0mmol)inacetonitrile(15ml)wasaddedmethyliodide(2.0ml,32.0mmol).Themixturewasstirredatroomtemperaturefor24h.SolventwasremovedinvacuotoyieldTargetcompoundasalightyellowsolid(2.71g,99%),whichwasusedinthenextstepwithoutfurtherpurification.Step3:Toasolutionof3-methyl-1-(methyl(phenyl)carbamoyl)-1H-imidazol-3-iumiodide(343mg,1.0mmol)inCH2C12(6ml)wasadded1,2,3,4-tetrahydroisoquinoline(0.133g,1.0mmol)andtriethylamine(0.14ml,1.0mmol).Themixturewasstirredatroomtemperaturefor24h,thenwashedtwicewith1.0MHC1(5ml),theorganiclayerdriedoveranhydrousMgSO4,filteredandconcentratedundervacuumtoyieldureaasastraw-colouredoil(256mg,96%).Theproductureascanbepurifiedbycolumnchromatography,butareusuallygreaterthan98%purity(NMR).2.6双（2,2,2-三氟乙基）碳酸酯双（2,2,2-三氟乙基）碳酸酯是是一种特殊的成脲试剂，它可以通过三光气和三氟乙醇反应得到。双（2,2,2-三氟乙基）碳酸酯与脂肪胺生成三氟乙基碳酸酯的反应具有高度的区域选择性，并不会进一步的生成对称的脲，且羟基、吡唑等基团在其介导的成脲反应中是耐受的。Scheme9.通过双（2,2,2-三氟乙基）碳酸酯合成脲2.6.1双（2,2,2-三氟乙基）碳酸酯与胺成脲实例ADDINEN.CITE<EndNote><Cite><Author>Bogolubsky</Author><Year>2014</Year><RecNum>14</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>14</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595135167">14</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Bogolubsky,A.V.</author><author>Moroz,Y.S.</author><author>Mykhailiuk,P.K.</author><author>Granat,D.S.</author><author>Pipko,S.E.</author><author>Konovets,A.I.</author><author>Doroschuk,R.</author><author>Tolmachev,A.</author></authors></contributors><auth-address>EnamineLtd.,23MatrosovaStreet,Kyiv,01103,Ukraine.</auth-address><titles><title>Bis(2,2,2-trifluoroethyl)carbonateasacondensingagentinone-potparallelsynthesisofunsymmetricalaliphaticureas</title><secondary-title>ACSCombSci</secondary-title></titles><periodical><full-title>ACSCombSci</full-title></periodical><pages>303-8</pages><volume>16</volume><number>6</number><edition>2014/04/04</edition><keywords><keyword>Esters/*chemistry</keyword><keyword>MolecularStructure</keyword><keyword>Urea/*analogs&derivatives/*chemicalsynthesis/chemistry</keyword></keywords><dates><year>2014</year><pub-dates><date>Jun9</date></pub-dates></dates><isbn>2156-8944(Electronic) 2156-8944(Linking)</isbn><accession-num>24693957</accession-num><urls><related-urls><url>/pubmed/24693957</url></related-urls></urls><electronic-resource-num>10.1021/co500025f</electronic-resource-num></record></Cite></EndNote>[8]Step1:Anacetonitrilesolution(2mL)ofalkyl2-methoxyethan-1-amine(0.7mmol),N,N-diisopropylethylamine(0.7mmol;1.5mmolwasusedincaseofhydrochlorides),andbis(2,2,2-trifluoroethyl)carbonate(1.05mmol)washeatedat75°Cinasealedtubeonawaterbathfor2hours.Then,0.3mLofxyleneswasaddedtoachieveacompleteremovalofbis(2,2,2-trifluoroethyl)carbonateandthesolutionwasevaporatedunderreducedpressure.Step2:Aftertheevaporation,0.84mmolof2-(3,4-dimethoxyphenyl)pyrrolidine,0.2mmolofDBU(0.4mmolwasusedincaseofhydrochlorides),and2mLofacetonitrilewereaddedtothecrudetrifluoroethylcarbamate.Theobtainedmixturewasheatedfor4hoursinthewaysimilartothefirststep.Afterthereactiontubecooleddowntoroomtemperature,chloroform(3mL)wasaddedinthetube.Theorganicphasewaswashedwithwater(3x7mL)andevaporatedunderreducedpressuretogivethecrudeurea,whichwaspurifiedbycolumntoafford2-(3,4-dimethoxyphenyl)-N-(2-methoxyethyl)pyrrolidine-1-carboxamide(46%).3、通过重排反应合成脲3.1霍夫曼重排（Hofmannrearrangement）霍夫曼重排是一级酰胺在氧化剂和碱的条件下重排变为伯胺并减少一个碳原子的反应，其反应机理中形成异氰酸酯中间态，其可以与胺反应生成脲，YoshihiroMatsumura等人在霍夫曼重排反应中捕捉到脲的副产物ADDINEN.CITE<EndNote><Cite><Author>Matsumura</Author><Year>1997</Year><RecNum>16</RecNum><DisplayText><styleface="superscript">[9]</style></DisplayText><record><rec-number>16</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595137775">16</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Matsumura,Yoshihiro</author><author>Maki,Toshihide</author><author>Satoh,Yuki</author></authors></contributors><titles><title>ElectrochemicallyinducedHofmannrearrangement</title><secondary-title>TetrahedronLetters</secondary-title></titles><periodical><full-title>TetrahedronLetters</full-title></periodical><pages>8879-8882</pages><volume>38</volume><number>51</number><section>8879</section><dates><year>1997</year></dates><isbn>00404039</isbn><urls></urls><electronic-resource-num>10.1016/s0040-4039(97)10324-0</electronic-resource-num></record></Cite></EndNote>[9]。该反应目前也发展出多种可供选择的氧化剂和碱，如：例如二乙酰氧基碘苯PhI(OAc)2、MeOBr、NBS-CH3ONa、NBS-KOH、乙酸铅（IV）和苄基三甲基铵三溴化铵ADDINEN.CITE<EndNote><Cite><Author>Ghosh</Author><Year>2020</Year><RecNum>5</RecNum><DisplayText><styleface="superscript">[10]</style></DisplayText><record><rec-number>5</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1594860916">5</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ghosh,A.K.</author><author>Brindisi,M.</author></authors></contributors><auth-address>DepartmentofChemistryandDepartmentofMedicinalChemistry,PurdueUniversity,WestLafayette,Indiana47907,UnitedStates. DepartmentofExcellenceofPharmacy,UniversityofNaplesFedericoII,80131Naples,Italy.</auth-address><titles><title>UreaDerivativesinModernDrugDiscoveryandMedicinalChemistry</title><secondary-title>JMedChem</secondary-title></titles><periodical><full-title>JMedChem</full-title><abbr-1>Journalofmedicinalchemistry</abbr-1></periodical><pages>2751-2788</pages><volume>63</volume><number>6</number><edition>2019/12/04</edition><dates><year>2020</year><pub-dates><date>Mar26</date></pub-dates></dates><isbn>1520-4804(Electronic) 0022-2623(Linking)</isbn><accession-num>31789518</accession-num><urls><related-urls><url>/pubmed/31789518</url></related-urls></urls><custom2>PMC7266097</custom2><electronic-resource-num>10.1021/acs.jmedchem.9b01541</electronic-resource-num></record></Cite></EndNote>[10]。Scheme10.通过霍夫曼重排合成脲3.1.1霍夫曼重排生成脲实例ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2012</Year><RecNum>18</RecNum><DisplayText><styleface="superscript">[11]</style></DisplayText><record><rec-number>18</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595139129">18</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,Peng</author><author>Wang,Zhiming</author><author>Hu,Xianming</author></authors></contributors><titles><title>HighlyEfficientSynthesisofUreasandCarbamatesfromAmidesbyIodosylbenzene-InducedHofmannRearrangement</title><secondary-title>EuropeanJournalofOrganicChemistry</secondary-title></titles><periodical><full-title>EuropeanJournalofOrganicChemistry</full-title></periodical><pages>1994-2000</pages><volume>2012</volume><number>10</number><section>1994</section><dates><year>2012</year></dates><isbn>1434193X</isbn><urls></urls><electronic-resource-num>10.1002/ejoc.201101784</electronic-resource-num></record></Cite></EndNote>[11]Amixtureofbenzamide(0.2mmol),iodosylbenzene(0.3mmol),andpropan-2-amine(0.3mmol)inCH2Cl2(1mL)wasstirredatroomtemperaturefor2h.Afterthereactionwascomplete,themixturewasconcentratedinvacuo.Flashchromatographyonsilicagel(ethylacetate/petroleumether,1:4)furnishedtheYellowsolid(96%).3.2Curtius重排Curtius重排中酸或酰卤与叠氮化物反应生成酰基叠氮衍生物，并重排形成异氰酸酯，异氰酸酯可以与胺反应生成脲。以下是一个羧酸衍生物与叠氮磷酸二苯酯（DPPA）发生Curtius重排生成异氰酸酯，并最终生成脲衍生物的例子。Scheme11.通过Curtius重排合成脲3.2.1Curtius重排生成脲实例ADDINEN.CITE<EndNote><Cite><Author>Liang</Author><Year>2016</Year><RecNum>19</RecNum><DisplayText><styleface="superscript">[12]</style></DisplayText><record><rec-number>19</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595140472">19</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liang,Jianglin</author><author>Cochran,JohnE.</author><author>Dorsch,WarrenA.</author><author>Davies,Ioana</author><author>Clark,MichaelP.</author></authors></contributors><titles><title>DevelopmentofaScalableSynthesisofanAzaindolyl-PyrimidineInhibitorofInfluenzaVirusReplication</title><secondary-title>OrganicProcessResearch&Development</secondary-title></titles><periodical><full-title>OrganicProcessResearch&Development</full-title></periodical><pages>965-969</pages><volume>20</volume><number>5</number><section>965</section><dates><year>2016</year></dates><isbn>1083-6160 1520-586X</isbn><urls></urls><electronic-resource-num>10.1021/acs.oprd.6b00063</electronic-resource-num></record></Cite></EndNote>[12]Tothesuspensionof(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexanecarboxylicacid(65g,174mmol)indryTHF(1.3L)wasaddedEt3N(34mL,244mmol).Thereactionwaspurgedwithnitrogenfor20min.DPPA(45mL,209mmol)wasaddedandthemixturewasheatedto50℃for2h.HPLCshowedthatallstartingmaterialwasconsumed.Morpholine(45.5mL,522mmol)wasaddedandthereactionwaskeptatrefluxovernight.Thereactionmixturewascooledto20℃,andEtOAc(1L)wasadded.ThemixturewaswashedwithsaturatedNaHCO3(2x1L),andevaporatedundervacuum.TheresidualoilwaspurifiedonanISCOCompanionXLusing1.5kgsilicagelcolumnandagradient0-20%ofMeOHinDCM.Thefractionswerecollectedandevaporated,affording68gofcrudewhitesolid.MTBE(800mL)wasaddedandheatedtorefluxfor0.5h,thencooleddown.Thesuspensionwasfiltered,andcakewasdriedundervacuuminovenat50℃.1HNMRshoweditwas1:1MTBEsolvate.Tothesolidwasaddedacetone/water(4:1,120mL)andthemixturewasstirredfor0.5h.Themixturewasfiltered,andcakewaswashedwithDCM(2x50mL),driedinovenundervacuumat50℃toyieldtargetcompoundaswhitesolidwith99%chemicalpurity(54g,67%).3.3Lossen重排Lossen重排中异羟肟酸与脱水剂反应，然后在碱或加热条件下得到异氰酸酯。异氰酸酯可以与胺反应生成相应的脲。芳常见的脱水剂有：对甲苯磺酰氯、EDCl/DMAP、CDI、T3P、4-NBsOXY等。Scheme12.通过Lossen重排合成脲3.3.1Lossen重排的成脲实例ADDINEN.CITE<EndNote><Cite><Author>Narendra</Author><Year>2009</Year><RecNum>20</RecNum><DisplayText><styleface="superscript">[13]</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595141033">20</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Narendra,N.</author><author>Chennakrishnareddy,G.</author><author>Sureshbabu,V.V.</author></authors></contributors><auth-address>PeptideResearchLaboratory,DepartmentofStudiesinChemistry,CentralCollegeCampus,BangaloreUniversity,DrB.R.AmbedkarVeedhi,Bangalore,560001,India.</auth-address><titles><title>ApplicationofcarbodiimidemediatedLossenrearrangementforthesynthesisofalpha-ureidopeptidesandpeptidylureasemployingN-urethanealpha-amino/peptidylhydroxamicacids</title><secondary-title>OrgBiomolChem</secondary-title></titles><periodical><full-title>OrgBiomolChem</full-title></periodical><pages>3520-6</pages><volume>7</volume><number>17</number><edition>2009/08/14</edition><keywords><keyword>AminoAcids/chemistry</keyword><keyword>Carbodiimides/*chemistry</keyword><keyword>HydroxamicAcids/chemistry</keyword><keyword>OrganicChemistryPhenomena</keyword><keyword>Peptides/*chemicalsynthesis/chemistry</keyword><keyword>Urea/*chemistry</keyword></keywords><dates><year>2009</year><pub-dates><date>Sep7</date></pub-dates></dates><isbn>1477-0539(Electronic) 1477-0520(Linking)</isbn><accession-num>19675909</accession-num><urls><related-urls><url>/pubmed/19675909</url></related-urls></urls><electronic-resource-num>10.1039/b905790k</electronic-resource-num></record></Cite></EndNote>[13]Toasolutionof201.3mg(1.05mmol)of1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride(EDC)and12.2mg(0.1mmol)of4-dimethylaminopyridine(DMAP)indryCH2Cl2ortetrahydrofuranwasaddedthefinelygroundpowderoftert-butyl(S)-(1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)carbamate(1.0mmol)insmallportionsatrt.Thereactionmixturewasstirredfor20minandthenmethylL-alaninate(1.0mmol)wasadded.Theresultingmixturewasstirredatrtfor4–5huntilcompletion(asmonitoredbyTLC).ThesolventwasremovedinvacuoandtheresiduewasdissolvedinEtOAc.Theorganiclayerwaswashedwith10%citricacidsolution,brineanddriedoveranhydrousNa2SO4.Thesolventwasremovedunderreducedpressuretoaffordcrudeurea,whichwaspurifiedbycolumntoaffordmethyl(((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)-L-alaninate(77%).3.4Tienmann重排Tienmann重排是酰胺肟（可从腈和羟胺获得）在苯磺酰氯（TsCl）或乙酸酐处理后，再水解得到单取代脲。该反应有点类似于Beckmann或者Lossen重排。Scheme13.通过Tienmann重排合成脲3.4.1Tienmann重排成脲实例ADDINEN.CITE<EndNote><Cite><Author>Chien</Author><Year>2015</Year><RecNum>21</RecNum><DisplayText><styleface="superscript">[14]</style></DisplayText><record><rec-number>21</rec-number><foreign-keys><keyapp="EN"db-id="zp0w9r025r52t7e05eexv0w20tvsvpxv2rtr"timestamp="1595142467">21</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Chien,Tun-Cheng</author><author>Wang,Chien-Hong</author><author>Hsieh,Tsung-Han</author><author>Lin,Chia-Chi</author><author>Yeh,Wen-Hsiung</author><author>Lin,Chih-An</author></authors></contributors><titles><title>One-PotSynthesisofN-MonosubstitutedUreasfromNitrilesviaTiemannRearrangement</title><secondary-title>Synlett</secondary-title></titles><periodical><full-title>Synlett</full-title></periodical><pages>1823-1826</pages><volume>26</volume><number>13</number><section>1823</section><dates><year>2015</year></dates><isbn>0936-5214 1437-2096</isbn><urls></urls><electronic-resource-num>10.1055/slt;/electronic-resource-num></record></Cite></EndNote>[14]TothesolutionofbenzonitrileinEtOH(0.1M)wasadded50wt%aqueoushydroxylaminesolution(1.2equiv).Themixturewasstirredatrefluxtemperaturefor1.5hundernitrogen.Aftercoolingtoroomtemperature,thereactionmixturewasconcentratedunderreducedpressure.Thecrude(Z)-N'-hydroxybenzimidamidewasdissolvedinCH2Cl2(0.1M),andthenArSO2Cl(TsCloro-NsCl,1.05equiv)andDIPEA(1.05equiv)wereaddedat0℃.Themixturewasstirredundernitrogenatmosphereatroomtemperaturefor3horatrefluxtemperaturefor1h.Themixturewasconcentratedunderreducedpressure.The