脲的合成方法總結(jié)

脲的合成方法隨著藥物化學(xué)的發(fā)展，脲結(jié)構(gòu)越來越多的在藥物中出現(xiàn)，以建立獨特的藥物-靶點相互作用模式和調(diào)節(jié)類藥性質(zhì)。本文主要總結(jié)含脲化合物的合成方法。通常含脲的分子可以分為對稱性脲和非對稱性脲兩大類，對稱性脲的合成相對簡單，而非對稱性脲的合成相對難一些。由于非對稱性脲的合成大多適用于對稱性脲的合成，所以我們著重介紹非對稱脲合成的一些常用方法。1、使用光氣或光氣等價物合成脲衍生物經(jīng)典的脲衍生物制備方法涉及到光氣或光氣衍生物（如三光氣）等試劑。這類方法通常是伯胺與三光氣在堿性條件下生成異氰酸酯中間體，異氰酸酯再與不同胺類親核試劑反應(yīng)生成N、N-二取代或N、N、N-三取代的脲衍生物。對于低沸點的異氰酸酯，第一步反最好將其蒸餾出來，這樣下一步反應(yīng)相對干凈。如果異氰酸酯沸點很高，采用“一鍋法”也可以，但必須嚴(yán)格控制三光氣的用量（三光氣的用量為底物胺的1/3）。Scheme1.通過三光氣合成脲1.1三光氣與胺生成脲實例將三光氣0.011g（0.037mmol）溶解在3mL二氯甲烷中，N2保護，冰鹽浴條件降溫至0℃，滴加含有（S）-1-（吡啶-3-基）乙-1-胺鹽酸鹽0.030g（0.107mmol）及三乙胺0.086g（0.852mmol）的二氯甲烷溶液(2mL)。反應(yīng)液在0℃溫攪拌反應(yīng)5min后。加入6-甲基-N-（5-甲基-1H-吡唑-3-基）-2-（哌啶-4-基）嘧啶-4-胺三氟乙酸鹽0.05g（0.107mmol）和三乙胺0.086g（0.852mmol），室溫攪拌20min。反應(yīng)完畢后，向反應(yīng)液中加入50mL的二氯甲烷稀釋，用10mL飽和食鹽水洗滌。收集有機相，無水硫酸鈉干燥，過濾。濃縮濾液所得粗品，經(jīng)柱層析純化得到白色粉末狀固體目標(biāo)物32mg。1.2使用氯甲酰胺與胺反應(yīng)生成脲對于仲胺由于無法形成異氰酸酯，可以通過其與三光氣反應(yīng)得到氯甲酰胺，然后再與另一個胺反應(yīng)。一般仲胺的氯甲酰胺中間體對水是穩(wěn)定的，可以分離純化出來。Scheme2.通過氯甲酰胺合成脲1.3仲胺通過氯甲酰胺反應(yīng)生成脲實例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、通過更安全的光氣替代物合成脲衍生物2.1N，N'-羰基二咪唑（CDI）CDI是一種廣泛使用的光氣替代物。胺先與CDI反應(yīng)，形成一個中間體，然后與另一分子胺反應(yīng)生成脲。該類反應(yīng)的優(yōu)點是CDI不產(chǎn)生氯或氯化副產(chǎn)物，但由于CDI不穩(wěn)定，放置時間久，遇水會分解，造成加料不準(zhǔn)確，容易生成較難分離的二聚體。因此反應(yīng)前確定CDI的質(zhì)量尤為關(guān)鍵。Scheme3.通過CDI合成脲2.1.1CDI與胺生成脲實例在一50ml的三口瓶中依次加入CDI0.104g(0.643mmol)、DCM5ml。氮氣保護下冰鹽浴降溫至0℃。在一10ml試管加入（S）-1-（吡啶-3-基）乙-1-胺鹽酸鹽0.146g(0.707mmol)，三乙胺0.390g(3.86mmol)，DCM5ml，混合均勻后緩慢將該溶液加入反應(yīng)體系中。低溫反應(yīng)約30min后，向反應(yīng)體系中加入含有6-甲基-N-（5-甲基-1H-吡唑-3-基）-2-（哌啶-4-基）嘧啶-4-胺三氟乙酸鹽0.35g(0.643mmol)，三乙胺0.390g(3.86mmol)的DCM溶液5ml。加畢后室溫下反應(yīng)。待反應(yīng)完畢后，將反應(yīng)液倒入100ml純化水中，DCM萃取。合并有機相加入無水硫酸鈉干燥。隨后過濾、濃縮并經(jīng)柱層析純化得到白色固體167mg。2.21,1'-羰基雙苯并三唑（CBT）CBT是一種安全，溫和的光氣替代品，適用于制備不對稱脲衍生物。例如，CBT與仲胺（7）反應(yīng)得到相應(yīng)的氨基甲?；讲⑷蜓苌铮?）。（8）隨后與另一種仲胺（9）反應(yīng)，溫和的生成了四取代的不對稱脲衍生物（10）。對于環(huán)狀和脂肪族胺衍生物，反應(yīng)只需在室溫下進行，并且產(chǎn)率較高，而對于芳香族胺可能需要更高的溫度或者回流條件。Scheme4.通過CBT合成脲2.2.1CBT與胺生成脲實例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可以作為光氣的有效替代品，該反應(yīng)可以在水中進行，方便高效的生成單取代，二取代和三取代的脲衍生物。Scheme6.通過DMDTC合成脲2.23.1DMDTC與胺生成脲實例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。胺先與氯甲酸酯反應(yīng)得到相應(yīng)的氧基碳酰胺，然后再與另一分子胺反應(yīng)生成脲。氨基甲酸酯與胺反應(yīng)的效率不同,取決于離去基團性質(zhì)。常見的氨基甲酸酯有：氯甲酸對硝基苯酯、氯甲酸苯酯、氯甲酸2-異丙烯酯、氯甲酸2-三氟乙基酯或氯甲酸2-三氯乙基酯等。2.4.1氯甲酸對硝基苯酯氯甲酸對硝基苯酯主要用于伯胺的反應(yīng)，其反應(yīng)機理是中間體對硝基苯氧基碳酰胺在堿性條件下，脫去對硝基苯酚得到相應(yīng)的異氰酸酯，然后再與另一分子胺反應(yīng)得到脲。使用本方法一個主要的注意點是第一步對硝基苯氧基碳酰胺的制備，一定要選擇好相應(yīng)的堿。氯甲酸對硝基苯酯也可以與仲胺反應(yīng)生成脲，一般在DMAP-CH3CN，加熱體系進行胺交換。Scheme7.通過氯甲酸對硝基苯酯合成脲氯甲酸對硝基苯酯與胺生成脲實例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，其首先與胺的反應(yīng)生成苯氧基碳酰胺，在堿性條件下，高溫條件下與另一分子胺反應(yīng)生成脲。其特點是相應(yīng)的中間體苯氧基碳酰胺，較為穩(wěn)定，易于制備及純化。若將氯甲酸苯酯用于仲胺的脲的合成，在第二步反應(yīng)一般用第二個胺的負(fù)離子反應(yīng)。氯甲酸苯酯與胺生成脲實例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咪唑鎓鹽咪唑鎓鹽常被用作穩(wěn)定的氨基甲?；D(zhuǎn)移試劑，用來合成不對稱四取代的脲。最常用氨基甲酰咪唑鎓鹽是由仲胺與CDI反應(yīng)，并與碘甲烷連續(xù)烷基化形成鹽。在三乙胺存在下，氨基甲酰咪唑鎓鹽中添加伯胺或仲胺可以分別有效地生成雙取代或四取代脲。所產(chǎn)生的副產(chǎn)物（N-甲基咪唑和三乙胺鹽酸鹽）可以用稀酸洗滌除去。氨基甲酰咪唑鎓鹽與脂肪胺反應(yīng)較好，但對于親核性較差的芳香胺，需要先將芳香胺與KHMDS或者n-BuLi處理生成相應(yīng)的負(fù)離子，再與咪唑鎓鹽反應(yīng)，才能得到相應(yīng)的脲。Scheme8.通過咪唑鎓鹽合成脲2.5.1咪唑鎓鹽與胺生成脲實例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雙（2,2,2-三氟乙基）碳酸酯雙（2,2,2-三氟乙基）碳酸酯是是一種特殊的成脲試劑，它可以通過三光氣和三氟乙醇反應(yīng)得到。雙（2,2,2-三氟乙基）碳酸酯與脂肪胺生成三氟乙基碳酸酯的反應(yīng)具有高度的區(qū)域選擇性，并不會進一步的生成對稱的脲，且羥基、吡唑等基團在其介導(dǎo)的成脲反應(yīng)中是耐受的。Scheme9.通過雙（2,2,2-三氟乙基）碳酸酯合成脲2.6.1雙（2,2,2-三氟乙基）碳酸酯與胺成脲實例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、通過重排反應(yīng)合成脲3.1霍夫曼重排（Hofmannrearrangement）霍夫曼重排是一級酰胺在氧化劑和堿的條件下重排變?yōu)椴凡p少一個碳原子的反應(yīng)，其反應(yīng)機理中形成異氰酸酯中間態(tài)，其可以與胺反應(yīng)生成脲，YoshihiroMatsumura等人在霍夫曼重排反應(yīng)中捕捉到脲的副產(chǎn)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]。該反應(yīng)目前也發(fā)展出多種可供選擇的氧化劑和堿，如：例如二乙酰氧基碘苯PhI(OAc)2、MeOBr、NBS-CH3ONa、NBS-KOH、乙酸鉛（IV）和芐基三甲基銨三溴化銨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.通過霍夫曼重排合成脲3.1.1霍夫曼重排生成脲實例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重排中酸或酰鹵與疊氮化物反應(yīng)生成?；B氮衍生物，并重排形成異氰酸酯，異氰酸酯可以與胺反應(yīng)生成脲。以下是一個羧酸衍生物與疊氮磷酸二苯酯（DPPA）發(fā)生Curtius重排生成異氰酸酯，并最終生成脲衍生物的例子。Scheme11.通過Curtius重排合成脲3.2.1Curtius重排生成脲實例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重排中異羥肟酸與脫水劑反應(yīng)，然后在堿或加熱條件下得到異氰酸酯。異氰酸酯可以與胺反應(yīng)生成相應(yīng)的脲。芳常見的脫水劑有：對甲苯磺酰氯、EDCl/DMAP、CDI、T3P、4-NBsOXY等。Scheme12.通過Lossen重排合成脲3.3.1Lossen重排的成脲實例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（可從腈和羥胺獲得）在苯磺酰氯（TsCl）或乙酸酐處理后，再水解得到單取代脲。該反應(yīng)有點類似于Beckmann或者Lossen重排。Scheme13.通過Tienmann重排合成脲3.4.1Tienmann重排成脲實例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