脲的合成方法總結

脲的合成方法隨著藥物化學的發(fā)展，脲結構越來越多的在藥物中出現，以建立獨特的藥物-靶點相互作用模式和調節(jié)類藥性質。本文主要總結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氤酸酯中間體，異氤酸酯再與不同胺類親核試劑反應生成N、N-二取代或N、N、N-三取代的脲衍生物。對于低沸點的異氤酸酯，第一步反最好將其蒸餾出來，這樣下一步反應相對干凈。如果異氤酸酯沸點很高，采用“一鍋法”也可以，但必須嚴格控制三光氣的用量(三光氣的用量為底物胺的1/3)。IhHtriphos^eneR2R3NHRiNHwRnCo|Ri丫Scheme1.通過三光氣合成月尿BaseScheme1.通過三光氣合成月尿1.1三光氣與胺生成尿實例將三光氣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口，滴加含有(S)-1-(毗啶-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)。反應液在0口溫攪拌反應5min后。加入6-甲基-N-(5-甲基-1H-毗唑-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。反應完畢后，向反應液中加入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，經柱層析純化得到白色粉末狀固體目標物32mg。1.2使用氯甲酰胺與胺反應生成脲對于仲胺由于無法形成異氤酸酯，可以通過其與三光氣反應得到氯甲酰胺，然后再與另一個胺反應。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。叫triphasgarier1,OR3RjNHr4粉HBaseciBaseR1R3Scheme2.通過氯甲酰胺合成服1.3仲胺通過氯甲酰胺反應生成脲實例[1，2]A100mLtwo-neckedflaskwithamagneticstirringbarwasevacuatedandbackfilledwithnitrogenthreetimes.Triphosgene(5.0mmol)andCH,Cl2(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，形成一個中間體，然后與另一分子胺反應生成脲。該類反應的優(yōu)點是CDI不產生氯或氯化副產物，但由于CDI不穩(wěn)定，放置時間久，遇水會分解，造成加料不準確，容易生成較難分離的二聚體。因此反應前確定CDI的質量尤為關鍵。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口。在一10ml試管加入3)-1-(毗啶-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體系中。低溫反應約30min后，向反應體系中加入含有6-甲基-N-(5-甲基-1H-毗唑-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。待反應完畢后，將反應液倒入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）反應得到相應的氨基甲?；讲⑷蜓苌铮?）。（8）隨后與另一種仲胺（9）反應，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，反應只需在室溫下進行，并且產率較高，而對于芳香族胺可能需要更高的溫度或者回流條件。Scheme4.Scheme4.通過CBT合成脲2.2.1CBT與胺生成腿實例[3]CBT(1.06g,4mmol)wasdissolvedindryTHF(40mL)underadryatmosphereofnitrogen,andaniline(0.37mL,4mmol)wasadded.Thereactionmixturewasstirredatroomtemperaturefor27h,octylamine(0.65mL,4mmol)wasthenadded,andtheresultingreactionmixturewasstirredatroomtemperaturefor27hbeforebeingextractedwithdiethylether(3x40mL).Theetherealextractsweresuccessivelywashedwith2NHCl(2x20mL),2NNaOH(2x20mL),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。RflIRzNHHRflIRzNHHZQ.25r尺出qNHRjf乂s”是H2o,5tH70'CScheme6.通過DMDTC合成脲2.23.1DMDTC與胺生成脲實例[4]H?Q,25'CH/5,知-也9Step1.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).Thecombinedorganicextractswerewashedwith耳0(30mL),dried(N02SO4),andevaporatedunderreducedpressuretogivecrudeProduct;yield:1.75g(ca.100%);99.9%purity(GCanalysis);mp56.5—57.5°CH?Q,25'CH/5,知-也9Step2.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(2x80mL);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得到相應的氧基碳酰胺，然后再與另一分子胺反應生成脲。氨基甲酸酯與胺反應的效率不同,取決于離去基團性質。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，其反應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的異氤酸酯，然后再與另一分子胺反應得到脲。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，一定要選擇好相應的堿。氯甲酸對硝基苯酯也可以與仲胺反應生成脲，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[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口underN2atmosphere.Theresultingmixturewasstirredfor30minandthenadded(S)-3-amino-4-(3,4-difluorophenyl)-1-phenylbutan-2-one(275mg,1.0mmol).Afterstirredat-20口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生成脲。其特點是相應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，在第二步反應一般用第二個胺的負離子反應。2.4.2.氯甲酸苯酯與胺生成脲實例[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咪唑蠲鹽咪唑金翁鹽常被用作穩(wěn)定的氨基甲?；D移試劑，用來合成不對稱四取代的服。最常用氨基甲酰咪唑金翁鹽是由仲胺與CDI反應，并與碘甲烷連續(xù)烷基化形成鹽。在三乙胺存在下，氨基甲酰咪唑金翁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服。所產生的副產物(N-甲基咪唑和三乙胺鹽酸鹽)可以用稀酸洗滌除去。氨基甲酰咪唑金翁鹽與脂肪胺反應較好，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處理生成相應的負離子，再與咪唑金翁鹽反應，才能得到相應的服。Scheme8.Scheme8.通過咪哩^鹽合成脲2.5.1咪唑^鹽與胺生成脲實例[7]Step1:ToasuspensionofCDI(9.73g,60mmol)inTHF(100ml)wasaddedN-methylaniline(5.96ml,55mmol).Themixturewasrefluxedfor24hbeforecoolingtoroomtemperature.RemovalofsolventundervacuumgaveaviscousorangeoilwhichwasdissolvedinCH2Cl2(100ml),andwashedtwicewith100mLportionsofwater.TheorganiclayerwasdriedoveranhydrousMgSQ,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、毗唑等基團在其介導的成脲反應中是耐受的。9R小電2R|R瀏HRSR八八又-八*昭兇乂口八逐*凡FuGooCF3TEA,75'Ch0眼'DBU,75'CH氐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)碳酸酯與胺成服實例[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,0.3mLofxyleneswasaddedtoachieveacomplete

removalofbis(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，其反應機理中形成異氤酸酯中間態(tài)，其可以與胺反應生成服，YoshihiroMatsumura等人在霍夫曼重排反應中捕捉到月尿的副產物［9］。該反應目前也發(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)和芐基三甲基銨三漠化銨［10］。只1用只1用Scheme10,通過霍夫曼重排合成脲3.1.1霍夫曼重排生成脲實例［11］Amixtureofbenzamide(0.2mmol),iodosylbenzene(0.3mmol),andpropan-2-amine(0.3mmol)inCH2Cl2(1mL)wasstirredatroomtemperaturefor2h.Afterthereactionwascomplete,themixturewasconcentratedinvacuo.Flashchromatographyonsilicagel(ethylacetate/petroleumether,1:4)furnishedtheYellowsolid(96%).Curtius重排

Curtius重排中酸或酰鹵與疊氮化物反應生成?；B氮衍生物，并重排形成異氤酸酯，異氤酸酯可以與胺反應生成脲。以下是一個羧酸衍生物與疊氮磷酸二苯酯（DPPA）發(fā)生Curtius重排生成異氤酸酯并最終生成脲衍生物的例子。DPPA,Ri-CgH酯（DPPA）發(fā)生Curtius重排生成異氤酸酯并最終生成脲衍生物的例子。DPPA,Ri-CgHEt3IN].TI1Fr2r3nhScheme11,通過Curtius重排合成脲3.2.1Curtius重排生成脈實例［⑵Tothesuspensionof(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口for2h.HPLCshowedthatallstartingmaterialwasconsumed.Morpholine(45.5mL,522mmol)wasaddedandthereactionwaskeptatrefluxovernight.Thereactionmixturewascooledto20口，andEtOAc(1L)wasadded.ThemixturewaswashedwithsaturatedNaHCO3(2x1L),andevaporatedundervacuum.TheresidualoilwaspurifiedonanISCOCompanionXLusing1.5kgsilicagelcolumnandagradient0-20%ofMeOHinDCM.Thefractionswerecollectedandevaporated,affording68gofcrudewhitesolid.MTBE(800mL)wasaddedandheatedtorefluxfor0.5h,thencooleddown.Thesuspensionwasfiltered,andcakewasdriedundervacuuminovenat50D.1HNMRshoweditwas1:1MTBEsolvate.Tothesolidwasaddedacetone/water(4:1,120mL)andthemixturewasstirredfor0.5h.Themixturewasfiltered,andcakewaswashedwithDCM(2x50mL),driedinovenundervacuumat50口toyieldtargetcompoundaswhitesolidwith99%chemicalpurity(54g,67%).Lossen重排Lossen重排中異羥肟酸與脫水劑反應，然后在堿或加熱條件下得到異氤酸酯。異氤酸酯可以與胺反應生成相應的脲。芳常見的脫水劑有：對甲苯磺酰氯、EDCl/DMAP、CDI、T3P、4-NBsOXY等。Scheme12.Scheme12.通過Lossen重排合成脲3.3.1Losse重排的成脲實例［⑶EDCIcat.DMAPEDCIcat.DMAPToasolutionof201.3mg(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%).Tienmann重排Tienmann重排是酰胺肟(可從臘和羥胺獲得)在苯磺酰氯(TsCl)或乙酸酐處理后，再水解得到單取代服。該反應有點類似于Beckmann或者Lossen重排。NH2OHR^-CN-*4痍MlPhSOnHH乩-RtSO.iHNH2OHR^-CN-*4痍MlPhSOnHH乩-RtSO.iHScheme13.通過Tienmann重排合成脲3.4.1Tienmann重排成脲實例[14]ArSO2ClDIPEACH2Cl2ArSO2ClDIPEACH2Cl2TothesolutionofbenzonitrileinEtOH(0.1M)wasadded50wt%aqueoushydroxylaminesolution(1.2equiv).Themixturewasstirredatrefluxtemperaturefor1.5hundernitrogen.Aftercoolingtoroomtemperature,thereactionmixturewasconcentratedunderreducedpressure.Thecrude(Z)-N'-hydroxybenzimidamidewasdissolvedinCH2Cl2(0.1M),andthenArSO2Cl(TsCloro-NsCl,1.05equiv)andDIPEA(1.05equiv)wereaddedat0D.Themixturewasstirredundernitrogenatmosphereatroomtemperaturefor3horatrefluxtemperaturefor1h.Themixturewasconcentratedunderreducedpressure.ThecrudeN-phenylcyanamidewasdissolvedinthemixtureof1NaqueousHClsolutionandEtOH(1NHCl/EtOH=1:4,v/v,reactionconcentration=0.1M).Themixturewasstirredatrefluxtemperaturefor3hundernitrogenatmosphere.Aftercoolingtoroomtemperature,thereactionmixturewasconcentratedunderreducedpressuretoaffordcrudeurea,whichwaspurifiedbycolumntoafford1-phenylurea(oil,0.5098g,3.74mmol,47%).4、通過屬催化方法合成脲近年來，通過金屬催化，將二氧化碳或一氧化碳作為羰基來源來合成脲，被廣泛開發(fā)。經典的Pd催化胺的羰基化中，Pd(ii)被還原為Pd(0)，氧化還原反應產生活性催化劑是反應的重要步驟［15］，通常使用的氧化劑有：氧氣、芳香族硝基化合物、碘以及醍。由于氧氣的經濟性和清潔環(huán)保，所以被廣泛應用，但是需要注意CO和氧氣的比率(避免接近可燃點)。4.1Pd/C/NaI介導的氧化裁基化Fukuoka［16］和Kelkar［17］報道了在O2存在下，使用Pd/C作為催化劑，碘化鹽作為促進劑，烷基胺可以發(fā)生氧化羰基化生成脲。RiNHR2NHRiNHR2NH2GO,V2O2FPdi-h2oScheme14.Pd/C/NaI介導的氧化羰基化4.1.1Pd/C/NaI介導成腿的實例［17］CH3NH-C-HNCHj2CH3NH2+CO+1/202奧削團灼CH3NH-C-HNCHjInatypicalexperiment,knownquantitiesofmethylamineinmethanol,catalyst,andiodidepromoterwerechargedtothereactor.Thecontentswereheatedtoadesiredtemperature.Afterthetemperaturewasattained,theautoclavewaspressurizedwithCO:O2mixture(inaratiodesiredfortheexperiment)uptoarequiredpressurelevel.Thereactionwasinitiatedbyswitchingthestirreron.ThereactionwascarriedoutataconstantpressurebysupplyingCO:O2=2:lfromareservoirasperthestoichiometricrequirement.Somereactionswerecarriedoutuntilabsorptionofthegasstoppedcompletely,whileinsomecasesthereactionswerecarriedoutforafixedtimeduration.Thecontentswerecooledbelowroomtemperature,andtheliquidsamplesandthegasphasewereanalyzedbyGC.4.2PdI2/KI介導的氧化羰基化Gabriele等人報道了在PdI2和O2條件下，生成線性和環(huán)狀脲的相關結果。伯脂肪胺的羰基化反應在100°C的條件下，在CO、空氣和CO2的混合物中進行，PdI2和KI組成的簡單催化系統。溶劑的選擇對產物至關重要，在低極性非質子溶液中(如DME)，反應效果較好，但在極性質子溶劑中(如MeOH)中，催化效果較差。由于需要生成異氤酸酯中間體，所以仲胺無法用該方法氨基羰基化，但生成異氤酸酯后可以與仲胺生成三取代的脲。以下是該氨基羰基化的機理［18］。IRNHj.C0!Scheme15.Pdl^/KI介導的氧化羰基化除了Pd催化劑，Au,Co,Ni,Rh,Ru,以及其他的過渡金屬也被證實可以用于催化生成脲衍生物。4.2.1PdI2/KI介導成脲的實例[19]a250mLstainlesssteelautoclavewaschargedinthepresenceofairwithPdI2(3.0mg,8.3x10-3mmol),KI(277mg,1.67mmol),BuNH2(8.3mmol)andBu2NH(12.5mmol)dissolvedinDME(21mL).TheautoclavewaspressurizedwithstirringatrtwithCO2(40atm),CO(upto56atm)andair(upto60atm)andthenheatedat90°Cwithstirringfortherequiredtime.Aftercooling,theautoclavewasdegassedandsolventremovedbyrotaryevaporation.Generally,someamountofcrudeproductwasalreadypresentinsuspensioninthereactionmixture.Ureaswereeasilypurifiedbycolumnchromatographyonsilicagelusinghexane-AcOEtfrom8:2to7:3aseluent.(75%isolatedyield)4.3Co(CO)8介導的氧化羰基化[20]為了避免多種可燃氣體混合的危險，研究人使用二鉆八羰基二鉆(Co(CO)8)做催化劑，在強度微波輻射條件下合成對稱和不對稱的脲衍生物的方法。環(huán)己胺與八羰基二鉆的反應生成相應的異氤酸酯衍生物，其與過量的仲胺反應后，以中等收率生成了三取代的不對稱脲衍生物Scheme16.Co(CO)g介導的氧化羰基化4.3.1Co(CO)8介導成脲的實例㈣洶"-dN乂TEA^eCNHH[1^^phenylmethanamine(0.60mmol),Co2(CO)8(0.40mmol,137mg),NEt3(121mg,1.2mmol)and2.5mLofacetonitrileweremixedina5mLvialwhichwasimmediatelycappedwithaTeflonseptumunderair.TheSmithmicrowavesynthesizerwassetto250°C,andtheirradiationtimeto10or13s.Aftercooling,thereactionmixturewasfilteredandtransferredtoaseparatingfunnel.Thevialwaswashedwith40mLofwarmCH2Cl2andtheorganicextractwasaddedtotheseparatingfunnel.Thecombinedorganiclayerwaswashedwith0.1MHCluntilitbecamecolorless.Theorganiclayerwasthereafterseparated,dried(K2CO3)andevaporatedtoacquiretheproduct.4.4Pd(OAc)2/PPh3/四乙基氯化銨介導的芳香硝基與芳香胺的成服[21]Heck報道了芳香硝基和CO在乙酸鈀/三苯膦/四基氯化鉉組成的催化體系中，發(fā)生還原羰基化再與過量的苯胺生成二芳基脲的現象。該方法也可以用來制備芳香硝基與脂肪胺之間的脲的合成?？赡艿臋C理如下圖：

Scheme17.Pd(OAc)2/PPh3/四乙基氯化銨介導的芳香硝基與芳香胺成脲的機理4.4.1Pd(OAc)2/PPh3/Scheme17.Pd(OAc)2/PPh3/四乙基氯化銨介導的芳香硝基與芳香胺成脲的機理4.4.1Pd(OAc)2/PPh3/四乙基氯化鉉介導成腿的實例㈤Intoa300mlautoclavewerecharged6.15g(50mmoles)ofnitrobenzene,27.9g(300mmoles)ofaniline,0.15gofpalladiumacetate,1goftriphenylphosphine,2goftetraethylammoniumchloride,t-butylbenzene(asaninternalstandardforgaschromatographicanalysis),and60gofxylene.Theautoclavewasinitiallypurgedwithpressurizedsynthesisgasat10atm,ofwhichthehydrogentocarbonmonoxidemolarratiois0.5,threetimes,andthesynthesisgaspressureof60atm.Wasestablishedatroomtemperature.Thereaction,mixturewasheatedwithstirringandheldat120°Cfor2.5hours.Duringthereaction,liquidsanplesweretakenthroughthesamplingvalve,Aftercompletionofthereaction,thereactionmixturewascooledtoroomtemperatureandthegaswasdischargedfromtheauto-clave.Afterthefiltrationofthereactionmixtureunderthereducedpressure,theprecipitateswerewashedwith18.6g(200mmoles)ofaniline,and50gofxylene,andthendried.Asaresult,18.5gofwhiteprecipitatewasobtained.Analysisoftheremainingsolutionrevealedthattheconversionofnitrobenzenewas99.1%andtheyieldofN,N-diphenylureawas97.1%.4.5Pd2(dba)3/tbutylBrettPhos介導的芳香鹵與氧酸鈉生成異氧酸酯[23]Buchwald等人在氤酸鈉存在下利用Pd2(dba)3催化，將芳基氯和三氟甲磺酸交叉偶聯制備異氤酸芳基酯。生成的異氤酸芳酯與親核胺反應生成不對稱的N,N'-二取代和N,N,N'-三取代脲。這種方法的優(yōu)點是適用底物范圍比較廣。該反

應路線應用于心臟肌凝蛋白的激活劑OmecamtivMecarbil的合成，該藥目前處于II期臨床階段。Scheme18.Pd應路線應用于心臟肌凝蛋白的激活劑OmecamtivMecarbil的合成，該藥目前處于II期臨床階段。Scheme18.Pd2(dba)3/t-butylBrettPhos介導芳香鹵與氰酸鈉的成脲4.5.1Pd2(dba)3/tbutylBrettPhos介導成腿的實例NaOCN(2Bq}Pd3(dba)3([].5oid%)Liga"d(1.2md%)TEAIolu4nt.110^.IShAnoven-driedtesttube,whichwasequippedwithamagneticstirbarandfittedwithaTeflonscrewcapseptum,waschargedwithPd2(dba)3(0.005mmol)andLigand(0.012mmol).Thevialwasevacuatedandbackfilledwithargon(thisprocesswasrepeatedatotalof3times),andsubsequentlyanhydroustoluene(2mL)wasaddedviasyringe.Theresultingpurpleslurrywasheatedat120°Cfor3minatwhichpointthecolorofthemixtureturneddarkorange-brown.Asecondoven-driedtesttube,equippedwithamagneticstirbarandfittedwithaTeflonscrewcapseptum,waschargedwithNaOCN(2mmol),andthearylhalideoraryltriflate(1mmol)ifsolidatroomtemperature.Thevialwasevacuatedandbackfilledwithargon(thisprocesswasrepeatedatotalof3times),andsubsequentlythearylchlorideortriflate(ifliquid)(1mmol)andtriethylamine(0.25mmol)wereaddedviasyringe.Thepremixedcatalystsolutionwasthentransferredtothevialviacannulaunderpositiveargonpressure.TheTeflonscrewcapseptumwasreplacedwithanunpuncturedseptumundercontinuousargonflowandthesolutionwasheatedto110Cfor16h.Thereactionmixturewasthencooledtoroomtemperature,afterwhichtheamine(1.2mmol)andtoluene(2mL)wereaddedintothevialunderpositiveargonflowandtheresultingmixturewasstirredat60°Cfor5h.Thereactionmixturewasthencooledtoroomtemperature,andfilteredthroughapadofCelite,washingwith

methanolandEtOAc.Thecrudeproductwasadsorbedontosilicagelandpurifiedbyflashchromatographyonsilicagel.4.6Pd/C催化單取代的脲與醛的還原烷基化Lemaire等人開發(fā)了在Pd的催化下，單取代服與醛的還原烷基化的方法。該方法中無水甲醇作為脫水劑，并促使縮醛胺生成亞胺，亞胺加氫最后以的優(yōu)異的收率生成了N,N-二取代服衍生物。這個方法在無溶劑條件下也適用。MeOH.WQ*CUrea(yield%)_H*\〃，F舷/■'MeOH.WQ*CUrea(yield%)_H*\〃，F舷/■'Ha,Pd.'ChydrogenatiorScheme19.Pd/C催化單取代的服與醛的還原烷基化4.6.1Pd/C催化單取代的脲的實例[24]Pd/C,H2rMeOHThebenzylurea(150mg,1mmol)andthedecanal15(0.56mL,3mmol)weredissolvedindrymethanol(10mL)inastainlesssteelautoclave(50mL),andthenPd(5%oncarbon;53.2mg,2.5mol-%)wasadded.Thereactorwastightlyclosedandpurgedthreetimes,andthenhydrogen(5bar)wasintroduced.Thereactorwasthenplacedinagraphitebathonamagneticstirrer,andthereactionmixturewasstirredat100°Cfor15h.Aftercoolingtoroomtemperature,thehydrogenpressurewasreleased.ThepalladiumwasremovedbyfiltrationundervacuumoveraMilliporefilterandthoroughlywashedwithmethanolseveraltimes.Thefiltratewasconcentratedunderreducedpressure.TheresiduewaspurifiedbyrecrystallizationfromEt2Otogive1-Benzyl-3-decylurea(250mg,86%)asawhitepowder.4.7Pd/C/XPhos催化芐基、烷基和芳基疊氮化物的羰基化四氮烯與胺的金屬催化羰基化在不對稱服的合成中被廣泛關注。Zhang等人介紹了Pd/C/XPhos催化的節(jié)基、烷基和芳基疊氮化物的羰基化，以合成不對稱的服衍生物的方法。與其他均相催化劑相比，Pd/C在安全處理、處理簡單、可回收

等方面有優(yōu)勢。使用磷配體可以提高反應產率。由于芳基疊氮化物的高反應性，這個反應可以在室溫下進行。Scheme20.Pd/C/XPhos催化芐基/烷基和芳基疊氮化物的羰基化4.7.1Pd/C/Xphos介導成脲的實例solvent,12hPd/C(5mol等方面有優(yōu)勢。使用磷配體可以提高反應產率。由于芳基疊氮化物的高反應性，這個反應可以在室溫下進行。Scheme20.Pd/C/XPhos催化芐基/烷基和芳基疊氮化物的羰基化4.7.1Pd/C/Xphos介導成脲的實例solvent,12hTheSchlenkreactionflaskwasdegassedfortwotimeswithnitrogen,underanitrogenatmosphere,Pd/C(21mg,0.02mmol),XPhos(19mg,0.04mmol)and4-methoxyaniline(59mg,0.48mmol)wereadded.Thentheflaskwassealedandevacuatedtoavacuumof15mmHgandfittedaCOballoon.Benzylazides(53mg,0.4mmol)andPhMe(4ml)wereaddedviasyringe.Themixturewasstirredat60Cuntil1adisappearedasjudgedbyTLC.Solutionwasremovedinvacuotoleavearesiduewhichwaspurifiedbyflashsilicagelchromatographyusingpetroleumether/EtOAc(from3:1to1:1)aseluentaffordpure1-benzyl-3-(4-methoxyphenyl)ureaasawhitesolid(94mg,91%).4.8釘螯合物介導的羰基化[26]Hong等人報道了使用釘螯合復合物合成服衍生物的方法。該方法通過一站式兩步法連續(xù)合成不對稱服，首先由胺和甲醇生成甲酰胺，然后使甲酰胺與第二種胺衍生物反應。Gunanathan等人也報道了類似釘配合物催化生成服衍生物的方法。

Ru-catalyst{1295649-41^0)Scheme21.釘螯合物介導的羰基化4.8.1釘螯合物介導成脲的實例[RuKO.5Ru-catalyst{1295649-41^0)Scheme21.釘螯合物介導的羰基化4.8.1釘螯合物介導成脲的實例[RuKO.5mol%)toluene,140ch3oh+ASchlenk-typethick-wallround-bottomflask(50mL)waschargedwithRu-MACHO-BH(CasNo:1295649-41-0)(0.01mmol,5.9mg),benzylamine(0.5mmol,54mg),andmethanol(2mL)inanargon-filledglovebox.Thereactiontubewasheatedto150°C(bathtemperature)underclosedconditions.After12h,thereactionwascooledto0°Cfor1h.Methanolwasremovedundervacuum.Ru-MACHO-BH(CasNo:1295649-41-0)(0.017mmol,9.9mg),cyclohexanamine(0.42mmol),andtoluene(1.5mL)werethenaddedtothereactiontubeunderanargonatmosphere.Thevesselwasheatedto120°C(bathtemperature)for16hunderclosedconditionsandthencooledto0°Cfor30min.ThegeneratedH2wasreleasedcarefullyinafumehood.n-Hexane(40mL)wasthenaddedtothereactionmixture.Theresultingsolidwascollectedandfurtherwashedwithcolddiethylethertoaffordthecorrespondingproduct(Whitesolid,80.8mg,0.348mmol,83%).5、使用氨基甲酸酯和異腈合成脲衍生物5.1氨基甲酸酯衍生物合成異氤酸酯Spyropoulos[27]等人報道了Boc和Cbz保護的胺，在三氟甲磺酰酐條件下生成異氤酸酯中間體，再與第二個胺形成服的方法。使用2-取代毗啶（如2-氯毗啶），可以提高反應活性。該方法適用于苯胺，空間受阻的叔丁胺和仲胺，生成三取代的服。

H點T2-ChlQrapyndiinAScheme22.H點T2-ChlQrapyndiinA5.1.氨基甲酸酯合成異氧酸酯實例Methyl(tert-butoxycarbonyl)-L-valinate(0.30mmol)wasplacedinaroundbottomflaskfollowedbydryCH2Cl2(10mL).2-Chloropyridine(0.09mL,0.90mmol)wasadded,followedbytrifluoromethanesulfonicanhydride(0.08mL,0.45mmol),andthereactionmixturewasstirredfor50minatroomtemperature.Then卵(1.80mmol)followedbyphenylmethanamine(0.90mmol)wasadded,andthereactionmixturewasstirredatroomtemperaturefor1h.Thecrudeproductwaspurifiedusingcolumnchromatography(30%-50%EtOAcinpetroleumether)toaffordthedesiredproduct(70mg,88%yield).5.2異氧衍生物合成異氧酸酯Ganem等人開發(fā)了異氤衍生物氧化為異氤酸酯的方法。使用DMSO作為氧R^NECDMSOTFAA(5mol%)CH見R^NECDMSOTFAA(5mol%)CH見Scheme23.通過異氤衍生物成脲5.2.1異氧衍生物合成異氧酸酯實例[28]DMSOTFAA(Smol%)CH2CIDMSOTFAA(Smol%)CH2CI2nh2ULJAsolutionoft-butylisonitrile(113四L,1mmol)indryCH2C12(1mL)anddryDMSO(78四L,1.1mmol)underN2ina25mLRBFwascooledto-60oC,thenTFAA(7四L,0.05mmol)wasadded.Theresultingsolutionwasstirredvigorouslyat-60oCfor5min,thenwarmedtortandstirredfor5min.Afterrecoolingthesolutionto-60oC,t-butylamine(315四L,3mmol)wasaddeddropwise.Theresultingsolutionwasstirredatrtfor2h,thenconcentratedinvacuotoaffordawhitesolid.Water(3mL)wasaddedandtheaqueousphasewasextractedwithethylacetate(4x5mL).Thecombinedorganicextractswerewashedwithbrine(2mL),dried(MgSq),filteredandconcentratedinvacuotoafforddi-t-butylurea(165mg,96%)asawhitesolid,m.p.252—254oC(sealedcapillarytube)(lit.1240oC).5.3肟衍生物合成脲Wang等人報道了通過臘與異臘衍生物生成服的方法。如下圖所示，1-苯基乙-1-酮臘和環(huán)己基異氤化物在20%NIS、TBHP水溶液條件下，加熱生成氨基甲酸酯衍生物，再與第二個胺形成服。Scheme24.通過肟衍生物成服5.3.1肟衍生物合成脲實例[28]Toastirredsolutionof(E)-1-phenylethan-1-oneoxime(1.0equiv)in1,4-dioxanewereaddedNIS(20mol%),TBHP(70%inH2O)(2.0equiv),andisocyanocyclohexane(1.2equiv).Theresultantmixturewasheatedat90°Cfor4h.AfterthecompletionofreactionbyTLC,thereactionmixturewascooledtortandp-

Wang等人報道了通過臘與異臘衍生物生成服的方法。如下圖所示，1-苯基乙-1-酮臘和環(huán)己基異氤化物在20%NIS、TBHP水溶液條件下，加熱生成氨基甲酸酯衍生物，再與第二個胺形成服。Scheme24.通過肟衍生物成服5.3.1肟衍生物合成脲實例[28]Toastirredsolutionof(E)-1-phenylethan-1-oneoxime(1.0equiv)in1,4-dioxanewereaddedNIS(20mol%),TBHP(70%inH2O)(2.0equiv),andisocyanocyclohexane(1.2equiv).Theresultantmixturewasheatedat90°Cfor4h.AfterthecompletionofreactionbyTLC,thereactionmixturewascooledtortandp-5.4氨基甲酸衍生物合成脲Peterson等人報道了氨基甲酸為起始原料制備服的方法，氨基甲酸可以由伯胺與二氧化碳在DBU催化下得到。該反應主要是氨基甲酸與Mitsunobu試劑反應生成異氤酸酯，再與第二個胺形成服。該方法適用于芐胺和苯胺生成氨基甲酸，再進一步生成服的衍生物。Scheme25.通過氨基甲酸衍生物成服Wang[29]等人在此基礎上開發(fā)了在通過PANI-g-C3N4-TiO2、BI-OA在可見光催化下合成服的方法，氨基甲酸衍生物首先在超價碘試劑BI-OAc的存在下轉化為氨基甲酰自由基。隨后在聚苯胺類復合物催化劑PANI-g-C3N4-TiO2及可見光的催化作用下原位生成對應的異氤酸酯，最后與另一底物胺反應生成不對稱服類衍生物。與傳統成服方法相比，該合成法底物耐受度好且產率較高，此外復合物催化劑可在簡單過濾后重復使用，避免了直接使用異氤酸酯作為反應原料，對環(huán)境更加友好。(1)PANI-C3N4-TiO2jBI-OAcRN^GOOHRN^GOOH⑵Et3N,R'-NH2VisiblelightScheme26.光催化合成非對稱服類衍生物5.4.1氨基甲酸衍生物合成脲實例[30]Benzylamine(0.051mL,0.467mmol)andDBU(0.007mL,0.047mmol)wereaddedtoaflaskcontainingMeCN(7mL)andallowedtostirunderCO2(balloon,1atm).After45minutes,tetrahydroisoquinoline(0.089mL,0.700mmol)wasaddedandthereactionwasstirredfortenminutesundernitrogen.Duringthistime,asolutionoftri-N-butylphosphine(0.242mL,0.980mmol)anddi-tert-butylazodicarboxylate(226mg,0.980mmol)waspreparedinMeCN(2mL)andstirredfortenminutesundernitrogen.Thissolutionwasthenaddeddropwisetothereactionmixture.Thereactionwasstirredforonehourundernitrogen.Thereactionwasthenconcentratedinvacuoandpurifiedbyflashcolumnchromatographyonsilicagel(0-50%EtOAc/hexanesgradient)togive117mg(0.439mmol,94%)oftheproductasacolorlesssolid.參考文獻：NISHIZAWAA,TAKAHIRAT,YASUIK,etal.Nickel-CatalyzedDecarboxylationofArylCarbamatesforConvertingPhenolsintoAromaticAmines[J].JAmChemSoc,2019,141(18):7261-5.SINGHDV,ADEPPAK,MISRAK.MechanismofisoproturonresistanceinPhalarisminor:insilicodesign,synthesisandtestingofsomenovelherbicidesforregainingsensitivity[J].JMolModel,2012,18(4):1431-45.KATRITZKYAR,PLEYNETDPM,YANGB.AGeneralSynthesisofUnsymmetricalTetrasubstitutedUreas[J].TheJournalofOrganicChemistry,1997,62(12):4155-8.FOCHIR,ARTUSOE,DEGANII,etal.PreparationofMono-,Di-,andTrisubstitutedUreasbyCarbonylationofAliphaticAmineswithS,S-DimethylDithiocarbonate[J].Synthesis,2007,2007(22):3497-506.ZHANGHC,DERIANCK,ANDRADE-GORDONP,etal.Discoveryandoptimizationofanovelseriesofthrombinreceptor(par-1)antagonists:potent,selectivepeptidemimeticsbasedonindoleandindazoletemplates[J].Journalofmedicinalchemistry,2001,44(7):1021-4.ATWALKS,FERRARAFN,DINGCZ,etal.CardioselectiveantiischemicATP-sensitivepotassiumchannelopeners.4.Structure-activitystud