经典化学合成反应标准操作药明康德新药开发有限公司化学合成部编写、八刖有机合成研究人员在做化学反应经常碰到常规的反应手边没有现成的标准操作步骤而要去查文献，在试同一类反应时，为了寻找各种反应条件方法也得去查资料。

为了提高大家的工作效率，因此化学合成部需要一份〈经典合成反应标准操作》。

在这份材料中，我们精选药物化学中各类经典的合成反应，每类反应有什么方法，并通过实际经验对每类反应的各种条件进行点评，供大家在摸索合成条件时进行比较。

同时每种反应的标准操作，均可作为模板套用于书写客户的final report，这样可以大大节省研究人员书写final report的时间，也相应减少在报告中的文法错误。

另外本版是初版，在今后的工作中我们将根据需要修订这份材料。

药明康德新药开发有限公司化学合成部2005-6-281•胺的合成a）还原胺化b）直接烷基化c）腈的还原d）酰胺的还原e）硝基的还原f）叠氮的还原g） Hoffman 降解h）羧酸通过Cris重排2. 羧酸衍生物的合成a）酰胺化的反应b）酯化反应c）腈转化为酯和酰胺d）钯催化的插羰反应e）酯交换为酰氨3. 羧酸的合成a）醇氧化b）酯水解c）酰胺的水解d）腈的水解e）有机金属试剂的羰基化反应f）芳香甲基的氧化4. 醛酮的合成a） Weinreb酰胺合成醛酮b）醇氧化c）酯的直接还原d）有机金属试剂对腈加成合成酮5•脂肪卤代物的合成a）醇转化为脂肪溴代物通过PBr3转化通过PPh3 与CBr4转化HBr直接交换通过相应的氯代物或磺酸酯与LiBr交换、b）醇转化为脂肪氯代物通过S0CI2转化通过PPh3与CCl4转化HCl直接交换c）醇转化为脂肪碘代物通过PPh3与12转化通过相应的氯代物或磺酸酯与Nal交换6. 芳香卤代物的合成a）San dermyyer 重氮化卤代b）直接卤代c）杂环的酚羟基或醚的卤代7. 醇的合成a）羧酸或酯的还原b）醛酮的还原c）卤代烃的水解d）吡啶的氧化转位8. 酚的合成a）San dermayer 重氮化反应b）醚的水解c）Bayer-vigerlar 氧化d）硼酸的氧化9. 腈的合成a）磺酸酯或卤代烃的取代b）酰胺的脱水c）芳卤代烃的氰基取代10. 硝化反应11. 醚的合成a）芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsu nobu 芳香醚化Buckwald 芳香醚化b）脂肪醚的合成醇的醚化12•脲的合成a）胺与异腈酸酯的反应b）用三光气合成脲c）羰基二咪唑（CDI）合成脲d）对硝基苯酚碳酰胺合成脲13. 烯烃的合成a） Wittig 反应b）羟基的消除c）Wittig-Horner 反应合成,-不饱和酯14. 磺酸及磺酰氯的合成a）氯磺化反应合成磺酰氯b）从硫醇合成磺酰氯c）磺化反应15. 氨基酸的合成a） Streck反应合成b）手性氨基酸的合成16. 偶联反应a） Suzuki Coupli ngb） Buckwald 芳胺化,芳酰胺化、c）Heck反应17. Mitsunobu 反应a）醇的反转b）胺的取代18. 脱羟基反应19. 酮还原为亚甲基20. 氨的保护及脱保护策略a）用碳酰胺作保护基b）苄基保护21. 醇的保护及脱保护策略a）用硅醚进行保护b）其他醚类保护22. 羧基的保护Boc 脱保护1格氏反应还原胺化卤化反应S u z u k i coupling ------------------------------------------------------------------------------------------------ - 2磺化反应n-BuLi -------------------------------------------------------------------------------------------------L i A l H 4 还原 -------------------------------------------------------------------------------------------------- 4P0CI3 的杂环氯代3水解反应-------------------------------------------------------------------------------------------- 5NaH ----------------------------------------------------------------------------------------------------___________NBS ---------------------------------------------------------------------------------------------------———————————氢化反应m-CPBA ----------------------------------------------------------------------------------------------6 EDC ---------------------------------------------------------------------------------------------------6用二光气成脲——7芳卤用n -B u L i i处理后与W e in r e b 酰胺成酮 -------------------------------------------------------------------------------------------------------------------------------------------- 7Boc上保护To a soluti on of A (2.72 g, 13.9 mmol) and tetramethylam monium hydroxide pen tahydrate (5.62 g, 31.0 mmol) in aceto nitrile (270 mL) was added di-tert-butyldicarb on ate (3.79 g; 17.4 mmol) and the resulting solution was allowed to stir 18 h at rt and concentrated. The residue was partitio ned betwee n Et2O/H2O; the phases were separated and the aqueous phase extracted twice more with Et2O. The aqueous phase was brought to pH 4 with solid citric acid and extracted with CHCI3 (3x100 mL). The orga nic extracts were comb in ed, dried (Na2SO4) andconcen trated to afford 2.58 g (63 perce nt) B as a white foam.Boc 脱保护Tert-Butyl 2-(2-methoxyphe no xy)ethylcarbamate (23.8 g, 89 mmol) in dichlorometha ne (10 ml) was cooled to 0 deg C and stirred as a mixture of trifluoroacetic acid: dichloromethane (1:1,40 ml) was added dropwise. The mixture was allowed to warm to rt, stirred for 2 hours and concen trated in vacuo. The residue was take n back up in dichlorometha ne (100 ml) and thesolutio n was washed with saturated aqueous sodium hydroge n carb on ate (3*20 ml) and aqueous sodium hydroxide (10percent, 3*20 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphe no xy)ethylam ine (13 g, 88perce nt yield) as a light yellow solid.Return格氏反应A stirred mixture of magn esium tur nings (23.6 g, 0.98 mol) and Et2O (200 mL) un der n itroge n is treated with a crystal of iodi ne and about 5perce nt of a soluti on of bromoetha ne (56.3 ml, 0.75 mol) in Et2O (375 mL). When the react ion starts, the rema in der of the bromoetha ne solutio n is added, dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour. T o this solution ofethylmagnesium bromide was slowly added a solution of 4-cya nopyridi ne (39 g, 0.375 mol) in Et2O (750 ml). The react ion mixture was warmed at reflux for 12 hours, treated with con ce ntrated H2SO4 (125 ml)/H2O (125 ml), and then washed three times with Et2O (250 ml). The aqueous portio n was made basic (PH 9) with 15perce nt NaOHReturnOsoluti on and extracted five times with 250 ml portions of Et20. The comb ined Et20 extracts were dried (MgSO4), and the solve nt was removed un der reduced pressure to afford a brow n oil (48.4 g, 95perce nt).卤化反应To a stirred solution of 8-methyl-1-nitro-naphthalene (10.6g, 56.32 mmol) and iron (III) chloride (0.45 g, 2.77 mmo) in CCI4 (150 ml) heated to 60 C was added dropwise (3.0 ml, 58.23 mmol) of bromine. After one hour, the react ion mixture was poured into saturated NaHCO3 solutio n, and the layers were separated. The aqueous layer was re-extracted with CH2CI2. The comb ined orga nic layers were dried (MgSO4) and the solve nt was removed un der reduced pressure. The crude residue was recrystallized from etha nol and the mother liquors were concen trated and then flash chromatographed on silica, eludi ng hexa nes:ethyl acetate (12: 1).ReturnReturn还原胺化 HO H 2NA solution of 2-ami no-4-ethylphe nol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1.13 g, 7.28 mmol), and p-tolue nesulfo nic acid (0.05 g) in metha no I (50 ML) was stirred at room temp for 24 h. To the resultant solution, sodium borohydride (0.82 g, 22 mmol) was added in small portions. After additi on was completed, the mixture was stirred at room temperature for 30 min and concen trated un der vacuum. The residue was the n subjected to colu mn chromatography on silica gel eluted with 10percent ethyl acetate in hexane and followed by recrystallization (aqueous metha nol) yielded 450 mg (22perce nt) of an alytically pure product.Retur n+V HSuzuki coupli ngTo a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol)and 3-bromobe nzene (0.87 ml, 8.3 mmol) in THF (28 ml) were added palladium catalystPd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in9 ml of water).The system was degassed and the n charged with n itroge n for three times. Themixture was stirred un der n itroge n at 70 ° C oTlbiatie^i6rheoiliuti on was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethylacetate soluti on was washed by brine, dried over Na2SO4 and concen trated. The residue waspurified on a silica gel colu mn eludi ng with hexa nes: EtOAc 9:1 to give 1.38 g (78%yield) of4-phenyl-1H-indole as a colorless liquid.Return磺化反应Chlorosulfo nic acid (4.66g, 40 mmol) is added dropwise to a cold (0 2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (2.9g, 8 mmol) in chloroform (800 ml).C for 30 minutes. ° The cold bath is then removed and the solution is stirred at room temperature for 1 hour thencautiously poured into ice water. The orga nic layer is separated, dried over magn esium sulfate and concen trated to afford the titlecompo und. The crude product is purified by colu mn chromatography eluted with 10% acetic ether in petroleum ether (2.36 g, 81% yield).酯化反应A mixture of 4-hydroxymethy In aphthoic acid (10 g, 50 mmol), metha no I (300 ml), and concen trate H2SO4 (2 ml) was refluxed overni ght. The in solubles were filtered off and the filtrate was concen trated. The residue was take n up in ethyl acetate and washed with aqueous NaHCO3 (2*), brine, dried over MgSO4, and concen trated to give a yellow oil. Silica gel colu mn chromatography using ethyl acetate/hexa ne (1/3) gave the desired product as a yellow oil (3.3 g,35%yield).Retur nC) solutio n ofThe result ing soluti on is stirred at 0HOHO水解反应sodium hydroxide (35ml) in tetrahydrofura n (130ml) was stirred un der reflux for 18 hours. The mixture was n eutralised using 2N hydrochloric acid, and extracted with dichlorometha ne (3x).The comb ined orga nic soluti ons were dried (MgSO4), and evaporated un der reduced pressure. The crude product was purified by column chromatography on silica gelusing an gradient of dichloromethane: methanol (100:0 to 97:3) to afford the title compound as a solid (3.11g,47.8%yield).硝化反应NO2To a cold (0 °C) suspension of 1-methylnaphthalene (5 g, 35.2 mmol) in HNO3 was added H2SO4 (5 ml) dropwise. After stirri ng the react ion for one hour, the soluti on was diluted with ethyl acetate and washed with water (3*), aqueous saturated NaHCO3 (2*) and brine, dried over MgSO4, and concen trated. The product was purified by silica gel colu mn chromatography using ReturnA solution of 1-Methyl-naphthalene-2-carboxylicacid methyl ester (7.20g, 35mmol) and 2NelutionRetur nOHethyl acetate: hexa ne (5: 95) and recrystallized from metha nol to give yellow n eedles (0.22g, 33% yield).n-BuLiTo a dry three-n ecked roun d-bottomed flask with an additi on funnel and at -78 inertatmosphere was charged with an hydrous THF (500 ml). A soluti on of n-butyllithium (2.5 Min hexane, 88 ml, 220 mmol) was added dropwise followed by addition of a solution of aceton itrile (10.43 ml, 200 mmol) in an hydrous THF (100 ml). The in ternal temperature wasmaintained below -70 °C duri ng the en tire additi on process. After 2 hr at -78 °C a soluti on of Trifluoro-acetic acid ethyl ester (14.2 g, 100 mmol) in an hydrous THF (30 ml) was added dropwise and the mixture was stirred for 1.5 hr. T o the mixture was added acetic an hydride to que nch the react ion. The reacti on mixture was allowed to warm up to rt. A precipitate was filtered and the filtrate was concentrated to give a brown oil, which was used in the next step withoutpurificatio n.ReturnLiAlH4还原A solution of 2,3-naphthale nedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, warmed toReturn°C under O50 ° to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 ml, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 ml) is added, and the resulting mixture is extracted 3 times with ether. The comb ined ether extracts are washed with water (2 times), with saturated sodium bicarb on ate soluti on (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g, 67.3%yield) as a light tan crystalline material.Retur n POCI3的杂环氯代HO ClTo a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) wasslowly added N,N-dimethyla nili ne (6.18 ml, 0.049 mol). The mixture was then refluxed at 125 Cfor 3 hours. After this time, the starti ng material completely dissolved in dicat ing that the reactio n was completed. The react ion mixture was cooled and the n poured slowly onto ice to que nchthe POCl3 (cauti on[ exothermic]). A precipitate formed, which was filtered and washed withice-cold water. The precipitate was dried un der high vacuum overni ght to yield2,4-dichloro-5,6-dimethyl-pyrimidine (7.2 g, 0.041 mol, 92%yield) as a yellow solid.Retur nNaHSodium hydride (50% in min eral oil, 5.5 g, 0.11 mol) was added porti on wise at 0 nitrogen atmosphere to a solution of 2-aminobenzenethiol (12 ml, 0.1 mol) in DMF (120 ml).After 0.5 h, ben zyl chloride (11.5 ml, 0.1 mol) in DMF (80 ml) was added in 0.5 h. The solutionwas stirred for 3 h while the temperature was allowed to rise to rt, then it was poured into ice/water (1000 g). The precipitate was filtered, dissolved in ethyl acetate and washed with brine. Theorga nic layer was dried over Na2SO4 and evaporated. The solid obta ined was ground in pentane (19.3 g, 90% yield).NBSA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimid ine (27.46 gand n-bromosucci nimide (27.02 g , 0.152mol) in CH2Cl2 (170 ml) wasrefluxed un der a nitroge natmosphere for 36 h. Then washed by water, the aqueous was extracted by CH2Cl2. The comb ined orga nic layer was washed by saturated Na2S2O3 and brine, dried over Na2SO4, and evaporated to give a white solid which was purified by colu mn chromatography eluted with 50% acetic ether in petroleum ether (34 g, 88.6%yield).°C under aRetur nNBS,0.14mol), AIBN (1.32 g)H 2NClClClm-CPBAA solution of 85% m-chloroperoxybe nzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at—-0 °C to a solution of 2-Benzylsulfanyl-phenylamine (19 g, 88 mmol) in CH2Cl2 (400 ml). Themixture was allowed to warm to rt in 3 h, then it was washed with a 5% Na2S2O3 soluti on, 10%NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and evaporated. Thesolid was ground in pentane (19 g, 95% yield).Return 氢化反应A mixture of ethyl 3-(N-be nzylam ino )-3-methylbutyrate hydrochloride (25g, 0.1 mol) andlOperce nt Pd-C (2g) in 250 ml of dried alcohol was hydroge nated un der 55 psi H2 for four days.The react ion medium was the n filtered and evaporated un der reduced pressure to provide anamber oil which gradually crystallized upon sta nding (18 g, 100% yield).Retur nHClNH 2ReturnEDCOTo a 0 ° C mixture of BoL-tyrosine (2.04 g, 7.26 mmol) and amylamine (0.63 gl, 7.26 mmol) inmethyle ne chloride (30 ml) is added 1-(3-dimethylami nopropyl)-3-ethylcarbodiimide (EDC) (1.53 resulting solution is diluted with methylene chloride (30 ml) and washed successively with 0.5 M HCl (40 ml), water (20 ml) and sat aq sodium bicarb on ate (25 ml). The orga nic phase is dried over magn esium sulfate and concen trated to a foam (1.84 g, 72.4%yield), sufficie ntly pure to carry into the n ext step. An an alytical sample is obta ined by HPLC.g, 9.9 mmol ). The white mixture is stirred at 0 C for 5 min and at room temp for 23 hrs. TheRetur n三光气成脲To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) in toluene (10 ml)triethylamine (0.13 ml, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. Thereaction mixture was stirred at 70 ° C for 2 hours, the n cooled to room temperature. Then more 2-(tert -butyldimethylsilyloxy)- 4-n itroa nil ine (200 mg, 0.75 mmol) was added. The result ingmixture was allowed to stir at 70 ° C for 48 hours the n cooled to room temperature. The react ion mixture was partiti oned betwee n water and ethyl acetate. The comb ined orga nic phase waswashed with brine, dried over MgSO4 and filtered. Removal of solve nt at reduced pressure andchromatography of the result ing oil on silica gel (hexa ne: ethyl acetate, 10:1) gave 1,3-Bis-(2-hydroxy-4-nitro-phenyl)-urea (130 mg, 31%yield). Retur n 芳卤用n-BuLi 处理后与Weinreb 酰胺成酮To a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at argon wasadded n-butyllithium (54.0 ml, 2.5M in hexa ne, 0.135 mole), followed after 5 min bydropwise a solution of 2-fluoro-4-methylpyrid ine (10 g, 0.090 mole) in THF (20 ml). After stirri ng for 15 min at -78 ° C, a solution of Nmethoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 ml) was added dropwise. After stirri ng for more 5 mi n, the react ion wasC and que nched by pouri ng into w^teo ml) and ethyl acetate (400 ml).The layers were separated, and the aqueous layer washed with ethyl acetate (200 ml). The ethyl acetate extracts were comb in ed, dried over an hydrous sodium sulfate, filtered, and concen trated to an oil whichCl O O Cl心丁 3NO 2—78 ° C underallowed to warm to 0was chromatographed on silica gel with 20perce nt ethyl acetate in hexa ne to give 21.6 g of 2-(2-Fluoro-pyridi n-4-yl)-1-(3-trifluoromethyl-phe nyl)-etha none (84.8%yield).Return。