其他方法合成胺-060123

1、其他方法合成胺060123经典化学合成反应标准操作其他方法合成胺编者：刘国超经典合成反应标准操作一其它方法制备胺PharmaTech Co., Ltd药明康德新药开发有限公司化学合成部药明康德内部保密资料Page 8 of 171. Curtius重排合成胺及相应的衍生物Curtius重排是一种常用的将竣酸转化为少一个碳的胺及相应衍生物的方法。其机理如下O1R OHR N_N_NR-NH2OXRHN NHR'首先酰氯被转化为酰基叠氮，其加热重排脱去一分子氮气后得到相应的异氟酸酯,酸酯水解或和其他亲核试剂反应得到胺及相应的衍生物。早期的合成方法都是将酸转变为相应的酰氯，再生成酰基叠氮。后

2、来Shiori (JACS, 1972, 94, 6203)等人报道了 DPPA和竣酸在室温下很温和的生成酰基叠氮，可一锅法合成胺。若直接用过量的醇或直接用醇做溶剂可得到相应的胺的衍生物。如用甲醇可一步得到Cbz保护的胺；用叔丁醇可一步得到Boc保护的胺。OPhOP-N3PhO'O人R OHDPPAR-N=C=O“0R-NH2OUR OHO PhOP-N3PhO'DPPAR'OHRN3AR-N=C=OR'OHOR'般情况下，用此方法直接做胺并不是一个好的方法,特别是制备烷基胺，其主要有两个原因：一是得到的胺特别是烷基胺不易纯化；二是加水分解异氟酸酯时得到

3、的胺另外也有人使用稀酸会和未反应完全的异氟酸酯反应成月尿，因此分解时要剧烈搅拌, 水解异氟酸酯得到相应的胺的盐酸盐1.1 酰基叠氮重排合成胺示例2,6-difluoro-4-methoxyphenyl carboxylic acid (2.00 g, 10.6 mmol) was dissolved in thionyl chloride (16 mL). One drop of DMF was added and the mixture was heated to reflux for 2 h. The crude mixture was evaporated to dryness and

4、the residue was dissolved in 5mL acetone. A solution of sodium azide (970 mg, 14.9 mmol) in water (2 mL ) was added dropwise at room temperature. After 30 min, water (10 mL) was added and the solution was extracted with toluene (50 mL). The organic layers were dried over sodium sulfate and heated to

5、 reflux for 30 min. Then 10 mL of a 45% sodium hydroxide solution was added and the mixture was heated for a further 30 min. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (dichloromethane) to yield 660 mg (39%) of the tit

6、le compound.Reference: Tetrahedron Lett., 2004, 45, 95 - 98.1.2 使用DPPA合成胺示例1. DPPA/THF>2. Heat78%CO2H aoxt_x: Yo，no22-benzyloxy-3-methoxy-4-nitroanilin acid (27.9 g, 91.8 mmol) was dissolved in THF (400 mL) and treated with Et 3N (30 mL). Diphenylphosphoryl azide (26.5 g, 96.4 mmol) was added dro

7、pwise and the reaction mixture was stirred for 3 h at 25 oC. H 2O (150 mL) was added and the reaction mixture was refluxed for 2 h. The solvent was removed in vacuo and the residue was treated with saturated aqueous K 2CO3 (100 mL), diluted with H 2O (500 mL), and extracted with EtOAc (2500 mL). The

8、 combined organic extracts werewashed with saturated aqueous NaCl (500 mL), dried (Na2SO4), and concentrated invacuo. The crude residue was purified by flash chromatography (SiO2, 25% EtOAc-hexanes) to afford the title compound (19.5 g, 78%) as a yellow so lid.Reference: J. Am. Chem. Soc., 2004, 126

9、,8396 - 8398.叠氮酰胺在H2O里加热重排成胺还是有一些报道的。如下:Field q，allablllty List鱼codeFidd Nameocc.RXReaction Details1Reaction 口etails倒匚Reacfion ClassificationMultistageMt. MStages2»tage 1Rtdjtjnidl ph bi lyljhus inhuryl aihd tEiNSolventdimelhylifiDmairnideTime3 hours'Te-nparature20 CStage 7SolventH2OTine1 h

10、our(Other ConditionsHeatingRef. 1437904'. Journal; Jia, Zha ash on g J; Wu, fanhoiig Huang, Weniong; Zhang, P'englie; Clizteb Lane A;Goldman, Erick A,; Sinha, Una; Arfster, Ann E.; Edwards, Susan I.; Alphonso, Medyn; Hutch al eel aha, Athiwat;毗 al,; BMCLE8;日iuocq. Med. Chem. Lett; EN; 1414;

11、5： 2004; 1221 1228.FEMI圜口!41CJReacflor Classifitsiion of OiacesStage 1R？agenlSolventTinftaTernperatureSlage 2 Heegent Solent TimeOther CnndltfonsDPPAEl3Mdineihlfcrmamlde0 hOLir(£)iu c比。cinieihfltc：rmannidt1 hnurg)HealingCoderi&ij NameOccReset an Dsiaiie1Reaction CetaiilsRof 1M37P00: J c urn

12、 si; Jis, Zhoaihang /snhong l-uang 岫31Ttlm Thing, Ponclic; Seng, Yorghcng;WDoiw. John; airti um 现用rsten, Am E., Etiwards, Susan T., Hutchaieeiana.Aifiiwai, hoi ten ba tn, StanlevJ.:eial. DMCLEe：Bmrti. Med.Chem.Lett: EN 14 5:200+: 1225-123<Field Avaj 出 bility Li5tCodeFi&dNameOcc.EXReaction Det

13、ails1Multibtdye 0圜口第Reaction 口stallsRediUtin CifltiilfkdUunN。口£归英£stage 1HeagentReaction hpeStage 2Reaceni(PhQzPONaOurius rearrangement scetons出0Fef. "63347T4, Joumsl; ihana Men, VAi, Bitji; VMa5nEr, Allan; Powel, Dennis W-； Rabiidran, Sridhar K; Kwhlcr, CcinMiinr町 9csrholli, Fnnk; MC

14、I RR； RiQDrg Msd rrhpxi I pf ； EM; 13; 2； 2a07：47i - 4?白1.3 使用DPPA和甲醇合成Cbz保护的胺示例Under an argon atmosphere, a mixture of acid (200 mg, 0.59 mmol), diisopropyl ethylamine (0.36 mL, 2.0 mmol), diphenylphosphoryl azide (0.32 mL, 1.5 mmol) in toluene (25 mL) was heated at reflux for 3 h. After being cool

15、ed to room temperature, benzyl alcohol (0.2 mL, 2 mmol) was added, and the mixture was stirred for another 1h.After removing the solvent in vacuo, silica gel column chromatography gave the title compound (230 mg, 0.50 mmol, 85%).Reference: J. Org. Chem., 2001, 6, 557 - 563.1.4 使用DPPA和叔丁醇合成Boc保护的胺示例由

16、于叔丁醇的活性不高，一般都使用叔丁醇作溶剂，在研究过程中我们发现若在反 应液中加入3-5当量的Boc2O可抑制副反应，提高反应产率。Dry tert-butyl alcohol (123 mL), triethylamine (16.7 g, 0.65 mol), and DPPA (45.5 g, 0.165 mol) were added to a solution of 5-fluoro-1,3-benzodioxole-4-carboxylic acid (29 g, 0.157mol) in dioxane (430 mL) under nitrogen. The mixture w

17、as heated at 100 C for 4.5 h. Upon cooling, the cloudy mixture was filtered. The filtrate was evaporated under vacuum, diluted in ethyl acetate, washed with a 5% aqueous citric acid, a 5% aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, and concentrated under vacuum to pro

18、vide desired compound (37.6 g, 93%).Reference: J. Med. Chem. 2004, 47, 871-8872. Hofmann 降解Hofmann降解是将伯酰胺通过氧化降解成少一个碳原子的伯胺，其机理如下:-Br-° NRH2OR NH2 + CO2最早期的Hofmann降解是使用NaOH水溶液和Br2来实施的。这个条件比较剧烈,后续有许多改进的方法陆续被报道，主要是通过改进氧化剂和碱。如 Keillor等人1997年报道了用NBS做氧化剂，DBU做碱，甲醇中回流25分钟就得到了甲氧染基保护的 胺(JOC, 1997, 62, 749

19、5-7496)2.1 经典的Br2-NaOH体系Hofmann降解示例Br2NaOHOOHTs、N ?HO nh2Sodium hydroxide (3.48 kg, 87.0 mol) was dissolved in water (22 L), and the solution was cooled to 0 C.°Bromine (0.63 L, 11.8 mol) was added over 30 min while the temperaturewas maintained at 0-10 C. In a second vessel, (R)-tosylasparagin

20、e (2.86 kg, 9.48 mol) was added in portions to a solution of NaOH (0.8 kg, 20.0 mol) in water (7.2 L) kept coldat 0-10 C. The solution was cooled to 0 C, and the sodium hypobromite solution was added over 10 min while maintaining a temperature <10 C. After the addition, the resulting yellow solut

21、ion was aged for 15 min at 10-15 C, and then heated to 40 C within 30 min. Heating was suspended and the reaction temperature was allowed to increase to50 C over 20 min due to the exothermic reaction. When the internal temperature dropped to 45 C, the reaction solution was heated to 70 C over 20

22、6; min and kept at 70 C for 10 min. HPLC analysis measured a 90% solution yield of compound 2. The reaction 经典合成反应标准操作一其它方法制备胺PharmaTech Co., Ltdwas cooled to 10-15 C, a nd with vigorous stirring the pH of the mixture was adjusted to7 by the addition of concentrated hydrochloric acid (4 L), whereupo

23、n the product precipitated. The mixture was stirred for 20 min at 15 C, and the product was filtered. The cake was slurry washed with water (2-8 L) and then displacement washed with water (8 L). The product was dried with a nitrogen stream at 20 C affording (2R)-3-amino tosylaminoalanine (1.67 kg, 7

24、0%).Reference: JOC, 1998, 63, 9533-9534.2.2NBS作氧化剂用于Hofmann降解示例药明康德内部保密资料Page 10 of 17p-Methoxybenzamide (76 mg, 0.5 mmol), NBS (90 mg, 0.5 mmol), and DBU (230 uL) in methanol (5 mL) were heated at reflux for 15 min, at which point more NBS (90 mg, 0.5 mmol) was added. The reaction was allowed to co

25、ntinue for another 10 min. Methanol was then removed by rotary evaporation, and the residue was dissolved in 50 mL ofEtOAc. The EtOAc solution was washed with 5% HCl and saturated NaHCO 3 and was then dried over MgSO4. The product, methyl (p-methoxyphenyl) carbamate, was purified by flash column chr

26、omatography (silica gel, eluant 5% EtOAc in CH2cl2) to give a white solid (86 mg, 95%),Reference: JOC, 1997, 62, 7495-7496.2.3 PhI(OCOCH 3)作氧化剂用于Hofmann降解示例OPIDA1一 NH CbzHO - NH 2A slurry of N-benzyloxycarbonyl-L-asparagine (140 g, 0.53 mol), ethyl acetate(680 mL), acetonitrile (680 mL), water (340

27、mL), and Iodobenzene I,I-diacetate (200 g, 0.62 mol) was cooled and stirred at 16 C for 3 0min. the temperature was allowed to reach to 20C, and the reaction was stirred until completion (4h). The mixture was cooled to 5 C, and the product was filtered, washed with ethyl acetate (100 mL), and dried

28、in vacuo at 50 C to afford the target compound (100 g, 79%) 1HNMR: zsf0303 73, TLC:(Chloroform/Methanol/acetic acid 5:3:1)Preparation of lodobenzene I,I-diacetateI(OAc) 2 40% peracetic acid I 一To a flask was charged with iodobenzene (20.4 g, 0.10 mol) and immersed in a water bath maintained at 30 c

29、Commercial 40% peracetic acid (31 mL., 0.24 mole) was added dropwise to the well-stirred iodobenzene over a period of 30 Y0 minutes. After further 20 minutes at a bath temperature of 30 C, a horh ogeneous yellow solution was formed. Crystallization of iodosobenzene diacetate may begin during this pe

30、riod. The beaker is chilled in an ice bath for 1 hour. The crystalline diacetate was collected on a B uchner funnel and washed with cold water (3 *20 mL). After drying for 30 minutes on the funnel with suction, the diacetate was dried overnight in a vacuum desiccator containing anhydrous calcium chl

31、oride to provide the diacetate (26.7-29.3 g. 83 -91%).2.4 NaClO作氧化剂用于Hofmann降解示例(JACS,1958,965)A mixture of indazole (4 g, 0.02 mole) and sodium hydroxide (4 g, 0.1 mole) in 30 ml of icewater containing 1.5 g. (0.02 mole) of chlorine was stirred at room temperature for 2 hours. Then the reaction was

32、 warmed on a steam-bath for 1 hour during which time the solution was effected. The solution was extracted four times with 50 ml. of ethyl acetate, and the extracts were dried with anhydrous magnesium sulfate. Ether containing hydrogen chloride was added, and the mixture was allowed to stand for sev

33、eral days. The solid was collected recrystallized from ethyl alcohol to give the target compound (3 g, 64% yield)Reference: JACS, 1958, 965Hofmann降解示例2.5 PhI(OCF 3)2(BTI)作氧化齐1J用于CONH 2 1. BTINH2HCl2. H2O3. HCl经典合成反应标准操作一其它方法制备胺PharmaTech Co., LtdA 500-mL, round-bottomed flask is equipped with a magn

34、etic stirring bar and covered with aluminum foil. To the flask was added a solution of BTI (16.13 g, 37.5 mmol) in 37.5 mL of acetonitrile, and the resulting solution was diluted with 37.5 mL of distilled deionized water. Cyclobutanecarboxamide (2.48 g, 25 mmol) was added; the amide quickly dissolve

35、s. Stirring was continued for 4 hr, and the acetonitrile was removed with a rotary evaporator. The aqueous layer was stirred with 250 mL of diethyl ether; to the stirring mixture was added 50 mL of concd hydrochloric acid. The mixture was transferred to a separatory funnel and the layers were separa

36、ted. The aqueous layer was extracted with ether (2*150 mL). The organic fractions were combined and extracted with 75 mL of 2 N hydrochloric acid. The aqueous fractions are combined and concentrated with a rotary evaporator using a vacuum pump. Benzene (50 mL) was added to the residue and the soluti

37、on was concentrated with the rotary evaporator, again using a vacuum pump. Addition of benzene and concentration was repeated five more times. The crude solid was dried under reduced pressure over sulfuric acid overnight. To the product was added 5 mL of absolute ethanol and 35 mL of anhydrous ether

38、, and the solution was heated at reflux on a steam bath. Ethanol was added slowly to the mixture, with swirling, until all the material was dissolved; the solution was cooled to room temperature. Anhydrous ether was added slowly until crystallization just begins. The flask was placed in the freezer

39、and the product was allowed to crystallize. Filtration of the product and drying overnight under reduced pressure over phosphorus pentoxide to provide cyclobutylamine hydrochloride (1.86 206 g, 69 37%).Reference： Organic Syntheses, Coll. Vol. 8, p.132; Vol. 66, p.132药明康德内部保密资料Page15 of 173 .通过Burges

40、s试剂直接将伯醇转化为烷氧玻基酰胺最近WOO中人报道了使用Burgess试剂可以一步将伯醇转化为相应的烷氧染基酰 胺，其机理如下：50OC-+RCH2OH + CbzNHSO 2Cl CbzNHSO 2OCH2R + NH3 -二 CbzN SO2OCH2R + HN Et3CbzNSO 2O-"Cl CbzNHCH 2R1RN NaOHCbzNSO 2ONaR3.1 通过Burgess试剂直接将伯醇转化为烷氧玻基酰胺示例PhCH2OHC1SO2NCO NEt3 a ClSO2NCbz Et3N+SO2N-CbzTo a stirred solution of chlorosulfo

41、nyl isocyanate (1.30 mL, 14.9 mmol) in dry benzene (35 mL) under nitrogen in a cool water bath was added anhydrous benzyl alcohol (Aldrich, 1.54 mL, 14.9 mmol) dropwise over 30 min. The water bath was then removed and the solution allowed to warm to ambient temperature for 20 min. The above solution

42、 was then transferred via cannula into a rapidly stirred solution of triethylamine (4.20 mL, 30.1 mmol) in dry benzene (17 mL) over the course of 1 h under nitrogen at ambient temperature. A slight exotherm and the formation of solid triethylamine hydrochloride were observed. After an additional 40

43、min, the contents of the reaction vessel, along with as much precipitate as possible, was transferred via cannula into a dry Schlenk filtration apparatus (medium porosity) to remove the triethylamine hydrochloride. The resulting clear, colorless, benzene solution of 1 thus prepared was estimated to

44、have a final concentration of 0.25 M. This solution could be stored in the freezer for at least a month with no deleterious effect on reaction yields, although a slight yellow color and a small amount of precipitate can develop over time. Attempts to isolate reagent 1 as a crystalline solid, similar

45、 to Burgess reagent, were unsuccessful.Et3N+SO2N-CbzO2N23NHCbzTo a flamedried reaction vessel equipped with a stir bar and septum was added 4-(4-nitrophenyl)butan-1-ol (0.21 mL, 1.25 mmol) followed by a benzene solution of 1 (5.0 mL, 1.25 mmol, 0.25 M). The septum was then removed and quickly replac

46、ed with a Teflon cap prior to the reaction being placed into a 50 C bath. After 1 h, the bath temperature was increased to 85 C and a small aliquot of the reaction mixture was removed to check for the formation of the initial adduct 2 (LC/MS generally shows M+18(H2O): 426). The reaction was stirred

47、for 12-16 h and then periodically monitored, by LC/MS, for the disappearance of 2. (CAUTION: Remove the reaction vessel from the heating bath and allow its temperature to drop below the boiling point of the solvent prior to removing an analytical sample.) Frequently, LC/MS spectra obtained prior to

48、work-up show numerous side products that disappear after work-up. After complete disappearance of 2, the reaction was cooled to ambient temperature, benzene was removed in vacuo, and the residue was partitioned between EtOAc and 0.5 M HCl. The organic layer was washed with 5% sodium bicarbonate and

49、brine, then dried over sodium sulfate. Filtration, solvent removal and silica gel chromatography (10-60% EtOAc in hexanes, linear gradient) provided the target compound (318 mg, 77%) as a white solid.Reference: Tetrahedron Letters 2002, 3887 W8904 Ritter reaction叔碳或苇位的碳正离子比较稳定，如果体系中有合适的亲核试剂，碳正离子可以与 这些亲核试剂反应。利用这一点，如果在体系中加入月青，酰胺，叠氮等亲核试剂做胺源,可以制备各种胺或胺的衍生物RORoRiNH2R3R2NH2H2so4R3R2H2NXR3O HQiN Ir xR2H2N ri14.1 经过叔碳正离子与睛，酰胺或月尿等反应制备胺的衍生物示例kovalev等人1997年报道了金刚醇在强酸性条件下失羟负离子，生成的碳正离子与 月青，酰胺，月尿等亲核试剂反应制备相应的胺衍生物。A sol