其他方法合成胺-060123

1、其他方法合成胺060123經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作其他方法合成胺編者：劉國超經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作一其它方法制備胺PharmaTech Co., Ltd藥明康德新藥開發(fā)有限公司化學(xué)合成部藥明康德內(nèi)部保密資料Page 8 of 171. Curtius重排合成胺及相應(yīng)的衍生物Curtius重排是一種常用的將竣酸轉(zhuǎn)化為少一個(gè)碳的胺及相應(yīng)衍生物的方法。其機(jī)理如下O1R OHR N_N_NR-NH2OXRHN NHR'首先酰氯被轉(zhuǎn)化為酰基疊氮，其加熱重排脫去一分子氮?dú)夂蟮玫较鄳?yīng)的異氟酸酯,酸酯水解或和其他親核試劑反應(yīng)得到胺及相應(yīng)的衍生物。早期的合成方法都是將酸轉(zhuǎn)變?yōu)橄鄳?yīng)的酰氯，再生成?；B氮。后

2、來Shiori (JACS, 1972, 94, 6203)等人報(bào)道了 DPPA和竣酸在室溫下很溫和的生成?；B氮，可一鍋法合成胺。若直接用過量的醇或直接用醇做溶劑可得到相應(yīng)的胺的衍生物。如用甲醇可一步得到Cbz保護(hù)的胺；用叔丁醇可一步得到Boc保護(hù)的胺。OPhOP-N3PhO'O人R OHDPPAR-N=C=O“0R-NH2OUR OHO PhOP-N3PhO'DPPAR'OHRN3AR-N=C=OR'OHOR'般情況下，用此方法直接做胺并不是一個(gè)好的方法,特別是制備烷基胺，其主要有兩個(gè)原因：一是得到的胺特別是烷基胺不易純化；二是加水分解異氟酸酯時(shí)得到

3、的胺另外也有人使用稀酸會(huì)和未反應(yīng)完全的異氟酸酯反應(yīng)成月尿，因此分解時(shí)要?jiǎng)×覕嚢? 水解異氟酸酯得到相應(yīng)的胺的鹽酸鹽1.1 酰基疊氮重排合成胺示例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.疊氮酰胺在H2O里加熱重排成胺還是有一些報(bào)道的。如下:Field q，allablllty List魚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 現(xiàn)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?？?#163;歸英£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保護(hù)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保護(hù)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劑，在研究過程中我們發(fā)現(xiàn)若在反 應(yīng)液中加入3-5當(dāng)量的Boc2O可抑制副反應(yīng)，提高反應(yīng)產(chǎn)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降解是將伯酰胺通過氧化降解成少一個(gè)碳原子的伯胺，其機(jī)理如下:-Br-° NRH2OR NH2 + CO2最早期的Hofmann降解是使用NaOH水溶液和Br2來實(shí)施的。這個(gè)條件比較劇烈,后續(xù)有許多改進(jìn)的方法陸續(xù)被報(bào)道，主要是通過改進(jìn)氧化劑和堿。如 Keillor等人1997年報(bào)道了用NBS做氧化劑，DBU做堿，甲醇中回流25分鐘就得到了甲氧染基保護(hù)的 胺(JOC, 1997, 62, 749

19、5-7496)2.1 經(jīng)典的Br2-NaOH體系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 經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作一其它方法制備胺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作氧化劑用于Hofmann降解示例藥明康德內(nèi)部保密資料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)作氧化劑用于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作氧化劑用于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)作氧化齊1J用于CONH 2 1. BTINH2HCl2. H2O3. HCl經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作一其它方法制備胺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藥明康德內(nèi)部保密資料Page15 of 173 .通過Burges

40、s試劑直接將伯醇轉(zhuǎn)化為烷氧?；０纷罱黈OO中人報(bào)道了使用Burgess試劑可以一步將伯醇轉(zhuǎn)化為相應(yīng)的烷氧染基酰 胺，其機(jī)理如下：50OC-+RCH2OH + CbzNHSO 2Cl CbzNHSO 2OCH2R + NH3 -二 CbzN SO2OCH2R + HN Et3CbzNSO 2O-"Cl CbzNHCH 2R1RN NaOHCbzNSO 2ONaR3.1 通過Burgess試劑直接將伯醇轉(zhuǎn)化為烷氧?；０肥纠齈hCH2OHC1SO2NCO 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叔碳或葦位的碳正離子比較穩(wěn)定，如果體系中有合適的親核試劑，碳正離子可以與 這些親核試劑反應(yīng)。利用這一點(diǎn)，如果在體系中加入月青，酰胺，疊氮等親核試劑做胺源,可以制備各種胺或胺的衍生物RORoRiNH2R3R2NH2H2so4R3R2H2NXR3O HQiN Ir xR2H2N ri14.1 經(jīng)過叔碳正離子與睛，酰胺或月尿等反應(yīng)制備胺的衍生物示例kovalev等人1997年報(bào)道了金剛醇在強(qiáng)酸性條件下失羥負(fù)離子，生成的碳正離子與 月青，酰胺，月尿等親核試劑反應(yīng)制備相應(yīng)的胺衍生物。A sol