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： 刘国超药明康德新药开发有限公司化学合成部1Curtius 重排合成胺及相应的衍生物Curtius重排是一种常用的将羧酸转化为少一个碳的胺及相应衍生物的方法。 其机理如下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氰酸酯，异氰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。 后来Shiori（JACS，1972，94，6203）等人报道了DPPA和羧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
2、生物。如用苄醇可一步得到Cbz保护的胺; 用叔丁醇可一步得到Boc保护的胺。一般情况下，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；二是加水分解异氰酸酯时得到的胺会和未反应完全的异氰酸酯反应成脲，因此分解时要剧烈搅拌， 另外也有人使用稀酸水解异氰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 o
3、f DMF was added and the mixture was heated to reflux for 2 h. The crude mixture was evaporated to dryness and 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 th
4、e solution was extracted with toluene (50 mL). The organic layers were dried over sodium sulfate and heated to 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 ev
5、aporated. The residue was purified by column chromatography (dichloromethane) to yield 660 mg (39%) of the title compound.Reference: Tetrahedron Lett., 2004, 45, 95 - 98.1.2 使用DPPA合成胺示例2-benzyloxy-3-methoxy-4-nitroanilin acid (27.9 g, 91.8 mmol) was dissolved in THF (400 mL) and treated with Et3N (3
6、0 mL). Diphenylphosphoryl azide (26.5 g, 96.4 mmol) was added dropwise and the reaction mixture was stirred for 3 h at 25 oC. H2O (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 K2CO3 (100 mL), dilu
7、ted with H2O (500 mL), and extracted with EtOAc (2 500 mL). The combined organic extracts were washed with saturated aqueous NaCl (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 25% EtOAchexanes) to afford the title compound (19.5 g,
8、 78%) as a yellow solid.Reference: J. Am. Chem. Soc., 2004, 126, 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：1.3 使用DPPA和苄醇合成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
9、) was heated at reflux for 3 h. After being cooled 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. Ch
10、em., 2001, 6, 557 - 563.1.4 使用DPPA和叔丁醇合成Boc保护的胺示例由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)
11、in dioxane (430 mL) under nitrogen. The mixture was 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 magnes
12、ium sulfate, and concentrated under vacuum to provide 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：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分钟就得到了甲氧羰基保
13、护的胺（JOC, 1997, 62, 7495-7496）.2.1 经典的Br2-NaOH体系Hofmann 降解示例Sodium hydroxide (3.48 kg, 87.0 mol) was dissolved in water (22 L), and the solution was cooled to 0C. Bromine (0.63 L, 11.8 mol) was added over 30 min while the temperature was maintained at 0-10C. In a second vessel, (R)-tosylasparagine (2
14、.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 cold at 0-10C. The solution was cooled to 0C, and the sodium hypobromite solution was added over 10 min while maintaining a temperature 10C. After the addition, the resulting yellow solution was ag
15、ed for 15 min at 10-15C, and then heated to 40C within 30 min. Heating was suspended and the reaction temperature was allowed to increase to 50C over 20 min due to the exothermic reaction. When the internal temperature dropped to 45C, the reaction solution was heated to 70C over 20 min and kept at 7
16、0C for 10 min. HPLC analysis measured a 90% solution yield of compound 2. The reaction was cooled to 10-15C, and with vigorous stirring the pH of the mixture was adjusted to 7 by the addition of concentrated hydrochloric acid (4 L), whereupon the product precipitated. The mixture was stirred for 20
17、min at 15C, 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 20C affording (2R)-3-amino tosylaminoalanine (1.67 kg, 70%).Reference: JOC, 1998, 63, 9533-9534.2.2 NBS作氧化剂用于Hofmann
18、降解示例p-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 continue for another 10 min. Methanol was then removed by rotary evaporation, and th
19、e residue was dissolved in 50 mL of EtOAc. The EtOAc solution was washed with 5% HCl and saturated NaHCO3 and was then dried over MgSO4. The product, methyl (p-methoxyphenyl) carbamate, was purified by flash column chromatography (silica gel, eluant 5% EtOAc in CH2Cl2) to give a white solid (86 mg,
20、95%),Reference: JOC, 1997, 62, 7495-7496.2.3 PhI(OCOCH3)作氧化剂用于Hofmann 降解示例A slurry of N-benzyloxycarbonyl-L-asparagine (140 g, 0.53 mol), ethyl acetate(680 mL), acetonitrile (680 mL), water (340 mL), and Iodobenzene I,I-diacetate (200 g, 0.62 mol) was cooled and stirred at 16C for 30min. the tempera
21、ture was allowed to reach to 20C, and the reaction was stirred until completion (4h). The mixture was cooled to 5C, and the product was filtered, washed with ethyl acetate (100 mL), and dried in vacuo at 50C to afford the target compound (100 g, 79%) 1HNMR: zsf0303 73， TLC:(Chloroform/Methanol/aceti
22、c acid 5:3:1)Preparation of Iodobenzene I,I-diacetateTo a flask was charged with iodobenzene (20.4 g, 0.10 mol) and immersed in a water bath maintained at 30C. Commercial 40% peracetic acid (31 mL., 0.24 mole) was added dropwise to the well-stirred iodobenzene over a period of 3040 minutes. After fu
23、rther 20 minutes at a bath temperature of 30C, a homogeneous yellow solution was formed. Crystallization of iodosobenzene diacetate may begin during this period. The beaker is chilled in an ice bath for 1 hour. The crystalline diacetate was collected on a Bchner funnel and washed with cold water (3*
24、20 mL). After drying for 30 minutes on the funnel with suction, the diacetate was dried overnight in a vacuum desiccator containing anhydrous calcium chloride to provide the diacetate (26.729.3 g. 8391%).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 hyd
25、roxide (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 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,
26、and the extracts were dried with anhydrous magnesium sulfate. Ether containing hydrogen chloride was added, and the mixture was allowed to stand for several days. The solid was collected recrystallized from ethyl alcohol to give the target compound (3 g, 64% yield)Reference: JACS, 1958, 9652.5 PhI(O
27、CF3)2 (BTI)作氧化剂用于Hofmann 降解示例A 500-mL, round-bottomed flask is equipped with a magnetic 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 wa
28、ter. Cyclobutanecarboxamide (2.48 g, 25 mmol) was added; the amide quickly dissolves. 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
29、acid. The mixture was transferred to a separatory funnel and the layers were separated. 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 evap
30、orator using a vacuum pump. Benzene (50 mL) was added to the residue and the solution 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 overni
31、ght. To the product was added 5 mL of absolute ethanol and 35 mL of anhydrous ether, 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 a
32、dded slowly until crystallization just begins. The flask was placed in the freezer and the product was allowed to crystallize. Filtration of the product and drying overnight under reduced pressure over phosphorus pentoxide to provide cyclobutylamine hydrochloride (1.862.06 g, 6977%).Reference: Organic Syntheses, Coll. Vol. 8, p.132; Vol. 66, p.1323. 通过Burgess试剂直接将伯醇转化为烷氧羰基酰胺最近Wood等人报道了使用Burgess试剂可以一步将伯醇转化为相应的烷氧羰基酰胺，其机理如下：3.1 通过Burgess试剂直接将伯醇转化为烷氧羰基酰胺示例To a stirred solution of chlorosulfonyl isocyanate (1.30 mL, 14.9 mmol)
