其他方法合成胺-060123

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
1．Curtius 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
R O
Cl R
O
N3R
O
N N N R
O
N N
R-N=C=O
+
N2
2
O
R-NH2
BnOH
R-NHCbz
R-NHBoc
R'NH2
O
NHR'
RHN
t BuOH
R O
OH
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。

R O
OH R-N=C=O
R-NH2 P
O
N3
PhO
PhO
DPPA
R
O
N3
H2O
R O
OH R-N=C=O
P
O
N3
PhO
PhO
DPPA
R
O
N3
R'OH
R'OH
R
N
H
O
O
R'
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
F F
O
CO2H
1. SOCl
2. NaN3, H2O, acetone
F F
O
NH2
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 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 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 title compound.
Reference: Tetrahedron Lett., 2004, 45, 95 - 98.
1.2 使用DPPA合成胺示例
CO2H
O
O NO2
NH2
O
O
NO2 78%
2-benzyloxy-3-methoxy-4-nitroanilin acid (27.9 g, 91.8 mmol) was dissolved in THF (400 mL) and treated with Et3N (30 mL). Diphenylphosphoryl azide (26.5 g, 96.4 mmol) was added dropwise and the reaction mixture was stirred for 3 h at 25 o C. 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), diluted 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% EtOAc−hexanes) to afford the title compound (19.5 g, 78%) as a yellow so lid. 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
O HO O +OH CbzHN NHCbz
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 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. Chem., 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Boc 2O 可抑制副反应，提高反应产率。

O O
F
O OH O O F
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 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 magnesium sulfate, and concentrated under vacuum to provide desired compound (37.6 g, 93%).
Reference: J. Med. Chem. 2004, 47, 871-887
2. 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： O N R H -OH O N
-R Br Br O N R H -OH O N -R Br
-O R H O OH
N R HO O R HO R NH 2+ CO 2
最早期的Hofmann 降解是使用NaOH 水溶液和Br 2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护的胺（JOC , 1997, 62, 7495-7496）.
2.1 经典的Br 2-NaOH 体系Hofmann 降解示例
O
OH N H
Ts 2O Br 2NaOH O OH N H Ts NH 2
Sodium 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 temperature was maintained at 0-10°C. In a second vessel, (R)-tosylasparagine (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 cold at 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 solution 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 to 50°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 min and kept at 70°C for 10 min. HPLC analysis measured a 90% solution yield of compound 2. The reaction
was cooled to 10-15°C, 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 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, 70%).
Reference: JOC , 1998, 63, 9533-9534.
2.2 NBS 作氧化剂用于Hofmann 降解示例 MeO NH 2
O
MeOH, reflux MeO H N O O
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 the residue was dissolved in 50 mL of EtOAc. The EtOAc solution was washed with 5% HCl and saturated NaHCO 3 and was then dried over MgSO 4. The product, methyl (p-methoxyphenyl) carbamate, was purified by flash column chromatography (silica gel, eluant 5% EtOAc in CH 2Cl 2) 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
2NH O
O Cbz 2NH O Cbz
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 16°C for 30min. the temperature was allowed to reach to 20°C, 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 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 Iodobenzene I,I-diacetate
I
I(OAc)2
40% peracetic acid
To a flask was charged with iodobenzene (20.4 g, 0.10 mol) and immersed in a water bath maintained at 30°C. Commercial 40% peracetic acid (31 mL., 0.24 mole) was added dropwise to the well-stirred iodobenzene over a period of 30–40 minutes. After further 20 minutes at a bath temperature of 30°C, 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 Büchner 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 chloride 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)
N
N CONH 2
2NaOH
N
N NH 2
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 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 several days. The solid was collected recrystallized from ethyl alcohol to give the target compound (3 g, 64% yield)
Reference: JACS , 1958, 965
2.5 PhI(OCF 3)2 (BTI)作氧化剂用于Hofmann 降解示例
CONH 2
2. H 2O
3. HCl
NH 2HCl
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 water. 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 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 evaporator 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 overnight. 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 added 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 (1.86–2.06 g, 69–77%).
Reference: Organic Syntheses, Coll. Vol. 8, p.132; Vol. 66, p.132
3. 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：
RCH 2OH +CbzNHSO 2Cl
CbzNHSO 2OCH 2R +NH 3
50o C
CbzN -SO 2OCH 2R + HN +Et 3
CbzNSO 2O -R CbzNHCH 2R
CbzNSO 2ONa
R
3.1 通过Burgess 试剂直接将伯醇转化为烷氧羰基酰胺示例
ClSO 2NCO
PhCH 2OH
ClSO 2NCbz
NEt 3
Et 3N +SO 2N -Cbz
1
To a stirred solution of chlorosulfonyl 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 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 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 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 to Burgess reagent, were unsuccessful.
O2N OH
Et3N+SO2N-Cbz
O2N
NHCbz
O2N
OSO2N-Cbz
23
To 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 replaced 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 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 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 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, 3887–3890
4
Ritter reaction
叔碳或苄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，如果在体系中加入腈，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。

1R 3
H 2SO 4R 1
H
N R 32
O
or NaCN, H 2SO 4
R 1H N
R 3R 2
O
H
NH 2
O
H 2SO 4
NH 2
O H 2SO 4
H 2N
NH 2O R 1
H N
R 3R 2
H 2O
H +
RO
NH 2
O R 1H
N
R 3R 2
O
+:N
CH 31R 3
N +H 2O
:
or
4.1 经过叔碳正离子与腈，酰胺或脲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，生成的碳正离子与腈，酰胺，脲等亲核试剂反应制备相应的胺衍生物。

OH +O H 2N
NH 2
H +
N H
NH 2
O
A solution of 1-adamantanol (0.304 g, 2 mmol) and urea (0.24 g, 4 mmol) in TFA (1.54 mL, 20 mmol) was heated at 115-120o C for 7 hr. After the reaction was complete, the mixture was kept at r.t. overnight. Then acetone (2 mL) was added to and precipitate was formed. The crude product was filtratrated after cooling, washed with pentane and dried to give 0.43 g target compound (83%). Reference: Synthesis , 1997, 9, 1034-1040.
浓硫酸用于Ritter反应的例子如下：
4.2经过苄位叔碳正离子与乙腈反应制备胺示例
苄位的碳正离子也能稳定存在，1995年，Merck的研究人员利用这一点，非常巧妙的合成了HIV蛋白酶抑制剂的关键中间体顺式-1-羟基-2-氨基二氢茚(TL, 1995, 36,
3993-3996)。

O H+
OH
+
OH
N+
O
N
-H+
2
OH
2N
N
N
O
t-BuHN
OH
H
N
O
OH
L-735,524
N
CH3
Into a 300 ml four-neck flask, cis-(+-)-1,2-epoxyindan (10.0 g, 75.8 mmol), acetonitrile (50 mL), and dichloromethane (40 mL) were introduced. This mixture was cooled to –30o C in a dry ice/acetone bath and 100 percent sulfuric acid (11.14 g, 113.6 mmol, prepared from 97 percent sulfuric acid and fuming sulfuric acid) was dropwise added at -30o C to -27o C in a period of 1 hour. When left for 1 hour to return to room temperature, the mixture became white and turbid to form slurry. The mixture was heated while water (72 mL) was added thereto, 100 ml of an azeotrope of acetonitrile/dichloromethane/water was distilled off in a period of 1 hour. The remaining mixture was cooled to room temperature, washed twice with 100 ml of dichloromethane, and then subjected to liquid separation. The water phase was adjusted to a strongly alkali state by an addition of 25 percent sodium hydroxide. The crystal deposited thereby was filtered off under reduced pressure, washed with water, and then dried to yield cis-(+-)-1-aminoindan-2-ol (7.53 g, 66.8%) as a white crystal.
Reference: USP 5648534.。