经典合成反应标准操作—氨基的保护及脱保护 药明康德新药开发有限公司

胺/甲酸对于除去Cbz要比前两者要好[7]。当HBr/HOAc脱去Cbz保护基时，产物往往带又一点颜色，而且分解产生的溴化苄会产生一些副反应并难以除尽，而催化氢解多数能得到无色得产物。由于硫能使催化剂中毒，因此，含有胱氨酸、半胱氨酸等含硫的肽等N-苄氧羰基氨基衍生物一般不用催化氢解法脱除。一般溶剂可以用甲醇，乙醇，乙酸乙酯， 四氢呋喃等，在醇类质子溶剂中反应速度要快的多。

1. G. Briefer, T. T. Nesftrick., Chem. Rew., 1974, 74, 567

2. A. E. Jackson, R. A. Johnstone., Synthesis., 1976, 685; G. M. Anantharamaiah, K. M. Sivanandaiah., J. Chem. Soc., Perkin Trans. 1, 1977, 490

3. M. Makowski, B. Rzeszotarska, L. Smelka et al., Liebigs Ann. Chem., 1985, 1457 4. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268

5. B. Eiamin, G. M. Anantharamaiah, G. P. Royer et al., J. Org. Chem., 1979, 44, 3442 6. M, J. O. Anteunis, C. Becu, F. Becu et al., Bull. Soc. Chim. Belg., 1987, 96, 775

7. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268 D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268

如果在Boc2O存在下用Pd/C进行氢化，则释放出的胺直接转变成Boc衍生物[1]。而且这类反应往往要比不加Boc2O来的快，其主要由于氢解出来的胺往往会与贵金属有一定的络合，使催化剂的活性降低，和Boc2O反应为酰胺后则去除了这一效果。另外有时在氢解时加入适当的酸促进反应也是一样的道理，避免了生成的胺降低反应的活性。 1. M. Sakaitani, K. Hori, Y. Ohfune., Tetrahedron Lett., 1988, 29, 2983

另外当分子中有卤原子(Cl, Br, I)存在时，一般直接用Pd/C会造成脱卤的发生，一般这种情况下，使用PdCl2为催化剂，以乙酸乙酯或二氯甲烷为溶剂可较好的避免脱卤的发生。

用MeOH/DMF为溶剂时，在Cbz-赖氨酸衍生物氢化的过程中会生成N-甲基化的赖氨酸[1]。使用氨为溶剂时，H2/Pd-C在-33℃下氢化，肽中的半胱氨酸或蛋氨酸单元不使催化剂毒化，此外，氨还会阻止BnO醚的还原，所以对Cbz可得到一些选择性[2-3]。

1. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268

2. J. P. Mazaleyrat, J. Xie, M. Wakselman., Tetrahedron Lett., 1992, 33, 4301 3. N. L. Benoiton., Int. J. Pept. Petein Res., 1993, 41, 611

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2.1.2.1 5-10%的钯-碳催化氢解示例

CbzHNOHH215%Pd/CMeOHH2NOH

C. Jaume; G. G. Santiago et al., Tetrahedron: Asymmetry, 2000, 11(22), 4549-4458 A solution of (R)-8 (0.170 g, 0.52 mmol) in absolute methanol (3 ml) was hydrogenated in the

presence of 15% Pd/C (0.026 g) at room temperature for 12 h. The mixture was filtered (Celite) and

washed with methanol. Then, perchloric acid (0.050 ml, 0.83 mmol) was added and the mixture was stirred for 5 min. The solvent was evaporated to afford (R)-7·HClO4, mp 233–235°C; [a]D23=?15.6 (c=0.68, methanol).

2.1.2.2 5-10%的钯-碳催化氢解示例

OHFHNHCbzH220%Pd(OH)2/CMeOHFHOHNH2

B. Pierfrancesco; C. silvia et al., Tetrahedron, 1999, 55(10), 3025

A solution of N-Cbz arylglycinol (17) (1.02 mmol) in MeOH (10 mL) was stirred for 15 min in the presence of an excess of Pd(OH)2/C under a dihydrogen atmosphere. The solution was then filtered on a Celite pad and the solvent removed in vaccuo. Purification of the crude afforded the desired free 2-arylglycinols (S)-21 in 87% yield, white solid; [a]D20=+47.0 (c=0.78, CHCl3); mp 94-96°C (AcOEt)。

2.1.2.3 Pd/C-甲酸铵催化氢解示例

OOHNO1OOHOOHNHCbzO10%Pd-COHCONH4HNO2OOOHNH2OOHO

Alargov, D. K; Naydenova, Z; Monatsh. Chem., 1997, 128(6-7), 725-732

576.6 mg of compound 1 (1 mmol) was dissolved in 20 ml of methanol. Then 150 mg of ammonium formate (3 mmol) and 75 mg of 10% Pd-C was added and the reaction mixture was stirred at room temperature 10 min and then heated to reflux for 45 min. The mixture was

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filtered through celite and the filtrate was evaporate to dryness to give 430 mg of compound 2 (98%). This compound was used without further purification in the subsequent step.

2.1.2.4 Pd/C-甲酸催化氢解示例

OOOO1NHNOOOO10%Pd-CHCOOHO2OOONH2NH2

Fyles, T. M.; Zeng, B.; J. Org. Chem., 1998, 63(23), 8337-8345

Compound 1 (0.6 g, 0.8 mmol) was dissolved in 1:1 formic acid/methanol (60 mL) and added to a round-bottom flask (100 mL) containing 1 equiv of palladium catalyst (10% Pd/C, 1.0 g, 0.9 mmol). The mixture was continuously stirred under reflux temperature for 24 h. The catalyst was removed by filtration and washed with an additional 10 mL of methanol. The combined solvents were removed by evaporation under reduced pressure to give Compound 2 (0.34 g, 81%, a white solid, mp 96-98 °C). This compound was used without further purification in the subsequent step.

2.1.2.5 Pd/C催化氢解脱Cbz上Boc示例

OOHNO1NHH2/10%Pd-C(Boc)2OBocHNONH2

WO2004092166

10%Pd-C was addede to a solution of compound 1 (596 mg , 1.77 mmol) and (Boc)2O (773 mg, 3.54 mmol) in etnyl acetate (30 ml). The reation vessel was evacuated and back-filled with nitrogen (three times), then back-filled with hydrogen (1 atm). After 2 h, the mixture was filtered and concentrated. Purification by silica gel chromatography (30% ethyl acetate/ hexanes - 50% ethyl acetate/ hexanes) gave compound 2 (289 mg, 54%).

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2.1.2.6 PdCl2催化氢解脱除带卤原子分子上的Cbz示例

HNNClCl1OEt3SiHNOOPdCl2ClCl2NNHNONNH

US20030144297

To a solution o compound 1 (900 mg) in methylene chloride (16.5 ml) was addede PdCl2 (30 mg) and triethylamine (0.229 ml). Triethyl silane was added (2 x 0.395 ml) over 2 h. The reaction mixture stirred 1 h and 2 ml of trifluoroacetic acid was added. After 30 min the reaction was basified with 2 N NaOH, extracted with methylene chloride, dried over MgSO4, filtered and concentrated. Chromatography was run on a biotage 40S column with 3-5% MeOH/CH2Cl2 with 0.5% NH4OH to provide compound 2 as a oil (501 mg, 74%).

2.1.2.7 Pd黑催化氢解，用氨为溶剂,半胱氨酸的Cbz脱除示例

OSOHNHCbz3H2Pd4SNH2OOH

Arthur M. Felix, Manuel H. Jimenz et a1., Org. Syn., 59, 159

A dry 1-L three-necked, round-bottomed flask is equipped with a dry ice reflux condenser, a gas-inlet tube, and a magnetic stirring bar as illustrated in the figure. The reaction vessel is

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