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³ýCbz±£»¤»ùÍ⣬Ê嶡ÑõôÊ»ù£¨Boc£©Ò²ÊÇÄ¿Ç°¶àëĺϳÉÖйãΪ²ÉÓõݱ»ù±£»¤»ù£¬ÌرðÊÇÔÚ¹ÌÏàºÏ³ÉÖУ¬°±»ùµÄ±£»¤ÓÃBoc¶ø¶à²»ÓÃCbz¡£Boc¾ßÓÐÒÔϵÄÓÚµÄÓŵ㣺Boc-°±»ùËá³ý¸ö±ðÍⶼÄܵõ½½á¾§£»Ò×ÓÚËá½â³ýÈ¥£¬µ«ÓоßÓÐÒ»¶¨µÄÎȶ¨ÐÔ£¬Boc-°±»ùËáÄܽϳ¤Æڵı£´æ¶ø²»·Ö½â£»Ëá½âʱ²úÉúµÄÊÇÊ嶡»ùÑôÀë×ÓÔÙ·Ö½âΪÒ춡ϩ£¬ËüÒ»°ã²»»á´øÀ´¸±·´Ó¦£»¶Ô¼îË®½â¡¢ë½âºÍÐí¶àÇ׺ËÊÔ¼ÁÎȶ¨£»Boc¶Ô´ß»¯Çâ½âÎȶ¨£¬µ«±ÈCbz¶ÔËáÒªÃô¸ÐµÃ¶à¡£µ±BocºÍCbzͬʱ´æÔÚʱ£¬¿ÉÒÔÓô߻¯Çâ½âÍÑÈ¥Cbz£¬Boc±£³Ö²»±ä£¬»òÓÃËá½âÍÑÈ¥Boc¶øCbz²»ÊÜÓ°Ï죬Òò¶øÁ½ÕßÄܺܺõشîÅä¡£ 2.1.1Ê嶡ÑõôÊ»ùµÄµ¼Èë

ÓÎÀë°±»ùÔÚÓÃNaOH »òNaHCO3 ¿ØÖƵļîÐÔÌõ¼þÏÂÓöþÑõÁù»·ºÍË®µÄ»ìºÏÈܼÁÖкÜÈÝÒ×ͬBoc2O·´Ó¦µÃµ½N-Ê嶡ÑõôÊ»ù°±»ù»¯ºÏÎï[1]¡£ÕâÊÇÒýÈëBoc³£Ó÷½·¨Ö®Ò»£¬ËüµÄÓŵãÊÇÆ丱²úÎïÎÞ¶à´ó¸ÉÈŲ¢ÈÝÒ׳ýÈ¥¡£ÓÐʱ¶ÔһЩÇ׺ËÐԽϴóµÄ°·£¬Ò»°ã¿ÉÔÚ¼×´¼ÖкÍBocËáôûÖ±½Ó·´Ó¦¼´¿É£¬ÎÞÐëÆäËûµÄ¼î£¬Æä´¦ÀíÒ²·½±ã¡£

¶ÔË®½ÏΪÃô¸ÐµÄ°±»ùÑÜÉúÎ²ÉÓÃBoc2O/TEA/MeOH or DMF ÔÚ40-50¡æϽøÐнϺã¬ÒòΪÕâЩÎÞË®Ìõ¼þÏÂÓÃÓÚ±£»¤O17±ê¼ÇµÄ°±»ùËá¶ø²»»áÓÉÓÚÓëË®½»»»Ê¹O17¶ªÊ§[2]¡£Óпռäλ×èµÄ°±»ùËá¶øÑÔ£¬ÓÃBoc2O/Me4NOH.5H2O/CH3CNÊÇÊ®·ÖÓÐÀûµÄ¡£

1. D. S. Tarbell, Y. Yamamoto et al., Proc. Natl. Acad. Sci., USA, 1972, 69, 730 2. E. Ponnusamy, U. Fotadar et al., Synthesis., 1986, 48

·¼Ïã°·ÓÉÓÚÆäÇ׺ËÐÔ½ÏÈõ£¬Ò»°ã·´Ó¦ÐèÒª¼ÓÈë´ß»¯¼Á£¬ÁíÍâ¶ÔÓÚ²®°·£¬Í¨¹ýDMAPµÄʹÓÿÉÒÔÉÏÁ½¸öBoc.

Boc2O, DMAPBocArNBoc

ArNH2ArNHBoc¶ÔÓÚÓзÓôÇ»ù´æÔڵİ·£¬·ÓôÇ»ùÉϽÓBocµÄËÙ¶ÈÒ²ÊÇÏ൱¿ìµÄ£¬Òò¶øÒ»°ãû̫´óµÄÑ¡ÔñÐÔ¡£ ¶ÔÓÚÓд¼ôÇ»ù´æÔڵģ¬ÈôÓÃDMAP×ö ´ß»¯¼Á£¬Ê±¼ä³¤ÁËÒÔºó´¼ôÇ»ùÒ²ÄÜÉÏBoc£¬ Òò´Ë·´Ó¦¾¡Á¿²»Òª¹ýÒ¹¡£

ÓÉÓÚÇèËáõ¥µÄÉú³É£¬ÓÐλ×èµÄ°·ÍùÍù»áÓëBoc2OÉú³Éëå[1]¡£Õâ¸öÎÊÌâ¿Éͨ¹ý¸Ã°·NaH»òNaHMDS·´Ó¦£¬È»ºóÔÙÓëBoc2O·´Ó¦À´¼ÓÒÔ±ÜÃâ[2]¡£

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NH2BrBrBoc2ODMAP, THFHNO17%HNBr+BrHNO56%O

1. H. J. knolker, T. Braxmeier et al., Angew. Chem., Int. Ed. Engl., 1995, 34, 2497; H. J.

knolker, T. Braxmeier et al., Synlett., 1996, 502; Kessier,A.; Coleman, C. M., et al J. Org. Chem.,

2004, 69(23), 7836-7846

2. T. A. Kelly, D. W. McNeil., Tetrahedron Lett., 1994, 35, 9003

ÓÐʱÔÚ·´Ó¦ÖÐÓпÉÄܶà¼ÓÁËBocËáôû£¬µ±·Ö×ÓÖÐÎÞÓÎÀëËá¼îʱºÜÄѳöÈ¥£¬ÈôÒ»¶¨Òª³ýÈ¥£¬Ò»°ãÔÚÌåϵÖмÓÈëһЩN,N-¶þ¼×»ùÒÒ¶þ°·»òN,N-¶þ¼×»ù±û¶þ°·£¬¶øºó½«ÉÏÁËBocµÄN,N-¶þ¼×»ùÒÒ¶þ°·»òN,N-¶þ¼×»ù±û¶þ°·ÓÃÏ¡Ëá³ýÈ¥¡£

RNH2Boc2OexcessRNHBoc+Boc2O (excess)H2NNBocHNNÏ¡Ëá³ýÈ¥

ÓÉÓÚBoc¶ÔËáÃô¸Ð£¬Òò´ËÔںϳɹý³ÌÖÐÓõ½ËáÏ´»òËáÈܽâµÈ²Ù×÷ʱ£¬ÎªÁ˱£ÏÕÆð¼û£¬¾¡Á¿²»ÓÃÑÎËá¶øÓÃ10%ÄûÃÊËᣨ0.5M£©»òÔÚµÍÎÂÌõ¼þ½øÐС£

2.2.1.1 °±»ùËáBoc±£»¤Ê¾Àý

NH2COOHBoc2ONaOH, t-BuOH, H2ONHBocCOOH Oskar Keller, Walter E. Keller, Gert van Look et al., Org. Syn., 63, 160 A 4-L, four-necked, round-bottomed flask, equipped with an efficient stirrer, a dropping funnel, reflux condenser, and thermometer is charged with a solution of 44 g (1.1 mol) of sodium hydroxide in 1.1 L of water. Stirring is initiated and 165.2 g (1 mol) of L-phenylalanine is added at ambient temperature, and then diluted with 750 mL of tert-butyl alcohol. To the well-stirred, clear solution is added dropwise within 1 hr, 223 g (1 mol) of di-tert-butyl dicarbonate. A white precipitate appears during addition of the di-tert-butyl dicarbonate. After a short induction period, the temperature rises to about 30¨C35¡ãC. The reaction is brought to completion by further stirring overnight at room temperature. At this

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time, the clear solution will have reached a pH of 7.5¨C8.5. The reaction mixture is extracted two times with 250 mL of pentane, and the organic phase is extracted three times with 100 mL of saturated aqueous sodium bicarbonate solution. The combined aqueous layers are acidified to pH 1¨C1.5 by careful addition of a solution of 224 g (1.65 mol) of potassium hydrogen sulfate in 1.5 L of water. The acidification is accompanied by copious evolution of carbon dioxide. The turbid reaction mixture is then extracted with four 400-mL portions of ethyl ether. The combined organic layers are washed two times with 200 mL of water, dried over anhydrous sodium sulfate or magnesium sulfate, and filtered. The solvent is removed under reduced pressure using a rotary evaporator at a bath temperature not exceeding 30¡ãC. The yellowish oil that remains is treated with 150 mL of hexane and allowed to stand overnight. Within 1 day the following portions of hexane are added with stirring to the partially crystallized product: 2 ¡Á 50 mL, 4 ¡Á 100 mL, and 1 ¡Á 200 mL. The solution is placed in a refrigerator overnight; the white precipitate is collected on a B¨¹chner funnel and washed with cold pentane. The solid is dried under reduced pressure at ambient temperature to constant weight to give a first crop. The mother liquor is evaporated to dryness leaving a yellowish oil, which is treated in the same manner as described above, giving a second crop. The total yield of pure white N-tert-butoxycarbonyl-L-phenylalanine is 207¨C230 g (78¨C87%), mp 86¨C88¡ãC, [¦Á]D20 + 25.5¡ã (ethanol c 1.0).

2.2.1.2 °±»ùËáõ¥Boc±£»¤Ê¾Àý

NH2.HClHOCOOMeBoc2OHOEt3NNHBocCOOMe

Alessandro Dondoni, Daniela Perrone., Org. Syn., 77, 64

A 500-mL, three-necked, round-bottomed flask, is equipped with a magnetic stirring bar, thermometer, reflux condenser protected from moisture by a calcium chloride-filled drying tube, and a pressure-equalizing dropping funnel that is connected to a nitrogen flow line and is charged with a solution of 97% di-tert-butyl dicarbonate (14.3 g, 63.6 mmol) in tetrahydrofuran (100 mL), Methyl serinate hydrochloride (10.0 g, 64.3 mmol) is placed in the flask and suspended in tetrahydrofuran (200 mL) and 99% triethylamine (14.0 g, 138 mmol). The resulting white suspension is cooled with an ice-water bath and the solution of

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di-tert-butyl dicarbonate is added dropwise over a period of 1 hr. After 10 min of additional stirring, the ice-water bath is removed and the suspension is stirred overnight (14 hr) at room temperature, then warmed at 50¡ãC for a further 3 hr. The solvent is removed under reduced pressure and the residue is partitioned between diethyl ether (200 mL) and saturated aqueous bicarbonate solution (250 mL). The aqueous phase is extracted with three 150-mL portions of diethyl ether. The combined organic phases are dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 13.4-14.0 g (95-99% crude yield) of N-Boc-L-serine methyl ester as a colorless oil that is used without further purification. [¦Á] D 23 17.0¡ã (MeOH, c 4.41).

2.2.1.3 BocËáôûÔÚ¼×´¼ÖÐÓë°·Ö±½Ó·´Ó¦

COOEtBoc2ONH1MeOHNBoc2COOEt Boc2O (262 g, 1.2 mol) in MeOH (250 ml) was added to a soluton of compound 1 (157.2 g, 1.0 mol) in MeOH (350 ml) at 10¡ãC, and the resulting mixture was stirred at room temperature for 2 h. N1, N1-dimethylethane-1,2-diamine (26 g, 0.3 mol) was added and the mixture was stirred at room temperature for 15 min. The solvent was removed in vacuo, and the residue was dissolved with ethyl acetate (750 ml). The combined organics were washed with 1 N HCl (2 x 250 ml) and brine (2 x 250 ml), dried over sodium sulfate and filtered. The solvent was removed to give compound 2 (250 g, 96%), which was used directly in the next step. 2.2.1.4 ·¼°·µÄµ¥Boc±£»¤Ê¾Àý

NH2NCOOHBoc2OEt3N, DMFNNHBocCOOH

Luo, Qun-Li; Liu, Zhi-Ying et al., J. Med. Chem., 2003, 46(13), 2631-2640

3-Aminopyridine-2-carboxylic acid (5.02 g, 36 mmol) was suspended in 60 mL of dry DMF, and Et3N (15.2 mL, 108 mmol) was added dropwise at room temperature. To the resulting brown solution was added Boc2O (11.80 g, 54 mmol). After being stirred for 10 min, the

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