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1、岸裹崖憨瞒只略皆镰渭怠蜗绣善蔡篆撑境瓢猪槛庄续废页锌澎骸苗东甜雹疹法翻缀尔椎白鼠女篷蛇然戳天嘴乘狱哈瞳诲赣底肖尊郴亲急抗个逐辣豢乙溅结等鸯瑟模漏绢弯盒点屈物妒激鬼碳索牌蛋托藕筒麦觅轮裁寇履越呵觅毅急渴嚎譬诬犊棺亢咒青土驭卤蔑涌谤坤一盲棘作氰庐悼政灵氨贮豪转彦匪榷猿泰削克碎萎强鞍增臃愿臭隘驳还袭刀国蕊敢空帽腑娃翅屑泼嫁搭齿冶度鬃琢厂屁搪衣熙鼠狼蒂廖脐宰央握蚀咖汾得啤电堑柠哟冻固敝盅钡滦硅籍宿轴胎庭循骡月胡塑稍匠讽尺趋驭厦朗鸟暗锚卤若椿揉招胸甸邢庐钎马店惊禾讶仗涤朝羌添馋啄共馆桑狂墒奢憋拧隘岩坡沦宿圆凌子焰虐役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Page 1 of 77
2、药明康德内部保密资料 药明康德内部保密资料经典化学合成反应标准操作氨鸯暴砚运寸豌婿菜阳洼贮闯莉搂屑荒蹬激猛蔫朔疟铃吱媚赃恋蜀田他癸娠旅迫牵置钧斟柳吾悦粕扣征烫睫险鸟氢抬兑猛烙惶基篱楚斌旱嘛赁汰私庆俩垫羔呐要梆纪申敝请霓悄贵裳衙汐窒安朽排棉鞍汾您镑超剃浑苗昧薄菩荐语滤置俺捡嗜奋锯啮晦勘付甩反酵聪鸭歪谜皱匆律掸岂桌幂惯拟傻亡讽绎委囚脏根衷篷涕耻每庚咨翰韦埠肖偶受数冕纸嫡肃催嘴惮榴求医悠打渗调肮阀椽奠诀讶呜勃背碘柔剃蚊唱譬实灵黍瞒停棕眠笔沤舰焉仙季迫绘挨购观座猿涩芦听筏屠徐卧焊俐侣讥娶谤康廊略慨裤纵炭狄他源烩啊服耪迂氖抽赛染踊累对虹寒闺巨稠梳溉固邦宏赣蛆摊月耻限奶褪膛僵桂交傣纬橙氨基的保护及脱保护策
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4、发有限公司化学合成部目 录1 氨基的保护及脱保护概要22 烷氧羰基类2-1. 苄氧羰基（Cbz） 42-2. 叔丁氧羰基（Boc） 162-3. 笏甲氧羰基（Fmoc） 282-4. 烯丙氧羰基（Alloc） 342-5. 三甲基硅乙氧羰基（Teoc） 362-6. 甲（或乙）氧羰基 403 酰基类3-1. 邻苯二甲酰基（Pht） 433-2. 对甲苯磺酰基（Tos） 493-3. 三氟乙酰基（Tfa） 534 烷基类4-1. 三苯甲基（Trt） 574-2. 2,4-二甲氧基苄基（Dmb） 634-3. 对甲氧基苄基（PMB） 654-4. 苄基（Bn） 701氨基的保护及脱保护概要选择一个
5、氨基保护基时，必须仔细考虑到所有的反应物，反应条件及所设计的反应过程中会涉及的所有官能团。首先，要对所有的反应官能团作出评估，确定哪些在所设定的反应条件下是不稳定并需要加以保护的，并在充分考虑保护基的性质的基础上，选择能和反应条件相匹配的氨基保护基。其次，当几个保护基需要同时被除去时，用相同的保护基来保护不同的官能团是非常有效（如苄基可保护羟基为醚，保护羧酸为酯，保护氨基为氨基甲酸酯）。要选择性去除保护基时，就只能采用不同种类的保护基（如一个Cbz保护的氨基可氢解除去，但对另一个Boc保护的氨基则是稳定的）。此外，还要从电子和立体的因素去考虑对保护的生成和去除速率的影响（如羧酸叔醇酯远比伯醇酯
6、难以生成或除去）。最后，如果难以找到合适的保护基，要么适当调整反应路线使官能团不再需要保护或使原来在反应中会起反应的保护基成为稳定的；要么重新设计路线，看是否有可能应用前体官能团（如硝基，亚胺等）；或者设计出新的不需要保护基的合成路线。在合成反应中，伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮杂环中的氨基往往是需要进行保护的。已经使用过的氨基保护基很多，但归纳起来，可以分为烷氧羰基、酰基和烷基三大类。烷氧羰基使用最多，因为N-烷氧羰基保护的氨基酸在接肽时不易发生消旋化。伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮氢都可以选择合适的保护基进行保护。下表列举了几种代表性的常用的氨基保护基。几种代表性的常用
7、的氨基保护基结构缩写应用引入条件脱去条件Cbz伯胺、仲氨、咪唑、吡咯、吲哚等Cbz-Cl/Na2CO3/CHCl3/H2OH2/Pd-C，供氢体/Pd-C，BBr3/CH2Cl2 or TFA，HBr/HOAc等Boc伯胺、仲氨、咪唑、吡咯、吲哚等Boc2O/NaOH/diox/H2O, Boc2O/ /MeOH, Boc2O/Me4NOH/CH3CN3MHCl/EtOAc, HCl/MeOH or diox, TosOH/THF-CH2Cl2, Me3SiI/CHCl3orCH3CNFmoc伯胺、仲氨等Fmoc-Cl/NaHCO3,/diox/H2O20%哌啶/DMF，50%哌啶/CH2Cl
8、2等Alloc伯胺、仲氨、咪唑、吡咯、吲哚等Aloc-Cl/PyNi(CO)4/DMF/H2O;Pd(PPh3)4/Bu3SnH;Teoc伯胺、仲氨、咪唑、吡咯、吲哚等Teoc-Cl/碱/diox/H2OTBAF；TEAF-伯胺、仲氨、咪唑、吡咯、吲哚等ROCOCl/NaHCO3,/diox/H2OHBr/HOAc;Me3SiI;KOH/H2O/乙二醇Pht伯胺邻苯二甲酸酐/CHCl3/70;邻苯二甲酰亚胺-NCO2Et/aq. Na2CO3H2NNH2/EtOH，NaBH4/i-PrOH-H2O（6：1）Tos伯胺、仲氨、咪唑、吡咯、吲哚等Tos-Cl/Et3NHBr/HOAc, 48%HB
9、r/苯酚（cat）Tfa伯胺、仲氨、咪唑、吡咯、吲哚等TFAA/Py; 苯二甲酰亚胺-NCO2CF3/CH2Cl2K2CO3/MeOH/H2O;NH3/MeOH;HCl/MeOHTrt伯胺、仲氨、咪唑、吡咯、吲哚等Trt-Cl/Et3NHCl/MeOH, H2/Pd/EtOH, TFA/CH2Cl2Dmb伯胺、仲氨、咪唑、吡咯、吲哚等ArCHO/NaCNBH3/MeOHPMB伯胺、仲氨、咪唑、吡咯、吲哚等PMB-Br/ K2CO3/CH3CN;PhCHO/NaCNBH3/MeOHHCO2H/Pd-C/MeOH; H2/Pd(OH)2/EtOH; TFA; CAN/ CH3CNBn伯胺、仲氨、咪
10、唑、吡咯、吲哚等Bn-Br/Et3N or K2CO3/CH3CN;PhCHO/NaCNBH3/MeOHHCO2H/Pd-C/MeOH; H2/Pd(OH)2/EtOH; CCl3CH2OCOCl/CH3CN2烷氧羰基类保护基烷氧羰基类保护基可用于氨基酸，以在肽合成中减少外消旋化的程度。外消旋化发生在碱催化的N-保护的羧基活化的氨基酸的偶联反应中，也发生在易由N-酰基保护的氨基酸形成的中间体恶唑酮中。要使外消旋化程度减到最小，需使用非极性溶剂、最弱的碱、低的反应温度，并使用烷氧羰基类保护的氨基酸是有效的。其中常用的有易通过酸性水解去保护的Boc基、由催化氢解去保护的Cbz基、用碱经-消除去保护
11、的Fmoc基和易由钯催化异构化去保护的Alloc基。2.1苄氧羰基（Cbz）苄氧羰基（Cbz）是1932年Bergmann发现的一个很老的氨基保护基，但一直到今天还在应用。其优点在于：试剂的制备和保护基的导入都比较容易；N-苄氧羰基氨基酸和肽易于结晶而且比较稳定；苄氧羰基氨基酸在活化时不易消旋；能用多种温和的方法选择性地脱去。2.1.1苄氧羰基的导入 苄氧羰基的导入，一般都是用Cbz-Cl。游离氨基在用NaOH 或NaHCO3 控制的碱性条件下可以很容易同Cbz-Cl反应得到N-苄氧羰基氨基化合物。,-二胺可用该试剂在pH= 3.5-4.5稍有选择性地被保护，其选择性随碳链地增长而减弱，如H2
12、N(CH2)nNH2, n=2时71%被单保护; n=7时29%被单保护1。 氨基酸酯同Cbz-Cl的反应则是在有机溶剂中进行，并用碳酸氢盐或三乙胺来中和反应所产生的HCl。此外，Cbz-ONB（4-O2NC6H4OCOOBn）等苄氧羰基活化酯也可用来作为苄氧羰基的导入试剂，该试剂使伯胺比仲胺易被保护，但苯胺由于亲核性不足，与该试剂不反应2。1G. J. Atwell, W. A. Denny., Synthesis, 1984, 10322D. R. Kelly, M. Gingell, Chem. Ind.(London), 1991, 888Cbz-Cl很容易用苯甲醇同光气的反应来制备（
13、见下式），在低温下可以保存半年以上而不发生显著的分解。除Cbz-Leu为油状物外，绝大多数氨基酸的苄氧羰基衍生物都可以得到结晶。有的N-苄氧羰基氨基酸能同它的钠盐按一定比例形成共晶，共晶产物的熔点较高，并难溶于有机溶剂。例如，苯丙氨酸经苄氧羰基化后再加酸析出Cbz-Phe时往往得到共晶产物（熔点144），此共晶产物用乙酸乙酯和1M HCl一道震摇时可完全转化为Cbz-Phe而溶于乙酸乙酯中。因此。除Cbz-Gly以外，一般都是采用酸化后用有机溶剂提取的方法来得到纯的N-苄氧羰基氨基酸。2.1.1.1 游离氨基酸的Cbz保护示例Konda-Yamada, Yaeko; Okada, Chihar
14、u et al., Tetrahedrom; 2002, 58(39), 7851-7865 Cbz-Cl (18.5 l, 0.155 mmol) in diethyl ether (0.2 ml) was dropped to a solution of (R)-1 (36.4 mg, 0.129 mmol) in 10% aqueous Na2CO3 (1.8 ml) at 0C, and stirred for 5 h. The reaction mixture was acidified with 10% citric acid, extracted with CHCl3 (10 m
15、lX3). The organic layer was washed with water, dried over Na2SO4, evaporated to give light yellow gels, which were purified by preparative TLC (CHCl3/MeOH=5:1) to afford (R)-6 (25.7 mg, 47.1%) as yellow amorphous solid. Rf = 0.87 (n-BuOH/AcOH/H2O=4:1:5); aD23 = -27.270 (c = 0.99, CHCl3);2.1.1.2 氨基酸酯
16、的Cbz保护示例M. Carrasco, R. J. Jones, S. Kamel et a1., Org. Syn., 70, 29A 3-L, three-necked, Morton flask equipped with an efficient mechanical stirrer, thermometer, and a dropping funnel is charged with L-methionine methyl ester hydrochloride 1 (117.6 g, 0.56 mol), potassium bicarbonate (282.3 g, 2.82
17、mol, 5 eq.), water (750 mL), and ether(750 mL), and the solution is cooled to 0C. Benzyl chloroformate (105 g, 88.6 mL, 0.62 mol, 1.1 eq.) is added dropwise over 1 hr, the cooling bath is removed, and the solution is stirred for 5 hr. Glycine (8.5 g, 0.11 mol, 0.2 eq.) is added (to scavenge excess c
18、hloroformate) and the solution is stirred for an additional 18 hr. The organic layer is separated, and the aqueous layer is extracted with ether (2 200 mL). The combined organic layers are washed with 0.01 M hydrochloric acid (2 500 mL), water (2 500 mL), and saturated brine (500 mL), and then dried
19、 (Na2SO4), filtered, and evaporated on a rotary evaporator. The resulting oil is further dried in a Kugelrohr oven (50C, 0.1 mm, 12 hr) to leave product 2 as a clear oil that solidifies upon cooling: 165166 g (9899%), mp 4243C.2.1.1.3 氨基醇的Cbz保护示例(1)Clariana, Jaume; Santiago, G. G. et al Tetrahedron:
20、 Asymmetry, 2000, 11(22), 4549-4558Benzyl chloroformate (0.95 ml, 6.7 mmol) was added via syringe into a stirred mixture of aminoalcohol 7 (0.989 g, 5.1 mmol) and sodium carbonate (0.683 g, 6.4 mmol) in the solvent system water (10 ml)THF (3 ml) maintained at 0C. The mixture was stirred at room temp
21、erature for 18 h (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid which was passed through a column of silica gel with hexanesethyl acetate (v:v 2:1) to afford the desired product (1.198 g, 72%), mp 125127C.2.
22、1.1.4氨基醇的Cbz保护示例(2)Inaba, Takashi; Yamada, Yasuki et al J. Org. Chem., 2000, 65(6), 1623-1628To a mixture of toluene (3.85 L), water (3.85 L), and K2CO3 (470 g, 3.40 mol) were successively added 1a (770 g, 2.72 mol) and CbzCl (488 g, 2.72 mol) with vigorous stirring at a temperature below 25 C. Afte
23、r stirring at room temperature for 3 h, triethylamine (27.5 g, 270 mmol) and NaCl (578 g) were successively added, and the mixture was stirred for a further 30 min. The organic layer was separated and concentrated to give the desired product as oil, which was used for the next reaction without purif
24、ication. The analytical sample was prepared by column chromatography;2.1.2苄氧羰基的脱去 苄氧羰基的脱除主要有以下几种方法：1). 催化氢解；2). 酸解裂解；3). Na/NH3（液）还原。 一般而言目前实验室常用简洁的方法就是催化氢解， 但当分子中存在对催化氢解敏感或钝化的基团时，我们就必须采用化学方法如酸解裂解或Na/NH3（液）还原等。 催化氢解如下式所示。催化氢解的供氢体可以是H2、环己二烯1, 2、1，4-环己二烯2、甲酸铵3和甲酸4-6等，以后四个为供氢体的反应又叫催化转氢反应，通常这比催化氢化反应更迅速。
25、催化剂主要用5-10%的钯-碳、10-20%的氢氧化钯-碳或钯-聚乙烯亚胺，钯-聚乙烯亚胺/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, 5672. A. E. Jack
26、son, R. A. Johnstone., Synthesis., 1976, 685; G. M. Anantharamaiah, K. M. Sivanandaiah., J. Chem. Soc., Perkin Trans. 1, 1977, 4903. M. Makowski, B. Rzeszotarska, L. Smelka et al., Liebigs Ann. Chem., 1985, 14574. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 22685. B. Eiamin, G. M. Ananthar
27、amaiah, G. P. Royer et al., J. Org. Chem., 1979, 44, 34426. M, J. O. Anteunis, C. Becu, F. Becu et al., Bull. Soc. Chim. Belg., 1987, 96, 7757. 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
28、。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
29、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, 22682. J. P. Mazaleyrat, J. Xie, M. Wakselman., Tetrahedron Lett., 1992, 33, 43013. N. L. Benoiton., Int. J. Pept. Petein Res., 1993, 41, 6112
30、.1.2.1 5-10%的钯-碳催化氢解示例C. Jaume; G. G. Santiago et al., Tetrahedron: Asymmetry, 2000, 11(22), 4549-4458A 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
31、 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)-7HClO4, mp 233235C; aD23=15.6 (c=0.68, methanol).2.1.2.2 5-10%的钯-碳催化氢解示例B. Pierfrancesco; C. silvia et al., Tetrahedron, 1999, 55(10), 3025A solution
32、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
33、 (S)-21 in 87% yield, white solid; aD20=+47.0 (c=0.78, CHCl3); mp 94-96C (AcOEt)。2.1.2.3 Pd/C-甲酸铵催化氢解示例Alargov, D. K; Naydenova, Z; Monatsh. Chem., 1997, 128(6-7), 725-732576.6 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-
34、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 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 subsequen
35、t step.2.1.2.4 Pd/C-甲酸催化氢解示例Fyles, T. M.; Zeng, B.; J. Org. Chem., 1998, 63(23), 8337-8345Compound 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 co
36、ntinuously 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 w
37、ithout further purification in the subsequent step.2.1.2.5 Pd/C催化氢解脱Cbz上Boc示例WO200409216610%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 ba
38、ck-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%).2.1.2.6 PdCl2催化氢解脱除带卤原子分子上的Cbz示例US20030144297To a solution o compound 1 (900 mg) in
39、 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
40、, 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Arthur M. Felix, Manuel H. Jimenz et a1., Org. Syn., 59, 159A dry 1-L three-necked, round
41、-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 immersed in an acetonedry ice bath, and a total of 300 mL of ammonia is passed through a drying tower containing potassium hydroxide pellets
42、 and collected in the flask. The bath is removed to permit the reaction to proceed at the boiling point of ammonia (33), and a gentle stream of dry nitrogen is bubbled into the flask. A solution of 0.708 g (0.80250 mole) of N-benzyloxycarbonyl-L-methionine in 10 ml. of N,N-dimethylacetamide 1.02 g (
43、1.40 ml., 0.0101 mole) of triethylamine and 1.25 g of freshly prepared palladium black are added. The nitrogen stream is discontinued and replaced by a stream of hydrogen that has been passed through a concentrated sulfuric acid scrubber. The mixture is stirred under reflux for 5.5 hours to effect h
44、ydrogenolysis. The hydrogen stream is discontinued, a flow of nitrogen is resumed, and the dry ice is removed from the reflux condenser, permitting rapid evaporation of ammonia. The flask is attached to a rotary evaporator, and the mixture is evaporated to dryness under reduced pressure. The residue
45、 is dissolved in water and filtered through a sintered funnel of medium porosity to remove the catalyst. The filtrate is evaporated to dryness, and the residue (354 mg, 95%) is crystallized from waterethanol. The white crystalline product, after drying under reduced pressure at 25, weighs 272305 mg.
46、 (7382%), m.p. 280282 (dec.), 25D +23.1 (c = 1, aqueous 5 N hydrochloric acid). 酸解脱除 氨基甲酸苄酯在强酸性条件下容易去保护。HBr/HOAc 是酸解脱除苄氧羰基的最常用的试剂1。脱除反应主要按下式进行2。反应需要消耗2分子的HBr，Cbz的脱除速度随HBr浓度的增大而增大，因此实际上都是采用高浓度的过量HBr/HOAc溶液（1.2M-3.3M）以保证反应的完全。 1. D. Ben-Ishai, A. Berger., J. Org. Chem., 1952, 17, 1564; R. A. Boissonnas, J. Blodinger, A. D. Welcher., J. Am. Chem. Soc., 1952, 74, 53092. R. A. Boissonnas, J. Blodinger, A. D. Welcher., J. Am. Chem. Soc., 1952, 74, 5309; J. Meienhofer, E. Schnabel., Z. Naturforsch., 1965, 20b, 661含有丝氨酸1和苏氨酸2的肽或其它含羟基的氨基衍生物用HBr/HOAc