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盐酸表柔比星英语

盐酸表柔比星英语
一、盐酸表柔比星的简介
盐酸表柔比星（Epirubicin Hydrochloride）是一种抗肿瘤抗生素，属于蒽环类药物。

在我国，盐酸表柔比星被广泛应用于治疗多种恶性肿瘤，如乳腺癌、肺癌、卵巢癌等。

二、盐酸表柔比星的作用机制
盐酸表柔比星通过干扰肿瘤细胞的DNA复制和RNA合成，从而抑制肿瘤细胞的生长和分裂。

此外，盐酸表柔比星还能激发人体免疫系统，增强对肿瘤细胞的攻击能力。

三、盐酸表柔比星的临床应用
1.乳腺癌：盐酸表柔比星是乳腺癌化疗的重要药物，可与其他药物如紫杉醇、环磷酰胺等联合应用。

2.肺癌：盐酸表柔比星适用于非小细胞肺癌的治疗，可与顺铂、紫杉醇等药物联合应用。

3.卵巢癌：盐酸表柔比星可用于治疗卵巢癌，可与紫杉醇、铂类药物等联合应用。

4.其他：盐酸表柔比星还可用于治疗胃肠道癌、淋巴瘤等恶性肿瘤。

四、盐酸表柔比星的注意事项
1.用药前应进行过敏试验，有过敏史者禁用。

2.肝肾功能不全者、骨髓功能减退者慎用。

3.孕妇及哺乳期妇女慎用。

4.避免接触破损皮肤和眼睛。

五、盐酸表柔比星的不良反应
1.骨髓抑制：白细胞、血小板减少。

2.消化道反应：恶心、呕吐、腹泻等。

3.皮肤反应：脱发、皮肤炎等。

4.心血管系统反应：心律失常、心功能不全等。

药物说明书drins-表柔比星-辉瑞

【儿童用药】
儿童用药无特殊要求。
【老年用药】
老年患者伴心功能减退者宜慎用或减量。
【药物相互作用】
表柔比星可与其他抗肿瘤药物合用，但表柔比星用量应减低。联合用药时，不得在同一注射器内使用。表柔比星不可与肝素混合注射，因为二者化学性质不配伍，在一定浓度时会发生沉淀反应。表柔比星主要在肝脏代谢，伴随治疗中任何能引起肝功能改变的药物将会影响表柔比星的代谢、药动、疗效和/或毒性。在表柔比星给药前使用紫杉醇类药物会引起表柔比星药物原形及代谢物血药浓度升高，其中代谢物既没有活性也没有毒性。当紫杉醇或多西紫杉醇类药物和表柔比星联合用药时，先给表柔比星则对其药代动力学没有影响。
【贮藏】
遮光、密封保存
【包装】
无色透明玻璃瓶，氯丁基橡胶塞，并用顶盖为聚丙烯塑料的嵌入式铝盖封口。包装规格：1瓶/盒
【有效期】
48个月
【执行标准】
YBH02502011
【批准文号】
10mg批准文号：国药准字H20000496 50mg批准文号：国药准字H20000497
【适应症】
治疗恶性淋巴瘤、乳腺癌、肺癌、软组织肉瘤、食道癌、胃癌、肝癌、胰腺癌、黑色素瘤、结肠直肠癌、卵巢癌、多发性骨髓瘤、白血病。膀胱内给药有助于浅表性膀胱癌、原位癌的治疗和预防其经尿道切除术后的复发。
【规格】
10mg；50mg；(按C27 H29 NO11 ·HCl计)
【用法用量】
常规剂量：表柔比星单独用药时，成人剂量为按体表面积一次60～120mg/m2，当表柔比星用来辅助治疗腋下淋巴阳性的乳腺癌患者联合化疗时，推荐的起始剂量为100～120mg/m2静脉注射，每个疗程的总起始剂量可以一次单独给药或者连续2-3天分次给药。根据患者血象可间隔21天重复使用。优化剂量：高剂量可用于治疗肺癌和乳腺癌。单独用药时，成人推荐起始剂量为按体表面积一次最高可达135mg/m2，在每疗程的第1天一次给药或在每疗程的第1、2、3天分次给药，3-4周一次。联合化疗时，推荐起始剂量按体表面积最高可达120mg/m2，在每疗程的第1天给药，3-4周一次。静脉注射给药。根据患者血象可间隔21天重复使用。膀胱内给药：表柔比星应用导管灌注并应在膀胱内保持一小时左右。在灌注期间，患者应时常变换体位，以保证膀胱粘膜能最大面积地接触药物。为了避免药物被尿液不适当的稀释，应告知患者灌注前12小时不要饮用任何液体。医生应指导患者在治疗结束时排空尿液。浅表性膀胱癌，表柔比星50mg溶于25至50mL生理盐水中，每周一次，灌注8次。对于有局部毒性 (化学性膀胱炎) 的病例，可将每次剂量减少至30mg，患者也可接受50mg每周一次共4次、然后每月一次共11次的同剂量药物膀胱灌注。医生可根据患者病情调整给药次数。

有机化学常用试剂英文缩写

Ac acetyl 乙酰基acac acetylacetonate 乙酰基丙酮化物AIBN 2,2'-azobisisobutyronitrile 偶氮二异丁腈Ar aryl 芳基的BBN borabicyclo[3.3.1]nonane 硼双环[3.3.1]壬烷BCME dis(chloromethyl)ether 双氯甲醚BHT butylated hydroxytoluene (2,6-di-t-butyl -p-cresol)别名抗氧化剂264 2,6-二叔丁基-4-甲基苯BINAL-H 2,2'-dihydroxy-1,1'-binaphthyl-lithium aluminum hydride 手性烷氧基联萘酚氢化铝锂BINAP 2,2' - bis(diphenylphosphino)-1,1' -binaphthyl双二苯基磷酰联萘BINOL 1,l'-bi-2,2'-naphthol 1,1'-联-2,2'-萘酚bipy 2,2' –bipyridyl 2,2'-联吡啶BMS borane-dimethyl sulfìde 硼烷吡啶Bn benzyl 苯甲基Boc t-butoxycarbonyl叔丁氧羰基BOM benzyloxymethyl苄氧甲基bp boiling point 沸点Bs brosyl (4-bromobenzenesulfonyl) 4-溴苯磺酰基BSA N, O-bis( trimethylsilyl )acetamide N,O-双三甲硅基乙酰胺Bu n-butyl 正丁基Bz benzoyl 苯甲酰CAN cerium(lV) ammonium nitrate 硝酸铈(Ⅳ)铵Cbz benzyloxycarbonyl 苄氧羰基CDI N,N-carbonyldiimidazole N,N'-羰基二咪唑CHIRAPHOS 2,3-bis(diphenylphosphino)butane 2,3-双(二苯基膦)丁烷Chx =Cy 环己基cod cyclooctadiene 环辛二烯cot cyclooctatetraene环辛四烯Cp cyclopentadienyl 环戊二烯基CRA complex reducing agent 复合还原试剂CSA 10-camphorsulfonic acid 10-樟脑磺酸CSI chlorosulfonyl isocyanate 氯磺酰异氰酸酯Cy cyclohexyl 环己基d density 密度DABCO 1,4-diazabicyclo[2.2.2]octane 1,4-重氮二环[2.2.2]辛烷DAST N,N'-diethylaminosulfur trifluoride二乙胺基三氟化硫dba dibenzylideneacetone二亚苄叉丙酮DBAD di-t-butyl azodicarboxylate偶氮二甲酸二叔丁酯DBN 1,5-diazabicyclo[4.3.0]non-5-ene 1,5-二氮杂二环[4,3,0]壬烯-5DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene 1,8-二氮杂二环-双环（5,4,0）-7-十一烯DCC N,N-dicyclohexylcarbodiimide N，N'二环己基碳二亚胺DCME dichloromethyl methyl ether二氯甲基甲醚DDO dimethyldioxirane双十二烷基二硫代乙二酰胺(又称钯试剂)DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 2,3-二氯-5,6-二氰-1,4-苯醌de diastereomeric excess 非对映体过量DEAD diethyl azodicarboxylate偶氮二甲酸二乙酯DET diethyl tartrate酒石酸二乙酯DIBAL diisobutylaluminum hydride二异丁基氢化铝DIEA =DIPEA 二异丙基乙胺DIOP 2,3-O-isopropylidene-2,3-dihydroxy-1,4- bis-(diphenylphosphino)butane异丙烯-2,3-二羟-1,4-双二丙基膦丁烷DIPEA diisopropylethylamine二异丙基乙基胺diphos =dppe 1,2-双(二苯基磷酰)乙烷DIPT diisopropyl tartrate 二异丙基酒石酸盐DMA dimethylacetamid 二甲基乙酰胺DMAD dimethyl acetylenedicarboxylate 丁炔二酸二甲酯，别名：催泪瓦斯DMAP 4-(dimethylamino)pyridine 4-二甲基氨基吡啶DME 1,2-dimethoxyethane乙二醇二甲醚（二甲氧基乙烷）DMF dimethylformamide 二甲基甲酰胺dmg dimethylglyoximato 丁二酮肟（与Ni2＋形成鲜红色螯合物）DMPU N,N' -dimethylpropyleneurea N,N-二甲基丙烯基脲DMS dimethyl sulfide 二甲基硫DMSO dimethyl sulfoxide 二甲基亚砜DMTSF dimethyl(methylthio)sulfonium tetrafluoroborate 二甲基(甲硫代)锍四氟硼酸盐dppb l ,4-bis(diphenylphosphino)butane 1,4-双(二苯基膦)丁烷dppe 1,2-bis(diphenylphosphino)ethane 1,2-双(二苯基磷)乙烷dppf l ,l'-bis(diphenylphosphino)ferrocene l , l'-双(二苯基磷)二茂铁dppp 1,3-bis(diphenylphosphino)propane 1,2-双(二苯基磷)丙烷DTBP di-t-butyl peroxide二叔丁基过氧化物EDA ethyl diazoacetate 重氮乙酸乙酯EDC l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI = EDCee enantiomeric excess对映体过量EE l-ethoxyethyl 乙氧基乙基Et ethyl 乙基ETSA ethyltrimethylsilylacetate (三甲基硅基)醋酸乙酯EWG electron withdrawing group 吸电基团Fc ferrocenyl 二茂铁基Fmoc 9-fluorenylmethoxycarbonyl 9-芴甲氧羰酰基fp ftash point 闪点Hex n-hexyl 正己基HMDS hexamethyldisilazane六甲基二硅胺烷HMPA hexamethylphosphoric triamide六甲基膦酸三酰胺HOBt 1-hydroxybenzotriazole 1-羟基苯并三唑HOBT =HOBtHOSu N-hydroxysuccinimide N-羟基琥珀酰亚胺Im imidazole (imidazolyl) 咪唑Ipc isopinocampheyl 异松蒎基IR infrared 红外KHDMS potassium hexamethyldisilazide 六甲基二硅胺钾LAH lithium aluminum hydride 氢化铝锂LD50 dose that is lethal to 50% of test subjects 致死量为受试者的50%LDA lithium diisopropylamide 二异丙基氨基锂LDMAN lithium1-(dimethylamino)naphthalenide ? 1-（二甲氨基）萘锂LHMDS(LiHMDS)lithium hexamethyldisilazide 六甲基叠氮乙硅锂, 六甲基二硅氨基锂LICA lithiuim isopropylcyclohexylamide 异丙基环己氨基锂LiTMP(LTMP) lithium2,2,6,6-tetramethylpiperidide 2,2,6,6-四甲基哌啶锂哌啶(氮杂环己烷)LTA lead tetraacetate 四乙酸铅lut 2,6-lutidine 二甲基吡啶MCPBA(m-CPBA) m-chloroperbenzoic acid 间氯过氧苯酸MA maleic anhydride 顺丁烯二酸酐MAD methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide) ?MAT methyl aluminum bis(2,4,6-tri-t-butylphenoxide) ?Me methyl 甲基MEK methyl ethyl ketone 甲基乙基酮MEM 2-methoxyethoxymethyl （2-甲氧基乙氧基）甲基－MIC methyl isocyanate 甲基异氰酸酯MMPP magnesium monoperoxyphthalate 单过氧邻苯二甲酸镁MOM methoxymethyl 甲氧甲基MoOPH oxodiperoxomolybdenum(pyridine)-(hexamethylphosphoric triamide)?mp melting point 熔点MPM methoxy(phenylthio)methyl 甲氧基（苯硫基）甲基，Ms methanesulfonyl (mesyl) 甲基磺酰基（保护羟基用）MS mass spectrometry 质谱MS Molecular sieves 分子筛MTEE (MTBE) methyl t-butyl ether 甲基叔丁基醚MTM methylthiomethyl 二甲硫醚MVK methyl vinyl ketone 甲基乙烯基酮n refractive index 折射率NaHDMS sodium hexamethyldisilazide 六甲基二硅胺钠Naph(Np) naphthyl 萘基NBA N-bromoacetamide N-溴乙酰胺NBD norbornadiene(bicyclo[2.2.1]hepta-2,5-diene) 二环庚二烯（别名：降冰片二烯）NBS N-bromosuccinimide N-溴代丁二酰亚胺（别名：N-溴代琥珀酰亚胺）NCS N-chlorosuccinimide N-氯代丁二酰亚胺. （别名：N-氯代琥珀酰亚胺）NIS N-iodosuccinimide N-碘代丁二酰亚胺（别名：N-碘代琥珀酰亚胺）NMO N-methylmorpholine N-oxide N-甲基氧化吗啉NMP N-methyl-2-pyrrolidone N-甲基-2-吡咯烷酮NMR nuclear magnetic resonance 核磁共振NORPHOS 5,6-bis(diphenylphosphino)-2-norbornene ?5，6-双（二苯基磷）-2-降冰片烯PCC pyridinium chlorochromate 吡啶氯铬酸盐PDC pyridinium dichromate 二氯吡啶酯Pent n-pentyl 正戊基Ph phenyl 苯基Phen 1,10-phenanthroline 1,10-菲罗啉Phth phthaloyl 邻苯二甲酰基Piv pivaloyl 新戊酰基PMB p-methoxybenzyl 对甲氧苄基；对甲氧苯甲基PMDTAPPA polyphosphoric acid 多聚磷酸PPE Polyphenylene Ether 聚苯醚PPTS pyridinium p-toluenesulfonate吡啶对甲苯磺酸Pr propyl丙基PTC phase-transfer catalysis (phase-transfer catalyst)相转移催化（相转移催化剂）PTSA(or TsOH) p-toluenesulfonic acid对甲苯磺酸Py (pyr) pyridine (or pyridyl)吡啶（或吡啶）PAMPrt room temperature 室温salen 双水杨酰胺乙基钴SAMP (S)-1-amino-2-(methoxymethyl)pyrrolidine(s)-1 -氨基- 2-(甲氧甲基)吡咯烷SET single electron transfer单电子转移Sia siamyl (s-isoamyl or 1,2-dimethylpropyl)TASF tris(diethylamino)sulfonium difluorotrimethylsilicateTBAB tetra-n-butylammonium bromide四丁基溴化铵TBAF tetra-n-butylammonium fluoride四丁基氟化TBADTBAI tetra-n-butylammonium iodide四丁基碘化TBAPTBDMS(TBS) t-butyldimethylsilyl二甲基硅烷TBDPS(BPS) t-butyldiphenylsilylTBHP t-butyl hydroperoxide叔丁基氢TBS t-butyldimethylsilyl二甲基硅烷TCNE tetracyanoethylene四氰基乙烯TCNQ 7,7,8,8-tetracyano-para-quinodimethaneTEA triethylamine三乙胺TEAB tetratehylammonium bromideTEBAC triethylbenzylammonium chloride三乙基氯化铵TEMPO 2,2,6,6-tetramethylpipedinyloxyTES triethylsilyl三乙基硅烷Tf trifluoromethanesulfonyl三氟甲基TFA trifluoroacetic acid三氟乙酸TFAA trifluoroacetic anhydride三氟乙酸酐THF tetrahydrofuran四氢呋喃THP 2-tetrahydropyranyl2 -吡喃ThxTIPS triisopropylsilylTMAO (TMANO) trimethylamine N-oxide三甲胺氮氧化物TMEDA N,N,N',N-tetramethyl- -hexaacetic acidTMG 1,1,3,3-tetramethylguanidineTMS tetramethylsilane四甲基Tol p-tolyl对甲苯TPAP tetra-n-propylammonium perruthenateTBHPTPP thiamine pyrophosphate5,10,15,20 -四苯基卟啉Tr triphenylmethyl (trityl)三苯（三苯甲基）Ts p-toluenesulfonyl (tosyl)对甲苯磺酰（磺酰）TTN thallium(III)-trinitrate硝酸铊（Ⅲ）UHP urea-hydrogen peroxide complex尿素过氧化氢复合Z benzyloxycarbonyl苄氧羰基。

百普乐(培哚普利吲达帕胺片)

[注意事项]
特殊警告与培哚普利相关：
● 在免疫功能低下患者发生中性白细胞减少症 / 粒细胞缺乏症的危险中性粒细胞减少症的危险与剂量及患者类型相关，并取决于患者的临床情况。没有并发症的患者极少会出现这种情况，但是与胶原血管性疾病相关的肾功能不全的患者可能发生，如系统性红斑狼疮或硬皮病患者以及使用免疫抑制剂治疗的患者。停止使用血管紧张素转化酶抑制剂治疗，危险性可消失。严格遵守预先规定的剂量用药可能是防止事件发生的最好办法。但是，如果这些患者需要使用血管紧张素转化酶抑制剂，应慎重评估风险 / 效益比值。
儿童百普乐不能用于儿童，因为儿童单独应用或联合应用培哚普利的疗效和耐受性尚未确定。
[不良反应]
服用培哚普利可抑制肾素－血管紧张素－醛固酮轴而使吲达帕胺所致的失钾减少。服用百普乐的 2％患者出现低钾血症（钾离子水平＜ 3.4mmol/l）。
胃肠道－通常发生（＞ 1/100, ＜ 1/10）：便秘、口干、恶心、上腹痛、厌食、腹痛、味觉障碍。－极少发生（＜ 1/10, 000）：胰腺炎。－在肝功能不全病例中，有引发肝性脑病的可能性（见禁忌和注意事项）。
一个月内血压即出现下降，无急速抗药反应；停药后无反弹作用。在临床试验中，同时给予培哚普利和吲达帕胺，与分别单独使用这二种药物相比，可产生具有协同作用的抗高血压疗效。
与培哚普利相关：培哚普利可以治疗各种程度的高血压：轻度到中度或重度。可以降低卧位和立位的收缩压和舒张压。最大降压作用出现在服用单一剂量后 4-6 小时，降压作用可持续 24 小时以上。
培哚普利在低或正常肾素水平的患者中也可产生抗高血压作用。
培哚普利通过它的活性代谢产物—培哚普利拉产生作用。其它的代谢产物均无活性。
培哚普利可减轻心脏负荷：－通过改变前列腺素代谢产生扩张静脉的作用：减轻前负荷，－通过降低总外周血管阻力：减轻后负荷。

阿司咪唑

合成方法
合成方法
化合物(I)和碘甲烷在乙醇中回流8h，环合得到化合物(Ⅱ)。再水解脱去酯基，得到化合物(Ⅲ)。用对甲氧基苯乙基溴进行N-烷基化，得化合物(Ⅳ)。再用对氟苄基溴烷基化，得阿司咪唑。
1. 1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮的制备
在反应瓶中加入2-羟基苯并咪唑5.0g(37.3mmol)和NaH 1.6g(53mmol)(NaH含量大约为80%,浸入矿物油中) 的DMF 100ml的悬浮液.加毕.在60ºC.(最好有N2保护)搅拌反应1h.再加入4-氟苄基氯(FBC)5.4g(37mmol),加热 ( 6 0 ºC ) 搅拌反应 5 . 5 h . 冷却至室温后加入冰水 7 0 0 m l , 用二氯甲烷 ( 5 0 0 m l × 2 ) 提取 . 有机层用食盐水洗 . 无水 N a 2 S O 4 干燥.过滤.滤液减压浓缩.剩余物用石油醚析晶.得1-[(4-氟苯基)甲基]-苯并咪唑-2-(3H)-酮固体8.0g,为无色结晶 m p 1 7 8 ~ 1 7 9 ºC , 收率 8 8 % .
治疗措施
阿司咪唑中毒的治疗要点为： 1.大量摄入者予洗胃，后灌服活性炭和导泻。 2.对心肌抑制和Q-T间期延长者予5%碳酸氢钠250ml静注可能有效。 3.对症、支持治疗。
专家点评
专家点评
阿司咪阿司咪唑自1983年上市以来，在许多国家得到了广泛应用。国外研究显示阿司咪唑治疗荨麻疹的总有效率为74%。国内的一项多中心双盲安慰剂对照试验表明阿司咪唑对急性荨麻疹的总有效率为82.9%，对慢性荨麻疹的总有效率为86.0%，均显著高于安慰剂，主要不良反应为嗜睡、倦怠、口干等，连续用药3个月的患者中，半数有食欲及体重增加。阿司咪唑的心脏毒性虽然发生率较低，但由于后果严重，已限制了它的应用。阿司咪唑为强效和长效的H1受体拮抗剂，无中枢镇静和抗毒蕈碱样作用。代谢产物去甲阿司咪唑仍有抗胆胺作用。长期服用可增进食欲和增加体重，服用过量可引起心脏Q-T间期延长和室性心律失常。适用于各种原因引起过敏性疾病。

常用药品理化性能

将二(2-氯乙基)胺盐酸盐说明书分享到：0纯度：99%包装：25kg/桶(有小样)结构式CAS：821-48-7分子式：C4H10Cl3N分子量：178.49中文名称：二(2-氯乙基)胺盐酸盐双(2-氯乙基)胺盐酸盐英文名称：2,2'-dichloro-diethylamin hydrochloride2,2'-dichlorodiethylamine hydrochloridebeta,beta'-dichlorodiethylamine hydrochloridebis(2-chloroethyl)amine hydrochloride性质描述：类白色结晶体，属可燃品，燃烧产生有毒氮氧化物, 氯化物和氯化氢烟雾。

质量标准：外观类白色结晶体含量≥98%熔点214-217℃用途：医药中间体。

对甲基苯胺CAS: 106-49-0MDL：MFCD00007906分子式: C7H9N分子质量: 107.15沸点: 200℃熔点:44-45℃中文名称: 对甲基苯胺；4-甲基苯胺；对甲苯胺；对胺；对氨基甲苯；4-氨基甲苯英文名称: 4-Toluidine；4-Methylaniline；4-methyl-Benzenamine；1-amino-4- methylbenzene；4-amino-1-methylbenzene；4-aminotoluen；4-aminotoluen (czech)；4-aminotoluene；4-methylbenzenamine；p-methyl-anilin；4-methyl- benzenamin 性质描述: 白色有光泽片状或叶状结晶。

可燃。

熔点44-45℃。

沸点200.2℃，82.2℃（1.33kPa），相对密度0.9619（20、4℃），折射率 1.5534（45℃），闪点87.2℃。

微溶于水，溶于乙醇；乙醚；二硫化碳和油类，溶于稀无机酸并生成盐。

二异丙基乙基胺分子量

二异丙基乙基胺分子量1. 什么是二异丙基乙基胺？二异丙基乙基胺（Diisopropylethylamine，简称DIPEA）是一种有机化合物，化学式为(C5H13N)，分子量约为101.19 g/mol。

它是一种无色液体，具有强烈的胺味。

DIPEA是一种常用的有机合成试剂，在有机合成中具有广泛的应用。

2. 分子结构DIPEA的分子结构如下所示：在DIPEA分子中，有一个主要的氮原子（N），它与两个异丙基基团（CH(CH3)2）和一个乙基基团（CH2CH3）相连。

这种结构使得DIPEA具有一定的碱性。

3. 分子量的计算DIPEA的分子量可以通过计算各个原子的相对原子质量，并将其相加得到。

DIPEA分子中包含5个碳原子（C），13个氢原子（H）和1个氮原子（N）。

根据元素周期表，碳原子的相对原子质量为12.01 g/mol，氢原子的相对原子质量为1.01 g/mol，氮原子的相对原子质量为14.01 g/mol。

因此，DIPEA的分子量可以计算为：分子量= 5 × 12.01 g/mol + 13 × 1.01 g/mol + 1 × 14.01 g/mol = 101.19 g/mol4. 应用领域由于DIPEA具有较强的碱性，它在有机合成中被广泛应用。

以下是一些常见的应用领域：4.1. 缩合反应DIPEA常用于缩合反应中的碱催化剂。

在缩合反应中，DIPEA可以中和酸性中间体，促进反应的进行，并帮助生成目标产物。

4.2. 底物保护DIPEA可以作为底物保护剂，保护活性基团不受其他反应物的干扰。

通过与底物中的酸性或碱性官能团反应，DIPEA可以形成稳定的保护基团，从而防止其发生不希望的反应。

4.3. 亲核取代反应DIPEA可以在亲核取代反应中作为碱催化剂。

它可以中和酸性中间体，提供一个亲核位点，促进亲核试剂的攻击，并帮助形成取代产物。

4.4. 脱保护反应DIPEA可以用于脱保护反应中。

三氟乙酸脱苄基O-debenzylation_of_ortho-substituted_phenols_with_trifluoroacetic_acid

Mild,efﬁcient and rapid O-debenzylation of ortho -substituted phenols with triﬂuoroacetic acidSteven Fletcher *,Patrick T.Gunning *Department of Chemistry,University of Toronto,Mississauga,ON L5L 1C6,Canadaa r t i c l e i n f o Article history:Received 21May 2008Revised 2June 2008Accepted 4June 2008Available online 10June 2008a b s t r a c tThe mild and efﬁcient deblocking of aryl benzyl ethers with TFA is reported.Cleavage was fastest with ortho -electron-withdrawing groups on the phenolic ring,which we have attributed to a proton chelation effect,furnishing the deprotected phenols in excellent yields.The corresponding para -methoxybenzyl,allyl and iso -propyl ethers were also cleanly removed under these conditions.In addition,the selective aryl benzyl ether debenzylation in the presence of benzyl ester,Cbz carbamate and Boc carbamate func-tionalities was also observed.Crown Copyright Ó2008Published by Elsevier Ltd.All rights reserved.Phosphotyrosines feature in the design of inhibitors of several protein targets,including protein tyrosine phosphatase 1B (PTP1B).1However,these moieties suffer from hydrolytic lability to cellular phosphatases and poor cell penetration due to the asso-ciated dianionic charge.1To address these issues,salicylic acid derivatives (and closely-related analogues)have become popular mimetics of phosphotyrosine in small molecule inhibitors.1–5Turk-son et al.have recently reported on NSC74859(1),a potent,sali-cylic acid-based inhibitor of the oncogenic protein Stat3.6As part of our structure–activity relationship (SAR)studies on NSC74859(1),we sought to debenzylate both the phenol ether and benzoate ester in 2without reducing the aryl-bromide bond,a common undesired side reaction that occurs with hydrogen gas and Pd/C catalyst.7O -Benzyl-protected phenols are known to undergo debenzyla-tion with triﬂuoroacetic acid (TFA)8by an initial protonation of the weakly basic phenol oxygen,although additives such as strongorganic acids (e.g.,triﬂuoromethanesulfonic acid 9)or a large excess of nucleophilic scavenger (e.g.,thioanisole,which accelerates the reaction by a ‘push–pull’mechanism 10)are typically required.Re-cent work by Ploypradith et al.describes the mild deprotection of aromatic ethers with sub-stoichiometric para -toluenesulfonic acid on solid support.11In a special case,O -benzyl-protected ortho -nitrophenol was cleaved rapidly (<5min)with neat TFA,12which we considered was due to the ability of the substrate to chelate a proton since the structurally-similar ortho -hydroxybenzoates (salicylates)are well-known to chelate copper ions and iron ions.We reasoned that 2(and indeed 3)may similarly undergo acceler-ated debenzylation with TFA.In fact,as shown in Scheme 1,treat-ment of 2(or 3)with a 1:1mixture of TFA/toluene led to rapid debenzylation (5min for 2;1h for 3)in 91%yield for 2(or 85%yield for 3).In this Letter,we will explore the structural require-ments of the phenol component that increase the lability of the O -benzyl phenol ether bond in the presence of TFA.In addition,0040-4039/$-see front matter Crown Copyright Ó2008Published by Elsevier Ltd.All rights reserved.*Tel.:+19058285354;fax:+19058285425(P.T.G.).E-mail addresses:steven.ﬂetcher@utoronto.ca (S.Fletcher),patrick.gunning@utoronto.ca (P.T.Gunning).Tetrahedron Letters 49(2008)4817–4819Contents lists available at ScienceDirectTetrahedron Lettersj o ur na l h om e pa ge :w w w.e ls e v ie r.c o m/lo c at e/t et l e twe will explore the selectivity of this mild debenzylation tech-nique with respect to other aromatic ethers and examine the sta-bility of other benzyl-based protecting groups to these reaction conditions.A series of 12O -benzyl-protected phenols was prepared by standard procedures in near quantitative yields.Each of these ethers was then deprotected with a 1:1mixture of TFA/toluene;our observations are summarized in Table 1.In certain cases,O ?C benzyl migration (Friedel–Crafts reaction)by-products (610%)were occasionally inseparable from the product by silica gel ﬂash column chromatography.Thus,several benzyl cation cap-tors were investigated for their abilities to improve yields and puri-ties of the debenzylation reactions.Three to ten equivalents of p -cresol,anisole and triethylsilane were employed,but these exerted little effects on reducing by-product formation.Conversely,we dis-covered that including the more nucleophilic scavenger thioanisole as an additive to the co-solvent toluene typically,after silica gel ﬂash column chromatography,furnished products in P 95%puri-ties (and higher yields),as judged by 1H NMR.Nevertheless,we envisaged any Friedel–Crafts impurities would be more readily separable on slightly more complex aryl benzyl ethers,as we ob-served with the substrates shown in Scheme 1and Tables 3and 4(>99%purities (1H NMR)in each case).Whilst likely leading to even higher yields and purities,large excesses of thioanisole (50equiv)are also known to accelerate TFA-mediated debenzyla-tion.10However,in our hands just 3equiv of thioanisole had little effect on the rate of debenzylation,allowing us to attribute the deprotection rates solely to the structure of the phenol.Electron-rich phenols are good scavengers of benzyl cations,13and since preliminary experiments with electron-rich phenols generated complex mixtures of Friedel–Crafts by-products under these deb-enzylation conditions,we chose to investigate only electron-poor phenols in this study.O -Benzyl-protected phenols with p -ortho -electron-withdraw-ing groups (6a ,6b ,6d ,6f )were swiftly (several in less than 3h cf.24h for unsubstituted phenol 6l )and cleanly debenzylated,with less than 5%of the undesired C-benzylated phenol by-prod-ucts.In contrast,meta -and para -electron-withdrawing groups slo-wed down the debenzylation (e.g.,entries 6g and 6h ),relative to the control compound 6l ,which itself could only be obtained in moderate purity by this method.The r -withdrawing (and p -donating)bromophenols 6i –k were insufﬁciently deactivated to benzyl cation scavenging and were contaminated with several by-products.Importantly,n -butyl benzyl ether 8was unaffected by TFA under the reaction conditions,indicating this procedure is selective for aryl benzyl ethers.In addition,the results in Table 1suggest that this procedure is suitable only for phenols substituted with p -electron-withdrawing groups.Since the debenzylation mechanism with TFA proceeds via an initial protonation of the phenol ether oxygen,the more available the ether oxygen lone pairs are,the faster the reaction will be.Hence,the slower reaction times for the phenols bearing meta -and para -electron-withdrawing groups make sense,although this is not true for the ortho -functionalized aryl benzyl ethers.As hypothesized for the bis-benzyl salicylate derivative 2earlier,we considered these ortho -substituted phenols were capable of chelat-ing the acidic hydrogen atom from TFA which therein facilitated the acid-mediated debenzylation via a six-membered cyclic inter-mediate,as proposed in Scheme 2.A similar chelation intermediate has been put forward by Baldwin and Haraldsson to account for the Lewis acid MgBr 2-mediated debenzylation of aromatic benzyl ethers ortho to an aldehyde group.14Accordingly,to test this hypothesis we expanded this series of ortho -substituted aryl benzyl ethers,and the results from their deb-enzylation reactions with TFA are summarized in Table 2.These substrates have been listed in order of increasing approximateTable 1TFA-mediated debenzylation of O -benzyl-protected phenols aTFAtolueneOBnROHR67Substrate RTime (h)b Yield c (%)6a o -CO 2Me,m d -NHAc 5min 936b o -CO 2Me 5min 946c p -CO 2Me 36e 63(85f )6d o -CO 2Bn 5min 936e p -CO 2Bn 36e 58(79f )6f o -NO 23976g m -NO 236e 75(98f )6h p -NO 236e 66(98f )6i o -Br 16—g 6j m -Br 30—g 6k p -Br 36—g 6lH 24—gn -BuOBn (8)—24No reactionaThe reaction was carried out with 6(0.5mmol)in a 1:1mixture of TFA/toluene (5ml)at rt,with 3equiv of thioanisole.bTime taken for all starting material to be consumed.cIsolated yield after silica gel ﬂash column chromatography.dmeta to phenol oxygen AND para to ester.eReaction was slow and incomplete after 3days.fYield based on recovered starting material.gComplex mixture of products.Table 2TFA-mediated debenzylation of O -benzyl-protected,ortho -substituted phenols aTFA tolueneOBnOH67RRSubstrate R p K aH b Time c (h)Yield d (%)Relative rate 6m CO 2NH 2À2248316n CHO À7 3.594e 6.96o CO 2H À8191246b CO 2Me À8.55min 942886d CO 2Bn À8.55min 932886p CN À10>4851(95f )—6f NO 2À1239786i Br —16—g 1.56lH—24—g1aThe reaction was carried out with 6(0.5mmol)in a 1:1mixture of TFA/toluene (5ml)at rt,with 3equiv of thioanisole.bApproximate p K aH of conjugate acid of R group.15cTime taken for all starting material to be consumed.dIsolated yield after silica gel ﬂash column chromatography.eIncluding thioanisole in the deprotection of 6n led to further by-products,thus no scavenger was used and compound 7n could be obtained in only 90%purity.fYield based on recovered starting material.gComplex mixture of products.4818S.Fletcher,P.T.Gunning /Tetrahedron Letters 49(2008)4817–4819acidity of the conjugate acid (decreasing p K aH )of the ortho -elec-tron-withdrawing substituent.15There appears to be an optimal p K aH of around À8.5,that is exhibited by carboxylic esters,which lead to the fastest rate of debenzylation with TFA.In an approxi-mate bell-shaped distribution of reaction rate versus ortho -substi-tuent p K aH —that was interrupted only by ortho -cyanophenol 6p —protonatable groups with p K aH ’s <À8.5or >À8.5were less effective at accelerating the TFA-mediated debenzylation.These data concur with our chelation hypothesis:groups that are too ba-sic bind more strongly to the TFA proton making it less available for sharing with,and ultimately releasing to,the phenol ether oxygen;groups that are weakly basic do not bind the TFA proton as well,leading to reduced chelation and hence less rate enhancement.The anomalous result for ortho -cyanophenol 6p was anticipated since this compound was selected as a negative control.Phenol 6p is geometrically incapable of chelating a proton,because the lin-ear,sp -hybridized nitrile functionality directs its basic nitrogen atom (p K aH %À10)away from the phenol oxygen.As predicted,there was no rate enhancement for the TFA-mediated debenzyla-tion of 6p relative to phenol 6l .In fact,6p was only slowly deben-zylated,at a rate that was comparable with the m -nitro and p -nitro derivatives 6g and 6h ,respectively.We next wanted to investigate the selectivity for the deprotec-tion of the benzyl group over other phenol protecting groups.Accordingly,the benzyl group in salicylate derivative 9a was varied with para -methoxybenzyl (PMB;9b ),methyl (9c ),allyl (9d )and iso -propyl (i -Pr;9e ).These substrates were then debenzylated with a 1:1mixture of TFA/toluene;our ﬁndings are reported in Table 3.Any impurities this time were minor and readily separable from the products,eliminating the need for the additive thioanisole.The relative rates at which these protecting groups were removed was para -methoxybenzyl >benzyl >allyl >iso -propyl )methyl,which reﬂects the stability of the carbocations.These data suggest that in salicylates such as 9,the benzyl phenol protecting group (R =Bn)can be removed with TFA in the presence of the corres-ponding allyl,iso -propyl and methyl ethers.Finally,we explored the selectivity of this mild debenzylation technique over other benzyl-based protecting groups,as shown in Table 4.As the results demonstrate,it was possible to deblock the O -benzyl ether in the presence of a benzyl ester (6d )and in the presence of a benzyl carbamate (11b ),thereby increasing the orthogonality of O -benzyl phenol ethers of salicylate derivatives.Interestingly,it was even possible to cleave the benzyl group in 11c with TFA in the presence of an N -Boc-protected aniline.In summary,we have presented the mild,efﬁcient and rapid deblocking of ortho -substituted aryl benzyl ethers with TFA.Deb-enzylation was fastest when the ortho group was a carboxylic ester,which we have attributed to a proton chelation effect.Other ortho groups that accelerated the TFA-mediated debenzylation included carboxylic acid,aldehyde and nitro.In addition,we have shown that in such ortho -functionalized phenols,benzyl could be removed in the presence of the corresponding iso -propyl,allyl and methyl ethers.Moreover,the benzyl ether could be selectively cleaved in the presence of benzyl ester,Cbz carbamate and Boc carbamate functionalities.AcknowledgementsThe authors gratefully acknowledge ﬁnancial support for this work from the Canadian Foundation of Innovation and the Univer-sity of Toronto (Connaught Foundation).References and notes1.Zhang,S.;Zhang,Z.-Y.Drug Discov.Today 2007,12,373–381.2.(a)Pei,Z.;Li,X.;Liu,G.;Abad-Zapatero,C.;Lubben,T.;Zhang,T.;Ballaron,S.J.;Hutchins,C.W.;Trevillyana,J.M.;Jirouseka,M.R.Bioorg.Med.Chem.Lett.2003,13,3129–3132;(b)Xin,Z.;Liu,G.;Abad-Zapatero,C.;Pei,Z.;Szczepankiewicz,B.G.;Li,X.;Zhang,T.;Hutchins,C.W.;Hajduk,P.J.;Ballaron,S.J.;Stashko,M.A.;Lubben,T.H.;Trevillyana,J.M.;Jirouseka,M.R.Bioorg.Med.Chem.Lett.2003,13,3947–3950.3.Tautz,L.;Bruckner,S.;Sareth,S.;Alonso,A.;Bogetz,J.;Bottini,N.;Pellecchia,M.;Mustelin,T.J.Biol.Chem.2005,280,9400–9408.4.Shrestha,S.;Bhattarai,B.R.;Chang,K.J.;Leea,K.-H.;Choa,H.Bioorg.Med.Chem.Lett.2007,17,2760–2764.5.Liljebris,C.;Larsen,S.D.;Ogg,D.;Palazuk,B.J.;Bleasdale,J.E.J.Med.Chem.2002,45,1785–1798.6.Siddiquee,K.;Zhang,S.;Guida,W.C.;Blaskovich,M.A.;Greedy,B.;Lawrence,H.R.;Yip,M.L.R.;Jove,R.;Laughlin,M.M.;Lawrence,N.J.;Sebti,S.M.;Turkson,J.Proc.Natl.Acad.Sci.U.S.A.2007,104,7391–7396.7.Pandey,P.N.;Purkayastha,M.L.Synthesis 1982,876–878.8.(a)Greene,T.W.;Wuts,P.G.M.Protective Groups in Organic Synthesis ,3rd ed.;John Wiley &Sons:New York,1999;(b)Kocienski,P.J.Protecting Groups ,3rd ed.;Georg Thieme:Stuttgart,Germany,2003.9.Kiso,Y.;Isawa,H.;Kitagawa,K.;Akita,T.Chem.Pharm.Bull.1978,26,2562–2564.10.Kiso,Y.;Ukawa,K.;Nakamura,S.;Ito,K.;Akita,T.Chem.Pharm.Bull.1980,28,673–676.11.Ploypradith,P.;Cheryklin,P.;Niyomtham,N.;Bertoni,D.R.;Ruchirawat,.Lett.2007,9,2637–2640.12.Marsh,J.P.,Jr.;Goodman,.Chem.1965,30,2491–2492.13.(a)Eberle,A.N.J.Chem.Soc.,Perkin Trans.11986,361–367;(b)Bodanszky,M.;Tolle,J.C.;Deshmane,S.S.;Bodanszky,A.Int.J.Pept.Protein Res.1978,12,57–68.14.Haraldsson,G.G.;Baldwin,J.E.Tetrahedron 1997,53,215–224.15.(a)Ionization Constants of Organic Acids in Solution ;Serjeant,E.P.,Dempsey,B.,Eds.IUPAC Chemical Data Series No.23;Pergamon Press:Oxford,UK,1979;(b)see also:/labs/evans/pdf/evans_pKa_table.pdf .Table 3TFA-mediated deprotection of O-blocked phenol ether derivatives of methyl 4-acetamidosalicylate aTFAtolueneNHAcNHAcORO OMeOH OMeO 910Substrate R Time b (h)Yield c (%)9a Bn 5min 919b PMB 2min 909c Me 480d 9d Allyl 20919ei -Pr3692aThe reaction was carried out with 9(0.5mmol)in a 1:1mixture of TFA/toluene (5ml)at rt.bTime taken for all starting material to be consumed.cIsolated yield after silica gel ﬂash column chromatography.dOnly starting material remained after 48h,at which point the reaction was aborted.Table 4Selectivity investigation into the TFA-mediated debenzylation of aryl benzyl ethers aTFA tolueneOBnOH2Bn2Bn1112RRSubstrate R Yield b (%)6d c H 9311a NHAc 9211b NHCbz 9311c dNHBoc54aThe reaction was carried out with 11(0.5mmol)in a 1:1mixture of TFA/toluene (5ml)at rt for 5min,then all solvents were evaporated.bIsolated yield after silica gel ﬂash column chromatography.cFor compound 6d ,3equiv of thioanisole were also used.dAfter 5min,the reaction mixture was diluted with CH 2Cl 2and then immedi-ately neutralized with 1M NaOH.The organic layer was then separated and evaporated.S.Fletcher,P.T.Gunning /Tetrahedron Letters 49(2008)4817–48194819。

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=====================================================================Acq. Operator : Wang Ke Cheng(LCMS-02) Seq. Line : 30
Acq. Instrument : HY-LCMS-02 Location : P1-C-06Injection Date : 1/27/2016 1:07:15 PM Inj : 1
Inj Volume : 3.000 µl
Acq. Method : D:\AGLIENT 1260\DATA\20160127\20160127 2016-01-27 09-32-41\100-1000MS+3MIN- 1.5_(0.02%FA).M
Last changed : 1/27/2016 9:32:41 AM by Wang Ke Cheng(LCMS-02)
Analysis Method : D:\AGLIENT 1260\DATA\20160127\20160127 2016-01-27 09-32-41\100-1000MS+3MIN- 1.5_(0.02%FA).M (Sequence Method)
Last changed : 1/27/2016 1:35:34 PM by Wang Ke Cheng(LCMS-02) (modified after loading)
Method Info : Postive,MS:100-1000,Column ID:A-RP-132,40℃
Catalog No : HY-N0226A Batch#22711 A-RP-134
Additional Info : Peak(s) manually integrated
min
0.5
1
1.5
2 2.53mAU 0
100200
300
400500600700 DAD1 B, Sig=214,4 Ref=off (D:\AGLIENT...0\DATA\20160127\20160127 2016-01-27 09-32-41\BIZ2016-127-WJ2-2.D)
1.540
1.769
2.222
2.747
3.002
===================================================================== Area Percent Report =====================================================================
Sorted By : Signal Multiplier : 1.0000Dilution : 1.0000
Do not use Multiplier & Dilution Factor with ISTDs
Signal 1: DAD1 B, Sig=214,4 Ref=off
Peak RetTime Type Width Area Height Area # [min] [min] [mAU*s] [mAU] %
----|-------|----|-------|----------|----------|--------| 1 1.540 MM 0.0642 3149.05078 817.63123 99.5971 2 1.769 MM 0.0436 2.18677 8.35606e-1 0.0692 3 2.222 MM 0.0451 2.66230 9.82952e-1 0.0842 4 2.747 MM 0.0531 4.01346 1.26057 0.1269 5 3.002 MM 0.0465 3.87770 1.39037 0.1226
Totals : 3161.79101 822.10073
===================================================================== *** End of Report ***
=====================================================================Acq. Operator : Wang Ke Cheng(LCMS-02) Seq. Line : 30
Acq. Instrument : HY-LCMS-02 Location : P1-C-06Injection Date : 1/27/2016 1:07:15 PM Inj : 1
Inj Volume : 3.000 µl
Acq. Method : D:\AGLIENT 1260\DATA\20160127\20160127 2016-01-27 09-32-41\100-1000MS+3MIN- 1.5_(0.02%FA).M
Last changed : 1/27/2016 9:32:41 AM by Wang Ke Cheng(LCMS-02)
Analysis Method : D:\AGLIENT 1260\DATA\20160127\20160127 2016-01-27 09-32-41\100-1000MS+3MIN- 1.5_(0.02%FA).M (Sequence Method)
Last changed : 1/27/2016 1:33:51 PM by Wang Ke Cheng(LCMS-02) (modified after loading)
Method Info : Postive,MS:100-1000,Column ID:A-RP-132,40℃
Catalog No : HY-N0226A Batch#22711 A-RP-134
Additional Info : Peak(s) manually integrated
min
0.5
1
1.5
2
2.5
3
100000
200000300000400000500000600000700000 MSD1 TIC, MS File (D:\AGLIENT 1260\DATA\20160127\20160127 2016-01-27 09-32-41\BIZ2016-127-WJ2-2.D) ES-API, Pos, Sca
1.546
MS Signal: MSD1 TIC, MS File, ES-API, Pos, Scan, Frag: 50 Spectra averaged over upper half of peaks. Noise Cutoff: 1000 counts.
Reportable Ion Abundance: > 10%.
Retention Mol. Weight Time (MS) MS Area or Ion
1.546 4577690 337.20 I 336.20 I
m/z
100
150
200
250
300
350
20406080100*MSD1 SPC, time=1.507:1.580 of D:\AGLIENT 1260\DATA\20160127\20160127 2016-01-27 09-32-41\BIZ2016-127-WJ2-2.D ES-API Max: 454182
337.2 336.2
*** End of Report ***。