(2S,4R)-N-(benzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine | 260417-93-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S,4R)-N-(benzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine
• 英文别名: benzyl (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylate；(2S,4R)-N-Benzoxycarbonyl-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine；benzyl (2S,4R)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-hydroxypyrrolidine-1-carboxylate；benzyl (2S,4R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxypyrrolidine-1-carboxylate
• CAS: 260417-93-4
• 化学式: C₁₉H₃₁NO₄Si
• 分子量: 365.545
• InChiKey: WAQPOQIWCNXVMW-DLBZAZTESA-N

物化性质

• 沸点：
  440.8±40.0 °C(Predicted)
• 密度：
  1.083±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.78
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,4R)-N-(benzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine 在 palladium on activated charcoal 、 镍 吡啶 、 草酰氯 、 potassium tert-butylate 、 氢气 、 氟化氢吡啶 、 一水合肼 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， -55.0~20.0 ℃ 、344.74 kPa 条件下， 反应 19.5h， 生成 1,1'-[(propane-1,3-diyl)dioxy]bis[(11S,11aS)-10-(allyloxycarbonyl)-11-hydroxy-7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]
  参考文献：
  名称：

  Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/C8‘ Ether-Linked C2-exo-Unsaturated Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Dimers

  摘要：

  A C2/C2'-exo-unsaturated pyrrolo [2, 1-c] [1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8-O(CH2)(n)O-C8' diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., > 3400-fold in IGROV1 ovarian cells) and interstrand DNA cross-linking reactivity (> 10-fold) compared to the shorter homologue 4a (SJG-136; n = 3). In contrast, for the C-ring unsubstituted series, the corresponding n = 5 dimer (3c) is generally less cytotoxic and has a lower interstrand cross-linking reactivity compared to its shorter n = 3 homologue (3a). Dimer 4b cross-links DNA with > 10-fold efficiency compared to 4a, and also inhibits the activity of the restriction endonuclease BamH1 more efficiently than either 3a or 4a. The C2-exo-unsaturated PBD dimers 4a,b are not only more effective than their C-ring saturated counterparts in terms of induced DeltaT(m) shift, but they also exert this effect more rapidly. Thus, while 3a and 3c exert 68 and 35% of their maximum effect immediately upon interaction with DNA, this level increases to 76 and 97% for 4a and 4b, respectively. Molecular modeling shows a rank order of 4b (n = 5) > 4a (n = 3) > 3a (n = 3) > 3c (n = 5) in terms of binding energy toward duplexes containing embedded target 5'-GAT(1-2)C cross-link sequences, reflecting the superior fit of the C2-exo-unsaturated rather than saturated C-rings of the PBD dimers. A novel synthesis of core synthetic building blocks for PBD dimers via stepwise Mitsunobu reaction and nitration with Cu(NO3)(2) is also reported.

  DOI：

  10.1021/jm030897l
• 作为产物：
  描述：

  L-羟基脯氨酸 在 sodium tetrahydroborate 、 硫酸 、 碳酸氢钠 、 三乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 反应 59.0h， 生成 (2S,4R)-N-(benzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine
  参考文献：
  名称：

  伊波沙霉素的实用革兰氏规模合成，一种有效的候选抗生素

  摘要：

  介绍了伊波沙霉素的克级合成，伊波沙霉素是一种带有融合双环氨基酸残基的候选抗生素。该路线的关键转变涉及分子内氢化硅烷化-氧化序列以设置双环支架的环融合立体中心。该合成的其他显着特征包括假苯胺酰胺的高产率、高度非对映选择性烷基化、会聚 sp 3 -sp 2 Negishi 偶联和一锅转缩醛化还原反应以形成目标化合物的氧杂环丁烷环。这种合成策略的实施提供了大量的伊波沙霉素，以允许其在小鼠感染模型中进行体内分析。

  DOI：

  10.1021/jacs.1c03529

文献信息

• Structure−Activity Relationships of Monomeric C2-Aryl Pyrrolo[2,1-<i>c</i>][1,4]benzodiazepine (PBD) Antitumor Agents
  作者：Dyeison Antonow、Maciej Kaliszczak、Gyoung-Dong Kang、Marissa Coffils、Arnaud C. Tiberghien、Nectaroula Cooper、Teresa Barata、Sibylle Heidelberger、Colin H. James、Mire Zloh、Terence C. Jenkins、Anthony P. Reszka、Stephen Neidle、Sylvie M. Guichard、Duncan I. Jodrell、John A. Hartley、Philip W. Howard、David E. Thurston

  DOI：10.1021/jm901722v

  日期：2010.4.8

  comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across

  吡咯烷[2,1- c]的C2位的SAR综合研究] [1,4]苯并二氮杂（PBD）单体抗肿瘤药物的报道，建立了最佳的体外细胞毒性和DNA结合亲和力的分子要求。碳环和杂环C2-芳基取代基的研究范围从单个芳基环到稠环系统，还有苯乙烯基取代基，在80个类似物库中建立，C2-芳基和苯乙烯基取代基可显着增强DNA结合亲和力和体外细胞毒性，两者之间具有相关性。发现DNA结合亲和力和细胞毒性的最佳C2分组是C2-喹啉基部分，根据分子模型，这是由于分子在DNA小沟中的整体适合性以及与功能性分子的潜在特异性接触所致。组在凹槽的地板和墙壁中。这个类似物（在HCT-116（bowel）人肿瘤异种移植模型中显示了14l）延迟肿瘤生长。
• NOVEL BENZODIAZEPINE DERIVATIVES AND USES THEREOF
  申请人：IntoCell, Inc.

  公开号：US20190367488A1

  公开（公告）日：2019-12-05

  The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.

  本公开提供了能够延长寿命的化合物和组合物，以及其使用方法。
• Scale-up Synthesis of Tesirine
  作者：Arnaud C. Tiberghien、Christina von Bulow、Conor Barry、Huajun Ge、Christian Noti、Florence Collet Leiris、Marc McCormick、Philip W. Howard、Jeremy S. Parker

  DOI：10.1021/acs.oprd.8b00205

  日期：2018.9.21

  This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody–drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity

  这项工作描述了能够合成合成的酪胺酸，一种吡咯并苯并二氮杂卓抗体-药物偶联物药物连接物。在四次合成运动过程中，开发了发现路线并扩大了规模，以提供可靠的制造过程。早期中间体以千克规模和高纯度生产，无需色谱。优化了中间阶段的反应，以最大程度地减少杂质的形成。使用少量关键的高压色谱步骤生产和纯化后期材料，最终在34个步骤后得到169 g批料。在撰写本文时，tesirine是多项临床试验中8种抗体-药物偶联物的药物连接物成分，其中4种是关键的。
• [EN] 11-HYDROXY-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE DERIVATIVES AS KEY INTERMEDIATES FOR THE PREPARATION OF C2 SUBSTITUTED PYRROLOBENZODIAZEPINES<br/>[FR] DERIVES DE 11-HYDROXY-5H-PYRROLO[2,1-C][1,4] BENZODIAZEPINE-5-ONE EN TANT QU'INTERMEDIAIRES CLES POUR LA PREPARATION DE PYRROLOBENZODIAZEPINES SUBSTITUEES C2
  申请人：SPIROGEN LTD

  公开号：WO2005085251A1

  公开（公告）日：2005-09-15

  The present inventors have developed a key intermediate for the production of C2 substituted PBDs, which has a leaving group at the C2 position, a carbamate protecting group at the N10 position and a protected hydroxy group at the C11 position. In a first aspect, the present invention comprises a compound with a the formula (I), wherein : R10 is a carbamate-based nitrogen protecting group; R11 is an oxygen protecting group; and R2 is a labile leaving group. In a further aspect, the present invention comprises a method of synthesising a compound of formula (III), or a solvate thereof, from a compound of formula (I) as defined in the first aspect, R16 is either O-R11, wherein R11 is as defined in the first aspect, or OH, or R10 and R16 together form a double bond between N10 and C11; and R15 is R. The other substituents are defined in the claims. Further aspects of the present invention relate to compounds of formula (III) (including solvates thereof when R10 and R16 form a double bond between N10 and C11, and pharmaceutical salts thereof), pharmaceutical compositions comprising these, and their use in the manufacture of a medicament for the treatment of a proliferative disease.

  本发明人已经开发出一种用于生产C2取代PBDs的关键中间体，该中间体在C2位置具有一个离去基团，在N10位置具有一个氨基甲酸酯保护基团，在C11位置具有一个受保护的羟基。根据第一方面，本发明涉及一种具有以下式（I）的化合物，其中：R10是一种基于氨基甲酸酯的氮保护基团；R11是一种氧保护基团；R2是一种不稳定的离去基团。根据进一步方面，本发明涉及一种从根据第一方面中定义的式（I）的化合物合成式（III）的方法，或者其溶剂化物，其中R16是O-R11，其中R11如第一方面中定义，或OH，或者R10和R16一起形成N10和C11之间的双键；R15是R。其他取代基在权利要求中定义。本发明的进一步方面涉及式（III）的化合物（包括当R10和R16形成N10和C11之间的双键时的溶剂化物，以及其药用盐），包括这些化合物的药用组合物，以及它们在制造用于治疗增殖性疾病的药物的药物的用途。
• Effect of C2-exo unsaturation on the cytotoxicity and DNA-binding reactivity of pyrrolo[2,1-c][1,4]benzodiazepines
  作者：Stephen J. Gregson、Philip W. Howard、Kathryn E. Corcoran、Simona Barcella、Maqsood M. Yasin、Abigail A. Hurst、Terence C. Jenkins、Lloyd R. Kelland、David E. Thurston

  DOI：10.1016/s0960-894x(00)00351-6

  日期：2000.8

  A series of novel C2-exo unsaturated pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) has been synthesised via a versatile pro-C2 ketone precursor. C2-exo-unsaturation enhances both DNA-binding reactivity and in vitro cytotoxic potency.

  一系列新型的C2-exo不饱和吡咯并[2,1-c] [1,4]苯并二氮杂（PBDs）已通过通用的pro-C2酮前体合成。C2-外不饱和键可增强DNA结合反应性和体外细胞毒性。