tert-butyl (4-(benzyloxy)-8-methylnaphthalen-2-yl)carbamate | 1662687-76-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: tert-butyl (4-(benzyloxy)-8-methylnaphthalen-2-yl)carbamate
• 英文别名: tert-Butyl (4-(benzyloxy)-8-methylnaphthalen-2-yl)carbamate；tert-butyl N-(8-methyl-4-phenylmethoxynaphthalen-2-yl)carbamate
• CAS: 1662687-76-4
• 化学式: C₂₃H₂₅NO₃
• 分子量: 363.456
• InChiKey: DKNNZNFXEAXOGR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  47.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl (4-(benzyloxy)-8-methylnaphthalen-2-yl)carbamate 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 、 palladium on activated charcoal 、 potassium tert-butylate 、 甲酸铵 、 sodium methylate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 正己烷 、 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 (S)-N-(2-(1-(chloromethyl)-5-hydroxy-9-methyl-2,3-dihydro-1H-benzo[e]indole-3-carbonyl)-imidazo[1,2-a]pyridin-6-yl)-4-(methoxymethoxy)benzamide
  参考文献：
  名称：

  [EN] IMPROVED PROCESS FOR MAKING DUOCARMYCIN PRODRUGS
  [FR] PROCÉDÉ AMÉLIORÉ DE PRODUCTION DE PROMÉDICAMENTS À BASE DE DUOCARMYCINE

  摘要：

  本发明涉及一种过程，包括将式（I）的化合物通过与有机锂试剂发生反应转化为式（II）的化合物，该化合物可以进一步转化为由DNA烷基化部分和DNA结合部分组成的杜卡霉素类似物，更进一步转化为相应的抗体药物结合物。

  公开号：

  WO2015185142A1
• 作为产物：
  描述：

  4-羟基-8-甲基-2-萘羧酸甲酯 在 叠氮磷酸二苯酯 、 水 、 potassium carbonate 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 5.0h， 生成 tert-butyl (4-(benzyloxy)-8-methylnaphthalen-2-yl)carbamate
  参考文献：
  名称：

  [EN] IMPROVED PROCESS FOR MAKING DUOCARMYCIN PRODRUGS
  [FR] PROCÉDÉ AMÉLIORÉ DE PRODUCTION DE PROMÉDICAMENTS À BASE DE DUOCARMYCINE

  摘要：

  本发明涉及一种过程，包括将式（I）的化合物通过与有机锂试剂发生反应转化为式（II）的化合物，该化合物可以进一步转化为由DNA烷基化部分和DNA结合部分组成的杜卡霉素类似物，更进一步转化为相应的抗体药物结合物。

  公开号：

  WO2015185142A1

文献信息

• PROCESS FOR MAKING DUOCARMYCIN PRODRUGS
  申请人：Synthon Biopharmaceuticals B.V.

  公开号：US20170145006A1

  公开（公告）日：2017-05-25

  The present invention relates to a process comprising converting a compound of formula (I) into a compound of formula (II) by reaction with an organolithium reagent, which compound can be further converted into duocarmycin analogues consisting of a DNA-alkylating and a DNA-binding part, and still further into corresponding antibody-drug conjugates.
• US9890159B2
  申请人：——

  公开号：US9890159B2

  公开（公告）日：2018-02-13
• Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody–Drug Conjugate SYD985
  作者：Ronald C. Elgersma、Ruud G. E. Coumans、Tijl Huijbregts、Wiro M. P. B. Menge、John A. F. Joosten、Henri J. Spijker、Franciscus M. H. de Groot、Miranda M. C. van der Lee、Ruud Ubink、Diels J. van den Dobbelsteen、David F. Egging、Wim H. A. Dokter、Gijs F. M. Verheijden、Jacques M. Lemmens、C. Marco Timmers、Patrick H. Beusker

  DOI：10.1021/mp500781a

  日期：2015.6.1

  Antibody-drug conjugates (ADCs) that are currently on the market or in clinical trials are predominantly based on two drug classes: auristatins and maytansinoids. Both are tubulin binders and block the cell in its progression through mitosis. We set out to develop a new class of linker-drugs based on duocarmycins, potent DNA-alkylating agents that are composed of a DNA-alkylating and a DNA-binding moiety and that bind into the minor groove of DNA. Linker-drugs were evaluated as ADCs by conjugation to the anti-HER2 antibody trastuzumab via reduced interchain disulfides. Duocarmycin 3b, bearing an imidazo[1,2-a]pyridine-based DNA-binding unit, was selected as the drug moiety, notably because of its rapid degradation in plasma. The drug was incorporated into the linker-drugs in its inactive prodrug form, seco-duocarmycin 3a. Linker attachment to the hydroxyl group in the DNA-alkylating moiety was favored over linking to the DNA-binding moiety, as the first approach gave more consistent results for in vitro cytotoxicity and generated ADCs with excellent human plasma stability. Linker-drug 2 was eventually selected based on the properties of the corresponding trastuzumab conjugate, SYD983, which had an average drug-to-antibody ratio (DAR) of about 2. SYD983 showed subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma. Studies comparing ADCs with a different average DAR showed that a higher average DAR leads to increased efficacy but also to somewhat less favorable physicochemical and toxicological properties. Fractionation of SYD983 with hydrophobic interaction chromatography resulted in SYD985, consisting of about 95% DAR2 and DAR4 species in an approximate 2:1 ratio and having an average DAR of about 2.8. SYD985 combines several favorable properties from the unfractionated ADCs with an improved homogeneity. It was selected for further development and recently entered clinical Phase I evaluation.
• [EN] IMPROVED PROCESS FOR MAKING DUOCARMYCIN PRODRUGS<br/>[FR] PROCÉDÉ AMÉLIORÉ DE PRODUCTION DE PROMÉDICAMENTS À BASE DE DUOCARMYCINE
  申请人：SYNTHON BIOPHARMACEUTICALS BV

  公开号：WO2015185142A1

  公开（公告）日：2015-12-10

  The present invention relates to a process comprising converting a compound of formula (I) into a compound of formula (II) by reaction with an organolithium reagent, which compound can be further converted into duocarmycin analogues consisting of a DNA- alkylating and a DNA-binding part, and still further into corresponding antibody-drug conjugates.

  本发明涉及一种过程，包括将式（I）的化合物通过与有机锂试剂发生反应转化为式（II）的化合物，该化合物可以进一步转化为由DNA烷基化部分和DNA结合部分组成的杜卡霉素类似物，更进一步转化为相应的抗体药物结合物。