苯酚,4-异氰基-,乙酸酯(ester) | 189832-33-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚酯
• 中文名称: 苯酚,4-异氰基-,乙酸酯(ester)
• 英文名称: 4-acetoxyphenyl isocyanide
• 英文别名: p-acetoxyphenylisonitrile；(4-Isocyanophenyl) acetate
• CAS: 189832-33-5
• 化学式: C₉H₇NO₂
• 分子量: 161.16
• InChiKey: BWNVSJBQIIWWJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  30.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  苯酚,4-异氰基-,乙酸酯(ester) 、 1-(3-tert-butyldimethylsilyl-2-propynyl)-6-iodo-1H-pyridin-2-one 在 六甲基二锡 作用下， 以 苯 为溶剂， 反应 9.0h， 以41%的产率得到(20S)-10-acetoxy-7-tert-butyldimethylsilylcamptothecin
  参考文献：
  名称：

  新型的硅酸酯罐7-叔丁基二甲基甲硅烷基-10-羟基喜树碱具有很高的亲脂性，改善了人类的血液稳定性，并具有强大的抗癌活性。

  摘要：

  我们描述了B和A，B环修饰喜树碱的合理设计和合成。与临床相关的喜树碱类似物相比，7-叔丁基二甲基甲硅烷基-10-羟基喜树碱（DB-67，14）中的关键α-羟基-δ-内酯药效基团在人血液中显示出优异的稳定性。在人类血液中，14在130分钟处显示为（1/2），内酯百分比为平衡值30％。叔丁基二甲基甲硅烷基使新试剂的亲脂性比喜树碱高25倍，并且14以其活性内酯的形式容易并入细胞和脂质体双层中。另外，在人血清白蛋白存在下，14中的7-烷基甲硅烷基和10-羟基双取代增强了药物稳定性。从而，净亲脂性和人类血清白蛋白相互作用的改变共同促进血液稳定性的增强。使用源自八种不同肿瘤类型的多种不同细胞系的体外细胞毒性试验表明，14种具有与喜树碱和10-羟基喜树碱以及FDA批准的喜树碱类似物拓扑替康和CPT-11相当的功效。此外，无细胞裂解分析显示14活性高，并且比喜树碱或SN-38形成更稳定的top1裂解复合物

  DOI：

  10.1021/jm000144o
• 作为产物：
  描述：

  4-acetoxyformanilide 在 四溴化碳 、 三乙胺 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以76%的产率得到苯酚,4-异氰基-,乙酸酯(ester)
  参考文献：
  名称：

  A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles

  摘要：

  A general and efficient synthesis of (20S)-camptothecin (1a) is reported. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-trimethylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharpless asymmetric dihydroxylation followed by lactol oxidation and iododesilylation produced the key intermediate in 94% enantiomeric excess. Alkylation with propargyl bromide and a cascade radical reaction with phenyl isonitrile then produced 1a. About 20 other penta- and hexacyclic analogues of camptothecin with differing single or multiple substituents at C7, C9, C10, C11, and/or C12 were made by changing the propargylating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthesis of the prodrug irinotecan is direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted isonitriles allows the regioselective synthesis of camptothecin analogues in cases where isomeric mixtures are formed from the parent isonitriles. The synthesis of the derivatives relies on the broad scope and functional group tolerance of the key cascade radical reaction.

  DOI：

  10.1002/(sici)1521-3765(199801)4:1<67::aid-chem67>3.0.co;2-f

文献信息

• Total Synthesis of Luotonin and a Small Library of AB-Ring SubstitutedAnalogues by Cascade Radical Annulation of Isonitriles
  作者：Dennis P. Curran、Raghuraman Tangirala、Smitha Antony、Keli Agama、Yves Pommier

  DOI：10.1055/s-2005-918923

  日期：——

  A four-step total synthesis of luotonin is deployed to make a small library of AB-ring substituted analogues. These analogues show weak activity in a standard topoisomerase I mediated DNA cleavage assay.

  采用四步骤全合成法，制备了一批AB环替换类似物的小型库。这些类似物在标准拓扑异构酶I介导的DNA切割实验中表现出较弱的活性。
• [EN] CAMPTOTHECIN ANALOGS AND METHODS OF PREPARATION THEREOF<br/>[FR] ANALOGUES DE LA CAMPTOTHECINE ET PROCEDE DE PREPARATION ASSOCIES
  申请人：UNIV PITTSBURGH

  公开号：WO2000061146A1

  公开（公告）日：2000-10-19

  A compound has formula (1) in racemic form, enantiomerically enriched form or enantiomerically pure form. R6 is preferably -Si(R8R9R1O) or -(R?7)Si(R8R9R10¿), wherein R7 is an alkylene group, an alkenylene group, or an alkynylene group; and R?8, R9 and R10¿ are independently a C¿1-10? alkyl group, a C?2-10¿ alkenyl group, a C2-10 alkynyl group, an aryl group or a -(CH¿2)NR?11 group, wherein N is an integer within the range of 1 through 10 and R11 is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, -SRc or a nitro group. R1-R4 can be broadly substituted. R5 is preferably a C¿1-10? alkyl group, an alkenyl group, an alkynyl group, or a benzyl group. R?13¿ is preferably H, F or -CH¿3. R?16 is -C(O)Rf or H. The E-ring (the lactone ring) may be opened. A method of synthesis of compound (1) and intermediates in the synthesis thereof are provided.

  该化合物的式子为(1)，可以是外消旋型，对映富集型或对映纯型。其中R6首选为-Si(R8R9R1O)或-(R7)Si(R8R9R10)，其中R7为烷基、烯基或炔基；而R8、R9和R10则分别是C1-10烷基、C2-10烯基、C2-10炔基、芳基或-(CH2)NR11，其中N为1至10的整数，而R11为羟基、烷氧基、氨基、烷基氨基、二烷基氨基、卤素原子、氰基、-SRc或硝基。R1-R4可以广泛取代。R5首选为C1-10烷基、C2-10烯基、C2-10炔基或苄基。R13首选为H、F或-CH3。R16为-C(O)Rf或H。E环（内酯环）可以打开。提供了化合物（1）的合成方法和合成中间体。
• [EN] CAMPTOTHECIN ANALOGS AND METHODS OF PREPARATION THEREOF<br/>[FR] ANALOGUES DE LA CAMPTOTHECINE ET PROCEDES D'ELABORATION
  申请人：UNIVERSITY OF PITTSBURGH

  公开号：WO1999009996A1

  公开（公告）日：1999-03-04

  (EN) The present invention provides generally a compound having general formula (1), wherein R1 and R2 are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, a carbonyloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, -SRc, wherein, Rc is hydrogen, an acyl group, an alkyl group, or an aryl group, or R1 and R2 together form a group of the formula -O(CH2)nO- wherein n represents the integer 1 or 2; R3 is H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano group; or R2 and R3 together form a group of the formula -O(CH2)nO- wherein n represents the integer 1 or 2; R4 is H, F, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkylnyl group, or a C1-3 alkoxyl group; R5 is a C1-10 alkyl group, or a propargyl group; and R6, R7 and R8 are independently a C1-10 alkyl group, a C2-10 alkenyl group, C2-10 alkynyl group, an aryl group or a -(CH2)NR9 group, wherein N is an integer within the range of 1 through 10 and R9 is a hydroxyl group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group; and pharmaceutically acceptable salts thereof.(FR) L'invention concerne globalement un composé de formule générale (1) et les sels pharmaceutiquement acceptables de ce composé. Dans ladite formule, R1 et R2 sont indépendamment identiques ou différents et représentent hydrogène, un groupe alkyle, un groupe alcényle, un groupe benzyle, un groupe alcynyle, un groupe alcoxyle, un groupe aryloxy, un groupe acyloxy, un groupe carbonyloxy, un groupe carbamoyloxy, un halogène, un groupe hydroxyle, un groupe nitro, un groupe cyano, un groupe azido, un groupe formyle, un groupe hydrazino, un groupe acyle, un groupe amino, -SRc, sachant que Rc est hydrogène, un groupe acyle, un groupe alkyle, ou un groupe aryle, ou bien R1 et R2 forment ensemble un groupe de formule -O(CH2)nO- où n est un entier égal à 1 ou à 2; R3 est H, F, un atome d'halogène, un groupe nitro, un groupe amino, un groupe hydroxyle, ou un groupe cyano; ou bien R2 et R3 forment ensemble un groupe de formule-O(CH2)nO- où n est un entier égal à 1 ou à 2; R4 est H, F, un groupe alkyle C1-3, un groupe alcényle C2-3, un groupe alcynyle C2-3, ou un groupe alcoxyle C1-3; R5 est un groupe alkyle C1-10, ou un groupe propargyle; et R6, R7 et R8 sont indépendamment un groupe alkyle C1-10, un groupe alcényle C2-10, un groupe alcynyle C2-10, un groupe aryle ou un groupe -(CH2)NR9 où N est un entier compris entre 1 et 10, et R9 est un groupe hydroxyle, un groupe alcoxy, un groupe amino, un groupe alkylamino, un groupe dialkylamino, un atome d'halogène, un groupe cyano ou un groupe nitro.

  本发明提供了一般式（1）的化合物，其中R1和R2分别独立相同或不同，可以是氢、烷基、烯基、苄基、炔基、烷氧基、芳氧基、酰氧基、羰基氧基、氨基甲酰氧基、卤素、羟基、硝基、氰基、叠氮基、甲酰基、肼基、酰基、氨基、-SRc，其中Rc是氢、酰基、烷基或芳基，或R1和R2共同形成公式为-O（CH2）nO-的基团，其中n表示整数1或2；R3是H、F、卤素原子、硝基、氨基、羟基或氰基；或R2和R3共同形成公式为-O（ ）nO-的基团，其中n表示整数1或2；R4是H、F、C1-3烷基、C2-3烯基、C2-3烷基基或C1-3烷氧基；R5是C1-10烷基或丙炔基；R6、R7和R8分别是C1-10烷基、C2-10烯基、C2-10炔基、芳基或-( )NR9基团，其中N是1到10的整数，R9是羟基、烷氧基、氨基、烷基氨基、二烷基氨基、卤素原子、氰基或硝基；以及其药学上可接受的盐。
• [EN] CAMPTOTHECIN ANALOGS AND METHODS OF PREPARATION THEREOF<br/>[FR] ANALOGUES DE CAMPTOTHECINE ET METHODES DE PREPARATION
  申请人：UNIV PITTSBURGH

  公开号：WO2000035924A1

  公开（公告）日：2000-06-22

  A compound and a method of synthesizing a compound having general formula (1): wherein R?1 and R2¿ are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, -OC(O)ORd, wherein Rd is an alkyl group, a carbamoyloxy group, a halogen, a hydroxy group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, -SRc, wherein Rc is hydrogen, an acyl group, an alkyl group, or an aryl group, or R?1 and R2¿ together form a group of the formula -O(CH¿2?)nO- wherein n represents the integer 1 or 2; R?3¿ is H, F, a halogen atom, a nitro group, an amino group, a hydroxy group, or a cyano group; or R?2 and R3¿ together form a group of the formula -O(CH¿2?)n O- wherein n represents the integer 1 or 2; R?4¿ is H, a trialkylsilyl group, F, a C¿1-3? alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, or a C1-3 alkoxy group; R?5¿ is a C¿1-10? alkyl group, an allyl group, a benzyl group or a propargyl group; and R?6, R7 and R8¿ are independently a C¿1-10? alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, an aryl group or a -(CH2)NR?9¿ group, wherein N is an integer within the range of 1 through 10 and R9 is a hydroxy group, alkoxy group, an amino group, alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group; and R11 is an alkylene group or an alkenylene group, and pharmaceutically acceptable salts thereof.

  一种化合物及其合成方法，其具有通式（1）： 其中R1和R2独立且相同或不同，可以是氢、烷基、烯基、苄基、炔基、烷氧基、芳氧基、酰氧基、-OC（O）ORd（其中Rd为烷基、氨基甲酰氧基、卤素、羟基、硝基、氰基、叠氮基、甲酰基、肼基、酰基、氨基、-SRc（其中Rc为氢、酰基、烷基或芳基），或R1和R2组成式为-O（CH2）nO-的基团，其中n表示整数1或2；R3为氢、氟、卤素原子、硝基、氨基、羟基或氰基；或R2和R3组成式为-O（ ）nO-的基团，其中n表示整数1或2；R4为氢、三烷基硅基、氟、C1-3烷基、C2-3烯基、C2-3炔基或C1-3烷氧基；R5为C1-10烷基、烯丙基、苄基或丙炔基；R6、R7和R8独立地为C1-10烷基、C2-10烯基、C2-10炔基、芳基或-( )NR9（其中N为1至10的整数，R9为羟基、烷氧基、氨基、烷基氨基、二烷基氨基、卤素原子、氰基或硝基）；R11为烷基或烯基，以及其药物可接受的盐。
• Camptothecin analogs and methods of preparation thereof
  申请人：——

  公开号：US20010003779A1

  公开（公告）日：2001-06-14

  A method of synthesizing a compound having the formula 1 via a cascade radical 4+1 annulation includes the step wherein the precursor 2 is reacted with an arylisonitrile having the formula 3 wherein X is a radical precursor such as Cl, Br or I. R 6 is preferably —Si(R 8 R 9 R 10 ) or —(R 7 )Si(R 8 R 9 R 10 ), wherein R 7 is an alkylene group, an alkenylene group, or an alkynylene group; and R 8 , R 9 and R 10 are independently a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, an aryl group or a —(CH 2 ) N R 11 group, wherein N is an integer within the range of 1 through 10 and R 11 is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, —SR c or a nitro group. R 1 -R 4 can be broadly substituted. R 5 is preferably a C 1-10 alkyl group, an alkenyl group, an alkynyl group, or a benzyl group. R 13 is preferably H, F or —CH 3 . R 16 is R 16 is —C(O)R f or H. The E-ring (the lactone ring) may be opened.

  通过级联自由基4+1环化合成具有公式1的化合物的方法包括步骤，其中前体2与具有公式3的芳基异腈反应，其中X是类似Cl、Br或I的基团前体。R6优选为—Si(R8R9R10)或—(R7)Si(R8R9R10)，其中R7是烷基、烯基或炔基；R8、R9和R10独立地是C1-10烷基、C2-10烯基、C2-10炔基、芳基或—(CH2)NR11基团，其中N在1到10范围内，R11是羟基、烷氧基、氨基、烷基氨基、二烷基氨基、卤素原子、氰基、—SRc或硝基。R1-R4可以广泛取代。R5优选为C1-10烷基、烯基、炔基或苄基。R13优选为H、F或—CH3。R16为C(O)R对于H。E环（内酯环）可以打开。