(S)-4-乙基-4-羟基-6-碘-3-氧代-1H-吡喃并[3,4-C]-8-吡啶酮 | 173442-34-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃吡啶类
• 中文名称: (S)-4-乙基-4-羟基-6-碘-3-氧代-1H-吡喃并[3,4-C]-8-吡啶酮
• 英文名称: (S)-4-ethyl-4-hydroxy-6-iodo-3-oxo-1H-pyrano[3,4-c]-8-pyridone
• 英文别名: (4S)-4-ethyl-4-hydroxy-6-iodo-1,7-dihydropyrano[3,4-c]pyridine-3,8-dione
• CAS: 173442-34-7
• 化学式: C₁₀H₁₀INO₄
• 分子量: 335.098
• InChiKey: HXJVOQIFVSAXBE-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-4-乙基-4-羟基-6-碘-3-氧代-1H-吡喃并[3,4-C]-8-吡啶酮 在 六甲基二锡 、 sodium hydride 、 lithium bromide 作用下， 以 乙二醇二甲醚 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 20.42h， 生成 喜树碱
  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
• 作为产物：
  描述：

  4-Ethyl-8-methoxy-6-trimethylsilanyl-1H-pyrano[3,4-c]pyridine 在 四氧化锇 、 hydroquinindine-2,5-diphenyl-4,6-pyrimidinediyl diether 、 氢碘酸 、 碘 、 一氯化碘 、 calcium carbonate 作用下， 生成 (S)-4-乙基-4-羟基-6-碘-3-氧代-1H-吡喃并[3,4-C]-8-吡啶酮
  参考文献：
  名称：

  Curran, Dennis P.; Ko, Sung-Bo; Josien, Hubert, Angewandte Chemie, 1995, vol. 107, # 23/24, p. 2948 - 2950

  摘要：

  DOI：

文献信息

• The Novel Silatecan 7-<i>tert</i>-Butyldimethylsilyl-10-hydroxycamptothecin Displays High Lipophilicity, Improved Human Blood Stability, and Potent Anticancer Activity
  作者：David Bom、Dennis P. Curran、Stefan Kruszewski、Stephen G. Zimmer、J. Thompson Strode、Glenda Kohlhagen、Wu Du、Ashok J. Chavan、Kimberly A. Fraley、Alex L. Bingcang、Lori J. Latus、Yves Pommier、Thomas G. Burke

  DOI：10.1021/jm000144o

  日期：2000.10.1

  incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell

  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
• Intermediates in the synthesis of camptothecin and related compounds and synthesis thereof
  申请人：University of Pittsburgh

  公开号：US06252079B1

  公开（公告）日：2001-06-26

  The present invention provides a short, convergent total synthesis of irinotecan and derivative compounds which comprises of a novel 4+1 radical annulation wherein the precursor is reacted with an aryl isonitrile having the formula wherein X is Br or I, and R4 is an alkyl group, an allyl group, a propargyl group or a benzyl group, and R16 is H, a C1-C6 alkoxy group, a group wherein p is an integer between 4 and 12, or a C1-C12 acyclic dialkylamino group. The present invention also provides novel chemical intermediates for such 4+1 radical annulations.

  本发明提供了伊立替康及其衍生化合物的短、收敛的全合成方法，包括一种新颖的4+1自由基环合反应，其中前体物质与具有以下结构的芳基异腈发生反应：其中X为Br或I，R4为烷基、烯丙基、丙炔基或苄基，R16为H、C1-C6烷氧基、p为4至12之间的整数的羟基，或C1-C12非环二烷基氨基基团。本发明还提供了用于这种4+1自由基环合反应的新型化学中间体。
• Catalytic Enantioselective Synthesis of (20S)-Camptothecin Intermediates Using Cyanosilylation of Ketones Promoted by D-Glucose-derived Lanthanide Catalyst
  作者：Masakatsu Shibasaki、Kazuo Yabu、Shuji Masumoto、Motomu Kanai、Wu Du、Dennis P. Curran

  DOI：10.3987/com-02-s49

  日期：——

  An efficient catalytic enantioselective synthetic route was developed for Curran's versatile camptothecin intermediate (5). The key step is the catalytic enantioselective cyanosilylation of ketone (7) using a chiral samarium (Sm) complex. The target ketone cyanohydrin (6) was obtained with 90% ee using 2 mol % of the catalyst. A gadolinium (Gd) complex derived from the same chiral ligand could also

  为 Curran 的多功能喜树碱中间体 (5) 开发了一种有效的催化对映选择性合成路线。关键步骤是使用手性钐 (Sm) 配合物对酮 (7) 进行催化对映选择性氰基化。使用 2 mol% 的催化剂获得目标酮合氰化氢 (6)，ee 为 90%。源自相同手性配体的钆 (Gd) 配合物也可用作对映选择性催化剂以合成 Corey 的中间体 (11)。
• [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（CH2）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-(CH2)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。
• Camptothecin analogs and methods of preparation thereof
  申请人：——

  公开号：US20020193598A1

  公开（公告）日：2002-12-19

  A compound and a method of synthesizing a compound having the following general formula (1): 1 wherein R 1 and R 2 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)OR d , wherein R d 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, —SR c , wherein, R c is hydrogen, an acyl group, an alkyl group, or an aryl group, or R 1 and R 2 together form a group of the formula —O(CH 2 ) n O— 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 R 3 together form a group of the formula —O(CH 2 ) n O— wherein n represents the integer 1 or 2; R 8 is H, a trialkylsilyl group, F, a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, or a C 1-3 alkoxy group; R 5 is a C 1-10 alkyl group, an allyl group, a benzyl group or a propargyl group; and R 6 , R 7 and R 8 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 9 group, wherein N is an integer within the range of 1 through 10 and R 9 is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group; and R 11 is an alkylene group or an alkenylene group, and pharmaceutically acceptable salts thereof.

  一种具有以下通式（1）的化合物及其合成方法：其中R1和R2独立地相同或不同，可以是氢、烷基、烯基、苯基、炔基、烷氧基、芳基氧基、酰氧基、—OC（O）ORd，其中Rd是烷基、氨基甲酰氧基、卤素、羟基、硝基、氰基、偶氮基、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共同形成式为—O（CH2）nO—的基团，其中n表示整数1或2；R8是H、三烷基硅基、F、C1-3烷基、C2-3烯基、C2-3炔基或C1-3烷氧基；R5是C1-10烷基、烯丙基、苯甲基或丙炔基；R6、R7和R8独立地是C1-10烷基、C2-10烯基、C2-10炔基、芳基或—（CH2）NR9基团，其中N在1至10范围内是整数，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；R11是烷基或烯基，以及其药学上可接受的盐。