5-碘甲基6alpha,9alpha-二氟-11beta-羟基-16alpha-甲基-3-氧代-17alpha-(丙酰氧基)-雄甾-1,4-二烯-17beta-硫代甲酸酯 | 80474-67-5

• 物质功能分类: 有机原料 - 酮类化合物
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 5-碘甲基6alpha,9alpha-二氟-11beta-羟基-16alpha-甲基-3-氧代-17alpha-(丙酰氧基)-雄甾-1,4-二烯-17beta-硫代甲酸酯
• 中文别名: 5-氯-2-甲基-4-异噻唑啉-3-酮
• 英文名称: S-iodomethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate
• 英文别名: [(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-17-(iodomethylsulfanylcarbonyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate
• CAS: 80474-67-5
• 化学式: C₂₅H₃₁F₂IO₅S
• 分子量: 608.485
• InChiKey: HKRIRGIBBWVEFV-CENSZEJFSA-N

物化性质

• 沸点：
  606.7±55.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿、二氯甲烷、DMF、乙醇、乙酸乙酯、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-碘甲基6alpha,9alpha-二氟-11beta-羟基-16alpha-甲基-3-氧代-17alpha-(丙酰氧基)-雄甾-1,4-二烯-17beta-硫代甲酸酯 在 potassium fluoride 、 aminopolyether 2.2.2 、 potassium iodide 作用下， 以 乙腈 为溶剂， 20.0~100.0 ℃ 、140.0 kPa 条件下， 反应 1.75h， 生成 [(6S,8S,9R,10S,11S,13S,14S,16R,17R)-17-[[(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-propanoyloxy-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carbonyl]sulfanylmethylsulfanylcarbonyl]-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate
  参考文献：
  名称：

  Automated radiosynthesis of no-carrier-added [S-fluoromethyl- 18F]fluticasone propionate as a radiotracer for lung deposition studies with PET

  摘要：

  Fluticasone propionate [(S)-fluoromethyl-6 alpha,9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha-(propionyloxy)-androsta-1,4-diene-17 beta-carbothioate; FP] is a potent anti-inflammatory steroid with several therapeutic indications, including use as an anti-asthmatic drug when administered as sized particles by inhalation from a pressurised metered-dose inhaler (pMDI). FP was successfully labelled with fluorine-18 (t(1/2) = 109.6 min; beta(+) = 100%) by displacement of tosylate with cyclotron-produced no-carrier-added [F-18]fluoride in an (S)-tosylmethyl precursor prepared from the known (S)-chloromethyl analogue of FP. Radiochemically pure [S-fluoromethyl-F-18]FP was separated by reverse phase HPLC in 35% radiochemical yield (decay-corrected) within 80 min form the end of radionuclide production (as verified by, radio-HPLC, LC-MS and LC-NMR). The radiosynthesis was automated for the safe production of high radioactivities (20-50 mCi) of [F-18]FP in a lead-shielded hot-cell for subsequent incorporation into formulated FP particles within a pMDI and subsequent study of FP deposition in human lung using positron emission tomography (PET).

  DOI：

  10.1002/(sici)1099-1344(199707)39:7<567::aid-jlcr999>3.0.co;2-p
• 作为产物：
  描述：

  (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic propionic thioanhydride 在 碳酸氢钠 、 二乙胺 、 sodium iodide 作用下， 以 N,N-二甲基乙酰胺 、 丙酮 为溶剂， 反应 3.0h， 生成 5-碘甲基6alpha,9alpha-二氟-11beta-羟基-16alpha-甲基-3-氧代-17alpha-(丙酰氧基)-雄甾-1,4-二烯-17beta-硫代甲酸酯
  参考文献：
  名称：

  Synthesis and Structure-Activity Relationships in a Series of Antiinflammatory Corticosteroid Analogs, Halomethyl Androstane-17.beta.-carbothioates and -17.beta.-carboselenoates

  摘要：

  The preparation and topical antiinflammatory potencies of a series of halomethyl 17 alpha-(acyloxy)11 beta-hydroxy-3 -oxoandrosta-1,4-diene-17 beta-carbothioates, carrying combinations of 6 alpha-fluoro, 9 alpha-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 17 beta-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anhydride with diethylamine, or by carboxyl activation with 1,1'-carbonyldiimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and reaction with hydrogen sulfide, the choice of reagent being governed by the 17 alpha-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17 beta-carboselenoat analogues. Antiinflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mice by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17 alpha-propionyloxy group. S-Fluoromethyl 6(alpha,9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha-(propionyloxy)androsta-1,4-diene-17 beta-carbothioate (fluticasone propionate, FP) was selected for clinical study as it showed high topical antiinflammatory activity but caused little hypothalamic-pituitary-adrenal suppression after topical or oral administration to rodents.

  DOI：

  10.1021/jm00048a008

文献信息

• NOVEL PROCESS AND INTERMEDIATES
  申请人：Gore Vinayak G.

  公开号：US20090177001A1

  公开（公告）日：2009-07-09

  The present invention relates to a process for the preparation of steroidal 17β-carboxylic thioates. More particularly the present invention relates to a convenient and efficient synthesis of steroidal 17β-carboxylic thioates, such as fluticasone propionate I, using soluble mixed fluorides to introduce fluorine by displacing an appropriate leaving group X in compounds II resulting in selective and controlled fluorination. The present invention also relates to intermediates II and their preparation.

  本发明涉及一种制备类固醇17β-羧基硫酸酯的过程。更具体地说，本发明涉及使用可溶性混合氟化物通过置换化合物II中适当的离去基X引入氟，从而选择性地和可控地氟化制备类固醇17β-羧基硫酸酯（如丙酸氟替卡松I）的方便和高效合成。本发明还涉及中间体II及其制备。
• WO2007/144668
  申请人：——

  公开号：——

  公开（公告）日：——
• J. Med. Chem. 1994, 37, 3717-3729
  作者：

  DOI：——

  日期：——
• PROCESS FOR THE PREPARATION OF S-FLUOROMETHYL-6 ,9 -DIFLUORO-11 -HYDROXY-16 -METHYL-17 -PROPIONYLOXY-3-OXO-ANDROSTA-1,4-DIENE-17 -CARBOTHIOATE AND INTERMEDIATES
  申请人：Generics [UK] Limited

  公开号：EP2044099B1

  公开（公告）日：2012-05-23
• Process for the preparation of S-fluoromethyl-6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxo-androsta-1,4-diene-17-carbothioate and intermediates
  申请人：Generics [UK] Limited

  公开号：EP2402360B1

  公开（公告）日：2020-04-01