tert-butyl (3S,4S)-4-[5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-3-fluoropiperidine-1-carboxylate | 1548129-20-9

• 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: tert-butyl (3S,4S)-4-[5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-3-fluoropiperidine-1-carboxylate
• CAS: 1548129-20-9
• 化学式: C₂₉H₂₇ClF₄N₄O₄S
• 分子量: 639.07
• InChiKey: DNYZCVXZFHBQQS-GMAHTHKFSA-N

物化性质

• 沸点：
  692.6±65.0 °C(predicted)
• 密度：
  1.46±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  43
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  110
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  3-bromo-1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazole-5-carbaldehyde 在 哌啶 、 5%-palladium/activated carbon 、 水 、 氢气 、 N,N-二异丙基乙胺 、 苯甲酸 作用下， 以 乙醇 、 乙酸乙酯 、 甲苯 为溶剂， 20.0 ℃ 、34.47 kPa 条件下， 反应 3.0h， 生成 1,1-dimethylethyl (3R,4R)-4-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-3-fluoropiperidine-1-carboxylate 、 tert-butyl (3S,4S)-4-[5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-3-fluoropiperidine-1-carboxylate
  参考文献：
  名称：

  Process Development for Scale-Up of a Novel 3,5-Substituted Thiazolidine-2,4-dione Compound as a Potent Inhibitor for Estrogen-Related Receptor 1

  摘要：

  The development of a reproducible process for multihundred gram production of (Z)-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazol-5-yl)methylene)-3-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione (26), a potent and selective inhibitor of estrogen-related receptor 1 (ERR!), is described. This multihundred gram synthesis was achieved via magnesium perchlorate-catalyzed regioselective epoxide ring-opening of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (9) with thiazolidine-2,4-dione (6, TZD) to form a diastereomeric mixture tert-butyl 4-(2,4-dioxothiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (17), of which the 3-hydroxyl group was functionally transformed to 3-fluoro derivative 19 after treatment with Deoxo-Fluor. Chiral separation of 19 provided the desired diastereomer (3R,4R)-21 that was converted to the secondary amine 23 TFA salt. Reductive amination of 23 produced the key intermediate N-methyl 24. Knoevenagel condensation of 24 with 1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazole-5-carbaldehyde (5) produced the final product 26 in 10% overall yield (99.7% HPLC area% with >= 99.5% de) after a convergent eight synthetic steps with the only column purification being the chiral HPLC separation of 3R,4R-21 from 3S,4S-22.

  DOI：

  10.1021/op400325r