1-(2-Chloroethyl)piperidine-4-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-(2-Chloroethyl)piperidine-4-carboxylic acid
• 英文别名: 1-(2-chloroethyl)piperidine-4-carboxylic acid
• 化学式: C₈H₁₄ClNO₂
• 分子量: 191.65
• InChiKey: JRZMCBFLUQUTBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  3

文献信息

• [EN] PROCESS FOR THE PREPARATION OF UMECLIDINIUM BROMIDE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE BROMURE D'UMÉCLIDINIUM
  申请人：HOVIONE SCIENTIA LTD

  公开号：WO2018087561A1

  公开（公告）日：2018-05-17

  The present invention discloses processes comprising a) reacting ethyl isonipecotate with 1 -bromo-2- chloroethane in the presence of an organic base in a solvent to form ethyl 1 -(2-chloroethyl)piperidine- 4-carboxylate (II) or a salt thereof. Process step a) may be included in a process for preparing umeclidinium bromide that comprises further process steps: b) reacting ethyl 1 -(2- chloroethyl)piperidine-4-carboxylate (II) or a salt thereof with lithium diisopropylamide in a solvent to form ethyl 1 -azabicyclo[2.2.2]octane-4-carboxylate (III); c) reacting ethyl 1 -azabicyclo[2.2.2]octane-4- carboxylate (III) with phenyl lithium in a solvent to form 1 -azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV); and d) reacting 1 -azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV) with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1 -[2-(phenylmethyl)oxy]ethyl]-1 - azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide. A process comprising d) reacting 1 - azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1 -[2-(phenylmethyl)oxy]ethyl]-1 -azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide, wherein the solvent is selected from cyclic ethers such as tetrahydrofuran, aromatic solvents, such as toluene, ketones such as acetone and protic solvents such as water or combinations thereof, optionally wherein the solvent is water is also disclosed. Umeclidinium bromide obtainable from the disclosed processes, ethyl 1 -(2-chloroethyl)piperidine-4-carboxylate (II) and pharmaceutical compositions are also disclosed.

  本发明公开了包括以下步骤的工艺：a）在有机碱存在的溶剂中，将异匹哌酸乙酯与1-溴-2-氯乙烷反应，形成乙基1-(2-氯乙基)哌啶-4-羧酸乙酯（II）或其盐。步骤a）可以包括在制备乌美克替尼溴化物的工艺中，该工艺包括进一步的工艺步骤：b）将乙基1-(2-氯乙基)哌啶-4-羧酸乙酯（II）或其盐与异丙基二异丙胺在溶剂中反应，形成乙基1-氮杂双环[2.2.2]辛烷-4-羧酸乙酯（III）；c）将乙基1-氮杂双环[2.2.2]辛烷-4-羧酸乙酯（III）与苯基锂在溶剂中反应，形成1-氮杂双环[2.2.2]辛-4-基(二苯基)甲醇（IV）；以及d）将1-氮杂双环[2.2.2]辛-4-基(二苯基)甲醇（IV）与((2-溴乙氧基)甲基)苯在溶剂中反应，形成4-[羟基(二苯基)甲基]-1-[2-(苯甲基)氧基]乙基]-1-氮杂双环[2.2.2]辛烷溴化物（I），即乌美克替尼溴化物。也公开了包括d）将1-氮杂双环[2.2.2]辛-4-基(二苯基)甲醇与((2-溴乙氧基)甲基)苯在溶剂中反应，形成4-[羟基(二苯基)甲基]-1-[2-(苯甲基)氧基]乙基]-1-氮杂双环[2.2.2]辛烷溴化物（I），即乌美克替尼溴化物的工艺，其中所选溶剂包括环氧化物，如四氢呋喃，芳香溶剂，如甲苯，酮类溶剂，如丙酮和质子溶剂，如水或其组合物，可选地还公开了溶剂为水的情况。还公开了从所述工艺中获得的乌美克替尼溴化物、乙基1-(2-氯乙基)哌啶-4-羧酸乙酯（II）和制药组合物。
• PROCESS FOR THE PREPARATION OF UMECLIDINIUM BROMIDE
  申请人：Hovione Scientia Limited

  公开号：EP3538524A1

  公开（公告）日：2019-09-18