diethyl 1,1'-(ethane-1,2-diyl)bis(piperidine-4-carboxylate)

• 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: diethyl 1,1'-(ethane-1,2-diyl)bis(piperidine-4-carboxylate)
• 英文别名: Ethyl 1-[2-(4-ethoxycarbonyl-1-piperidyl)ethyl]piperidine-4-carboxylate；ethyl 1-[2-(4-ethoxycarbonylpiperidin-1-yl)ethyl]piperidine-4-carboxylate
• 化学式: C₁₈H₃₂N₂O₄
• 分子量: 340.463
• InChiKey: JQOLBOXYHLTPJD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  59.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  哌啶-4-甲酸乙酯 、 1-溴-2-氯乙烷 在 三乙胺 作用下， 以 丙酮 为溶剂， 反应 24.0h， 以65.6%的产率得到1-(2-氯乙基)哌啶-4-甲酸乙酯
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF UMECLIDINIUM BROMIDE
  [FR] PROCÉDÉ DE PRÉPARATION DE BROMURE D'UMÉCLIDINIUM

  摘要：

  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。

  公开号：

  WO2018087561A1

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。
• [EN] CHEMICAL PROCESS<br/>[FR] PROCESSUS CHIMIQUE
  申请人：GLAXO GROUP LTD

  公开号：WO2014027045A1

  公开（公告）日：2014-02-20

  The present invention relates to a process for the preparation of umeclidinium bromide, and to processes for preparing intermediates used in the preparation of umeclidinium bromide.

  本发明涉及一种制备溴化乌美克莪啶的方法，以及用于制备溴化乌美克莪啶的中间体的制备方法。
• CHEMICAL PROCESS
  申请人：Glaxo Group Limited

  公开号：US20150232423A1

  公开（公告）日：2015-08-20

  The present invention relates to a process for the preparation of umeclidinium bromide, and to processes for preparing intermediates used in the preparation of umeclidinium bromide.

  本发明涉及一种制备溴化乌美克林的方法，以及用于制备溴化乌美克林的中间体的制备方法。
• PROCESS FOR THE PREPARATION OF UMECLIDINIUM BROMIDE
  申请人：Hovione Scientia Limited

  公开号：EP3831826A1

  公开（公告）日：2021-06-09

  The present invention discloses 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 water. The process may further comprise 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; 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); and 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). The process may further comprise e) recrystallizing umeclidinium bromide in a solvent. The process may further comprise f) micronizing the umeclidinium bromide.

  本发明公开了一种工艺，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)苯在溶剂中反应生成 4-[羟基(二苯基)甲基]-1-[2-(苯基甲基)氧基]乙基]-1-氮杂双环[2.2.2]辛烷溴化物 (I)，其中溶剂选自环醚如四氢呋喃、芳香族溶剂如甲苯、酮类如丙酮和水。该工艺可进一步包括 a) 在有机碱存在下，在溶剂中将异哌啶酸乙酯与 1-溴-2-氯乙烷反应，生成 1-(2-氯乙基)哌啶-4-羧酸乙酯 (II) 或其盐；b) 在溶剂中将 1-(2-氯乙基)哌啶-4-羧酸乙酯 (II) 或其盐与二异丙基酰胺锂反应，生成 1-氮杂双环[2.2.2.2]辛烷-4-羧酸乙酯(III)；和 c) 将 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生成 1-氮杂双环[2.2.2]辛-4-基(二苯基)甲醇(IV)。该工艺可进一步包括 e) 在溶剂中重结晶乌美溴铵。该工艺可进一步包括 f) 将乌美溴铵微粉化。
• Process for the preparation of umeclidinium bromide
  申请人：Hovione Scientia Limited

  公开号：US10759801B2

  公开（公告）日：2020-09-01

  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.

  本发明公开的工艺包括 a) 在有机碱存在下，在溶剂中使异哌酸乙酯与 1-溴-2-氯乙烷反应，生成 1-(2-氯乙基)哌啶-4-甲酸乙酯(II)或其盐。工艺步骤 a)可包括在制备乌美司溴铵的工艺中，该工艺包括进一步的工艺步骤： b) 将 1-(2-氯乙基)哌啶-4-羧酸乙酯(II)或其盐与二异丙基酰胺锂在溶剂中反应，生成 1-氮杂双环[2.2.2]辛烷-4-羧酸乙酯(III)； c) 将 1-氮杂双环[2.2.2]辛烷-4-羧酸乙酯与二异丙基酰胺锂在溶剂中反应，生成 1-氮杂双环[2.2.2]辛烷-4-羧酸乙酯(III)。2]辛烷-4-甲酸乙酯(III)与苯基锂在溶剂中反应生成 1-氮杂双环[2.2.2]辛-4-基(二苯基)甲醇(IV)；以及 d) 将 1-azabicyclo[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，生成 4-[羟基(二苯基)甲基]-1-[2-(苯基甲基)氧基]乙基]-1-氮杂双环[2.2.2]辛烷溴化物(I)，umeclidinium bromide。一种工艺，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)苯在溶剂中反应生成 4-[羟基(二苯基)甲基]-1-[2-(苯基甲基)氧基]乙基]-1-氮杂双环[2.2.2]辛烷溴化物(I)，umeclidinium bromide。2]octane bromide (I)、umeclidinium bromide，其中溶剂选自四氢呋喃等环状醚、甲苯等芳香族溶剂、丙酮等酮类溶剂和水等原生质溶剂或其组合，也公开了溶剂为水的任选情况。本发明还公开了可从所公开的工艺中获得的乌美拉啶溴化物、1-(2-氯乙基)哌啶-4-羧酸乙酯(II)和药物组合物。