(1R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (1R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate
• 英文别名: 1-azabicyclo[2.2.2]octan-3-yl (1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate；1-azabicyclo[2.2.2]octan-3-yl (1R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate
• 化学式: C₂₃H₂₆N₂O₂
• 分子量: 362.472
• InChiKey: FBOUYBDGKBSUES-FOIFJWKZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate 、 奎宁环-3-醇 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 生成 (1R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate
  参考文献：
  名称：

  [EN] PROCESS FOR PREPARING CHEMICALLY AND CHIRALLY PURE SOLIFENACIN BASE AND ITS SALTS
  [FR] PROCÉDÉ DE PRÉPARATION D'UNE SOLIFÉNACINE BASE DE PURETÉ CHIMIQUE ET DE PURETÉ CHIRALE ET DE SES SELS

  摘要：

  本发明提供了改进的制备化学纯和对映纯索利那辛碱的方法。本发明还提供了一种含有至少98%纯度的索利那辛盐的组合物。本发明还披露了索利那辛的某些新盐以及索利那辛盐酸盐和索利那辛草酸盐的新多形态，均为纯形式。

  公开号：

  WO2009087664A1

文献信息

• Process for the Preparation of Solifenacin and Salts Thereof
  申请人：Bessa Bellunt Jordi

  公开号：US20140228575A1

  公开（公告）日：2014-08-14

  The invention provides a new process for the preparation of solifenacin or a pharmaceutically acceptable acid addition salt thereof, comprising reacting (R)-quinuclidin-3-yl phenethylcarbamate with benzaldehyde in the presence of an acid to obtain a diasteroisomeric mixture (S,R)—((R)-quinuclidin-3-yl) 1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate of formula (IV) which can be resolved and the solifenacin or a pharmaceutically acceptable acid addition salt thereof recovered. The invention also provides the new key intermediate (R)-quinuclidin-3-yl phenethylcarbamate involved in the process. Further the invention provides a method for the transformation of (R)—((R)-quinuclidin-3-yl) 1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate into a diasteroisomeric mixture (S,R)—((R)-quinuclidin-3-yl) 1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate.

  该发明提供了一种制备索利那辛或其药用可接受的酸盐的新工艺，包括在酸的存在下将(R)-喹诺啡啶-3-基苯乙基氨基甲酸酯与苯甲醛反应，以获得一个立体异构混合物(S,R)-((R)-喹诺啡啶-3-基) 1-苯基-3,4-二氢异喹啉-2(1H)-羧酸酯的公式(IV)，该混合物可以被分离，并可回收索利那辛或其药用可接受的酸盐。该发明还提供了参与该工艺的新关键中间体(R)-喹诺啡啶-3-基苯乙基氨基甲酸酯。此外，该发明提供了一种将(R)-((R)-喹诺啡啶-3-基) 1-苯基-3,4-二氢异喹啉-2(1H)-羧酸酯转化为一个立体异构混合物(S,R)-((R)-喹诺啡啶-3-基) 1-苯基-3,4-二氢异喹啉-2(1H)-羧酸酯的方法。
• [EN] A NEW METHOD FOR THE PREPARATION OF SOLIFENACIN AND NEW INTERMEDIATE THEREOF<br/>[FR] NOUVEAU PROCÉDÉ DE PRÉPARATION DE LA SOLIFÉNACINE ET NOUVEL INTERMÉDIAIRE DANS SA PRÉPARATION
  申请人：MEGAFINE PHARMA P LTD

  公开号：WO2010103529A1

  公开（公告）日：2010-09-16

  A new method for the preparation of solifenacin by reacting quinuclidin-3-ol and bis (aryl) carbonate to form (3R)-l -azabicyclo[2.2.2]oct-3-yl 4-aryl carbonate of formula (IVa); and treating (3R)-I - azabicyclo[2.2.2]oct-3-yl 4-aryl carbonate of formula (IVa) with (1S)- I -phenyl- 1, 2, 3, 4- tetrahydroisoquinoline in an inert atmosphere to form a Solifenacin base which is converted into its pharmaceutically acceptable salts. The invention also provide new compound, (3R)-1 - azabicyclo[2.2.2]oct-3-yl 4-aryl carbonate, which is used as an intermediate for the preparation of Solifenacin base and a process for the preparation thereof.

  一种通过将quinuclidin-3-ol和双(芳基)碳酸酯反应以形成式(IVa)的(3R)-1-azabicyclo[2.2.2]辛-3-基4-芳基碳酸酯来制备索利那新的方法；并在惰性气氛中处理式(IVa)的(3R)-1-azabicyclo[2.2.2]辛-3-基4-芳基碳酸酯，与(1S)-1-苯基-1,2,3,4-四氢异喹啉反应，形成转化为其药用可接受盐的索利那新碱。该发明还提供了新化合物(3R)-1-azabicyclo[2.2.2]辛-3-基4-芳基碳酸酯，用作制备索利那新碱的中间体及其制备方法。
• METHOD FOR THE PREPARATION OF SOLIFENACIN AND INTERMEDIATE THEREOF
  申请人：Mathad Vijayvitthal Thippannachar

  公开号：US20110319621A1

  公开（公告）日：2011-12-29

  A method for the preparation of solifenacin by reacting quinuclidin-3-ol and bis(aryl) carbonate to form (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-aryl carbonate of formula (IVa); and treating (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-aryl carbonate of formula (IVa) with (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of formula (V) in an inert atmosphere to form a Solifenacin base, which is converted into its pharmaceutically acceptable salts. The invention also provides a compound, (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-aryl carbonate of formula (IVa), which is used as an intermediate for the preparation of Solifenacin base and a process for the preparation thereof.

  一种制备索利那新的方法，通过反应三氢喹啉醇和双(芳基)碳酸酯生成公式(IVa)的(3R)-1-氮杂双环[2.2.2]辛-3-基4-芳基碳酸酯; 并在惰性气氛下处理公式(IVa)的(3R)-1-氮杂双环[2.2.2]辛-3-基4-芳基碳酸酯和公式(V)的(1S)-1-苯基-1,2,3,4-四氢异喹啉，形成索利那新碱，再转化为其药学上可接受的盐。本发明还提供一种化合物，公式为(IVa)的(3R)-1-氮杂双环[2.2.2]辛-3-基4-芳基碳酸酯，用作制备索利那新碱的中间体以及其制备方法。
• PROCESS FOR PREPARING CHEMICALLY AND CHIRALLY PURE SOLIFENACIN BASE AND ITS SALTS
  申请人：Dave Mayank Ghanshyambhai

  公开号：US20100298371A1

  公开（公告）日：2010-11-25

  The present invention provides improved processes for preparing chemically and chirally pure Solifenacin base. The present invention also provides for a composition comprising of a salt of Solifenacin having at least 98% purity. The present invention also disclose certain new salts of Solifenacin as well as well as new polymorphic forms of Solifenacin hydrochloride and Solifenacin oxalate, in pure form.

  本发明提供了改进的过程，用于制备化学和手性纯度Solifenacin碱。本发明还提供了一种包含至少98％纯度的Solifenacin盐的组合物。本发明还披露了某些Solifenacin的新盐以及纯形式的Solifenacin盐酸盐和草酸盐的新多晶形式。
• PROCESS FOR PRODUCING SOLIFENACIN OR ITS SALT
  申请人：Astellas Pharma Inc.

  公开号：EP1757604A1

  公开（公告）日：2007-02-28

  There is provided a novel method for producing solifenacin or a salt thereof which is useful as a medicine, particularly a therapeutic agent and/or a preventive agent for a urinary organ system disease such as pollakiuria or urinary incontinence. Illustratively, there are provided (1) a method for producing solifenacin in which 2-(1H-imidazolylcarbonyl)-1-phenyltetrahydroisoquinoline is used as the starting material, (2) a method for producing solifenacin succinate in which (1RS)-phenyltetrahydroisoquinoline-carboxylic acid quinuclidinyl ester is used as the starting material, (3) a method for producing solifenacin in which a lower alkyl quinuclidinyl carbonate is used as the starting material and (4) a method for producing solifenacin in which phenyltetrahydroisoquinoline-carboxylic acid secondary lower alkyl or tertiary lower alkyl ester is used as the starting material and allowed to react with an alkali metal lower alkoxide.

  本发明提供了一种生产索利芬那新或其盐的新方法，该方法可用作药物，特别是泌尿器官系统疾病（如花粉尿症或尿失禁）的治疗剂和/或预防剂。示例性地，提供了(1)一种生产索利那新的方法，其中使用 2-(1H-咪唑羰基)-1-苯基四氢异喹啉作为起始原料；(2)一种生产索利那新琥珀酸酯的方法，其中使用(1RS)-苯基四氢异喹啉-羧酸奎宁酯作为起始原料、(4) 以苯基四氢异喹啉-羧酸仲低级烷基酯或叔低级烷基酯为起始原料，使其与碱金属低级烷氧基化合物反应，生产索利那新的方法。