公开(公告)号：US20190077745A1

公开(公告)日：2019-03-14

申请号：US16052695

申请日：2018-08-02

Applicant: BRACCO IMAGING S.P.A.

Inventor： Elisa BATTISTINI ,  Federica BUONSANTI ,  Daniela IMPERIO ,  Luciano LATTUADA ,  Roberta NAPOLITANO

IPC: C07C231/14 ,  C07C231/02 ,  C07F5/04 ,  C07F5/05 ,  C07F5/02 ,  C07C201/12 ,  C07C227/04 ,  C07C231/12 ,  C07C237/46

Abstract: The present invention discloses a process for the preparation of Iopamidol of formula (II) and comprising the following steps: a) reacting the Compound (I) wherein X is OR2 or R3, and wherein R2 and R3 are a C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, C6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl, with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the acetyloxy derivative of Compound (I); b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7, by adding water or a diluted alkaline solution such as sodium hydroxide or potassium hydroxide, freeing the hydroxyls from the boron-containing protective groups, obtaining the N-(S)-2-(acetyloxy)propanoyl derivative of Compound (II); c) alkaline hydrolysis to restore the (S)-2-(hydroxy)propanoyl group and to obtain Iopamidol (II) and optional recovery of the boron derivative from the solution obtained in step b). The boron-containing protective group is versatile, efficient and recyclable. A one-pot synthesis, without intermediate isolation is provided, leading to a decreasing of recovered and recycled solvents and a significant increasing in the yield, representing a significant advantage in terms of cost-effectiveness of the entire process and environmental awareness.

公开(公告)号：US20160237026A1

公开(公告)日：2016-08-18

申请号：US15033737

申请日：2014-11-04

Applicant: BRACCO IMAGING S.P.A.

Inventor： Elisa BATTISTINI ,  Federica BUONSANTI ,  Daniela IMPERIO ,  Luciano LATTUADA ,  Roberta NAPOLITANO

IPC: C07C231/14 ,  C07C231/12 ,  C07C227/04 ,  C07C231/02 ,  C07F5/02 ,  C07C201/12

CPC classification number: C07C231/14 ,  C07C201/12 ,  C07C227/04 ,  C07C231/02 ,  C07C231/12 ,  C07F5/025 ,  C07F5/04 ,  C07F5/05 ,  Y02P20/55 ,  Y02P20/582 ,  C07C237/46

Abstract: The present invention discloses a process for the preparation of Iopamidol of formula (II) and comprising the following steps: a) reacting the Compound (I) wherein X is OR2 or R3, and wherein R2 and R3 are a Ci-C6 linear or branched alkyl, C3-C6 cycloalkyl, C6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl, with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the acetyloxy derivative of Compound (I); b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7, by adding water or a diluted alkaline solution such as sodium hydroxide or potassium hydroxide, freeing the hydroxyls from the boron-containing protective groups, obtaining the N—(S)-2-(acetyloxy)propanoyl derivative of Compound (II); c) alkaline hydrolysis to restore the (S)-2-(hydroxy)propanoyl group and to obtain Iopamidol (II) and optional recovery of the boron derivative from the solution obtained in step b). The boron-containing protective group is versatile, efficient and recyclable. A one-pot synthesis, without intermediate isolation is provided, leading to a decreasing of recovered and recycled solvents and a significant increasing in the yield, representing a significant advantage in terms of cost-effectiveness of the entire process and environmental awareness.

Abstract translation: 本发明公开了一种制备式（II）的叶帕醇的方法，其包括以下步骤：a）使其中X为OR 2或R 3的化合物（I）反应，其中R 2和R 3为C 1 -C 6直链或支链 烷基，C 3 -C 6环烷基，C 6芳基，任选被选自甲基，乙基，正丙基，异丙基，正丁基，仲丁基，叔丁基和苯基的基团取代，与酰化 （S）-2-（乙酰氧基）丙酰氯在反应介质中提供化合物（I）的乙酰氧基衍生物; b）通过加入水或稀释的碱性溶液如氢氧化钠或氢氧化钾，使水溶液在0至7的pH下水解步骤a）中的中间体，从含硼保护基中释出羟基，得到 化合物（II）的N-（S）-2-（乙酰氧基）丙酰基衍生物; c）碱性水解以还原（S）-2-（羟基）丙酰基并获得Iopamidol（II）并任选地从步骤b）中获得的溶液中回收硼衍生物。 含硼保护基是多功能，高效和可循环利用的。 提供了一种不进行中间隔离的单锅合成，导致回收和再循环溶剂减少，产率显着提高，在整个过程的成本效益和环境意识方面具有显着的优势。

公开(公告)号：US20190071392A1

公开(公告)日：2019-03-07

申请号：US15912772

申请日：2018-03-06

Applicant: BRACCO IMAGING S.P.A.

Inventor： Elisa BATTISTINI ,  Federica BUONSANTI ,  Daniela IMPERIO ,  Luciano LATTUADA ,  Roberta NAPOLITANO

IPC: C07C231/14 ,  C07F5/02 ,  C07C231/12 ,  C07C227/04 ,  C07C201/12 ,  C07C231/02 ,  C07F5/05 ,  C07F5/04 ,  C07C237/46

CPC classification number: C07C231/14 ,  C07C201/12 ,  C07C227/04 ,  C07C231/02 ,  C07C231/12 ,  C07C237/46 ,  C07F5/025 ,  C07F5/04 ,  C07F5/05 ,  Y02P20/55 ,  Y02P20/582

Abstract: The present invention discloses a process for the preparation of Iopamidol of formula (II) and comprising the following steps: a) reacting the Compound (I) wherein X is OR2 or R3, and wherein R2 and R3 are a Ci-C6 linear or branched alkyl, C3-C6 cycloalkyl, C6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl, with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the acetyloxy derivative of Compound (I); b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7, by adding water or a diluted alkaline solution such as sodium hydroxide or potassium hydroxide, freeing the hydroxyls from the boron-containing protective groups, obtaining the N—(S)-2-(acetyloxy)propanoyl derivative of Compound (II); c) alkaline N hydrolysis to restore the (S)-2-(hydroxy)propanoyl group and to obtain Iopamidol (II) and optional recovery of the boron derivative from the solution obtained in step b). The boron-containing protective group is versatile, efficient and recyclable. A one-pot synthesis, without intermediate isolation is provided, leading to a decreasing of recovered and recycled solvents and a significant increasing in the yield, representing a significant advantage in terms of cost-effectiveness of the entire process and environmental awareness.