Synthesis of ioversol

• US 5,489,708 A
• Filed: 12/01/1993
• Issued: 02/06/1996
• Est. Priority Date: 05/15/1992
• Status: Expired due to Term

• Current Assignee: Mallinckrodt Brand Pharmaceuticals, Inc. (Delaware) (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Medical Inc. (Mallinckrodt plc)
• Inventors: Kneller, Mills T., Spears, Andre T., Sathe, Sharad S., Wisneski, Richard C., Bailey, Allan R.
• Primary Examiner(s): Hollrah, Glennon H.
• Assistant Examiner(s): Burn, Brian M.
• Application Number:
  US08/161,181
• Time in Patent Office: 797 Days
• Field of Search: 564/153
• US Class Current: 564/153
• CPC Class Codes: C07C 231/10 from compounds not provided for in groups C07C231/02 - C07C231/08
• CPC Class Codes: C07C 237/46 having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring

Abstract

The reduction of the O-alkyl isomer content of 5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N'"'"'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide to thereby reduce and/or eliminate the production of impurities comparatively more difficult to remove during the purification of crude ioversol.

Claims

1. A process for the production of ioversol from 5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N'"'"'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide and an O-alkyl isomer of 5-[N-(2-acetoxyethyl) acetoxyacetamidol]-N,N'"'"'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide, comprising the steps of:

a.) selectively hydrolyzing said O-alkyl isomer of 5-[N-(2-acetoxyethyl) acetoxyacetamido]-N,N'"'"'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide n 5-[N-(2-acetoxyethyl)-acetoyacetamido]-N,N'"'"'-bis(2,3-diacetoypropyl)-2,4,6-triiodoisophthalamide with water in a suitable solvent under selectively hydrolyzing conditions to produce 5-acetoxyacetamido-N,N'"'"'-bis(2,3-diacetoxypropyl)2,4,6-triiodoisophthalamide in 5-[N-(2-acetoxyethyl) acetoxyacetamido]-N,N'"'"'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide;

b.) acid hydrolyzing said 5-acetoxyacetamido-N,N'"'"'-bis(2,3-diacetoxypropyl)2,4,6-triiodoisophthalamide and 5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide under acid hydrolyzing conditions to produce ioversol and N,N'"'"'-bis-(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophthalamide; and

c.) purifying said ioversol produced to achieve purification thereof by removing said N,N'"'"'-bis-(2,3-dihydroxypropyl)5-glycamido-2,4,6-triiodoisophthalamide therefrom.

2. The process of claim 1, wherein said selectively hydrolyzing conditions include achieving an elevated temperature within the range of 50 to 90 degrees Celcius.

3. The process of claim 1, wherein said purification is achieved through crystallization, reverse osmosis, continuous deionization, liquid chromatography or any suitable combination thereof.

4. The process of claim 1, wherein said solvent is selected from the group consisting of dimethylformamide, acetonitrile, dimethylacetamide, trichloromethane, carbon tetrachloride, dichloromethane, chloroform, dichloroethane, trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane and 1,1,2-trichloroethane.