Mallinckrodt Medical, Inc.

Mallinckrodt, Inc.

Other

Mills T Kneller

David H White

Youlin Lin

Thomas J Dunn

Michelle M Jones

Allan R Bailey

Rebecca A Wallace

David M Wong

William Z McCarthy

Narciso Ocampo Doran, Iii

Steven R Woulfe

Mark E Bosworth

Richard G Johnson

James R Wheatley

Warren E Hall

Fiona Rooney

Oliver Egan

Alexander N Petrov

Sharad S Sathe

Richard C Wisneski

Andre T Spears

A process for the preparation of iosimenol comprising reacting 5,5'-[(1,3-dioxo-1,3-propanediyl)diimino]bis[N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide] (C-VI) with a 3-halo-1,2-propanediol in an aqueous solvent. A process for the preparation of C-VI comprising reacting 3,3&#x2032;-[(1,3-dioxo-1,3-propanediyl)diimino]bis[5-(aminocarbonyl)-2,4,6-triiodobenzoyl chloride] (C-V) with 3-amino-1,2-propanediol in the presence of an inorganic base and a suitable non-aqueous polar solvent. A process for the preparation of C-V comprising reacting 3-amino-5-(aminocarbonyl)-2,4,6-triiodobenzoyl chloride (C-IV) with malonyl dichloride in a solvent comprising a suitable ester solvent, a suitable nitrile solvent or mixtures thereof.

Process for the preparation of iosimenol

Process for producing ioversol

The present invention discloses a new process for producing ioversol (marketed as OPTIRAY.RTM.) comprising:

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.

Synthesis of ioversol

Methods and compositions are disclosed for enhancing .sup.19 F magnetic resonance imaging which utilize trifluoromethyl derivatives of iodinated X-ray contrast media. Typical magnetic resonance contrast media within the scope of the present invention include bis(trifluoromethyl)benzene derivatives, tris(trifluoromethyl)benzene derivatives, tetrakis(trifluoromethyl)benzene derivatives, and other related trifluoromethylated benzene derivatives.

Trifluoromethyl analogs of X-ray contrast media for magnetic resonance

The use of a minimal excess of acetoxyacetylchloride as a reagent in the synthesis of N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxy-ethyl)glycolamido-2,4,6-triio doisophthalamide.

Synthesis of ioversol using a minimal excess of acetoxyacetylchloride

The use of continuous deionization as an alternative or substitute method for the purification of a crude magnetic resonate.

Purification of a crude MRI agent using continuous deionization

Methods and compositions are disclosed for enhancing .sup.19 F magnetic resonance imaging which utilize trifluorometyl derivatives of iodinated X-ray contrast media. Typical magnetic resonance contrast media within the scope of the present invention include bis(trifluoromethyl)benzene derivatives, tris(trifluoromethyl)benzene derivatives, tetrakis(trifluoromethyl)benzene derivatives, and other related trifluoromethylated benzene derivatives.

The use of azeotropic distillation to dry 5-amino-N,N'bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, an intermediate in the production of N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod oisophthalamide.

Use of azeotropic distillation in process to dry 5-amino-N,N'bis

The use of reverse osmosis as an alternative or substitute method for the purification of a crude diagnostic agent. X-ray contrast agent, magnetic resonance imaging agent, or radiopharmaceuticals are purified by passing through a cross-linked reverse osmosis membrane.

Purification of X-ray contrast agent, magnetic resonance imaging agent,

The use of continuous deionization as an alternative or substitute method for the purification of a crude contrast agent.

Purification of crude Ioversol using continuous deionization

An improved process for the reversed phase chromatographic decolorization, separation, and purification of water-soluble, nonionic contrast media compounds from solutions containing nonionic compound impurities involves the steps of (a) packing a chromatographic column with a chromatographic packing material; (b) passing through the column a solution containing a water-soluble, nonionic contrast media compound and nonionic compounds as impurities at a loading ratio between approximately 10 to 1 and 1.5 to 1 wt. packing material/total wt. nonionic compounds; and (c) eluting the column to produce an eluate containing substantially pure, water-soluble, nonionic contrast media compound or MRI agent. The process can be economically practiced on a factory scale and efficiently removes non-polar impurities difficult to remove by conventional methods.

Reversed phase chromatographic process

Triiodinated isophthalamide derivatives, useful as X-ray contrast agents, having at least one amide group derived from the amino-alcohol, 3-(N-2-hydroxyethyl)amino-1,2-propanediol, which provides high water solubility and low mammalian toxicity, and methods of preparing them. Methods of preparing 3-(N-2-hydroxyethyl)amino-1,2-propanediol are provided.

Process for preparing nonionic X-ray contrast agents

The use of chloroacetylchloride as an alternative or substitute reagent for acetoxychloride in the synthesis of N,N'- bis (2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophth alamide.

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University City, MO, United States of America

Mills T Kneller