Synthesis process for high purity isosulfan blue using flash chromatography in commercial plant scale

A substantially pure N-[4-[[4-(diethyl amino) phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium sodium salt having a desethyl isosulfan blue impurity and wherein the desethyl isosulfan blue impurity is less than 0.07% by weight made by a process comprising the steps of:

• a sulphonating step comprising sulphonating 2-chlorobenzaldehyde with a sulphonating agent to obtain 4-chloro-3-formyl sulphonic acid;
• a treatment step comprising treating 4-chloro-3-formyl sulphonic acid with sodium sulphite and subsequent basification thereof to obtain 1-formyl benzene-2,5-sulphonic acid disodium salt;
• a condensation step comprising condensation reacting of 1-formyl benzene-2,5-sulphonic acid disodium salt with N,N-diethylaniline using a first acid to obtain a 4-[Bis[4-diethylamino)phenyl]methyl]benzene-2,5-disulphonic acid disodium salt;
• wherein the condensation step further comprises adjusting the pH with sodium hydroxide;
• an oxidation step comprising oxidation reacting of 4-[bis[4-(diethylamino)phenyl]methyl]benzene-2,5-disulphonic acid disodium salt with an oxidizing agent, using a second acid and a solvent, to obtain N-4-4-(diethylamino)phenyl (2,5-disulfophenyl)methylene-2,5-cyclohexadien-1-ylidene-N-ethylethanaminium sodium salt;
• a purification step comprising purification of N-4-4-(diethylamino)phenyl (2,5-disulfophenyl)methylene-2,5-cyclohexadien-1-ylidene-N-ethylethanaminium sodium salt;
• and
• utilizing HPLC to monitor the sulphonating step, the treatment step, the condensation step, and/or the oxidation step, to determine when one or more reactions of such sulphonating step, treatment step, condensation step, and/or oxidation step are substantially complete and ending such one or more reactions on the basis of the HPLC monitoring.