Description
Trometamol (2-amino-2-(hydroxymethyl)-1,3-
propanediol) salt . Lodoxamide is
an antiallergic drug acting as a mast-cell stabilizer, which is effective in the treatment of allergic
conjunctivitis .
Manufacturing Process
To a solution of 1.56 mole of stannous chloride dihydrate in 860 ml of
concentrated hydrochloric acid is added 0.2195 mole of 4-chloro-3,5-
dinitrobenzonitrile. The mixture is stirred at room temperature for 2 hours and
cooled to 0°C in an ice-salt bath. A cold solution of 50% sodium hydroxide is
added to the mixture until strongly basic. During the addition the temperature
is kept below 30°C.The precipitate is removed by filtration and extracted three
times with 400 ml of ethyl acetate. The extracts are combined and added to
the aqueous filtrate. The phases are shaken well for ten minutes and
separated. The organic phase is evaporated to dryness in vacuo. The solid
residue is recrystallized from ethanol-water. There is obtained 25.0 g (68%) of
4-chloro-3,5-diaminobenzonitrile, melting point 169-170°C.
To a solution of 0.34 mole of 4-chloro-3,5-diaminobenzonitrile in 160 ml of dry
DMF is added 0.82 mole of triethylamine. The solution is cooled to 5°C andthere is added 0.82 mole of ethyloxalyl chloride dropwise, keeping the
temperature less than 15°C. The mixture is stirred for 1 hour and warmed to
room temperature. The mixture is stirred at room temperature for 24 hours.
The precipitate is removed by filtration and washed two times with ethyl
acetate. The filtrate and washes are combined and the ethyl acetate distilled
off in vacuo. The DMF solution is poured into 3 L of water. The semi-solid
residue is removed by filtration. The residue is recrystallized from ethanol.
There is obtained 72.4 g (58%) of diethyl N,N'-(2-chloro-5-cyano-mphenylene)dioxamate, melting point 177-179°C.
A solution of 0.197 mole of diethyl (N,N'-(2-chloro-5-cyano-m-phenylene)
dioxamate in 750 ml of methylene chloride is extracted with 465 ml of 1 N
sodium hydroxide. The aqueous phase is separated and stirred for 20 min at
room temperature. The solution is acidified with dilute hydrochloric acid. The
precipitate is removed by filtration and washed with water. There is obtained
59.1 g (96%) of N,N'-(2-chloro-5-cyano-m-phenylene)dioxamic acid, melting
point 212°C (dec.).
