Manufacturing Process
To a solution of 2-(2-carboxy-4-chlorophenoxy)acetic acid in concentrated
sulfuric acid is added dropwise a mixed liquid of fuming nitric acid and
concentrated sulfuric acid under stirring with keeping at a temperature below
10°C. After the addition, the reaction mixture is stirred and poured into 10 L
of ice-cold water. The precipitated crystals are collected by filtration, washed
with 2 L of water four times and them dried to give 2-(2-carboxy-4-chloro-6-
nitrophenoxy)acetic acid.
To a solution of ferrous sulfate heptahydrate in of hot water is added a
solution of 2-(2-carboxy-4-chloro-6-nitrophenoxy)acetic acid and aqueous
concentrated ammonia solution in water under stirring. After stirring, to the
reaction mixture is twice added aqueous concentrated ammonia solution.
While the reaction mixture becomes exothermic, stirring is continued. The
resultant mixture is filtered through a celite layer under reduced pressure and
washed with hot water twice. The filtrate is cooled and made acid with
concentrated hydrochloric acid. The precipitated crystals are washed with
water and dried to give 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-
carboxylic acid.
A mixture of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic
acid, methanol and concentrated sulfuric acid is refluxed under heating with
stirring, and then cooled. The precipitated crystals are collected by filtration,
washed with methanol and dried to give methyl 6-chloro-3,4-dihydro-3-oxo-
2H-1,4-benzoxazine-8-carboxylate, melting point 239°-241°C.
To a solution of methyl 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylate in dimethylformamide is added potassium t-butoxide and solution
stirred at room temperature. To the resultant solution is added dropwise a
solution of methyl iodide in dimethylformainide under stirring. After the
reaction solution is stirred, water is added thereto. The insoluble substance is
collected by filtration, washed with water and dried to give methyl 6-chloro-
3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate.
A mixture of methyl 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-
benzoxazine-8-carboxylate, ethanol and 4% aqueous potassium hydroxide
solution is refluxed with heating. The resultant solution is cooled and water is
added thereto followed by filtration. The filtrate is made acid with
concentrated hydrochloric acid. The precipitated crystals are collected by
filtration, washed with water and dried, and then recrystallized from ethanol
to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic
acid, melting point 241°-243°C.
A solution of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-
carboxylic acid in tetrahydrofuran and dimethylformamide is cooled to below
0°C and triethylamine is added under stirring thereto. Further, ethyl
chlorocarbonate is added and the mixture is stirred at room temperature. To
the resultant mixture is added 3-amino-8-azabicyclo[3.2.1]octane and the
mixture stirred. After completion of the reaction, aqueous sodium hydrogen
carbonate and ethyl acetate are added. The organic layer is separated,
washed with water and dried over magnesium sulfate. The solvent is distilled
off to give 6-chloro-3,4-dihydro-4-methyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-3-
oxo-2H-1,4-benzoxazine-8-carboxamide.
In practice it is usually used as hydrochloride.
