Manufacturing Process
4,6-Dioxo-10-propyl-4H,6H-pyrano[3,2-]quinoline-2,8-dicarbxylic acid
disodium salt was prepared in 8 steps
1. 4-Acetamido-2-allylacetophenone
4-Acetamido-2-hydroxyacetophenone (19.3 g), allyl bromide (12.1 ml) and
hydrous potassium carbonate (21.5 g) were stirred in dry dimethylformamide
(250 ml) at room temperature for 24 hours. The reaction mixture was poured
into water and the product was extracted with ethyl acetate. The organic
solution was then washed well with water dried over magnesium sulphate and
evaporated to dryness. The sub-title product was obtained as buff coloured
solid (20.5 g). The structure of the product was confirmed by NMR and mass
spectroscopy.
2. 4-Acetamido-3-allyl-2-hydroxyacetophenone
The above allyl ether (18.4 g) was heated at 200-210°C for 4 hours. 17.1 g of
the thermally rearranged sub- title product was obtained as a brown solid.
Again the structure was confirmed by NMR and mass spectroscopy.
3. 4-Acetamido-2-hydroxy-3-propyl acetophenone
The product of step 2 (17 g) was dissolved in glacial acetic acid and
hydrogenated in the presence of Adams catalyst until hydrogen uptake had
ceased. The catalyst was filtered off through a keiselguhr filter and the filtrate
was evaporated to leave 13.0 g of almost colorless solid. The mass and NMR
spectra confirmed the structure of product.
4. Ethyl-7-acetamido-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylate
A mixture of diethyl oxalate (19.3 g; 17.9 ml) and the above product of step
3 (12.4 g) in dry ethanol (100 ml) was added to a stirred solution of sodium
ethoxide in ethanol (prepared by dissolving sodium (6.1 g) in dry ethanol
(200 ml)). The reaction mixture was refluxed for 3 hours and then poured into
dilute hydrochloric acid and chloroform. The chloroform layer was separated,
washed with water and dried. The solvent was evaporated to leave a brown
solid which was dissolved in ethanol (300 ml) containing concentrated
hydrochloric acid (3 ml) and the whole was refluxed for 1 hour. The reaction
mixture was poured into water and the product was extracted into ethyl
acetate which was washed with water and dried. The solvent was evaporated
to leave 10 g of a sticky solid which had mass and NMR spectra consistent
with the expected product.
5. Ethyl 7-amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
A solution of the amide of step 4 (10 g) in ethanol (300 ml), containing
concentrated hydrochloric acid (5 ml), was refluxed for 8 hours. The reaction
mixture was diluted with water and extracted into ethyl acetate. The extract
was washed with water, dried and the solvent was evaporated to leave a dark
brown semi-solid. This was chromatographed on a silica gel column, using
ether as eluant to give 4.8 g of the required product whose structure was
confirmed by mass and NMR spectral evidence; mp 84-87°C.
6.8-Ethoxycarbonyl-2-methoxycarbonyl-4,6-dioxo-10-propyl-4H,6Hpyrano[3.2-g]quinoline
The amino benzopyran of step 5 (2.0 g) and dimethyl acetylene dicarboxylate
(1.24 g; 1.01 ml) were refluxed in ethanol (30 ml) for 26 hours. The reaction
mixture was cooled to 0°C and the insoluble yellow-brown solid was collected
by filtration and washed with a little ethanol and dried to give 2.0 g of a
product which was a mixture of maleic and fumaric esters obtained by Michael
addition of the amine to the acetylene. This mixture of esters (2.0 g) was
treated with polyphosphoric acid (30 ml) and heated on the steam bath with
stirring for 20 minutes. The reaction mixture was then poured onto ice and
stirred with ethyl acetate. The organic layer was separated, washed with
water and dried. The solvent was evaporated to leave 1.6 g of a yellow orange
solid. Recrystallisation of this solid from ethyl acetate gave the required
product as fluffy orange needles, mp 187°-188°C.
7. 4,6-Dioxo-10-propyl-4H,6H-pyrano[3.2-g]quinoline-2,8-dicarboxylic acid
The above bis ester (2.5 g) was refluxed with sodium bicarbonate (1.64 g) in
ethanol (100 ml) and water (50 ml) for 1.5 hours. The whole was poured into
water and acidified to precipitate a gelatinous solid. This was collected by
filtration, refluxed with ethanol and the product was separated by
centrifugation (1.4 g), mp 303°-304°C dec. The structure of the product was
confirmed by mass and NMR evidence.
8. Disodium 4,6-dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinoline-2,8-
dicarboxylate
The bis acid from step 6 (1.35 g) and sodium bicarbonate (0.661 g) in water
(150 ml) were warmed and stirred until a clear solution was obtained. This
solution was filtered and the filtrate was freeze dried to give 1.43 g of the
required disodium salt.
