6-Methoxy-8-nitro (CAS NO.: ), which is known as Quinoline, 6-methoxy-8-nitro-, could be produced through the following synthetic routes.

In a 5-l. three-necked round-bottomed flask, a homogeneous slurry of the following compounds is made by mixing in the order given: 588 g. (2.45 moles) of powdered arsenic oxide, 588 g. (3.5 moles) of 3-nitro-4-aminoanisole, and 1.2 kg. (950 ml., 13 moles) of u.s.p. glycerol. The flask is fitted with an efficient mechanical stirrer and a 500-ml. dropping funnel in which is placed 315 ml. (579 g., 5.9 moles) of concentrated sulfuric acid (sp. gr. 1.84). With good mechanical stirring the sulfuric acid is dropped into the orange reaction mixture over a period of 30–45 minutes. During this addition, the temperature spontaneously rises to 65–70°.

The stirrer and dropping funnel are removed, and a thermometer is inserted in one neck of the flask by means of a stopper so that the bulb is well below the surface of the reaction mixture. A 10-mm. bent glass tube is attached to the second neck by a rubber stopper and attached through a trap to a water aspirator. The third neck is closed with a stopper, and the flask and its contents are weighed. The flask, clamped in place in an oil bath which rests on a hot plate, is evacuated, and heat is carefully applied at such a rate that the internal temperature slowly rises to 105°. The mixture is kept between 105° and 110° until the loss in weight amounts to 235–285 g., which requires approximately 2–3 hours, depending on the efficiency of the aspirator. If the temperature shows any tendency to rise above 110°, the oil bath should be lowered and the mixture cooled.

When the removal of the water is complete, the suction tube is removed and the stirrer and dropping funnel are replaced. The internal temperature is raised with extreme care to 118° and is held rigidly between 117° and 119° during the subsequent addition of 438 g. (236 ml.) of concentrated sulfuric acid (sp. gr. 1.84) from the dropping funnel. The sulfuric acid must be added dropwise over a period of 2.5–3.5 hours, and the temperature must not vary from 117–119° . After the addition is complete the temperature is maintained at 120° for 4 hours and finally at 123° for 3 hours. The reaction mixture is cooled below 100°, diluted with 1.5 l. of water, and allowed to cool overnight, preferably with stirring. The diluted reaction mixture is poured with stirring into a mixture of 1.8 l. (1580 g.) of concentrated ammonium hydroxide (sp. gr. 0.9) and 3.5 kg. of ice in a 12-l. enameled pail. The resultant thick slurry is filtered through a large Büchner funnel (24–30 cm.), and the filtrate is discarded. The earth-colored precipitate is washed with four 700-ml. portions of water and then transferred to a 3-l. beaker and stirred with 1 l. of methanol for 15 minutes. The slurry is filtered and this process repeated. The crude product at this point is a light chocolate brown and weighs about 800 g. when dried. It is purified by boiling for 30 minutes with 4.5 l. of chloroform to which has been added 30 g. of decolorizing carbon. The carbon and other humus-like material are removed by filtration from the hot chloroform solution by means of a 24-cm. warm Büchner funnel. The insoluble material is boiled with 500 ml. of chloroform, the resultant mixture filtered, and the combined filtrates concentrated by distillation from a steam bath to a volume of 1.5–2.5 l., at which point crystals of the 6-methoxy-8-nitroquinoline separate. The solution is then cooled to 5°, and the first crop of crystals is obtained by collection on a 24-cm. Büchner funnel. The crystals are transferred to a 1-l. beaker, stirred with 400 ml. of methanol for 15 minutes, and again collected on a Büchner funnel and washed with 200 ml. of methanol. The product consists of light-tan crystals which weigh 435–500 g. and melt at 158–160°. By concentrating the filtrate to 400–500 ml., a second crop of crystals weighing 25–65 g. is obtained which, after washing with methanol in the same way as above, melts at 158–159°. The total yield is 460–540 g. (65–76%).

Notice: This preparation must be carried out with careful attention to the times and temperatures specified, since Skraup reactions are likely to become violent. The operator should wear goggles, and there should be a safety shower close at hand.