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Step 1: 8-Cyano-5-nitroquinoline 5.80 g of 8-bromo-5-nitroquinoline and 2.00 g of copper(I) cyanide in 15 ml of dimethylformamide were heated to 150 C. for 5 hours. After cooling, methylene chloride was added, insoluble particles were filtered off and the filtrate was concentrated. Yield: 3.90 g (1H-NMR (CDCl3; delta in ppm): 7.84 (m,1H); 8.37 (m,1H); 8.40 (m,1H); 9.00 (m,1H); 9.24 (m,1H))
Step 2: 5-Nitroquinoline-8-carboxylic Acid At 150 C., 1.50 g of <strong>[205046-59-9]8-cyano-5-nitroquinoline</strong> were added a little at a time to 3.50 g of 75% strength sulfuric acid. After stirring for one hour, the reaction mixture was cooled, poured into ice water and extracted with ethyl acetate. The organic phase was dried and the solvent was removed under reduced pressure. Yield: 1.1 g (Melting point: 210 C.) (1H-NMR (d6-DMSO; delta in ppm): 8.00 (m,1H); 8.49 (m,1H); 8.58 (m,1H); 9.01 (m,1H); 9.22 (m,1H); 15.0 (bs,1H))
Step 2: 5-Nitroquinoline-8-carboxylic acid At 150 C., 1.50 g of <strong>[205046-59-9]8-cyano-5-nitroquinoline</strong> were added a little at a time to 3.50 g of 75% strength sulfuric acid. After stirring for one hour, the reaction mixture was cooled, poured into ice water and extracted with ethyl acetate. The organic phase was dried and the solvent was removed under reduced pressure. Yield: 1.1 g (Melting point: 210 C.) (1H-NMR (d6-DMSO; delta in ppm): 8.00 (m,1H); 8.49 (m,1H); 8.58 (m,1H); 9.01 (m,1H); 9.22 (m,1H); 15.0 (bs,1H))
12C. 5-Nitroquinoline-8-carbonitrile To a suspension of compound 12B (600 mg, 2.75 mmol) in anhydrous THF (25 mL) cooled to -15 C. was added Et3N (0.46 mL, 3.3 mmol), followed by a dropwise addition of ethyl chloroformate (0.33 mL, 3.44 mmol). The reaction mixture was stirred at -15 C. for 30 min, then NH3 gas was bubbled into the reaction for 5 min followed by warming of the reaction to rt for 1 h. The solvent was evaporated to give 850 mg (>100%) of the amide as a yellow solid which was carried on to the next step without further purification. The amide (850 mg) was dissolved in pyridine (25 mL), and imidazole (377 mg, 5.49 mmol) was added. The mixture was cooled to -30 C. under nitrogen, POCl3 (1.01 mL, 10.7 mmol) was added and the reaction was warmed to 0 C. for 30 min, and then evaporated to dryness. The residue was chromatographed (silica gel) eluding with CH2Cl2 to afford the title compound (416 mg, 76%, 2 steps). LC/MS m/z 200 [M+H]+.
76%
12C. 5-Nitroquinoline-8-carbonitrile To a suspension of compound 12B (600 mg, 2.75 mmol) in anhydrous THF (25 mL) cooled to -15 C. was added Et3N (0.46 mL, 3.3 mmol), followed by a dropwise addition of ethyl chloroformate (0.33 mL, 3.44 mmol). The reaction mixture was stirred at -15 C. for 30 min, then NH3 gas was bubbled into the reaction for 5 min followed by warming of the reaction to rt for 1h. The solvent was evaporated to give 850 mg (>100%) of the amide as a yellow solid which was carried on to the next step without further purification. The amide (850 mg) was dissolved in pyridine (25 mL), and imidazole (377 mg, 5.49 mmol) was added. The mixture was cooled to -30 C. under nitrogen, POCl3 (1.01 mL, 10.7 mmol) was added and the reaction was warmed to 0 C. for 30 min, and then evaporated to dryness. The residue was chromatographed (silica gel) eluding with CH2Cl2 to afford the title compound (416 mg, 76%, 2 steps). LC/MS m/z 200 [M+H]+.
4
[ 205046-59-9 ]
ammonium chloride[ No CAS ]
[ 7439-89-6 ]
[ 573758-03-9 ]
Yield
Reaction Conditions
Operation in experiment
5.09 g (100%)
In tetrahydrofuran; ethanol;
C. 5-Amino-quinoline-8-carbonitrile (464C) Compound 464B (6.00 g, 30.1 mmol) was dissolved in THF (150 mL) at reflux with mechanical stirring. EtOH (150 mL) was then added followed by aqueous ammonium chloride (2.4 g/225 mL water). The mixture was heated at 70 C. and then iron powder (325 mesh, 6.75 g, 120 mmol) was added with vigorous mechanical stirring. After 1 h, the reaction was cooled to 22 C. and filtered through Celite rinsing with methylene chloride. The filtrate was then concentrated to ~250 mL and the pH was adjusted to 10 by addition of 1N NaOH. The solution was then extracted with ethyl acetate (5*150 mL). The combined organic layers were washed once with brine (250 mL) and then dried over anhydrous magnesium sulfate. Concentration in vacuo gave 5.09 g (100%) of compound 464C as a yellow solid. HPLC: 99% at 1.143 min (retention time) (YMC S5 ODS column, 4.6*50 mm, eluding with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 170.16 [M+H]+.
B. 5-Nitro-quinoline-8-carbonitrile (464B) Compound 464A (15.0 g, 59.3 mmol) was dissolved in DMF (120 mL) and zinc cyanide (4.20 g, 35.9 mmol) was added. Bis(diphenylphosphino)ferrocene (3.00 g, 5.40 mmol) and tris(benzylidineacetone)dipalladium (3.00 g, 3.30 mmol) were then added and the reaction was heated to 100 C. for 1.5 h. The reaction was cooled to 22 C. and then poured into concentrated ammonium hydroxide (900 mL) resulting in an orange precipitate which was filtered and rinsed with cold water (1 L). The resulting precipitate was dissolved in methylene chloride, washed with brine (1*300 mL) and then dried over anhydrous sodium sulfate. Concentration in vacuo gave the crude material as an orange solid which was purified by flash chromatography on silica gel eluding with methylene chloride to give 6.01 g (51%) of compound 464B as a yellow solid. HPLC: 99% at 1.900 min (retention time) (YMC S5 ODS column, 4.6*50 mm, eluding with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
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