5-Bromo-8-nitroisoquinoline

5-Bromo-isoquinoline (100 mg, 0.48 mmol) was suspended in 0.58 mL of concentrated H2S04. To this solution was added KN03 (68 mg, 0.58 mmol) in 0.48 mL of concentrated H2SO4. The reaction mixture was stirred at room temperature for 1.5 hours, poured into WATER/ICE, neutralized with 2.0 M NA2C03, and extracted with EtOAc three times The combined organic layers were washed brine, dried (MGS04), filtered and concentrated under vacuum to give 121 mg (995) of the title product.. MS (DCI) m/e 255 (M+H) + ; H NMR (500 MHz, CDC13) 8 10. 0 (S, 1H), 9.39 (s, 1H), 8.85 (d, J=5.76 Hz, 1H), 8.17-8. 22 (m, 2H), 8.12 (d, J=8.14 Hz, 1H).STR9 STR9 STR10 EXAMPLE 25 Synthesis of 5-bromo-8-nitroisoquinoline A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2 x 500 mL), and dried in a vacuum oven to provide 5-bromo-8-nitroisoquinoline in 90percent yield as a yellow solid.Synthesis of 5-bromo-8-nitroisoquinoline 2. Synthesis of 5-bromo-8-nitroisoquinoline; A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2.x.500 mL), and dried in a vacuum oven to provide 5-bromo-8-nitroisoquinoline in 90percent yield as a yellow solid.2. Synthesis of 5-bromo-8-nitroisoquinoline.A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2 x 500 mL), and dried in a vacuum oven to provide 5-bromo-8-nitroisoquinoline in 90percent yield as a yellow solid.A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2.x.500 mL), and dried in a vacuum oven to provide 5-bromo-8-nitroisoquinoline in 90percent yield as a yellow solid.2. Synthesis of 5-bromo-8-nitroisoquinoline.A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2 x 500 mL), and dried in a vacuum oven to provide 5-bromo-8-nitroisoquinoline in 90percent yield as a yellow solid.A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. Into a 500 mL 3-necked round bottom flask was placed a solution of 5-bromoisoquinoline(22.24 g, 106.87 mmol) in HPotassium nitrate (1.17 g, 11.59 mmol) was added portion- wise to a solution of5-bromo-isoquinoline (2.0 g, 9.66 mmol) in concentrated sulphuric acid (10 mL) and stirred at ambient temperature for 1 h. The reaction mixture was quenched with water and basified with aqueous ammonia. The aqueous layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 5-bromo-8- nitro-isoquinoline (2.0 g, 82percent) as a yellow solid.(2) The reaction flask in 250mL three, 5-bromo - isoquinoline (14g, 66mmol) and concentrated sulfuricAcid (100mL) stir, cooling to 5 , was added potassium nitrate (10.1g, 100mmol) were mixedThe reaction is then warmed to 25 2h, the reaction solution obtained. The reaction mixture was added to ice water, followed byAqueous ammonia and filtration to give the crude product, and then recrystallized from methanol to give 8-nitro-5-bromo - isoquinoline 9g, The yield was 53percentjV-Bromosuccinimide (17.80 g, 100 mmol) was added in portions over 15 min to a solution of isoquinoline (11.00 g, 85 mmol) in HA 3-neck flask was charged with A suspension of 8 -Amino iso quino line 5-Bromo-8-mtroisoquinoline (1.00 g, 3.95 mmol) in MeOH (70 mL) was hydrogenated at ambient temperature and pressure over palladium on active carbon (10% Pd, 200 mg) for 18 h. The mixture was filtered through Celite and concentrated.The residue was purified by chromatography (EtOAc :heptane) to give the title compound (100 mg, 18%) as a green-brown solid. 1H NMR (DMSO-de, 400 MHz) delta 9.43 (s, IH), 8.32 (d, IH), 7.54 (d, IH)5 7.40 (dd, IH), 6.99 (d, IH), 6.72 (d, IH), 6.22 (s, 2H).EXAMPLE 57C Isoquinolin-8-amine The product from Example 57B was treated with Pd/C under a hydrogen atmosphere to provide the title compound. The product from Example 57C and trichloroacetylchloride were processed as described in to provide the title compound.EXAMPLE 57C isoquinolin-8-amine The product from Example 57B was treated with Pd/C under a hydrogen atmosphere to provide the title compound.EXAMPLE 57C isoquinolin-8-amine The product from Example 57B was treated with Pd/C under a hydrogen atmosphere to provide the title compound.Example 57C isoquinolin-8-amine The product from Example 57B was treated with Pd/C under a hydrogen atmosphere to provide the title compound.jV-Bromosuccinimide (17.80 g, 100 mmol) was added in portions over 15 min to a solution of isoquinoline (11.00 g, 85 mmol) in H2SO4 (cone, 100 mL) cooled to -25 C. After stirring at rt for 22 h, KNO3 (11.12 g, 110 mmol) was added and the mixture was stirred for 70 min. The mixture was poured onto crushed ice and neutralised with NH3 (aq, sat, 100 mL). The precipitate was filtered off, washed with water and dried. Crystallisation from MeOH gave the sub-title product (9.27 g, 43%) as a dark brown solid.1H NMR (DMSO-^6, 400 MHz) delta 10.01 (s, IH), 8.84 (d, IH), 8.19 (d, IH), 8.15 (d, IH), 8.11 (d, IH).5-Bromo-8-nitroisoQuinoline; (IFl5-Bromo-8-nitro.soquino.ine was prepared from the corresponding isoquinoline (I) according to the procedure found in William Dalby Brown and Alex Haahr Gouliaev, Organic Syntheses Vol. 81, p 98. was prepared from the corresponding isoquinoline (2A) according to the procedure found in William Dalby Brown and Alex Haahr Gouliaev, Organic Syntheses Vol. 81, p 98.5-Bromo-isoquinoline (100 mg, 0.48 mmol) was suspended in 0.58 mL of concentrated H2S04. To this solution was added KN03 (68 mg, 0.58 mmol) in 0.48 mL of concentrated H2SO4. The reaction mixture was stirred at room temperature for 1.5 hours, poured into WATER/ICE, neutralized with 2.0 M NA2C03, and extracted with EtOAc three times The combined organic layers were washed brine, dried (MGS04), filtered and concentrated under vacuum to give 121 mg (995) of the title product.. MS (DCI) m/e 255 (M+H) + ; H NMR (500 MHz, CDC13) 8 10. 0 (S, 1H), 9.39 (s, 1H), 8.85 (d, J=5.76 Hz, 1H), 8.17-8. 22 (m, 2H), 8.12 (d, J=8.14 Hz, 1H).A solution of potassium nitrate (1.78 g, 8.56 mmol) was added slowly to a solution of 5-bromoisoquinoline in 12 ML H2O4 After stirring for 3 hours the reaction mixture was poured onto ice and neutralized with conc. ammonium hydroxide. The yellow precipitate was extracted with ethyl acetate (3x), and the combined organic layers were washed with saturated NaCI, dried over MgSO4 filtered and concentrated. The residue was chromatographed on silica gel (40% ethyl acetate in hexane as eluent) to give STR9 A solution of potassium nitrate (1.78 g, 8.56 mmol) was added slowly to a solution of 5-bromoisoquinoline in 12 mL H2 SO4. After stirring for 3 hours the reaction mixture was poured onto ice and neutralized with conc. ammonium hydroxide. The yellow precipitate was extracted with ethyl acetate (3*), and the combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (40% ethyl acetate in hexane as eluent) to give STR9 A solution of potassium nitrate (1.78 g, 8.56 mmol) was added slowly to a solution of 5-bromoisoquinoline in 12 mL H2 SO4. After stirring for 3 h the reaction mixture was poured onto ice and neutralized with conc. ammonium hydroxide. The yellow precipitate was extracted with ethyl acetate (3*), and the combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The residue was chromatographed over silica gel (40% ethyl acetate in hexane) to give A solution of potassium nitrate (1.78 g, 8.56 mmol) was added slowly to a solution of 5-bromoisoquinoline in 12 mL H2SO4. After stirring for 3 h the reaction mixture was poured onto ice and neutralized with conc. ammonium hydroxide. The yellow precipitate was extracted with ethyl acetate (3x), and the combined organic layers were washed with saturated NaCI, dried over MgSO4, filtered and concentrated. The residue was chromatographed over silica gel (40% ethyl acetate in hexane) to give STR10 A solution of potassium nitrate (1.78 g, 8.56 mmol) was added slowly to a solution of 5-bromoisoquinoline in 12 mL H2 SO4. After stirring for 3 hours the reaction mixture was poured onto ice and neutralized with conc. ammonium hydroxide. The yellow precipitate was extracted with ethyl acetate (3x), and the combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (40% ethyl acetate in hexane as eluent) to give EXAMPLE 25 Synthesis of A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2 x 500 mL), and dried in a vacuum oven to provide Synthesis of 2. Synthesis of 2. Synthesis of A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2×500 mL), and dried in a vacuum oven to provide 2. Synthesis of A solution of potassium nitrate (149 mmol) in sulfuric acid (100 mL) was added over 1 h to a solution of 5-bromoisoquinoline (107 mmol) in sulfuric acid (120 mL) at rt. The reaction mixture was maintained at rt for 1 h and was diluted with ice water (600 mL). The pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide and the precipitated solids were collected by filtration, washed with water (2*500 mL), and dried in a vacuum oven to provide Into a 500 mL 3-necked round bottom flask was placed a solution of 5-bromoisoquinoline(22.24 g, 106.87 mmol) in H2SO4 (120 mL). This was followed by the addition of a solution of KNO3 (15.1 g, 149.36 mmol) in H2SO4 (100 mL), which was added dropwise with stirring, while cooling to a temperature of 20 0C over a time period of 1 hour. The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1 :5). The reaction mixture was then quenched by the adding 600 mL Of H2O /ice. Adjustment of the pH to S-10 was accomplished by the addition of NH3. H2O (30 %). A filtration was performed. The filter cake was washed 2 times with 500 mL ofH2O. The solid was dried in an oven under reduced pressure. This resulted in 25.59 g (90%) of 5- bromo-8-nitroisoquinoline as a yellow solid.Potassium nitrate (1.17 g, 11.59 mmol) was added portion- wise to a solution of5-bromo-isoquinoline (2.0 g, 9.66 mmol) in concentrated sulphuric acid (10 mL) and stirred at ambient temperature for 1 h. The reaction mixture was quenched with water and basified with aqueous ammonia. The aqueous layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 5-bromo-8- nitro-isoquinoline (2.0 g, 82%) as a yellow solid.(2) The reaction flask in 250mL three, 5-bromo - isoquinoline (14g, 66mmol) and concentrated sulfuricAcid (100mL) stir, cooling to 5 , was added potassium nitrate (10.1g, 100mmol) were mixedThe reaction is then warmed to 25 2h, the reaction solution obtained. The reaction mixture was added to ice water, followed byAqueous ammonia and filtration to give the crude product, and then recrystallized from methanol to give 8-nitro-5-bromo - isoquinoline 9g, The yield was 53%EXAMPLE 57B STR10 A solution of potassium nitrate (1.78 g, 8.56 mmol) in 2 ml concentrated H2 SO4 was added slowly to a solution of 5-bromoisoquinoline in 12 mL concentrated H2 SO4. After stirring for 3 hours the reaction mixture was poured onto ice and neutralized with conc. ammonium hydroxide. The yellow precipitate was extracted with ethyl acetate (3*), and the combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (40% ethyl acetate in hexane as eluent) to give EXAMPLE 57B EXAMPLE 57B KNO3 (5. Ig, 50mmol) was suspended in sulfuric acid (4OmL) and chilled to 0 0C. 5-bromoisoquinoline (4g, 19.2mmol) was added slowly over the course of 20 minutes. The yellow, heterogeneous solution was brought to pEta 8 by slow addition of ammonium hydroxide. Yellow solid was filtered off and recrystallized from methanol to give 7.5g of 5-bromo-8- nitroisoquinoline. LCMS showed an m/z of 253.0/255.0 with a retention time of 1.797min, method [I].Example 57B N-Bromosuccinimide (17.8 g, 10 mmol) was added in portions to a solution of isoquinoline 1 (10.1 mL, 8.5 mmol) in concentrated H2SO4 (100 mL) at -10 C. The mixture was stirred for 2 h at 20 C, followed by the addition of KNO3 (11.2 g, 11.1 mmol) and standing at room temperature for 48 h. Then, the mixture was poured in ice and neutralized with saturated aqueous NH3, the precipitate formed was collected by filtration and recrystallized from MeOH. The yield was 14.2 g (65%).EXAMPLE 26 5-Bromo-2-ethyl-1, 2, 3, 4-tetrahydro-8-nitroisoquinoline A solution of 4-Chloraphenyl)aniline Was prepared according to method D from 4-(4-chlorophenyl)-nitrobenzene. The product was isolated as an oil. Yield 72%.A. The crude product was suspended in heptane (1500 ml), heated to reflux, and then filtered warm through celite. The filtrate was evaporated until precipitation occured (appoximate when 900 ml was left). It was then heated to reflux again and heptane (250 ml) was added to give a clear solution, which was slowly cooled and left for precipitation over night. Filtration and air drying to constant weight gave 22.8 g (73% from 97% pure isoquinoline) of pure B. The crude product was suspended in heptane/toluene (300 ml/150 ml) heated to reflux and then filtered warm through celite. The filtrate was evaporated until approximately 250 ml was left. The clear solution was slowly cooled and left for precipitation over night. Filtration and air drying to constant weight gave 21.7 g (69 % from 97% pure isoquinoline) of pure Benzylmercaptane (0.71 mL, 6 mmol) and Et3N (0.83 mL, 6 mmol) were added to a suspension of bromide 2 (1.52 g, 6 mmol) in MeOH (25 mL). The reaction mixture was stirred for 24 h at 20 C and poured into water (150 mL), the precipitate formed was collected by filtration and recrystallized from MeOH. The yield was 0.64 g (37%).

Molecular Weight:253.05
XLogP3:2.6
Hydrogen Bond Acceptor Count:3
Exact Mass:251.95344
Monoisotopic Mass:251.95344
Topological Polar Surface Area:58.7
Heavy Atom Count:14
Complexity:231
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes