* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.75 h;
To a solution of n-butyllithium (19.3 mL of 2.5 M in hexanes, 48 mmol) in a mixture of ether (80 mL) and THF (80 mL) at -78° C. was added dropwise a solution of bromoisoquinoline (5.0 g, 24 mmol) in THF (10 mL). The reaction mixture was stirred at -78° C. under argon for 30 minutes. Following the general procedures described by Pearson, et al., in J. Heterocycl. Chem., Vol. 6 (2), pp. 243-245 (1969), a solution of DMF (3.30 g, 45 mmol) in THF (10 mL) was cooled to -78° C. and quickly added to the isoquinolyllithium solution. The mixture was stirred at -78° C. for 15 minutes. Ethanol (20 mL) was added followed by saturated NH4Cl solution. The resulting suspension was warmed to room temperature. The organic layer, combined with the ether extraction layer, was dried over Na2SO4. A pale yellow solid (2.4 g, 15 mmol, 64percent yield) was obtained from chromatography (SiO2 Type-H, 50percent EtOAc in hexanes) and recrystallization (ethanol): mp 114-116° C.; 1H NMR (DMSO-d6) δ 10.40 (s, 1H), 9.44 (s, 1H), 8.85 (d, 1H, J=6.0 Hz), 8.69(d, 1H, J=6.0 Hz), 8.45 (m, 2H), 7.90 (t, 1H, J=7.2 Hz); 13C NMR (DMSO-d6) δ 194.23, 153.5, 146.2, 140.2, 135.2, 132.6, 130.2, 128.6, 127.5, and 117.2. Anal. Calcd. for C10H7NO.0.05H2O: C, 75.99; H, 4.53; N, 8.86. Found: C, 75.98, H, 4.66; N, 8.68.
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3660 - 3668
[2] Patent: US2007/155720, 2007, A1, . Location in patent: Page/Page column 24
Stage #1: at -25 - 20℃; Stage #2: With ammonia In water at 0℃;
Synthesis of 5-bromoisoquinoline Into a 250 mL 3-necked round-bottom flask, was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0° C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25-22° C. The resulting solution was allowed to react, with stirring, for 2 h while the temperature was maintained at -25° to -22° C. The resulting solution was allowed to react with stirring overnight, while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:5). The reaction mixture was then quenched by the adding 1000 mL of H2O/ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3.H2O (30percent). The resulting solution was extracted four times with 500 mL of EtOAc and the organic layers combined and dried over Na2SO4. The residue was purified by eluding through a column with a 1:5 EtOAc/PE solvent system. This resulted in 22.24 g (81percent) of 5-bromoisoquinoline as a white solid.
81%
Stage #1: at -25 - 20℃; for 18 h; Stage #2: With ammonia In water
Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 °C. The reaction mixture was cooled at -25 °C and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 <n="107"/>niL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: With N-Bromosuccinimide; sulfuric acid In water at -25 - 20℃; Stage #2: With ammonium hydroxide In water
Synthesis of 5-bromoisoquinoline Into a 250 mL 3-necked round-bottom flask was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0° C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25-22° C. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at -25-22° C. The resulting solution was allowed to react, with stirring, overnight 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 1000 mL of H2O/ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30percent). The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluding through a column with a 1:5 ethyl acetate/petroleum ether solvent system. This resulted in 22.24 g (81percent) of 5-bromoisoquinoline as a white solid.
81%
Stage #1: at 0℃; Stage #2: at -25 - 20℃; Stage #3: With ammonium hydroxide In waterCooling with ice
Intermediate 13: Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride; 1. Synthesis of 5-bromoisoquinoline; Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0° C. The reaction mixture was cooled at -25° C. and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4.x.500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at 0℃; Stage #2: at -25 - 20℃; Stage #3: With ammonia In water
Intermediate 19: Synthesis of 2-methyl-l,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride.1. Synthesis of 5-bromoisoquinoline.Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 niL) at O 0C. The reaction mixture was cooled at -25 0C and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5- bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at -25 - 20℃; Stage #2: With ammonia In water
Oxalyl chloride (157.6 mmol) was added dropwise at rt to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (22.0 mmol) in dichloromethane (100 mL) and N,N-dimethylformamide (10 mL). The resulting solution was maintained for 2 h, then was diluted with iced water (200 mL). The resulting solution was extracted with dichloromethane (2.x.100 mL) and the combined organics were dried (sodium sulfate), filtered and concentrated. The residue was purified by Flash chromatography (1/4 ethyl acetate/petroleum ether) to afford 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride in 20percent yield as a yellow solid. 1H NMR (CDCl3) δ 7.69 (d, 1H), 7.51 (s, 1H), 6.54 (d, 1H), 3.57 (t, 2H), 3.02 (s, 3H), 2.78 (d, 2H), 1.98 (m, 2H).
81%
Stage #1: at -25 - 20℃; Stage #2: With ammonium hydroxide In waterCooling with ice water
Intermediate 19: Synthesis of 2-methyl-l,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride.1. Synthesis of 5-bromoisoquinoline.Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 0C. The reaction mixture was cooled at -25 0C and TV-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5- bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at -25 - 20℃; Stage #2: With ammonia In water
Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0° C. The reaction mixture was cooled at -25° C. and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4*500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at -25 - 20℃; Stage #2: With ammonia In water
Into a 250 mL 3-necked round bottom flask was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0 0C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25 - -22 0C. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at -25 - -220C. The resulting solution was allowed to react, with stirring, overnight 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 1000 mL of H2O /ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30 percent). The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluting through a column with a 1:5 ethyl acetate/petroleum ether solvent system. This resulted in 22.24 g (81percent) of 5- <n="129"/>bromoisoquinoline as a white solid.
79%
at -25 - -18℃; for 4 h;
To mechanically stirred concd H 2 SO 4 (170 mL), isoquinoline (1; 21.8 g,169.2 mmol, 1.0 equiv) was slowly added at 0 °C. The mixture wascooled to –25 °C and NBS (39.3 g, 220.5 mmol, 1.3 equiv) was added atsuch a rate that the reaction temperature was kept between at –25and –22 °C. The mixture was stirred between –25 and –20 °C for 2 hand at –18 °C for 2 h. It was then poured onto crushed ice (600 g) andmade alkaline (pH 8–9) by using concd aq NH 3 solution with intensivecooling. The alkaline slurry was extracted with Et 2 O (3 × 300 mL). Thecombined organic layer was washed with 1.0 M aq NaOH (2 × 300 mL)and H 2 O (300 mL), dried over anhyd Na 2 SO 4 , filtered, and evaporatedto give a brown oil. The crude product was purified by vacuum distil-lation (128–130 °C/2 Torr) to give 2 as a white powder.Yield: 27.8 g (79percent); mp 82–83 °C.IR (ATR): 1580, 1485, 1368, 1263, 1199, 1136, 962, 817, 750, 673, 627,525 cm –1 .1 H NMR (400 MHz, CDCl 3 ): δ = 9.23 (s, 1 H), 8.64 (d, J = 6.0 Hz, 1 H),7.99–7.94 (m, 3 H), 7.48 (t, J = 7.8 Hz, 1 H).13 C NMR (100 MHz, CDCl 3 ): δ = 152.7, 144.5, 135.2, 134.2, 129.8,127.9, 127.6, 121.7, 119.6.
77%
at -10 - 25℃; for 24 h; Inert atmosphere
(1) The reaction flask in 250mL three, -10 under nitrogen, was added isoquinoline (11g,85mmol) and concentrated sulfuric acid (100mL) Stir, then add N- bromosuccinimide (17.8g,100mmol) were mixed and the reaction warmed to 25 24h, to obtain a reaction solution. The reaction solution was addedInto ice water, followed by aqueous ammonia and ethyl acetate (50mL × 3) extraction, water (50mL × 3) wash,Saturated brine (100mL), dried over anhydrous sodium sulfate and concentrated to give 5-bromo - isoquinoline 14g,The yield was 77percent
71%
With N-Bromosuccinimide; sulfuric acid In tetrahydrofuran at -25 - 25℃; for 26 h;
Isoquinoline 38 (1156 mg, 8.95 mmol) was suspended in conc. H2SO4 (9.7 mL) at 0 °C. After cooling to -25 °C, NBS (1912 mg, 10.74 mmol) was added. The reaction mixture was stirred at -25 °C for 2 h and then at 25 °C for additional 24 h. Subsequently, ice was added and the mixture was treated with conc. NH4OH (10 mL) to pH = 8-10. The resulting solution was extracted with EtOAc (3 * 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (20percent EtOAc in petroleum ether) to afford the title compound as a pale pink solid (71percent yield). 1H NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 8.65 (d, J = 5.9 Hz, 1H), 8.00-7.95 (m, 3H), 7.48 (t, J = 7.8 Hz, 1H); ESI-MS m/z 209.1 [M+H]+.
50%
Stage #1: at -30 - 0℃; for 5 h; Stage #2: With ammonia In water
EXAMPLE 57A 5-bromoisoquinoline Concentrated H2SO4 (260 mL) was cooled to -25° C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0° C. After the addition was complete. the red solution was recooled to -25° C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed -20° C. The reaction mixture was stirred for 5 hours keeping the temperature between -30° C. and -18° C. The reaction mixture was then allowed to warm to -10° C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25percent NH4OH. The mixture was then extracted with diethyl ether (3*600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2*200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50percent). mp 78°-80° C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
28%
Stage #1: With aluminum (III) chloride In dichloromethaneHeating / reflux Stage #2: at 75 - 100℃; Neat (no solvent)
To a suspension of AIC13 (156.7 g, 1.18 mol) in CH2CI2 (500 mL), a solution of isoquinoline (605 mmol, 71 mL) in CH2CI2 (100 mL) was dropwise added at such rate that the reaction mixture was refluxed gently. After addition, CH2CI2 was removed by distillation. The blackish residue was melted at 120 C then the temperature was adjusted to 100 C. To the mixture, Br2 (31 mL, 605 mmol) was dropwise added over 2hrs at 100 C and stirred for 30min at same temperature, then was stirred at 75 C overnight. The mixture was cooled to RT then carefully poured into ice-water. The aqueous mixture was basified with NaOHaq. and extracted with ether. The organics was dried overNa2SO4 then evaporated. Sequence purification onSi02 column chromatography twice and recrystalisation (from hexane) gave the title compound (34.5 g, 28percent).
28%
Stage #1: With aluminum (III) chloride In dichloromethaneHeating / reflux Stage #2: at 75 - 100℃; Neat (no solvent)
To a suspension of AICI3 (156.7 g, 1.18 mol) inCH2CI2 (500 mL), a solution of isoquinoline (1) (605 mmol, 71 mL) inCH2CI2 (100 mL) was dropwise added at such rate that the reaction mixture was refluxed gently. After addition,CH2CI2 was removed by distillation. The blackish residue was melted at120 C then the temperature was adjusted to100 C. To the mixture, Br2 (31 mL, 605mmol) was dropwise added over 2hrs at100 C and stirred for 30min at same temperature, then was stirred at75 C overnight. The mixture was cooled to room temperature then carefully poured into ice-water. The aqueous mixture was basified with NaOHaq. and extracted with ether. The organic layer was dried overNa2SO4 then evaporated. Sequence purification on Si02 column chromatography twice andrecrystallization from hexane gave the title compound (34.5g, 28 percent). MS (ESI) (M+H) + 208,210
26%
at 75 - 85℃; for 5 h;
5-Bromoisoquinoline. The apparatus was a 500 mL three-necked flask equipped with a condenser, dropping funnel, and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafluroethylene paddle. To the isoquinoline (57.6 g, 447 mmol) in the flask was added AlCl3 (123 g, 920 mmol). The mixture was heated to 75-85°C. Bromine (48.0 g, 300 mmol) was added using a dropping funnel over a period of 4 hours. The resulting mixture was stirred for one hour at 75°C. The almost black mixture was poured into vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10 N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from a fraction of about 1250C was obtained (26percent yield). The product was further purified by recrystallization (pentane or hexanes)
26%
at 75 - 85℃; for 5 h;
The apparatus was a 500 mL three-necked flask equipped with a condenser, dropping funnel, and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafluroethylene paddle. To the isoquinoline (57.6 g, 447 mmol) in the flask was added AiCl3 (123 g, 920 mmol). The mixture was heated to 75-85° C. Bromine (48.0 g, 300 mmol) was added using a dropping funnel over a period of 4 hours. The resulting mixture was stirred for one hour at 75° C. The almost black mixture was poured into vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10 N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from a fraction of about 125° C. was obtained (26percent yield). The product was further purified by recrystallization (pentane or hexanes): mp 80-81° C.; 1H NMR (DMSO-d6) δ 9.34 (s, 1H), 8.63 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=7,5 Hz), 8.11 (d, 1H, J=6.6 Hz), 7.90 (d, 1H, J=6.0 Hz), 7.60 (t, 1H, J=7.5 Hz); 13C NMR (DMSO-d6) δ 153.0, 144.7, 134.3, 134.0, 129.3, 128.5, 128.0, 120.3, and 118.6. Anal. Calcd. for C9H6BrN: C, 51.96; H, 2.91; N, 6.73. Found: C, 51.82; H, 2.91; N, 6.64.
Reference：
[1] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 105-106
[3] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 45; 45-46
[4] Patent: US2010/16297, 2010, A1, . Location in patent: Page/Page column 25
[5] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 68
[6] Patent: US2010/29629, 2010, A1, . Location in patent: Page/Page column 52
[7] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 86; 87
[8] Patent: US2010/22581, 2010, A1, . Location in patent: Page/Page column 35; 36
[9] Patent: WO2007/98418, 2007, A1, . Location in patent: Page/Page column 127-128
[10] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
[11] Patent: CN105669547, 2016, A, . Location in patent: Paragraph 0076; 0077
[12] European Journal of Medicinal Chemistry, 2019, p. 290 - 320
[13] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5567 - 5573
[14] Organic Letters, 2017, vol. 19, # 1, p. 262 - 265
[15] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 29
[16] Organic Syntheses, 2005, vol. 81, p. 96 - 104
[17] Patent: WO2005/49576, 2005, A1, . Location in patent: Page/Page column 27
[18] Patent: WO2005/49577, 2005, A1, . Location in patent: Page/Page column 28
[19] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3660 - 3668
[20] Patent: WO2006/12640, 2006, A2, . Location in patent: Page/Page column 52
[21] Patent: US2007/155720, 2007, A1, . Location in patent: Page/Page column 24
[22] Phosphorus, Sulfur and Silicon and Related Elements, 2000, vol. 164, p. 131 - 143
[23] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2623 - 2628
[24] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 4972 - 4982
[25] Patent: US2003/158188, 2003, A1,
[26] Patent: US6933311, 2005, B2,
[27] Patent: US2005/182079, 2005, A1, . Location in patent: Page/Page column 17
[28] Reactive and Functional Polymers, 2011, vol. 71, # 8, p. 849 - 856
[29] ChemMedChem, 2014, vol. 9, # 1, p. 129 - 150
[30] Inorganic Chemistry, 2016, vol. 55, # 15, p. 7388 - 7395
[31] Patent: US2004/157849, 2004, A1,
6
[ 1125-60-6 ]
[ 34784-04-8 ]
Yield
Reaction Conditions
Operation in experiment
53%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.5 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 0 - 20℃;
A solution of sodium nitrite (2.15 g, 31.21 mmol) in water (2 mL) was added to a solution of isoquinolin-5-ylamine (3.0 g, 20.80 mmol) in aqueous 46percent hydrogen bromide (9.98 g, 124.84 mmol) at 0 °C. The mixture was stirred at 0 0C for 30 min then a solution of cuprous bromide (3.58 g, 24.96 mmol) in aqueous 46percent hydrogen bromide (9.98 g, 124.84 mmol) was added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The resulting mixture was basified with aqueous ammonium and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to afford the crude compound. Purification by column chromatography over silica gel (100-200 mesh) with 20percent ethyl acetate in petroleum ether as eluent afforded 5-bromoisoquinoline (2.3 g, 53percent) as a pale yellow solid.
50%
Stage #1: With hydrogen bromide; sodium nitrite In HBr; water at 0℃; for 0.333333 h; Stage #2: With copper(I) bromide In water at 0 - 20℃; for 1 h; Stage #3: With sodium hydroxide In water
Example 78A 5-Bromoisoquinoline To a solution of 5-aminoisoquinoline (2.0 g, 13.8 mmol) and 48percent HBr (6 mL) in 20 mL water cooled to 0° C. was added a solution of sodium nitrite (0.95 g, 13.8 mmol) in 6 mL water. The solution was stirred at 0° C. for 20 minutes. The solution, while kept at 0° C., was added to a solution of CuBr (2.11 g, 15.9 mmol) in 48percent HBr (4.77 mL) and water (10 mL). The reaction was stirred at room temperature for an additional 1 hr. The reaction was neutralized with NaOH (50percent) and extracted with ethyl acetate (3*). The combined organic layer was concentrated in vacuo and chromatographed using 1:1 hexanes/ethyl acetate to yield 1.4 g product (50percent).
36%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; Stage #2: With hydrogen bromide; copper(I) bromide In water at 20 - 75℃; Stage #3: With sodium hydroxide In water at 0℃;
PREPARATION 40; (Isoquinolin-5-yl) oxoacetic acid methyl ester; 5-Aminoisoquinoline (20 g, 139 mmol) is dissolved in hydrobromic acid (48percent, 100 mL) in a 500 mL round bottom flask, and then a solution of sodium nitrite (9.6g, 139 mmol) in water (50 mL) added cautiously at 0°C. The white slurry turns bright red upon complete addition of the salt, and then this solution is transferred to another 500 mL vessel containing CuBr (25g, 174 mmol) stirring in hydrobromic acid (48percent, 200 mL) at 75°C. This transfer is performed slowly and carefully. After complete addition, the mixture is allowed to stir at 75°C for one hour, then cooled to room temperature, and kept stirring overnight. The mixture is then placed onto an ice bath and some ice added to the solution, then basified using sodium hydroxide aqueous solution (20percent, 250 mL) solution. The slurry is filtered and then filtrate is extracted with diethyl ether. The solid and the extract are then combined and sonicated for one hour in chloroform. This sludge is filtered through a plug of Celite, and the chloroform removed by rotovap. The final compound is obtained in pure form by column chromatography in chloroform with 36percent yield, 10.4g (50 mmol) of 5-Bromo-isoquinoline. MS (ES, m/z): 208.0 (M+ (79Br) +l), 210.0 (M+(81Br)+1).
50%
With sodium nitrite In water; hydrogen bromide
Example 78A 5-Bromoisoquinoline To a solution of 5-aminoisoquinoline (2.0 g, 13.8 mmol) and 48percent HBr (6 mL) in 20 mL water cooled to 0° C. was added a solution of sodium nitrite (0.95 g, 13.8 mmol) in 6 mL water. The solution was stirred at 0° C. for 20 minutes. The solution, while kept at 0° C., was added to a solution of CuBr (2.11 g, 15.9 mmol) in 48percent HBr (4.77 mL) and water (10 mL). The reaction was stirred at room temperature for an additional 1 hr. The reaction was neutralized with NaOH (50percent) and extracted with ethyl acetate (3*). The combined organic layer was concentrated in vacuo and chromatographed using 1:1 hexanes/ethyl acetate to yield 1.4 g product (50percent).
Reference：
[1] Canadian Journal of Chemistry, 2005, vol. 83, # 3, p. 213 - 219
[2] Patent: WO2009/130481, 2009, A1, . Location in patent: Page/Page column 142
[3] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 34
[4] Patent: WO2003/76398, 2003, A2, . Location in patent: Page/Page column 27
[5] Patent: US2004/180874, 2004, A1, . Location in patent: Page/Page column 18-19
[6] Patent: WO2003/76442, 2003, A1, . Location in patent: Page/Page column 40
[7] Patent: US2003/187026, 2003, A1,
7
[ 1125-60-6 ]
[ 12775-96-1 ]
[ 34784-04-8 ]
Yield
Reaction Conditions
Operation in experiment
53%
With aqueous HBr; sodium nitrite In water
Step 1 5-Aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 48percent aqueous HBr (65 mL) at -78° C. for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise. After stirring for 15 min at -78° C., the mixture was warmed to 0° C. Copper powder (0.3 g) was added very slowly to avoid excessive foaming. After addition was completed, the reaction vessel was fitted with a reflux condensor and the mixture was heated to 100° C. for 4 h. The mixture was poured onto ice (ca. 200 g) and was made basic (pH=10) with KOH. The aqueous mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, were dried (MgSO4), were filtered, and were concentrated in vacuo. Purification by silica gel chromatography (10:1 hexanes-ethyl acetate) afforded 3.8 g (53percent yield) of 5-bromoisoquinoline; 1H NMR (400 MHz, CD3OD) δ 9.25 (s, 1H), 8.57 (d, J=6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/CI): 208.0, 210.0 (M+H)+.
53%
With aqueous HBr; sodium nitrite In water
Step 1 5-Aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 48percent aqueous HBr (65 mL) at -78° C. for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise. After stirring for 15 min at -78° C., the mixture was warmed to 0° C. Copper powder (0.3 g) was added very slowly to avoid excessive foaming. After addition was completed, the reaction vessel was fitted with a reflux condensor and the mixture was heated to 100° C. for 4 h. The mixture was poured onto ice (ca. 200 g) and was made basic (pH=10) with KOH. The aqueous mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, were dried (MgSO4), were filtered, and were concentrated in vacuo. Purification by silica gel chromatography (10:1 hexanes-ethyl acetate) afforded 3.8 g (53percent yield) of 5-bromoisoquinoline; 1H NMR (400 MHz, CD3OD) δ9.25 (s, 1H), 8.57 (d, J=6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/CI): 208.0, 210.0 (M+H)+.
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 25, p. 9014 - 9019
[2] Patent: WO2010/123545, 2010, A2, . Location in patent: Page/Page column 68
9
[ 1336-21-6 ]
[ 1125-60-6 ]
[ 34784-04-8 ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium nitrite In hexane; water; hydrogen bromide; ethyl acetate
EXAMPLE 57 5-Bromoisoquinoline The procedure described by Osborn AR, et al, J Chem Soc 1956:4191 was used. 5-Aminoisoquinoline (43.6 g, 0.302 mol) was dissolved in 300 ml 48percent HBr and 200 mL water and cooled in an ice bath. NaNO2 (21.21 g, 0.307 mol) in 130 mL of water was added dropwise to the HBr solution and the reaction stirred for 1 hour. CuBr (52 g, 0.363 mol) in 500 mL of 48percent HBr was heated to 85° C., the diazonium solution added dropwise from an ice-cooled jacketed-addition funnel, and the reaction stirred overnight at 50° C. The reaction mixture was cooled in an ice bath and the acid neutralized by dropwise addition of concentrated NH4OH solution. The solid precipitates were filtered off, washed with concentrated NH4OH until colorless, and then water. The solid was dissolved in ethyl acetate, washed with brine (2*), and dried over magnesium sulfate, filtered, and evaporated. The reside was chromatographed on silica gel (30percent ethyl acetate in hexane as eluant) to give 53.7 g (86percent) of the product as an off-white solid.
Reference：
[1] Helvetica Chimica Acta, 1985, vol. 68, p. 1828 - 1834
[2] Helvetica Chimica Acta, 1985, vol. 68, p. 1828 - 1834
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 744 - 752
13
[ 119-65-3 ]
[ 34784-04-8 ]
Yield
Reaction Conditions
Operation in experiment
15.2 g (59 % from 97% isoquinoline)
With N-Bromosuccinimide; sulfuric acid In hexane; n-heptane
5-Bromoisoquinoline. Isoquinoline (15 ml; 128 mmol) was slowly added to a mechanically stirred solution of concentrated H2SO4 (130 ml) (Note 1) at -20° C., at such a speed that the temperature did not exceed +8° C. The reaction mixture was then re-cooled to -20° C., and solid N-bromosuccinimide (27.29 g; 153 mmol) (Note 2 and 3) was added at such a speed that the reaction temperature did not exceed -15°C. (Note 4). The reaction mixture was stirred at -20° C. until all isoquinoline was consumed (Note 5). The reaction was then allowed to warm to -9° C. over 20 min. The reaction mixture was poured onto 300 g of crushed ice and pH adjusted to 10 using 25percent NH3 (aq.), while the temperature was kept below 50-60° C. Extraction with diethyl ether (2*250 ml) filtration through celite and evaporation to dryness gave a red-brown oil which crystalized upon cooling. The precipitate was suspended in boiling heptane (300 ml) under rapid stirring and decanted while warm. This procedure was repeated with hexane (2*100 ml). The combined organic fractions was evaporated to dryness to give 18.2 g crude product as a slightly yellow powder. Recrystalization from heptane gave 15.2 g (59 percent from 97percent isoquinoline) of pure product as a slightly yellow powder. M.p. 82-83° C. (Litt. 82-83° C.4, 79.5-80.5° C.1, 82-84° C.3,9, 83.0-83.5° C.2, 83-85° C.5); 1H-NMR (DMSO-d6): δ 9.38 (d, J=0.9 Hz); 8.67 (d, J=5.9 Hz); 8.21 (d, J=8.2 Hz); 8.16 (dd, JA=0.9 Hz, JB=7.5 Hz); 7.94 (d, J=5.9 Hz); 7.64 (t.dagger., J=7.8 Hz). .dagger.A dd with JA=8.2 Hz and JB=7.5 Hz was expected.
Reference：
[1] Patent: US6500954, 2002, B1,
14
[ 81237-69-6 ]
[ 34784-04-8 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 14, p. 2358 - 2363
15
[ 3132-99-8 ]
[ 645-36-3 ]
[ 34784-04-8 ]
Reference：
[1] Patent: US2002/6923, 2002, A1,
16
[ 119-65-3 ]
[ 34784-04-8 ]
[ 63927-22-0 ]
[ 81045-39-8 ]
Reference：
[1] Synthesis, 2002, # 1, p. 83 - 86
17
[ 34784-04-8 ]
[ 58142-99-7 ]
Reference：
[1] Phosphorus, Sulfur and Silicon and Related Elements, 2000, vol. 164, p. 131 - 143
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).
96%
With potassium nitrate In H2O4; hexane; ethyl acetate
Example 2 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 (40percent ethyl acetate in hexane as eluent) to give 5-bromo-8-nitroisoquinoline in 96percent yield.
96%
With potassium nitrate In hexane; sulfuric acid; ethyl acetate
EXAMPLE 2 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 (40percent ethyl acetate in hexane as eluent) to give 5-bromo-8-nitroisoquinoline in 96percent yield.
96%
With potassium nitrate In hexane; sulfuric acid; ethyl acetate
EXAMPLE 9 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 (40percent ethyl acetate in hexane) to give 5-bromo-8-nitroisoquinoline in 96percent yield.
96%
With potassium nitrate In hexane; sulfuric acid; ethyl acetate
Example 1 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 (40percent ethyl acetate in hexane) to give 5-bromo-8-nitroisoquinoline in 96percent yield.
96%
With potassium nitrate In hexane; sulfuric acid; ethyl acetate
EXAMPLE 2 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 (40percent ethyl acetate in hexane as eluent) to give 5-bromo-8-nitroisoquinoline in 96percent yield.
93%
With KNO3 In hexane; chloroform; sulfuric acid; ethyl acetate
EXAMPLE 25 5-Bromo-8-nitroisoquinoline The procedure described by Osborn AR, et al, J Chem Soc 1956:41191 was used. 5-Bromoisoquinoline (101 g, 0.485 mol) was dissolved in 300 mL concentrated H2SO4. KNO3 (58.85 g, 0.582 mol) was dissolved in 200 mL of concentrated H2SO4 and added dropwise to the isoquinoline/acid solution. After addition, the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice and the acid quenched carefully with the addition of NH4OH until the solution was strongly basic. The solids were dissolved in chloroform and filtered through a silica gel plug and eluted with chloroform. Evaporation, followed by trituration of the yellow solid with 5percent ethyl acetate in hexane, gave the product (114.2 g, 93percent). 1H-NMR (200 MHz, CDCl3) δ 10.01 (s, 1H), 8.84 (d, 1H, J=5.9 Hz), 8.2 (d, 1H, J=8.1 Hz), 8.15 (d, 1H, J=5.6 Hz), 8.1 (d, 1H, J=8.2 Hz).
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonia In water at 0℃;
Synthesis of 5-bromo-8-nitroisoquinoline 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° C. over a time period of 1 h. The resulting solution was allowed to react, with stirring, for 1 h while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE 1:5). The reaction mixture was then quenched by the adding 600 mL of H2O/ice-Adjustment of the pH to 8-10 was accomplished by the addition of NH3.H2O (30percent). A filtration was performed. The filter cake was washed 2 times with 500 mL of H2O. The solid was dried in an oven under reduced pressure. This resulted in 25.59 g (90percent) of 5-bromo-8-nitroisoquinoline as a yellow solid.
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonia In water
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.
90%
With sulfuric acid; potassium nitrate In water at 20℃; for 2 h;
Synthesis of 5-bromo-8-nitroisoquinoline 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° C. 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 8-10 was accomplished by the addition of NH3. H2O (30percent). A filtration was performed. The filter cake was washed 2 times with 500 mL of H2O. The solid was dried in an oven under reduced pressure. This resulted in 25.59 g (90percent) of 5-bromo-8-nitroisoquinoline as a yellow solid.
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonium hydroxide In waterCooling with ice
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.
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonia In water
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.
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonia In water
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.
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonium hydroxide In waterCooling with ice water
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.
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonia In water
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 5-bromo-8-nitroisoquinoline in 90percent yield as a yellow solid.
90%
Stage #1: at 20℃; for 2 h; Stage #2: With ammonia In water
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 percent). 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 (90percent) of 5- bromo-8-nitroisoquinoline as a yellow solid.
82%
at 20℃; for 1 h;
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, 82percent) as a yellow solid.
53%
at 5 - 25℃; for 2 h;
(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 53percent
Reference：
[1] Patent: WO2004/76424, 2004, A1, . Location in patent: Page 174-175
[2] Patent: EP698025, 1997, B1,
[3] Patent: US5917053, 1999, A,
[4] Patent: US5436250, 1995, A,
[5] Patent: EP633262, 1995, A1,
[6] Patent: US5780493, 1998, A,
[7] Journal of Medicinal Chemistry, 1995, vol. 38, # 19, p. 3720 - 3740
[8] Patent: US2003/114422, 2003, A1,
[9] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 22-23
[10] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 105-106
[11] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 45; 46
[12] Patent: US2010/16297, 2010, A1, . Location in patent: Page/Page column 25
[13] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 68
[14] Patent: US2010/29629, 2010, A1, . Location in patent: Page/Page column 52-53
[15] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 87
[16] Patent: US2010/22581, 2010, A1, . Location in patent: Page/Page column 35; 36
[17] Patent: WO2007/98418, 2007, A1, . Location in patent: Page/Page column 127; 128
[18] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 4, p. 715 - 734
[19] Patent: WO2009/130481, 2009, A1, . Location in patent: Page/Page column 142
[20] Patent: CN105669547, 2016, A, . Location in patent: Paragraph 0076; 0078
[21] Journal of the Chemical Society, 1956, p. 4191,4205
[22] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2623 - 2628
[23] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 4972 - 4982
[24] Patent: US2003/158188, 2003, A1,
[25] Patent: US5801174, 1998, A,
[26] Patent: US6933311, 2005, B2,
[27] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 29
[28] Patent: WO2010/91310, 2010, A1, . Location in patent: Page/Page column 168
[29] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5521 - 5527
[30] ChemMedChem, 2014, vol. 9, # 1, p. 129 - 150
[31] Patent: US2004/157849, 2004, A1,
20
[ 34784-04-8 ]
[ 90721-35-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 4, p. 715 - 734
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5521 - 5527
21
[ 497863-61-3 ]
[ 34784-04-8 ]
[ 58794-09-5 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 25, p. 9014 - 9019
[2] Patent: WO2010/123545, 2010, A2, . Location in patent: Page/Page column 68
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 4972 - 4982
24
[ 119-65-3 ]
[ 34784-04-8 ]
[ 63927-22-0 ]
[ 81045-39-8 ]
Reference：
[1] Synthesis, 2002, # 1, p. 83 - 86
25
[ 34784-04-8 ]
[ 34551-41-2 ]
Yield
Reaction Conditions
Operation in experiment
33 g
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 40℃; for 20 h; Stage #2: With trichlorophosphate In dichloromethane at 45℃; for 18 h;
To a solution of 2 (60 g, 288 mmoles) in methylene chloride (1.5 L) there are added (75 g, 436 mmoles) of 75percent m-CPBA. The mixture is heated at 40° C. for 20 hours. After HPLC monitoring and return to ambient temperature, 75 g of sodium thiosulphate are added in the course of 10 minutes, followed by 300 mL of water. The whole is decanted, the organic phase is washed with a 1N sodium hydroxide solution, and the organic phase is dried by passage over MgSO4. Evaporation under reduced pressure yields a white solid (42 g), which is used without additional treatment in the following step. A solution of the intermediate that forms (37 g, 165 mmoles) in methylene chloride (900 mL) and POCl3 (37 mL) is stirred for 18 hours at 45° C. After HPLC and/or GC monitoring, the reaction mixture is concentrated in vacuo. The residue is treated carefully with water, and the aqueous phase is extracted with methylene chloride. The organic phase is washed carefully with a saturated NaHCO3 solution and then with a saturated aqueous NaCl solution. Evaporation under reduced pressure yields intermediate 123 (33 g) in the form of a beige solid, which can be used without additional treatment in the following step. 1H NMR (400 MHz-CDCl3): δ 8.35 (2d, 2H), 8.00 (2d, 2H), 7.55 (t, 1H) GC-EI (70 eV): M+.=241
Dissolve 5-bromoisoquinoline (25 g, 120.2 mmol) with acetic acid (250 mL).Add 3eq NaBH4 (13.6 g, 359.5 mmol), react at room temperature, and monitor the reaction with LC-MS.Adjust pH~8 with saturated aqueous NaHCO3 solution, extract with ethyl acetate, collect and wash the organic phase, dry, remove the solvent and purify by column chromatography.5-Bromo-1,2,3,4-tetrahydroisoquinoline (10 g, yield: 40percent).
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 42, p. 17592 - 17598,7
[2] Patent: CN107540659, 2018, A, . Location in patent: Paragraph 0225-0226
30
[ 34784-04-8 ]
[ 104737-00-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 19, p. 3720 - 3740
31
[ 34784-04-8 ]
[ 190777-77-6 ]
Yield
Reaction Conditions
Operation in experiment
43%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 0.5 h; Stage #2: for 1 h; Reflux
Commercially available 5-bromoisoquinoline (4.85 g, 23.3 mmol) was dissolved in dichloromethane (78 mL), and m-CPBA (9.28 g, 35.0 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted by adding chloroform, and washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetic anhydride (78.0 mL), and stirred for 1 hour under reflux. A 2.0 mol/L sodium hydroxide aqueous solution (156 mL) was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was stirred for 2 hours under reflux. The reaction mixture was cooled to room temperature, and neutralized with a 2.0 mol/L hydrochloric acid aqueous solution. The precipitated crystals were collected by filtration, and dried under reduced pressure to give 5-bromoisoquinolin-1(2H)-one (2.28 g, 10.1 mmol, 43percent).
Reference：
[1] Patent: EP2708540, 2014, A1, . Location in patent: Paragraph 0122
[2] Patent: US2014/302987, 2014, A1,
[3] Chemistry - A European Journal, 2015, vol. 21, # 18, p. 6906 - 6912
32
[ 34784-04-8 ]
[ 371766-08-4 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With Triisopropyl borate; tert.-butyl lithium In tetrahydrofuran at -78 - 20℃; Stage #2: With hydrogenchloride; water In tetrahydrofuran
To a solution of 5-bromoisoquinoline (1.46 g, 7.0 mmol), prepared according to a known procedure (Reference: Brown, W. D. et. al. Synthesis 2002,83), in THF (20 mL) at-78 °C were added triisopropyl borate (2.4 mL, 10.5 mmol) and t- butyllithium (1.7 M, 9.5 mL). The solution was then slowly warmed to room temperature and kept stirring overnight. The solution was quenched with 1N HCl (10 mL) and the solid was obtained after decanting THF. The solid was identified as isoquinolinyl-5-boronic acid (1.0 g, 82percent). MS (ESI) (M+1) = 174.12.
58%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.75 h; Stage #2: With Triisopropyl borate In tetrahydrofuran at -78 - 20℃; for 1.08333 h;
A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to -78°C, was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45'. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5' and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5percent NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of 10percent HCl at O0C. <n="7"/>Extraction with ethyl acetate, evaporation of the organic phase and crystallisation from diethyl ether gave 250 mg of a white solid. Yield = 58percent. 1H NMR (d6-DMSO, 200 MHz) δ 7.66 (IH, t, J= 7.2 Hz), 8.07 (IH, d, J= 5.8 Hz), 8.13 (IH, d, J= 8.0 Hz), 8.34 (IH, d), 8.47 (IH, d), 8.50 (2H, bs), 9.29 (IH, s); [M+1] 174.1 (C9H8BNO2 requires 172.98
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.75 h; Stage #2: at -78 - 20℃; for 1.08333 h; Stage #3: With sodium hydroxide; water In tetrahydrofuran
Synthesis of isoquinolin-5-yl-5-boronic acid; A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to -78°C was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45'. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5' and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5percent NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of HCl 10percent at O°C. Extraction with ethyl acetate, evaporation of the organic phase and crystallisation from diethyl ether gave 250 mg of a white solid. Yield = 58percent. 1H NMR (d6-DMSO, 200 MHz) δ 7.66 (1H, t, J= 7.2 Hz), 8.07 (1H, d, J= 5.8 Hz), 8.13 (1H, d, J= 8.0 Hz), 8.32 (1 H, d, J= 6.2 Hz), 8.47 (1H, d), 8.50 (2H, bs), 9.29 (1 H, s); [M+1] 174.1 (C9H8BNO2 requires 172.98).
With sulfuric acid; nitric acid; at 20℃; for 1.5h;
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).
96%
With potassium nitrate; In H2O4; hexane; ethyl acetate;
Example 2 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 5-bromo-8-nitroisoquinoline in 96% yield.
96%
With potassium nitrate; In hexane; sulfuric acid; ethyl acetate;
EXAMPLE 2 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 5-bromo-8-nitroisoquinoline in 96% yield.
96%
With potassium nitrate; In hexane; sulfuric acid; ethyl acetate;
EXAMPLE 9 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 5-bromo-8-nitroisoquinoline in 96% yield.
96%
With potassium nitrate; In hexane; sulfuric acid; ethyl acetate;
Example 1 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 5-bromo-8-nitroisoquinoline in 96% yield.
96%
With potassium nitrate; In hexane; sulfuric acid; ethyl acetate;
EXAMPLE 2 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 5-bromo-8-nitroisoquinoline in 96% yield.
93%
With KNO3; In hexane; chloroform; sulfuric acid; ethyl acetate;
EXAMPLE 25 5-Bromo-8-nitroisoquinoline The procedure described by Osborn AR, et al, J Chem Soc 1956:41191 was used. 5-Bromoisoquinoline (101 g, 0.485 mol) was dissolved in 300 mL concentrated H2SO4. KNO3 (58.85 g, 0.582 mol) was dissolved in 200 mL of concentrated H2SO4 and added dropwise to the isoquinoline/acid solution. After addition, the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice and the acid quenched carefully with the addition of NH4OH until the solution was strongly basic. The solids were dissolved in chloroform and filtered through a silica gel plug and eluted with chloroform. Evaporation, followed by trituration of the yellow solid with 5% ethyl acetate in hexane, gave the product (114.2 g, 93%). 1H-NMR (200 MHz, CDCl3) delta 10.01 (s, 1H), 8.84 (d, 1H, J=5.9 Hz), 8.2 (d, 1H, J=8.1 Hz), 8.15 (d, 1H, J=5.6 Hz), 8.1 (d, 1H, J=8.2 Hz).
90%
Synthesis of 5-bromo-8-nitroisoquinoline 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 C. over a time period of 1 h. The resulting solution was allowed to react, with stirring, for 1 h while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE 1:5). The reaction mixture was then quenched by the adding 600 mL of H2O/ice-Adjustment of the pH to 8-10 was accomplished by the addition of NH3.H2O (30%). A filtration was performed. The filter cake was washed 2 times with 500 mL of H2O. 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.
90%
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 90% yield as a yellow solid.
90%
With sulfuric acid; potassium nitrate; In water; at 20℃; for 2h;
Synthesis of 5-bromo-8-nitroisoquinoline 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 C. 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 8-10 was accomplished by the addition of NH3. H2O (30%). A filtration was performed. The filter cake was washed 2 times with 500 mL of H2O. 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.
90%
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 (2×500 mL), and dried in a vacuum oven to provide 5-bromo-8-nitroisoquinoline in 90% yield as a yellow solid.
90%
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 90% yield as a yellow solid.
90%
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 5-bromo-8-nitroisoquinoline in 90% yield as a yellow solid.
90%
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 90% yield as a yellow solid.
90%
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 5-bromo-8-nitroisoquinoline in 90% yield as a yellow solid.
90%
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.
82%
With sulfuric acid; potassium nitrate; at 20℃; for 1h;
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.
53%
With sulfuric acid; potassium nitrate; at 5 - 25℃; for 2h;
(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%
With potassium nitrate; In methanol;
EXAMPLE 57B 5-bromo-8-nitroisoquinoline The diethyl ether solution from Example 57A was treated with potassium nitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture was poured onto ice and neutralized with concentrated ammonium hydroxide (300 ml). The crude product was collected by filtration, dried, and recrystalization from methanol to provide the title compound (8.83 g).
With potassium nitrate; In concentrated H2 SO4; hexane; ethyl acetate;
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 5-bromo-8-nitroisoquinoline.
With potassium nitrate; In methanol;
EXAMPLE 57B 5-bromo-8-nitroisoquinoline The diethyl ether solution from Example 57A was treated with potassium nitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture was poured onto ice and neutralized with concentrated ammonium hydroxide (~300 ml). The crude product was collected by filtration, dried, and recrystalization from methanol to provide the title compound (8.83 g).
With potassium nitrate; In diethyl ether; for 1h;
EXAMPLE 57B 5-bromo-8-nitroisoquinoline The diethyl ether solution from Example 57A was treated with potassium nitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture was poured onto ice and neutralized with concentrated ammonium hydroxide (~300 ml). The crude product was collected by filtration, dried, and recrystalization from methanol to provide the title compound (8.83 g).
With sulfuric acid; potassium nitrate; at 0℃; for 0.333333h;
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].
With potassium nitrate; In methanol;
Example 57B 5-bromo-8-nitroisoquinoline The diethyl ether solution from Example 57A was treated with potassium nitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture was poured onto ice and neutralized with concentrated ammonium hydroxide (~300 ml). The crude product was collected by filtration, dried, and recrystalization from methanol to provide the title compound (8.83 g).
14.2 g
With sulfuric acid; potassium nitrate; at 20℃; for 48h;
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%).
Synthesis of 5-bromoisoquinoline Into a 250 mL 3-necked round-bottom flask, was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0 C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25-22 C. The resulting solution was allowed to react, with stirring, for 2 h while the temperature was maintained at -25 to -22 C. The resulting solution was allowed to react with stirring overnight, while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:5). The reaction mixture was then quenched by the adding 1000 mL of H2O/ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3.H2O (30%). The resulting solution was extracted four times with 500 mL of EtOAc and the organic layers combined and dried over Na2SO4. The residue was purified by eluding through a column with a 1:5 EtOAc/PE solvent system. This resulted in 22.24 g (81%) of 5-bromoisoquinoline as a white solid.
81%
Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 C. The reaction mixture was cooled at -25 C and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 <n="107"/>niL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81% yield as a white solid.
81%
Synthesis of 5-bromoisoquinoline Into a 250 mL 3-necked round-bottom flask was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0 C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25-22 C. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at -25-22 C. The resulting solution was allowed to react, with stirring, overnight 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 1000 mL of H2O/ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30%). The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluding through a column with a 1:5 ethyl acetate/petroleum ether solvent system. This resulted in 22.24 g (81%) of 5-bromoisoquinoline as a white solid.
81%
Intermediate 13: Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride; 1. Synthesis of 5-bromoisoquinoline; Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 C. The reaction mixture was cooled at -25 C. and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4×500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81% yield as a white solid.
81%
Intermediate 19: Synthesis of 2-methyl-l,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride.1. Synthesis of 5-bromoisoquinoline.Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 niL) at O 0C. The reaction mixture was cooled at -25 0C and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5- bromoisoquinoline in 81% yield as a white solid.
81%
Oxalyl chloride (157.6 mmol) was added dropwise at rt to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (22.0 mmol) in dichloromethane (100 mL) and N,N-dimethylformamide (10 mL). The resulting solution was maintained for 2 h, then was diluted with iced water (200 mL). The resulting solution was extracted with dichloromethane (2×100 mL) and the combined organics were dried (sodium sulfate), filtered and concentrated. The residue was purified by Flash chromatography (1/4 ethyl acetate/petroleum ether) to afford 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride in 20% yield as a yellow solid. 1H NMR (CDCl3) delta 7.69 (d, 1H), 7.51 (s, 1H), 6.54 (d, 1H), 3.57 (t, 2H), 3.02 (s, 3H), 2.78 (d, 2H), 1.98 (m, 2H).
81%
Intermediate 19: Synthesis of 2-methyl-l,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride.1. Synthesis of 5-bromoisoquinoline.Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 0C. The reaction mixture was cooled at -25 0C and TV-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5- bromoisoquinoline in 81% yield as a white solid.
81%
Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 C. The reaction mixture was cooled at -25 C. and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4*500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81% yield as a white solid.
81%
Into a 250 mL 3-necked round bottom flask was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0 0C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25 - -22 0C. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at -25 - -220C. The resulting solution was allowed to react, with stirring, overnight 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 1000 mL of H2O /ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30 %). The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluting through a column with a 1:5 ethyl acetate/petroleum ether solvent system. This resulted in 22.24 g (81%) of 5- <n="129"/>bromoisoquinoline as a white solid.
79%
With N-Bromosuccinimide; sulfuric acid; at -25 - -18℃; for 4h;
To mechanically stirred concd H 2 SO 4 (170 mL), isoquinoline (1; 21.8 g,169.2 mmol, 1.0 equiv) was slowly added at 0 C. The mixture wascooled to -25 C and NBS (39.3 g, 220.5 mmol, 1.3 equiv) was added atsuch a rate that the reaction temperature was kept between at -25and -22 C. The mixture was stirred between -25 and -20 C for 2 hand at -18 C for 2 h. It was then poured onto crushed ice (600 g) andmade alkaline (pH 8-9) by using concd aq NH 3 solution with intensivecooling. The alkaline slurry was extracted with Et 2 O (3 × 300 mL). Thecombined organic layer was washed with 1.0 M aq NaOH (2 × 300 mL)and H 2 O (300 mL), dried over anhyd Na 2 SO 4 , filtered, and evaporatedto give a brown oil. The crude product was purified by vacuum distil-lation (128-130 C/2 Torr) to give 2 as a white powder.Yield: 27.8 g (79%); mp 82-83 C.IR (ATR): 1580, 1485, 1368, 1263, 1199, 1136, 962, 817, 750, 673, 627,525 cm -1 .1 H NMR (400 MHz, CDCl 3 ): delta = 9.23 (s, 1 H), 8.64 (d, J = 6.0 Hz, 1 H),7.99-7.94 (m, 3 H), 7.48 (t, J = 7.8 Hz, 1 H).13 C NMR (100 MHz, CDCl 3 ): delta = 152.7, 144.5, 135.2, 134.2, 129.8,127.9, 127.6, 121.7, 119.6.
77%
With N-Bromosuccinimide; sulfuric acid; at -10 - 25℃; for 24h;Inert atmosphere;
(1) The reaction flask in 250mL three, -10 under nitrogen, was added isoquinoline (11g,85mmol) and concentrated sulfuric acid (100mL) Stir, then add N- bromosuccinimide (17.8g,100mmol) were mixed and the reaction warmed to 25 24h, to obtain a reaction solution. The reaction solution was addedInto ice water, followed by aqueous ammonia and ethyl acetate (50mL × 3) extraction, water (50mL × 3) wash,Saturated brine (100mL), dried over anhydrous sodium sulfate and concentrated to give 5-bromo - isoquinoline 14g,The yield was 77%
71%
With N-Bromosuccinimide; sulfuric acid; In tetrahydrofuran; at -25 - 25℃; for 26h;
Isoquinoline 38 (1156?mg, 8.95?mmol) was suspended in conc. H2SO4 (9.7?mL) at 0?C. After cooling to -25?C, NBS (1912?mg, 10.74?mmol) was added. The reaction mixture was stirred at -25?C for 2?h and then at 25?C for additional 24?h. Subsequently, ice was added and the mixture was treated with conc. NH4OH (10?mL) to pH?=?8-10. The resulting solution was extracted with EtOAc (3?*?10?mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (20% EtOAc in petroleum ether) to afford the title compound as a pale pink solid (71% yield). 1H NMR (300?MHz, CDCl3) delta 9.24 (s, 1H), 8.65 (d, J?=?5.9?Hz, 1H), 8.00-7.95 (m, 3H), 7.48 (t, J?=?7.8?Hz, 1H); ESI-MS m/z 209.1 [M+H]+.
50%
EXAMPLE 57A 5-bromoisoquinoline Concentrated H2SO4 (260 mL) was cooled to -25 C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0 C. After the addition was complete. the red solution was recooled to -25 C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed -20 C. The reaction mixture was stirred for 5 hours keeping the temperature between -30 C. and -18 C. The reaction mixture was then allowed to warm to -10 C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH. The mixture was then extracted with diethyl ether (3*600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2*200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50%). mp 78-80 C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) delta 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
28%
To a suspension of AIC13 (156.7 g, 1.18 mol) in CH2CI2 (500 mL), a solution of isoquinoline (605 mmol, 71 mL) in CH2CI2 (100 mL) was dropwise added at such rate that the reaction mixture was refluxed gently. After addition, CH2CI2 was removed by distillation. The blackish residue was melted at 120 C then the temperature was adjusted to 100 C. To the mixture, Br2 (31 mL, 605 mmol) was dropwise added over 2hrs at 100 C and stirred for 30min at same temperature, then was stirred at 75 C overnight. The mixture was cooled to RT then carefully poured into ice-water. The aqueous mixture was basified with NaOHaq. and extracted with ether. The organics was dried overNa2SO4 then evaporated. Sequence purification onSi02 column chromatography twice and recrystalisation (from hexane) gave the title compound (34.5 g, 28%).
28%
To a suspension of AICI3 (156.7 g, 1.18 mol) inCH2CI2 (500 mL), a solution of isoquinoline (1) (605 mmol, 71 mL) inCH2CI2 (100 mL) was dropwise added at such rate that the reaction mixture was refluxed gently. After addition,CH2CI2 was removed by distillation. The blackish residue was melted at120 C then the temperature was adjusted to100 C. To the mixture, Br2 (31 mL, 605mmol) was dropwise added over 2hrs at100 C and stirred for 30min at same temperature, then was stirred at75 C overnight. The mixture was cooled to room temperature then carefully poured into ice-water. The aqueous mixture was basified with NaOHaq. and extracted with ether. The organic layer was dried overNa2SO4 then evaporated. Sequence purification on Si02 column chromatography twice andrecrystallization from hexane gave the title compound (34.5g, 28 %). MS (ESI) (M+H) + 208,210
26%
With aluminum (III) chloride; bromine; at 75 - 85℃; for 5h;
5-Bromoisoquinoline. The apparatus was a 500 mL three-necked flask equipped with a condenser, dropping funnel, and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafluroethylene paddle. To the isoquinoline (57.6 g, 447 mmol) in the flask was added AlCl3 (123 g, 920 mmol). The mixture was heated to 75-85C. Bromine (48.0 g, 300 mmol) was added using a dropping funnel over a period of 4 hours. The resulting mixture was stirred for one hour at 75C. The almost black mixture was poured into vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10 N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from a fraction of about 1250C was obtained (26% yield). The product was further purified by recrystallization (pentane or hexanes)
26%
With bromine;aluminum (III) chloride; at 75 - 85℃; for 5h;
The apparatus was a 500 mL three-necked flask equipped with a condenser, dropping funnel, and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafluroethylene paddle. To the isoquinoline (57.6 g, 447 mmol) in the flask was added AiCl3 (123 g, 920 mmol). The mixture was heated to 75-85 C. Bromine (48.0 g, 300 mmol) was added using a dropping funnel over a period of 4 hours. The resulting mixture was stirred for one hour at 75 C. The almost black mixture was poured into vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10 N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from a fraction of about 125 C. was obtained (26% yield). The product was further purified by recrystallization (pentane or hexanes): mp 80-81 C.; 1H NMR (DMSO-d6) delta 9.34 (s, 1H), 8.63 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=7,5 Hz), 8.11 (d, 1H, J=6.6 Hz), 7.90 (d, 1H, J=6.0 Hz), 7.60 (t, 1H, J=7.5 Hz); 13C NMR (DMSO-d6) delta 153.0, 144.7, 134.3, 134.0, 129.3, 128.5, 128.0, 120.3, and 118.6. Anal. Calcd. for C9H6BrN: C, 51.96; H, 2.91; N, 6.73. Found: C, 51.82; H, 2.91; N, 6.64.
With N-Bromosuccinimide; sulfuric acid; In hexane; n-heptane;
EXAMPLE 57A 5-bromoisoquinoline Concentrated H2SO4 (260 mL) was cooled to -25 C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0 C. After the addition was complete. the red solution was recooled to -25 C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed -20 C. The reaction mixture was stirred for 5 hours keeping the temperature between -30 C. and -18 C. The reaction mixture was then allowed to warm to -10 C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH. The mixture was then extracted with diethyl ether (3*600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2*200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50%). mp 78-80 C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) 6 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
With N-Bromosuccinimide; sulfuric acid; In hexane; n-heptane;
EXAMPLE 57A 5-bromoisoquinoline Concentrated H2SO4 (260 mL) was cooled to -25 C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0 C. After the addition was complete the red solution was recooled to -25 C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed -20 C. The reaction mixture was stirred for 5 hours keeping the temperature between -30 C. and -18 C. The reaction mixture was then allowed to warm to -10 C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH. The mixture was then extracted with diethyl ether (3*600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2*200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50%). mp 78-80 C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) delta 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
With N-Bromosuccinimide; sulfuric acid; In hexane; n-heptane;
Example 57A 5-bromoisoquinoline Concentrated H2SO4 (260 mL) was cooled to -25 C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0 C. After the addition was complete the red solution was recooled to -25 C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed -20 C. The reaction mixture was stirred for 5 hours keeping the temperature between -30 C. and -18 C. The reaction mixture was then allowed to warm to -10 C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH. The mixture was then extracted with diethyl ether (3*600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2*200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50%). mp 78-80 C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) delta 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
With N-Bromosuccinimide; sulfuric acid; at 20℃; for 2h;
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%).
With n-butyllithium; In tetrahydrofuran; diethyl ether; hexane; at -78℃; for 0.75h;
To a solution of n-butyllithium (19.3 mL of 2.5 M in hexanes, 48 mmol) in a mixture of ether (80 mL) and THF (80 mL) at -78° C. was added dropwise a solution of bromoisoquinoline (5.0 g, 24 mmol) in THF (10 mL). The reaction mixture was stirred at -78° C. under argon for 30 minutes. Following the general procedures described by Pearson, et al., in J. Heterocycl. Chem., Vol. 6 (2), pp. 243-245 (1969), a solution of DMF (3.30 g, 45 mmol) in THF (10 mL) was cooled to -78° C. and quickly added to the isoquinolyllithium solution. The mixture was stirred at -78° C. for 15 minutes. Ethanol (20 mL) was added followed by saturated NH4Cl solution. The resulting suspension was warmed to room temperature. The organic layer, combined with the ether extraction layer, was dried over Na2SO4. A pale yellow solid (2.4 g, 15 mmol, 64percent yield) was obtained from chromatography (SiO2 Type-H, 50percent EtOAc in hexanes) and recrystallization (ethanol): mp 114-116° C.; 1H NMR (DMSO-d6) delta 10.40 (s, 1H), 9.44 (s, 1H), 8.85 (d, 1H, J=6.0 Hz), 8.69(d, 1H, J=6.0 Hz), 8.45 (m, 2H), 7.90 (t, 1H, J=7.2 Hz); 13C NMR (DMSO-d6) delta 194.23, 153.5, 146.2, 140.2, 135.2, 132.6, 130.2, 128.6, 127.5, and 117.2. Anal. Calcd. for C10H7NO.0.05H2O: C, 75.99; H, 4.53; N, 8.86. Found: C, 75.98, H, 4.66; N, 8.68.
A solution of sodium nitrite (2.15 g, 31.21 mmol) in water (2 mL) was added to a solution of isoquinolin-5-ylamine (3.0 g, 20.80 mmol) in aqueous 46% hydrogen bromide (9.98 g, 124.84 mmol) at 0 C. The mixture was stirred at 0 0C for 30 min then a solution of cuprous bromide (3.58 g, 24.96 mmol) in aqueous 46% hydrogen bromide (9.98 g, 124.84 mmol) was added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The resulting mixture was basified with aqueous ammonium and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to afford the crude compound. Purification by column chromatography over silica gel (100-200 mesh) with 20% ethyl acetate in petroleum ether as eluent afforded 5-bromoisoquinoline (2.3 g, 53%) as a pale yellow solid.
50%
Example 78A 5-Bromoisoquinoline To a solution of 5-aminoisoquinoline (2.0 g, 13.8 mmol) and 48% HBr (6 mL) in 20 mL water cooled to 0 C. was added a solution of sodium nitrite (0.95 g, 13.8 mmol) in 6 mL water. The solution was stirred at 0 C. for 20 minutes. The solution, while kept at 0 C., was added to a solution of CuBr (2.11 g, 15.9 mmol) in 48% HBr (4.77 mL) and water (10 mL). The reaction was stirred at room temperature for an additional 1 hr. The reaction was neutralized with NaOH (50%) and extracted with ethyl acetate (3*). The combined organic layer was concentrated in vacuo and chromatographed using 1:1 hexanes/ethyl acetate to yield 1.4 g product (50%).
36%
PREPARATION 40; (Isoquinolin-5-yl) oxoacetic acid methyl ester; 5-Aminoisoquinoline (20 g, 139 mmol) is dissolved in hydrobromic acid (48%, 100 mL) in a 500 mL round bottom flask, and then a solution of sodium nitrite (9.6g, 139 mmol) in water (50 mL) added cautiously at 0C. The white slurry turns bright red upon complete addition of the salt, and then this solution is transferred to another 500 mL vessel containing CuBr (25g, 174 mmol) stirring in hydrobromic acid (48%, 200 mL) at 75C. This transfer is performed slowly and carefully. After complete addition, the mixture is allowed to stir at 75C for one hour, then cooled to room temperature, and kept stirring overnight. The mixture is then placed onto an ice bath and some ice added to the solution, then basified using sodium hydroxide aqueous solution (20%, 250 mL) solution. The slurry is filtered and then filtrate is extracted with diethyl ether. The solid and the extract are then combined and sonicated for one hour in chloroform. This sludge is filtered through a plug of Celite, and the chloroform removed by rotovap. The final compound is obtained in pure form by column chromatography in chloroform with 36% yield, 10.4g (50 mmol) of 5-Bromo-isoquinoline. MS (ES, m/z): 208.0 (M+ (79Br) +l), 210.0 (M+(81Br)+1).
5-Aminoisoquinoline was purchased from Aldrich Chemical Co. (Cat. No. 13,610-7) and used in this step without purification. 5-Aminoisoquinoline (7.87 g was added to 100 ML of bromic acid (HBr) ((HBr) (48%) at -78 C. and stirred.To the stirred solution was added 4.74 g of sodium nitrate (NaNO3) in(NaNO3) in portions.The mixture was allowed to stir for 1 hour at -78 C. following addition of the NaNO3, after which 0.48 g of copper dust (Cu0) was added.The reaction was allowed to warm to room temperature, and then was heated to 100 C. for one hour.The reaction mix was poured over ice and the resultant aqueous solution was basified to PH 14 by addition of sodium hydroxide (NaOH) (2M).The precipitated solids were collected and chromatographed to yield 2.4 g of 5-bromoisoquinoline as a white solid.
Preparation 22; 5-Bromoisoquinoline; Add a solution of sodium nitrite (9.6g, 139 mmol) in water (50 mL) cautiously to 5-aminoisoquinoline (20 g, 139 mmol) in hydrobromic acid (48%, 100 mL) at 0C. Transfer this mixture to a vessel containing CuBr (25g, 174 mmol) in hydrobromic acid (48%, 200 mL) at 75 C. After complete addition, stir the mixture at 75 C for one hour, cool to room temperature and stir overnight. Place the mixture in an ice bath, add ice to the reaction mixture, and then add sodium hydroxide aqueous solution (20%, 250 mL). Filter the slurry and extract the filtrate with diethyl ether. Combine the solid and the extract sonicate for one hour in chloroform. Filter the suspension through a plug of CeliteTM, and concentrate the filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with chloroform. MS (ES): m/z = 208.0 (M+ (79Br) +l), 210.0 (M+ (8lBr) +l)
1.4 g product (50%)
With sodium nitrite;copper(I) bromide; In water; hydrogen bromide;
Example 78A 5-Bromoisoquinoline To a solution of 5-aminoisoquinoline (2.0 g, 13.8 mmol) and 48% HBr (6 mL) in 20 mL water cooled to 0 C. was added a solution of sodium nitrite (0.95 g, 13.8 mmol) in 6 mL water. The solution was stirred at 0 C. for 20 minutes. The solution, while kept at 0 C., was added to a solution of CuBr (2.11 g, 15.9 mmol) in 48% HBr (4.77 mL) and water (10 mL). The reaction was stirred at room temperature for an additional 1 hr. The reaction was neutralized with NaOH (50%) and extracted with ethyl acetate (3*). The combined organic layer was concentrated in vacuo and chromatographed using 1:1 hexanes/ethyl acetate to yield 1.4 g product (50%).
With tris(dibenzylideneacetone)dipalladium (0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80℃;
With sodium t-butanolate In toluene at 100℃; for 8h;
1.2; D.2
5-Bromoisoquinoline (1.37 g) from Step 1 was dissolved in 10 ML of toluene.To this solution was added palladium acetate (74 mg), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (205 mg), 1-(tert-butoxycarbonyl)piperazine (1.29 g) and sodium tert-butoxide (885 mg).This reaction mixture was heated to 100° C. for 8 hours and then allowed to cool to room temperature.The cooled reaction mix was diluted with ethyl acetate (EtOAc) and washed with water, and the organic layer was separated, dried over magnesium sulfate (MgSO4), and concentrated in vacuo.The resulting residue was chromatographed to yield 4-isoquinoline-5-yl-piperazine-1-carboxylic acid tert-butyl ester as 1.5 g of a white solid.
With 2-((dicyclohexylphosphino)methyl)-1,3-bis(2,6-diisopropylphenyl)-4,5-dimethyl-1H-imidazol-3-ium iodide; ammonia; palladium diacetate; sodium t-butanolate In 1,4-dioxane at 120℃; for 24h; Autoclave; Inert atmosphere;
79%
With lithium amide In 1,2-dimethoxyethane at 90℃; for 24h;
78 %Chromat.
With ammonia; palladium diacetate; sodium t-butanolate; 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole In 1,4-dioxane at 120℃; for 24h; Autoclave; Inert atmosphere;
Stage #1: 5-bromoisoquinoline With lithium amide In 1,2-dimethoxyethane at 90℃; for 24h; Sealed vial;
Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water at 20℃; for 0.0833333h;
Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; water
19
5-Bromo-z.so-quinoline (0.208 g, 1.00 mmol), (CyPF-Z-Bu)PdCl2 (7.30 mg, 1.00 x 10"2 mmol), and LiNH2 (0.230 g, 10.0 mmol) in 2.0 mL DME gave 0.114 g (79%) of 5-Amino-wø-quinoline as a solid.
70%
Stage #1: 5-bromoisoquinoline With ammonia; sodium t-butanolate In 1,2-dimethoxyethane at 90℃; for 20h;
Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water at 20℃; for 0.0833333h;
Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; water
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); johnphos; In toluene; at 70℃; for 3h;
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (252 mg), tris(dibenzylideneacetone)palladium(0) (59 mg), 2-(di-tert-butylphosphino)biphenyl (74 mg), <strong>[150349-36-3](3-aminopropyl)methylcarbamic acid tert-butyl ester</strong> (274 mg, Asta Tech), and sodium tert-butoxide (163 mg) in toluene was stirred with heating at 70 C. for 3 hours. The reaction mixture was returned to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (325 mg).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 100℃;
A mixture of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (4.16 g, 20mmol), Pd (PPh3) 4 (290 mg, 0.25mmol) and3-nitrophenylboronic acid (3.67 g, 22mmol) was flushed N2 gas then added dioxane (200 mL), ethanol (40 mL) and 2MK2CO3aq (200 mL). The mixture was stirred at100oC overnight. After cooling, the mixture was evaporated to remove dioxane then extracted with AcOEt. The organic layer was washed with brine then dried overNa2SO4. After evaporation, the residue was purified on Si02 column chromatography to give the title compound (4.65 g, 93%).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 45℃;Inert atmosphere;
Step 1: Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (15.3 g, 73.54 mmol,1.00 equiv) in dichloromethane (300 mL), then 3-chlorobenzene-1-carboperoxoic acid (mCPBA; 17.4 g, 80%/W 80.89 mmol, 1.10 equiv) was added in portions. The resultingsolution was stirred overnight at 45 C. The reaction was then cooled to RT, quenched by the addition of 200 mL of saturated aqueous Na2S2O3 solution and the separated water layer wasextracted with dichloromethane. The combined organic layer was washed with 2N aqueous sodium hydroxide aqueous solution, 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to deliver 16.5 g (100%) of <strong>[34784-04-8]5-bromoisoquinolin</strong>-2-ium-2- olate as a yellow solid.
90%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 45℃;
To a solution of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (20.8 g, 100mmol) in CH2CI2 (500 mL),mCPBA (80 % assay, 23.7 g, 110mmol) was added and stirred at45 C overnight. After cooling, the mixture was quenched with Na2S2O3 then extracted with CH2Cl2. The organic layer was washed with NaOHaq. , dried overNa2SO4 then evaporated. Sequence recrystalisation (fromCH2CI2-ether) gave the title compound (20.1 g, 90 %).
90%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 45℃;
To a solution of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (2) (20.8g, 100mmol) inCH2CI2 (500 mL),mCPBA (80 % assay, 23.7g, 110mmol) was added and stirred at45 C overnight. After cooling, the mixture was quenched with Na2S203 then extracted withCH2C12. The organic layer was washed with NaOHaq. , dried overNa2SO4 then evaporated. Sequence recrystallization fromCH2CI2-ether gave the title compound (20.1 g, 90 %). MS (ESI) (M+H)+ 224,226.
84%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 2.33333h;
No. I.1-247: 5-[4-(Methylsulphanyl)phenyl]isoquinolin-1(2H)-one 5.45 g (26.19 mmol) of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> were dissolved in 250 ml of dichloromethane, and 6.78 g (27.50 mmol) of 3-chloroperoxybenzoic acid monohydrate were added a little at a time over a period of 20 min. The suspension was stirred at room temperature for 2 h. The solution was extracted with saturated sodium bicarbonate solution. The phases were separated, the organic phase was stirred with solid sodium sulphite and the solution was filtered off. The organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. This gave 4.94 g (84% of theory) of the desired <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> 2-oxide. 1H-NMR (400 MHz, d6-DMSO delta, ppm) 9.02 (s, 1H), 8.26 (d, 1H), 7.99-7.90 (m, 3H), 7.58 (t, 1H).
50%
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 20℃; for 1h;
Aqueous meta-chloroperbenzoic acid (65%, 29 g) was added to a solution of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (20.7 g) in chloroform (250 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and small amounts of chloroform and diethyl ether were added to the residue. The deposit was filtrated to obtain compound ( 1a) (11.8 g, 50%).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane;
REFERENCE EXAMPLE 11 To a solution of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (0.266 g) in dichloromethane (5 ml) was added m-chloroperbenzoic acid (0.27 g) at ambient temperature. After stirring at ambient temperature for 6 hours, the reaction mixture was taken up into ethyl acetate. The mixture was washed in turn with an aqueous potassium carbonate solution (10%) and brine, dried over potassium carbonate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong>-2-oxide (0.28 g). APCI-mass; 224, 226 (m/z, [M+H]+), NMR (DMSO-d6, delta): 7.58 (1H, t, J=7.7 Hz), 7.88-8.08 (3H, m), 8.27 (1H, dd, J=1.8, 7.4 Hz), 9.03 (1H, d, J=1.8 Hz).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; for 20h;Heating / reflux;
Example 33:<strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong>-N-oxide. To a solution of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (10.65 g, 51.19 mmol) in CH2Cl2 (250 mL), m-CPBA (9.717 g, 56.31 mmol) was added and the mixture refluxed for 20 h and allowed to cool to rt. The mixture was washed with sat Na2SSO3 (75 mL), then 3x IN NaOH, then brine. The organic layer was dried w/Na2SO4, filtered and evaporated. The residue was crystallized from CH2Cl2 : Et2O to yield the title compound as a white fluffy solid (4.58 g). MS (ESI pos. ion) m/z: 224 (MH+). Calc'd exact mass for C9H5BrNO : 224.
With magnesium bis(monoperoxyphthalate)hexahydrate; In isopropyl alcohol; at 20℃; for 50h;
Example 8 - Synthesis of Compound 4; slurry of 6.24 g (30.0 mmol) <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> and 17.5 g (30 mmol) magnesium monoperoxyphthalate hexahydrate (85%) in 120 ml 2-propanol was stirred for 50 hours at room temperature. The volume of the reaction mixture was reduced in vacuo. Brine, saturated sodium bicarbonate solution and dichloro methane were added. The organic phase was separated and washed several times with brine. The organic phase was dried over sodium sulphate and evaporated. The residue was triturated with tert-butyl-methyl-ether yielding <strong>[34784-04-8]5-bromo-isoquinoline</strong> 2-oxide as colourless crystals, HPLC/MS: 1.51 min, [M+H] 224/226.
With magnesium bis(monoperoxyphthalate)hexahydrate; In isopropyl alcohol; at 20℃; for 50h;
1. A slurry of 6.24 g (30.0 mmol) <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> and 17.5 g (30 mmol) magnesium monoperoxyphthalate hexahydrate (85%) in 120 ml 2-propanol was stirred for 50 hours at room temperature. The volume of the reaction mixture was reduced in vacuo. Brine, saturated sodium bicarbonate solution and dichloromethane were added. The organic phase was separated and washed several times with brine. The organic phase was dried over sodium sulphate and evaporated. The residue was triturated with tert-butyl-methyl-ether yielding <strong>[34784-04-8]5-bromo-isoquinoline</strong> 2-oxide as colourless crystals, HPLC/MS: 1.51 min, [M+H] 224/226.
With magnesium bis(monoperoxyphthalate)hexahydrate; In isopropyl alcohol; at 20℃; for 50h;
Example 3 Preparation of <strong>[34784-04-8]5-bromoisoquinolin</strong>-1-ylamine 3.1 A suspension of 6.24 g (30.0 mmol) of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> and 17.5 g (30 mmol) of magnesium monoperoxyphthalate hexahydrate (85%) in 120 ml of 2-propanol is stirred at room temperature for 50 hours. The reaction mixture is evaporated in vacuo, and saturated sodium chloride solution, saturated sodium hydrogencarbonate solution and dichloromethane are added. The organic phase is separated off and washed a number of times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is stirred with tert-butyl methyl ether, giving <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> 2-oxide as colourless crystals; HPLC/MS: 1.51 min, [M+H] 224/226.
To a solution of 5-bromoisoquinoline (1.46 g, 7.0 mmol), prepared according to a known procedure (Reference: Brown, W. D. et. al. Synthesis 2002,83), in THF (20 mL) at-78 C were added triisopropyl borate (2.4 mL, 10.5 mmol) and t- butyllithium (1.7 M, 9.5 mL). The solution was then slowly warmed to room temperature and kept stirring overnight. The solution was quenched with 1N HCl (10 mL) and the solid was obtained after decanting THF. The solid was identified as isoquinolinyl-5-boronic acid (1.0 g, 82%). MS (ESI) (M+1) = 174.12.
58%
A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to -78C, was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45'. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5' and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5% NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of 10% HCl at O0C. <n="7"/>Extraction with ethyl acetate, evaporation of the organic phase and crystallisation from diethyl ether gave 250 mg of a white solid. Yield = 58%. 1H NMR (d6-DMSO, 200 MHz) delta 7.66 (IH, t, J= 7.2 Hz), 8.07 (IH, d, J= 5.8 Hz), 8.13 (IH, d, J= 8.0 Hz), 8.34 (IH, d), 8.47 (IH, d), 8.50 (2H, bs), 9.29 (IH, s); [M+1] 174.1 (C9H8BNO2 requires 172.98
6.1 Step 1
Step 1 5-Aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 48% aqueous HBr (65 mL) at -78° C. for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise. After stirring for 15 min at -78° C., the mixture was warmed to 0° C. Copper powder (0.3 g) was added very slowly to avoid excessive foaming. After addition was completed, the reaction vessel was fitted with a reflux condensor and the mixture was heated to 100° C. for 4 h. The mixture was poured onto ice (ca. 200 g) and was made basic (pH=10) with KOH. The aqueous mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, were dried (MgSO4), were filtered, and were concentrated in vacuo. Purification by silica gel chromatography (10:1 hexanes-ethyl acetate) afforded 3.8 g (53% yield) of 5-bromoisoquinoline; 1H NMR (400 MHz, CD3OD) δ 9.25 (s, 1H), 8.57 (d, J=6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/CI): 208.0, 210.0 (M+H)+.
53%
With aqueous HBr; sodium nitrite In water
6.1 Step 1
Step 1 5-Aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 48% aqueous HBr (65 mL) at -78° C. for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise. After stirring for 15 min at -78° C., the mixture was warmed to 0° C. Copper powder (0.3 g) was added very slowly to avoid excessive foaming. After addition was completed, the reaction vessel was fitted with a reflux condensor and the mixture was heated to 100° C. for 4 h. The mixture was poured onto ice (ca. 200 g) and was made basic (pH=10) with KOH. The aqueous mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, were dried (MgSO4), were filtered, and were concentrated in vacuo. Purification by silica gel chromatography (10:1 hexanes-ethyl acetate) afforded 3.8 g (53% yield) of 5-bromoisoquinoline; 1H NMR (400 MHz, CD3OD) δ9.25 (s, 1H), 8.57 (d, J=6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/CI): 208.0, 210.0 (M+H)+.
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 85℃; for 4h;
To a suspension of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (200 mg, 0.96 mmol), benzhydrylidene-hydrazine (189 mg, 0.96 mmol), palladium diacetate (2.2 mg, 0.0096 mmol) and 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP, 6 mg, 0.0096 mmol) in dry toluene (1 ml_), sodium tert-butoxide (130 mg, 1.34 mmol) was added and the mixture was heated at 85 0C for 4 hours. The mixture, cooled to room temperature, was filtered over celite and the pad was washed with diethylether. The solvent was evaporated under vacuum and the residue was purified by flash chromatography with hexane/ethylacetate 7/3 as eluant, affording 268 mg of the title compound (86% yield).1 H NMR (400 MHz, DMSO-D6) delta ppm 7.35 (d, J=6.10 Hz, 1 H) 7.38 - 7.45 (m, 3 H)7.48 - 7.52 (m, 2 H) 7.57 - 7.74 (m, 7 H) 7.88 (dd, J=7.44, 1.10 Hz, 1 H) 8.39 (d, J=5.97Hz, 1 H) 8.76 (s, 1 H) 9.24 (s, 1 H).[M+H]+= 324
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120.0℃; for 18.0h;
The synthesis of compounds of this embodiment is shown in FIG. 1. As shown, pyridine, quinolines or isoquinolines were coupled with various piperazines through nucleophilic aromatic substitution or Hartwig Buchwald aryl amination.
Synthesis of isoquinolin-5-yl-5-boronic acid; A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to -78C was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45'. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5' and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5% NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of HCl 10% at OC. Extraction with ethyl acetate, evaporation of the organic phase and crystallisation from diethyl ether gave 250 mg of a white solid. Yield = 58%. 1H NMR (d6-DMSO, 200 MHz) delta 7.66 (1H, t, J= 7.2 Hz), 8.07 (1H, d, J= 5.8 Hz), 8.13 (1H, d, J= 8.0 Hz), 8.32 (1 H, d, J= 6.2 Hz), 8.47 (1H, d), 8.50 (2H, bs), 9.29 (1 H, s); [M+1] 174.1 (C9H8BNO2 requires 172.98).
32%
Isoquinolin-5-ylboronic acid was prepared from 5-bromoisoquinoline according to literature procedure [25]. AnhydrousTHF (19 mL) was cooled to -78 C then a 2.5 M n-butyllithiumsolution in hexane (1.2 mL, 3.0 mmol, 1.25 eq.) was addedunder argon. A solution of 5-bromoisoquinoline (502 mg,2.41 mmol, 1 eq.) in anhydrous THF (5 mL) was added. The mixturewas stirred at -78 C for 1 h. Triisopropyl borate (0.70 mL,3.0 mmol, 1.25 eq.) was added dropwise and the mixture wasstirred at room temperature for 2 h. A 5% aqueous NaOH solution(1 mL) was slowly added to quench the reaction. Aqueous phasewas acidified to pH 5 at 0 C with a 10% aqueous HCl solution, thenwas extracted with EtOAc. The organic phasewas dried over MgSO4and filtered. After evaporation, the obtained solid was washed withdiethyl ether to give isoquinolin-5-ylboronic acid (135.5 mg,0.783 mmol, 32%).
With sodium tetrahydroborate; acetic acid; at 20℃;
Dissolve 5-bromoisoquinoline (25 g, 120.2 mmol) with acetic acid (250 mL).Add 3eq NaBH4 (13.6 g, 359.5 mmol), react at room temperature, and monitor the reaction with LC-MS.Adjust pH~8 with saturated aqueous NaHCO3 solution, extract with ethyl acetate, collect and wash the organic phase, dry, remove the solvent and purify by column chromatography.5-Bromo-1,2,3,4-tetrahydroisoquinoline (10 g, yield: 40%).
In a 500 mL round bottom three-necked flask, outfitted with a mechanical stirrer and an addition funnel, phosphorous pentoxide (60.0 g) and concentrated sulfuric acid (15 mL) were mixed and stirred until a thick beige colored gum was formed. Next, m- bromobenzalaminoacetal (30 g, 1 10 mmol, 1 equiv) was dissolved in cold (5 C) concentrated sulfuric acid (150 mL) and added slowly to the mixture OfP2O5 and H2SO4 prepared above. The resulting dark colored reaction mixture was vigorously stirred and heated at 160 C for 30 minutes. After cooling to room temperature, the dark brown viscous reaction mixture was carefully poured into ice water (1.5 L) while vigorously stirring. The pH was adjusted to 7 using ION NaOH and the black tarry precipitate was filtered. The pH was then further increased to 9 using 1 ON NaOH. This basic aqueous phase was extracted with Et2O (3 x 400 mL) and EtOAc (3 x 250 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over MgSO4 and evaporated to afford 11.5 g of brown oil. The crude product was then subjected to column chromatography (hexanes:EtOAc = 3:1 - >; 2:1) to yield 8.5 g (37%) of pale yellow solid that is the 3:2 mixture of 7-bromoisquinoline and 5-bromoisoquinoline, respectively.
A mixture of 5-bromoisoquinoline (1 mole equivalent), palladium acetate (0.15 mole equivalent), R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.15 mole equivalent), and cesium carbonate (1.6 mole equivalent) in toluene (10 mL per gram of 5-bromoisoquinoline) is purged with nitrogen and stirred at 80 C. for 30 min. A solution of (1RS,3rs,5SR)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (1.2 mole equivalent) in a minimum volume of toluene is added, and the mixture is stirred at 80 C. for 18 h. An additional quantity of palladium acetate and phosphine ligand (0.03 equivalents each) is added, and heating is continued for an additional 18 h. The reaction mixture is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulfate and evaporated to a residue. Chromatography of the residue on silica gel affords the title compound as the BOC-protected material.
With potassium carbonate;C96H36F72P4Pd; In methanol; water; at 110℃; for 1h;Inert atmosphere;
Example 6Preparation of isoquinoline derivatives by Suzuki coupling, using the catalyst of formula (I)General prescription:14 mg (0.25 mole % related to the <strong>[34784-04-8]5-bromo-isoquinoline</strong> substrate) of the catalyst of formula (I), 3 mmoles of the dioxaborolane reagent, 553 mg (4 mmoles) of potassium carbonate and 416 mg (2 mmoles) of <strong>[34784-04-8]5-bromo-isoquinoline</strong> were weighed into a flask. Thereafter the flask was placed under argon atmosphere, and 10 ml of methanol and 1 ml of water were added. The flask was then closed, and the reaction mixture was stirred for 1 hour at 1 10C under a pressure required to maintain a liquid reaction mixture. The resulting reaction mixtures were processed as described in Example 2.
4-bromo-8-(4-methylbenzoyl)-10-phenyl-8,8a,11a,11b-tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With cetyltrimethylammonim bromide; triethylamine In water at 20℃; for 1h; Green chemistry; regioselective reaction;
General reaction procedure for the synthesis of tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione:
General procedure: One mmol each of the isoquinoline (1a-b), phenacyl bromide (2a-d), and phenyl maleimide (3a-b) derivatives were taken in a 100 ml RB flask. Then water (50 ml), CTAB (4 mmol) and NEt3 (1 mmol) were added and the mixture was stirred continuously for 1 h at room temperature. After completion of the reaction (monitored by TLC), the solid was filtered off, washed thoroughly with water (until free from CTAB and base) and further purified by recrystallization from chloroform to yield the tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione (4a-p).
4-bromo-8-(4-chlorobenzoyl)-10-phenyl-8,8a,11a,11b-tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With cetyltrimethylammonim bromide; triethylamine In water at 20℃; for 1h; Green chemistry; regioselective reaction;
General reaction procedure for the synthesis of tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione:
General procedure: One mmol each of the isoquinoline (1a-b), phenacyl bromide (2a-d), and phenyl maleimide (3a-b) derivatives were taken in a 100 ml RB flask. Then water (50 ml), CTAB (4 mmol) and NEt3 (1 mmol) were added and the mixture was stirred continuously for 1 h at room temperature. After completion of the reaction (monitored by TLC), the solid was filtered off, washed thoroughly with water (until free from CTAB and base) and further purified by recrystallization from chloroform to yield the tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione (4a-p).
4-bromo-8-(4-chlorobenzoyl)-10-(3,4-dimethylphenyl)-8,8a,11a,11b-tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With cetyltrimethylammonim bromide; triethylamine In water at 20℃; for 1h; Green chemistry; regioselective reaction;
General reaction procedure for the synthesis of tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione:
General procedure: One mmol each of the isoquinoline (1a-b), phenacyl bromide (2a-d), and phenyl maleimide (3a-b) derivatives were taken in a 100 ml RB flask. Then water (50 ml), CTAB (4 mmol) and NEt3 (1 mmol) were added and the mixture was stirred continuously for 1 h at room temperature. After completion of the reaction (monitored by TLC), the solid was filtered off, washed thoroughly with water (until free from CTAB and base) and further purified by recrystallization from chloroform to yield the tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione (4a-p).
4-bromo-8-(4-fluorobenzoyl)-10-phenyl-8,8a,11a,11b-tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With cetyltrimethylammonim bromide; triethylamine In water at 20℃; for 1h; Green chemistry; regioselective reaction;
General reaction procedure for the synthesis of tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione:
General procedure: One mmol each of the isoquinoline (1a-b), phenacyl bromide (2a-d), and phenyl maleimide (3a-b) derivatives were taken in a 100 ml RB flask. Then water (50 ml), CTAB (4 mmol) and NEt3 (1 mmol) were added and the mixture was stirred continuously for 1 h at room temperature. After completion of the reaction (monitored by TLC), the solid was filtered off, washed thoroughly with water (until free from CTAB and base) and further purified by recrystallization from chloroform to yield the tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione (4a-p).
8-benzoyl-4-bromo-10-phenyl-8,8a,11a,11b-tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With cetyltrimethylammonim bromide; triethylamine In water at 20℃; for 1h; Green chemistry; regioselective reaction;
General reaction procedure for the synthesis of tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione:
General procedure: One mmol each of the isoquinoline (1a-b), phenacyl bromide (2a-d), and phenyl maleimide (3a-b) derivatives were taken in a 100 ml RB flask. Then water (50 ml), CTAB (4 mmol) and NEt3 (1 mmol) were added and the mixture was stirred continuously for 1 h at room temperature. After completion of the reaction (monitored by TLC), the solid was filtered off, washed thoroughly with water (until free from CTAB and base) and further purified by recrystallization from chloroform to yield the tetrahydropyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione (4a-p).
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 130℃; for 0.333333h;Microwave irradiation;
To 5- bromoisoquinoline (1 g, 4.81 mmol), 4-(pyrrolidin-l-yl)piperidine (1.1 12 g, 7.21 mmol), and sodium tert-butoxide (0.647 g, 6.73 mmol), was added toluene (10 mL) and the mixture was degassed with argon. BINAP (0.090 g, 0.144 mmol) and Pd2(dba)3 (0.044 g, 0.048 mmol) were added and the reaction was heated to 130 C in a microwave for 20 min. Purification by normal phase chromatography afforded 0.84g (62.7%) of 80A as a tan solid. MS (ESI) m/z: 282.1 (M+H)+.
To a solution of 2 (60 g, 288 mmoles) in methylene chloride (1.5 L) there are added (75 g, 436 mmoles) of 75% m-CPBA. The mixture is heated at 40 C. for 20 hours. After HPLC monitoring and return to ambient temperature, 75 g of sodium thiosulphate are added in the course of 10 minutes, followed by 300 mL of water. The whole is decanted, the organic phase is washed with a 1N sodium hydroxide solution, and the organic phase is dried by passage over MgSO4. Evaporation under reduced pressure yields a white solid (42 g), which is used without additional treatment in the following step. A solution of the intermediate that forms (37 g, 165 mmoles) in methylene chloride (900 mL) and POCl3 (37 mL) is stirred for 18 hours at 45 C. After HPLC and/or GC monitoring, the reaction mixture is concentrated in vacuo. The residue is treated carefully with water, and the aqueous phase is extracted with methylene chloride. The organic phase is washed carefully with a saturated NaHCO3 solution and then with a saturated aqueous NaCl solution. Evaporation under reduced pressure yields intermediate 123 (33 g) in the form of a beige solid, which can be used without additional treatment in the following step. 1H NMR (400 MHz-CDCl3): delta 8.35 (2d, 2H), 8.00 (2d, 2H), 7.55 (t, 1H) GC-EI (70 eV): M+.=241
Commercially available 5-bromoisoquinoline (4.85 g, 23.3 mmol) was dissolved in dichloromethane (78 mL), and m-CPBA (9.28 g, 35.0 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted by adding chloroform, and washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetic anhydride (78.0 mL), and stirred for 1 hour under reflux. A 2.0 mol/L sodium hydroxide aqueous solution (156 mL) was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was stirred for 2 hours under reflux. The reaction mixture was cooled to room temperature, and neutralized with a 2.0 mol/L hydrochloric acid aqueous solution. The precipitated crystals were collected by filtration, and dried under reduced pressure to give 5-bromoisoquinolin-1(2H)-one (2.28 g, 10.1 mmol, 43%).
Stage #1: 5-bromoisoquinoline With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 0.5h;
Stage #2: With acetic anhydride for 3h; Reflux;
Stage #3: methyl iodide Further stages;
9
Commercially available 5-bromoisoquinoline (1.09 g, 5.24 mmol) was dissolved in dichloromethane (20 mL), and m-CPBA (2.09 g, 7.86 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted by adding chloroform, and washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetic anhydride (18 mL), and stirred for 3 hours under heat and reflux. A 2.0 mol/L sodium hydroxide aqueous solution (36 mL) was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was stirred for 1 hour under reflux. After extracting the reaction mixture with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in DMF (26 mL), and potassium carbonate (2.89 g, 20.9 mmol) and methyl iodide (0.978 mL, 15.7 mmol) were added. The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was extracted with ethyl acetate after adding water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give Compound j (0.355 g, 4 steps 28%). ESI-MS: m/z 238, 240 [M + H]+. 1H-NMR (CDCl3) δ (ppm): 3.61 (s, 3H), 6.83 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 7.9, 7.9 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H)
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 85 - 105℃; for 27h;Inert atmosphere;
[00243] Intermediate 3A: 5-(4-methoxypiperidin-l-yl)isoquinoline: To 5- bromoisoquinoline (10.40 g, 50 mmol), <strong>[4045-24-3]4-methoxypiperidine</strong> (4.92 mL, 50.0 mmol), Pd2(dba)3 (0.458 g, 0.500 mmol), BINAP (0.934 g, 1.500 mmol), and ?-BuONa (6.73 g, 70.0 mmol) was added degassed toluene (60 mL) and the reaction was heated under 2 to 85 C for 24 h and then to 105 C for 3 h. The reaction mixture was cooled to ambient temperature and water was added. The phases were separated and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried (Na2S04), filtered and purified by silica gel chromatography to afford 6.34g (52.4%) of Intermediate 3 A as a pale yellow solid. MS (ESI) m/z: 243.2 (M+H)+.
52.4%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 85 - 105℃; for 27h;Inert atmosphere;
To 5-bromoisoquinoline (10.40 g, 50 mmol), <strong>[4045-24-3]4-methoxypiperidine</strong> (4.92 mL, 50.0 mmol), Pd2(dba)3 (0.458 g, 0.500 mmol), BINAP (0.934 g, 1.500 mmol), and t-BuONa (6.73 g, 70.0 mmol) was added degassed toluene (60 mL) and the reaction was heated, under N2, to 85 C for 24 h and then to 105 C for 3 h. The reaction mixture was cooled to ambient temperature and water was added. The phases were separated and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4), filtered and purified by silica gel chromatography to afford 6.34g (52.4%) of Intermediate 3A as a pale yellow solid. MS (ESI) m/z: 243.2 (M+H)+.
52.4%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 85 - 105℃; for 27h;Inert atmosphere;
Intermediate 4A. 5-(4-Methoxypiperidin-l-yl)isoquinoline: To 5- bromoisoquinoline (10.40 g, 50 mmol), <strong>[4045-24-3]4-methoxypiperidine</strong> (4.92 mL, 50.0 mmol), Pd2(dba)3 (0.458 g, 0.500 mmol), BetaGammaNuAlphaRho (0.934 g, 1.500 mmol), and ?-BuONa (6.73 g, 70.0 mmol) was added degassed toluene (60 mL) and the reaction was heated under 2 to 85 C for 24 h and then to 105 C for 3 h. The reaction mixture was cooled to ambient temperature and water was added. The phases were separated and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried (Na2S04), filtered and purified by silica gel chromatography to afford 6.34g (52.4%) of Intermediate 4A as a pale yellow solid. MS (ESI) m/z: 243.2 (M+H)+.
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In dimethyl sulfoxide; at 130℃;Inert atmosphere;
[00249] 5A: l-(isoquinolin-5-yl)-<strong>[34770-60-0]4-methylpiperazin-2-one</strong>: To 5-bromoisoquinoline (1.657 g, 7.96 mmol) and <strong>[34770-60-0]4-methylpiperazin-2-one</strong> (1, 8.76 mmol) was added DMSO (7 mL), 1,10-phenanthroline (0.144 g, 0.796 mmol), potassium carbonate (3.30 g, 23.89 mmol) and the mixture was degassed with Ar for 30 min. Copper(I)iodide (1.213 g, 6.37 mmol) was added and the reaction was heated in oil bath at 130 C overnight. The reaction was cooled to room temperature and quenched with NH4OH (10 mL) and water (20 mL) and diluted with EtOAc. The aqueous layer was extracted EtOAc (2 x 50 mL) and then, nBuOH (lx 30 mL). Combined organic layers were washed with brine and dried (MgS04). Purification by silica gel chromatography afforded 1.5g ( 78%) yellow solid. MS (ESI) m/z: 242.0 (M+H)+.
78%
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In dimethyl sulfoxide; at 130℃;Inert atmosphere;
Intermediate 5A. l -(Isoquinolin-5-yl)-<strong>[34770-60-0]4-methylpiperazin-2-one</strong>: To 5- bromoisoquinoline (1.66 g, 7.96 mmol) and <strong>[34770-60-0]4-methylpiperazin-2-one</strong> (1, 8.76 mmol) was added DMSO (7 mL), 1, 10-phenanthroline (0.144 g, 0.796 mmol), potassium carbonate (3.30 g, 23.89 mmol) and the mixture was degassed with Ar for 30 min., copper(I)iodide (1.213 g, 6.37 mmol) was added and the reaction was heated in oil bath at 130 C overnight. The reaction was cooled to room temperature and quenched with NuEta4OmicronEta (10 mL) and water (20 mL) and diluted with EtOAc. The aqueous layer was extracted EtOAc (2 x 50 mL) and then, nBuOH (lx 30 mL). Combined organic layers were washed with - I l l - brine and dried (MgS04). Purification by silica gel chromatography afforded 1.5g (78%) yellow solid. MS (ESI) m/z: 242.0 (M+H)+.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃;Schlenk technique; Inert atmosphere;
General procedure: Into a Schlenk bomb, the appropriate haloisoquinoline (2.40 mmol,1.0 equiv), PhB(OH) 2 (352 mg, 2.9 mmol, 1.2 equiv), Na 2 CO 3 (510 mg,4.81 mmol, 2 equiv), DME (10 mL), and distilled H 2 O (5 mL) wereplaced under an inert atmosphere. N 2 gas was bubbled through thestirred mixture for 10 min. Then Pd(PPh 3 ) 4 (167 mg, 0.144 mmol, 0.06equiv) was added. The reaction mixture was heated to 85 C and keptat this temperature. The progress of the reaction was monitored byTLC. After completion, the mixture was cooled to r.t. and diluted withH 2 O (16 mL) and EtOAc (27 mL). The aqueous phase was extractedwith EtOAc (2 × 15 mL). The combined organic layer was washed withbrine (15 mL), dried over anhyd Na 2 SO 4 , filtered, and evaporated. Theresidue was purified by flash chromatography (silica gel, hexane-EtOAc) to give the corresponding phenylisoquinoline derivative.5-Phenylisoquinoline (20) 17According to the general procedure, starting from 5-bromoisoquino-line (2; 500 mg, 2.40 mmol, 1.0 equiv), the product was obtained afterchromatography (silica gel, hexane-EtOAc, 91:9) as a pale yellow oil.Yield: 415 mg (84%).IR (ATR): 1616, 1584, 1485, 1443, 1379, 1029, 829, 754, 700, 629, 532cm -1 .1 H NMR (500 MHz, CDCl 3 ): delta = 9.32 (s, 1 H), 8.49 (d, J = 6.0 Hz, 1 H),8.02-7.99 (q, 1 H), 7.75 (d, J = 6.0 Hz, 1 H), 7.68 (s, 1 H), 7.67 (d, J = 1.2Hz, 1 H), 7.53-7.47 (m, 5 H).13 C NMR (125 MHz, CDCl 3 ): delta = 152.7, 143.0, 139.5, 139.1, 134.4,131.3, 130.0, 129.1, 128.7, 128.0, 127.4, 127.1, 118.9.
1 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 18h;Inert atmosphere;
Step a. To a solution of <strong>[34784-04-8]<strong>[34784-04-8]5-bromoisoquinolin</strong>e</strong> (CAS Number 34784-04-8) (1 g, 4.8 mmol) in toluene (10 ml), water (5 ml) and EtOH (2.5 ml) were added Na2C03 (1.02 g, 9.6 mmol) and phenylboronic acid (0.586 g, 4.8 mmol) at rt. The reaction mixture was degassed for 20 min. Pd(PPh3)4 (0.278 g, 0.24 mmol) was added to the reaction mixture at rt. The reaction mixture was heated at 90C for 18 h. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was dried over Na2S0 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EtOAc in Hexane) yielding the 5-phenylisoquinoline (1 g, 4.87 mmol) LCMS: Method C, 1.782 min, MS: ES+ 205.8.
Multi-step reaction with 3 steps
1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 4 h / 100 °C
2: hydrogenchloride; water / water / 6 h / 100 °C
3: sulfuric acid / 20 h / Reflux
Multi-step reaction with 3 steps
1: Ph(PPH)4 / N,N-dimethyl-formamide / 4 h / 100 °C
2: hydrogenchloride; water / 6 h / 100 °C
3: sulfuric acid / 20 h / Reflux
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 4h;
5-Bromoisoquinoline (8 g, 38.65 mmol) and dimethyl formamide (100 mL) were mixed and stirred. The reaction solution was added with Zn(CN)2 (2.72 g, 23.19 mmol) and Ph(PPH)4 (1.78 g, 1.55 mmol), followed by stirring for about 4 hours at 100C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (5.8 g, 97 %). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.72 (d, 1H), 8.50 (d, 1H), 8.39 (d, 1H), 7.94 (d, 1H), 7.85 (t, 1H). MS (ESI+, m/z): 155 [M+H]+
97%
With Ph(PPH)4; In N,N-dimethyl-formamide; at 100℃; for 4h;
5-Bromoisoquinoline (8 g, 38.65 mmol) and dimethyl formamide (100 mL) were mixed and stirred. The reaction solution was added with Zn(CN)2 (2.72 g, 23.19 mmol) and Ph(PPH)4 (1.78 g, 1.55 mmol), followed by stirring for about 4 hours at 100 C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (5.8 g, 97%). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.72 (d, 1H), 8.50 (d, 1H), 8.39 (d, 1H), 7.94 (d, 1H), 7.85 (t, 1H). MS (ESI+, m/z): 155 [M+H]+
24 g
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;
To a solution (degassed with nitrogen) of intermediate 2 (45 g, 216 mmoles) in DMF (450 mL) there are added Zn(CN)2 (30 g) and Pd(PPh3)4(9.8 g). The mixture is heated at 100 C. for 2 hours. After return to ambient temperature, the mixture is taken up in AcOEt (200 mL) and water (2 L). The mixture is brought to pH>8 by addition of a 20% aqueous NaOH solution. After addition of AcOEt (200 mL), the organic phase is recovered by decantation, filtered over Celite, washed with a saturated aqueous NaCl solution and then dried over MgSO4 before being concentrated in vacuo. The solid is ground and dried in vacuo and taken up in a 1N aqueous HCl solution (1 L), and the acidic aqueous phase is washed with AcOEt and then treated with a 20% aqueous NaOH solution, the precipitate that forms is collected and dissolved in methylene chloride. The solution is dried over MgSO4, and evaporation in vacuo yields intermediate 653 in the form of a beige solid (24 g). 1H NMR (400 MHz; DMSO-d6): δ 9.53 (s, 1H), 8.76 (d, 1H), 8.54 (d, 1H), 8.45 (d, 1H), 7.96 (d, 1H), 7.87 (t, 1H). IR (cm-1): 2226.
With Ethyl 2-mercaptopropionate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; toluene-4-sulfonic acid In dimethyl sulfoxide at 23℃; UV-irradiation;
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 16h;Reflux; Inert atmosphere;
A stirred solution of 1001 (100 mg, 0.48 mmol) in toluene (1.0 mL) was charged with 1002 (78 mg, 0.48 mmol), i-BuOK (107 mg, 0.96 mmol) and the mixture was purged with argon for 20 min. Pd2(dba)3 (21 mg, 0.02 mmol) and BINAP (22 mg, 0.03 mmol) were added into this mixture and refluxed at 1 10C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resultant dark brown slurry was filtered through Celite pad and pad was washed with ethyl acetate (30 mL). The solvent was concentrated in vacuo to give a dark brown residue. This residue was further purified by Combiflash column chromatography using 12 g redisep column (hexane/EtOAc, 1 : 1) to afford 45 (20 mg, 14%) as an off-white solid.MS (MM) m/z 292 [M+H]+; HPLC: 95.9%, Eclipse XDB C-18, 220 nm;1H NMR (300 MHz, DMSC 6): delta 9.29 (s, 1H), 8.52 (d, J= 5.1 Hz, 1H), 7.92 (d, J= 4.8 Hz, 1H), 7.82 (d, J= 7.5 Hz, 1H), 7.62 (t, J= 1.2 Hz, 1H), 7.40 (d, J = 6.9 Hz, 1H), 3.42 (bs, 4H), 3.14 (bs, 4H), 2.99 (s, 3H).
391A Example 391A: tert-butyl {3-[(isoquinolin-5-yl)amino]bicyclo[1.1.1]pentan-1-yl}carbamate
A mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (PharmaBlock, 0.875 g, 4.41 mmol), 5-bromoisoquinoline (0.900 g, 4.33 mmol), and six HPMC catalyst capsules (115 mg loading per capsule with 1 weight % of Allyl Pd, 4 weight % of cBRIDP, and 95 weight % of KOtBu) in water (12 mL) was degassed and stirred at 50 °C for 2 hours. The reaction mixture was diluted with brine and saturated, aqueous Na2SO4 and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on an 80 g column using the Biotage Isolera One flash system eluting with heptanes/ethyl acetate (4:6 to 3:7) to provide the title compound (0.262 g, 0.81mmol, 19% yield). HPMC: (hydroxypropyl)methyl cellulose. cBRIDP: di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine. MS (ESI+) m/z 326.2 (M+H)+.
19%
In water at 50℃; for 2h; Inert atmosphere;
391.391A Example 391A: tert-butyl {3-[(isoquinolin-5-yl)amino]bicyclo[l.l.l]pentan-l-yl}carbamate
A mixture of teri-butyl (3-aminobicyclo[l . l . l]pentan-l-yl)carbamate (PharmaBlock, 0.875 g, 4.41 mmol), 5-bromoisoquinoline (0.900 g, 4.33 mmol), and six HPMC catalyst capsules (115 mg loading per capsule with 1 weight % of Allyl Pd, 4 weight % of cBRIDP, and 95 weig ht % of KO'Bu) in water (12 mL) was degassed and stirred at 50 °C for 2 hours. The reaction mixture was diluted with brine and saturated, aqueous Na2SC>4 and extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous MgSC , filtered, and concentrated under reduced pressure. The residue was purified on an 80 g column using the Biotage Isolera One flash system eluting with heptanes/ethyl acetate (4:6 to 3:7) to provide the title compound (0.262 g, 0.81mmol, 19% yield). HPMC: (hydroxypropyl)methyl cellulose. cBRIDP: di-teri-butyl(2,2-diphenyl- 1 -methyl- l-cyclopropyl)phosphine. MS (ESI+) m/z 326.2 (M+H)+.
With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 70℃; for 24h; Inert atmosphere;
1.6 g
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; triethylamine at 120℃; for 5h; Inert atmosphere;
1.1 The first step: preparation of methyl isoquinoline-5-carboxylate (compound 1-2)
To the autoclave were added compound 1-1 (2 g, 9.61 mmol), TEA (4.86 g, 48.06 mmol),Pd(dppf)Cl 2 ·DCM (785.03 mg, 961.29 μmol) and MeOH (8.3 mL) were replaced with nitrogen for two times, and carbon monoxide was introduced to the pressure to reach a pressure of 1.0-1.2 MPa, and then the temperature was raised to 120° C. to react for 5 hours.After the reaction, the reaction solution was directly concentrated to dryness under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (EA/PE=1/4) to obtain compound 1-2 (1.6 g).
With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere; Irradiation; Green chemistry; regioselective reaction;
Procedure A for compounds (3a-3p) in Schemes 2
General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
61%
Stage #1: 5-bromoisoquinoline; 2,2-diethoxy acetic acid With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 20h; Inert atmosphere; Irradiation;
Stage #2: With hydrogenchloride In water; dimethyl sulfoxide for 20h;
3 The implementation of the example three, this embodiment a hydroformylation of the heterocyclic derivatives preparation method is as follows
At room temperature, will be 83 mg (0.4 mmol) 5-bromoquinoline, 414 mg (2.8 mmol) 2,2-diacetoxyacetic acid, 182 mg (0.8 mmol) of the ammonium persulfate and 260 mg (0.8 mmol) Cs2CO3Dissolved in 6 ml in dimethyl sulfoxide, mix, nitrogen 30 min after the blue LEDs arranged under the lamp illumination reaction 20 h, adding 7.2 concentration is 3 M hydrochloric acid catalytic hydrolysis 20 h, using sodium carbonate adjusting pH to neutral, extraction, the combined organic phase, by the rotary concentrate by the Rotavapor after turns on lathe does, then to the volume ratio of 20:1 petroleum ether: ethyl acetate mixed solution of eluant, performing silica gel column chromatography purification and separation, to obtain the corresponding formylation heterocyclic derivatives, its reaction is Product purity is 99%, and the yield is 61%
(5-bromoisoquinolin-1-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With ammonium peroxydisulfate; iridium(lll) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate In dimethyl sulfoxide at 20℃; for 12h; Inert atmosphere; Irradiation; Green chemistry; regioselective reaction;
Procedure B for compounds (5a-5z,5bb) in Schemes 3
General procedure: Heterocycle (0.10mmol, 1 equiv)ammonium persulfate (0.20 mmol, 2equiv),[Ir{dF(CF3ppy)}2(dtbbpy)]PF6 ( 0.2 mol%),α-keto acids(1.0mmol10equiv)wereplaced in a dry glass tube.Then, anhydrous DMSO1mLwereinjected into the tubeby syringe under a N2 atmosphere.The solution was then stirred at roomtemperatureunder the irradiation of 15W blue LEDs strip for 12h.After completion of thereaction,then saturated Na2CO3solution was added to adjust pH to basic.Thecombined organic layer was washed with brine and then dried overanhydrousNa2SO4.The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum andethylacetate.
76%
With sodium persulfate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate In water; acetonitrile at 20℃; Inert atmosphere; Sealed tube; Irradiation;
73%
With 2-hydroxy-N,N,N-trimethyl ethanaminium peroxydisulfate In water at 40℃; for 24h; Sealed tube;
To a solution of 3-bromobenzaldehyde (50.0 g,0.27 mol) in toluene (250 mE) was added aminoacetaldehyde dimethyl acetal (31.1 g, 0.30 mol) was stirred at room temperature for few minutes, then heated at 1000 C. overnight. The reaction solvent was evaporated to afford 3-bro- mobenzalaminoacetal (70 g, 95%) as yellow oil which was directly used to next step without thrther purification. To a solution of phosphorus pentoxide (140 g, 2v) in concentrated sulphuric acid (70 mE, lv) stirred at room temperature for few minutes, then stirred at 0 C., 3-bro- mobenzalaminoacetal (70 g, 0.26 mol) was added slowly to the mixture prepared above. Then the mixture was heated to 160 C. for 30 minutes. After cooling to room temperature, the reaction mixture was careffilly poured into ice water (100 mE) while vigorously stirred, then filtered, the pH was further increased to 9 using saturated sodium hydroxide and extracted with dichloromethane (100 mEx3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, and purified by silica gel (petroleum ether/ethyl acetate=6: 1) to give mixture of 7-bro- moisoquinoline and 5-bromoisoquinoline (15.0 g, 28%) as a yellow solid.
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium <i>tert</i>-butylate In toluene at 125℃; for 5h;
(Production of Compound (i))
To a flask, 2.08 g (10 mmol) of 5-bromoisoquinoline, 10 mL of toluene, 2.65 g (11 mmol) of bis(2-ethylhexyl)amine, 0.13 g (0.2 mmol) of a Pd catalyst (PEPPSI-IPr), and 1.34 g (12 mmol) of t-butoxypotassium were added, and a reaction was carried out at 120° C. for five hours. After the reaction was finished, solids in a reaction solution were removed by filtration, the filtrate was condensed, and then refinement was performed by a column chromatography method. As a result, a compound (i) (1.36 g, 3.7 mmol, yield: 37%) was obtained.
With ammonium peroxydisulfate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; toluene-4-sulfonic acid In dimethyl sulfoxide at 25℃; for 16h; Inert atmosphere; Sealed tube; Irradiation;
With ammonium peroxydisulfate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; toluene-4-sulfonic acid In dimethyl sulfoxide at 25℃; for 16h; Inert atmosphere; Sealed tube; Irradiation;
ethyl 2-isopropyl-5-(isoquinolin-5-yl)thiazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In N,N-dimethyl acetamide at 150℃;
5.1.2 Synthesis of 13a-13r
General procedure: In round bottom flask, added 12a (100mg, 0.5mmol) followed by 47 4-bromo-1,2-(methylenedioxy)benzene (0.45mmol), 13 PdCl2(PPh3)2 (5mol%) and 48 KOAc (0.5mmol) sequentially in dry 49 DMA (10ml). The reaction mixture was stirred at 150°C for 18h. The reaction mixture was diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer dried over Na2SO4, filtered and evaporated to give crude product which was finally purified by column chromatography to afford 50 13a.
(S)-2-chloro-4-(1-(2-(isoquinolin-5-ylamino)propyl)-1H-pyrazol-3-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.8%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 110℃; Inert atmosphere;
(S)-2-chloro-4-(1-(2-(quinolin-7-ylamino)propyl)-1H-pyrazol-3-yl)benzonitrile (3l)
General procedure: A suspension of intermediate 15(104.0 mg, 0.4 mmol), 7-bromoquinoline (124.8 mg, 0.6 mmol), t-BuONa (96.0 mg, 1.0 mmol), Pd2(dba)3 (18.0 mg, 0.019 mmol) andX-phos (9.6 mg, 0.02 mmol) in PhMe (2.8 ml) was degassed under astream of nitrogen over 10 min. The mixture was heated to 110 °Cand stirred overnight. The resulting mixturewas filtered off and thesolution was concentrated under vacuum. The crude product waspurified by column chromatography on silica using a solvent of 60%ethyl acetate in hexanes. Compound 3l was obtained as a lightgreen solid (Yield: 60.0 mg, 38.8%).
40 mg
With metformin hydrochloride; caesium carbonate In ethanol at 80℃;
22 Example 5. Synthesis of Compound SKLB-C 4651 in the Present Invention
General procedure: Intermediate (S)-4-(1-(2-aminopropyl) -1 H-pyrazol-3-yl)-2-chlorobenzonitrile was synthesized using the procedure described in Example 1 (C).Iodobenzene (100 mg, 0.48 mmol), (S)-4-(1-(2-aminopropyl) -1 H-pyrazol-3-yl)-2-chlorobenzonitrile (104.4 mg, 0.4 mmol), cesium carbonate (260.6 mg, 0.8 mmol), metformin hydrochloride (13.2 mg, 0.08 mmol) and ethanol (2 mL) were added to the reaction tube, nitrogen was pumped 3 times, heated to 80°C overnightCold to room temperature, brown. Ethyl acetate was diluted, washed with water, washed with saturated sodium chloride, and purified by column 25% ethyl acetate/petroleum ether via column to give 90 mg of an yellow viscous, ie, SKLB-C 4651
With tris(pentafluorophenyl)borate In chloroform-d1 at 20 - 110℃; for 2h; Inert atmosphere;
Synthesis of Cyclic Amidines 6 from Isoquinolines 4 and Tosyl Azide 10a (Scheme 2); General Procedure
General procedure: Step 1: Tris(pentafluorophenyl)borane (B(C6F5)3) catalyst (0.025 mmol, 5 mol%) in an NMR tube was dissolved in CDCl3 (0.5 mL) under argon atmosphere. MePhSiH2 (0.6 mmol, 1.2 equiv) was added at r.t. (H2 bubbles were evolved), and TCE (0.3 mmol) was added into the reaction mixture as internal standard. Isoquinoline 4a-k (0.5 mmol, 1.0 equiv) was subsequently added to the reaction mixture, which was then heated to 110 °C in an oil bath for the indicated time. The resulting mixture was subjected to NMR analysis to monitor the conversion. Step 2: To the resulting mixture from the first step in an NMR cell was added tosyl azide 10a (0.5 mmol, 1.0 equiv) at 0 °C and the mixture was warmed to r.t. (N2 bubbling was observed) with NMR spectra recorded every 2 h. The reaction was quenched with MeOH and the mixture was filtered through silica with CH2Cl2 washing. The resulting crude mixture was purified by column chromatography.
With tris(pentafluorophenyl)borate In chloroform-d1 at 110℃; for 2.5h;
Step 1:
General procedure: To a B(C6F5)3 catalyst (0.025 mmol, 5 mol%) in NMR tube was added CDCl3 (0.5 mL) andsilanes (0.6 mmol, 1.2 equiv.) at room temperature, H2 bubbles were observed and TCE (0.3 mmol) ormesitylene was added as internal standard. Isoquinolines (1a, 1i-1p) (0.5 mmol, 1.0 equiv.) wassubsequently added to the above solution and quickly shaken once before heating up to 110 C in oil bathfor indicated reaction time. The mixture was subjected to NMR to check conversion and yields ofreactions.
Stage #1: 5-bromoisoquinoline With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere;
Stage #2: Triisopropyl borate In tetrahydrofuran; hexane at 20℃; for 2h;
Stage #3: water With hydrogenchloride
1
6-(Benzyloxy)-5-(isoquinolin-5-yl)-N-phenylpyridin-3-amine (18). lsoquinolin-5-ylboronic acid was prepared from 5-bromoisoquinoline according to literature procedure (W02008006480). Anhydrous THF (19 ml.) was cooled to -78 °C then a 2.5 M n-butyllithium solution in hexane (1.2 ml_, 3.0 mmol, 1.25 eq.) was added under argon. A solution of 5-bromoisoquinoline (502 mg, 2.41 mmol, 1 eq.) in anhydrous THF (5 ml.) was added. The mixture was stirred at -78 °C for 1 h. Triisopropyl borate (0.70 ml_, 3.0 mmol, 1.25 eq.) was added dropwise and the mixture was stirred at room temperature for 2 h. A 5% aqueous NaOH solution (1 ml.) was slowly added to quench the reaction. Aqueous phase was acidified to pH 5 at 0 °C with a 10% aqueous HCI solution, then was extracted with EtOAc. The organic phase was dried over MgSC and filtered. After evaporation, the obtained solid was washed with diethyl ether to give isoquinolin-5-ylboronic acid (135.5 mg, 0.783 mmol, 32%).
With palladium diacetate; sodium hexamethyldisilazane; nixantphos In 2-methyltetrahydrofuran at 85℃; Inert atmosphere; chemoselective reaction;
General procedure for the coupling reaction
General procedure: A mixture of Pd(OAc)2 (5 mol %)and Nixantphos (7.5 mol %) in 2-MeTHF (1.25 mL) was stirred under an Argon atmosphere at r.t. for 2 h. Then, Erlotinib (1.0 equiv.), NaHMDS (2.5 equiv.) and aryl bromides (1.5 equiv.) were added subsequently to the stirred mixture. The mixture was stirred at 85 for 24 h. After cooling down to room temperature, the reaction mixture was quenched with 1.0 mL water, dried over anhydrous Na2SO4 filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford the desired products.
64 %
With palladium diacetate; sodium hexamethyldisilazane; nixantphos In 2-methyltetrahydrofuran at 85℃; Inert atmosphere; chemoselective reaction;
General procedure for the coupling reaction
General procedure: A mixture of Pd(OAc)2 (5 mol %)and Nixantphos (7.5 mol %) in 2-MeTHF (1.25 mL) was stirred under an Argon atmosphere at r.t. for 2 h. Then, Erlotinib (1.0 equiv.), NaHMDS (2.5 equiv.) and aryl bromides (1.5 equiv.) were added subsequently to the stirred mixture. The mixture was stirred at 85 for 24 h. After cooling down to room temperature, the reaction mixture was quenched with 1.0 mL water, dried over anhydrous Na2SO4 filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford the desired products.
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