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Product Details of [ 34784-04-8 ]

CAS No. :34784-04-8 MDL No. :MFCD01646405
Formula : C9H6BrN Boiling Point : -
Linear Structure Formula :- InChI Key :CYJZJGYYTFQQBY-UHFFFAOYSA-N
M.W :208.05 Pubchem ID :736487
Synonyms :

Calculated chemistry of [ 34784-04-8 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 49.44
TPSA : 12.89 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.59 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.02
Log Po/w (XLOGP3) : 2.79
Log Po/w (WLOGP) : 3.0
Log Po/w (MLOGP) : 2.3
Log Po/w (SILICOS-IT) : 3.17
Consensus Log Po/w : 2.65

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.56
Solubility : 0.0573 mg/ml ; 0.000275 mol/l
Class : Soluble
Log S (Ali) : -2.72
Solubility : 0.399 mg/ml ; 0.00192 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.56
Solubility : 0.00574 mg/ml ; 0.0000276 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.19

Safety of [ 34784-04-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 34784-04-8 ]

* 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.

  • Upstream synthesis route of [ 34784-04-8 ]
  • Downstream synthetic route of [ 34784-04-8 ]

[ 34784-04-8 ] Synthesis Path-Upstream   1~36

  • 1
  • [ 34784-04-8 ]
  • [ 68-12-2 ]
  • [ 80278-67-7 ]
YieldReaction ConditionsOperation in experiment
64% 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
  • 2
  • [ 34784-04-8 ]
  • [ 23687-27-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 4972 - 4982
[2] Patent: US2004/157849, 2004, A1,
[3] Patent: WO2009/130481, 2009, A1,
  • 3
  • [ 34784-04-8 ]
  • [ 34784-07-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 4972 - 4982
[2] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 4
  • [ 34784-04-8 ]
  • [ 34784-07-1 ]
  • [ 91-21-4 ]
  • [ 75416-50-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 5
  • [ 119-65-3 ]
  • [ 34784-04-8 ]
YieldReaction ConditionsOperation in experiment
81%
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.

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[2] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 105-106
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[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
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  • 6
  • [ 1125-60-6 ]
  • [ 34784-04-8 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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] Patent: US2003/83352, 2003, A1,
[2] Patent: US2002/119963, 2002, A1,
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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 ]
YieldReaction ConditionsOperation 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] Patent: US2003/114422, 2003, A1,
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Reference: [1] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 1054; 1055; 1056; 10567
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  • [ 81237-69-6 ]
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Reference: [1] Organometallics, 2018, vol. 37, # 4, p. 584 - 591
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  • [ 81045-39-8 ]
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 ]
YieldReaction ConditionsOperation 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,
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Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 14, p. 2358 - 2363
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Reference: [1] Patent: US2002/6923, 2002, A1,
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  • [ 63927-22-0 ]
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Reference: [1] Synthesis, 2002, # 1, p. 83 - 86
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Reference: [1] Phosphorus, Sulfur and Silicon and Related Elements, 2000, vol. 164, p. 131 - 143
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Reference: [1] Patent: EP2876107, 2015, A1,
[2] Patent: US2015/191450, 2015, A1,
  • 19
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  • [ 63927-23-1 ]
YieldReaction ConditionsOperation in experiment
99% at 20℃; for 1.5 h; 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

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[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
  • 22
  • [ 3132-99-8 ]
  • [ 22483-09-6 ]
  • [ 34784-04-8 ]
  • [ 58794-09-5 ]
Reference: [1] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 1054; 1055; 1056; 10567
  • 23
  • [ 34784-04-8 ]
  • [ 63927-22-0 ]
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 ]
YieldReaction ConditionsOperation 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
Reference: [1] Patent: US2013/296320, 2013, A1,
[2] Patent: WO2016/201052, 2016, A1,
[3] Patent: US2017/137385, 2017, A1, . Location in patent: Paragraph 0203; 0204; 0205; 0206
  • 26
  • [ 119-65-3 ]
  • [ 34784-04-8 ]
  • [ 81045-39-8 ]
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
  • 27
  • [ 119-65-3 ]
  • [ 34784-04-8 ]
  • [ 63927-22-0 ]
  • [ 81045-39-8 ]
Reference: [1] Synthesis, 2002, # 1, p. 83 - 86
  • 28
  • [ 34784-04-8 ]
  • [ 34784-07-1 ]
  • [ 91-21-4 ]
  • [ 75416-50-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 29
  • [ 34784-04-8 ]
  • [ 81237-69-6 ]
YieldReaction ConditionsOperation in experiment
40% 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: 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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
Reference: [1] Patent: WO2005/72732, 2005, A1, . Location in patent: Page/Page column 61
[2] Patent: WO2008/6480, 2008, A1, . Location in patent: Page/Page column 5-6
  • 33
  • [ 34784-04-8 ]
  • [ 5419-55-6 ]
  • [ 371766-08-4 ]
YieldReaction ConditionsOperation in experiment
58%
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).
Reference: [1] Patent: EP2048133, 2009, A1, . Location in patent: Page/Page column 4
  • 34
  • [ 34784-04-8 ]
  • [ 121-43-7 ]
  • [ 371766-08-4 ]
Reference: [1] Heterocycles, 2005, vol. 65, # 10, p. 2505 - 2511
  • 35
  • [ 34784-04-8 ]
  • [ 679433-94-4 ]
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
  • 36
  • [ 34784-04-8 ]
  • [ 852570-80-0 ]
Reference: [1] Patent: US2013/310391, 2013, A1,
[2] Patent: WO2016/201052, 2016, A1,
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