* 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.
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
2
[ 67-66-3 ]
[ 121-69-7 ]
[ 91-22-5 ]
[ 612-59-9 ]
[ 19493-45-9 ]
[ 25836-11-7 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
3
[ 7742-73-6 ]
[ 19493-45-9 ]
Yield
Reaction Conditions
Operation in experiment
24%
With phosphorus; hydrogen iodide In water; acetic acid for 24 h; Reflux
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pΗ 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10percentEtOAc/hexanes) to provide 1.01 g (24percent) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
24%
With phosphorus; hydrogen iodide In water; acetic acid for 24 h; Reflux
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pΗ 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10percentEtOAc/hexanes) to provide 1.01 g (24percent) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
23%
Stage #1: With hydrogenchloride; tin; acetic acid In water at 55 - 60℃; for 3 h; Stage #2: With ammonia In water
EXAMPLE 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60° C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23percent).
Reference：
[1] Patent: WO2010/45401, 2010, A1, . Location in patent: Page/Page column 88
[2] Patent: WO2010/45402, 2010, A1, . Location in patent: Page/Page column 87
[3] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 30
[4] Chemische Berichte, 1886, vol. 19, p. 1655,2356
[5] Chemische Berichte, 1886, vol. 19, p. 1655,2356
[6] Journal of the Chemical Society, 1948, p. 777,781
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
[8] Patent: US4409017, 1983, A,
[9] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 136; 137
4
[ 7742-73-6 ]
[ 119-65-3 ]
[ 19493-45-9 ]
Yield
Reaction Conditions
Operation in experiment
71%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 25℃; for 2.5 h; Inert atmosphere
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 molpercent), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2014, vol. 393, p. 191 - 209
5
[ 25475-67-6 ]
[ 19493-45-9 ]
Yield
Reaction Conditions
Operation in experiment
51%
With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 3.08333 h;
Synthesis 4-1 -A 3-Chloroisoquinoline 3-Aminoisoquinoline (1.44 g, 10 mmol) was suspended in 10M HCI (5 mL) and cooled to 0°C. Sodium nitrite (689 mg, 10 mmol) was added in portions over 5 minutes. The reaction mixture was stirred at 0°C for 2 hours and allowed to warm to room temperature over 1 hour. The reaction mixture was added carefully to saturated NaHCO3 solution (200 mL) and extracted into ethyl acetate. The insoluble byproduct was removed by filtration and the aqueous layer was re-extracted into ethyl acetate. The combined organics were washed with water and brine, dried (Na2SO4) and concentrated to a brown oil which solidified on standing. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (827 mg, 5.05 mmol, 51percent). 1H <n="96"/>NMR (Cl6-DMSO, 400 MHz) δ 9.12 (s, 1 H), 8.41 (s, 1 H), 8.12 (dd, 1 H, J = 7.5, 1.0 Hz), 7.93-7.90 (m, 1 H), 7.84-7.80 (m, 1 H), 7.74-7.70 (m, 1 H). LCMS (1) Rt = 1.79min; m/z (ESI+) 164 (MH+).
With 3-chloro-benzenecarboperoxoic acid; In benzene;
A mixture of <strong>[19493-45-9]3-chloroisoquinoline</strong> (18.23 g), m-chloroperbenzoic acid (36.46 g) and benzene (180 ml) was stirred at ambient temperature for a period of 2.5 days. The mixture was diluted with dichloromethane and the resultant solution was washed several times with a aqueous 5% sodium bicarbonate solution and finally with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated to give a solid residue. The solid was recrystallized from ethyl acetate to give <strong>[19493-45-9]3-chloroisoquinoline</strong>-2-oxide (6.53 g) as colourless crystals mp 147-151 C.
With phosphorus; hydrogen iodide; In water; acetic acid; for 24.0h;Reflux;
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pEta 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10%EtOAc/hexanes) to provide 1.01 g (24%) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
24%
With phosphorus; hydrogen iodide; In water; acetic acid; for 24.0h;Reflux;
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pEta 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10%EtOAc/hexanes) to provide 1.01 g (24%) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
23%
EXAMPLE 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60 C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).
With phosphorus; hydrogen iodide; acetic acid;
(a) A mixture of 1,3-dichloroisoquinoline (26.0 g; prepared according to the method of G Simchen, Angew. Chem. Internat. Ed. 5 (7), 663, 1966), acetic acid (125 ml), hydrogen iodide (55 ml) and red phosphorus (9.0 g) was heated with stirring at a temperature of 170 C. for a period of 3 hours. After cooling the mixture was poured into ice-water and the aqueous mixture was neutralized with aqueous sodium hydroxide. The aqueous mixture was extracted with dichloromethane and the organic extract was dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give 3-chloroisoquinoline (18.23 g) mp<50 C.
Step-b product (5 g, 0.025 mol) was suspended in a mixture of glacial acetic acid (27.5 mL) and concentrated hydrochloric acid (9.7 mL). Tin powder was added to it and the mixture was heated at 55 0C for 3 hours. TLC showed complete consumption of starting material. The reaction mixture was filtered through sintered funnel and the filtrate was diluted with water. The overall filtrate was basified with ammonium hydroxide solution up to pH = 9 and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with sodium bi carbonate solution and brine. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the crude compound 4, which was directly taken to next step (yield: 2 g).
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 18.0h;
To a solution of Example 81A (LOO g, 6.11 mmol) in concentrated sulfuric acid (24 niL) at 0 0C was added a solution of potassium nitrate (0.655 g, 6.48 mmol) in concentrated sulfuric acid (6.48 mL). The reaction was stirred at 0 0C for 2 hours, then allowed to warm to ambient temperature and stirred an additional 16 hours. The reaction mixture was poured onto ice. The precipitate that formed was collected by filtration and dried to provide 1.29 g (100%) of the title compound. MS (DCI/NH3) m/z 208 (M+H)+.
100%
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 18.0h;
To a solution of Example 81A (LOO g, 6.11 mmol) in concentrated sulfuric acid (24 niL) at 0 0C was added a solution of potassium nitrate (0.655 g, 6.48 mmol) in concentrated sulfuric acid (6.48 mL). The reaction was stirred at 0 0C for 2 hours, then allowed to warm to ambient temperature and stirred an additional 16 hours. The reaction mixture was poured onto ice. The precipitate that formed was collected by filtration and dried to provide 1.29 g (100%) of the title compound. MS (DCI/NH3) m/z 208 (M+H)+.
90%
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 4.0h;
To a solution of <strong>[19493-45-9]3-chloroisoquinoline</strong> (2.0 g, 12.2 mmol) in concentrated sulfuric acid (48 mL) was added potassium nitrate (1.48 g, 14.6 mmol) in portions at 0 C. The resulting solution was stirred for 4 hours at ambient temperature and then poured onto ice-water (300 g). The precipitate wasd collected by filtration and dried to afford 3-chloro-5-nitroisoquinoline as a light yellow solid: MS (ESI, m/z): 209.0 [M + 1]+; 1H MR (300 MHz, DMSO- 6) delta 9.46 (s, 1H), 8.75-8.72 (m, 1H), 8.66-8.63 (m, 1H), 8.45(s, 1H), 7.94-7.89 (m, 1H).
28%
With KNO3; In sulfuric acid; water;
EXAMPLE 60D 3-chloro-5-nitroisoquinoline The product from Example 60C (1.28 g, 7.85 mmol) in concentrated H2SO4 (30 mL) at 0 C. was treated with a solution of KNO3 (0.84 g, 8.32 mmol) in concentrated H2SO4 (5 mL) dropwise over 5 minutes. The mixture was stirred at 0 C. for 10 minutes, allowed to warm to room temperature, and stirred overnight. The mixture was poured onto 65 g of ice and the precipitated yellow solid was collected by filtration. The solid was slurried in water, collected by filtration, washed with water, and allowed to air-dry to provide the title compound as a pale yellow solid (0.45 g, 28%).
28%
With KNO3; In sulfuric acid; water;
EXAMPLE 60D 3-chloro-5-nitroisoquinoline The product from Example 60C (1.28 g, 7.85 mmol) in concentrated H2SO4 (30 mL) at 0 C. was treated with a solution of KNO3 (0.84 g, 8.32 mmol) in concentrated H2SO4 (5 mL) dropwise over 5 minutes. The mixture was stirred at 0 C. for 10 minutes, allowed to warm to room temperature, and stirred overnight. The mixture was poured onto 65 g of ice and the precipitated yellow solid was collected by filtration. The solid was slurried in water, collected by filtration, washed with water, and allowed to air-dry to provide the title compound as a pale yellow solid (0.45 g, 28%).
28%
With sulfuric acid; potassium nitrate; at 0 - 20℃;
EXAMPLE 60D 3-chloro-5-nitroisoquinoline The product from Example 60C (1.28 g, 7.85 mmol) in concentrated H2SO4 (30 mL) at 0 C. was treated with a solution of KNO3 (0.84 g, 8.32 mmol) in concentrated H2SO4 (5 mL) dropwise over 5 minutes. The mixture was stirred at 0 C. for 10 minutes, allowed to warm to room temperature, and stirred overnight. The mixture was poured onto 65 g of ice and the precipitated yellow solid was collected by filtration. The solid was slurried in water, collected by filtration, washed with water, and allowed to air-dry to provide the title compound as a pale yellow solid (0.45 g, 28%).
28%
With KNO3; In sulfuric acid; water;
Example 60D 3-chloro-5-nitroisoquinoline The product from Example 60C (1.28 g, 7.85 mmol) in concentrated H2SO4 (30 mL) at 0 C. was treated with a solution of KNO3 (0.84 g, 8.32 mmol) in concentrated H2SO4 (5 mL) dropwise over 5 minutes. The mixture was stirred at 0 C. for 10 minutes, allowed to warm to room temperature, and stirred overnight. The mixture was poured onto 65 g of ice and the precipitated yellow solid was collected by filtration. The solid was slurried in water, collected by filtration, washed with water, and allowed to air-dry to provide the title compound as a pale yellow solid (0.45 g, 28%).
With sulfuric acid; potassium nitrate; at -15℃; for 12.5h;
To a stirred solution of crude step-c product (17 g, 0.104 mol) in concentrated sulfuric acid (10 mL) was added pottasium nitrate (11 g, 0.109 mol) in concentrated sulfuric acid solution slowly at -15 0C in 30 minutes. It was allowed to stir for 12 hours. After complete conversion the reaction mixture was poured into crushed ice. A yellow precipitate came out which was filtered and washed with water (3 x 50 mL). The solid was dried under vacuum at 80 0C to afford 20 crude compound.
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 16.0h;
j00295j To a solution of 3 -chloroisoquinoline (0.50 g, 3.1 mmol) in concentrated sulfuric acid (10 mL) at 0 C was added a solution of potassium nitrate (0.34 g, 3.4 mmol) in concentrated sulfuric acid (5 mL). The mixture solution was stirred at 0 C for 2 hours and at room temperature for another 14 hours. On completion, the mixture was poured into ice-water (30 mL), resulting in formation of a precipitate. The precipitate was collected by filtration and dried in vacuo to give compound B-il (0.6 g, cmde) as a yellow solid. ?H-NMR (CDC13, 400 MHz): 9.25 (s, 1H), 8.70-8.66 (m, 2H), 8.35 (d, J=8 Hz, 1H), 7.76 (t, J=8 Hz, 1H).
With potassium nitrate; In sulfuric acid;
EXAMPLE 1 This example illustrates the preparation of 3-chloro-5-nitro-isoquinoline having the formula: SPC6 <strong>[19493-45-9]3-chloro-isoquinoline</strong> (16.35 g., 0.1 mole) was dissolved in concentrated sulphuric acid (80 ml) and the solution was cooled to approximately 5C in an ice-water bath. Potassium nitrate (11 g. 0.11 mole) was dissolved in concentrated sulphuric acid (60 ml), the solution was cooled to approximately 5C and added dropwise, with stirring, over a period of 2 hours to the <strong>[19493-45-9]3-chloro-isoquinoline</strong> solution, the temperature of the reaction mixture being maintained in the region of from 3 to 8C by means of the ice-water bath. The bath was then removed and the mixture stirred for a further 2 hours, and allowed to stand overnight. Next day the reaction mixture was poured into a water (800 ml)-ice (800 g.) mixture, and 3-chloro-5-nitro-isoquinoline precipitated as fine white crystals. The precipitate was filtered off, slurried with water, filtered again, washed thoroughly with water, and then recrystallized from a 3:1 v/v mixture of ethanol/acetone to yield 16.33 g. of 3-chloro-5 -nitro-isoquinoline of melting point 163 - 164C.
EXAMPLE 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60 C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).
With hydrogenchloride; In acetic acid;
Example 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60 C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).
3-(4-(2-Hydroxyethyl)-piperazin-1-yl)-isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 3 3-(4-(2-Hydroxyethyl)-piperazin-1-yl)-isoquinoline Prepared analogously to Example 1 from <strong>[19493-45-9]3-chloroisoquinoline</strong> and N-(2-hydroxyethyl)-piperazine. Melting point of base 134-136 C.; melting point of dihydrochloride 282-283 C. The 3-substituted isoquinolines of the examples in Table 1 are prepared as above from the <strong>[19493-45-9]3-chloroisoquinoline</strong>s and the corresponding bases.
Intermediate 23 :3-(piperazin-l-yl)isoquinoline[00436] A mixture of <strong>[19493-45-9]3-chloroisoquinoline</strong> (200 mg, 1.22 mmol) and piperazine (2.10 g, 24.4 mmol) in ethylene glycol (2 ml) was heated to 150C and stirred at that temperature for 24 hours. The reaction was allowed to cool down to room temperature. The crude mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuo. The residue was and purified on silica gel by flash column chromatography to give the title compound as a pale brown solid (131 mg, 50% yield).[00437 ] 1H NMR (CDCl3, 400 MHz) delta 3.18 (4H, t), 3.67 (4H, t), 6.81 (IH, s), 7.31 (IH, t), 7.54 (1 H, t), 7.62 (IH, d), 7.82 (IH, d), 8.97 (IH, s); MS (ES+) 214.
In diethylene glycol dimethyl ether;
EXAMPLE 2 3-(Piperazin-1-yl)-isoquinoline 2.0 g of <strong>[19493-45-9]3-chloroisoquinoline</strong> are boiled under reflux for 120 hours with 20 g of piperazine in 100 ml of diethylene glycol dimethyl ether. Working up as in Example 1 gives 2.4 g of 3-(piperazin-1-yl)-isoquinoline, melting point 95-96; its hydrochloride decomposes at 266-268 C.
EXAMPLE 1 3-(4-Methylpiperazin-1-yl)-isoquinoline 6.5 g of <strong>[19493-45-9]3-chloroisoquinoline</strong> in 30 ml of N-methylpiperazine are boiled under reflux for 48 hours. The reaction mixture is cooled and partitioned between water and toluene, the toluene phase is washed thoroughly with water and, after drying, the solvent is removed in vacuo. The residue is recrystallized from diisopropyl ether, giving 3.8 g of 3-(4-methylpiperazin-1-yl)-isoquinoline, melting point 93-94 C.; the dihydrochloride decomposes at 255-257 C.
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; toluene; at 140℃;Microwave irradiation; Inert atmosphere;
Synthesis 4-1 -B3-(1-(Dimethylamino)propan-2-yloxy)-5-(isoquinolin-3-ylamino)pyrazine-2-carbonitrile(AA-001) A mixture of palladium (II) acetate (24 mg, O.Hmmol) and (+/-)-2,2"- bis(diphenylphosphino)-1 ,1"-binaphthalene (140 mg, 0.22 mmol) in toluene (2 ml_) was degassed under a stream of nitrogen gas with stirring for 10 minutes. After addition of 3- chloroisoquinoline (59 mg, 0.36 mmol), 5-amino-3-(1-(dimethylamino)propan-2- yloxy)pyrazine-2-carbonitrile (80 mg, 0.36 mmol) in DMF (0.5 ml_), and sodium tert- butoxide (42 mg, 0.43 mmol), the mixture was degassed for a further 5 minutes and then heated at 140C for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. Preparative HPLC gave the title compound (8.9 mg, 0.026 mmol, 7%). 1H NMR (d6-DMSO, 400 MHz) delta 9.22 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1 H), 8.09 (d, 1H1 J = 9.1 Hz), 7.84 (d, 1 H1 J = 8.1 Hz), 7.77-7.73 (m, 1 H), 7.58-7.54 (m, 1 H), 5.53-5.49 (m, 1H), 2.67-2.63 (m, 1 H), 2.34-2.32 (m, 1 H), 2.21 (s, 6H), 1.46 (d, 3H, J = 6.3 Hz). LC-MS (2) Rt = 2.93 min m/z (ESI-) 347 (M-H).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; toluene; at 100 - 130℃;Microwave irradiation; Inert atmosphere;
Synthesis 21-1 -AEthyl 2-(3-cyano-6-(isoquinolin-3-ylamino)pyrazin-2-yloxy)acetate (AA-068) A mixture of tris(dibenzylideneacetone)dipalladium (0) (39 mg, 0.043 mmol) and 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (50 mg, 0.086 mmol) in toluene (1.5 mL) and DMF (1.5 mL) was degassed under a stream of nitrogen gas with stirring for15 minutes. 3-Chloroisoquinoline (70 mg, 0.428 mmol), caesium carbonate (279 mg, 0.856 mmol) and ethyl 2-(6-amino-3-cyanopyrazin-2-yloxy)acetate (105 mg, 0.471 mmol) were added and the mixture was degassed for a further 5 minutes. The mixture was then heated at 100C for 20 minutes, then at 13OC for 20 minutes in a microwave reactor. The reaction mixture was partitioned between aqueous Na2HCO3 solution (2.5%) and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4), passed sequentially through two PS-Thiol cartridges and concentrated to dryness. The residue was triturated with methanol and then ether affording ethyl 2-(3-cyano-6-(isoquinolin-3-ylamino)pyrazin-2- yloxy)acetate (37 mg, 0.107 mmol, 25%). LC-MS (2) Rt 2.89 min; m/z (ESI+) 350 (M+H).
With hydrogenchloride; sodium nitrite; In water; at 0 - 20℃; for 3.08333h;
Synthesis 4-1 -A 3-Chloroisoquinoline 3-Aminoisoquinoline (1.44 g, 10 mmol) was suspended in 10M HCI (5 mL) and cooled to 0°C. Sodium nitrite (689 mg, 10 mmol) was added in portions over 5 minutes. The reaction mixture was stirred at 0°C for 2 hours and allowed to warm to room temperature over 1 hour. The reaction mixture was added carefully to saturated NaHCO3 solution (200 mL) and extracted into ethyl acetate. The insoluble byproduct was removed by filtration and the aqueous layer was re-extracted into ethyl acetate. The combined organics were washed with water and brine, dried (Na2SO4) and concentrated to a brown oil which solidified on standing. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (827 mg, 5.05 mmol, 51percent). 1H <n="96"/>NMR (Cl6-DMSO, 400 MHz) delta 9.12 (s, 1 H), 8.41 (s, 1 H), 8.12 (dd, 1 H, J = 7.5, 1.0 Hz), 7.93-7.90 (m, 1 H), 7.84-7.80 (m, 1 H), 7.74-7.70 (m, 1 H). LCMS (1) Rt = 1.79min; m/z (ESI+) 164 (MH+).
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃; for 12.0h;Inert atmosphere;
Tris(dibenzylideneacetone)dipalladium (0) (0.05 g, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.015 g, 0.03 mmol), cesium carbonate (0.5 g, 2.0 mmol) and <strong>[19493-45-9]2-chloroquinoline</strong> (0.085 g, 0.52 mmol) were added sequentially to a stirred solution of N-[1-(4-amino-benzenesulfonyl)-piperidin-4-yl]-acrylamide in dry dioxane (5 ml) under a nitrogen atmosphere. The mixture was heated to 110 C. for 12 hours. After this time the mixture was cooled to room temperature, filtered through a pad of celite, the celite was washed with EtOAc (50 ml) and the filtrate was washed sequentially with citric acid (10% solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by prep HPLC to give the title compound (0.002 g, 0.5% yield) as a white solid.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 25℃; for 2.5h;Inert atmosphere;
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 mol%), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 60℃; for 8.0h;Inert atmosphere;
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 mol%), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 18h;Inert atmosphere; Sealed tube;
Example 3b 3-(isoquinolin-3-yl)-4-methylaniline To a round-bottom flask containing 5-amino-2-methyl-phenylboronic acid pinacol ester (233 mg, 1 mmol), <strong>[19493-45-9]3-chloro-isoquinoline</strong> (2-(5 mg, 1.5 mmol), Pd(PPh3)4 (128 mg, 0.1 mmol) is added toluene (4 ml), EtOH (1 ml) and aqueous 2M Na2CO3 solution (2 ml). The flask is purged with argon and sealed. The mixture is stirred at 90 C. for 18 hours, cooled to room temperature and extracted using water and ethyl acetate. The organic layer is separated, washed with brine, dried over MgSO4 and concentrated. The residue is subjected to silica gel flash chromatography, eluted with ethyl acetate in hexanes from 30% to 50% to afford 3-(isoquinolin-3-yl)-4-methylaniline as a brown oil. LC-MS m/z: 235.1 (M+1).
(4aR,6S,8aS)-8a-(2-fluoro-5-(isoquinolin-3-yloxy)phenyl)-2-imino-3,6-dimethylhexahydro-1H-pyrano[3,4-d]pyrimidin-4(4aH)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 100℃; for 14.0h;
Method AA Step 1 A mixture of F6 (20.0 mg, 0.049 mmol), Cul (3.7 mg, 0.019 mmol), 3- chloroisoquinoline (16.1 mg, 0.098 mmol), N,N-dimethylglycine (4.1 mg, 0.039 mmol) and Cs2C03 (35.2 mg, 0.108 mmol) in dioxane (3 mL) was stirred at 100 C for 14 h. The reaction mixture was quenched with water and extracted with EtOAc (15 mL x 4). The combined extracts were washed with brine (10 mL), dried over Na2S04, filtered and the filtrate was concentrated in vacuo. The residue was purified by p-HPLC (TFA condition) to give Example 77.
tert-butyl 3-(isoquinolin-3-ylamino)-2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.4 g
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; ruphos; In toluene; at 20 - 110℃; for 2.5h;
To a solution of tert-butyl 3-amino-2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (0.700 g, 2.944 mmol) in toluene (5 ml) was added <strong>[19493-45-9]3-chloroisoquinoline</strong> (CAS Number 19493-45-9; 0.400 g, 2.453 mmol), potassium tert-butoxide (0.549 g, 4.906 mmol) and Ru-Phos (0.114 g, 0.245 mmol) at rt. The reaction mixture was degassed for 15 min before addition of Pd2(dba)3 (0.224 g, 0.245 mmol). The reaction mixture was heated at 110C for 2.5 h. The resulting reaction mixture was cooled to rt. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (4 x 20 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (62% EtOAc in hexane) yielding tert-butyl 3-(isoquinolin-3-ylamino)-2-methyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (0.400 g, 1.095 mmol). LCMS: Method 1, 2.295 min, MS: ES+ 366.33.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In Dimethyl ether; water; for 24.0h;Inert atmosphere; Reflux;
Compound A1 (5 mmol) and compound B1 (6 mmol) were weighed into a three-neck flask and Pd(pph3)4 (0.15 mmol) was added as a catalyst.K2CO3 (16 mmol) was added, vacuum was applied to the double-row tubes, nitrogen-filled vacuum was applied, and the mixture was recycled three times. Finally, the reaction system was protected with nitrogen.Add 15 mL each of dimethyl ether and water with a syringe and heat to reflux. The reaction was refluxed for 24 h and cooled to room temperature. After vortexing, the column was purified and product 11 was obtained.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In Dimethyl ether; water; for 24.0h;Inert atmosphere; Reflux;
Compound A1 (5 mmol) and compound B5 (6 mmol) were weighed into a three-necked flask, Pd(pph3)4 (0.15 mmol) was added as a catalyst, and K2CO3 (16 mmol) was added.In a double-row tube, vacuum-nitrogen gas-vacuum was evacuated and the cycle was repeated three times. Finally, the reaction system was protected with nitrogen gas.Add 15 mL each of dimethyl ether and water with a syringe and heat to reflux.The reaction was refluxed for 24 h and cooled to room temperature. After vortexing, the column was purified to give the product 51.
With platinum(IV) oxide; trifluorormethanesulfonic acid; hydrogen; trifluoroacetic acid; at 28℃; for 15.0h;
A mixed solvent of 10 ml of trifluoroacetic acid and 3 ml of trifluoromethanesulfonic acid was added to the reaction vessel, 1 g of <strong>[19493-45-9]3-chloroisoquinoline</strong> and 42 mg of platinum dioxide, were replaced with hydrogen, and the mixture was stirred at normal pressure for 28C degree for 15 hours. The catalyst is concentrated to remove the mixed solvent, and the residue is added with methyl tert-butyl ether, and the mixture is adjusted to pH 9 with saturated sodium hydrogencarbonate, and then purified by concentrated column chromatography to give 3-chloro-5,6,7,8-tetrahydroisoquine. The porphyrin product (light yellow oil 0.85 g, yield 83%).
With [bis(acetoxy)iodo]benzene; pentafluorobenzoylchloride; In 1,2-dichloro-ethane; at 50℃; for 17.0h;
General procedure: To an 8 mL dram vial was added iodobenzene diacetate (0.6 mmol, 1.5 equiv), and heteroarene(0.4 mmol, 1 eq.), anhydrous dichloroethane (1 mL), then chloride source (5 equiv). The solutionwas allowed to stir (1000 rpm) at 50 C for the indicated amount of time. After which the solutionwas washed with saturated sodium bicarbonate, followed by saturated sodium thiosulfate andconcentrated. The crude mixture was then purified by column chromatography.
N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1-yl}methyl)isoquinolin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃;
{2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 300 mg, 1 .39mmol), 3- chloroisoquinoline (249.57 mg, 1.53 mmol), sodium tert-butoxide (266.55 mg, 2.77 mmol) and [1 -(2-diphenylphosphino-1 -naphthalenyl)-2-naphthalenyl]-diphenylphosphine (86.35 mg, 0.140 mmol) were dissolved in Toluene (5 ml_) and degassed for 10 min, then Pd2(dba)3 (38.1 mg, 0.040 mmol) was added. The resulting mixture was stirred at 100 C overnight. The day after it was cooled to RT and diluted with water and EtOAc. The organic phase was dried and evaporated, the residue was purified by FC on NH column (eluting from cHex to 50% EtOAc) to afford N-({2-benzyl-2-azabicyclo[3.1 .1 ]heptan-1 - yl}methyl)isoquinolin-3-amine (p35, 300 mg, y= 63%). MS (/T7/z): 344.1 [MH]+.
(R)-tert-butyl 3-(isoquinolin-3-ylamino)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 6.0h;
To a solution of <strong>[19493-45-9]3-chloroisoquinoline</strong> (200 mg, 1.22 mmol) in dioxane (10 mL) was added (R )-tert- butyl 3-aminopiperidine-l-carboxylate (269 mg, 1.34 mmol), CS2CO3 (795 mg, 2.44 mmol), Pd(OAc)2 (27 mg, 0.12 mmol), BINAP (75 mg, 0.12 mmol). The mixture was stirred at 100 C for 6 h and concentrated in vaccuo. The residue was purified by silica gel chromatography (PE/EA=3/l) to afford (R)-/er/-butyl 3-(isoquinolin-3-ylamino)piperidine-l-carboxylate (360 mg, 90%). MS Calcd.: 327, MS Found: 328 ([M+H]+).
(R)-tert-butyl 3-(isoquinolin-3-ylamino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 6.0h;
To a solution of <strong>[19493-45-9]3-chloroisoquinoline</strong> (250 mg, 1.53 mmol) in dioxane (10 mL) was added (R )-tert- butyl 3-aminopyrrolidine-l-carboxylate (285 mg, 1.53 mmol), Cs2C03 (997 mg, 3.06 mmol), Pd(OAc)2 (35 mg, 0.153 mmol) and BINAP (188 mg, 0.306 mmol). The mixture was stirred at 100 C for 6 h and concentrated. The residue was purified by silica gel chromatography (PE/EA=3 : l) to afford (R)-fert-butyl 3-(isoquinolin-3-ylamino)pyrrolidine-l-carboxylate (400 mg, 84%). MS Calcd.: 313 MS Found: 314 ([M+H]+).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
