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CAS No. : | 1125-60-6 | MDL No. : | MFCD00006907 |
Formula : | C9H8N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DTVYNUOOZIKEEX-UHFFFAOYSA-N |
M.W : | 144.17 | Pubchem ID : | 70766 |
Synonyms : |
|
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 : | 1.0 |
Molar Refractivity : | 46.15 |
TPSA : | 38.91 Ų |
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) : | -6.17 cm/s |
Log Po/w (iLOGP) : | 1.27 |
Log Po/w (XLOGP3) : | 1.42 |
Log Po/w (WLOGP) : | 1.82 |
Log Po/w (MLOGP) : | 0.92 |
Log Po/w (SILICOS-IT) : | 1.77 |
Consensus Log Po/w : | 1.44 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.3 |
Solubility : | 0.721 mg/ml ; 0.005 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.84 |
Solubility : | 2.08 mg/ml ; 0.0144 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.32 |
Solubility : | 0.0693 mg/ml ; 0.000481 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
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). |
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)+. |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.5 g | With hydrogenchloride; potassium iodide; sodium nitrite In water at 0℃; for 1 h; Reflux | Step A - Preparation of Int Int 58-1 To a solution of 5-aminoisoquinoline (14 g, 97.2 mmol) in HCI/H2O (40 mL/ 40 mL) was added a 02 (8 g, 1 16 mmol) by portions at 0°C. The mixture was stirred at 0°C for 1 hour then Kl (32 g, 194 mmol) was added slowly and the mixture was refluxed overnight. After cooling to room temperature, the mixture was poured into NH4OH (40 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried and concentrated. The residue was purified by column chromatography (EtOAc : Petroleum Ether = 1 : 10) to give Int 58-1 (6.5 g). MS (ESI): m/z (M+H)+ 256. |
6.5 g | Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 1 h; Stage #2: With potassium iodide In water at 0℃; Reflux |
Step A - Preparation of Int 58-1 Int 58-1 To a solution of 5-aminoisoquinoline (14 g, 97.2 mmol) in HC1/H20 (40 mL/ 40 mL) was added NaN02 (8 g, 116 mmol) by portions at 0°C. The mixture was stirred at 0°C for 1 hour then KI (32 g, 194 mmol) was added slowly and the mixture was refluxed overnight. After cooling to room temperature, the mixture was poured into NH4OH (40 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried and concentrated. The residue was purified by column chromatography (EtOAc : Petroleum Ether = 1 : 10) to give Int 58-1 (6.5 g). MS (ESI): m/z (M+H)+ 256. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: at 80℃; for 4 h; Stage #2: With sodium hydroxide In waterAlkaline aqueous solution |
EXAMPLE 73A 8-bromoisoquinolin-5-amine 5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, 113 mmol) were combined and heated at 80° C. in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glass funnel and the vapour diffused onto the complex over a period of 2 hours. Heating was continued for 2 hours. The suspension was added portionwise to crushed ice and the solution basified with concentrated NaOH solution. The aqueous layer was extracted with ethyl acetate (4*100 mL) and the layers were separated. The organic layers were combined, dried (Na2SO4), filtered and the filtrate was concentrated to give a grey solid. The grey solid was subjected to column chromatography (hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g, 35percent). MS (ESI+) m/z 225 (M+H)+; MS (ESI-) m/z 223 (M-H)-; 1H NMR (CDCl3, 300 MHz) δ 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 1H), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8, 1H), 9.56 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | With palladium 10% on activated carbon; hydrogen; at 20℃; for 1h; | In a 100 ml round bottom flask,To a solution of 1.31 g (7.52 mmol) of 5-nitroquinolineIn 50 mL of methanol,262 mg of 10% palladium on carbon was added.The air in the round bottom flask was taken out,Rushed into the hydrogen, repeated three times.Reduction was carried out at room temperature for 1 hour,The reaction solution was filtered through a small portion of diatomaceous earth to remove the palladium carbon,Vacuum distillation,To give an off-white solid,I.e., 1.08 g of 5-aminoisoquinoline (2)Yield:> 99%. |
95% | With hydrazine hydrate; In ethanol; at 20℃; under 760.051 Torr; for 0.333333h; | General procedure: TAPEHA-Pd (0.015 g) was added to a solution of nitroarenes (1.0 mmol) in EtOH (20 mL). After N2H4 .H2O(4.0 mmol) was added the color of the catalyst was turned to black rapidly in the same way as reducing with NaBH4 . This color change means formation of palladium nanoparticles43 TAPEHA-PdNPs as mentioned above. After being stirred for 20 min at room temperature and atmospheric pressure, the catalyst was removedby ltering and EtOH was removed under a vacuum. |
94% | With sodium tetrahydroborate; In ethanol; water; at 25℃; for 4h; | General procedure: SAC (300mg) and NaBH4 (4.0mmol) were added to a solution of nitroarenes (1.0mmol) in EtOH/water (1/1) (20ml). The reaction mixture was stirred for 4h at the temperature indicated in Table3. At the end of the reaction, the catalyst was removed by filtering and the filtrate was extracted with 3×70ml EtOAc. The combined organic layers were dried over MgSO4 and concentrated in a vacuum. |
80% | With sodium tetrahydroborate; In methanol; water; at 0 - 50℃; for 2.5h; | General procedure: A mixture of nitroarene (1 mmol), SS-Pd (2 mol% Pd) and sodium borohydride (3 mmol) were taken in a 25 ml round bottomed flask. 3 ml of MeOH:H2O (3:7) was added to the mixture by a syringe at 0 oC in stirring condition. After 10 minutes the reaction mixture was heated to 50 oC. Progress of the reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Na2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines. |
73% | With tetrahydroxydiboron; copper diacetate; In acetonitrile; at 80℃; for 24h;Schlenk technique; | General procedure: A 20 mL Schlenk tube was charged with 8-nitroquinoline (1k; 87 mg, 0.5 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol), B2(OH)4(135 mg, 1.5 mmol), and MeCN (2.0 mL). The mixture was stirred at 80 C for 24 h, then cooled to room temperature and concentrated under reduced pressure. Similar workup to 2a gave a brown solid (4a: 63 mg, 87% yield). |
71% | With tetrahydroxydiboron; 5%-palladium/activated carbon; water; In acetonitrile; at 50℃; for 24h; | General procedure: Nitrobenzene (0.6mmol), 5wt% Pd/C (0.5mmol %, 0.003mmol), H2O (10 equiv, 6.0mmol), B2(OH)4 (3.3 equiv, 2.0mmol), and CH3CN (1.0mL) were added in a 10mL tube. The reaction mixture was stirred at 50C for 24h. When the reaction was complete monitored by TLC, the mixture was cooled to room temperature. Water (5mL) was added, and extracted with EtOAc (3×5mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give aniline 2a (55mg, 99%). |
54% | With iron; ammonium chloride; In ethanol; water; at 80℃; for 10h; | To a solution of <strong>[607-32-9]5-nitro-isoquinoline</strong> (150g, 0.861 mol) in EtOH/H20=4:1 (5L) was added NH4CI (92.2g, 1 .723mol) and Fe (193g, 3.445mol) at room temperature. Then the mixture was heated to 80 C and stirred for 10 hours. TLC (petroleum ether: ethyl acetate= 1 : 1 ) showed the reaction was complete. The mixture was cooled to room temperature and filtered though a pad of celite. The filter cake was washed with EtOH (2L x 2). The filtrate was concentrated in vacuo to remove most of EtOH. The residue was extracted with EtOAc (500ml x 10).The combined layers were dried over Na2S04, filtered and then concentrated in vacuo to afford 5-amino-isoquinoline (67 g, 54%) as a yellow solid. |
54% | With iron; ammonium chloride; In ethanol; water; at 20 - 80℃; for 10h; | To a solution of <strong>[607-32-9]5-nitro-isoquinoline</strong> (150 g, 0.861 mol) in EtOH/H2O=4:1 (5 L) was added NH4Cl (92.2 g, 1.723 mol) and Fe (193 g, 3.445 mol) at room temperature. Then the mixture was heated to 80 C. and stirred for 10 hours. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was cooled to room temperature and filtered though a pad of celite. The filter cake was washed with EtOH (2 L*2). The filtrate was concentrated in vacuo to remove most of EtOH. The residue was extracted with EtOAc (500 ml*10). The combined layers were dried over Na2SO4, filtered and then concentrated in vacuo to afford 5-amino-isoquinoline (67 g, 54%) as a yellow solid. |
54% | With iron; ammonium chloride; In ethanol; water; at 20 - 80℃; for 10h; | To a solution of <strong>[607-32-9]5-nitro-isoquinoline</strong> (150 g, 0.861 mol) in EtOH/H20=4:1 (5 L) was added NH4CI (92.2 g, 1.723 mol) and Fe (193 g, 3.445 mol)at room temperature. Then the mixture was heated to 80C and stirred for 10 hours. TLC (petroleum ether: ethyl acetate= 1: 1) showed complete conversion. The mixture was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with EtOH (2 L x 2) and the filtrate concentrated under vacuum. The residue was extracted with EtOAc (500 mL x 10) and the combined layers dried over Na2SO4, filtered and then concentrated under vacuum to afford 5-amino-isoquinoline (67 g, 54%) as a yellow solid. |
81.24 g (98%) | aluminum nickel; In methanol; chloroform; Petroleum ether; | EXAMPLE 56 5-Isoquinolinamine <strong>[607-32-9]5-Nitroisoquinoline</strong> (100.3 g, 0.576 mol) was dissolved in MeOH and shaken with Raney nickel (10 g) on a Parr apparatus under a H2 atmosphere (50 psi) for 21 hours. The MeOH was removed in vacuo, the residue dissolved in chloroform (150 mL), and filtered into 600 mL petroleum ether. The solid was collected by filtration. This trituration procedure was repeated several times to give 81.24 g (98%) of the desired product. |
With hydrogenchloride; tin(ll) chloride; In water; for 1h;Reflux; | To a mixture of <strong>[607-32-9]5-nitroisoquinoline</strong> 2 (0.017 mol, 2.95 g) and SnCl2 (0.04 mol, 7.5 g), 20 mL of conc. hydrochloric acid were added. The reaction mixture was maintained at reflux for 1 hr. After cooling, the reaction mixture was neutralized with 10% aqueous sodium hydroxide. The neutral solution was then extracted successively by dichloromethane (~200 mL). The organic extract was then dried over anhydrous sodium sulphate, filtered and then concentrated in vacuo, yielding an impure greenish brown solid of 5-aminoisoquinoline (3, 1.85 g, 74.6%). | |
With palladium 10% on activated carbon; In methanol; at 20℃; for 3h;Inert atmosphere; | To a solution of isoquinoline (3.0 g, 23.2 mmol) in 40 mL H2SO4 at-15 C was added solid KNO3 (2.8 g, 27.8 mmol) in four successiveequal portions in 30 min. The reaction mixture was warmed to roomtemperature and stirred for 3 h, then poured into ice-water (100 mL).The pH of the mixture was adjusted to 8-10 with a few drops of ammonia.The precipitated solids were collected by filtration, washed withmethyl-tert-butyl ether (100 mL×2) and dried to provide 5 (4.0 g,100% yield) as a yellow solid. To compound 5 (2.5 g, 14.4 mmol) inMeOH (50 mL) was added 10% Pd/C (300 mg), and the mixture wasstirred under an atmosphere of hydrogen at room temperature for 3 h.The mixture was filtered and the filtrate was concentrated under vacuumto give the 6 (0.85 g, 41% yield) as a tan solid | |
palladium on charcoal; In methanol; | EXAMPLE 1 5-Aminoisoquinoline <strong>[607-32-9]5-Nitroisoquinoline</strong> (16.4 g) was dissolved in methanol (200 ml) and hydrogenated over palladium on charcoal (1.64 g) at 45 psi. When the hydrogenation was complete, the catalyst was removed by filtration and the solvent removed in vacuo to yield 15.2 g of 5-aminoisoquinoline as a brown powder. This was recrystallized from chloroform-ligroin (b.p. 60-90 C.) to yield 5-aminoisoquinoline (12.1 g) as a light tan powder, m.p. 127-129 C. (lit. value, 128 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | Stage #1: isoquinolin-5-ylamine With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h; Stage #2: With tin(II) chloride dihdyrate In water at 20℃; for 3h; | 112.A A. 5-hydrazinylisoquinoline, 112a To a stirring solution of isoquinolin-5-amine (30 g, 208.1 mmol) in concentrated HCl (300 mL) at 0° C. was added a solution of sodium nitrite (21.5 g, 312.1 mmol) in H2O (85 mL) below 0° C. The reaction mixture was stirred at 0° C. for 30 min and a solution of tin(II) chloride dehydrate (117.4 g, 520.2 mmol) dissolved in concentrated HCl (55 mL) was added dropwise. The mixture was stirred at room temperature for 3 h. The mixture was adjusted to pH 12-14 with 20% aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title product as a yellow solid (27 g, 81.5% yield). |
36% | Stage #1: isoquinolin-5-ylamine With hydrogenchloride In water at 0℃; for 1.5h; Stage #2: With hydrogenchloride; sodium nitrite In water Cooling with ice; Stage #3: With hydrogenchloride; tin(ll) chloride In water at 8℃; Cooling with ice; | |
With hydrogenchloride; tin(ll) chloride; sodium nitrite 1.) H2O; 2.) H2O; Yield given. Multistep reaction; |
Stage #1: isoquinolin-5-ylamine With hydrogenchloride In water at 0℃; for 0.5h; Stage #2: With sodium nitrite In water at 0 - 20℃; for 1h; Stage #3: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0 - 20℃; for 4.5h; | 24.a To a round bottom flask equipped with a stir bar containing isoquinolin-5-amine (15.4 g, 10.0 mmol) was slowly added concentrated hydrochloric acid (90 mL). The reaction slurry was stirred at 0° C. for 30 min and a solution of NaNO2 (7.3 g, 105.8 mmol) in minimal amount of deionized water was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 30 min to form a deep red solution. The reaction mixture was re-cooled to 0° C., and a solution of SnCl2.2H2O (47.4, 210.0 mmol) dissolved in minimal amount of concentrated hydrochloric acid was added then dropwise. The thick, brown mixture was stirred at 0° C. for 30 min and then at room temperature for 4 h. The solid was collected by filtration and washed with cold ethanol (200 mL). The yellow solid was suspended in 2:1 CHCl3/iPrOH (300 mL) and the solution was adjusted to pH 12-14 with 2 M aqueous sodium hydroxide (300 mL). The phases were separated and the aqueous layer was further extracted with CHCl3/iPrOH (2×300 mL). The combined organic layers were dried with anhydrous magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The resulting crude product was used directly without further purification (12.7 g, 79.8 mmol, 75%). | |
Stage #1: isoquinolin-5-ylamine With hydrogenchloride In water at 0℃; for 0.5h; Stage #2: With sodium nitrite In water at 0℃; for 1h; Stage #3: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0 - 20℃; for 4.5h; | 24.a Synthesis of 4-t-butyl-N-(2-(isoquino- lin-5-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)benzenesulfonamide To a round bottom flask equipped with a stir bar containing isoquinolin-5-amine (15.4 g, 10.0 mmol) was slowly added concentrated hydrochloric acid (90 mE). The reaction slurry was stirred at 00 C. for 30 mm and a solution of NaNO2 (7.3 g, 105.8 mmol) in minimal amount of deionized water was added dropwise. The reaction mixture was stirred at 00 C. for 30 mm and then at room temperature for 30 mm to form a deep red solution. The reaction mixture was re-cooled to 00 C., and a solution of SnC12.2H20 (47.4, 210.0 mmol) dissolved in minimal amount of concentrated hydrochloric acid was added then dropwise. The thick, brown mixture was stirred at 0° C. for 30 mm and then at room temperature for 4 h. The solid was collected by filtration and washed with cold ethanol (200 mE). The yellow solid was suspended in 2:1 CHC13/iPrOH (300 mE) and the solution was adjusted to pH -12-14 with 2 M aqueous sodium hydroxide (300 mE). The phases were separated and the aqueous layer was further extracted with CHC13/iPrOH (2x300 mE). The combined organic layers were dried with anhydrous magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The resulting crude product was used directly without further purification (12.7 g, 79.8 mmol, 75%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | Stage #1: isoquinolin-5-ylamine With sulfuric acid In water at 0℃; for 0.0833333h; Stage #2: With sodium azide In water at 20℃; for 0.166667h; | 1 Synthesis of INT 13-b A mixture of isoquinolin-5 -amine (1.4 g, 9.71 mmol) in sulfuric acid (2.5 mL) and H2O (7 mL) was cooled to 0 °C and sodium nitrite (800 mg, 11.6 mmol) in H2O (5 mL ) was added. The mixture was stirred at 0 °C for 5 min. Then NaN3 (631 mg, 9.71 mmol) in H2O (5 mL) was added and the reaction mixture was stirred at 20 °C for 10 min. The reaction mixture was neutralized with NH3.H2O. The solid was collected by filtration to give 5-azidoisoquinoline (1.60 g, 96.9% yield) as a solid which was used for next step directly m/z: [M + H]+ Calcd for C9H6N4 171.1; Found 170.9. |
95% | Stage #1: isoquinolin-5-ylamine With hydrogenchloride; sodium nitrite In water at 0℃; for 1h; Stage #2: With sodium azide; sodium acetate In water at 20℃; for 15h; | Procedure A: General Method of Preparing Substituted Azidobenzenes General procedure: Azidobenzene(1a): Aniline (306 mg, 3.29 mmol) was dissolved in 1:1HCl/H2O (20 mL) at 0 C. NaNO2 (495 mg, 7.18mmol) was then added to the solution carefully with stirring. After the mixturewas stirred for 1 h, it was added carefully to a suspension of sodium acetate(4 g, 48.8 mmol) and sodium azide (508 mg, 7.8 mmol) in water (30 mL) solution.The mixture was stirred at ambient temperature for 15 h. The mixture wasextracted with dichloromethane (30 mL × 3). The combination of the organicsolution was washed by brine (20 mL), dried over Na2SO4and purified using a silica gel column chromatography using ethyl acetate/hexane (1/20, v/v) as the mobile phase to afford a product as a yellow oil (0.3g, 51%). |
With hydrogenchloride; sodium azide; sodium acetate; sodium nitrite 1.) water, 5 deg C; Yield given. Multistep reaction; |
Stage #1: isoquinolin-5-ylamine With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.5h; Stage #2: With sodium azide In water at 0 - 20℃; | General procedure for the preparation of 5. General procedure: Compound 4(10 mmol) was dissolved in HCl (6 mol/mL, 10 mL) at 0 °C. To theabove reaction mixture, the solution of sodium nitrite (0.6 g,8.5 mmol) in H2O (25 mL) was added dropwise at 5 to 0 °C within30 min. The solution was vigorously stirred at 0-5 °C for 30 min. Sodium azide (40 mmol) in H2O (50 mL) was added dropwise intothe reaction mixture at 0-5 °C. The resulting solution was stirred at room temperature for 2-4 h followed by diluting with ice water(200 mL) and extracting with EtOAc (3 x 100 mL). The combined organic layer was washed with water (2 x 60 mL), saturated aqueous NaHCO3 (2 x 60 mL) and brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford compound 5. The residual crude product was used directly without purification. |
Yield | Reaction Conditions | Operation in experiment |
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35% | With bromine;aluminium trichloride; | EXAMPLE 73A 8-bromoisoquinolin-5-amine 5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, 113 mmol) were combined and heated at 80 C. in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glass funnel and the vapour diffused onto the complex over a period of 2 hours. Heating was continued for 2 hours. The suspension was added portionwise to crushed ice and the solution basified with concentrated NaOH solution. The aqueous layer was extracted with ethyl acetate (4*100 mL) and the layers were separated. The organic layers were combined, dried (Na2SO4), filtered and the filtrate was concentrated to give a grey solid. The grey solid was subjected to column chromatography (hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g, 35%). MS (ESI+) m/z 225 (M+H)+; MS (ESI-) m/z 223 (M-H)-; 1H NMR (CDCl3, 300 MHz) delta 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 1H), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8, 1H), 9.56 (s, 1H). |
35% | With bromine;aluminium trichloride; | EXAMPLE 73A 8-bromoisoquinolin-5-amine 5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, 113 mmol) were combined and heated at 80 C. in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glass funnel and the vapour diffused onto the complex over a period of 2 hours. Heating was continued for 2 hours. The suspension was added portionwise to crushed ice and the solution basified with concentrated NaOH solution. The aqueous layer was extracted with ethyl acetate (4*100 mL) and the layers were separated. The organic layers were combined, dried (Na2SO4), filtered and the filtrate was concentrated to give a grey solid. The grey solid was subjected to column chromatography (hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g, 35%). MS (ESI+) m/z 225 (M+H)+; MS (ESI-) m/z 223 (M-H)-; 1H NMR (CDCl3, 300 MHz) delta 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 11H), 7.61 (d, J 8.1, 11H), 8.59 (d, J 5.8, 11H), 9.56 (s, 1H). |
35% | EXAMPLE 73A 8-bromoisoquinolin-5-amine 5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, 113 mmol) were combined and heated at 80 C. in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glass funnel and the vapour diffused onto the complex over a period of 2 hours. Heating was continued for 2 hours. The suspension was added portionwise to crushed ice and the solution basified with concentrated NaOH solution. The aqueous layer was extracted with ethyl acetate (4*100 mL) and the layers were separated. The organic layers were combined, dried (Na2SO4), filtered and the filtrate was concentrated to give a grey solid. The grey solid was subjected to column chromatography (hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g, 35%). MS (ESI+) m/z 225 (M+H)+; MS (ESI-) m/z 223 (M-H)-; 1H NMR (CDCl3, 300 MHz) delta 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 1H), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8, 1H), 9.56 (s, 1H). |
35% | With bromine;aluminium trichloride; | Example 73A 8-bromoisoquinolin-5-amine 5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, 113 mmol) were combined and heated at 80 C. in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glass funnel and the vapour diffused onto the complex over a period of 2 hours. Heating was continued for 2 hours. The suspension was added portionwise to crushed ice and the solution basified with concentrated NaOH solution. The aqueous layer was extracted with ethyl acetate (4*100 mL) and the layers were separated. The organic layers were combined, dried (Na2SO4), filtered and the filtrate was concentrated to give a grey solid. The grey solid was subjected to column chromatography (hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g, 35%). MS (ESI+) m/z 225 (M+H)+; MS (ESI-) m/z 223 (M-H)-; 1H NMR (CDCl3, 300 MHz) delta 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 11H), 7.61 (d, J 8.1, 11H), 8.59 (d, J 5.8, 11H), 9.56 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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93% | With hydrogen In n-heptane at 150℃; for 72h; Sealed tube; chemoselective reaction; | |
6.45 g | With sulfuric acid; hydrogen In acetic acid for 20h; | |
In methanol | 265.a Step 265a. Step 265a. 5-amino-1,2,3,4-tetrahydroisoquinoline A 1.0 g (0.69 mmol) sample of 5-aminoisoquinoline (Aldrich Chemical Co.) was dissolved in 100 mL of methanol and reduced with 250 mg PtO2 catalyst at 25° C. under 4 atmospheres of H2 for 8 hours. The catalyst was removed by filtration, the solvent was removed on a rotary evaporator, and the residue was dried under vacuum to give 1.01 g of crude product. The material was crystallized from i-propanol and dried under vacuum, yield 602 mg. mp=153°-154° C. MS M/Z: 149 (M+H)+, 166 (M+NH4)+. |
In acetic acid | 9.a 4-[5-(Phenylsulphonamido)-1,2,3,4-tetrahydroisoquinolin-2-yl]butyric acid hydrochloride (a) A solution of 5-aminoisoquinoline (20 g) in glacial acetic acid (500 ml) was shaken under hydrogen in the presence of a platinum oxide catalyst (2.0 g) at room temperature and approximately 345 kilopascals pressure until uptake of hydrogen stopped. The catalyst was removed by filtration and the filtrate was evaporated to a small volume under reduced pressure. Residual solvent was removed by co-evaporation with water, then isopropyl alcohol, and the resulting solid was recrystallized from isopropyl alcohol to give 5-amino-1,2,3,4-tetrahydroisoquinoline as a white solid, 19 g, m.p. 153°-154° C. | |
With platinum(IV) oxide; hydrogen In ethanol | 334.A 334A. l,2,3,4-Tetrahydroisoquinolin-5-amine: 334A. l,2,3,4-Tetrahydroisoquinolin-5-amine: Isoquinolin-5 -amine (1.4 g, 9.71 mmol) was hydrogenated in the presence of Ρ( in EtOH (100 mL). The reaction mixture was filtered and concentrated to give 335A. MS (ESI) m/z: 149.0 (M+H)+. | |
With hydrogen In pentan-1-ol; water at 130℃; for 2h; Autoclave; | Hydrogenation of quinolines and isoquinolines General procedure: In a typical experiment, the above-prepared thermoregulated phasetransferPt nanocatalyst, n-decane (100 mg) and a certain amount ofsubstrates were added in the autoclave. Then the reactor was replacedthree times with 2 MPa H2 and stirred under hydrogen pressure at adesignated temperature for an appointed time. After reaction, the reactorwas cooled to room temperature and depressurized. The upperproduct phase was easily separated from the lower catalyst phase anddirectly analysed by GC and GC-MS. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 44A 5-iodoisoquinoline The desired product was prepared by substituting 5-aminoisoquinoline for 5-aminoquinoline in Example 43A. 1H NMR (300 MHz, CDCl3) delta 9.15 (s, 1H), 8.64 (d, 1H), 8.28 (d, 1H), 7.99 (d, 1H), 7.85 (d, 1H), 7.37 (t, 1H). | ||
6.5 g | With hydrogenchloride; potassium iodide; sodium nitrite; In water; at 0℃; for 1h;Reflux; | Step A - Preparation of Int Int 58-1 To a solution of 5-aminoisoquinoline (14 g, 97.2 mmol) in HCI/H2O (40 mL/ 40 mL) was added a 02 (8 g, 1 16 mmol) by portions at 0C. The mixture was stirred at 0C for 1 hour then Kl (32 g, 194 mmol) was added slowly and the mixture was refluxed overnight. After cooling to room temperature, the mixture was poured into NH4OH (40 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried and concentrated. The residue was purified by column chromatography (EtOAc : Petroleum Ether = 1 : 10) to give Int 58-1 (6.5 g). MS (ESI): m/z (M+H)+ 256. |
6.5 g | Step A - Preparation of Int 58-1 Int 58-1 To a solution of 5-aminoisoquinoline (14 g, 97.2 mmol) in HC1/H20 (40 mL/ 40 mL) was added NaN02 (8 g, 116 mmol) by portions at 0C. The mixture was stirred at 0C for 1 hour then KI (32 g, 194 mmol) was added slowly and the mixture was refluxed overnight. After cooling to room temperature, the mixture was poured into NH4OH (40 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried and concentrated. The residue was purified by column chromatography (EtOAc : Petroleum Ether = 1 : 10) to give Int 58-1 (6.5 g). MS (ESI): m/z (M+H)+ 256. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: isoquinolin-5-ylamine With pyridine In acetonitrile at 20℃; Stage #2: phenyl chloroformate In acetonitrile at 20℃; for 1h; | 2 Example 2 Preparation of isoquinolin-5-yl-carbamic acid phenyl ester (4) In a 100 ml round-bottomed flask,A solution of 200 mg (1.39 mmol) of 5-aminoisoquinoline was dissolvedIn 50 mL of acetonitrile,0.14 mL (1.67 mmol) of pyridine was added at room temperature;After completion,0.18 mL (1.46 mmol) of phenoxyformyl chloride was slowly added dropwise.At room temperature,Stirred for 1 hour,The solvent was distilled off under reduced pressure,Extracted with ethyl acetate (100 mL x 3), the organic phases were combined,Dried with anhydrous sodium sulphate powder, distilled under reduced pressure,The residue was purified by silica gel column chromatography,To give a white solid,355 mg of phenylisoquinolin-5-yl-carbamic acid phenyl ester (4)Yield: 97%. |
92% | With sodium hydrogencarbonate In dichloromethane | |
72% | at 0 - 20℃; |
60% | With pyridine In tetrahydrofuran at 15 - 20℃; | 1.1 To a stirred solution of 5-Aminoisoquinoline (3 g, 0.021 mole) dissolved in tetrahydrofuran (THF) (30 ml), was added pyridine (8.9 ml, 0.105 mole) at room temperature and the reaction mass was cooled to 15 0C. Phenyl chloroformate (4.4 ml, 0.035 mole) was added at 15 °C and the reaction mass was allowed to room temperature. Stirred the reaction mixture at room temperature for overnight and quenched with water (30 ml). Reaction mass was extracted with dichloromethane (2 X 20 ml) and the combined organic layer was washed with water (3 X 50 ml). Dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography to afford the desired product (3.3 g, yield.0/ O. ).1H-NMR (300 MHz, CDCl3): δ 7.20 - 7.29 (m, 3H), 7.32 - 7.44 (m, 2H), 7.65 (t, J= 7.9 Hz, IH), 7.72 - 7.85 (m, 3H), 8.23 (d, J= 6.4 Hz, IH), 8.59 (d, J= 5.9 Hz, IH)5 9.31 (s, IH).MS: 265.2 (M++l) |
With pyridine In tetrahydrofuran for 3h; | 21.6 Step 6: phenyl isoquinolin-5-ylcarbamate; To 5-aminoisoquinoline (2.7 g) were added phenyl chloroformate (2.85 ml), pyridine (2.0 ml) and tetrahydrofuran (50 ml), and the mixture was stirred for 3 hrs. The reaction mixture was diluted with dichloromethane, and washed with water and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give the title compound (3 g). | |
With pyridine In N,N-dimethyl-formamide | 48.1 Step-1: Phenyl isoquinolin-5-ylcarbamate. Isoquinolin-5-amine (0.150 g, 1.040 mmol) was reacted with phenylchloroformate(0.180 g, 1.144 mmol) and pidine (0.251 mL, 3.120 mmol) in N,N-dimethylformamide(5 mL) to give the titled compound (0.500 g, crude) as a solid. The crude product wastaken to the next step without further purification. | |
With pyridine In tetrahydrofuran; acetonitrile at 0 - 20℃; | 4.1.2.9 Carbamation General procedure: To a solution of the appropriate amine (1.0mmol) in THF was added pyridine (1.1mmol) and phenyl chloroformate (1.0mmol) at 0°C and stirred at room temperature for 1h. The reaction mixture was quenched with water and extracted with EtOAc several times. The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel colunm chromatography to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
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101 mg | Stage #1: 1-propyl-4-piperidone; isoquinolin-5-ylamine With titanium(IV) isopropylate at 20℃; for 0.5h; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 3h; | |
Stage #1: 1-propyl-4-piperidone; isoquinolin-5-ylamine With titanium(IV) isopropylate at 20℃; for 0.5h; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
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83% | Compound 7 (497.52 mg, 2.50 mmol), 5-aminoisoquinoline(300.00 mg, 2.08 mmol)Was dissolved in isopropyl titanate (5 mL)After stirring at room temperature for 30 minutes, anhydrous ethanol (5 mL) was added,Sodium cyanoborohydride (261.53 mg, 4.16 mmol) was added under ice-cooling,The reaction was stirred at room temperature for 3 hours. The solid was removed by filtration through celite,The reaction was quenched by the addition of saturated NaHCO3 solution, the aqueous phase was extracted with ethyl acetate,The combined organic phases were washed with saturated brine (10 mL x 1)After drying in anhydrous Na2SO4, the solvent was removed by steaming,The residue was purified by silica gel column chromatography to give compound 8 as a yellow solid (566.00 mg, yield 83%). | |
(R)-pyrrolidinol (Tokyo Chemical Industry Co., Ltd., 12.4 g, 100 mmol) was dissolved in 100 ml of a 3 N aqueous solution of sodium hydroxide. A solution (50 ml) of di-tert-butyl dicarbonate (Tokyo Chemical Industry Co., Ltd., 25.0 g, 120 mmol) in tetrahydrofuran was added dropwise thereto at 0C. The pH value of the mixture was confirmed to be 11 with a pH test paper. The mixture was stirred at room temperature for 2 hr and was then concentrated to remove a major part of tetrahydrofuran. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product and triethylamine (20 ml) were dissolved in anhydrous dimethylsulfoxide (100 ml). Finely triturated sulfur trioxide/trimethylamine complex (Aldrich, 28.0 g, 200 mmol) was added thereto little by little at room temperature. The mixture was stirred at room temperature for 18 hr. Thereafter, 200 ml of water was added to stop the reaction. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product was purified by a silica gel column eluted with chloroform. The development was carried out with chloroform to give an intermediate (15.6 g). The intermediate (3.70 g, 20 mmol) and 5-aminoisoquinoline (Aldrich, 2.48 g, 17 mmol) were dissolved in 100 ml of acetic acid. Sodium sulfate (14.2 g, 100 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0C. Sodium hydride triacetate (Aldrich, 4.44 g, 20 mmol) was added thereto little by little, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under the reduced pressure to remove a major part of acetic acid. The reaction mixture was then adjusted to pH 8 by the addition of a saturated sodium hydrogencarbonate solution and was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product dissolved in methylene chloride was purified by a silica gel column and developed with hexane. The development was first carried out with hexane only, then with hexane/chloroform (1 : 1), and finally with chloroform only to collect a fraction having UV absorption with Rf = 0.6 to give the title compound (3.720 g, 12 mmol). 1H-NMR (CDCl3, 400 MHz): 1.44 (s, 9H), 1.48 - 1.68 (m, 1 H), 1.73 - 1.83 (m, 2H), 1.90 - 2.10 (m, 1 H), 3.10 - 3.32 (m, 2H), 3.52 - 3.65 (m, 2H), 3.92 - 3.98 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.54 (d, J = 5.8 Hz, 1 H), 8.42 (d, J = 5.8 Hz, 1 H), 9.13 (s, 1 H). Mass spectrometric value (ESI-MS, m/z): 328 (M++1) |
Yield | Reaction Conditions | Operation in experiment |
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65% | With triethylamine In dichloromethane at 20℃; for 14h; | |
65% | Stage #1: isoquinolin-5-ylamine; trifluoroacetyl chloride With triethylamine In dichloromethane at 5 - 20℃; for 14h; Stage #2: With hydrogenchloride In water; ethyl acetate Stage #3: With sodium hydrogencarbonate In water | 1A 2,2,2-trichloro-N-isoquinolin-5-ylacetamide EXAMPLE 1A 2,2,2-trichloro-N-isoquinolin-5-ylacetamide A solution of 5-aminoisoquinoline (1.0 g, 6.9 mmol) in dichloromethane (40 mL) and Et3N (1 mL) at 5° C. was treated with trichloroacetyl chloride (1.38 g, 7.6 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 14 hours, concentrated, diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was treated with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer the was washed with water and concentrated. The solid residue was suspended in ethyl acetate (5 mL) and filtered to obtain 1.3 g (65%) of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ 11.20 (broad s, 1H), 9.41, (s, 1H), 8.60 (d, 1H), 8.18 (m, 1H), 7.77 (m, 2H), 7.66 (d, 1H); MS (DCI/NH3) m/z 289 (M+H)+. |
65% | With triethylamine In dichloromethane at 0 - 20℃; for 4h; | 2.1.1. 2,2,2-Trichloro-N-isoquinolin-5-yl-acetamide (3) To a solution of 5-aminoisoquinoline 2 (3.0 g, 20.7mmol) in dichloromethane (120 mL) and triethylamine (3mL) at 0 °C, trichloroacetyl chloride (4.14 g, 22.8 mmol) was added dropwise and the reaction mixture was stirred from 0 °C to room temperature for 4 h. Upon completion of the reaction, the reaction mixture was concentrated and the crude product was basified with aqueous sodium bicarbonate(15 mL) and the mixture was extracted three times with ethylacetate(3 x 30 mL). The organic phases were dried oversodium sulfate, concentrated under reduced pressure to obtain a solid residue. Digestion with ethyl acetate resulted inthe precipitation of product 3 as a dark tan solid (1.3 g,65%). 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 11.24 (s,NH, 1H), 9.43, (s, 1H), 8.61-8.60 (d, J = 5.92 Hz, 1H), 8.18-8.17 (d, J = 7 Hz, 1H), 7.80-7.75 (m, 2H), 7.70-7.68 (d, J =5.92 Hz, 1H); MS m/e: 289 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
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53% | 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%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | 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; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: isoquinolin-5-ylamine; 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid In tetrahydrofuran at 32℃; for 0.166667 - 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20 - 32℃; for 6h; | 1 Preparation of tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-l- carboxylate (Scheme 5, Step 1)A 5L flask (Flask A) equipped with a mechanical stirrer, internal temperature probe and addition funnel was charged with 5-aminoisoquinoline (300 g, 2.08 mol) and 2.7 L of tetrahydrofuran. Trifluoroacetic acid (543 mL, 7.29 mol) was added slowly while maintaining an internal temperature of <320C. l-Boc-3-pyrrolidinone (462.5 g, 2.50 mol) was added and the mixture was stirred for 10-30 minutes. A separate 12L flask (Flask B) equipped with an internal temperature probe, mechanical stirrer and nitrogen inlet was flushed with nitrogen and charged with sodium triacetoxyborohydride (662.5 g, 3.13 mol) and 1.5 L of tetrahydrofuran. The contents of Flask A were slowly transferred to Flask B while maintaining an internal temperature in Flask B of < 320C. The reaction was stirred at 20-320C for 6 hours and all 5-aminoisoquinoline was consumed. The reaction was quenched with 3L of 5N NaOH maintaining a temperature of < 450C. After 20 minutes, the aqueous layer was separated. The organic phase was washed with 3L of 2N NaOH at 4O0C (with external heating). The organic phase was diluted with isopropyl acetate (2.25 L), washed with 1.5 L of water at 4O0C (with external heating), and concentrated to ~2 L by distillation. The resulting solution was cooled to ~20°C. The resulting slurry was filtered, washed (3 x 200 mL of MTBE), and dried in a vacuum oven at ~ 6O0C. Approximately 536 g of tert- Butyl 3-(isoquinolin-5-ylamino)pyrrolidine-l-carboxylate was isolated as a solid (82% yield).1H NMR (DMSO-d6, 300 MHz, 6O0C) δ 9.12 (d, IH. J = 0.9 Hz), 8.40 (d, IH, J = 6.0 Hz), 8.10 (dt, IH, J = 0.9 Hz), 7.45 (t, IH, J = 7.9 Hz), 7.30 (dt, IH, J - 0.9 Hz), 6.79 (m, IH), 6.15 (d, IH, J - 6.0 Hz), 4.19 (m, IH), 3.69 (dd, IH, J = 10.9, 6.4 Hz), 3.30 (m, IH, J - 10.9, 4.7 Hz), 3.49 (m, IH), 3.38 (m, IH), 2.25 (m, IH), 2.00 (m, IH), 1.41 (s, 9H);13C NMR (DMSO-d6, 75 MHz, 6O0C) δ 151.78, 141.05, 114.79, 125.56, 142.10, 107.15, 127.86, 114.59, 128.91, 51.77, 50.57, 43.88, 30.10, 153.38, 77.96, 27.94. |
65% | With sodium tris(acetoxy)borohydride; acetic acid; sodium sulfate at 20℃; | |
With sodium tris(acetoxy)borohydride; acetic acid at 0 - 20℃; | To a homogenous solution of isoquinolin-5-amine (15g, 104 mmol) and tert-butyl 3-oxopyrrolidine- 1 -carboxylate (23.12g, 125 mmol, 1 .2 eq) in AcOH (300 mL) at 0°C was added dropwise a solution of NaBH(OAc)3 (44.1 g, 208 mmol, 2eq) in AcOH (200 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Then, the residue was adjusted to pH 10 by addition of saturated aqueous solution of Na2C03 and extracted with DCM (x3). The combined organic layers were dried over Na2S04, filtered and then concentrated in vacuo to afford the expected compound, which was used directly in the next step without further purification. |
With sodium tris(acetoxy)borohydride; acetic acid at 0 - 20℃; | B.B.1 Intermediate 6: 3-[3-(Isoquinolin-5-ylamino)-pyrrolidin-1-ylmethyl]-benzoic acid To a homogenous solution of isoquinolin-5-amine (15 g, 104 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (23.12 g, 125 mmol, 1.2 eq) in AcOH (300 mL) at 0° C. was added dropwise a solution of NaBH(OAc)3 (44.1 g, 208 mmol, 2 eq) in AcOH (200 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Then, the residue was adjusted to pH 10 by addition of saturated aqueous solution of Na2CO3 and extracted with DCM (*3). The combined organic layers were dried over Na2SO4, filtered and then concentrated in vacuo to afford the expected compound, which was used directly in the next step without further purification. | |
Stage #1: isoquinolin-5-ylamine; 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium sulfate In acetic acid at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In acetic acid at 0 - 20℃; for 18h; Stage #3: With sodium hydrogencarbonate In water | 1 (R)-pyrrolidinol (Tokyo Chemical Industry Co., Ltd., 12.4 g, 100 mmol) was dissolved in 100 ml of a 3 N aqueous solution of sodium hydroxide. A solution (50 ml) of di-tert-butyl dicarbonate (Tokyo Chemical Industry Co., Ltd., 25.0 g, 120 mmol) in tetrahydrofuran was added dropwise thereto at 0°C. The pH value of the mixture was determined with a pH test paper and was found to be 11. The mixture was then stirred at room temperature for 2 hr and was then concentrated to remove a major part of tetrahydrofuran. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product and triethylamine (20 ml) were dissolved in anhydrous dimethylsulfoxide (100 ml), and a trituated sulfur trioxide/trimethylamine complex (Aldrich, 28.0 g, 200 mmol) was added little by little thereto at room temperature. The mixture was stirred at room temperature for 18 hr. Water (200 ml) was then added to the reaction solution to stop the reaction. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product was loaded on a silica gel column and developed with chloroform, followed by development with chloroform only to give an intermediate (11.25 g). The intermediate (3.70 g, 20 mmol) and 5-aminoisoquinoline (Aldrich, 2.48 g, 17 mmol) were dissolved in 100 ml of acetic acid. Sodium sulfate (14.2 g, 100 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0°C, sodium hydride triacetate (Aldrich, 4.44 g, 20 mmol) was added thereto little by little, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under the reduced pressure to remove a major part of acetic acid. The reaction mixture was then adjusted to pH = 8 by the addition of a saturated sodium hydrogencarbonate solution and was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product in methylene chloride was loaded on a silica gel column and developed with hexane. The development was first carried out with hexane only, subsequently with hexane/chloroform (1 : 1), and finally with chloroform only to collect a fraction having UV absorption with Rf = 0.6 to give the title compound (3.70 g, 12 mmol). 1H-NMR (CDCl3, 400 MHz): 1.46 (s, 9H), 1.75 - 1.94 (m, 1H), 2.02 - 2.10 (m, 1 H), 3.35 - 3.55 (m, 31 H), 3.75 - 3.86 (m, 1 H), 4.17 - 4.24 (m, 1 H), 4.705 - 4.90 (m, 1 H), 6.91 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 8.42 (d, J = 6.4 Hz, 1 H), 9.20 (s, 1 H). Mass spectrometric value (ESI-MS, m/z): 314 (M++1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | 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 | 9 5-Bromo-/.yø-quinoline (0.208 g, 1.00 mmol), (CyPF-J-Bu)PdCl2 (7.30 mg, 1.00 x 10"2 mmol), and NaOrBu (0.192 g, 2.00 mmol) in 4.0 mL DME gave 0.101 g (70%) of 5-Amhκw.rø-quinoline as a solid (Ethyl acetate/methanol: 90/10). 1H NMR (CDCl3) δ 9.15 (s, 1 H), 8.45 (d, J= 5.6 Hz, 1 H), 7.55 (d, J= 6.0 Hz, 1 H)5 7.37 (d, J = 5.2 Hz, 2 H), 6.91 (t, J = 4.8 Hz, 1 H)5 4.26 (s, br, 2 H); 13C NMR (CDCl3) δ 152.85, 141.88, 141.30, 129.33, 127.72, 125.88, 117.80, 114.06, 112.96. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 20h; | 1 The acid 1 was prepared from the commercially available β-ionone by haloformic reaction as described 'i the literature.2 1.0 mmo. (194 mg) of acid 1 was dissolved in 8 ml of anhydrous DMF. EDCI (1.2 equiv., 1.2 mmol, 230 mg), HOBt (1.2 equiv., 1.2 mmol, 162 mg) and 5-aminoisoquinoline (1.2 equiv., 1.2 mmol, 173 mg) were added sequentially at 00C. The reaction mixture was stirred at room temperarture for 20 h. The solvent was evaporated under reduced pressure and the residue was dissolved in 50 ml of ethyl acetate. The organic phase was washed with water (2 X 20 ml), saturated sodium chloride solution (1 X 10 ml), dried over sodium sulphate and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel, 3/7 ethyl acetate/hexane followed by ethyl acetate) and finally recrystallized from diethyl ether to give 150 mg of a beige solid. Yield = 47%. Mp: (diethyl ether) 131-133°C. 1H NMR (CDCI3, 400 MHz) δ 1.10 (6H, s), 1.49 (2H1 m), 1.62 (2H1 m), 1.81 (3H, s), 2.05 (2H, m), 6.18 (1 H1 d), 7.62 (2H, m), 7.70 (2H1 m), 7.81 (1 H, d), 8.38 (1 H, bs), 8.53 (1 H, d, J = 5.6 Hz), 9.25 (1 H, s); [M+1] 321.7 (C21 H24N2O requires 320.43). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 20h; | 2.2 1.0 mmol (224 mg) of acid 4 was dissolved in 10 ml of anhydrous DMF. EDCI (1.2 equiv., 1.2 mmol, 230 mg), HOBt (1.2 equiv., 1.2 mmol, 162 mg) and 5-aminoisoquinoline (1.2 equiv., 1.2 mmol, 173 mg) were added sequentially at 00C. The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure and the residue was dissolved in 50 ml of ethyl acetate. The organic phase was washed with water (3 X 20 ml), and with saturated sodium chloride solution (1 X 10 ml), dried over sodium sulphate and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel, ethyl acetate) and finally recrystallized from diethyl ether to give 160 mg of a yellow amorphous solid. Yield = 45%. 1H NMR (CDCI3, 400 MHz) δ 1.07 (6H, s), 1.42 (2H, m),A CC M U . i i ι , m), 7.65 (3H, m), 7.84 (1 H1 d), 8.38 (1 H1 bs), 8.55 (1 H1 d, J = 6 Hz), 9.26 (1 H1 s); [M+1] 351.2 (C22H26N2O2 requires 350.45). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.5% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 20h; | 3.2 0.5 mmol (143 mg) of acid 6c were dissolved in 5 ml of anhydrous DMF. EDCI (1.2 equiv., 0.6 mmol, 115.2 mg), HOBt (1.2 equiv., 0.6 mmol, 81 mg) and 5-aminoisoquinoline (1.2 equiv., 0.6 mmol, 86.51 mg) were added sequentially at 00C. The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure and the residue was dissolved in 30 ml of ethyl acetate. The organic phase was washed with water (2 X 10 ml) and with a saturated sodium chloride solution (1 X 10 ml), dried over sodium sulphate and concentrated under vacuum. The crude solid was purified by column chromatography (silica gel, ethyl acetate/petroleum ether 8:2) and finally recrystallized from diethyl ether to give 100 mg of a white solid. Yield = 48.5%. Mp: (diethyl ether) 141-143°C. 1H NMR (CDCI3, 400 MHz) δ 1.14 (3H, s), 1.17 (3H, s), 1.47 (2H, m), 1.78 (2H1 m), 1.95 (3H, s), 4.60 (1 H, m), 6.41 (1 H, d), 6.97 (2H1 d, J = 7.2 Hz), 7.26 (4H, m), 7.59 (1 H, d, J = 16 Hz), 7.80 (1 H, t, J = 8 Hz), 7.92 (1 H, d, J = 8 Hz), 8.17 (1 H, m), 8.37 (1 H, m), 8.52 (1 H, bs), 9.26 (1 H, s); [M+1] 413.6 (C27H28N2O2 requires 412.52) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (±)-2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl; sodium t-butanolate In para-xylene at 130℃; for 12h; | 5 Example 5 N- {54-TRIFLUOROMETHYLPHENYL] PYRIDIN-2-YL} ISOQUINOLIN-5-AMINE To a mixture of 5-aminoisoquinoline (2.53 g, 17.5 mmol) and 2,5-dibromopyridine (3.62 g, 15.3 mmol) was added palladium acetate (0.17 g, 0.76 mmol) and rac-2,2'- bis (diphenylphosphino)-1, 1'-binaphthyl (0.47 g, 0.76 mmol). The flask was flushed with nitrogen and P-XYLENE was added followed by sodium tert-butoxide (2.2 g, 22.9 mmol). Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 130 °C for 12 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and poured onto a mixture of chloroform/water (200 ml/ 20 ml). The phases were separated and the aqueous phase was extracted twice with chloroform. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash chromatography (50% ethyl acetate-iso- hexane) followed by recrystallisation from ethanol gave N- (5-BROMOPYRIDIN-2-YL) isoquinolin- 5-amine (3.4 g, 74 %). A portion (0.71 g, 2.37 mmol) was added to 4- (trifluoromethyl) phenylboronic acid (0.68 g, 3.59 mmol) in anhydrous dioxane (10 ml) and tetrakis (triphenylphosphino) -palladium (0) (0.14 g, 0.12 mmol) and saturated aqueous sodium carbonate solution (4 ml) were added. Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100 °C for 12 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and poured into a mixture of ethyl acetate/water (100 ML/30 ml). The phases were separated and the aqueous phase was extracted two times more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash chromatography (50% ethyl acetate-iso-hexane) followed by recrystallisation from methanol/water (1: 1) yielded the title compound (0.22 g, 25 %). M/Z (ES+) 366 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine hydrochloride; In 1-ethoxyethanol; at 200℃; for 2h;Alkaline aqueous solution; | A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.288 g of 5-aminoisoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200C for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.100 g of 4-(isoquinolin-5-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 140C (decomposed); mass spectrum (EI, m/e): M 356.1279. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With sodium t-butanolate In para-xylene at 100℃; for 16h; | 72 Description 72: N-(6-CHLOROPYRIMIDIN-4-YL) ISOGUINOLIN-5-AMINE A mixture of 4, 6-dichloropyrimidine (5 g, 34 mmol), isoquinolin-5-amine (5.3 g, 37 mmol), 2'- (dimethylamino)-2-biphenylyl palladium (II) chloride DINORBORNYLPHOSPHINE complex [see ANGEW. CHEM., 2002,41, 3668 ; CAS number 359803-53-5] (940 mg, 2 mmol) and sodium tert-butoxide (4.8 g, 50 mmol) in P-XYLENE (100 ml) was degassed thoroughly and heated under nitrogen at 100 °C for 16 hours. The cooled reaction mixture was purified by column chromatography over silica (eluant 1% MEOH in DCM) to give the title compound (1. 5g, 17%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With zinc(II) chloride In acetonitrile at 0℃; for 3h; Heating / reflux; | 2-(Isoquinolin-5-ylamino)-2-methylpropionitrile: 5.0 g (34.7 mmol) of 5-aminoisoquinoline, 5.1 ml (69.4 mmol) of acetone and 945 mg (6.94 mmol) of zinc chloride were dissolved in 100 ml of acetonitrile and treated at 0° C. with 6.9 g (69.4 mmol) of trimethylsilyl cyanide. The mixture was refluxed for 3 hours, the solvent was then evaporated off and the residue was taken up in 200 ml of sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined organic phases were dried and the residue remaining after evaporation was purified by flash chromatography (SiO2, methylene chloride/methanol=95/5) to give 6.0 g (82%) of the desired product. M+H+=212. LC/MS retention time=0.696. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In 1,2-dichloro-ethane; at 60℃; for 72.0h; | Step 1 : Preparation of (1, 3-dimethylimidazolidin-2-ylidene) isoquinolin-5-ylamine A mixture of 5-aminoisoquinoline (0.3 g, 2.09 mmol) and 2-chloro-1, 3-dimethylimid- azolidinium hexafluorophosphate (0.7 g, 2.51 mmol) in 15 mL of DCE, was heated to 60C for 72 hours. The crude was purified by flash column eluting with CH2CL2 : MeOH: NH40H (94.5 : 5: 0.5) to afford 0.25 g (50%) of the above titled compound as a dark FOAM. LU NMR (CD30D 3.31) 5 2.74 (s, 6 H), 3.79 (s, 4 H), 7.75 (d, 1 H, J = 1.17), 7.77 (s, 1 H), 8.01 (dt, 1H, J= 6.03, 0.96), 8.15 (m, 1 H), 8.59 (d, 1H, J= 6.03), 9.35 (d, 1H, J= 0.99) ; MS (ES+) M/Z 241.2 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In dichloromethane; toluene at 20℃; for 14h; | 111 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea EXAMPLE 111 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea 5-Aminoisoquinoline (0.64 g, 4.42 mmol) in dichloromethane (20 mL) was treated with 1-bromo-4-(1-isocyanatoethyl)benzene (1.0 g, 4.42 mmol) in toluene (10 mL). The mixture was stirred 14 hours at ambient temperature and filtered to obtain 1.2 g (74%) of the product as light grey solid. 1H NMR (300 MHz, d6-DMSO) δ 9.28 (s, 1H), 8.68 (broad s, 1H), 8.56 (d, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.59 (m, 2H), 7.35 (m, 2H), 7.10 (d, 1H), 4.85 (m, 1H), 1.40 (d, 3H); MS (DCI/NH3) m/z 370 (M+H)+; Anal. Calcd. For C18H16N3BrO. 0.1H2O: C, 58.11; H, 4.39; N, 11.29. Found: C, 57.79; H, 4.21; N, 11.16. |
1.2 g (74%) | In dichloromethane; toluene | 11 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea EXAMPLE 11 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea 5-Aminoisoquinoline (0.64 g, 4.42 mmol) in dichloromethane (20 mL) was treated with 1-bromo-4-(1-isocyanatoethyl)benzene (1.0 g, 4.42 mmol) in toluene (10 mL). The mixture was stirred 14 hours at ambient temperature and filtered to obtain 1.2 g (74%) of the product as light grey solid. 1H NMR (300 MHz, d6-DMSO) δ 9.28 (s, 1H), 8.68 (broad s, 1H), 8.56 (d, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.59 (m, 2H), 7.35 (m, 2H), 7.10 (d, 1H), 4.85 (m, 1H), 1.40 (d, 3H); MS (DCI/NH3) m/z 370 (M+H)+; Anal. Calcd. For C18H16N3BrO.0.1H2O: C 58.11; H 4.39;N 11.29. Found: C 57.79;1H4.21;N 11.16. |
1.2 g (74%) | In dichloromethane; toluene | 11 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea EXAMPLE 11 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea 5-Aminoisoquinoline (0.64 g, 4.42 mmol) in dichloromethane (20 mL) was treated with 1-bromo-4-(1-isocyanatoethyl)benzene (1.0 g, 4.42 mmol) in toluene (10 mL). The mixture was stirred 14 hours at ambient temperature and filtered to obtain 1.2 g (74%) of the product as light grey solid. 1H NMR (300 MHz, d6-DMSO) δ 9.28 (s, 1H), 8.68 (broad s, 1H), 8.56 (d, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.59 (m, 2H), 7.35 (m, 2H), 7.10 (d, 1H), 4.85 (m, 1H), 1.40 (d, 3H); MS (DCI/NH3) m/z 370 (M+H)+; Anal. Calcd. For C18H16N3BrO.0.1H2O: C, 58.11; H, 4.39; N, 11.29. Found: C, 57.79; H, 4.21; N, 11.16. |
1.2 g (74%) | In dichloromethane; toluene | 11 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea EXAMPLE 11 N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea 5-Aminoisoquinoline (0.64 g, 4.42 mmol) in dichloromethane (20 mL) was treated with 1-bromo-4-(1-isocyanatoethyl)benzene (1.0 g, 4.42 mmol) in toluene (10 mL). The mixture was stirred 14 hours at ambient temperature and filtered to obtain 1.2 g (74%) of the product as light grey solid. 1H NMR (300 MHz, d6-DMSO) δ 9.28 (s, 1H), 8.68 (broad s, 1H), 8.56 (d, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.59 (m, 2H), 7.35 (m, 2H), 7.10 (d, 1H), 4.85 (m, 1H), 1.40 (d, 3H); MS (DCI/NH3) m/z 370 (M+H)+; Anal. Calcd. For C18H16N3BrO.0.1H2O: C, 58.11; H, 4.39; N, 11.29. Found: C, 57.79; H, 4.21; N, 11.16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine;mercury dichloride; In dichloromethane; at 20℃; for 15h; | To a solution of Isoquinolin-5-amine (1.11 g, 7.69 mmol, Aldrich) and <strong>[107819-90-9]1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea</strong> (2.28 g, 7.85 mmol, Aldrich) in DCM (25 mL) was added triethylamine (1.60 g, 15.78 mmol, Aldrich) and mercuric chloride (2.1 g, 7.74 mmol, Aldrich). The reaction mixture was stirred at room temperature for 15 h and filtered. The filter cake was washed with DCM (2*25 mL). The combined filtrates were concentrated and the residue was purified by silica gel column chromatography, eluding with EtOAc/hexane (1:5) to give 2.29 mg (77percent) of the title compound as a pale-yellow amorphous solid. MS (ESI, pos. ion) m/z: 387 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With sodium hydrogencarbonate; sodium nitrite; In hydrogenchloride; water; ethyl acetate; toluene; | A. 5-Cyanoisoquinoline To a cold (0 C.) solution of 10.0 g (61.4 mmol) of 5-aminoisoquinoline in 288 mL of 1.5N hydrochloric acid, was added 15 mL of 5.2M sodium nitrite in water. After approximately 5 minutes, a cool saturated solution of sodium bicarbonate was added to the reaction mixture until the reaction solution tested negative using the iodide and start paper test. The resultant solution was poured into a cold (0-5 C.) biphasic mixture containing 300 ml of toluene and 150 mL of an aqueous solution containing 8.4 g (177 mmol) of sodium cyanide and 7.6 g (85 mmol) of copper cyanide. The resultant reaction mixture was warmed to room temperature, reacted for approximately 1 hour, and then diluted with a mixture of ethyl acetate and water. The resulting layers were separated, and the organic phase was dried over sodium sulfate, filtered, and then reduced to dryness under reduced pressure to provide 5.9 g of a yellow solid. Yield: 56%. 1 H NMR (CDCl3): δ 9.38 (s, 1H), 8.76 (d, J=5.89 Hz, 1H), 8.25 (d, J=8.29 Hz, 1H), 8.13 (d, J=8.30 Hz, 1H), 8.03 (d, J=8.59 Hz, 1H), 7.71 (t, J=7.78 Hz, 1H); IR (KBr): 3433, 3090, 3026, 2924, 2226, 1618, 1574, 1495, 1433, 1373, 1277, 1225, 1034, 829, 766, 714. |
56% | With sodium hydrogencarbonate; sodium nitrite; In hydrogenchloride; water; ethyl acetate; toluene; | A. 5-Cyanoisoquinoline To a cold (0 C.) solution of 10.0 g (61.4 mmol) of 5-aminoisoquinoline in 288 mL of 1.5N hydrochloric acid, was added 15 mL of 5.2M sodium nitrite in water. After approximately 5 minutes, a cool saturated solution of sodium bicarbonate was added to the reaction mixture until the reaction solution tested negative using the iodide and starch paper test. The resultant solution was poured into a cold (0-5 C.) biphasic mixture containing 300 ml of toluene and 150 mL of an aqueous solution containing 8.4 g (177 mmol) of sodium cyanide and 7.6 g (85 mmol) of copper cyanide. The resultant reaction mixture was warmed to room temperature, reacted for approximately 1 hour, and then diluted with a mixture of ethyl acetate and water. The resulting layers were separated, and the organic phase was dried over sodium sulfate, filtered, and then reduced to dryness under reduced pressure to provide 5.9 g of a yellow solid. Yield: 56%. 1 H NMR (CDCl3): δ9.38 (s, 1H), 8.76 (d, J=5.89 Hz, 1H), 8.25 (d, J=8.29 Hz, 1H), 8.13 (d, J=8.30 Hz, 1H), 8.03 (d, J=8.59 Hz, 1H), 7.71 (t, J=7.78 Hz, 1H); IR (KBr): 3433, 3090, 3026, 2924, 2226, 1618, 1574, 1495, 1433, 1373, 1277, 1225, 1034, 829, 766, 714. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine hydrochloride; sodium carbonate; In water; | EXAMPLE 133 4-(Isoquinolin-5-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.288 g of 5-aminoisoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200 C. for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.100 g of 4-(isoquinolin-5-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 140 C. (decomposed); mass spectrum (EI, m/e): M 356.1279. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In ethanol; for 3 - 4h;Heating / reflux; | lsoquinolin-5-ylamine (4 g, 27.9 mmol) and <strong>[50607-30-2]piperidine-2,4-dione</strong> (4.1 g, 36.2 mmol) were heated at reflux in absolute ethanol (200 ml.) with a Dean-Stark apparatus for 3-4 hours. The solvent was concentrated under vacuum and the resulting solid <n="25"/>foam, corresponding to the title compound, was dried under vacuum and used in the next step without further purification (4.45 g, yield 67percent).1 H NMR (400 MHz, CD3OD) delta ppm 2.76 (t, J=7.95, 2 H) 3.48 (t, J=8.01 , 2 H) 4.58 (s, 1H) 7.73 (m, 2H) 7.89 (d, J=7.89, 1 H) 8.03 (m, 1 H) 8.48 (d, J=8.04, 1 H) 9.28 (s, 1 H). [M+H]+= 240 |
Yield | Reaction Conditions | Operation in experiment |
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52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 60℃; for 7h; | 10 Example 10 (E)-N-(Isoquinolin-5-yl)-5,5-bis[4-(trifluoromethyl)phenyl]-2,4-pentadienamide (Compound 11); Compound b (2.32 g, 6.00 mmol) was dissolved in DMF (30 mL), and 5-aminoisoquinoline (720 mg, 5.00 mmol), EDC hydrochloride (1.92 g, 10.0 mmol), and HOBt (1.15 g, 7.50 mmol) were added thereto, and then, the mixture was stirred at 60°C for 7 hours. After the reaction mixture was left to cool, a saturated sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the organic layer was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/1), and then recrystallized from isopropyl ether/hexane to give Compound 11 (1.34 g, 52%). mp : 164-166°C; 1H NMR (CDCl3, δ ppm): 6.38 (d, J = 14.7 Hz, 1H), 6.93 (d, J = 11.6 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.46 (dd, J = 11.6, 14.7 Hz, 1H), 7.58-7.64 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.83-7.85 (m, 1H), 8.20 (brs, 1H), 8.56-8.58 (m, 1H), 9.27 (s, 1H); APCIMS m/z: [M+H]+ 513. |
52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 60℃; for 7h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With triethylamine; HATU In dichloromethane at 20℃; for 16h; | 5.D Example 5 D. 3-(2-Fluoro-phenyl)-N-quinolin-5-yl-2-(4-trifluoromethyl-phenyl)-propionamide. To a solution of Compound 5c (51 mg, 0.16 mmol) and 5-aminoisoquinoline (47 mg, 0.33 mmol) in CH2Cl2 (3 mL) at room temperature was added Et3N (0.14 mL, 1.0 mmol) followed by HATU (124 mg, 0.33 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2, washed sequentially with aq. 10% HCl solution and aq. NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 40% EtOAc/heptane) afforded Compound 55 (30 mg, 42%). MS: 439 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In dichloromethane at 20℃; for 24h; Inert atmosphere; | 27 Example 27: 5-Isothiocyanatoisoquinoline (27.2) [00466] l,l'-thiocarbonyldiimidazole (3.78 g, 21.24 mmol) was added to a stirred solution of intermediate 27.1 (2.04 g) in CH2CI2 (20 mL), and the reaction was stirred at r.t. for 24 h. The mixture was concentrated under reduced pressure and purified by flash chromatography (PET/EtOAc from 85:15 to 60:40 v/v). 2.01 g of the title intermediate 27.2 were obtained (76%). [00467] MS-ESI(+) m/z: 187.3 (M+H). |
55% | In tetrahydrofuran; dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1; Synthesis of N-{ [3-(4-fluoro-2-methylphenvn-2-pyridinyl"|methyl) -5- isoquinolinamine; 1) N-[(3-Bromo-2-pyridinvOmethyl]-5-isoquinolinamine; To a solution of 3-bromo-2-pyridinecarboaldehyde (130 mg) in methanol (3.5 ml) was added 5-aminoisoquinoline (121 mg) and acetic acid (0.12 ml), and the reaction solution was stirred for 1 hour at room temperature. The reaction solution was cooled to 0C, and then sodium cyanoborohydride (67 mg) was added and stirring was conducted further for 1 hour at room temperature. The reaction solution was diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by a silica gel chromatography (hexane:ethyl acetate=9: l to 8:2) to obtain the title compound (163 mg) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: isoquinolin-5-ylamine; tert‐butyl 3‐aminopiperidine‐1‐carboxylate With acetic acid; sodium sulfate at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride at 20℃; for 18h; | To a solution of 5-amino-isoquinoline (47g, 0.320mol) in CH3COOH (1800mL) was added 3-amino- piperidine-1 -carboxylic acid tert-butyl ester (69.6g, 0.376mol) and Na2S04 (267g, 1 .88mol) at room temperature. The mixture was stirred at room temperate for 0.5 hour. Then to the mixture was added NaBH(OAc)3 (84.6g, 0.376mol) little by little. The mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH 8 by the addition of K2C03 and extracted with EtOAc(2L x 3). (The combined layers were dried over Na2S04, filtered and then concentrated in vacuo to afford crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate= 5: 1 ) to give 3-(isoquinolin-5-ylamino)-piperidine-1 -carboxylic acid tert-butyl ester (55g, 53%) as a yellow oil. |
53% | Stage #1: isoquinolin-5-ylamine; tert‐butyl 3‐aminopiperidine‐1‐carboxylate With acetic acid; sodium sulfate at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride at 20℃; for 18h; | B.B.1 Intermediate 4: Isoquinolin-5-yl-piperidin-3-yl-amine hydrochloric acid salt To a solution of 5-amino-isoquinoline (47 g, 0.320 mol) in CH3COOH (1800 mL) was added 3-amino-piperidine-1-carboxylic acid tert-butyl ester (69.6 g, 0.376 mol) and Na2SO4 (267 g, 1.88 mol) at room temperature. The mixture was stirred at room temperate for 0.5 hour. Then to the mixture was added NaBH(OAc)3 (84.6 g, 0.376 mol) little by little. The mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH 8 by the addition of K2CO3 and extracted with EtOAc(2 L*3). (The combined layers were dried over Na2SO4, filtered and then concentrated in vacuo to afford crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5: 1) to give 3-(isoquinolin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (55 g, 53%) as a yellow oil. |
53% | Stage #1: isoquinolin-5-ylamine; tert‐butyl 3‐aminopiperidine‐1‐carboxylate With sodium sulfate In acetic acid at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride at 20℃; for 18h; | To a solution of 5-amino-isoquinoline (47 g, 0.320 mol) in CH3COOH (1800 mL) was added 3- amino-piperidine-1-carboxylic acid tert-butyl ester (69.6 g, 0.376 mol) and Na2SO4 (267 g, 1.88 mol) at room temperature. The mixture was stirred at room temperature for 0.5 hour. Then to the mixture was added NaBH(OAc)3 (84.6 g, 0.376 mol) by portions. The mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH 8 by the addition of K2C03 and extracted with EtOAc (2 L x 3). The combined layers were dried over Na2SO4, filtered and then concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate= 5: 1) to give 3-(isoquinolin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (55 g, 53%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triethylamine In dichloromethane; acetonitrile at 0 - 20℃; | 4.1.2. General procedure for thiourea coupling General procedure: Procedure A: The isothiocyanate compound (1 equiv) was added to the solution of amine (1 equiv) in 5 ml of a mixture of dichloromethane and acetonitrile (1:1, v/v). The mixture was cooled to 0°C. Then, triethylamine (2 equiv) was added gradually. The mixture was stirred at 0°C for 15 min, after which stirring was continued at room temperature for 2-10 h. The reaction mixture was concentrated, extracted with dichloromethane, and washed with brine.The organic layer was dried over MgSO4 and purified by column chromatography (MeOH/CH2Cl2) or by preparative TLC (MeOH/CH2Cl2) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: isoquinolin-5-ylamine; 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium tris(acetoxy)borohydride In acetic acid at 0 - 20℃; Stage #2: With hydrogenchloride In diethyl ether for 6h; | Intermediate 2: N-(pyrrolidin-3-yI)isoquinolin-5-amine To a homogenous solution of isoquinolin-5-amine (15 g, 104 mmol) and tert-butyl 3-oxopyrrolidine- 1-carboxylate (23.12 g, 125 mmol, 1.2 eq) in AcOH (300 mL) at 0°C was added dropwise a solution of NaBH(OAc)3 (44.1 g, 208 mmol, 2 eq) in AcOH (200 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Then, the residue was adjusted to pH 10 by addition of saturated aqueous solution of Na2003 and extracted with DCM (x3). The combined organic layers were dried over Na2SO4, filtered and then concentrated under vacuum to afford the expected compound, which was used directly in the next step without further purification.To a solution of previous compound (104 mmol) in diethylether (1 L) was bubbled HCI gas for 1 hour. The suspension was stirred for 5 h and the solvent evaporated. Then, the residue was dissolved in water and the pH adjusted to pH >12 by addition of NaOH 5 M. The aqueous layer was extracted with DCM (x3) and the combined organic layers, dried over Na2SO4, filtered and concentrated under vacuum to give the intermediate 2 (20.5 g, 92%) as a brown powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With titanium(IV) dioxide In ethanol; water at 25 - 28℃; for 6h; | General experimental procedure for the synthesis of chromeno-oxazine derivatives General procedure: A mixture of 3-hydroxycoumarin (1mmol), amine (1 mmol), formaldehyde (2.2mmol, 37-41 % aqueous solution) and a catalytic amount of TiO2 nanopowder (10 mol %) inethyl alcohol (5 mL) were taken in a 25 mL round-bottomed with stirring at rt (25-28°C) open to air for 4-6 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered to remove TiO2 nanopowder.The solvent ethyl alcohol was then pumped out by rotary evaporation. The crude product thus obtained was purified directly by recrystallization from ethyl alcohol-water mixture (5:1 v/v).The spectral and analytical data of all compounds (4a-4q) reported in Table 2, are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.7% | With triethylamine; In pyridine; at 100℃; for 4h;Sealed tube; | 247A. 5-(4H-l,2,4-Triazol-4-yl)isoquinoline: Using a modified procedure described by Varano (Varano, F. et al, J. Med. Chem., 45(5): 1035-1044 (2002)). To two large microwave vials containing in equal portions a suspension of isoquinolin-5-amine (0.865 g, 6.0 mmol) and <strong>[628-36-4]N'-formylformohydrazide</strong> (0.793 g, 9 mmol) in pyridine (24 mL) was added, TMSI (5.71 mL, 45 mmol) dropwise followed by TEA (2.84 mL, 20.4 mmol). The reaction vessels were sealed and heated at 100 °C for 4 h. The reaction was cooled to room temperature, concentrated, the residue dissolved in EtOAc, washed with 1.5M potassium phosphate, brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by normal phase column chromatography to give a solid (0.467g, 39.7percent yield). NMR (400MHz, DMSO-d6) delta 9.45 (d, J = 0.7 Hz, 1H), 8.95 (s, 2H), 8.56 (d, J = 6.2 Hz, 1H), 8.35 - 8.30 (m, 1H), 7.93 (dd, J = 7.5, 1.1 Hz, 1H), 7.80 (dd, J = 8.1, 7.5 Hz, 1H), 7.29 (d, J = 6.2 Hz, 1H). MS (ESI) m/z: 197 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In acetonitrile at 20 - 85℃; | 5-Amino-2-cyclopropylmethyl-isoguinolinium bromide 5-Aminoisoquinoline (6 g, 41.6 mmol) is suspended in 30 mL MeCN and bromomethylcyclopropane (5.6 g, 41.6 mmol) is added. The reaction mixture is heated at 85°C for 2.5 h then stirred at RT overnight. Then bromomethylcyclopropane (1 g, 7.4 mmol) is added and the mixture is heated at 85°C for 5 h. The mixture is allowed to cool to RT andthe resulting solid is filtered over a sintered funnel then washed with ether and dried underHV. This yields 10.58 g (91%) of the sub-title compound as a yellow solid.LC-A: tR = 0.49 mm; [M] = 199.2 (Mass of cation) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | General procedure: To a well stirred 8-aminoquinoline (1 mmol) indry DMF (5 mL), sodium hydride (1.2 mmol, 60% in mineral oil) was added at 0 C.After 10 min stirring, the corresponding heterocyclic chloro compound (1.2mmol) was added and stirred for 10 min at rt then heated at 60 C for 5-12 h.Upon completion, the reaction mixture was poured into crushed ice and theresulting solid was filtered, washed with water and dried under vacuum. Thesolid was triturated with methanol and dried under vacuum to afford targetcompound as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: bis(trichloromethyl) carbonate; (4S)-7-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine With triethylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: isoquinolin-5-ylamine In tetrahydrofuran at 65℃; for 16h; Inert atmosphere; | 237 Synthesis of (4S)-N-(isoquinolin-5-yl)-7-(6-methylpyridin-3-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide To a solution of (4S)-7-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine (0.750 g, 2.97 mmol) in Tetrahydrofuran (THF) (40 mL) stirred under nitrogen at room temperature was added triethylamine (2.486 mL, 17.83 mmol) and triphosgene (0.882 g, 2.97 mmol). The reaction mixture was stirred at room temperature for 30 minutes before isoquinolin-5-amine (1.286 g, 8.92 mmol) was added. The reaction mixture was stirred at 65° C. for 16 hr and then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and Dichloromethane (100 mL). Organic layer was separated and was dried over anhydrous Na2SO4, filtered and filtrate was evaporated to give crude as brown solid (TLC eluent: 100% EtOAc: Rf-0.2; UV active). The crude was purified by column chromatography using neutral alumina and was eluted with 100% Dichloromethane to afford pure (4S)-N-(isoquinolin-5-yl)-7-(6-methylpyridin-3-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (0.315 g, 0.743 mmol, 25.00% yield) as a off-white solid, LCMS (m/z): 423.3 [M+H]+. 1H NMR (400 MHz, CDCl3): δ ppm 13.21 (s, 1H), 9.20 (s, 1H), 8.88 (d, J=2.19 Hz, 1H), 8.37 (d, J=7.23 Hz, 1H), 7.94 (d, J=6.14 Hz, 1H), 7.88 (dd, J=8.11, 2.41 Hz, 1H), 7.75 (d, J=8.11 Hz, 1H), 7.61-7.69 (m, 2H), 7.47 (d, J=5.92 Hz, 1H), 7.31 (d, J=7.89 Hz, 1H), 7.08 (d, J=7.89 Hz, 1H), 5.77 (dd, J=5.92, 3.29 Hz, 1H), 3.21-3.36 (m, 3H), 3.06 (dd, J=12.06, 3.07 Hz, 1H), 2.59 (s, 3H), 2.32-2.43 (m, 1H), 2.17 (dt, J=14.03, 7.02 Hz, 1H |
25% | Stage #1: bis(trichloromethyl) carbonate; (4S)-7-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine With triethylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: isoquinolin-5-ylamine In tetrahydrofuran at 65℃; for 16h; Inert atmosphere; | 209 Example 209 Synthesis of (4S)-N-(isoquinolin-5-yl)-7-(6-methylpyridin-3-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide To a solution of (4S)-7-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3- b][l,4]diazepine (0.750 g, 2.97 mmol) in Tetrahydrofuran (THF) (40 mL) stirred under nitrogen at room temperature was added triethylamine (2.486 mL, 17.83 mmol) and triphosgene (0.882 g, 2.97 mmol). The reaction mixture was stirred at room temperature for 30 minutes before isoquinolin-5-amine (1.286 g, 8.92 mmol) was added. The reaction mixture was stirred at 65 °C for 16 hr and then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and Dichloromethane (100 mL). Organic layer was separated and was dried over anhydrous Na2SC"4, filtered and filtrate was evaporated to give crude as brown solid (TLC eluent: 100% EtOAc: Rf-0.2; UV active). The crude was purified by column chromatography using neutral alumina and was eluted with 100% Dichloromethane to afford pure (4S)-N-(isoquinolin-5-yl)-7-(6-methylpyridin-3-yl)-3,4- dihydro-l,4-methanopyrido[2,3-b][l,4]diazepine-5(2H)-carboxamide (0.315 g, 0.743 mmol, 25.00 % yield) as a off- white solid, LCMS (m/z): 423.3 [M+H]+.1H NMR (400 MHz, CDC13): δ ppm 13.21 (s, 1 H), 9.20 (s, 1 H), 8.88 (d, J=2.19 Hz, 1 H), 8.37 (d, J=7.23 Hz, 1 H), 7.94 (d, J=6.14 Hz, 1 H), 7.88 (dd, J=8.11, 2.41 Hz, 1 H), 7.75 (d, J=8.11 Hz, 1 H), 7.61 - 7.69 (m, 2 H), 7.47 (d, J=5.92 Hz, 1 H), 7.31 (d, J=7.89 Hz, 1 H), 7.08 (d, J=7.89 Hz, 1 H), 5.77 (dd, J=5.92, 3.29 Hz, 1 H), 3.21 - 3.36 (m, 3 H), 3.06 (dd, J=12.06, 3.07 Hz, 1 H), 2.59 (s, 3 H), 2.32 - 2.43 (m, 1 H), 2.17 (dt, J=14.03, 7.02 Hz, 1 H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With trifluoroacetic acid In trifluoroacetic acid at 25℃; Inert atmosphere; diastereoselective reaction; | Synthesis of 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,7 (7-10) and 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,8phenanthrolines (11-14) (general procedure). The compound CF3COOH (0.08 mL, 1 mmol), a freshly distilled cyclopentadiene (0.33 mL, 4 mmol), and the corresponding aldehyde 3-6 (1 mmol) were sequentially added to a solution of aminoquinoline 1 or 2 (144 mg, 1 mmol) in anhydrous CF3CH2OH (15 mL) (Ar, ~25 °C). The reaction mixture was stirred at room temperature until the amine disappeared (2-3 h, TLC monitoring, eluent ethyl acetate). The solvent was evaporated, a saturated solution of NaHSO3-NaHCO3 was added to the residue untilneutrality (~5 mL), followed by extraction with ethyl acetate (3×10 mL). The organic layer was concentrated, the residue was subjected to chromatography (SiO2, n-hexane/ethyl acetate,4 : 1) to isolate the corresponding 1,7- (7-10) or 1,8- phenanthrolines (11-14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With trifluoroacetic acid In trifluoroacetic acid at 25℃; Inert atmosphere; diastereoselective reaction; | Synthesis of 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,7 (7-10) and 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,8phenanthrolines (11-14) (general procedure). The compound CF3COOH (0.08 mL, 1 mmol), a freshly distilled cyclopentadiene (0.33 mL, 4 mmol), and the corresponding aldehyde 3-6 (1 mmol) were sequentially added to a solution of aminoquinoline 1 or 2 (144 mg, 1 mmol) in anhydrous CF3CH2OH (15 mL) (Ar, ~25 °C). The reaction mixture was stirred at room temperature until the amine disappeared (2-3 h, TLC monitoring, eluent ethyl acetate). The solvent was evaporated, a saturated solution of NaHSO3-NaHCO3 was added to the residue untilneutrality (~5 mL), followed by extraction with ethyl acetate (3×10 mL). The organic layer was concentrated, the residue was subjected to chromatography (SiO2, n-hexane/ethyl acetate,4 : 1) to isolate the corresponding 1,7- (7-10) or 1,8- phenanthrolines (11-14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With trifluoroacetic acid In trifluoroacetic acid at 25℃; Inert atmosphere; diastereoselective reaction; | Synthesis of 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,7 (7-10) and 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,8phenanthrolines (11-14) (general procedure). The compound CF3COOH (0.08 mL, 1 mmol), a freshly distilled cyclopentadiene (0.33 mL, 4 mmol), and the corresponding aldehyde 3-6 (1 mmol) were sequentially added to a solution of aminoquinoline 1 or 2 (144 mg, 1 mmol) in anhydrous CF3CH2OH (15 mL) (Ar, ~25 °C). The reaction mixture was stirred at room temperature until the amine disappeared (2-3 h, TLC monitoring, eluent ethyl acetate). The solvent was evaporated, a saturated solution of NaHSO3-NaHCO3 was added to the residue untilneutrality (~5 mL), followed by extraction with ethyl acetate (3×10 mL). The organic layer was concentrated, the residue was subjected to chromatography (SiO2, n-hexane/ethyl acetate,4 : 1) to isolate the corresponding 1,7- (7-10) or 1,8- phenanthrolines (11-14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With trifluoroacetic acid In trifluoroacetic acid at 25℃; Inert atmosphere; diastereoselective reaction; | Synthesis of 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,7 (7-10) and 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,8phenanthrolines (11-14) (general procedure). The compound CF3COOH (0.08 mL, 1 mmol), a freshly distilled cyclopentadiene (0.33 mL, 4 mmol), and the corresponding aldehyde 3-6 (1 mmol) were sequentially added to a solution of aminoquinoline 1 or 2 (144 mg, 1 mmol) in anhydrous CF3CH2OH (15 mL) (Ar, ~25 °C). The reaction mixture was stirred at room temperature until the amine disappeared (2-3 h, TLC monitoring, eluent ethyl acetate). The solvent was evaporated, a saturated solution of NaHSO3-NaHCO3 was added to the residue untilneutrality (~5 mL), followed by extraction with ethyl acetate (3×10 mL). The organic layer was concentrated, the residue was subjected to chromatography (SiO2, n-hexane/ethyl acetate,4 : 1) to isolate the corresponding 1,7- (7-10) or 1,8- phenanthrolines (11-14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In neat (no solvent) at 120℃; for 0.166667h; Microwave irradiation; | General procedure for the synthesis of 7-chloro-4-aryl amino-substituted quinoline compounds General procedure: A mixture of 4,7-dichloroquinoline (1, 1.2 mmol) and therespective aryl/heteroaryl amino compounds (2a-2g,1.0 mol) was mixed thoroughly with the use of glass rod ina microwave vessel and subjected to microwave irradiation(Biotage microwave oven, 120 C, 2 bar pressure) for10 min. The progress of the reaction was monitored bythin-layer chromatography. After completion of the reaction,the reaction mixture was cooled and washed withaqueous methanol. The crude product obtained was driedand recrystallized from methanol to afford pure 4-arylaminosubstituted quinoline compounds 3a-3g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap In tetrahydrofuran at 0 - 20℃; | 3 General procedure for the synthesis of 3-bromo-N-substituted propanamide derivatives (2-8) General procedure: A solution of the appropriate amine (1 equiv) and 4-(dimethylamino)pyridine (DMAP) (0.47 equiv) in dry THF was added dropwise to a solution of 3-bromopropionyl chloride (1.5equiv) in THF (10mL) cooled at 0°C. The reaction mixture was kept under vigorous stirring at rt for 4h and then was quenched with H2O and extracted with CHCl3. The organic phase was washed with a saturated aqueous solution of NaHCO3 and brine, and dried over anhydrous Na2SO4. After the solvent was removed in vacuo, the residue was purified by flash chromatography using a silica gel column with a cyclohexane/AcOEt (7/3) solvent system to give the compounds (1-7) as solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With pyridine In dichloromethane at 0 - 20℃; for 1h; | 1 Synthesis of compound 28 A solution 1003 (75 mg, 0.29 mmol) in CH2CI2 (5 mL) was treated with pyridine (0.1 mL) followed by 1004 (42 mg, 0.29 mmol) at 0°C. After being stirred at room temperature for Ih, the reaction mixture was diluted with CH2CI2 (15 mL), washed with water (5 mL) and brine (5mL). The organic phase was separated, dried over anhydrous NaiSC^, filtered and concentrated in vacuo to give a brown solid residue. This residue was further purified by Combiflash column chromatography using 4 g redisep column (hexane/EtOAc, 1 : 1 ) to afford 28 (35 mg, 33%) as an off-white solid. MS (MM) m/z 356 [M+H]+; HPLC: 99%, Symmetry C-18 column, 220 nm;1H NMR (300 MHz, DMSC /,,): δ 10.3 (s, IH), 9.48 (s,lH), 8.50 (d, J = 6.3 Hz, IH), 8.09 (t, J= 9.0 Hz, 2H), 7.72 (t, J= 8.1 Hz, IH), 7.58 (d, J= 7.5 Hz, IH), 6.86-6.84 (m, J= 2H), 6.69 (d, J= 8.4 Hz, 1H), 4.23 (t, J= 3.9 Hz , 2H), 3.21 (t, J= 3.9 Hz, 2H), 2.69 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrabutylammomium bromide; sodium carbonate; sulfur In water at 80℃; for 5h; | 47 Example 47 Preparation of 5-isothiocyanatoisoquinoline (12) To a 100 ml two-neck flask equipped with a magnetic stirrer was added 1.44 g (10 mmol) of Compound 2,0.058 g (4% wt) of sulfur,0.058 g (4% wt) of sodium carbonate,0.058 g (4% wt) of tetrabutylammonium bromide,Water 15ml,At 80 & lt;0.84 g (10 mmol) of carbon disulfide was slowly added dropwise under rapid stirring.The reaction is highly exothermic and produces hydrogen sulphide gas.After completion, stirring was continued for 5 hours until pale yellow crystals precipitated,Filtration, washing, drying,Ethyl acetate,A white flake crystal was obtained,That is, 1.77 g of 5-isothiocyanatoisoquinoline (12)Yield: 95%. |
100 %Chromat. | Stage #1: carbon disulfide; isoquinolin-5-ylamine With triethylamine In tetrahydrofuran at 20℃; Stage #2: With dmap; di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 0 - 20℃; | 4 5.1.2. General procedure for the synthesis of isothiocyanates for electron rich aromatic amines (2) General procedure: This procedure was employed to generate corresponding isothiocyanates for final thioureas 3-9 and 14-23. The reverse process,where 1H-indole-5-isothiocyanate was firstly generated followedby subsequent coupling with corresponding amine, was used forfinal thioureas with free phenolic groups (4-7, 17, 19, 21 and 23). An amine (1; 3 mmol) was dissolved in THF (5 mL). While stirring,CS2 (30 mmol, 2.28 g, 1.80 mL) and Et3N (3 mmol, 0.30 g,0.42 mL) were added. After the complete conversion to dithiocarbamic acid salt (monitored via TLC, generally within 30-60 min),the reaction mixture was cooled on an ice bath with immediate addition of Boc2O (2.97 mmol, 0.65 g, 1 mL THF solution) and DMAP (0.03 mmol, 11 mg, 0.5 mL THF solution). Complete consumption of dithiocarbamic acid salt proceeded within 15-60 min. Solvent and other volatiles were removed under reduced pressure yielding isothiocyanate (2) quantitatively (TLC) and used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol at 20℃; for 1h; Green chemistry; | 1 3-[(isoquinolin-5-yl)amino]-2-benzofuran-1(3H)-one (Ia) At room temperature, 2-carboxy benzaldehyde (1.1mol) with 5-amino-isoquinoline (1mol) in methanol solvent system, followed by stirring for 1 hour and then filtered, the solid washed with 95% ethanol to obtain a crude product. Silica gel column chromatography (eluent : chloroform / methanol (40/1)) and concentrated to give a white solid after purification, a yield of 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran at 20℃; for 24h; | 2.3.2. General procedure for synthesis of the compounds 2a-2ofrom the compound 2 General procedure: A solution of the compound 2 (0.50 g, 0.580 mmol) and primaryamine derivatives (6.960 mmol) in THF (50 mL) was stirred for24 h at room temperature. THF was removed under vacuum. AfterCH2Cl2 (5 mL) was poured into the residual mixture, the solutionwas slowly added to ethanol (80 mL) and a solid precipitated out.The resulting solidwas filtered,washed with hexane and then driedat room temperature. (The name of the color of the compoundswasmentioned in the web site: http://en.wikipedia.org) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In tetrahydrofuran at 20℃; for 24h; | 2.3.4. General procedure for synthesis of the compounds 3a-3ofrom the compound 3 General procedure: A solution of the compound 3 (0.4 g, 0.384 mmol) and primaryamine derivatives (4.608 mmol) in THF (50 mL) was stirred for24 h at room temperature. THF was removed under vacuum. AfterCH2Cl2 (5 mL) was poured into the residual mixture, the solutionwas slowly added to ethanol (80 mL) and a solid precipitated out.The resulting solidwas filtered,washed with hexane and then driedat room temperature. (The name of the color of the compoundswasmentioned in the web site: http://en.wikipedia.org) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | With sodium cyanoborohydride; acetic acid; sodium sulfate at 20℃; Cooling with ice; | 3 According to the above synthetic line PT109,Compound 5 (442.31 mg, 2.07 mmol),5-aminoisoquinoline (230.00 mg, 1.60 mmol) and anhydrous Na2SO4 (1.13 g, 7.98 mmol) were dissolved in glacial acetic acid (10 mL)Sodium cyanoborohydride (200.50 mg, 3.19 mmol) was added under ice-cooling,The ice bath was removed and the reaction was stirred overnight at room temperature.After completion of the reaction, glacial acetic acid was removed by a rotary evaporator, and the saturated NaHCO3 solution was added to the residue,The aqueous phase was extracted with DCM.The combined organic phases were washed with saturated brine (10 mL x 1), dried over anhydrous Na2SO4, and the solvent was removed by rotary distillation. The residue was passed through a silica gel columnChromatography to give compound 6 as a yellow solid (372 mg, yield 68.3%). |
68.3% | With sodium cyanoborohydride; acetic acid; sodium sulfate In methanol at 0 - 20℃; | Synthesis of tert-butyl (4-(isoquinolin-5-ylamino)cyclohexyl)carbamate (14): To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (442.31mg, 2.07mmol), isoquinolin-5-amine (230.00mg, 1.60mmol) and anhydrous Na2SO4 (1.13g, 7.98mmol) in AcOH (10ml), NaBH3CN (200.50mg, 3.19mmol) was added dropwise at 0°C. The reaction mixture was stirred at rt overnight and evaporated to remove AcOH. The resulting mixture was basified with saturated NaHCO3 aq (10ml). The aqueous layer was extracted with DCM (20ml×3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (MeOH/DCM 1/100-1/50) to give the compound 14 as a dense yellow oil (372mg, 1.09mmol, 68.3% yield). 1H NMR (400MHz, CDCl3) δ 9.15 (s, 1H), 8.46 (s, 1H), 7.53 (s, 1H), 7.49-7.39 (m, 1H), 7.30 (s, 1H), 6.77 (s, 1H), 4.71-4.12 (m, 2H), 3.55 (m, 3H), 2.27 (d, J=12.0Hz, 1H), 2.14 (d, J=12.6Hz, 1H), 2.06-1.88 (m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.34 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.2% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 5 A mixture of compound 10 (279.89 mg, 1.22 mmol), 5-aminoisoquinoline (160.00 mg, 1.11 mmol), DMAP(13.56 mg, 110.98 [mu] mol) was dissolved in anhydrous DCM (8 ml) and triethylamine (461.50 [mu] L, 3.33 mmol)And EDCI (319.12 mg, 1.66 mmol) were added and stirred at room temperature overnight. After completion of the reaction, water (10 mL) was quenched and the aqueous phaseThe combined organic phases were washed with saturated brine (10 mL x 1), dried over anhydrous Na2SO4 and evaporated to remove the solvent,The residue was purified by silica gel column chromatography to give white solid intermediate 11 (174.30 mg, 490.39 μmol, yield 44.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | Stage #1: isoquinolin-5-ylamine; 4-(N-tert-butoxycarbonyl)aminobenzoic acid With dmap; triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 6 Compound 12 (200.00 mg, 1.39 mmol), 5-aminoisoquinoline was synthesized according to the above synthetic scheme of PT133(427.86 mg, 1.80 mmol), DMAP (16.95 mg, 138.72 mol), triethylamine (576.87 [mu] L, 4.16 mmol) was dissolved in dry DCM,After stirring at room temperature for 30 minutes, EDCI (797.80 mg, 4.16 mmol) was added in one portion,The reaction was complete overnight and quenched with water (10 mL). The aqueous phase was extracted with DCM and the combined organic phases were washed with saturated brine (10 mL x 1)Washed, dried over anhydrous Na2SO4, and the residue was purified by silica gel column chromatography to give white solid intermediate 13(426, 1.17 mmol, yield 84.5%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In 1,4-dioxane at 90℃; | 348 Example 348: Synthesis of Ethyl 4-(3-(isoguinolin-5-yl)ureido)benzoate To a solution of 4-isocyanato-benzoic acid ethyl ester (100 mg, 0.523 mmol) in dioxane(20 mL) was added isoquinolin-5-ylamine (90.5 mg, 0.628 mmol), followed by TEA (158 mg, 1.57mmol). The resulting mixture was stirred at 90°C overnight. The reaction was monitored by LC-MS.Then the mixture was concentrated in vacuum to give a residue, which was purified by prep-TLC(DCMIMeOH = 20/1) to afford ethyl 4-(3-(isoquinolin-5-yl)ureido)benzoate (167.2 mg, yield: 95%)as a brown solid. ‘H NIVIR (400 IVIHz, DMSO-d6): 5= 9.49 (brs, 1H), 9.34 (s, 1H), 9.03 (s, 1H),8.61 (d, J= 6.0 Hz, 1H), 8.29 (d, J= 7.6 Hz, 1H), 7.98 (d, J 5.6 Hz, 1H), 7.93 (d, J 8.4 Hz, 2H),7.87 (d, J= 8.4 Hz, 1H), 7.71-7.62 (m, 3H), 4.29 (q, J= 7.2 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H). MS:m/z 336.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.5% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: C11H14N2O*ClH In dichloromethane at 20℃; for 12h; Inert atmosphere; | 1 4.2.4. General procedure for the preparation of 3a-w General procedure: The solution of 6 (300 mg, 2.08 mmol) in CH2Cl2 (20 mL) was addeddropwise to a stirred solution of triphosgene (415 mg, 1.39 mmol) inCH2Cl2 (20 mL) under nitrogen. Then DMAP (750 mg, 6.15 mmol) wasadded to the mixture. The reaction mixture was stirred for 30 min,followed by added solution of 10a-w (2.08 mmol) in CH2Cl2 (20 mL)and stirred for an additional 12 h at room temperature. The reactionmixture was monitored by TLC and washed with water to removeDMAP. The organic layer was dried over Na2SO4 and concentrated byrotary evaporation to give the red-brown crude product. The residuewas purified by flash column chromatography eluting with CH2Cl2/CH3OH (20:1) to obtain 3a-w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: C11H13BrN2O*ClH In dichloromethane at 20℃; for 12h; Inert atmosphere; | 2 4.2.4. General procedure for the preparation of 3a-w General procedure: The solution of 6 (300 mg, 2.08 mmol) in CH2Cl2 (20 mL) was addeddropwise to a stirred solution of triphosgene (415 mg, 1.39 mmol) inCH2Cl2 (20 mL) under nitrogen. Then DMAP (750 mg, 6.15 mmol) wasadded to the mixture. The reaction mixture was stirred for 30 min,followed by added solution of 10a-w (2.08 mmol) in CH2Cl2 (20 mL)and stirred for an additional 12 h at room temperature. The reactionmixture was monitored by TLC and washed with water to removeDMAP. The organic layer was dried over Na2SO4 and concentrated byrotary evaporation to give the red-brown crude product. The residuewas purified by flash column chromatography eluting with CH2Cl2/CH3OH (20:1) to obtain 3a-w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.3% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: C12H16N2O*ClH In dichloromethane at 20℃; for 12h; Inert atmosphere; | 10 4.2.4. General procedure for the preparation of 3a-w General procedure: The solution of 6 (300 mg, 2.08 mmol) in CH2Cl2 (20 mL) was addeddropwise to a stirred solution of triphosgene (415 mg, 1.39 mmol) inCH2Cl2 (20 mL) under nitrogen. Then DMAP (750 mg, 6.15 mmol) wasadded to the mixture. The reaction mixture was stirred for 30 min,followed by added solution of 10a-w (2.08 mmol) in CH2Cl2 (20 mL)and stirred for an additional 12 h at room temperature. The reactionmixture was monitored by TLC and washed with water to removeDMAP. The organic layer was dried over Na2SO4 and concentrated byrotary evaporation to give the red-brown crude product. The residuewas purified by flash column chromatography eluting with CH2Cl2/CH3OH (20:1) to obtain 3a-w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: C12H16N2O*ClH In dichloromethane at 20℃; for 12h; Inert atmosphere; | 11 4.2.4. General procedure for the preparation of 3a-w General procedure: The solution of 6 (300 mg, 2.08 mmol) in CH2Cl2 (20 mL) was addeddropwise to a stirred solution of triphosgene (415 mg, 1.39 mmol) inCH2Cl2 (20 mL) under nitrogen. Then DMAP (750 mg, 6.15 mmol) wasadded to the mixture. The reaction mixture was stirred for 30 min,followed by added solution of 10a-w (2.08 mmol) in CH2Cl2 (20 mL)and stirred for an additional 12 h at room temperature. The reactionmixture was monitored by TLC and washed with water to removeDMAP. The organic layer was dried over Na2SO4 and concentrated byrotary evaporation to give the red-brown crude product. The residuewas purified by flash column chromatography eluting with CH2Cl2/CH3OH (20:1) to obtain 3a-w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.7% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: C13H18N2O3*ClH In dichloromethane at 20℃; for 12h; Inert atmosphere; | 22 4.2.4. General procedure for the preparation of 3a-w General procedure: The solution of 6 (300 mg, 2.08 mmol) in CH2Cl2 (20 mL) was addeddropwise to a stirred solution of triphosgene (415 mg, 1.39 mmol) inCH2Cl2 (20 mL) under nitrogen. Then DMAP (750 mg, 6.15 mmol) wasadded to the mixture. The reaction mixture was stirred for 30 min,followed by added solution of 10a-w (2.08 mmol) in CH2Cl2 (20 mL)and stirred for an additional 12 h at room temperature. The reactionmixture was monitored by TLC and washed with water to removeDMAP. The organic layer was dried over Na2SO4 and concentrated byrotary evaporation to give the red-brown crude product. The residuewas purified by flash column chromatography eluting with CH2Cl2/CH3OH (20:1) to obtain 3a-w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | In neat (no solvent); at 180℃; for 0.5h; | General procedure: 2-Chloro-NH substituted quinoline amines were prepared asdescribed, by one of the co-authors, in literature (Vennilaet al. 2010; Prabha and Prasad 2014). In a typical experiment, an equimolar mixture of 8-methyl or 6-chloroquinoline (0.01 mol) and varieties of aminoquinoline/aminocarboxylicacids (0.01 mol) was heated under neat condition.The reaction was monitored by TLC. The productobtained was washed with water, dried and purified bysilica gel column chromatography ethylacetate:methanol(99:1) as an eluent to get the respective 4-amino substitutedproducts which was recrystallized using ethanol (Scheme2). The reaction temperature and time are collected in Table2. The prepared compounds were characterized by elementalanalysis, IR, 1H NMR and mass studies (Fig. S2).The results obtained are accordance with those reportedearlier. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
36% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | 3 2-Chloro-N-(isoquinolin-5-yl)acetamide (TRH 1-163). To a solution 5- aminoisoquinoline (289 mg, 2.0 mmol) in dichloromethane (10 mL) was added chloroacetyl chloride (0.19 mL, 2.4 mmol) followed by triethylamine (0.34 mL, 2.4 mmol) at 0 C under N2 atmosphere. After stirring for 20 minutes, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, and the resulting crude was purified by chromatography on basic alumina (30% ethyl acetate in hexanes to 4% ethanol in ethyl acetate) to yield 157 mg of yellow solid (36% yield).1H NMR (600 MHz, MeOD): d 9.26 (s, 1H), 8.48 (d, J = 6.1 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 4.39, (s, 2H).13C NMR (150 MHz, MeOD): d 167.4, 152.1, 141.7, 131.8, 131.2, 129.2, 127.3, 127.0, 126.1, 115.7, 42.3. HRMS (+ESI): Calculated: 221.0476 (C11H10N2O). Observed: 221.0473. |
31% | With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | General procedure D: Synthesis of acetamides 3n-w General procedure: To a solution of a substituted aniline 24n-w (1 equiv.) and triethylamine (1.2 equiv.) in CH2Cl2 at 0 C was added chloroacetyl chloride (1.2 equiv.) over 15 minutes and the reaction stirred for 1 h at 0 C, followed by 2 h at r.t.. The salt was filtered off and washed with CH2Cl2 and EtOAc. This was dissolved in 1:1 MeOH/H2O, basified with sat. NaHCO3 and extracted with CH2Cl2 followed by drying with Na2SO4. The solvent was removed in vacuo to give the acetamides 3n-w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With water; sodium cyanoborohydride In acetonitrile at 0 - 20℃; | 2-(Isoquinolin-5-ylamino)acetic acid To a solution of 5-aminoisoquinoline (1g, 6.94 mmol) in 15 mL MeCN cooled to 0°C is added 1.54 mL 50% glyoxylic acid soln. in water and NaBH3CN (872 mg, 13.9 mmol). The mixture is allowed to warm up to RT and is stirred at this temperature overnight. Then MeCN isevaporated under reduced pressure, the residue is taken up in water (pH=9). The resulting aq. phase is extracted with ether. The aq. phase is then acidified with 1 N HCI soln. and the solvent is evaporated under reduced pressure. The residue is dissolved with MeOH and eluted on a SiliaBond SCX acid column. It is released with ammonia. After evaporation, the crude is dissolved in 1 N HCI aq. soln. and heated up at 85°C for 2 h. Evaporation of thevolatiles to dryness and under HV yields 820 mg (58%) of the title compound as a whitesolid.1H-NMR (d6-DMSO) ö: 9.59 Cs, 1 H), 8.64 Cd, J = 6.8 Hz, 1 H), 8.48 (dd, J1 = 6.9 Hz, J2 = 0.6Hz, 1 H), 7.86 Ct, J= 8.1 Hz, 1 H), 7.75 Cm, 1 H), 7.13 Cd, J= 7.8 Hz, 1 H), 4.23 (s,2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.6% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: tetrahydrobetacarboline In dichloromethane at 20℃; for 12h; Inert atmosphere; | General procedure for the preparation of7. The solution oftriphosgene (0.88 mmol) in CH2Cl2(5 mL) was added dropwise to a stirred solution of aromatic amine (2.75 mmol) in CH2Cl2(20 mL) under nitrogen. Then DMAP (7.5 mmol) was added to the mixture. The reaction mixture was stirred for 30 min, followed by added solution of1,2,3,4-Tetrahydro-9H-pyrido[3,4-b]indole (5, 2.5 mmol)in CH2Cl2(20 mL) and stirred for an additional 12 h at room temperature. Upon completion of the reaction, 10 mL of water added to terminate the reaction. Then the organic layer was washed with 2N hydrochloric acid (40 mL × 2), saturated NaHCO3aqueous solution (40 mL × 2), aqueous brine (40 mL × 2), dried over Na2SO4, and concentrated to yield crude product. The residue was purified by flash column chromatography eluting with CH2Cl2/CH3OH (80:1) to obtain7a-w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In acetonitrile at 70 - 75℃; for 11h; Inert atmosphere; | |
95% | In acetonitrile at 70 - 75℃; for 11h; chemoselective reaction; | 1,3-Bisphosphoryl-1,2,3,4-tetrahydroisoquinolines 3a-e (general procedure). General procedure: A mixture of isoquinoline 1a,b (1.0 mmol) and secondary phosphine oxide 2a-c (2.0 mmol) in MeCN (0.1-0.2 mL) or without solvent (see Table 1) was stirred at 70-75°C for 10-15 h until the signal of the starting phosphine oxide completely disappeared from the 31P NMR spectrum. After the reaction completion in the case of tetrahydroisoquinoline 3-c,e, the products were reprecipitated from CHCl3 into hex-ane. In the case of tetrahydroisoquinoline 3d, the product was recrystallized from acetone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In acetonitrile at 70 - 75℃; for 14h; Inert atmosphere; | |
91% | In acetonitrile at 70 - 75℃; for 14h; chemoselective reaction; | 1,3-Bisphosphoryl-1,2,3,4-tetrahydroisoquinolines 3a-e (general procedure). General procedure: A mixture of isoquinoline 1a,b (1.0 mmol) and secondary phosphine oxide 2a-c (2.0 mmol) in MeCN (0.1-0.2 mL) or without solvent (see Table 1) was stirred at 70-75°C for 10-15 h until the signal of the starting phosphine oxide completely disappeared from the 31P NMR spectrum. After the reaction completion in the case of tetrahydroisoquinoline 3-c,e, the products were reprecipitated from CHCl3 into hex-ane. In the case of tetrahydroisoquinoline 3d, the product was recrystallized from acetone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetone at 20℃; for 2h; | 11.a a. 5-Amino-2-methylisoquinolin-2-ium (83A) To a solution of isoquinolin-5-amine (82A) (2.0 g, 13.9 mmol, 1.0 eq) in acetone (42 mL) was added iodomethane (2 mL, 32.1 mmol, 2.3 eq). After stirring for 2 hours at room temperature, the precipitated yellow solid was filtered and washed with acetone. After drying under vacuum the compound (83A) (2.2 g, quantitative yield) was isolated as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 86.4% 2: 13.4% | With 1 % platinum on carbon; hydrogen In tetrahydrofuran at 40℃; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 64.9% 2: 27.8% 3: 6.8% | With 1 % platinum on carbon; hydrogen In tetrahydrofuran at 110℃; Flow reactor; | |
1: 41.615% 2: 39.3% 3: 19.1% | With 1 % platinum on carbon; hydrogen In tetrahydrofuran at 150℃; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: isoquinolin-5-ylamine With ethylmagnesium bromide In tetrahydrofuran; diethyl ether for 0.0833333h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; diethyl ether at 20℃; for 3h; Inert atmosphere; | 39 Example 39: A-Methylisoquinolin-5-amine (39.1) [00498] 3.0 M EtMgBr in Et20 (E16 mL, 3.47 mmol) was added dropwise to a solution of intermediate 27.1 (500 mg, 3.47 mmol) in THF (8 mL) maintained under N2 atmosphere. After 5 minutes, Mel (195 mL, 3.12 mmol) was added dropwise and the resulting fine suspension was reacted at r.t. for 3 h. The mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 0.5 M aq. citric acid (30 mL), H2O (30 mL), and brine (30 mL), dried over anhydrous Na2SC>4, and evaporated to dryness. After purification by flash chromatography (DCM/MeOH, from 98:2 v/v to 94:6 v/v) the title intermediate 39.1 (265 mg, 1.66 mmol) was obtained. Yield: 48%. MS-ESI(+) m/z: 159.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: (3R,4R)-1-(tert-butoxycarbonyl)-4-(1,3-thiazol-2-yl)pyrrolidine-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 20℃; for 0.75h; Inert atmosphere; Stage #2: isoquinolin-5-ylamine With ethylmagnesium bromide In tetrahydrofuran; diethyl ether at 20℃; for 16h; Inert atmosphere; | 121.1 Step 1: tert-Butyl (3R, 4R)-4-(1, 3-thiazol-2-yl)-3-(isoauinolin-5-ylcarbamoyl)pyrrolidine-l- carboxylate (121.1) [00712] Intermediate 121.1 was prepared according to the procedure described in Step 1 of Example 64 starting from a solution of intermediate 21.7 (300 mg, 0.95 mmol), HATU (472 mg, 1.24 mmol), DIPEA (0.49 mL, 2.85 mmol), 3.0 M EtMgBr in Et20 (0.95 mL, 2.85 mmol), and intermediate 27.1 (205 mg, 1.42mmol) in THF (5 mL + 5 mL). Stirring was continued at r.t. for 16h. After purification by flash chromatography (DCM/MeOH from 100% DCM to 97:3 v/v DCM/MeOH), the intermediate 121.1 (150 mg, 0.35 mmol) was obtained as a colorless oil. Yield 37%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: (3R,4S)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 20℃; for 0.75h; Inert atmosphere; Stage #2: isoquinolin-5-ylamine With ethylmagnesium bromide In tetrahydrofuran; diethyl ether at 20℃; for 16h; Inert atmosphere; | 144.1 Step 1: tert-Butyl (3R, 4S)-4-(4-fluorovhenyl)-N-(isoqumolm-5-yl)vyrrolidine-3-carboxamide- 1-carboxylate (144.1) [00773] Intermediate 144.1 was prepared according to the procedure described in Step 1 of Example 64 starting from a solution of intermediate 23.5 (250 mg, 0.81 mmol), HATU (399 mg, 1.05 mmol), DIPEA (0.42 mL, 2.43 mmol), 3.0 M EtMgBr in Et20 (0.81 mL, 2.43 mmol), and intermediate 27.1 (140 mg, 0.97 mmol) in THF (5 mL + 5 mL). Stirring was continued at r.t. for 16h. After purification by flash chromatography on NH-based silica gel, eluting with (PET/EtOAc from 100% PET to 70:30 v/v PET/EtOAc), the intermediate 144.1 (160 mg, 0.45 mmol) was obtained as a brownish oil. Yield 56%. MS-ESI(+) m/z: 436.6 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.3% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: (S)-5-phenyl-2-(pyrrolidin-2-yl)thiazole In dichloromethane for 12h; Inert atmosphere; | 4.2.9 General procedure for the preparation of 7 General procedure: The solution of substituted aniline (3.138mmol) in dry CH2Cl2 (20mL) was added dropwise to a stirred solution of triphosgene (317mg, 1.070mmol) in CH2Cl2 (20mL) under nitrogen. Then 4-dimethylaminopyridine (1.153g, 9.414mmol) was added to the mixture. The reaction mixture was stirred for 30min, followed by added solution of intermediate 14 in CH2Cl2 (20mL) and reacted overnight (12h). Water (2mL) was added to stop the reaction, the reaction solution was washed with brine (30mL×3), and the aqueous phase was extracted with CH2Cl2 (30mL×2). The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2: MeOH=80:1) to obtain 7a-aa. |
78.3% | Stage #1: isoquinolin-5-ylamine; bis(trichloromethyl) carbonate With dmap In dichloromethane for 0.5h; Inert atmosphere; Stage #2: (S)-5-phenyl-2-(pyrrolidin-2-yl)thiazole In dichloromethane for 12h; Inert atmosphere; | 4.2.9 General procedure for the preparation of 7 General procedure: The solution of substituted aniline (3.138mmol) in dry CH2Cl2 (20mL) was added dropwise to a stirred solution of triphosgene (317mg, 1.070mmol) in CH2Cl2 (20mL) under nitrogen. Then 4-dimethylaminopyridine (1.153g, 9.414mmol) was added to the mixture. The reaction mixture was stirred for 30min, followed by added solution of intermediate 14 in CH2Cl2 (20mL) and reacted overnight (12h). Water (2mL) was added to stop the reaction, the reaction solution was washed with brine (30mL×3), and the aqueous phase was extracted with CH2Cl2 (30mL×2). The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2: MeOH=80:1) to obtain 7a-aa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane In 1,4-dioxane at 120℃; for 16h; Sealed tube; | 60 Example 60: SN39323 1-Cyclopentyl-6-(isoquinolin-5-ylamino)-3-methyl-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2-one (66). A degassed mixture of chloride 6 (120 mg, 0.48 mmol), isoquinolin-5-amine (83 mg, 0.57 mmol), Pd2dba3(22 mg, 24 µmol), XPhos (46 mg, 96 µmol) and Cs2CO3(344 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 h. The mixture was cooled, diluted with EtOAc (30 mL), filtered through diatomaceous earth and the filtrate was evaporated. The residue was partitioned between EtOAc (50 ml) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give imidazopyridinone 66 (73 mg, 43%) as a cream powder: mp (EtOAc/MeOH) 234-237 °C;1H NMR (CDCl3) δ 9.28 (d, J = 0.6 Hz, 1 H, H-1), 8.53 (d, J = 6.0 Hz, 1 H, H-3), 7.86 (s, 1 H, H-4), 7.73-7.82 (m, 3 H, H-4, H-6, H-8), 7.58 (dd, J = 7.9, 7.8 Hz, 1 H, H-7), 6.83 (br s, 1 H, 6-NH), 6.44 (d, J = 0.6 Hz, 1 H, H-7), 4.74 (pent, J = 8.8 Hz, 1 H, 1-CH), 3.41 (s, 3 H, 3-CH3), 1.83-1.99 (m, 4 H, 2 × CH2), 1.54-1.67 (m, 4 H, 2 × CH2); MS m/z 360.2 (MH+, 100%); HRMS calcd for C21H22N5O (MH+) m/z 360.1819, found 360.1822 (-0.9 ppm). HPLC purity 93.6 |
43% | With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane In 1,4-dioxane at 120℃; for 16h; Sealed tube; | 60 Example 60: SN39323 1-Cyclopentyl-6-(isoquinolin-5-ylamino)-3-methyl-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2-one (66). A degassed mixture of chloride 6 (120 mg, 0.48 mmol), isoquinolin-5-amine (83 mg, 0.57 mmol), Pd2dba3(22 mg, 24 µmol), XPhos (46 mg, 96 µmol) and Cs2CO3(344 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 h. The mixture was cooled, diluted with EtOAc (30 mL), filtered through diatomaceous earth and the filtrate was evaporated. The residue was partitioned between EtOAc (50 ml) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give imidazopyridinone 66 (73 mg, 43%) as a cream powder: mp (EtOAc/MeOH) 234-237 °C;1H NMR (CDCl3) δ 9.28 (d, J = 0.6 Hz, 1 H, H-1), 8.53 (d, J = 6.0 Hz, 1 H, H-3), 7.86 (s, 1 H, H-4), 7.73-7.82 (m, 3 H, H-4, H-6, H-8), 7.58 (dd, J = 7.9, 7.8 Hz, 1 H, H-7), 6.83 (br s, 1 H, 6-NH), 6.44 (d, J = 0.6 Hz, 1 H, H-7), 4.74 (pent, J = 8.8 Hz, 1 H, 1-CH), 3.41 (s, 3 H, 3-CH3), 1.83-1.99 (m, 4 H, 2 × CH2), 1.54-1.67 (m, 4 H, 2 × CH2); MS m/z 360.2 (MH+, 100%); HRMS calcd for C21H22N5O (MH+) m/z 360.1819, found 360.1822 (-0.9 ppm). HPLC purity 93.6 |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
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P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
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P233 | Keep container tightly closed. |
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P240 | Ground/bond container and receiving equipment. |
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P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
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P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
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P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
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P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
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P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
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P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
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P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
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P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
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P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
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P401 | |
P402 | Store in a dry place. |
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P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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