Structure of 1015070-56-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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| CAS No. : | 1015070-56-0 |
| Formula : | C9H6BrNO |
| M.W : | 224.05 |
| SMILES Code : | OC1=CN=CC2=C1C=C(Br)C=C2 |
| English Name : | 6-Bromoisoquinolin-4-ol |
| MDL No. : | MFCD18257891 |
| InChI Key : | KXGSBBRPEPMUTK-UHFFFAOYSA-N |
| Pubchem ID : | 57346151 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 10 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 0 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 51.47 |
| TPSA ? Topological Polar Surface Area: Calculated from |
33.12 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.81 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.44 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.7 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.64 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.64 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.24 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-3.38 |
| Solubility | 0.0928 mg/ml ; 0.000414 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.78 |
| Solubility | 0.373 mg/ml ; 0.00166 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.98 |
| Solubility | 0.0232 mg/ml ; 0.000104 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.93 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.38 |
* 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 |
|---|---|---|
| 34% | Stage #1: 6-bromoisoquinolin-4-ol; diazomethyl-trimethyl-silane In hexanes; N,N-dimethyl-formamide at 20℃; for 2.5h; Stage #2: With acetic acid In hexanes; N,N-dimethyl-formamide for 0.333333h; | 5.1.42.E E. 6-Bromo-4-methoxyisoquinoline. To a solution of 6-bromoisoquinolin-4-ol (293 mg, 1.31 mmol) in DMF (6 mL) was added methanol (0.6 mL), and (trimethylsilyl)diazomethane (0.658 mL, 1.31 mmol, 2.0 M in hexanes). The reaction was stirred at room temperature for 90 minutes then additional (trimethylsilyl)diazomethane (1.32 mL, 2.62 mmol, 2.0 M in hexanes) was added. The reaction was stirred at room temperature for 60 minutes, quenched with acetic acid (3 mL), and stirred an additional 20 minutes. The mixture was neutralized with saturated aqueous sodium bicarbonate and extracted three times with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and the volatiles were evaporated. The resulting material was purified using chromatography on a normal phase silica gel column with 0 to 45% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated. The material was dried under vacuum at room temperature to provide the title compound (312 mg, 34%). MS (ESI) m/z 238 [M+1]+ and MS (ESI) m/z 238 [M+1]+. |
| 31 % | In methanol; hexane; dichloromethane at 20℃; | 1 Step 1. Synthesis of 6-bromo-4-methoxyisoquinoline To a solution of compound Int-3 (50 mg, 0.22 mmol) in DCM (3 mL) and MeOH (0.75 mL) was added TMSCHN2 (0.9 mL, 0.45 mmol, 2 M in hexane). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated and the residue was purified by flash silica gel column (PE/EtOAc = 1/2) to give 6-bromo-4-methoxyisoquinoline (25 mg, yield: 31%) as an off- white solid.’H NMR (400 MHz, DMSO-d6) δ 4.06 (3H, s), 7.84-7.88 (1H, m), 8.09 (1H, d, J= 8.8 Hz), 8.22-8.31 (2H, m), 8.98 (1H, s). |
| 31 % | In methanol; hexane; dichloromethane at 20℃; | 1 Step 1. Synthesis of 6-bromo-4-methoxyisoquinoline To a solution of compound Int-3 (50 mg, 0.22 mmol) in DCM (3 mL) and MeOH (0.75 mL) was added TMSCHN2 (0.9 mL, 0.45 mmol, 2 M in hexane). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated and the residue was purified by flash silica gel column (PE/EtOAc = 1/2) to give 6-bromo-4-methoxyisoquinoline (25 mg, yield: 31%) as an off- white solid.’H NMR (400 MHz, DMSO-d6) δ 4.06 (3H, s), 7.84-7.88 (1H, m), 8.09 (1H, d, J= 8.8 Hz), 8.22-8.31 (2H, m), 8.98 (1H, s). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85.4% | With N-ethyl-N,N-diisopropylamine at 60℃; for 8h; carbon monoxide atmosphere; | 15.15b 6-Bromo-4-hydroxyisoquinoline (15.7 g, 70.0 mmol) produced in Example 15 (15a) was dissolved in dimethylformamide (100 mL), to which 2-trimethylsilylethanol (100 mL), diisopropylethylamine (27.1 g, 210 mmol), 1,3-bis(diphenylphosphino)propane (8.57 g, 21.0 mmol), and palladium chloride (3.72 g, 21.0 mmol) were then added, followed by stirring at 60°C for eight hours under a carbon monoxide atmosphere. The solvent was distilled off under reduced pressure. Water was added to the residue thus obtained, and the resulting mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography((a mixed solvent of hexane : ethyl acetate - 1 : 1) : methanol, 100 : 0 - 70 : 30, V/V) to give the desired title compound (17.3 g, yield 85.4%). 1H-NMR (CDCl3 δ: 0. 11 (9H, s), 1.11-1.24 (2H, m), 4.46-4.55 (2H, m), 8.02 (1H, d, J = 8.4 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.38 (1H, s), 8.87 (1H, s), 9.09 (1H, s). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1,3-bis-(diphenylphosphino)propane; palladium dichloride / 8 h / 60 °C / carbon monoxide atmosphere 2.1: pyridine / dichloromethane / 1 h / -25 - 20 °C 3.1: potassium carbonate / DavePhos; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1.5 h / Reflux; Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 20 °C 4.2: 13 h / 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 1,3-bis-(diphenylphosphino)propane; palladium dichloride / 8 h / 60 °C / carbon monoxide atmosphere 2: pyridine / dichloromethane / 1 h / -25 - 20 °C 3: potassium carbonate / DavePhos; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1.5 h / Reflux; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1,3-bis-(diphenylphosphino)propane; palladium dichloride / 8 h / 60 °C / carbon monoxide atmosphere 2: pyridine / dichloromethane / 1 h / -25 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | Stage #1: 6-Bromo-2-(phenylsulfonyl)-2,3-dihydroisoquinoline-4(1H)-one With sodium ethanolate In ethanol at 20℃; for 1h; Stage #2: With hydrogenchloride In ethanol; water | 15.15a 6-Bromo-2-(phenylsulfonyl)-2,3-dihydroisoquinoline-4(1H)-one (29 g, 79.2 mmol) was produced from 4-bromobenzyl bromide in accordance with the method described in Tetrahedron 61 (2005) 8282 to 8287, and then suspended in ethanol (300 ml). To the resulting mixture, a 21% sodium ethoxide/ethanol solution (88.6 ml, 238 mmol) was added, followed by stirring at room temperature for one hour. To the resulting reaction liquid, 5M hydrochloric acid (approximately 50 ml) was added for neutralization, and then ethanol was distilled off under reduced pressure. A solid precipitate was collected by filtration. The solid was dried and then purified by silica gel column chromatography (dichloromethane : methanol, 100 : 0 - 50 : 50, V/V) to give the desired title compound (13.2 g, yield 75%). 1H-NMR (DMSO-D6) δ: 7.79 (1H, dd, J = 8.7, 1.8 Hz), 8.03 (1H, d, J = 8.7 Hz), 8.11 (1H, s), 8.25-8.27 (1H, m), 8.82 (1H, s), 10.62 (1H, s). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | Intermediate 201. 6-bromo-4-(2,2,2-trifluoroethoxy)isoquinoline To a solution of 6-bromoisoquinolin-4-ol (0.5 g, 2.23 mmol, 1 equiv) in DMF (5mL) was added potassium carbonate (925 mg, 6.69 mmol, 3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (777 mg, 3.35 mmol, 1.5 equiv). The reaction mixture was heated to 80oC. After 3 hours, the reaction mixture was diluted with brine (50 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by SiO2 chromatography (0-100% EtOAc/Hex), affording 6- bromo-4-(2,2,2-trifluoroethoxy)isoquinoline. ES/MS m/z: 306.00 [M+H];1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.42 - 8.37 (m, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 4.63 (q, J = 7.9 Hz, 2H).19F NMR (376 MHz, Chloroform-d) δ -74.28 (t, J = 7.9 Hz). | |
| With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | Intermediate 201. 6-bromo-4-(2,2,2-trifluoroethoxy)isoquinoline To a solution of 6-bromoisoquinolin-4-ol (0.5 g, 2.23 mmol, 1 equiv) in DMF (5mL) was added potassium carbonate (925 mg, 6.69 mmol, 3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (777 mg, 3.35 mmol, 1.5 equiv). The reaction mixture was heated to 80oC. After 3 hours, the reaction mixture was diluted with brine (50 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by SiO2 chromatography (0-100% EtOAc/Hex), affording 6- bromo-4-(2,2,2-trifluoroethoxy)isoquinoline. ES/MS m/z: 306.00 [M+H];1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.42 - 8.37 (m, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 4.63 (q, J = 7.9 Hz, 2H).19F NMR (376 MHz, Chloroform-d) δ -74.28 (t, J = 7.9 Hz). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: azodicarboxylic acid bis(dimethylamide); tributylphosphine / toluene / 16 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: azodicarboxylic acid bis(dimethylamide); tributylphosphine / toluene / 16 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 12 h / 90 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: azodicarboxylic acid bis(dimethylamide); tributylphosphine / toluene / 16 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 12 h / 90 °C / Inert atmosphere 4: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 2 h / 25 °C |