(aza-)isoquinolinone derivatives
A technology for compounds and mixtures, used in the preparation of these compounds, those compounds for the preparation of medicines, and in the field of treatment of diseases
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
Embodiment 1
[0253] Synthesis of 3-(4-tert-butyl-phenyl)-2H-[2,6]naphthyridine-1-one ("A1")
[0254]
[0255] To a solution of 3-bromo-isonicotinic acid methyl ester (648 mg, 3.00 mmol) in DMF (6 ml) was added bis(triphenylphosphine)-palladium(II) chloride (210 mg, 0.30 mmol), phosphide Copper(I) (17.1 mg, 0.090 mmol), triethylamine (1.25 ml, 9.00 mmol) and 1-tert-butyl-4-ethynyl-benzene (570 mg, 3.60 mmol). The resulting dark brown solution was purged with nitrogen, heated to 80° C. and stirred at this temperature for 3 hours in a closed reaction vial. The reaction mixture was cooled to room temperature and the volume was reduced under vacuum. The residue was chromatographed on a silica gel column using cyclohexane / ethyl acetate as eluent to give 3-(4-tert-butyl-phenylethynyl)-isonicotinic acid methyl ester as a brown oil; HPLC / MS 2.28 min (A), [M+H] 294.
[0256] A mixture of 3-(4-tert-butyl-phenylethynyl)-isonicotinic acid methyl ester (786 mg, 2.68 mmol) and polyphosphoric acid (...
Embodiment 2
[0261] 4-(1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoic acid methyl ester ("A2") and 3-[4-(1-hydroxy-1-methyl-ethyl yl)-phenyl]-2H-isoquinolin-1-one ("A3") synthesis
[0262]
[0263] To a solution of methyl 2-iodo-benzoate (1.31 g, 5.00 mmol) in DMF (10 ml) was added bis(triphenylphosphine)-palladium(II) chloride (351 mg, 0.50 mmol), cuprous iodide (I) (28.5 mg, 0.15 mmol), triethylamine (2.08 ml, 15.0 mmol) and 1-bromo-4-ethynyl-benzene (905 mg, 5.00 mmol). The resulting dark brown solution was purged with nitrogen, heated to 80°C and stirred at this temperature for 16 hours in a closed reaction vial. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was washed with 1 N HCl, dried over sodium sulfate and evaporated in vacuo. The residue was subjected to silica gel column chromatography with cyclohexane / ethyl acetate as the eluent to give 2-(4-bromo-phenylethynyl)-benzoic acid methyl ester as a brown o...
Embodiment 3
[0312] Synthesis of 3-(4-Hydroxymethyl-phenyl)-2H-isoquinolin-1-one ("A8")
[0313]
[0314] Lithium aluminum hydride (22.8 mg, 0.60 mmol) was added to 4-(1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoic acid methyl ester (83.8 mg, 0.301 mmol) under nitrogen. ) (for preparation see previous example) in suspension in THF (3 ml). The reaction mixture was stirred at room temperature for 16 hours. A few drops of methanol followed by HCl (2 N aqueous solution, 0.5 ml) were slowly added to the reaction mixture. It was then filtered through a pad of celite. The filtrate was evaporated and the residue was triturated with tert-butyl methyl ether to give 3-(4-hydroxymethyl-phenyl)-2H-isoquinolin-1-one as a brown powder; HPLC / MS 1.55 min (A), [M +H] 252;
[0315] 1 H NMR (400 MHz, DMSO) δ = 11.49 (s, 1H), 8.20 (dd, J =7.8, 0.6, 1H), 7.76 (d, J =8.3, 2H), 7.71 (m, 2H), 7.48 (ddd, J =8.2, 4.8, 3.6, 1H), 7.43 (d, J =8.4, 2H), 6.91 (s, 1H), 5.25 (s, 1H), 4.56 (s, 2H).
PUM
| Property | Measurement | Unit |
|---|---|---|
| particle size | aaaaa | aaaaa |
| wavelength | aaaaa | aaaaa |
Abstract
Description
Claims
Application Information
Login to View More