Isoquinoline compounds and uses thereof
A compound and an independent technology, applied in the field of isoquinoline compounds and their uses, can solve the problems of easy mutation of tumor cells, drug resistance, damage to healthy cells, etc.
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[0643] LC / MS method
[0644] Method K: The experiment uses a Shimadzu 20AD HPLC coupled with a Shimadzu LCMS2020 mass spectrometer system, which uses ESI as the ion source, Shim-Pack XR-ODS C18 2.2 μm, 3.0 × 50 mm chromatographic column, and the flow rate is 1.2 mL / min . The solvent system was a gradient starting with 95% 0.05% TFA in water (solvent A) and 5% 0.05% TFA in acetonitrile (solvent B), rising to 95% solvent B over 2.0 minutes. The final solvent system was held constant for 0.7 minutes.
[0645] Method L: The experiment used a Shimadzu 30AD HPLC coupled with a Shimadzu LCMS2020 mass spectrometer system, which used ESI as the ion source, an Ascentis Express C18 2.7 μm, 2.1×50 mm chromatographic column, and the flow rate was 1.0 mL / min. The solvent system was a gradient starting with 95% 0.05% TFA in water (solvent A) and 5% 0.05% TFA in acetonitrile (solvent B), rising to 95% solvent B over 2.0 minutes. The final solvent system was held constant for 0.7 minutes. ...
example 1
[0652] 6-Bromo-7-fluoro-isoquinolin-3-amine
[0653]
[0654] Step 1: (4-Bromo-3-fluorophenyl)methanamine
[0655]
[0656] 4-Bromo-3-fluoro-benzonitrile (5.0 g, 25 mmol) in BH 3 · THF (80 mL, 1 mol / L, 80 mmol) solution was stirred at 60 °C for 3 h. The reaction was quenched with MeOH (20 mL) and HCl (20 mL, 12M). The resulting solution was extracted with EtOAc (3 x 200 mL), with anhydrous MgSO 4 Dry and concentrate in vacuo to give (4-bromo-3-fluorophenyl)methanamine (4.5 g, crude) which was used directly in the next step without purification. LCMS(ESI)[M+H] + = 204.
[0657] Step 2: Methyl 2,2-diethoxyacetimidate
[0658]
[0659] A solution of 2,2-diethoxyacetonitrile (4.0 g, 30.97 mmol) and sodium methoxide (1.2 mL, 5.4 mol / L, 6.19 mmol) in methanol (40 mL) was stirred at 25 °C for 3 h, then concentrated to dryness. The residue was taken up in dichloromethane (200 mL), washed with water (3 x 80 mL) and brine, and anhydrous MgSO 4 Dry, filter and concentrat...
example 2
[0667] 8-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2,3-dihydropyrido[2,3 -b][1,4]oxazine-1-carboxylate tert-butyl ester
[0668]
[0669] Step 1: 7-Bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl ester
[0670]
[0671] To 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (1 g, 4.37 mmol) in tetrahydrofuran (2 mL) at 0 °C ) solution was added dropwise LiHMDS (8.73 mL, 8.73 mmol, 1 mol / L). The resulting solution was stirred at 0 °C for 0.5 h under nitrogen protection. Di-tert-butyl dicarbonate (2.85 g, 13.07 mmol) was then added and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with methanol (50 mL). The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (methyl acetate / petroleum ether, 1 / 4) to give 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1 ,4] tert-butyl oxazine-1-carboxylate (800 mg, 2.43 mmol) as a yellow oil. LCMS(ESI...
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