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With hydrogenchloride; tin(II) chloride dihdyrate In water at 100℃;
16.2
To a solution of 4-chloro-5-nitroisoquinoline 16b (2.00 g, 9.62 mmol) in 34 mL concentrated hydrochloric acid was added SnCl2.2H2O (13 g, 57.7 mmol) at 0° C. The reaction mixture was stirred at 100° C. overnight, and then was cooled down to room temperature, adjusted pH to 8 using solid NaHCO3. The mixture was extracted with EtOAc (100 mL*2), and the combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (0-100% EtOAc/PE) to give 4-chloroisoquinolin-5-amine 16c (1.57 g, yellow solid, yield: 92%). MS-ESI calc'd. [M+H]+ 179, found 179.
43.79%
With ammonium chloride; zinc In tetrahydrofuran; water at 0 - 15℃; for 3h;
27
Compound 27-3: To a solution of 4-chloro-5-nitroisoquinoline (4 g, 19.18 mmol, 1 eq) and NH4Cl (8.21 g, 153.40 mmol, 8 eq) in THF (50 mL) and H2O (25 mL) Zn (10.03 g, 153.40 mmol, 8 eq) was added at 0° C. The resulting mixture was stirred at 15° C. for 3 hr. The reaction mixture was filtered, and the filtrate was added to H2O (200 mL) and extracted with EtOAc (150 mL*2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 0/1). Compound 27-3, 4-chloroisoquinolin-5-amine (1.5 g, 8.40 mmol, 43.79% yield), was obtained as a light yellow solid.
With hydrogenchloride; tin(ll) chloride In water at 0℃; for 2h; Heating / reflux;
118.D (Step D) Synthesis of 4-chloro-5-aminoisoquinoline (Intermediate 90)
Tin(II) chloride dihydrate (1.70 g) was dissolved in concentrated hydrochloric acid (1 ml), added with a mixture of Intermediate 89 (315 mg) and 2 N aqueous hydrochloric acid (2 ml) with ice cooling and refluxed with heating for 2 hours. The reaction mixture was cooled to room temperature, added with 5 N aqueous sodium hydroxide (7 ml) and extracted twice with chloroform (20 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (182 mg).
Stage #1: 4-chloroisoquinolin-5-amine With hydrogenchloride; sodium nitrite In water at -5℃; for 1h;
Stage #2: With sulfur dioxide; acetic acid; copper(l) chloride In water at 20℃;
16.3
To a solution of 4-chloroisoquinolin-5-amine (1.57 g, 8.82 mmol) in 14 mL concentrated hydrochloric acid was added a solution of NaNO2 (620 mg, 8.82 mmol) in 2 mL water at -5° C., and the resulting mixture was allowed to stir for 1 h at this temperature, and then was transferred to a solution of 30 mL acetic acid with CuCl (224 mg, 2.20 mmol, in 2 mL water) saturated by SO2 in one portion. The reaction was stirred at room temperature until no more bubble formed. To the reaction mixture was added 100 mL ice water, and the pH was adjusted to 8 using saturated aq. NaHCO3. The mixture was then extracted with dichloromethane (100 mL*2), the combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give 4-chloroisoquinoline-5-sulfonyl chloride 16d (1.07 g, yellow solid, yield: 46%). MS-ESI calc'd. [M+H]+ 262, found 262.
Stage #1: 4-chloroisoquinolin-5-amine With hydrogenchloride; sodium nitrite In water at -5℃; for 1h; Inert atmosphere;
Stage #2: With sulfur dioxide; acetic acid; copper(l) chloride In water for 2.5h;
27
Preparation of Solution 1: To a mixture of 4-chloroisoquinolin-5-amine (1.5 g, 8.40 mmol, 1 eq) in conc. HCl (15 mL) was added NaNO2 (579.45 mg, 8.40 mmol, 1 eq) in one portion at -5° C. under N2. The mixture was stirred at -5° C. for 1 hr. Preparation of Solution 2: SO2 was bubbled into a solution of CuCl (207.85 mg, 2.10 mmol, 0.25 eq) in HOAc (15 mL) and H2O (3 mL) at 0° C. for 30 minutes. Compound 27-4: To solution 1 solution 2 was added slowly. The mixture was stirred at 15° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (500 mL) and extracted with DCM (300 mL*3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used with no further purification. Compound 27-4, 4-chloroisoquinoline-5-sulfonylchloride (1.5 g, crude), was obtained as a yellow solid.
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