5-methoxyisoquinoline

Under zero degree and nitrogen protection, To the compound 5-hydroxyisoquinoline (1.45 g, 10 mmol), Triphenylphosphine (3.14 g, 12 mmol), DIAD (2.83 g, slowly added to a solution of methanol (0.5 ml, 12 mmol) in tetrahydrofuran.14 mmol). The reaction was stirred at room temperature for 4 hours and then filtered.Dry the solvent under reduced pressure and pass through the column.Compound 46A (1.5 g, 95% yield).To a stirred suspension of 5-hydroxisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was preabsorbed onto silica gel and purified (elution with 40% ethyl acetate/hexanes) to afford Cap-138, step a as a light yellow solid (1.00 g, 45%). 1H NMR (CDCl3, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); Rt=0.66 min (Cond. D2); 95% homogeneity index; LCMS: Anal. Calc. for [M+H]+ C10H10NO; 160.08; found 160.10.To a stirred suspension of 5-hydroxisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 rnL) was added dry methanol (0.8 niL) and diethyl azodicarboxylate (3.0 mL, 16.50 mmol) portion wise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried with Na2SO, ^ filtered and concentrated. The residue was preabsorbed onto silica gel and purified, eluting with 40% ethyl acetate/hexanes to afford Cap-138, step a as a light yellow solid (1.00 g, 45%). 1H NMR (CDCl3, 500 MHz) delta 9.19 (s, IH), 8.51 (d, J- 6.0 Hz, IH), 7.99 (d, J= 6.0 Hz, IH), 7.52-7.50 (m, 2H), 7.00-6.99 (m, IH), 4.01 (s, 3H); R1= 0.66 min (Cond. D 2); 95% homogeneity index; LCMS:Anal. CaIc. for [M+H]+ C10H10NO: 160.08; found 160.1.To a stirred suspension of 5-hydroxisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13.8 mmol) and triphenylphosphine (43 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0, 8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was preabsorbed onto silica gel and purified (elution with 40% ethyl acetate/hexanes) to afford Cap- 138, step a as a light yellow solid (1.00 g, 45%). 1H NMR (CDCl3, 500 MHz) delta 9.19 (s, IH), 8.51 (d, J- 6.0 Hz, IH)5 7.99 (d, J- 6.0 Hz, IH), 7.52-7.50 (m, 2H), 7.00- 6.99 (m, IH), 4.01 (s, 3H); Rt = 0.66 min (Cond. D2); 95% homogeneity index;LCMS: Anal. CaIc. for [M+H]+ C10H10NO: 160.08; found 160.10.To a stirred suspension of 5-hydroxisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2S04, filtered and concentrated. The residue was preabsorbed onto silica gel and purified (elution with 40% ethyl acetate/hexanes) to afford Cap- 138, step a as a light yellow solid (1.00 g, 45%). ¾ NMR (CDC13, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J= 6.0 Hz, 1H), 7.99 (d, J= 6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00- 6.99 (m, 1H), 4.01 (s, 3H); Rt = 0.66 min (Cond. D2); 95% homogeneity index; LCMS: Anal. Calc. for [M+H]+ Ci0H10NO: 160.08; found 160.10.To a stirred suspension of 5-hydroxisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2S04, filtered and concentrated. The residue was preabsorbed onto silica gel and purified (elution with 40% ethyl acetate/hexanes) to afford Cap- 138, step a as a light yellow solid (1.00 g, 45%). 1H NMR (CDC13, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J= 6.0 Hz, 1H), 7.99 (d, J= 6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); Rt = 0.66 min (Cond. D2); 95% homogeneity index; LCMS: Anal. Calc. for [M+H]+ C10H10NO: 160.08; found 160.10.[00241] To a stirred suspension of 5-hydroxisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2S04, filtered and concentrated. The residue was preabsorbed onto silica gel and purified (elution with 40% ethyl acetate/hexanes) to afford Cap- 138, Step a as a light yellow solid (1.00 g, 45%). XH NMR (CDC13, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J= 6.0 Hz, 1H), 7.99 (d, J= 6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); Rt = 0.66 min (Cond. D2); 95% homogeneity index; LC-MS: Anal. Calc. for [M+H]+ CioHio O: 160.08; found 160.10.To a stirred suspension of 5-hydroxyisoquinoline (prepared according to the procedure in WO 2003/ 099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2S04, filtered and concentrated. The residue was preabsorbed onto silica gel and chromatographed (elution with 40% ethyl acetate/hexanes) to afford Cap-138, step a (1.00 g, 45%) as a light yellow solid. XH NMR (CDC13, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J= 6.0 Hz, 1H), 7.99 (d, J= 6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); Rt = 0.66 min (Cond.-D2); 95%homogeneity index; LCMS: Anal. Calc. for [M+H]+ Ci0H10NO: 160.08; found 160.1.Cap-138, step a To a stirred suspension of 5-hydroxyisoquinoline (prepared according to the procedure in WO 2003/ 099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2S04, filtered and concentrated. The residue was preabsorbed onto silica gel and chromatographed (elution with 40% ethyl acetate/hexanes) to afford Cap-138, step a (1.00 g, 45%) as a light yellow solid. XH NMR (CDC13, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J = 6.0 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); Rt = 0.66 min (Cond.-D2); 95% homogeneity index; LCMS: Anal. Calc. for [M+H]+ Ci0H10NO: 160.08; found 160.1. -138, To a stirred suspension of 5-hydroxyisoquinoline (prepared according to the procedure in WO 2003/099274)(2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol(0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperaturefor 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was preabsorbed onto silica gel and chromatographed (elution with 40% ethyl acetate/hexanes) to affordCap-138, step a (1.00 g, 45%) as a light yellow solid. 1H NMR (CDCl3, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J = 6.0 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); Rt= 0.66 min (Cond.-D2); 95% homogeneityindex; LCMS: Anal. Calc. for [M+H]+ C10H10NO: 160.08; found 160.1.To a stirred suspension of 5-hydroxyisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13.8 mmol) and triphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) was added dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5 mmol) portionwise. The mixture was stirred at room temperature for 20 h before it was diluted with ethyl acetate and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was preabsorbed onto silica gel and chromatographed (elution with 40% ethyl acetate/hexanes) to afford Cap-138, step a (1.00 g, 45%) as a light yellow solid. 1H NMR (CDCl3, 500 MHz) delta 9.19 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); Rt=0.66 min (Cond.-D2); 95% homogeneity index; LCMS: Anal. Calc. for [M+H]+ C10H10NO: 160.08; found 160.1.[CAS Reg. No. 90806-58-9] Diisopropyl azodicarboxylate (DIAD; 2.98 mL, 15.2 mmol) was added to a suspension of isoquinolin-5-ol (2.00 g, 13.8 mmol), MeOH (0.780 mL, 19.3 mmol) and PPh3 (3.98 g, 15.2 mmol) in anhyd THF (65 mL) at 0 C under N2. The resulting mixture was allowed to warm to r.t. and stirred for 18 h. The mixture was diluted with EtOAc (100 mL) and washed with sat. brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated onto silica gel. The crude product was purified by flash silica gel chromatography (eluent: gradient 0 to 40% EtOAc in heptane). Fractions containing the desired product were evaporated and the residue was further purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7 N NH3 in MeOH and pure fractions were evaporated to dryness to afford the title compound 12 (670 mg, 31%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): delta = 9.21 (d, J = 0.8 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H), 8.01 (dd, J = 5.8 Hz, 1H), 7.58-7.47 (m, 2 H), 7.01 (dd, J = 7.0, 1.6 Hz, 1H), 4.02 (s, 3 H). MS (ES+): m/z = 161 [M + H]+.In a hydrogen atmosphere, Compound 46A (0.954 g, 6 mmol)And the acetic acid solution of platinum dioxide is raised to70 CAfter stirring for 6 hours, it was filtered.The solvent was dried under reduced pressure, and the pH was adjusted to about 11 with a 1 M sodium hydroxide solution.Extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered.Spin dry to give compound 46B (0.970 g, 99% yield).

Molecular Weight:159.18
XLogP3:2.1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:159.068413911
Monoisotopic Mass:159.068413911
Topological Polar Surface Area:22.1
Heavy Atom Count:12
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes