Synthesis of Spirochromane-Quinoline Carboxamide

Example 175

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Step 1.

tert-Butyl 6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxylate. A solution of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chromane-2,4′-piperidine]-1′-carboxylate (0.90 g, 2.1 mmol), 7-bromo-8-methoxy-quinoline (0.50 g, 2.1 mmol), palladium(II) acetate (0.024 g, 0.11 mmol), triphenylphosphine (0.11 g, 0.42 mmol), 1,4-dioxane (30 mL), and DMF (50 mL) was added aq. Na₂CO₃ (0.5 M) (8.0 mL, 4.0 mmol). The mixture was vacuum degassed then heated at 85° C. overnight. The mixture was treated with water (120 mL) then cooled to RT and extracted with EtOAc (3×70 mL). The organic extract was washed with a mixture of water:brine (9:1, 100 mL) then with brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was dried overnight under vacuum then the residue was dissolved in DCM, applied to a silica gel loading cartridge (25 g) and purified on silica gel (40 g, 0-40% ethyl acetate:hexane) to afford tert-butyl 6-(8-methoxy-7-quinolyl)-spiro[chromane-2,4′-piperidine]-1′-carboxylate as a white solid. Analysis: LCMS m/z 461 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.94 (dd, J=4.3, 1.8 Hz, 1H), 8.38 (dd, J=8.4, 1.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.56-7.52 (m, 1H), 7.42-7.36 (m, 2H), 6.90 (d, J=8.3 Hz, 1H), 3.93 (s, 3H), 3.78-3.68 (m, 2H), 3.29-3.11 (m, 2H), 2.82 (t, J=6.7 Hz, 2H), 1.85 (t, J=6.8 Hz, 2H), 1.79-1.70 (m, 2H), 1.62-1.52 (m, 2H), 1.42 (s, 9H).

Step 2.

6-(8-Methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine] 2HCl. tert-Butyl 6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxylate was dissolved in HCl (2M in 1,4-dioxane) (6.0 mL, 12 mmol) and after 5 min a precipitate formed. The reaction was diluted with ethanol (6.0 mL), stirred at RT overnight, then concentrated in vacuo to afford 6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine] 2HCl. Analysis: LCMS 361 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.16-9.02 (m, 2H), 9.00-8.89 (m, 1H), 8.87-8.77 (m, 1H), 7.98 (br d, J=8.8 Hz, 1H), 7.88-7.72 (m, 2H), 7.52-7.48 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 3.80 (s, 3H), 3.27-3.19 (m, 2H), 3.18-3.07 (m, 2H), 2.87 (br t, J=6.7 Hz, 2H), 2.00-1.86 (m, 6H).

Step 3.

6-(8-Methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide. A suspension of 6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine] 2HCl (0.101 g, 0.233 mmol) in THF (2.0 mL) was treated with DIPEA (0.11 g, 0.15 mL, 0.86 mmol). After stirring for 2 min, a white precipitate formed. ACN (1.0 mL) was added, followed by DMF (2.0 mL) to give a homogenous solution. Trimethylsilyl isocyanate (0.085 g, 0.10 mL, 0.63 mmol) was then added to the mixture. After 90 min, water (11 mL) was added to the mixture and was aged at RT then at 4° C. overnight. The fine precipitate was collected on a Hirsch funnel, washed with water and dried under vacuum to afford crude product. The solids were dissolved in DMSO and purified by preparative HPLC (5-50% ACN: water, containing 0.1% TFA) to afford 6-(8-methoxy-7-quinolyl)spiro[chromane-2,4′-piperidine]-1′-carboxamide (0.064 g, 0.16 mmol, 68%). The pure fractions (freebased) treated with aq. Na₂CO₃ (10 mL) then extracted with DCM (2×30 mL), dried, concentrated and reconcentrated from ethanol and further dried. Analysis: LCMS 404 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.94 (dd, J=4.0, 1.8 Hz, 1H), 8.38 (dd, J=8.3, 1.8 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.56-7.52 (m, 1H), 7.41-7.35 (m, 2H), 6.90 (d, J=8.3 Hz, 1H), 5.96 (s, 2H), 3.93 (s, 3H), 3.74-3.65 (m, 2H), 3.22-3.12 (m, 2H), 2.83 (t, J=6.7 Hz, 2H), 1.85 (t, J=6.8 Hz, 2H), 1.75-1.66 (m, 2H), 1.60-1.51 (m, 2H).