Synthesis of 5-(4-Methyl-3-quinolyl)spiro[3H-benzofuran-2,4'-piperidine] derivatives

Example 161

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Step 1.

tert-butyl 5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate was synthesized using tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate and 3-bromo-4-methyl-quinoline Analysis: LCMS m/z=431 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.71 (s, 1H), 8.18 (dd, J=8.4, 0.9 Hz, 1H), 8.03 (dd, J=8.3, 1.0 Hz, 1H), 7.76 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.71-7.64 (m, J=8.3, 6.5, 1.4 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 7.19 (dd, J=8.3, 2.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 3.62-3.50 (m, 2H), 3.48-3.36 (m, 2H), 3.13 (s, 2H), 2.62 (s, 3H), 1.91-1.68 (m, 4H), 1.43 (s, 9H).

Step 2.

5-(4-Methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine] 2HCl was synthesized using tert-butyl 5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate and 2N HCL in dioxane. Analysis: LCMS m/z=331 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.24 (br s, 1H), 9.06 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.13-8.03 (m, 1H), 7.97-7.88 (m, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.3, 2.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.22 (s, 6H), 2.81 (s, 3H), 2.14-2.02 (m, 4H).

Step 3.

5-(4-Methyl-3-quinolyl)-N-tetrahydropyran-2-yloxy-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide was synthesize using o-(tetrahydro-2H-pyran-2-yl)hydroxylamine and 5-(4-methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine] 2HCl. LCMS m/z=474 (M+1).

Step 4.

5-(4-Methyl-3-quinolyl)spiro[3H-benzofuran-2,4′-piperidine]-1′-carbohydroxamic acid was synthesized using 5-(4-methyl-3-quinolyl)-N-tetrahydropyran-2-yloxy-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxamide and TFA. Analysis: LCMS m/z=390 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ: 9.13 (s, 1H), 8.71 (s, 1H), 8.18 (dd, J=8.5, 0.8 Hz, 1H), 8.03 (dd, J=8.3, 1.0 Hz, 2H), 7.76 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.71-7.63 (m, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.19 (dd, J=8.2, 1.9 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 3.53-3.38 (m, 4H), 3.13 (s, 2H), 2.62 (s, 3H), 1.87-1.69 (m, 4H).