1-Piperidinecarboxylic acid, 4-(3,4-dihydro-1(2H)-quinolinyl)-, 1,1-dimethylethyl ester synthesis

Yield:356072-30-5 37.4%

Reaction Conditions:

Stage #1: 1,2,3,4-tetrahydroisoquinoline;N-tert-butyloxycarbonylpiperidin-4-onewith sodium tris(acetoxy)borohydride;acetic acid in 1,2-dichloro-ethane at 20;
Stage #2: with sodium hydroxide;water in 1,2-dichloro-ethane at 0; for 0.333333 h;

Steps:

47

Example 47 tert-butyl 4-(3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylate A solution of 1,2,3,4-tetrahydroquinoline (1.06 g, 7.51 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.24 g, 11.26 mmol) in 20 mL 1,2-dichloroethane was treated with sodium triacetoxyborohydride (4.77 g, 22.53 mmol) then acetic acid (1.28 mL, 22.53 mmol). The suspension was stirred at room temperature overnight. At this time, a TLC analysis indicated that 1,2,3,4-tetrahydroquinoline is present along with a more polar spot. To the reaction mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (1.12 g, 5.63 mmol) and sodium triacetoxyborohydride (2.39 g, 11.28 mmol). The suspension was stirred at room temperature for 4 days. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with 50 mL CH₂Cl₂. The combined organic layer was dried over Na₂SO₄, filtered and concentrated to give a yellow residue. This residue was purified by the Biotage purification system using a silica gel 40M column. A gradient of 5% ethyl acetate:hexanes to 30% ethyl acetate:hexanes over 10 column volumes was used to give the title compound (0.89 g, 37.4%). ¹H-NMR (CDCl₃) δ 7.09-7.03 (m, 1H), 6.97-6.94 (m, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.60-6.55 (m, 1H), 4.30-4.19 (m, 2H), 3.80-3.70 (m, 1H), 3.17 (t, J=5.7 Hz, 2H), 2.84-2.71 (m, 2H), 2.73 (t, J=6.3 Hz, 2H), 1.93-1.85 (m, 2H), 1.78-1.63 (m, 4H), 1.48 (s, 9H). MS (ESI): 317.2 (M+1).

References:

US2008/234237,2008,A1 Location in patent:Page/Page column 81