6-fluoro-3,4-dihydro-2H-chromen-4-amine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 10A for the product of Example 7A. 1H NMR (300 MHz, CDCl3) δ 7.03 (dd, 1H, J=9.1 and 3.1 Hz), 6.85 (m, 1H), 6.74 (m, 1H), 4.15-4.29 (m, 2H), 4.02 (m, 1H), 2.10-2.20 (m, 1H), 1.79-1.89 (m, 1H). MS (DCI) m/e 168 (M+H)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.063 g, 0.204 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.059 g, 0.305 mmol) and 6-fluorochroman-4-amine (0.037 g, 0.224 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring for approximately 60 hours, the reaction was loaded directly onto a SF15-12 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.22-7.31 (m, 2H), 7.15-7.22 (m, 5H), 7.05-7.10 (m, 2H), 6.85-6.94 (m, 3H), 6.75-6.81 (m, 1H), 5.13 (dt, J=8.5, 5.8 Hz, 2H), 4.18 (d, J=14.6 Hz, 1H), 4.10-4.21 (m, 1H), 3.97-4.09 (m, 1H), 4.01 (d, J=14.6 Hz, 1H), 3.54-3.62 (m, 2H), 2.54-2.64 (m, 2H), 2.12-2.25 (m, 1H), 1.91-2.02 (m, 1H), 1.81-1.90 (m, 2H); MS (ESI−) m/z 457 (M−H)−. the title compound was eluted over 25 minutes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: These amines were prepared via procedures described in Example 29 for the synthesis of 8-fluorochroman-4-amine. The corresponding chroman-4-ones were commercially available as advanced intermediates for the synthesis of chroman-4-amine, 6-fluorochroman-4-amine, 6-chlorochroman-4-amine, 6-methylchroman-4-amine, and 6-methoxychroman-4-amine. For the synthesis of 5-fluorochroman-4-amine, the intermediate 5-fluorochroman-4-one was obtained using procedures from GB 2355264, which also provided 7-fluorochroman-4-one. 7-Fluorochroman-4-one could be used in the synthesis of 7-fluorochroman-4-amine. Chroman-4-amine, 5-fluorochroman-4-amine, 6-fluorochroman-4-amine, 7-fluorochroman-4-amine, 5,8-difluorochroman-4-amine, and 6,8-difluorochroman-4-amine were resolved via the procedure described in Example 29 for the resolution of 8-fluorochroman-4-amine.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 10A for the product of Example 7A. 1H NMR (300 MHz, CDCl3) δ 7.03 (dd, 1H, J=9.1 and 3.1 Hz), 6.85 (m, 1H), 6.74 (m, 1H,), 4.15-4.29 (m, 2H), 4.02 (m, 1H), 2.10-2.20 (m, 1H), 1.79-1.89 (m, 1H). MS (DCI) m/e 168 (M+H)+.