4-Propoxypiperidine → (R)-6-Fluoro-4-[2-methyl-3-(4-propoxy-piperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one

HRID 1986754Notes

Reaction equation

[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH3:20]>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][N:25]3[CH2:26][CH2:27][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:23][CH2:24]3)[C:6]=2[CH:17]=1

Participants

Conditions

Temperature: 70 °C

Procedure

The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.400 g, 1.15 mmol) and 4-propoxy-piperidine (79KS66) (0.332 g, 2.29 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 3 days and at 70° C. for 1 day. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50→1:20) to give the title compound (108LM30-27) (0.263 g, 63%). 1H NMR (CDCl3) δ 6.96 (dd, J=9.7 Hz, J=2.9 Hz, 1H), 6.91 (dd, J=8.9 Hz, J=4.9 Hz, 1H), 6.66 (dt, J=8.9 Hz, J=2.9 Hz, 1H), 4.56 (ABq, J=15.5 Hz, J=31.7 Hz, CH2), 3.95 (dd, J=13.5 Hz, J=8.1 Hz, 1H), 3.88 (dd, J=13.5 Hz, J=4.7 Hz, 1H), 3.38 (t, J=6.7 Hz, CH2), 3.32-3.23 (m, 1H), 2.79 (bs, 1H), 2.62 (bs, 1H), 2.26-2.12 (m, 3H), 2.19-1.95 (m, 2H), 1.94-1.84 (m, 2H), 1.66-1.53 (m, 4H), 0.95-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=952.8 Hz, 1H), 141.7 (d, J=9.2 Hz, 1H), 130.0 (d, J=42.4 Hz, 1H), 117.7 (d, J=38.4 Hz, 1H), 109.6 (d, J=93.2 Hz, 1H), 103.4 (d, J=114.4 Hz, 1H), 75.2, 69.8, 67.9, 63.7, 52.8, 52.0, 45.7, 31.8, 31.6, 29.5, 23.5, 17.1, 10.9; HPLC-MS (ammonium acetate) [M+H]+=365.3.

Workup

customPurified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50→1:20)

Sources & evidence

ORD record: ord-f8247c474e5e47a682b02073d906e5a9
Source dataset: uspto-grants-2009_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07550459B2

Reaction notes

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