Piperidine → 2-Methyl-8-(piperidin-1-ylmethyl)-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene

HRID 2414847Notes

Reaction equation

CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[O:14]3

Participants

Conditions

Temperature: 80 °C

Procedure

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.38 g, 1 mmole) and piperidine 15 ml were combined and heated at 80° C. under nitrogen for 4 hours. After completion, piperidine was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.24 g of white solid, m.p. 109-112° C.

Workup

customAfter completion, piperidine was removed under vacuum
customthe residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate
washThe organic phase was washed with brine
dry with materialdried over magnesium sulfate
concentrationconcentrated in vacuum
customchromatographed on silica gel using first methylene chloride
customto remove impurities
wash1% methanol/methylene chloride to elute the (S)-enantiomer of the title compound

Sources & evidence

ORD record: ord-558f0206061c40b0a89a0d08857c5b7d
Source dataset: uspto-grants-2004_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06815448B2

Reaction notes

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