Dimethylformamide → 3-[5-Chloro-2-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

HRID 237308Notes

Reaction equation

[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([OH:24])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.O[NH:31][C:32](=[NH:34])[CH3:33].C(N(CC)C(C)C)(C)C>C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[O:24][N:34]=[C:32]([CH3:33])[N:31]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]

Participants

Conditions

Temperature: 155 °C

Procedure

To the title compound of Step B (0.15 g, 0.42 mmol) in CH2Cl2 (4 mL) was added DMF (catalytic) and 2M COCl2 in CH2Cl2 (0.3 mL, 0.6 mmol). After 2 h, the reaction was concentrated and THF (2 mL) was added. This solution was added to N-hydroxy-acetamidine (0.035 g, 0.46 mmol) and N,N-diisopropylethylamine (0.065 g, 0.088 mL, 0.50 mmol) in THF (2 mL). The mixture was then heated for 20 min at 155° C. in a microwave reactor, cooled to rt and concentrated. Silica gel chromatography (5-30% EtOAc in hexanes) gave 0.155 g (93%) of the title compound as a clear oil. MS (ESI): mass calcd. for C18H22ClN3O6, 395.1; m/z found, 295.3 [M-100]+. 1H NMR (400 MHz): 6.94 (d, J=8.6 Hz, 1H), 6.91 (dd, J=8.6, 2.2 Hz, 1H), 6.57 (d, J=2.1 Hz, 1H), 5.27 (s, 2H), 4.89-4.85 (m, 1H), 4.32-4.29 (m, 2H), 4.04 (dd, J=10.4, 4.2 Hz, 2H), 2.43 (s, 3H), 1.45 (s, 9H).

Workup

concentrationthe reaction was concentrated
additionTHF (2 mL) was added
temperaturecooled to rt
concentrationconcentrated

Sources & evidence

ORD record: ord-5f8a581638e0457b88c150a73b2ba27c
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08642583B2

Reaction notes

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