Triphenylphosphine → 1-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine

HRID 470165

Reaction equation

[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@H:9](O)[C@@H:4]2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[C:35]([F:41])=[CH:34][N:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:40]3[C:36]4[C:35]([F:41])=[CH:34][N:33]=[C:32]([F:31])[C:37]=4[N:38]=[CH:39]3)[C@@H:4]2[O:3]1.[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@@H:9]([N:38]3[C:37]4[C:32]([F:31])=[N:33][CH:34]=[C:35]([F:41])[C:36]=4[N:40]=[CH:39]3)[C@@H:4]2[O:3]1

Participants

Conditions

Temperature: 0 °C

Procedure

(3 aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-3) (4.3 g, 27.2 mmol, 1 equiv) was dissolved in dry THF (136 mL). Triphenylphosphine (10.7 g, 40.8 mmol, 1.5 equiv) was added, followed by 4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-4, 5.1 g, 32.6 mmol, 1.2 equiv). The mixture was cooled to 0° C. and DIAD (7.9 mL, 40.8 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at ambient temperature for 14 hours and then heated to 50° C. for an additional 72 hours. The solvent was removed at reduced pressure and the yellow residue was purified via flash chromatography on 2-330 g silica gel columns (gradient elution 0 to 100% ethyl acetate in hexanes) to yield 1-[(3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-6) and 3-((3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4,7-difluoro-3H-imidazo[4,5-c]pyridine (1-5) as a 1:1 regioisomeric mixture. 1H NMR (1-6) (500 MHz, CDCl3): δ 7.85 (m, 2H); 5.00 (brs, 1H); 4.90 (t, J=5.6 Hz, 1H); 4.82 (t, J=7.3 Hz, 1H); 2.56 (m, 1H); 2.04-2.19 (m, 3H); 1.55 (s, 3H); 1.34 (s, 3H). LRMS rn/z (M+H) 296.0 found, 296.1 required. 1H NMR (1-5) (500 MHz, CDCl3): δ 7.92 (s, 1H); 7.82 (m, 1H); 5.00 (brs, 1H); 4.90 (t, J=5.6 Hz, 1H); 4.82 (t, J=7.3 Hz, 1H); 2.56 (m, 1H); 2.04-2.19 (m, 3H); 1.55 (s, 3H); 1.34 (s, 3H). LRMS m/z (M+H) 296.0 found, 296.1 required.

Workup

temperatureheated to 50° C. for an additional 72 hours
customThe solvent was removed at reduced pressure
customthe yellow residue was purified via flash chromatography on 2-330 g silica gel columns (gradient elution 0 to 100% ethyl acetate in hexanes)

Sources & evidence

ORD record: ord-a70b6ca10b3541c19c70ef65c26be915
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08629275B2

Linked notes

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