Sodium Iodide → 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3,5-difluorobenzonitrile

HRID 1877941Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:38])[C:9]=1[CH:10](O)[CH2:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:5]#[N:6].CCN(CC)CC.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[CH:17]1[N:16]=[CH:15][N:14]2[CH:10]([C:9]3[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=3[F:38])[CH2:11][CH2:12][C:13]=12

Participants

Conditions

Temperature: 0 °C

Procedure

3,5-Difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile (0.105 g, 0.21 mmol) is dissolved in DMF (5 mL) and cooled down to 0° C. To this is added Et3N (0.043 mL, 0.31 mmol) and methanesulfonyl chloride (0.019 mL, 0.25 mmol). After 2 h, LCMS showed the presence of the intermediate mesylate [MS (ESI) m/z 584.3 (M+H)]. The solution is evaporated to dryness and dissolved in DMF (5 mL), to which is added K2CO3 (0.086 g, 0.62 mmol) and NaI (0.093 g, 0.62 mmol) and the mixture is heated to 90° C. for 0.5 h. The solution is then evaporated, dissolved in MeCN and filtered. The crude residue is purified via flash column chromatography (MeOH/DCM 1:99→MeOH/DCM 1:9) to give 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3,5-difluorobenzonitrile. MS (ESI) m/z 246.2 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.72-2.85 (m, 1 H), 2.93-3.05 (m, 1 H), 3.08-3.21 (m, 2 H), 5.75 (app t, J=7.2 Hz, 1 H), 6.79 (s, 1 H), 7.18-7.41 (m, 3 H).

Workup

customThe solution is evaporated to dryness
dissolutiondissolved in DMF (5 mL), to which
temperaturethe mixture is heated to 90° C. for 0.5 h
customThe solution is then evaporated
dissolutiondissolved in MeCN
filtrationfiltered
customThe crude residue is purified via flash column chromatography (MeOH/DCM 1:99→MeOH/DCM 1:9)

Sources & evidence

ORD record: ord-47744efc098e4fecad4571e464086a82
Source dataset: uspto-grants-2012_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08314097B2

Reaction notes

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