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

HRID 76880Notes

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, 1H), 2.93-3.05 (m, 1H), 3.08-3.21 (m, 2H), 5.75 (app t, J=7.2 Hz, 1H), 6.79 (s, 1H), 7.18-7.41 (m, 3H).

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-5e7c922fa6e14125befbf8c5dcd37253
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08835646B2

Reaction notes

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