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

HRID 923261Notes

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-b019b6266f3a4ba9b54b17965cda559d
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09278969B2

Reaction notes

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