1-(1,1-Difluoroethyl)-4-iodobenzene → 4-((5R,7S)-7-(4-(1,1-difluoroethyl)phenyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile

HRID 2036031

Reaction equation

HRID 2036031 reaction equation
[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)([F:4])[CH3:3].C([Mg]Cl)(C)C.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[C@@H:26]1[N:30]2[CH:31]=[N:32][CH:33]=[C:29]2[C:28](=[O:34])[CH2:27]1)[C:21]#[N:22]>C1COCC1>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C@:28]2([OH:34])[C:29]3[N:30]([CH:31]=[N:32][CH:33]=3)[C@@H:26]([C:25]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:17])[CH2:27]2)=[CH:7][CH:6]=1)([F:4])[CH3:3]

Participants

5

Reactant 3

HCID 667620211-(1,1-Difluoroethyl)-4-iodobenzeneHCID 67216150(R)-3-fluoro-4-(7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrileHCID 178418918HCID 178418918, compound

Product 1

HCID 532364384-((5R,7S)-7-(4-(1,1-difluoroethyl)phenyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrileYield 18.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-40 °C

Procedure

To a solution of 1-(1,1-difluoro-ethyl)-4-iodo-benzene, (167 mg, 0.62 mmol) in THF (2 mL) cooled to −40° C. was added a 2 M solution of i-PrMgCl in THF (0.42 mL, 0.83 mmol) dropwise. The crude was stirred at −40° C. for 1 hr. 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (125 mg, 0.52 mmol) in THF (2 mL) was added. The crude was allowed to slowly warm to room temperature over 3 hrs. The crude was quenched with NH4Cl aq. The crude diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate two times using 2M NH3 in MeOH/CH2Cl2 to give 37 mgs of the entitled product. MS 384.3 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.83 (t, 3H), 2.94 (dd, 1H), 3.24 (dd, 1H), 5.70 (d, 1H), 6.47 (s, 1H), 7.11 (t, 1H), 7.19 (s, 1H), 7.33 (d, 2H), 7.38 (m, 2H), 7.46 (m, 2H).

Workup

  1. temperatureto slowly warm to room temperature over 3 hrs
  2. customThe crude was quenched with NH4Cl aq. The crude
  3. additiondiluted in EtOAc
  4. washThe organic layer was washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude was purified via preparation plate two times

Sources & evidence

ORD record
ord-fd7b4866f0df4a9296ca825142e5d7f6
Source dataset
uspto-grants-2013_11
Patent number
US08575160B2

Linked notes

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