Iodine → 3-cyclopropyl-1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-1-(pyridin-2-yl)propan-1-ol

HRID 1773681Notes

Reaction equation

HRID 1773681 reaction equation
[Mg].II.Br[CH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C1(CC[Mg]Br)CC1.[CH3:17][C:18]1[C:22]([C:23]2[CH:24]=[C:25]([C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[O:36])[C:26]3[N:30]=[C:29]([O:31][CH2:32][CH3:33])[NH:28][C:27]=3[CH:34]=2)=[C:21]([CH3:43])[O:20][N:19]=1>C(OCC)C.C1COCC1>[CH:7]1([CH2:6][CH2:5][C:35]([C:25]2[C:26]3[N:30]=[C:29]([O:31][CH2:32][CH3:33])[NH:28][C:27]=3[CH:34]=[C:23]([C:22]3[C:18]([CH3:17])=[N:19][O:20][C:21]=3[CH3:43])[CH:24]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[OH:36])[CH2:9][CH2:8]1

Participants

8

Reactant 5

HCID 807Iodine2×HCID 5462224MagnesiumHCID 22636989(2-Bromoethyl)cyclopropaneHCID 117601753(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin 2-yl)methanoneHCID 178419669HCID 178419669, compound

Product 1

HCID 1176014043-cyclopropyl-1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-1-(pyridin-2-yl)propan-1-ol

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

Magnesium metal (39.0 mg, 2.0 mmol) and iodine (one crystal) was taken up in dry diethyl ether (1.2 mL) and (2-bromoethyl)cyclopropane (200 mg, 1.3 mmol) was added dropwise until iodine color faded. The remainder was then added dropwise over 15 minutes to maintain a gentle reflux and then cooled to 0° C. (2-cyclopropylethyl)magnesium bromide (1.1 M, 0.38 mL, 0.41 mmol) was added to a cooled (0° C.) solution of (6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) in dry THF (1.0 mL) under argon and allowed to stir for 10 minutes. The reaction was quenched with water, extracted three times with EtOAc, and combined organic layers were concentrated and purified by reverse-phase HPLC to give 3-cyclopropyl-1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-1-(pyridin-2-yl)propan-1-ol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mL concentrated HCl and heated to 65° C. for 2 hours and concentrated to afford the desired product as a white powder.

Workup

  1. additionThe remainder was then added dropwise over 15 minutes
  2. temperatureto maintain
  3. temperaturea gentle reflux
  4. additionwas added to
  5. customThe reaction was quenched with water
  6. extractionextracted three times with EtOAc
  7. concentrationwere concentrated
  8. custompurified by reverse-phase HPLC

Sources & evidence

ORD record
ord-4ecd79c8b9054532806637d20b36c1f6
Source dataset
uspto-grants-2016_02
Patent number
US09255089B2

Reaction notes

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