Diethyl Ether → (S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(3-hydroxy-3-methylbutyl)-2-methyl-1H-imidazole-4-carboxamide

HRID 872845Notes

Reaction equation

HRID 872845 reaction equation
C[Mg]Br.[CH3:4]COCC.[Cl:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][C@@H:25]([NH:27][C:28]([C:30]3[N:31]=[C:32]([CH3:40])[N:33]([CH2:35][CH2:36][C:37](=[O:39])[CH3:38])[CH:34]=3)=[O:29])[CH3:26])[N:20]=2)[CH:13]=[C:14]([F:18])[C:15]=1[C:16]#[N:17].[Cl-].[NH4+]>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][C@@H:25]([NH:27][C:28]([C:30]3[N:31]=[C:32]([CH3:40])[N:33]([CH2:35][CH2:36][C:37]([OH:39])([CH3:4])[CH3:38])[CH:34]=3)=[O:29])[CH3:26])[N:20]=2)[CH:13]=[C:14]([F:18])[C:15]=1[C:16]#[N:17]

Participants

6

Reactant 4

HCID 3283Diethyl EtherHCID 25517Ammonium ChlorideHCID 66576682(S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamideHCID 178418573HCID 178418573, compound2×

Product 1

HCID 66576684(S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(3-hydroxy-3-methylbutyl)-2-methyl-1H-imidazole-4-carboxamideYield 19.32%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
45 °C

Procedure

Methylmagnesium bromide 3M in Et2O-solution (0.128 ml, 0.383 mmol) and dry THF (1 ml) were added into a flask and heated to 30° C. (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (35 mg, 0.077 mmol) of Example 286(b) dissolved in THF (5 ml) was added very slowly. The reaction mixture was heated to 45° C. and stirred for 5 h. Another batch of methylmagnesium bromide 3M in EtO2-solution (0.128 ml, 0.383 mmol) was added and the mixture was stirred at RT overnight. Next day the reaction mixture was poured into 10 ml of saturated ammonium chloride, THF was evaporated and the remaining water phase was extracted with ethyl acetate. The ethyl acetate phases were combined, dried and evaporated. The product was purified by flash-chromatography. Yield 19.32%. 1H-NMR (400 MHz; DMSO-d6): δ 1.06 (d, 3H), 1.12 (s, 6H), 1.69-1.77 (m, 2H), 2.34 (s, 3H), 3.92-3.98 (m, 2H), 4.25-4.46 (m, 4H), 7.01 (d, 1H), 7.50 (s, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 8.00 (s, 1H), 8.03 (d, 1H).

Workup

  1. additionwas added very slowly
  2. stirringthe mixture was stirred at RT overnight
  3. customwas evaporated
  4. extractionthe remaining water phase was extracted with ethyl acetate
  5. customdried
  6. customevaporated
  7. customThe product was purified by flash-chromatography

Sources & evidence

ORD record
ord-dc1a08cf42aa423080e8fe69575d7b59
Source dataset
uspto-grants-2015_03
Patent number
US08975254B2

Reaction notes

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