Sodium hydride → (4-chlorophenyl)(2-((1-isopropylpiperidin-4-yl)methoxy)-3-methyl-3H-imidazol-4-yl)methanone

HRID 1158263Notes

Reaction equation

HRID 1158263 reaction equation
[H-].[Na+].[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)([CH3:5])[CH3:4].Cl[C:15]1[N:19]([CH3:20])[C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:22])=[CH:17][N:16]=1>C1COCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]([C:18]2[N:19]([CH3:20])[C:15]([O:13][CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8]3)=[N:16][CH:17]=2)=[O:22])=[CH:28][CH:27]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 11147855(1-Isopropylpiperidin-4-yl)methanolHCID 11219026(2-chloro-3-methyl-3H-imidazol-4-yl)-(4-chloro-phenyl)-methanone

Product 1

HCID 10134089(4-chlorophenyl)(2-((1-isopropylpiperidin-4-yl)methoxy)-3-methyl-3H-imidazol-4-yl)methanoneYield 78%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and an addition funnel was added NaH (1.45 g, 0.061 mol) and THF (300 mL). The stirred suspension was cooled to 0° C. and (1-isopropyl-piperidin-4-yl)-methanol (9.5 g, 0.06 mol) was added. The cooling bath was removed, and the reaction warmed to rt. After 2 h, a solution of (2-chloro-3-methyl-3H-imidazol-4-yl)-(4-chloro-phenyl)-methanone (15.56 g, 0.061 mol) in dry THF (100 mL) was added. The reaction mixture was stirred at 60° C. and monitored by HPLC every 4-8 h. After 36 h, the reaction was judged complete. The reaction mixture was cooled to rt, poured into ice-cold water, and extracted with EtOAc (2×250 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to provide the crude material as a brown solid. Recrystallization from EtOAc afforded the desired product (17.5 g, 78%) as a white crystalline solid. mp 126-127° C. IR (film): 2963, 1615, 1585, 1529, 1481, 1362, 1287, 1213, 1173, 1104, 1020, 897, 846, 727, 698 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.13 (s, 1H), 4.22 (d, J=6.0 Hz, 2H), 3.68 (s, 3H), 2.84 (m, 2H), 2.61 (m, 1H), 2.09 (m, 2H), 1.74 (m, 3H), 1.30 (m, 2H), 0.97 (d, J=6.5 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 183.4, 157.0, 138.3, 138.2, 137.3, 130.2, 128.7, 127.1, 74.9, 54.6, 48.4, 35.9, 30.7, 29.1, 18.3. HRMS (EI): m/z calcd for C20H27ClN3O2 [M+H]+, 376.1792; found, 376.1801. Anal. Calcd for C20H26ClN3O2: C, 63.91; H, 6.97; N, 11.17. Found: C, 63.55; H, 6.77; N, 11.05.

Workup

  1. customThe cooling bath was removed
  2. temperaturethe reaction warmed to rt
  3. waitmonitored by HPLC every 4-8 h
  4. waitAfter 36 h
  5. temperatureThe reaction mixture was cooled to rt
  6. additionpoured into ice-cold water
  7. extractionextracted with EtOAc (2×250 mL)
  8. dry with materialThe combined organic extracts were dried over anhydrous Na2SO4
  9. filtrationfiltered
  10. customevaporated under reduced pressure
  11. customto provide the crude material as a brown solid
  12. customRecrystallization from EtOAc

Sources & evidence

ORD record
ord-3bf9348647374c7390d6eb3e5c8a6b2c
Source dataset
uspto-grants-2010_10
Patent number
US07807837B2

Reaction notes

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