Dimethyl Sulfoxide → 4-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester

HRID 1685216Notes

Reaction equation

HRID 1685216 reaction equation
CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+].Cl.Cl[CH2:38][CH2:39][N:40]([CH3:42])[CH3:41]>O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 14798Sodium HydroxideHCID 11636816N,N-Dimethylaminoethyl chloride hydrochlorideHCID 178451792HCID 178451792, compound

Product 1

HCID 672648444-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl esterYield 90.8%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
45.5 °C

Procedure

In a 22 L 3 neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, drying tube and thermocouple charge DMSO (1385 mL) and 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (206.71 g, 0.5 mol, 1 eq). Heat the resulting suspension to 43-48° C. then add sodium hydroxide powder (50 g, 1.25 mol, 2.5 eq) in one portion. Stir the resulting suspension for 1 hour at 43-48° C. To this suspension add 2-chloro-N,N-dimethylethanamine hydrochloride (90 g, 0.625 mol, 1.25 eq). Stir the resulting suspension for 35-40 minutes. Cool the reaction mixture to 18-23° C. and add cold water (227.4 mL). Once water addition is complete, bring the reaction mixture temperature to 20-25° C., stir for 60-90 minutes and filter the suspension. Wash the solids with a mixture of DMSO (103.4 mL) and water (51.7 mL) two times. Wash the solids with water (2×517 mL) and dry solids on a filter with suction to afford the target compound (219.9 g, 87.5% yield) as a tan solid. 1H NMR (300 MHz, DMSO): 8.04-8.00 (m, 2H), 7.74 (s, 1H), 7.46 (t, J=9.9 Hz, 1H), 4.06-3.99 (m, 4H), 3.03-2.93 (m, 3H), 2.57 (t, J=6.3 Hz, 2H), 2.19 (s, 6H), 1.81-1.77 (m, 2H), 1.70-1.55 (m, 2H), 1.42 (s, 9H).

Workup

  1. customdrying tube
  2. stirringStir the resulting suspension for 35-40 minutes
  3. temperatureCool the reaction mixture to 18-23° C.
  4. customto 20-25° C.
  5. stirringstir for 60-90 minutes
  6. filtrationfilter the suspension
  7. washWash the solids
  8. additionwith a mixture of DMSO (103.4 mL) and water (51.7 mL) two times
  9. washWash the solids with water (2×517 mL)
  10. customdry solids on
  11. filtrationa filter with suction

Sources & evidence

ORD record
ord-aff7edfb7d03438ead01415eea10a70a
Source dataset
uspto-grants-2012_04
Patent number
US08148387B2

Reaction notes

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