Succinic Acid → tert-Butyl 4-(4-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate succinate

HRID 2088882Notes

Reaction equation

HRID 2088882 reaction equation
[Cl-].ClCC[NH+]1CCCC1.FC(F)(F)C1N=C(C2CCN(C(OC(C)(C)C)=O)CC2)NC=1.[OH-].[K+].[F:34][C:35]([F:62])([F:61])[C:36]1[N:37]=[C:38]([CH:48]2[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]2)[N:39]([CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:40]=1.FC(F)(F)C1N(CCN2CCCC2)C(C2CCN(C(OC(C)(C)C)=O)CC2)=NC=1.[C:92]([OH:99])(=[O:98])[CH2:93][CH2:94][C:95]([OH:97])=[O:96]>CS(C)=O.C(O)(C)C>[C:92]([OH:99])(=[O:98])[CH2:93][CH2:94][C:95]([OH:97])=[O:96].[F:62][C:35]([F:34])([F:61])[C:36]1[N:37]=[C:38]([CH:48]2[CH2:49][CH2:50][N:51]([C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[CH2:52][CH2:53]2)[N:39]([CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:40]=1

Participants

9

Reactant 6

HCID 1110Succinic AcidHCID 14797Potassium HydroxideHCID 110083397250-67-1HCID 67954292tert-butyl 4-(4-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylateHCID 67955124tert-butyl 4-(5-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylateHCID 178451801HCID 178451801, compound

Product 1

HCID 67954408tert-Butyl 4-(4-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate succinateYield 82%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 3776IsopropanolSolvent2×

Conditions

Temperature
50 °C

Procedure

Add 1-(2-chloro-ethyl)-pyrrolidinium chloride (73.50 g, 1.15 eq) to a mixture of tert-butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (120.00 g, 375.79 mmol) and potassium hydroxide (54.82 g, 2.60 eq) in dimethyl sulfoxide (1.1 L). Stir the resulting suspension at 50° C. overnight. Cool the reaction mixture to room temperature and add ice/water (1.50 l). Extract with ethyl acetate (3×500 mL). Wash the organics with water (2×300 mL) and saturated aqueous sodium chloride (300 mL), dry over anhydrous sodium sulfate. Purify by silica gel chromatography, eluting with 5% to 15% isopropyl alcohol in dichloromethane, to give a mixture of tert-butyl 4-(4-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (122.00 g, 78%) and tert-butyl 4-(5-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (14.00 g, 9%). Add isopropyl alcohol (470 mL) and heat to 70° C. Add a solution of butanedioic acid (35 g, 1 eq) in isopropyl alcohol (350 mL) preheated at 75° C. Stop heating and let stir at room temperature overnight. Filter the solid and wash with isopropyl alcohol (300 mL). Suspend the solid in isopropyl alcohol (500 mL) and stir 15 minutes. Filter and stir the solid in isopropyl alcohol (500 mL) 15 minutes one more time, then filter to give the title compound (124.00 g, 82%) as a white solid. MS (ES) m/z=417 [M]+.

Workup

  1. temperatureCool the reaction mixture to room temperature
  2. extractionExtract with ethyl acetate (3×500 mL)
  3. washWash the organics with water (2×300 mL) and saturated aqueous sodium chloride (300 mL)
  4. dry with materialdry over anhydrous sodium sulfate
  5. customPurify by silica gel chromatography
  6. washeluting with 5% to 15% isopropyl alcohol in dichloromethane
  7. customto give
  8. custompreheated at 75° C
  9. temperatureStop heating
  10. stirringlet stir at room temperature overnight
  11. filtrationFilter the solid
  12. washwash with isopropyl alcohol (300 mL)
  13. stirringstir 15 minutes
  14. filtrationFilter
  15. stirringstir the solid in isopropyl alcohol (500 mL) 15 minutes one more time
  16. filtrationfilter

Sources & evidence

ORD record
ord-396b1c3f7f9742fcb9937d2b210e2303
Source dataset
uspto-grants-2013_05
Patent number
US08436002B2

Reaction notes

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