1,1'-Carbonyldiimidazole → (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone

HRID 1969741Notes

Reaction equation

HRID 1969741 reaction equation
Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH2:3]1.C1N=CN([C:25]([N:27]2[CH:31]=N[CH:29]=[CH:28]2)=[O:26])C=1.Cl.[F:33][C:34]1([F:40])CCNC[CH2:35]1>N1C=CC=CC=1>[C:8]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:25]([N:27]3[CH2:28][CH2:29][C:34]([F:40])([F:33])[CH2:35][CH2:31]3)=[O:26])[CH2:3]2)[N:12]2[C:13]3[CH:19]=[CH:18][NH:17][C:14]=3[N:15]=[CH:16][C:11]2=[CH:10][N:9]=1

Participants

5

Reactant 3

HCID 682631,1'-Carbonyldiimidazole2×HCID 27583514,4-Difluoropiperidine hydrochlorideHCID 67216656(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride

Product 1

HCID 58557191(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanoneYield 49.5%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.24 g, 0.76 mmol) in pyridine (7.2 mL) was added CDI (0.14 g, 0.87 mmol) and the reaction mixture was stirred at about 50° C. for about 2 h. Additional CDI (0.02 g, 0.14 mmol) was added and the reaction mixture was stirred for about 1 h. To the reaction mixture was added 4,4-difluoropiperidine hydrochloride (0.12 g, 0.76 mmol). The reaction mixture was heated to about 55° C. for about 1 h, cooled to ambient temperature, and stirred for about 2 d. The solvent was removed under reduced pressure and the crude residue dissolved with DCM (5 mL) and washed with water (2 mL). The aqueous layer was back extracted with DCM (2 mL). The combined organic extracts were washed with brine (3 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone (0.146 g, 49%) as an off white solid: LC/MS (Table 1, Method b) Rt=1.70 min; MS m/z: 389 (M+H)+.

Workup

  1. stirringthe reaction mixture was stirred for about 1 h
  2. temperatureThe reaction mixture was heated to about 55° C. for about 1 h
  3. temperaturecooled to ambient temperature
  4. stirringstirred for about 2 d
  5. customThe solvent was removed under reduced pressure
  6. dissolutionthe crude residue dissolved with DCM (5 mL)
  7. washwashed with water (2 mL)
  8. extractionThe aqueous layer was back extracted with DCM (2 mL)
  9. washThe combined organic extracts were washed with brine (3 mL)
  10. dry with materialdried over anhydrous MgSO4
  11. filtrationfiltered
  12. customThe crude material was purified by silica gel chromatography
  13. washeluting with a gradient of 0-5% MeOH in DCM

Sources & evidence

ORD record
ord-a5a5e04237d642bc8256814e749c3ea5
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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