Acetic Acid → HCID 178523096, compound

HRID 245677Notes

Reaction equation

HRID 245677 reaction equation
Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.[Cl:8][C:9]1[C:10]([CH2:15][NH:16][C:17]([CH:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:11][CH:12]=[CH:13][N:14]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[Cl:8][C:9]1[C:10]([CH2:15][NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([N:5]3[CH2:6][C:3]([F:7])([F:2])[CH2:4]3)[CH2:21][CH2:20]2)=[O:18])=[N:11][CH:12]=[CH:13][N:14]=1.[Cl:8][C:9]1[C:10]([CH2:15][NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@@H:22]([N:5]3[CH2:6][C:3]([F:7])([F:2])[CH2:4]3)[CH2:21][CH2:20]2)=[O:18])=[N:11][CH:12]=[CH:13][N:14]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 5003444Sodium cyanoborohydrideHCID 86674630N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide

Product 2

HCID 178523096HCID 178523096, compoundHCID 178523097HCID 178523097, compound

Reagents, catalysts & solvents 1

HCID 21226129Dichloromethane methanolSolvent2×

Procedure

3,3-Difluoroazetidine hydrochloride (5.60 mmol, 0.726 g) was dissolved in dichloromethane/methanol (20 mL; 1/1) and 15 g Si-Carbonate (Silicycle, Loading 0.7 mmol/g) was added. After 20 minutes this slurry was put on a column with 7 g of Si-Carbonate (Silicycle, Loading 0.7 mmol/g) and eluated with dichloromethane/methanol (40 mL; 1/1). The solution was concentrated (900 mbar, bath 45 deg) to a volume of 30 mL. To this solution N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (3.74 mmol, 1 g), acetic acid (0.1 mL) and sodium cyanoborohydride (7.47 mmol, 0.469 g) were added and the reaction mixture stirred at room temperature. After 3 days the reaction mixture was concentrated, dichloromethane added and washed with aqueous sodium hydrogencarbonate and water. Both aqueous layers were extracted four times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography (silica gel, gradient heptanes/ethyl acetate 2/1 to ethyl acetate) yielded (trans)-N-((3-chloropyrazin-2-yl)methyl)-4-(3,3-difluoroazetidin-1-yl)cyclohexanecarboxamide (0.47 g) and (cis)-N-((3-chloropyrazin-2-yl)methyl)-4-(3,3-difluoroazetidin-1-yl)cyclohexanecarboxamide (0.49 g).

Workup

  1. concentrationThe solution was concentrated (900 mbar, bath 45 deg) to a volume of 30 mL
  2. concentrationAfter 3 days the reaction mixture was concentrated
  3. additiondichloromethane added
  4. washwashed with aqueous sodium hydrogencarbonate and water
  5. extractionBoth aqueous layers were extracted four times with dichloromethane
  6. dry with materialThe combined organic extracts were dried (sodium sulfate)
  7. concentrationconcentrated in vacuo
  8. customPurification by column chromatography (silica gel, gradient heptanes/ethyl acetate 2/1 to ethyl acetate)

Sources & evidence

ORD record
ord-f401fdde1e5f4548b64e7f7325fa3c63
Source dataset
uspto-grants-2014_02
Patent number
US08658794B2

Reaction notes

Loading…