Hydrochloric Acid → Tert-butyl 4-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]piperidine-1-carboxylate

HRID 2421052Notes

Reaction equation

HRID 2421052 reaction equation
Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.C(=O)([O-])[O-].O=[C:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[O:17]=[C:9]1[N:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH2:7][CH2:6]2)[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]2[NH:10]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 19660Carbonate IonHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5003444Sodium cyanoborohydrideHCID 59025441(3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one

Product 1

HCID 24882729Tert-butyl 4-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]piperidine-1-carboxylateYield 88%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent3×

Procedure

HCl salt of (3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one (2 g, 7.72 mmol) was dissolved in MeOH (30 mL) and MP carbonate (12 g) was added. The mixture was stirred for one hour at rt and then filtered and concentrated in vacuo to provide a white solid. To a stirred solution of above freebase and tert-butyl 4-oxopiperidine-1-carboxylate (1.8 g, 9.04 mmol) in MeOH (40 mL) was added a solution of sodium cyanoborohydride (1 g, 14.49 mmol) and zinc chloride (0.73 g, 5.36 mmol) in MeOH (20 mL). The resulting solution was stirred at room temperature over night then concentrated in vacuo. A solution of 1N NaOH was added and aqueous phase was extracted several times with dichloromethane. The combined organic phases were washed with brine, dried and then concentrated in vacuo. The residue was purified using flash chromatography (linear gradient starting from 1-12% methanol in dichloromethane) to provide the desired compound as a white solid (2 g, 88%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.21-1.49 (m, 4H), 1.41 (s, 9H), 1.57-1.67 (m, 1H), 1.66-1.84 (m, 7H), 1.93 (d, J=11.13 Hz, 1H), 2.05-2.32 (m, 5H), 2.29-2.43 (m, 1H), 2.53-2.71 (m, 2H), 2.76-3.05 (m, 4H), 3.56-3.79 (m, 1H), 3.90-4.24 (m, 2H), 4.76 (s, 1H). MS (M+1): 407.3

Workup

  1. filtrationfiltered
  2. concentrationconcentrated in vacuo
  3. customto provide a white solid
  4. stirringThe resulting solution was stirred at room temperature over night
  5. concentrationthen concentrated in vacuo
  6. additionA solution of 1N NaOH was added
  7. extractionaqueous phase was extracted several times with dichloromethane
  8. washThe combined organic phases were washed with brine
  9. customdried
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified

Sources & evidence

ORD record
ord-79106a0ea5b345d99c1e88c0214c97b8
Source dataset
uspto-grants-2011_06
Patent number
US07956069B2

Reaction notes

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