2-Bromopyridine → (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-(2-pyridinyl)pyrrolidin-3-yl]-2-piperidinecarboxamide

HRID 412638Notes

Reaction equation

HRID 412638 reaction equation
C(=O)([O-])O.[Na+].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>C(#N)C>[CH2:16]([NH:15][CH2:20][CH3:19])[CH3:17].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:25]1)=[O:22]

Participants

6

Reactant 3

HCID 79732-BromopyridineHCID 516892Sodium Bicarbonate2×HCID 57068119(2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide

Product 2

HCID 8021DiethylamineHCID 59063197(2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-(2-pyridinyl)pyrrolidin-3-yl]-2-piperidinecarboxamideYield 16.8%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
75 °C

Procedure

Sodium hydrogen carbonate (28.6 mg) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide (104.9 mg) [see Example 4] and 2-bromopyridine (52.7 mg) in acetonitrile (5 ml). The reaction mixture was heated to 75° C. for 48 hours, after which time additional sodium hydrogen carbonate (28.6 mg) was added and the mixture was heated under reflux for a further 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 93:7:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution, and was then further purified by a second column eluting with 95:5, by volume, ethyl acetate:diethylamine to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-(2-pyridinyl)pyrrolidin-3-yl]-2-piperidinecarboxamide (11 mg) as a brown oil.

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder reflux for a further 24 hours
  3. customThe solvent was removed under reduced pressure
  4. customthe residue was partitioned between ethyl acetate and water
  5. customthe organic layer was separated
  6. dry with materialdried over magnesium sulphate
  7. customthe solvent removed under reduced pressure
  8. customThe crude product was purified by column chromatography on silica gel eluting with a solvent system of 93:7:1, by volume, dichloromethane
  9. custommethanol:0.88 aqueous ammonia solution, and was then further purified by a second column
  10. washeluting with 95:5, by volume, ethyl acetate

Sources & evidence

ORD record
ord-f5ba6f3fde1547da8290be2aaa2c7a3b
Source dataset
uspto-grants-2003_05
Patent number
US06562964B1

Reaction notes

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