p-Toluenesulfonic acid → 1-(5-methyl-6-{2-[(1S,2R)-2-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}pyridin-3-yl)imidazolidin-2-one

HRID 1850743Notes

Reaction equation

HRID 1850743 reaction equation
[CH3:1][C:2]1[C:3]([O:14][CH2:15][CH2:16][C@@H:17]2[CH2:19][C@@H:18]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:7]=1.[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[N:4][C:3]=1[O:14][CH2:15][CH2:16][C@@H:17]1[CH2:19][C@@H:18]1[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[O:28][N:29]=[C:30]([CH:31]([CH3:33])[CH3:32])[N:27]=2)[CH2:22][CH2:21]1

Participants

6

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 867111894-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridine-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carbonitrileHCID 178449908HCID 178449908, compound

Product 1

HCID 708560501-(5-methyl-6-{2-[(1S,2R)-2-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}pyridin-3-yl)imidazolidin-2-one

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

The mixture of 4-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridine-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carbonitrile (13 mg, 0.035 mmol), N-hydroxy-2-methylpropanimidamide (5 mg., 0.05 mmol) and zinc chloride (0.1 mL., 0.05 mmol) in 1 mL of DMF was stirred 2 hrs at 80° C., then PTSA (7 mg, 0.037 mmol) was added and stirred for additional 2 hrs at 85° C. The mixture was cooled to room temperature and then quenched by sat'd aq soln of NaHCO3. The mixture was extracted with EtOAc (2×5 mL), and the combined organics were then washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified Gilson HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA as buffer. The fractions containing product were collected into a 20 mL scintillation vial and frozen via a dry ice/acetone bath. The frozen material was then lyophilized overnight to give the product as a white fluffy solid. LCMS (ESI) m/z 455 [M+H]+.

Workup

  1. stirringstirred for additional 2 hrs at 85° C
  2. temperatureThe mixture was cooled to room temperature
  3. customquenched by sat'd aq soln of NaHCO3
  4. extractionThe mixture was extracted with EtOAc (2×5 mL)
  5. washthe combined organics were then washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationthe filtrate concentrated in vacuo
  9. customThe residue was purified Gilson HPLC
  10. washeluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA as buffer
  11. additionThe fractions containing product
  12. customwere collected into a 20 mL scintillation vial
  13. temperaturefrozen via a dry ice/acetone bath
  14. waitThe frozen material was then lyophilized overnight

Sources & evidence

ORD record
ord-0c1eb8d1ac404daea39fb115de343170
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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