Diisopropylethylamine → 3-(2,5-Difluoro-4-(methylsulfonyl)phenoxy)-1'-(5-ethylpyrimidine-2-yl)-1,4'-bipiperidine-2-one

HRID 407898Notes

Reaction equation

HRID 407898 reaction equation
Cl.[F:2][C:3]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([F:27])=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]1=[O:18].CCN(C(C)C)C(C)C.Cl[C:38]1[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=1>CS(C)=O.O.CCOC(C)=O>[F:2][C:3]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([F:27])=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:38]3[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=3)[CH2:14][CH2:13]2)[C:7]1=[O:18]

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 35727632-Chloro-5-ethylpyrimidineHCID 866880843-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4'-bipiperidin-2-one HCl salt

Product 1

HCID 761660633-(2,5-Difluoro-4-(methylsulfonyl)phenoxy)-1'-(5-ethylpyrimidine-2-yl)-1,4'-bipiperidine-2-oneYield 20.2%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4′-bipiperidin-2-one HCl salt (64 mg, 0.15 mmol) and DIEA (0.080 mL, 0.45 mmol) in DMSO (2 mL) was added 2-chloro-5-ethylpyrimidine (26 mg, 0.18 mmol). The reaction was heated at 120° C. overnight. The reaction was cooled to ambient temperature and diluted with water (2 mL) and EtOAc (5 mL). The organic layer was separated and the aqueous washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified by reverse phase HPLC (5 to 95% acetonitrile in water with 0.1% TFA). The combined fractions were concentrated to remove CH3CN and the pH adjusted to neutral by the addition of NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were dried with MgSO4 and concentrated to give 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1′-(5-ethylpyrimidine-2-yl)-1,4′-bipiperidine-2-one (15 mg, 20%) as an off white solid. Mass spectrum (apci) m/z=495.2 (M+H).

Workup

  1. temperatureThe reaction was cooled to ambient temperature
  2. customThe organic layer was separated
  3. washthe aqueous washed with EtOAc
  4. dry with materialThe combined organic layers were dried with MgSO4
  5. concentrationconcentrated
  6. customThe crude residue was purified by reverse phase HPLC (5 to 95% acetonitrile in water with 0.1% TFA)
  7. concentrationThe combined fractions were concentrated
  8. customto remove CH3CN
  9. additionneutral by the addition of NaHCO3
  10. extractionThe aqueous layer was extracted with EtOAc
  11. dry with materialThe combined organic layers were dried with MgSO4
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-b203ae07997749639149da066fab459c
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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