1,2-Diaminocyclohexane, trans- → (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one

HRID 407987Notes

Reaction equation

HRID 407987 reaction equation
Br[C:2]1[C:28]([CH3:29])=[CH:27][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[C@@H]1(N)CCCC[C@H]1N.[CH3:39][S:40]([O-:42])=[O:41].[Na+]>CS(C)=O>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:9]3[CH2:10][CH2:11][C@H:7]([O:6][C:5]4[CH:27]=[C:28]([CH3:29])[C:2]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:3][C:4]=4[F:30])[C:8]3=[O:26])[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]

Participants

5

Reactant 3

HCID 438061,2-Diaminocyclohexane, trans-2×HCID 2733271Sodium methanesulfinate2×HCID 54671182(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one

Product 1

HCID 54671184(S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenoxy)pyrrolidin-2-oneYield 60%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (200 mg, 0.42 mmol), trans-cyclohexane-1,2-diamine (20 μL, 0.17 mmol), sodium methanesulfinate (64 mg, 0.63 mmol) was dissolved in DMSO (3 mL) and nitrogen bubbled through for 15 minutes. Cu(I) triflate benzene-complex (21 mg, 0.04 mmol) was added and the reaction was plunged into 110° C. oil bath and stirred under nitrogen overnight. Additional trans-cyclohexane-1,2-diamine (20 μL, 0.17 mmol), sodium methanesulfinate (64 mg, 0.63 mmol) and Cu(I) triflate benzene-complex (21 mg, 0.04 mmol) were added and stirred for another 4 hours at 110° C. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (119.8 mg, 0.25 mmol, 60% yield) as a white solid. Mass spectrum (apci) m/z=477.3 (M+H).

Workup

  1. customnitrogen bubbled through for 15 minutes
  2. customwas plunged into 110° C.
  3. stirringstirred for another 4 hours at 110° C
  4. custompartitioned between water and EtOAc
  5. extractionextracted with EtOAc
  6. washwashed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified over silica gel (100% EtOAc)

Sources & evidence

ORD record
ord-7a9b4d7048224a589f3e994629d02f57
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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