Cesium carbonate → (S)-3-(6-chloro-4-oxochroman-7-ylamino)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one

HRID 407907Notes

Reaction equation

HRID 407907 reaction equation
[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:74]1[CH:83]=[C:82]2[C:77]([C:78](=[O:84])[CH2:79][CH2:80][O:81]2)=[CH:76][C:75]=1[Cl:85])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:85][C:75]1[CH:76]=[C:77]2[C:82](=[CH:83][C:74]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]4[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=4)[CH2:9][CH2:8]3)[C:3]1=[O:21])[O:81][CH2:80][CH2:79][C:78]2=[O:84]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 67469717(S)-3-amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-oneHCID 866880886-Chloro-4-oxochroman-7-yl trifluoromethanesulfonate

Product 1

HCID 54669966(S)-3-(6-chloro-4-oxochroman-7-ylamino)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-oneYield 5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

(S)-3-Amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 34, Steps A-D; 120 mg, 0.42 mmol) was dissolved in toluene (3 mL). 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (26 mg, 0.042 mmol), 6-chloro-4-oxochroman-7-yl trifluoromethanesulfonate (206 mg, 0.62 mmol) and Cs2CO3 (162 mg, 0.498 mmol) were added and the reaction was bubbled through with nitrogen for 5 minutes. Pd2 dba3 (19.0 mg, 0.021 mmol) was added and the reaction plunged into 95° C. oil bath overnight. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (75 to 100% EtOAc in hexanes) to afford a mixture. The mixture was further purified by reverse phase chromatography (25 to 95% ACN in water) to afford (S)-3-(6-chloro-4-oxochroman-7-ylamino)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (10 mg, 0.022 mmol, 5% yield. Mass spectrum (apci) m/z=470.3 (M+H).

Workup

  1. customthe reaction was bubbled through with nitrogen for 5 minutes
  2. customplunged into 95° C.
  3. customovernight
  4. custompartitioned between water and EtOAc
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified over silica gel (75 to 100% EtOAc in hexanes)
  9. customto afford a mixture
  10. customThe mixture was further purified by reverse phase chromatography (25 to 95% ACN in water)

Sources & evidence

ORD record
ord-865030744fae48ef8b0099d7e35502c8
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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