Cesium carbonate → US9718822, 45 Diastereomer 1

HRID 1426989Notes

Reaction equation

HRID 1426989 reaction equation
Cl[CH2:2][C@@H:3]([OH:32])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C:20]([F:23])([F:22])[CH2:19][CH:18]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[OH:31])=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:22][C:20]1([F:23])[CH2:19][CH:18]2[N:17]([C:14]3[CH:15]=[CH:16][N:11]4[C:12]([N:13]=3)=[C:8]([C:6](=[O:7])[NH:5][CH2:4][C@H:3]([OH:32])[CH2:2][O:31][C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=32)[CH:9]=[N:10]4)[CH2:21]1

Participants

4

Reactant 2

HCID 10796Cesium carbonateHCID 86691760N-((S)-3-chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Product 1

HCID 70168632US9718822, 45 Diastereomer 1Yield 20%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of N-((S)-3-chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.060 g, 0.128 mmol) and Cs2CO3 (0.208 g, 0.639 mmol) in DMF (6.4 mL) was heated at 85° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude material which was purified by silica gel flash column chromatography (CH2Cl2 to NH4OH:MeOH:CH2Cl2=0.5:5:95) to afford a mixture of the diastereomers. The isolated diastereomers were further purified by chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes). Fractions having a retention time of about 17.1 minutes were isolated to afford the title compound designated as Diastereomer 1 (11 mg, 20% yield; MS (APCI) m/z=434.2 (M+H). Fractions having a retention time of about 21.0 minutes were isolated to provide the title compound designated as Diastereomer 2 (13 mg; 24% yield); MS (APCI) m/z=434.2 (M+H).

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated under reduced pressure
  4. customto give the crude material which
  5. customwas purified by silica gel flash column chromatography (CH2Cl2 to NH4OH:MeOH:CH2Cl2=0.5:5:95)
  6. customto afford
  7. additiona mixture of the diastereomers
  8. customThe isolated diastereomers were further purified by chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes)
  9. customwere isolated

Sources & evidence

ORD record
ord-c540299b86d9436d9ca52265641bd287
Source dataset
uspto-grants-2015_01
Patent number
US08933084B2

Reaction notes

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