Thionyl Chloride → 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide

HRID 1631366Notes

Reaction equation

HRID 1631366 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1([CH3:48])[O:44][C@H:43]([CH2:45][O:46][NH2:47])[CH2:42][O:41]1>C(Cl)(Cl)(Cl)Cl.C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:47][O:46][CH2:45][C@@H:43]3[CH2:42][O:41][C:40]([CH3:48])([CH3:39])[O:44]3)=[O:24])=[C:16]2[N:15]=1

Participants

9

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 14814202(S)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamineHCID 66847716(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

Product 1

HCID 866645775-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 5943Carbon TetrachlorideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 100 mg, 0.290 mmol) in CCl4 (1.5 mL) was added thionyl chloride (0.10 mL, 1.37 mmol) and the mixture was heated at reflux for 2.5 hours. The mixture was cooled to ambient temperature and was concentrated to give a residual brittle foam. The foam was dissolved in dry THF (2.0 mL) and the solution was sequentially treated with DMAP, DIEA and (S)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (85.5 mg, 0.581 mmol). The reaction was stirred at ambient temperature for 4.5 hours and was concentrated to approx. 0.5 mL. The mixture was diluted with H2O (5 mL) and extracted with 50% EtOAc-hexanes. The combined extracts were washed with 1M HCl, H2O, 1M Na2CO3 and saturated NaCl. The solution was dried over MgSO4 and activated carbon, then filtered through a short SiO2 plug, eluting first with 50% EtOAc-hexanes then 10% MeOH-EtOAc. The MeOH-EtOAc pool was concentrated to give a colorless foam. The foam was dissolved in minimal CH2Cl2 and treated with hexanes to give a white suspension. The suspension was concentrated to afford the title compound as white solid that was dried in vacuum (137 mg, 100%). MS (apci) m/z=474.1 (M+H).

Workup

  1. temperaturethe mixture was heated
  2. temperatureat reflux for 2.5 hours
  3. concentrationwas concentrated
  4. customto give a residual brittle foam
  5. concentrationwas concentrated to approx. 0.5 mL
  6. additionThe mixture was diluted with H2O (5 mL)
  7. extractionextracted with 50% EtOAc-hexanes
  8. washThe combined extracts were washed with 1M HCl, H2O, 1M Na2CO3 and saturated NaCl
  9. dry with materialThe solution was dried over MgSO4 and activated carbon
  10. filtrationfiltered through a short SiO2 plug
  11. washeluting first with 50% EtOAc-hexanes
  12. concentrationThe MeOH-EtOAc pool was concentrated
  13. customto give a colorless foam
  14. customto give a white suspension
  15. concentrationThe suspension was concentrated

Sources & evidence

ORD record
ord-033b4d555bc44378bb2ff8f1ec648c22
Source dataset
uspto-grants-2014_07
Patent number
US08791123B2

Reaction notes

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