Diisopropylethylamine → (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

HRID 1426986Notes

Reaction equation

HRID 1426986 reaction equation
O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:44][C:45]1[CH:46]=[CH:47][C:48]([O:57][CH3:58])=[C:49]([CH:51]2[NH:55][CH2:54][C@H:53]([OH:56])[CH2:52]2)[CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[F:44][C:45]1[CH:46]=[CH:47][C:48]([O:57][CH3:58])=[C:49]([C@H:51]2[CH2:52][CH:53]([OH:56])[CH2:54][N:55]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:50]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 67470690(R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochlorideHCID 178469952HCID 178469952, compound

Product 1

HCID 86691712(R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylateYield 77.6%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

To a suspension of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.541 g, 2.61 mmol) and BOP reagent (1.57 g, 3.56 mmol) in DMF/CH2Cl2 (3 mL/3 mL) at 0° C. was added (R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.588 g, 2.37 mmol) followed by DIEA (1.66 mL, 9.50 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was diluted again with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCO3 followed by brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography, eluting with CH2Cl2 to 5% MeOH in CH2Cl2 to afford (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.735 g, 1.84 mmol, 77.3% yield). LC/MS (ES+APCI) m/z=401.1 (M+H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customto give the crude material that
  3. washThe organic layer was washed with saturated aqueous NaHCO3
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto give the crude material that
  8. customwas purified by silica gel flash column chromatography
  9. washeluting with CH2Cl2 to 5% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-67ee4369e7dc49d4a6b90300d5f30e8f
Source dataset
uspto-grants-2015_01
Patent number
US08933084B2

Reaction notes

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