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

HRID 1426897Notes

Reaction equation

HRID 1426897 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.FC(F)(F)C(O)=O.[Si:50]([O:57][CH:58]1[CH2:62][NH:61][C@@H:60]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[O:70][CH3:71])[CH2:59]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[Si:50]([O:57][CH:58]1[CH2:62][N:61]([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)[C@@H:60]([C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:64]=2[O:70][CH3:71])[CH2:59]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 67470685(R)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetateHCID 178469952HCID 178469952, compound

Product 1

HCID 86691711(R)-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylateYield 19.6%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.100 g, 0.483 mmol) and BOP reagent (0.320 g, 0.724 mmol) in DMF (1 mL) at 0° C. was added a solution of (R)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate (Preparation C, 0.167 g, 0.483 mmol) in CH2Cl2 (1 mL) and N,N-diisopropylethylamine (0.420 mL, 2.41 mmol) sequentially. The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL), and washed with saturated aqueous NaHCO3 and brine. The brine phase was back-extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica column chromatography, eluting with 0-50% EtOAc/Hexanes to afford (R)-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (as a mixture of cis and trans isomers) (0.0487 g, 19.6% yield). LC/MS (ES+APCI) m/z=515.2 (M+H).

Workup

  1. washwashed with saturated aqueous NaHCO3 and brine
  2. extractionThe brine phase was back-extracted with EtOAc (3×)
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customto give the crude material that
  7. customwas purified by silica column chromatography
  8. washeluting with 0-50% EtOAc/Hexanes

Sources & evidence

ORD record
ord-92378169516a4e759a850ae3037cf515
Source dataset
uspto-grants-2015_01
Patent number
US08933084B2

Reaction notes

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