Lithium hydride → methyl 5-((R)-2-(1-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

HRID 1426972Notes

Reaction equation

HRID 1426972 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]3[N:15]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Li+].Br[CH2:30][C@H:31]([CH3:44])[CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43]>CN(C=O)C.CCOC(C)=O>[O:43]=[C:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41](=[O:42])[N:33]1[CH2:32][C@@H:31]([CH3:44])[CH2:30][N:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]3[N:15]=2)[C:5]1=[O:8]

Participants

6

Reactant 3

HCID 62714Lithium hydrideHCID 10564807(R)-2-(3-bromo-2-methylpropyl)isoindoline-1,3-dioneHCID 178498897HCID 178498897, compound

Product 1

HCID 67471119methyl 5-((R)-2-(1-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylateYield 34.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of (R)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (202 mg, 0.565 mmol) in DMF (5 mL) was added lithium hydride (22.5 mg, 2.83 mmol) and (R)-2-(3-bromo-2-methylpropyl)isoindoline-1,3-dione (prepared according to the procedure described in Euro. J. Med. Chem. 2000, 147-156) (239 mg, 0.848 mmol). The reaction was stirred for 2 hours at 70° C., and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2×10 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 66% EtOAc/Hexanes to afford the product (110 mg, 34.8% yield). MS (apci) m/z=559.0 (M+H).

Workup

  1. customprepared
  2. temperaturecooled to ambient temperature
  3. washwashed with water (2×10 mL)
  4. dry with materialThe organic layer was dried with Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica column chromatography
  8. washeluting with 66% EtOAc/Hexanes

Sources & evidence

ORD record
ord-fbf931c00a724ef2878439ccce8be449
Source dataset
uspto-grants-2015_01
Patent number
US08933084B2

Reaction notes

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