Water → (3~{r})-3-[[5-Fluoranyl-2-(5-Fluoranyl-1~{h}-Pyrrolo[2,3-B]pyridin-3-Yl)pyrimidin-4-Yl]amino]-4,4-Dimethyl-Pentanoic Acid

HRID 2171835Notes

Reaction equation

HRID 2171835 reaction equation
[F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([O:23]C)=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-].O>O1CCCC1>[F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1

Participants

5

Reactant 3

HCID 962WaterHCID 3939Lithium HydroxideHCID 71247865(R)-methyl 3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate2×

Product 1

HCID 71251236(3~{r})-3-[[5-Fluoranyl-2-(5-Fluoranyl-1~{h}-Pyrrolo[2,3-B]pyridin-3-Yl)pyrimidin-4-Yl]amino]-4,4-Dimethyl-Pentanoic Acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

(R)-Methyl 3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate, 9a, (18.4 g, 47.1 mmol) was dissolved in tetrahydrofuran (275 mL) and aqueous 1M LiOH (141 mL) was added. The mixture was heated to 50° C. for 3.5 h. The reaction mixture was cooled to room temperature and 180 mL of water was added. The tetrahydrofuran was removed under reduced pressure and the residue was then flushed twice with hexanes. Diethylether (60 mL) was added and the layers separated. The pH of the aqueous layer was adjusted to 6 with 1N HCl. Ethyl acetate (540 mL) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (720 mL), then again with ethyl acetate (300 mL). The organic layers were combined, washed with brine (100 mL) and dried (Na2SO4). The solvents were removed while flushing with heptanes to provide the desired product, 2, (17.5 g): 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 12.03 (s, 1H), 8.68-8.52 (m, 1H), 8.27 (s, 1H), 8.19 (d, J=2.5 Hz, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 4.83 (t, J=9.3 Hz, 1H), 2.71-2.51 (m, 2H), 0.97 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=1.96 minutes (M+H) 377.02.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customThe tetrahydrofuran was removed under reduced pressure
  3. customthe residue was then flushed twice with hexanes
  4. additionDiethylether (60 mL) was added
  5. customthe layers separated
  6. additionEthyl acetate (540 mL) was added
  7. customthe layers were separated
  8. extractionthe aqueous layer was extracted with ethyl acetate (720 mL)
  9. washwashed with brine (100 mL)
  10. dry with materialdried (Na2SO4)
  11. customThe solvents were removed
  12. customwhile flushing with heptanes

Sources & evidence

ORD record
ord-8e826475459e477a8a0ead723c9068dc
Source dataset
uspto-grants-2015_06
Patent number
US09051319B2

Reaction notes

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