2-Fluoro-4-iodoaniline → (R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

HRID 1260434Notes

Reaction equation

HRID 1260434 reaction equation
Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C@@H:14]3[CH2:18][O:17]C(C)(C)[O:15]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[CH3:23].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:15][C@@H:14]([CH2:18][OH:17])[CH2:13][N:9]1[C:10](=[O:12])[C:11]2[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=3[F:24])=[C:3]([CH3:23])[C:4](=[O:22])[N:5]([CH3:21])[C:6]=2[N:7]=[CH:8]1

Participants

7

Reactant 4

HCID 1856942-Fluoro-4-iodoanilineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 59823054HCID 59823054, compound2×

Product 1

HCID 24966075(R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dioneYield 31%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

(R)-5-Chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (9.2 g, 27.1 mmol, 1 eq, compound 8E), 2-fluoro-4-iodoaniline (12.9 g, 54.2 mmol, 2 eq), tris(dibenzylideneacetone)dipalladium(0) (1.99 g, 2.17 mmol, 0.08 eq), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (1.25 g, 2.17 mmol, 0.08 eq) and sodium tert-butoxide (7.81 g, 81.4 mmol, 3 eq) were heated in degassed anhydrous 1,4-dioxane (80 mL) at 100° C. for 1 hour. Upon cooling, the solution was filtered and the solid washed with DCM. The filtrate was evaporated in vacuo and the residue (crude 8F) was taken up in H2O (20 mL) and THF (20 mL). 1N HCl (15 mL) was added and the solution heated at 70° C. for 30 minutes. Upon cooling an off-white solid precipitated which was collected by filtration, washed with water and dried. The solid was purified by HPLC to give 4.2 g of title compound (31%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63 (s, 3H) 3.38 (t, J=6.06 Hz, 1H) 3.41-3.51 (m, 1H) 3.61 (s, 3H) 3.62-3.68 (m, 1H) 3.75 (br. s., 1H) 4.81 (t, J=5.56 Hz, 1H) 5.11 (d, J=5.31 Hz, 1H) 6.60 (t, J=8.72 Hz, 1H) 7.45 (d, J=9.60 Hz, 1H) 7.66 (d, J=10.61 Hz, 1H) 8.48 (s, 1H) 10.16 (s, 1H). [M+H] calc'd for C18H18FIN4O4, 501. found, 501.

Workup

  1. temperatureUpon cooling
  2. filtrationthe solution was filtered
  3. washthe solid washed with DCM
  4. customThe filtrate was evaporated in vacuo
  5. addition1N HCl (15 mL) was added
  6. temperatureUpon cooling an off-white solid
  7. customprecipitated which
  8. filtrationwas collected by filtration
  9. washwashed with water
  10. customdried
  11. customThe solid was purified by HPLC

Sources & evidence

ORD record
ord-f03c384f9b19478ea64eb6f1ac86bcf9
Source dataset
uspto-grants-2013_06
Patent number
US08470837B2

Reaction notes

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