Isopropyl Acetate → (R)-3-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

HRID 2090559Notes

Reaction equation

HRID 2090559 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:16]([CH3:20])([CH3:19])[O:15]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[F:23].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(OC(C)C)(=O)C>C(Cl)Cl.O>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][N:9]2[C:10](=[O:12])[C:11]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=4[F:24])=[C:3]([F:23])[C:4](=[O:22])[N:5]([CH3:21])[C:6]=3[N:7]=[CH:8]2)[CH2:18][O:17]1

Participants

8

Reactant 5

HCID 7915Isopropyl AcetateHCID 8028Tetrahydrofuran2×HCID 1856942-Fluoro-4-iodoanilineHCID 2733832Lithium HexamethyldisilazideHCID 67378564(R)-5-Chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Product 1

HCID 67368877(R)-3-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Combine (R)-5-chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (4.00 g, 11.6 mmol), 2-fluoro-4-iodoaniline (2.76 g, 11.6 mmol) and tetrahydrofuran (16.0 mL, 197 mmol). Cool to 0° C. to 5° C. in an ice bath, add 1.0 M lithium hexamethyldisilazide in tetrahydrofuran (23.3 mL, 23.3 mmol) while keeping the temperature below 10° C. Agitate in an ice bath for no less than 30 min and then warm to ambient temperature and stir overnight. Add water (20.0 mL) and methylene chloride (40.0 mL) and agitate, then separate the phases. Combine the organic phase and 40 mL of water, adjust the pH to 7 with 2 N HCl. Separate the organic phase extract with water (20 mL), dry over MgSO4, concentrate to 20 mL to give a solid. Add isopropyl acetate (40.0 mL, 342 mmol) to the suspension, stir at ambient temperature for no less than 2 hours, collect the solid by filtration, rinse with isopropyl acetate (20 mL), and dry overnight at 30° C. under vacuum to give the title compound.

Workup

  1. temperatureCool to 0° C. to 5° C. in an ice bath
  2. customthe temperature below 10° C
  3. stirringstir overnight
  4. customseparate the phases
  5. customSeparate the organic phase
  6. extractionextract with water (20 mL)
  7. dry with materialdry over MgSO4
  8. concentrationconcentrate to 20 mL
  9. customto give a solid
  10. customcollect the solid
  11. filtrationby filtration
  12. washrinse with isopropyl acetate (20 mL)
  13. customdry overnight at 30° C. under vacuum

Sources & evidence

ORD record
ord-ac9109b0dd8643b69681c74202100b6c
Source dataset
uspto-grants-2013_05
Patent number
US08436200B2

Reaction notes

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