Methyl phenylacetate → 7-Chloro-2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine

HRID 1984632Notes

Reaction equation

HRID 1984632 reaction equation
[C:1]1([CH2:7][C:8](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:22][C:23]1[C:28]([CH:29]=O)=[CH:27][N:26]=[C:25]([S:31][CH2:32][CH3:33])[N:24]=1.P(Cl)(Cl)([Cl:36])=O>C1COCC1.CC#N>[Cl:36][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:29][C:28]2[CH:27]=[N:26][C:25]([S:31][CH2:32][CH3:33])=[N:24][C:23]=2[N:22]=1

Participants

7

Reactant 4

HCID 7559Methyl phenylacetateHCID 24813Phosphorus oxychlorideHCID 2733832Lithium HexamethyldisilazideHCID 591088604-Amino-2-(ethylthio)pyrimidine-5-carbaldehyde

Product 1

HCID 577139457-Chloro-2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of methyl phenylacetate (15.5 mL, 110 mmol) in THF (300 mL) at −78° C. was added LHMDS (1 M, 120 mL, 2.3 mmol) and stirred for 1 hr. 4-amino-2-(ethylthio)pyrimidine-5-carbaldehyde (6-2) (9.6 g, 52 mmol) was added. The mixture was warmed to room temperature and stirred for 12 hr. The reaction was quenched with saturated NH4Cl solution and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The resulting solid was triturated with Et2O and the white purified solid was filtered. A portion of the solid (2.5 g, 8.8 mmol) was dissolved in CH3CN and phosphorus oxychloride (8.0 mL, 88 mmol) was added. The mixture was heated to reflux for 12 hr. After 12 hr, the solvent and POCl3 were distilled off using a dean stark apparatus until 15 mL remained in the flask. Upon cooling, a white solid formed and was filtered. The solid washed with Et2O and dried under vacuum to afford the salt of (6-3). The mother liquor was basified by slowly adding Et3N dropwise until pH=7, diluted with water, and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The residue was purified by trituration with Et2O and filtered to yield pure (6-3) as a free base. LRMS m/z (M+H) Calcd: 302.0, found: 302.0.

Workup

  1. stirringstirred for 12 hr
  2. customThe reaction was quenched with saturated NH4Cl solution
  3. extractionextracted with CH2Cl2
  4. customThe combined organic layer was dried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting solid was triturated with Et2O
  8. customthe white purified solid
  9. filtrationwas filtered
  10. temperatureThe mixture was heated
  11. temperatureto reflux for 12 hr
  12. waitAfter 12 hr
  13. distillationthe solvent and POCl3 were distilled off
  14. temperatureUpon cooling
  15. customa white solid formed
  16. filtrationwas filtered
  17. washThe solid washed with Et2O
  18. customdried under vacuum

Sources & evidence

ORD record
ord-7f3f8ad241264e5781371a35f47644d3
Source dataset
uspto-grants-2009_06
Patent number
US07544677B2

Reaction notes

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