4-Chlorobenzaldehyde → 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60423Notes

Reaction equation

HRID 60423 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:16](=[O:17])[C:11]=3[CH:10]=2)[CH:5]=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1.CC(=O)OCC.O>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]([OH:46])[C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:14](=[O:28])[N:13]([CH3:29])[C:12]=3[N:30]=[CH:31][C:9]=2[O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:43][CH:42]=1

Participants

7

Reactant 3

HCID 77264-ChlorobenzaldehydeHCID 2724682Lithium diisopropylamideHCID 1188755406-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Product 1

HCID 1188754815-((4-chlorophenyl)(hydroxy)methyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 25.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 0.35 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 0.7 mL, 1.40 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 4-chlorobenzaldehyde (98 mg, 0.70 mmol) in THF (2 mL) was added. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 25.1% yield) as an oil. LCMS: [MH+-THP] 487 and TR=1.423 min. Used without further purification.

Workup

  1. stirringThe reaction was stirred for 30 min at −78° C.
  2. dry with materialThe organic layer was dried over Na2SO4
  3. concentrationconcentrated to a residue which
  4. customwas purified by Prep TLC
  5. washeluted with PE/EA (1:1)

Sources & evidence

ORD record
ord-b2e38dada27644a889ca5ff66560fd4d
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

Loading…