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

HRID 60435Notes

Reaction equation

HRID 60435 reaction equation
[CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:3]1=[O:31].[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:11]2[C:6]3[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:3](=[O:31])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:43][CH:42]=1

Participants

7

Reactant 3

HCID 77264-ChlorobenzaldehydeHCID 2724682Lithium diisopropylamideHCID 1188754911-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Product 1

HCID 1188755505-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 6.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (450 mg, 1.06 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 2.11 mL, 4.24 mmol) dropwise. The reaction was stirred at −78° C. for 1 h. then a solution of 4-chlorobenzaldehyde (296.6 mg, 2.11 mmol) in THF (2 mL) was added dropwise. 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 chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 6.7% yield) as an oil. LCMS: MH+ 567 and TR=1.400 min.

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 chromatography
  5. washeluted with PE/EA (10:1 to 1:1)

Sources & evidence

ORD record
ord-cf62063713f443ab9dded579bba51691
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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