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

HRID 60419Notes

Reaction equation

HRID 60419 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][CH:16]=[CH:17][CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:19])[N:4]([CH2:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:3]1=[O:30].[Li+].CC([N-]C(C)C)C.[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>C1COCC1.CC(=O)OCC.O>[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]([OH:45])[C:11]2[C:6]3[C:5](=[O:19])[N:4]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:3](=[O:30])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:42][CH:41]=1

Participants

7

Reactant 3

HCID 77264-ChlorobenzaldehydeHCID 2724682Lithium diisopropylamideHCID 1188755141-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Product 1

HCID 1188755475-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 13.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (400 mg, 0.97 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 1.94 mL, 3.88 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (273.5 mg, 1.94 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at −78° C. for 30 min. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (71 mg, 13.2% yield) as an oil. LCMS: [MH+-THP] 469 and TR=1.499 min.

Workup

  1. stirringThe reaction was stirred at −78° C. for 30 min.
  2. dry with materialThe organic layer was dried over Na2SO4
  3. concentrationconcentrated to a residue
  4. customwas purified by chromatography
  5. washeluted with PE/EA (10:1 to 1:1)

Sources & evidence

ORD record
ord-9b1b0ea9b55c4038a39b980c6ad6e8ea
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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