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

HRID 60444Notes

Reaction equation

HRID 60444 reaction equation
[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=1>C1COCC1>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:38]([C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=1)[OH:39]

Participants

5

Reactant 3

HCID 77264-ChlorobenzaldehydeHCID 2724682Lithium diisopropylamideHCID 1188755356-bromo-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Product 1

HCID 1188755116-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 18.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 6-bromo-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.6 g, 1.51 mmol) in THF (10 mL) at −78° C. was added LDA (1.8 M in THF, 4.2 mL, 7.56 mmol) dropwise. The reaction was stirred at −78° C. for 30 min then a solution of 4-chlorobenzaldehyde (0.42 g, 3 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NaHCO3 (5 mL) then diluted with EA (50 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (4:1) to give 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 18.5% yield) as a white solid. LCMS: [M+-THP] 436 and TR=1.900 min.

Workup

  1. stirringThe reaction was stirred at −78° C. for 1 h
  2. customquenched with aq. NaHCO3 (5 mL)
  3. additionthen diluted with EA (50 mL) and water (20 mL)
  4. dry with materialThe organic layer was dried over Na2SO4
  5. concentrationconcentrated to a residue which
  6. customwas purified by chromatography PE/EA (4:1)

Sources & evidence

ORD record
ord-6980aee83a044beb80aae18a0b549922
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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