4-Chlorobenzaldehyde → 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-chloropyridin-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 60427Notes

Reaction equation

HRID 60427 reaction equation
[Cl: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]([Cl:1])[CH:3]=2)=[CH:43][CH:42]=1

Participants

7

Reactant 3

HCID 77264-ChlorobenzaldehydeHCID 2724682Lithium diisopropylamideHCID 1188754876-((5-chloropyridin-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 1188755275-((4-chlorophenyl)(hydroxy)methyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dioneYield 19.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (470 mg, 1.06 mmol) in THF (10 mL) at −78° C. was added LDA (2M in THF, 2.12 mL, 4.24 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 4-chlorobenzaldehyde (298.8 mg, 2.12 mmol) in THF (2 mL) was added. 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 which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (120 mg, 19.4% yield) as an oil. LCMS: [MH+-THP] 503 and TR=1.508 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 which
  4. customwas purified by chromatography
  5. washeluted with PE/EA (10:1 to 1:1)

Sources & evidence

ORD record
ord-b9e5bab2fc8945fdba95f096b6579cf8
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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