Lithium diisopropylamide → 6-bromo-5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60484Notes

Reaction equation

HRID 60484 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[C:3]=1[CH:25]([C:27]1C=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[OH:26].[Li+].CC([N-:38]C(C)C)C.ClC1C=CC(C=O)=NC=1>C1COCC1.CC(=O)OCC.O>[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:25]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][N:38]=1)[OH:26]

Participants

7

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 101032675-Chloropyridine-2-carboxaldehydeHCID 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)-dione2×

Product 1

HCID 1188755266-bromo-5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 138.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 6-bromo-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4, 398 mg, 0.10 mmol) in THF (10 mL) at −78° C. was added LDA (2M in THF, 2.50 mL, 5.00 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 5-chloropicolinaldehyde (211 mg, 1.50 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 40 min then diluted with EA (20 mL) and water (10 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (8:1) to give 6-bromo-5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (75 mg, 13.9% yield) as a solid. LCMS: MH+ 541 and TR=1.773 min.

Workup

  1. stirringThe reaction was stirred at −78° C. for 40 min
  2. washThe organic layer was washed with brine (30 mL)
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated to a residue which
  5. customwas purified by chromatography
  6. washeluted with PE/EA (8:1)

Sources & evidence

ORD record
ord-79455322b64c424a8f46d067234cf86a
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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