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

HRID 60453Notes

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]1[CH:32]=[CH:31]C(Cl)=CC=1)[OH:26].[Li+].[CH3:35]C([N-]C(C)C)C.CC(C)CC=O>C1COCC1.C(Cl)Cl.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]([OH:26])[CH2:27][CH:32]([CH3:35])[CH3:31]

Participants

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, 300 mg, 0.753 mmol) in THF (10 mL) at −78° C. was added LDA (1.8M in THF, 2.1 mL, 3.765 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (129.8 mg, 1.506 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 30 min then diluted with DCM (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 give 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (65 mg, 17.8% yield) as a solid. LCMS: [M+-THP-OH] 382 and TR=2.155 min.

Workup

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

Sources & evidence

ORD record: ord-153e23c2ff454ff38ae59eeabd682dc4
Source dataset: uspto-grants-2016_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09440972B2

Reaction notes

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