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

HRID 60492Notes

Reaction equation

HRID 60492 reaction equation
[CH:1]([O:4][C:5]1[CH:27]=[N:26][C:8]2[N:9]([CH3:25])[C:10](=[O:24])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12](=[O:13])[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:36][CH:37]([CH3:41])[CH2:38][CH:39]=[O:40]>C1COCC1>[OH:40][CH:39]([C:6]1[C:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:10](=[O:24])[N:9]([CH3:25])[C:8]=2[N:26]=[CH:27][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[CH2:38][CH:37]([CH3:41])[CH3:36]

Participants

5

Reactant 3

HCID 115523-MethylbutanalHCID 2724682Lithium diisopropylamideHCID 1188754856-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione2×

Product 1

HCID 1188755445-(1-hydroxy-3-methylbutyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 32.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 3, 150 mg, 0.4 mmol) in THF (6 mL) at −78° C. was added LDA (2M in THF, 1.0 mL, 2.0 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (68.8 mg, 0.8 mmol) in THF (1.5 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (5 mL) diluted with water (13 mL) then extracted with EA (30 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 5-(1-hydroxy-3-methylbutyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 32.4% yield) as a white solid. LCMS: [M+-THP-OH] 362 and TR=2.616 min.

Workup

  1. stirringThe reaction was stirred at −78° C. for 1 h
  2. customquenched with aq. NH4Cl (5 mL)
  3. additiondiluted with water (13 mL)
  4. extractionthen extracted with EA (30 mL)
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated to a residue which
  7. customwas purified by Prep TLC
  8. washeluted with PE/EA (2:1)

Sources & evidence

ORD record
ord-aa867592396648c79bb9eba04cdb16be
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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