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

HRID 60507Notes

Reaction equation

HRID 60507 reaction equation
[CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:3]1=[O:35].[Li+].CC([N-]C(C)C)C.[CH3:44][CH:45]([CH3:49])[CH2:46][CH:47]=[O:48]>C1COCC1>[OH:48][CH:47]([C:11]1[C:6]2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:3](=[O:35])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=1)[CH2:46][CH:45]([CH3:49])[CH3:44]

Participants

5

Reactant 3

HCID 115523-MethylbutanalHCID 2724682Lithium diisopropylamideHCID 1188755201-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione2×

Product 1

HCID 1188755245-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 51.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 45, step 1, 100 mg, 0.2 mmol) in THF (4 mL) at −78° C. was added LDA (2M in THF, 0.4 mL, 0.8 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (34 mg, 0.4 mmol) in THF (1 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (10 mL) 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 Prep TLC eluted with PE/EA (2:1) to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 51.7% yield) as a solid. LCMS: [MH+-THP] 498 and TR=1.733 min.

Workup

  1. stirringThe reaction was stirred at −78° C. for 1 h
  2. customquenched with aq. NH4Cl (10 mL)
  3. additionthen diluted with EA (10 mL) and water (10 mL)
  4. dry with materialThe organic layer was dried over Na2SO4
  5. concentrationconcentrated to a residue which
  6. customwas purified by Prep TLC
  7. washeluted with PE/EA (2:1)

Sources & evidence

ORD record
ord-c9c96d727fbd4eb6ad53079050b0a2bd
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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