N,N-Dimethylglycine → 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60510

Reaction equation

HRID 60510 reaction equation
[Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19](C(C3C=CC(Cl)=CC=3)O)=[C:20](C3C=CC=CC=3C(C)C)[CH:21]=[N:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])(C(C)(C)C)(C)C.[C:43]([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.[F:56][C:57]([F:66])([F:65])[C:58]1[CH:59]=[C:60]([OH:64])[CH:61]=[CH:62][CH:63]=1.O1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>CC(=O)OCC.O.[Cu]I>[CH3:41][N:14]1[C:15]2[N:22]=[CH:21][C:20]([O:64][C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([C:57]([F:65])([F:66])[F:56])[CH:59]=3)=[CH:19][C:16]=2[C:17](=[O:18])[N:12]([CH2:11][CH2:10][CH2:9][O:8][CH:71]2[CH2:72][CH2:43][CH2:68][CH2:69][O:70]2)[C:13]1=[O:42]

Participants

9

Reactant 5

HCID 673N,N-DimethylglycineHCID 73763-(Trifluoromethyl)phenolHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 1317370933-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-((4-chlorophenyl) (hydroxy)methyl)-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione2×

Product 1

HCID 1188755091-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 62.3%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture 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, 200 mg, 0.50 mmol), CuI (28.7 mg, 0.15 mmol), Cs2CO3 (327.2 mg, 1.00 mmol) and 2-(dimethylamino)acetic acid (10.4 mg, 0.10 mmol) in dioxane (3 mL) was added 3-(trifluoromethyl)phenol (162.8 mg, 1.00 mmol). The reaction was heated at 140° C. (MW) for 2 h, cooled to RT then diluted with EA (15 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 62.3% yield) as a white solid. LCMS: [MH+-THP] 396 and TR=1.941 min.

Workup

  1. temperatureThe reaction was heated at 140° C. (MW) for 2 h
  2. washThe organic layer was washed with water (20 mL) and brine (20 mL)
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated to a residue which
  5. customwas purified by chromatography
  6. washeluted with PE/EA (10:1 to 1:1)

Sources & evidence

ORD record
ord-0c593c27c4b24b1eaad4ecdbeff8abe7
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Linked notes

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