N,N-Dimethylglycine → 1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60463Notes

Reaction equation

HRID 60463 reaction equation
[OH: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[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([CH3:45])[CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[CH3:22][N:6]1[C:5]2[N:23]=[CH:24][C:2]([O:1][C:39]3[CH:40]=[N:41][CH:42]=[C:43]([CH3:45])[CH:44]=3)=[CH:3][C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]

Participants

9

Reactant 4

HCID 673N,N-DimethylglycineHCID 10796Cesium carbonateHCID 8177133-Bromo-5-methylpyridineHCID 1188754886-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione2×

Product 1

HCID 1188755041-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 81%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a suspension of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 600 mg, 1.8 mmol), CuI (45 mg, 0.23 mmol), Cs2CO3 (1.69 mg, 5.4 mmol) and 2-(dimethylamino)acetic acid (93 mg, 0.9 mmol) in dioxane (10 mL) was added 3-bromo-5-methylpyridine (0.45 mL, 3.6 mmol). The reaction was heated at 140° C. (MW) in a sealed tube for 2 h, cooled to RT and diluted with EA (50 mL) and water (50 mL). The organic layer was washed with water (30 mL) and brine (50 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1) to give 1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (610 mg, 81% yield) as a yellow solid. LCMS MH+ 427 and TR=1.403 min.

Workup

  1. temperatureThe reaction was heated at 140° C. (MW) in a sealed tube for 2 h
  2. washThe organic layer was washed with water (30 mL) and brine (50 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)

Sources & evidence

ORD record
ord-5f286bb182a44764a4bf9ed898a9d638
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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