3-Chlorophenol → 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60516Notes

Reaction equation

HRID 60516 reaction equation
C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25])=O.[Cl:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CCC(O)=O>O1CCOCC1.C(Cl)Cl.O.[Cu]I>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[O:33][C:15]1[CH:16]=[N:17][C:10]2[N:9]([CH3:24])[C:8](=[O:25])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=2[C:14]=1[CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23]

Participants

9

Reactant 4

HCID 79333-ChlorophenolHCID 10796Cesium carbonateHCID 2398283-(Dimethylamino)propanoic acidHCID 1188759113-(6-bromo-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate

Product 1

HCID 1188758966-(3-chlorophenoxy)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 17%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 3-(6-bromo-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (42 mg, 0.109 mmol) in dioxane (2 mL) was added 3-chlorophenol (28 mg, 0.218 mmol), CuI (6 mg, 0.0327 mmol), Cs2CO3 (71 mg, 0.218 mmol) and 3-(dimethylamino)propanoic acid (3 mg, 0.0327 mmol). The reaction was stirred at 130° C. (MW) for 2 h, cooled to RT 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 Prep HPLC to give 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 15.5% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 7.02-7.00 (m, 1H), 6.93 (dd, J=8.0, 2.4 Hz, 1H), 4.50 (t, J=5.2 Hz, 1H), 4.00 (t, J=7.2 Hz, 2H), 3.58 (s, 3H), 3.45-3.50 (m, 2H), 3.15-3.10 (m, 2H), 1.77-1.72 (m, 2H), 1.57-1.52 (m, 1H), 1.23-1.34 (m, 2H), 0.82 (d, J=6.8 Hz, 6H). LCMS: MH+ 432 and TR=3.366 min.

Workup

  1. dry with materialThe organic layer was dried over Na2SO4
  2. concentrationconcentrated to a residue which
  3. customwas purified by Prep HPLC

Sources & evidence

ORD record
ord-82435b04912c4e78a61962dc4633096b
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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