N,N-Dimethylglycine → 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methyl-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60506Notes

Reaction equation

HRID 60506 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][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.[Cl:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[O:39][C:15]1[CH:16]=[N:17][C:10]2[N:9]([CH3:30])[C:8](=[O:31])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=2[C:14]=1[CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1

Participants

7

Reactant 4

HCID 673N,N-DimethylglycineHCID 79333-ChlorophenolHCID 10796Cesium carbonateHCID 1188758833-(6-bromo-1-methyl-2,4-dioxo-5((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propylformate

Product 1

HCID 1188755236-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methyl-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 12.5%

Reagents, catalysts & solvents 2

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

Procedure

To a mixture of 3-(6-bromo-1-methyl-2,4-dioxo-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (40 mg, 0.08 mmol) and 3-chlorophenol (26 mg, 0.2 mmol) in dioxane (2 mL) was added Cs2CO3 (78 mg, 0.24 mmol), 2-(dimethylamino)acetic acid (4.1 mg, 0.04 mmol) and CuI (1.9 mg, 0.01 mmol). The reaction was degassed with nitrogen (3×), heated at 130° C. (MW) for 1.5 h, cooled to RT, diluted with water (10 mL) then extracted with EA (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methyl-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (5.2 mg, 12.5% yield) as a white solid. 1H NMR (CDCl3) δ: 8.66 (s, 1H), 8.39 (s, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.30-7.25 (overlap with CDCl3, 1H), 7.12 (dd, J=8.0, 0.8 Hz, 1H), 6.87-6.79 (m, 2H), 4.81 (s, 2H), 4.23 (t, J=6.4 Hz, 2H), 3.72 (s, 3H), 3.55-3.58 (m, 2H), 2.95 (brd s, 1H), 1.95-1.90 (m, 2H). LCMS: MH+ 521 and TR=3.068 min.

Workup

  1. customThe reaction was degassed with nitrogen (3×)
  2. temperatureheated at 130° C. (MW) for 1.5 h
  3. additiondiluted with water (10 mL)
  4. extractionthen extracted with EA (2×10 mL)
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. concentrationconcentrated to a residue which
  7. customwas purified by Prep HPLC

Sources & evidence

ORD record
ord-ebfc22c87dcb433190ab7ed8736038fb
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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