Lithium hydroxide, monohydrate → 3-(3-hydroxypropyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60504Notes

Reaction equation

HRID 60504 reaction equation
O[CH:2]([C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17]C3CCCCO3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=1.O[Li].O>C(O)=O.CC(=O)OCC.O.[Zn]>[OH:17][CH2:16][CH2:15][CH2:14][N:10]1[C:11](=[O:13])[C:12]2[C:3]([CH2:2][C:34]3[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)=[C:4]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=3)[CH:5]=[N:6][C:7]=2[N:8]([CH3:25])[C:9]1=[O:24]

Participants

7

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 1188755185-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-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

Product 1

HCID 1188755073-(3-hydroxypropyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 20%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 284Formic AcidSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 5-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-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 (24 mg, 0.04 mmol) in HCOOH (1 mL) was added Zn dust (13 mg, 0.2 mmol). The reaction was heated at 100° C. for 1 h, cooled to RT and filtered. The filtrate was concentrated to a crude intermediate which was dissolved in THF (2 mL) and water (2 mL) then LiOH.H2O (33.6 mg, 0.8 mmol) was added. The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.0 mg, 20% yield) as a white solid. 1H NMR (CDCl3) δ: 8.68 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.86 (s, 2H), 4.25 (t, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.57-3.61 (m, 2H), 2.96 (brd s, 1H), 2.34 (s, 3H), 1.92-1.97 (m, 2H). LCMS: MH+ 502 and TR=2.285 min.

Workup

  1. temperaturecooled to RT
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated to a crude intermediate which
  4. dissolutionwas dissolved in THF (2 mL)
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated a residue which
  7. customwas purified by Prep HPLC

Sources & evidence

ORD record
ord-893dfdb644f74f0f8ff1625f82ad0d65
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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