Isopropyl iodide → 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60488Notes

Reaction equation

HRID 60488 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.[CH:25](I)([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:25]([O: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)([CH3:27])[CH3:26]

Participants

6

Reactant 3

HCID 6362Isopropyl iodideHCID 11430Potassium CarbonateHCID 1188754886-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Product 1

HCID 1188754856-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 46%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 6-hydroxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.1 g, 6.3 mmol) in DMF (20 mL) was added isopropyl iodide (2.14 g, 12.6 mmol) followed by K2CO3 (1.74 g, 12.6 mmol). The reaction was heated at 80° C. for 2 h, cooled to RT, diluted with water (100 mL) then extracted with EA (3×100 mL). The combined organic layers were washed with water (100 mL) then brine (100 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography to give 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.08 g, 46% yield over 3 steps) as a solid. 1H NMR (CDCl3) δ: 8.34 (d, J=3.1 Hz, 1H), 7.90 (d, J=3.1 Hz, 1H), 4.69-4.51 (m, 2H), 4.10-4.30 (m, 2H), 3.90-3.78 (m, 2H), 3.69 (s, 3H), 3.51), 3.40-3.70 (m, 2H), 2.01 (dd, J=13.4, 6.7 Hz, 2H), 1.86-1.45 (m, 6H), 1.38 (d, J=6.1 Hz, 6H), 1.26 (t, J=7.1 Hz, 2H). LCMS: [MH+-THP] 294 and TR=1.668 min.

Workup

  1. temperaturecooled to RT
  2. extractionthen extracted with EA (3×100 mL)
  3. washThe combined organic layers were washed with water (100 mL)
  4. dry with materialbrine (100 mL), dried over Na2SO4
  5. concentrationconcentrated to a residue which
  6. customwas purified by chromatography

Sources & evidence

ORD record
ord-2216bd192b624ce1ba4faa3c76330743
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

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