Triethylamine → 6-(3-[1,3]Dioxolan-2-yl-5-methyl-phenoxy)-1-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-1H-pyrimidine-2,4-dione

HRID 426211Notes

Reaction equation

HRID 426211 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[O:32]1[CH2:36][CH2:35][O:34][CH:33]1[C:37]1[CH:38]=[C:39]([CH:52]=[C:53]([CH3:55])[CH:54]=1)[O:40][C:41]1[NH:46][C:45](=[O:47])[NH:44][C:43](=[O:48])[C:42]=1[CH:49]([CH3:51])[CH3:50].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[O:34]1[CH2:35][CH2:36][O:32][CH:33]1[C:37]1[CH:38]=[C:39]([CH:52]=[C:53]([CH3:55])[CH:54]=1)[O:40][C:41]1[N:46]([CH2:8][C:6]2[CH:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=[C:2]([F:1])[CH:7]=2)[C:45](=[O:47])[NH:44][C:43](=[O:48])[C:42]=1[CH:49]([CH3:51])[CH3:50]

Participants

10

Reactant 6

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 66321Lithium iodideHCID 59184650HCID 59184650, compoundHCID 591846836-(3-[1,3]Dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione

Product 1

HCID 591847436-(3-[1,3]Dioxolan-2-yl-5-methyl-phenoxy)-1-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-1H-pyrimidine-2,4-dioneYield 53%

Reagents, catalysts & solvents 3

HCID 6212ChloroformSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 2-fluoro-6-(p-methoxybenzylamino)-4-pyridine-methanol (664 mg, 2.53 mmol) in chloroform (25 ml) at 0° C. (ice bat), was added triethylamine (532 μl, 3.8 mmol) followed by methanesulfonyl chloride (228 μl, 3.0 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (842 mg, 2.53 mmol), anhydrous powdered potassium carbonate (349 mg, 2.53 mmol), and lithium iodide (339 mg, 2.53 mmol). Anhydrous DMF (25 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through a celite pad, and the pad was washed with dichloromethane. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 771 mg (53%) of a white foam. 1H NMR (200 MHz, CDCl3) δ 1.12 (6H, d, J=7.2 Hz), 2.30 (3H, s), 2.73 (1H, m), 3.79 (3H, s), 3.94-4.14 (4H, m), 4.32 (2H, d, J=5.4 Hz), 4.71 (2H, s), 5.00 (1H, t, J=5.4 Hz), 5.67 (1H, s), 5.95 (2H, s), 6.59 (1H, s), 6.81-6.91 (3H, m), 7.02 (1H, s), 7.21-7.29 (2H, m), 9.06 (1H, s).

Workup

  1. washwashed with aqueous saturated sodium bicarbonate solution
  2. dry with materialdried with anhydrous magnesium sulfate
  3. filtrationfiltered
  4. customevaporated in vacuo
  5. customThe residue was further dried in high vacuo
  6. stirringstirred for overnight at room temperature
  7. customThe mixture was evaporated in vacuo
  8. dissolutionThe residue was dissolved in methanol-dichloromethane (1:9)
  9. filtrationfiltered through a celite pad
  10. washthe pad was washed with dichloromethane
  11. customThe combined filtrate was evaporated in vacuo
  12. customthe residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2))

Sources & evidence

ORD record
ord-6660ee764b14420f9f0c7fbd079736eb
Source dataset
uspto-grants-2012_01
Patent number
US08106064B2

Reaction notes

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