p-Toluenesulfonic acid → N-(1,3-dihydroxypropan-2-yloxy)-6-(2-fluoro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HRID 548790Notes

Reaction equation

HRID 548790 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1(C2[O:40][CH2:39][CH:38]([O:41][NH2:42])[CH2:37][O:36]2)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[OH:36][CH2:37][CH:38]([O:41][NH:42][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])[CH2:39][OH:40]

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 15350941O-(2-phenyl-1,3-dioxan-5-yl)hydroxylamineHCID 59259226Phenyl 6-(2-fluoro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate2×

Product 1

HCID 25108896N-(1,3-dihydroxypropan-2-yloxy)-6-(2-fluoro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

Phenyl 6-(2-fluoro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (compound 2A, 100 mg, 0.2 mmol, 1 eq) and O-(2-phenyl-1,3-dioxan-5-yl)hydroxylamine (79 mg, 0.404 mmol, 2 eq) (see, Vonhoff et al., Helv. Chim. Acta, 81(9), 1998; 1710-1725; European Patent Application No. EP1666485) were mixed in THF and subjected to microwave irradiation at 100° C. for 45 minutes. The reaction was complete by LCMS. Upon cooling, the intended product precipitated as a tan solid. 62 mg (51%). This solid was then dissolved in methanol (2 ml) and THF (2 ml) with ethylene glycol (100 μl). p-Toluenesulfonic acid (18 mg, 1 eq) was added and the mixture heated at 50° C. for 30 minutes. Purification by HPLC chromatography afforded the title compound as a white solid. 28 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (s, 3H) 3.22 (s, 3H) 3.42-3.58 (m, 4H) 4.00-4.08 (m, J=1.67, 0.78, 0.78, 0.78, 0.78 Hz, 2H) 4.75 (t, J=5.94 Hz, 2H) 5.76 (s, 1H) 7.53-7.62 (m, 1H) 7.80 (dd, J=9.73, 1.39 Hz, 1H) 11.99 (s, 1H) 12.23 (s, 1H) [M+H] calc'd for C16H18FIN4O6, 509. found, 509.

Workup

  1. customirradiation at 100° C. for 45 minutes
  2. temperatureUpon cooling
  3. customthe intended product precipitated as a tan solid
  4. dissolutionThis solid was then dissolved in methanol (2 ml)
  5. customPurification by HPLC chromatography

Sources & evidence

ORD record
ord-0133feee6a1143508ea018a07aa4c6c3
Source dataset
uspto-grants-2011_05
Patent number
US07943626B2

Reaction notes

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