Sodium Hypochlorite → 6-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide

HRID 572651Notes

Reaction equation

HRID 572651 reaction equation
[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[N:17][OH:18])[N:13]=[C:12]([CH3:19])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[CH:24]1([N:27]2[CH:32]=[C:31]([CH:33]=[CH2:34])[CH:30]=[CH:29][C:28]2=[O:35])[CH2:26][CH2:25]1.[Cl:36][O-].[Na+]>C(Cl)Cl.O>[Cl:36][C:29]1[C:28](=[O:35])[N:27]([CH:24]2[CH2:26][CH2:25]2)[CH:32]=[C:31]([CH:33]2[O:18][N:17]=[C:16]([C:14]3[N:13]=[C:12]([CH3:19])[N:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:20]=[CH:21][C:2]([F:1])=[C:3]([O:22][CH3:23])[CH:4]=4)=[O:9])[CH:15]=3)[CH2:34]2)[CH:30]=1

Participants

6

Reactant 3

HCID 23665760Sodium HypochloriteHCID 687603891-cyclopropyl-5-vinylpyridin-2(1H)-oneHCID 136413230N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide

Product 1

HCID 891567406-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (4.0 g, 12.57 mmol, Preparation #9) and 1-cyclopropyl-5-vinylpyridin-2(1H)-one (2.026, 12.57 mmol, Preparation #F.1.33) in DCM (60 mL) was added 9% aqueous sodium hypochlorite solution (60 mL, 12.57 mmol, Avra labs) drop wise at 10-15° C. for about 30 min. The reaction mixture was allowed to stir for another 15-30 min, reaction mixture was diluted with water (100 mL) and the product extracted with DCM (100 mL). The combined organic layers were dried over sodiumsulphate and evaporated to dryness. The resulting crude material contained two products, and these were separated by silica gel column chromatography eluting with 2% methanol in DCM. Relevant fractions containing product were combined and evaporated under reduced pressure to obtain the first eluting compound as 6-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide, 1H NMR (400 MHz, DMSO): δ 9.518-9.486 (m, 1H), 8.177 (s, 1H), 7.889-7.883 (d, J=2.4 Hz, 1H), 7.753-7.747 (d, J=2.4 Hz, 1H), 7.186-7.120 (m, 2H), 6.907-6.871 (m, 1H), 5.757-5.672 (m, 1H), 4.492-4.476 (d, J=6.4, Hz, 2H), 3.820 (s, 3H), 3.784-3.740 (m, 1H), 3.502-3.371 (m, 2H), 2.762 (s, 3H), 1.091-0.902 (m, 4H); MS m/z: 512.2 (M+H)+. and the second eluting compound as 6-(5-(5-chloro-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0.28 g (4.67%) as a brown color solid. 1HNMR (400 MHz, DMSO): δ 9.515-9.485 (m, 1H), 8.179 (s, 1H), 7.680-7.675 (d, J=2 Hz, 1H), 7.489-7.459 (dd, J=9.6 Hz, 1H), 7.180-7.119 (m, 2H), 6.900-6.874 (m, 1H), 6.448-6.390 (dd, J=13.6 Hz, 1H), 5.757-5.661 (m, 1H), 4.489-4.474 (d, J=6 Hz, 2H), 3.817 (s, 3H), 3.805-3.732 (m, 1H), 3.472-3.342 (m, 2H), 2.759 (s, 3H), 1.073-0.863 (m, 4H); MS m/z: 478.2 (M+H)+.

Workup

  1. customreaction mixture
  2. extractionthe product extracted with DCM (100 mL)
  3. dry with materialThe combined organic layers were dried over sodiumsulphate
  4. customevaporated to dryness
  5. customthese were separated by silica gel column chromatography
  6. washeluting with 2% methanol in DCM
  7. additionRelevant fractions containing product
  8. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-eb1f9e60c72f47618318e46ea01245ff
Source dataset
uspto-grants-2015_05
Patent number
US09029409B2

Reaction notes

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