Water → N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide

HRID 572655

Reaction equation

HRID 572655 reaction equation
CC1C=CC(S([O:11][CH2:12][C@@H:13]2[CH2:18][O:17][C@@H:16]([C@@H:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[C:28]([C:30](=[O:42])[NH:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([F:39])=[C:35]([O:40][CH3:41])[CH:34]=5)[N:27]=[C:26]([CH3:43])[N:25]=4)[CH2:20]3)[CH2:15][O:14]2)(=O)=O)=CC=1.O.[OH-].[Na+]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:30]([C:28]2[CH:29]=[C:24]([C:21]3[CH2:20][C@H:19]([C@H:16]4[CH2:15][O:14][C@H:13]([CH2:12][OH:11])[CH2:18][O:17]4)[O:23][N:22]=3)[N:25]=[C:26]([CH3:43])[N:27]=2)=[O:42])=[CH:34][C:35]=1[O:40][CH3:41]

Participants

7

Reactant 3

HCID 962WaterHCID 14798Sodium HydroxideHCID 86675913((2S,5R)-5-((R)-3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate

Product 1

HCID 86675912N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamideYield 61.5%

Reagents, catalysts & solvents 3

HCID 82707Tetrabutylammonium AcetateCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of ((2S,5R)-5-((R)-3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (0.7 g, 1.13 mmol, Preparation #G.6) and tetra butyl ammonium acetate (0.72 g, 2.34 mmol, Aldrich) in DMF (5 mL) were stirred for 3 h at 70° C. The reaction mixture was cooled to RT, the reaction vessel was charged sequentially with water (10 mL) and 1.0N aqueous sodium hydroxide (5 mL). After string for 20 minu at RT it was diluted with EtOAc (200 mL) and washed with 50% aqueous sodiumchloride solution (2×150 mL). The organic layer was dried over sodiumsulphate and evaporated to dryness. The resulting crude material was purified by column chromatography on silica gel eluting with 60% EtOAc in hexane to afford N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide 0.32 g (61%); 1H NMR (400 MHz, DMSO): δ 9.48 (t, J=6.4 Hz, 1H), 8.11 (s, 1H), 7.15-7.09 (m, 2H), 6.86-6.81 (m, 1H), 4.80-4.70 (m, 2H), 4.69 (t, J=5.2 Hz, 1H), 4.46 (d, J=6.4 Hz, 2H), 3.88-3.82 (m, 2H), 3.79 (s, 3H), 3.56-3.34 (m, 6H), 2.75 (s, 3H); LC/MS (Table 1, Method d) Rt=0.74 min; MS m/z: 461.1 (m+H)+.

Workup

  1. washwashed with 50% aqueous sodiumchloride solution (2×150 mL)
  2. dry with materialThe organic layer was dried over sodiumsulphate
  3. customevaporated to dryness
  4. customThe resulting crude material was purified by column chromatography on silica gel eluting with 60% EtOAc in hexane

Sources & evidence

ORD record
ord-2b6b7f73e7b14c36848b49ad5e58b418
Source dataset
uspto-grants-2015_05
Patent number
US09029409B2

Linked notes

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