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

Reaktionsgleichung

Reaktionsgleichung von HRID 572655
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]

Komponenten

7

Edukt 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

Produkt 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-carboxamideAusbeute 61,5 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 82707Tetrabutylammonium AcetateKatalysatorHCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

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)+.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-2b6b7f73e7b14c36848b49ad5e58b418
Quelldatensatz
uspto-grants-2015_05
Patentnummer
US09029409B2

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