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

반응식

HRID 572655 반응식
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]

참가 물질

7

반응물 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

생성물 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-carboxamide수율 61.5%

시약·촉매·용매 3

HCID 82707Tetrabutylammonium Acetate촉매HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

실험 절차

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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-2b6b7f73e7b14c36848b49ad5e58b418
출처 데이터셋
uspto-grants-2015_05
특허 번호
US09029409B2

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