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Iodo benzene diacetate → ((2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate

HRID 572654
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HRID 572654 반응식
[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].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:34][CH2:35][C@@H:36]2[CH2:41][O:40][C@@H:39]([CH:42]=[CH2:43])[CH2:38][O:37]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:34][CH2:35][C@@H:36]2[CH2:41][O:40][C@@H:39]([C@H:42]3[O:18][N:17]=[C:16]([C:14]4[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]5[CH:20]=[CH:21][C:2]([F:1])=[C:3]([O:22][CH3:23])[CH:4]=5)[N:11]=[C:12]([CH3:19])[N:13]=4)[CH2:43]3)[CH2:38][O:37]2)(=[O:32])=[O:33])=[CH:27][CH:26]=1
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참가 물질

4

반응물 3

HCID 12217721Iodo benzene diacetateHCID 86675911((2S,5S)-5-vinyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonateHCID 136413230N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide

생성물 1

HCID 86675910((2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate수율 24.3%

실험 절차

To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methyl pyrimidine-4-carboxamide (3.84 g, 12.08 mmol, Preparation #9) and ((2S,5S)-5-vinyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.0 g, 10.06 mmol, Preparation#11) in CHC3 (30 mL), was added iodobenzene diacetate (6.48 g, 20.13 mmol, Aldrich) portion wise (divided in to 4 equal portions and added over a period of 4 hrs). After the addition is completed, the reaction mixture was stirred for another 5 h and quenched with water (100 mL). The product was extracted with DCM (2×100 mL). Combined organic layers were washed with brine solution (100 mL), dried over sodiumsulphate and evaporated to dryness. The residue obtained containing two diastereomers and other impurities was purified by flash column chromatography using silica gel (230-400 mesh) eluting with 40% EtOAc in n-hexane. First eluting compound fractions were combined and evaporated to dryness under reduced pressure, triturated with 40% EtOAc in hexane to afford ((2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 1.5 g (24%). 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 8.28 (t, J=6.4 Hz, 1H), 7.79 (d, J=8 Hz, 2H), 7.36 (d, J=8 Hz, 2H), 7.08-6.96 (m, 2H), 6.90-6.86 (m, 1H), 4.68-4.60 (m, 3H), 4.02-3.93 (m, 2H), 3.88 (s, 3H), 3.85-3.72 (m, 5H), 3.59-3.38 (m, 5H), 2.75 (s, 3H), 2.42 (s, 3H); MS m/z: 615 (m+H)+.

후처리

  1. additionadded over a period of 4 hrs)
  2. additionAfter the addition
  3. customquenched with water (100 mL)
  4. extractionThe product was extracted with DCM (2×100 mL)
  5. washCombined organic layers were washed with brine solution (100 mL)
  6. dry with materialdried over sodiumsulphate
  7. customevaporated to dryness
  8. customThe residue obtained
  9. additioncontaining two diastereomers and other impurities
  10. customwas purified by flash column chromatography
  11. washeluting with 40% EtOAc in n-hexane
  12. customevaporated to dryness under reduced pressure
  13. customtriturated with 40% EtOAc in hexane

출처 및 근거

ORD 기록
ord-aa6766e118e64cff939f8b65299eaddf
출처 데이터셋
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09029409B2

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