Sulfuric Acid → N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 68417

反応式

HRID 68417 の反応式
[CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.[C:11]([NH:19][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:29][C@H:28]([C:30](OC)=O)[O:27][CH2:26][C@:24]2([C:34]2[CH:39]=[C:38]([Br:40])[CH:37]=[CH:36][C:35]=2[F:41])[N:25]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1>[Br:40][C:38]1[CH:37]=[CH:36][C:35]([F:41])=[C:34]([C@:24]23[CH2:26][O:27][C@@H:28]([C:30]4[O:5][N:4]=[C:2]([CH3:3])[CH:1]=4)[CH2:29][C@H:23]2[CH2:22][S:21][C:20]([NH:19][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:25]3)[CH:39]=1

参加物

7

反応物 5

HCID 1118Sulfuric AcidHCID 14798Sodium HydroxideHCID 67180Acetone, oximeHCID 86762655methyl (4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylateHCID 178418339Butyllithium

生成物 1

HCID 86762654N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

実験手順

A solution of propan-2-one oxime (0.216 g, 2.96 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. To this solution was added n-butyllithium (2.5 M in hexanes, 2.40 mL, 6.00 mmol) in a drop-wise manner. The resulting solution was allowed to warm to room temperature and left stirring at room temperature for 25 minutes. The resulting solution was cooled again to 0° C., followed by a drop-wise addition of methyl (4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylate (C35) (1.09 g, 2.03 mmol) in tetrahydrofuran (3 mL). The reaction mixture was allowed to warm to room temperature and was left stirring for 25 minutes. The reaction mixture was cooled to 0° C. again, and sulfuric acid (0.840 mL, 15.8 mmol) was added in a drop-wise manner. The reaction mixture was allowed to warm up to room temperature and was left stirring for 16 hours at room temperature. The reaction mixture was basified to pH 12 with sodium hydroxide (5 N, ˜4 mL) and then extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oily residue. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid. Yield: 330 mg, 63%. LCMS m/z 532.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br s, 1H), 7.47-7.61 (m, 4H), 7.19 (dd, J=12.0, 8.9 Hz, 1H), 4.97 (br d, J=9.4 Hz, 1H), 4.31 (dd, J=11.8, 1.5 Hz, 1H), 4.00-4.14 (m, 2H), 3.00 (dd, J=13.2, 4.0 Hz, 1H), 2.83 (dd, J=13.1, 2.9 Hz, 1H), 2.10 (d, J=12.1 Hz, 1H).

後処理

  1. waitleft
  2. temperatureThe resulting solution was cooled again to 0° C.
  3. temperatureto warm to room temperature
  4. waitwas left
  5. stirringstirring for 25 minutes
  6. temperatureThe reaction mixture was cooled to 0° C. again
  7. temperatureto warm up to room temperature
  8. waitwas left
  9. stirringstirring for 16 hours at room temperature
  10. extractionextracted with ethyl acetate (3×100 mL)
  11. dry with materialThe combined organics were dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customto give an oily residue
  15. customPurification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane)

出典と根拠

ORDレコード
ord-7b1a46e16a564111947ce32e2155ed84
出典データセット
uspto-grants-2014_09
特許番号
US08822456B2

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