Ammonium Chloride → tert-butyl ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-(3-cyano-5-fluorophenyl)-4-hydroxybutyl)carbamate

HRID 513010ノート

反応式

HRID 513010 の反応式
Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C([Mg]Cl)(C)C.[Si:16]([O:23][C@H:24]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](=[O:36])[CH2:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.C(OCC)C.CO>[Si:16]([O:23][C@H:24]([CH2:25][CH:26]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)[OH:36])[CH2:28][NH:27][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]

参加物

9

反応物 5

HCID 25517Ammonium ChlorideHCID 27833303-Bromo-5-fluorobenzonitrileHCID 4311764Sodium borohydrideHCID 11220792(R)-1-Boc-4-[(tert-butyldimethylsilyl)oxy]pyrrolidin-2-oneHCID 178418918HCID 178418918、化合物

生成物 1

HCID 66694346tert-butyl ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-(3-cyano-5-fluorophenyl)-4-hydroxybutyl)carbamate

試薬・触媒・溶媒 3

HCID 887Methanol溶媒HCID 3283Diethyl Ether溶媒HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
-30 °C

実験手順

To a solution of 3-bromo-5-fluorobenzonitrile (5.2 g, 0.26 mmol) in THF (26 mL) at −78° C. was slowly added isopropylmagnesium chloride (13.6 mL of a 2.0 M solution in diethyl ether, 0.27 mmol). The mixture was warmed and stirred at −30° C. for 1 hour then cooled to −78° C. The resulting aryl Grignard was added to a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate (I-1) (7.8 g, 25 mmol) in THF (25 mL) at −78° C. The reaction mixture was stirred at 0° C. for 30 minutes. Methanol (20 mL) was added to the reaction mixture followed by NaBH4 (1.4 g, 37 mmol). The mixture was stirred to room temperature for 12 hours then poured into 10% aqueous NH4Cl. The mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield tert-butyl ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-(3-cyano-5-fluorophenyl)-4-hydroxybutyl)carbamate (I-10). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1 H), 7.38-7.33 (m, 1 H), 7.25-7.20 (m, 1 H), 4.95 (d, J=9.2 Hz, 1 H), 4.81 (bs, 1 H), 4.12-4.05 (m, 1 H), 3.76 (bs, 1 H), 3.45-3.35 (m, 1 H), 3.23-3.12 (m, 1 H), 1.87-1.71 (m, 2 H), 1.45 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 6 H). MS m/z 461.2 (M+23)+.

後処理

  1. customat −78° C.
  2. temperatureThe mixture was warmed
  3. temperaturethen cooled to −78° C
  4. stirringThe reaction mixture was stirred at 0° C. for 30 minutes
  5. stirringThe mixture was stirred to room temperature for 12 hours
  6. extractionThe mixture was extracted with EtOAc
  7. washwashed with brine
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant

出典と根拠

ORDレコード
ord-bb80369f67784152a561646e2cd2b97f
出典データセット
uspto-grants-2015_08
特許番号
US09102671B2

反応ノート

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