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

HRID 513010Notes

Reaction equation

HRID 513010 reaction equation
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]

Participants

9

Reactant 5

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

Product 1

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

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-30 °C

Procedure

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)+.

Workup

  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

Sources & evidence

ORD record
ord-bb80369f67784152a561646e2cd2b97f
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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