Trimethylsilyl cyanide → HCID 16743582, compound

HRID 1993619Notes

Reaction equation

HRID 1993619 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)=[N:9][C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)=[N:6][CH:7]=1.[Si]([C:32]#[N:33])(C)(C)C>CO.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:9][C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([F:27])[CH:18]=2)[C:32]#[N:33])=[N:6][CH:7]=1

Participants

5

Reactant 2

HCID 82115Trimethylsilyl cyanideHCID 72456423HCID 72456423, compound

Product 1

HCID 16743582HCID 16743582, compound

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent

Procedure

At 0° C. to a solution of N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-4,5-dimethylthiazol-2-amine (848 mg, 2.05 mmol) in MeOH (10 mL) was added ZnCl2 (214 mg, 1.43 mmol), followed by the addition of TMSCN (830 μL, 6.19 mmol). The reaction was allowed to slowly warm up to room temperature and heated at 65° C. for 18 h. The reaction mixture was cooled down to room temperature and concentrated. The residue was diluted by addition of DCM. The solid was removed by filtration and the filtrate was concentrated. A portion of the residue was purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-300%) over 22 min. Methyl 2-(5-chloropyridin-2-yl)-2-(4,5-dimethylthiazol-2-ylamino)-2-(3-fluoro-5-(trifluoromethyl)phenyl)acetate eluted at a retention time of 7-8 min. LCMS RT=3.25 min [M+H] 473.84 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.74 ppm, 1H, s; 7.67 ppm, 1H, dd, J=8.57, 2.42 Hz; 7.56 ppm, 1H, m; 7.30 ppm, 2H, m; 3.76 ppm, 3H, m; 2.09 ppm, 6H, m.

Workup

  1. temperatureheated at 65° C. for 18 h
  2. temperatureThe reaction mixture was cooled down to room temperature
  3. concentrationconcentrated
  4. additionThe residue was diluted by addition of DCM
  5. customThe solid was removed by filtration
  6. concentrationthe filtrate was concentrated
  7. customA portion of the residue was purified by ISCO chromatography (12 g column)
  8. customover 22 min
  9. washMethyl 2-(5-chloropyridin-2-yl)-2-(4,5-dimethylthiazol-2-ylamino)-2-(3-fluoro-5-(trifluoromethyl)phenyl)acetate eluted at a retention time of 7-8 min
  10. washLCMS RT=3.25 min [M+H] 473.84 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm)

Sources & evidence

ORD record
ord-6c0475d82d594936862491bdb262657d
Source dataset
uspto-grants-2010_01
Patent number
US07652023B2

Reaction notes

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