Acetic Acid → 4-[2-(3,5,5-Trimethyl-2-oxoimidazolidin-1-yl)-1,3-thiazol-4-yl]benzonitrile

HRID 1436425Notes

Reaction equation

HRID 1436425 reaction equation
[CH3:1][C:2]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[N:11]=1)([CH3:5])[CH:3]=O.[C:20]([OH:23])(=O)C.CN.[C:26]([BH3-])#[N:27].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C.O1CCCC1.C(Cl)Cl>[CH3:26][N:27]1[CH2:3][C:2]([CH3:5])([CH3:1])[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:20]1=[O:23]

Participants

13

Reactant 8

HCID 176Acetic AcidHCID 6329MethylamineHCID 8471TriethylamineHCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 5049666Sodium triacetoxyborohydrideHCID 866186094-{2-[(1,1-Dimethyl-2-oxoethyl)amino]-1,3-thiazol-4-yl}benzonitrile

Product 1

HCID 247832464-[2-(3,5,5-Trimethyl-2-oxoimidazolidin-1-yl)-1,3-thiazol-4-yl]benzonitrileYield 28.7%

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-{2-[(1,1-dimethyl-2-oxoethyl)amino]-1,3-thiazol-4-yl}benzonitrile (318 mg, 1.17 mmol), prepared in the previous step, was dissolved in 12 mL of methanol and 1 g of molecular sieves was added. Acetic acid (0.13 mL, 2.3 mmol) and a 2M solution of methylamine in methanol (1.76 mL, 3.52 mmol) were added followed by sodium cyanoborohydride (0.44 g, 7.0 mmol) and the mixture was stirred for 16 h. Sodium triacetoxyborohydride (1.5 g, 7.0 mmol) was added and the mixture was stirred for 72 h. The mixture was diluted with ethyl acetate and washed with H2O, NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated to give 380 mg of crude product. This material was dissolved in 15 mL tetrahydrofuran and triethylamine (1.0 mL, 7.3 mmol) was added followed by triphosgene (0.59 g, 2.0 mmol). The mixture was stirred for 2 h, poured into saturated NaHCO3, diluted with methylene chloride and washed with H2O, 1N HCl, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (20% ethyl acetate/hexane) afforded the title compound (0.105 g, 25%) as a white solid. HRMS: calcd for C16H16N4OS+H+, 313.11176; found (ESI, [M+H]+), 313.1104; Analytical HPLC: purity 100% at 210-370 nm, 9.7 min; 100% at 252 nm, 9.7 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Workup

  1. addition1 g of molecular sieves was added
  2. stirringthe mixture was stirred for 72 h
  3. washwashed with H2O, NaHCO3, brine
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give 380 mg of crude product
  8. stirringThe mixture was stirred for 2 h
  9. washwashed with H2O, 1N HCl, brine
  10. dry with materialdried over anhydrous MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-13c93d076376402fb5113099b420f103
Source dataset
uspto-grants-2009_11
Patent number
US07618990B2

Reaction notes

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