Isopropyl chloroformate → N-Methyl (8-Carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanamide

HRID 2098281Notes

Reaction equation

HRID 2098281 reaction equation
ClC(OC(C)C)=O.[CH3:8][N:9]1CCOCC1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].Cl.CN.C(N(CC)CC)C>CN(C)C=O.CCOCC>[CH3:8][NH:9][C:29](=[O:31])[CH2:28][N:25]1[C:26](=[O:27])[N:21]2[CH:20]=[N:19][C:18]([C:15](=[O:17])[NH2:16])=[C:22]2[N:23]=[N:24]1

Participants

8

Reactant 5

HCID 7917Isopropyl chloroformateHCID 79724-MethylmorpholineHCID 8471TriethylamineHCID 6364545Methylamine hydrochlorideHCID 118314662-(8-Carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)acetic acid

Product 1

HCID 44128648N-Methyl (8-Carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanamide

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent2×

Procedure

Isopropyl chloroformate (1 M in toluene, 1.155 mL, 1.155 mmol) then N-methyl morpholine (0.127 mL, 1.155 mmol) were added to a stirred solution of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.25 g, 1.050 mmol) in dimethylformamide (1.34 mL) under nitrogen at −10° C. to −15° C. After 1 hour, methylamine hydrochloride (142 mg, 2.100 mmol) then triethylamine (0.292 mL, 2.100 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one hour then allowed to warm to room temperature. After 16 hours, ether (5 mL) was added and the resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL), then purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane), recrystallized from acetonitrile and triturated with ether to furnish the desired product as a pale pink solid. Yield: 82 mg, 0.33 mmol, 31%. LCMS (ES+) m/z 252 (M+H)+ at solvent front. 1H NMR (400 MHz, d6-DMSO) δ: 8.86 (1H, s), 8.14 (1H, br q), 7.83 (1H, br s), 7.69 (1H, bs), 4.89 (2H, s), 2.60 (3H, d).

Workup

  1. waitAfter 16 hours
  2. washthe resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL)
  3. custompurified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane)
  4. customrecrystallized from acetonitrile
  5. customtriturated with ether

Sources & evidence

ORD record
ord-d14660f0e34149a78f094da95d4cc590
Source dataset
uspto-grants-2013_05
Patent number
US08450479B2

Reaction notes

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