Synthesis
GENERAL STEPS: Assemble a 2L three-necked round-bottomed flask equipped with a stir bar, nitrogen inlet, rubber septum, cryogenic thermometer, and place in an ice/acetone cooling bath. To the reactor was added tert-butyl 1H-pyrrol-1-ylcarbamate (99.0 g, 0.543 mol), dissolved with anhydrous acetonitrile (700 mL), and the stirred solution was cooled to 0°C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added slowly dropwise through a syringe, keeping the internal temperature below 5 °C, and a suspension was formed after about 20 min. After 45 min, anhydrous N,N-dimethylformamide (100 mL) was added dropwise through a dosing funnel, keeping the internal temperature below 5 °C, and the reaction mixture was changed to a solution. Stirring was continued at 0 °C for 45 min, and then the reaction was slowly warmed to room temperature. Completion of the reaction was confirmed by monitoring the progress of the reaction by TLC (silica gel plate, 1:3 ethyl acetate/hexane, UV detection, ninhydrin staining). The reaction mixture was poured into ice (~2L) and ethyl acetate (2L) was added and stirred. The organic layer was separated and dried with magnesium sulfate. The dried solution was filtered through a 30/40 Magnesol pad and the filtrate was concentrated to dryness under vacuum. The residue was dissolved in a minimum volume of dichloromethane and separated by silica gel column chromatography, eluting with a 0-50% ethyl acetate/hexane gradient. The fractions containing the pure product were combined and concentrated to dryness in vacuum to give 69.8 g (62%) of the target product (2-cyano-1H-pyrrol-1-yl)carbamic acid tert-butyl ester in white solid form. Another portion of slightly impure product was treated to give 16.8 g (15%) in a total yield of 86.6 g (77%).1H-NMR (CD3OD): δ 7.01 (dd, 1H, J=3.0,1.6 Hz), 6.82 (dd, 1H, J=4.4,1.7 Hz), 6.19 (dd, 1H, J=4.2,2.9 Hz). 4.88 (s, 1H, H2O/NH), 1.50 (br s, 9H, HN-BOC); MS: LC/MS (+esi), m/z=207.9 [M+H].
References
[1] ChemMedChem, 2018, vol. 13, # 5, p. 437 - 445
[2] Patent: WO2007/64883, 2007, A2. Location in patent: Page/Page column 253-254
[3] Patent: WO2007/56170, 2007, A2. Location in patent: Page/Page column 72.-73; 78-79
[4] Patent: WO2007/64931, 2007, A2. Location in patent: Page/Page column 161-162
[5] Patent: WO2010/14930, 2010, A2. Location in patent: Page/Page column 29; 33-34
