1,3,5-trichloro-2-isocyanatobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of CC-16313 (0.450 g, 1.22 mmol) and 2,4,6-trichlorophenyl isocyanate (0.271 g, 1.22 mmol) in acetonitrile (10 mL), was added triethylamine (0.34 mL, 2.44 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (10 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(2,4,6-trichloro-phenyl urea as a white solid (0.42 g, 69% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.22 min (99.7%); mp: 264-266° C.; 1H NMR (DMSO-d6) δ 1.91-2.06 (m, 1H, CH), 2.31-2.47 (m, 1H, CH), 2.60 (d, J=17.0 Hz, 1H, CH), 2.83-3.02 (m, 1H, CH), 4.21-4.54 (m, 4H, CH2, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, NCH), 7.01 (t, J=5.9 Hz, 1H, NH), 7.44 (d, J=7.9 Hz, 1H. Ar), 7.51 (s, 1H, Ar), 7.66-7.75 (m, 311, Ar), 8.24 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.48, 31.20, 43.02, 47.07, 51.56, 121.66, 122.87, 126.72, 128.09, 130.23, 131.24, 133.34, 134.87, 142.29, 144.84, 154.97, 167.95, 170.99, 172.86; LCMS: MH=495, 497; Anal Calcd for C21H17N4O4Cl3: C, 50.51; H, 3.45; N, 11.22; Cl, 22.01. Found: C, 50.28; H, 3.17; N, 11.13; Cl, 21.96. The product was isolated by filtration washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) dried overnight in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of CC-16313 (0.450 g, 1.22 mmol) and 2,4,6-trichlorophenyl isocyanate (0.271 g, 1.22 mmol) in acetonitrile (10 mL), was added triethylamine (0.34 mL, 2.44 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (10 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(2,4,6-trichloro-phenyl urea as a white solid (0.42 g, 69% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.22 min (99.7%); mp: 264-266° C.; 1H NMR (DMSO-d6) δ 1.91-2.06 (m, 1H, CH), 2.31-2.47 (m, 1H, CH), 2.60 (d, J=17.0 Hz, 1H, CH), 2.83-3.02 (m, 1H, CH), 4.21-4.54 (m, 4H, CH2, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, NCH), 7.01 (t, J=5.9 Hz, 1H, NH), 7.44 (d, J=7.9 Hz, 1H. Ar), 7.51 (s, 1H, Ar), 7.66-7.75 (m, 311, Ar), 8.24 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.48, 31.20, 43.02, 47.07, 51.56, 121.66, 122.87, 126.72, 128.09, 130.23, 131.24, 133.34, 134.87, 142.29, 144.84, 154.97, 167.95, 170.99, 172.86; LCMS: MH=495, 497; Anal Calcd for C21H17N4O4Cl3: C, 50.51; H, 3.45; N, 11.22; Cl, 22.01. Found: C, 50.28; H, 3.17; N, 11.13; Cl, 21.96. The product was isolated by filtration washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) dried overnight in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of CC-16313 (0.450 g, 1.22 mmol) and 2,4,6-trichlorophenyl isocyanate (0.271 g, 1.22 mmol) in acetonitrile (10 mL), was added triethylamine (0.34 mL, 2.44 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (10 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(2,4,6-trichloro-phenyl urea as a white solid (0.42 g, 69% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.22 min (99.7%); mp: 264-266° C.; 1H NMR (DMSO-d6) δ 1.91-2.06 (m, 1H, CH), 2.31-2.47 (m, 1H, CH), 2.60 (d, J=17.0 Hz, 1H, CH), 2.83-3.02 (m, 1H, CH), 4.21-4.54 (m, 4H, CH2, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, NCH), 7.01 (t, J=5.9 Hz, 1H, NH), 7.44 (d, J=7.9 Hz, 1H. Ar), 7.51 (s, 1H, Ar), 7.66-7.75 (m, 311, Ar), 8.24 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.48, 31.20, 43.02, 47.07, 51.56, 121.66, 122.87, 126.72, 128.09, 130.23, 131.24, 133.34, 134.87, 142.29, 144.84, 154.97, 167.95, 170.99, 172.86; LCMS: MH=495, 497; Anal Calcd for C21H17N4O4Cl3: C, 50.51; H, 3.45; N, 11.22; Cl, 22.01. Found: C, 50.28; H, 3.17; N, 11.13; Cl, 21.96. The product was isolated by filtration washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) dried overnight in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The hydrochloride salt of 2-imino-1-methylpyrrolidine (5.52 g.; 0.041 mole) is converted to free base in benzene in the usual manner. Then 9.08 g. (0.041 mole) of 2,4,6-trichlorophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added with stirring. The reaction mixture is stirred for 2 hours and the solvent is evaporated in vacuo to give a solid residue of 1-(2,4,6-trichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 160°-162° C. is added The reaction mixture is stirred for 2 hours the solvent is evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The hydrochloride salt of 2-imino-1-methylpyrrolidine (5.52 g., 0.041 mole) is converted to free base in benzene in the usual manner. Then 9.08 g. (0.041 mole) of 2,4,6-trichlorophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added with stirring. The reaction mixture is stirred for 2 hours and the solvent is evaporated in vacuo to give a solid residue of 1-(2,4,6-trichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 160°-162° C. is added The reaction mixture is stirred for 2 hours the solvent is evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1,3,3-tetramethylurea (1.52 ml, 12.75 mmoles) was added to a solution of phosgene (50.0 g, 505.43 mmoles) dissolved in toluene (150 ml). The resulting solution was stirred for 10 min. at which time 2,4,6-trichloroaniline (10.0 g, 50.90 mmoles) was added. The solution was heated to a temperature of 70°-80° C. for 1.5 hr. and then refluxed for 1.5 hr. while phosgene was bubbled in. After removing excess phosgene under reduced pressure, the clear upper layer solution was collected by decantation from the bottom oil layer, and the bottom oil layer was discarded. The solution was then evaporated to give a solid. The solid was dried under a vacuum to give a white solid (11.3 g, 99.3 pct). This product was recrystallized from dry carbon tetrachloride to give a colorless crystalline compound, m.p. 65°-66° C.; Infrared (IR): γ max 2,282 cm-1 (NCO); nuclear magnetic resonance (NMR) (chloroform-d): τ, 2.7 (2-proton singlet, H-3,5, aromatic protons). was added The solution was heated to a temperature of 70°-80° C. for 1.5 hr and then refluxed for 1.5 hr while phosgene was bubbled in After removing excess phosgene under reduced pressure the clear upper layer solution was collected by decantation from the bottom oil layer The solution was then evaporated to give a solid The solid was dried under a vacuum to give a white solid (11.3 g, 99.3 pct) This product was recrystallized from dry carbon tetrachloride to give a colorless crystalline compound, m.p. 65°-66° C.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Aminophthalimide (100 mg, 0.62 mmol) and 2,4,6-trichlorophenyl isocyanate (150.9 mg, 0.68 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Aminopyridine (500 mg, 3.56 mmol) and 2,4,6-trichlorophenyl isocyanate (503.6 mg, 3.56 mmol 1.0 moleg), were dissolved in toluene, and the mixture was then stirred at 110° C. for 3 hr.