1-chloro-3-isocyanato-2-methylbenzene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NC h, 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43. the mixture stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of aluminium chloride 4.71 g, sodium azide 6.89 g and tetrahydrofuran 100 mL was stirred with heating under reflux for one hour. After the reaction mixtures were cooled under ice-cooling, thereto were added a mixture of the above-mentioned 1-chloro-3-isocyanato-2-methylbenzene and tetrahydrofuran 10 mL and the resulting mixtures were stirred with heating under reflux for five hours. After cooling the mixtures, to a mixture of sodium nitrite 10.59 g and water 300 mL was added the reaction mixtures with stirring. The mixtures were acidified with concentrated hydrochloric acid and were extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one. with heating under reflux for one hour After the reaction mixtures were cooled under ice- cooling were added the resulting mixtures were stirred with heating under reflux for five hours After cooling the mixtures was added the reaction mixtures with stirring were extracted with ethyl acetate The organic layers were dried over anhydrous sodium sulfate were then concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of aluminium chloride 4.71 g, sodium azide 6.89 g and tetrahydrofuran 100 mL was stirred with heating under reflux for one hour. After the reaction mixtures were cooled under ice-cooling, thereto were added a mixture of the above-mentioned 1-chloro-3-isocyanato-2-methylbenzene and tetrahydrofuran 10 mL and the resulting mixtures were stirred with heating under reflux for five hours. After cooling the mixtures, to a mixture of sodium nitrite 10.59 g and water 300 mL was added the reaction mixtures with stirring. The mixtures were acidified with concentrated hydrochloric acid and were extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one. with heating under reflux for one hour After the reaction mixtures were cooled under ice- cooling were added the resulting mixtures were stirred with heating under reflux for five hours After cooling the mixtures was added the reaction mixtures with stirring were extracted with ethyl acetate The organic layers were dried over anhydrous sodium sulfate were then concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of the above-mentioned 1-chloro-2-methyl-3-methoxycarbonylaminobenzene 5.80 g, phosphorus pentachloride 7.53 g and chlorobenzene 50 mL was stirred with heating under reflux for one hour. The reaction mixtures were concentrated under reduced pressure to give 1-chloro-3-isocyanato-2-methylbenzene. with heating under reflux for one hour The reaction mixtures were concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under ice-cooling, to N,N-dimethylformamide 250 mL was added anhydrous aluminum chloride 21.9 g and the resulting mixtures were stirred for fifteen minutes. Thereto was added sodium azide 10.7 g and the resulting mixtures were stirred for fifteen minutes and thereto was then added 1-chloro-3-isocyanato-2-methylbenzene 25.0 g and the resulting mixtures were heated at 80° C. for five hours. After cooling the mixtures, to a mixture of sodium nitrite g, water 2 L and ice 500 g was added the reaction solutions with stirring. The mixtures were acidified with 10% hydrochloric acid and were extracted with ethyl acetate. The organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one 17.0 g. the resulting mixtures were stirred for fifteen minutes After cooling the mixtures with stirring were extracted with ethyl acetate The organic layers were washed with water and saturated saline were dried over anhydrous magnesium sulfate were then concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under ice-cooling, to N,N-dimethylformamide 250 mL was added anhydrous aluminum chloride 21.9 g and the resulting mixtures were stirred for fifteen minutes. Thereto was added sodium azide 10.7 g and the resulting mixtures were stirred for fifteen minutes and thereto was then added 1-chloro-3-isocyanato-2-methylbenzene 25.0 g and the resulting mixtures were heated at 80° C. for five hours. After cooling the mixtures, to a mixture of sodium nitrite g, water 2 L and ice 500 g was added the reaction solutions with stirring. The mixtures were acidified with 10% hydrochloric acid and were extracted with ethyl acetate. The organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one 17.0 g. the resulting mixtures were stirred for fifteen minutes After cooling the mixtures with stirring were extracted with ethyl acetate The organic layers were washed with water and saturated saline were dried over anhydrous magnesium sulfate were then concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NC h, 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43. the mixture stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NC h, 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43. the mixture stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m., 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05 HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43. the mixture stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m., 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05 HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43. the mixture stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The cyclohexylsulfamic acid salt of 1-2-butyl-2-iminopyrrolidine (7.99 g.; 0.025 mole) is converted to free base (3.5 g.; 0.025 mole) by adding 2.5 ml. of 50% NaOH to an aqueous slurry of the salt and benzene extraction. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.19 g. (0.025 mole) of 3-chloro-2-methylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 3 hours and then taken to dryness in vacuo to give an oily residue of 1-(1-n-butyl-2-pyrrolidylidene)-3-(3-chloro-2-methylphenyl)urea which is dissolved in ether and converted to the hydrochloride salt. Recrystallization from methanol-ether yields the product, 1-(1-n-butyl-2-pyrrolidylidene)-3-(3-chloro-2-methylphenyl)urea HCl hydrate, m.p. = 126°-128° C. by adding 2.5 ml of 50% NaOH to an aqueous slurry of the salt and benzene extraction After drying over K2CO3 the benzene solution is filtered through diatomaceous earth and 4.19 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of aluminium chloride 4.71 g, sodium azide 6.89 g and tetrahydrofuran 100 mL was stirred with heating under reflux for one hour. After the reaction mixtures were cooled under ice-cooling, thereto were added a mixture of the above-mentioned 1-chloro-3-isocyanato-2-methylbenzene and tetrahydrofuran 10 mL and the resulting mixtures were stirred with heating under reflux for five hours. After cooling the mixtures, to a mixture of sodium nitrite 10.59 g and water 300 mL was added the reaction mixtures with stirring. The mixtures were acidified with concentrated hydrochloric acid and were extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one. with heating under reflux for one hour After the reaction mixtures were cooled under ice- cooling were added the resulting mixtures were stirred with heating under reflux for five hours After cooling the mixtures was added the reaction mixtures with stirring were extracted with ethyl acetate The organic layers were dried over anhydrous sodium sulfate were then concentrated under reduced pressure