N-(oxomethylidene)carbamoyl chloride

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

Procedure: In 6 ml of chloroform dried with molecular sieve is dissolved 390 mg (1.21 mmole) of (3S,4S)-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-hydroxymethyl-2-azetidinone, and a solution of 0.11 ml (1.33 mmole) of chlorocarbonyl isocyanate in 2 ml of dried chloroform is added dropwise to the solution under ice-cooling with stirring. After the stirring under ice-cooling for 30 minutes, the same amount of chlorocarbonyl isocyanate is furthermore added to the reaction solution in the same manner. After the stirring under ice-cooling for further 30 minutes, 10 ml of saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution. The chloroform is distilled off under reduced pressure, and 10 ml of 3N hydrochloric acid and ethyl acetate are added to the residue, followed by thorough shaking. The ethyl acetate layer is separated, while the aqueous layer is extracted again with ethyl acetate, and the ethyl acetate layers are combined, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ether and n-hexaneare added to the residue, and the resulting crystals are recovered by filtration to give 320 mg of (3S,4S)-1benzyloxy-3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-2azetidinone. In 6 ml of chloroform dried with molecular sieve cooling After the stirring under ice-cooling for 30 minutes After the stirring under ice-cooling for further 30 minutes The chloroform is distilled off under reduced pressure, and 10 ml of 3N hydrochloric acid and ethyl acetate are added to the residue The ethyl acetate layer is separated, while the aqueous layer is extracted again with ethyl acetate washed with aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure Ether and n-hexaneare added to the residue the resulting crystals are recovered by filtration

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

Procedure: A mixture of 1-(5-acetamido-2-chloro-4-fluorophenyl)-3-(2-propynyl)urea (4.50 g, 15.9 mmol), and pyridine (2.56 mL, 31.8 mmol) in methylene chloride is treated with N-(chlorocarbonyl) isocyanate (1.92 mL, 23.9 mmol), stirred at room temperature overnight, refluxed for 90 minutes, cooled to room temperature, treated with additional pyridine (1.30 mL) and N-(chlorocarbonyl) isocyanate (1.92 mL), stirred for 10 minutes, cooled to room temperature, and filtered to obtain a solid. The solid is washed sequentially with water and hexanes, and dried to give the title product as a tan solid. refluxed for 90 minutes cooled to room temperature stirred for 10 minutes cooled to room temperature filtered to obtain a solid The solid is washed sequentially with water and hexanes dried

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

Procedure: 1,3-Bis[4-(N-hydroxyaminomethyl)phenoxy]benzene (0.704 g) was dissolved in 21 ml of tetrahydrofuran to which, with ice-cooling and in an atmosphere of argon, was subsequently added dropwise 0.354 ml of chlorocarbonyl isocyanate. After 10 minutes of stirring at the same temperature, the stirring was continued for 2 hours at room temperature. The solvent was evaporated under a reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.44 g of 1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene from fractions of chloroform-methanol (30:1) elution. cooling and in an atmosphere of argon the stirring was continued for 2 hours at room temperature The solvent was evaporated under a reduced pressure

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

Procedure: 1,3-Bis[4-(N-hydroxyaminomethyl)phenoxy]benzene (0.704 g) was dissolved in 21 ml of tetrahydrofuran to which, with ice-cooling and in an atmosphere of argon, was subsequently added dropwise 0.354 ml of chlorocarbonyl isocyanate. After 10 minutes of stirring at the same temperature, the stirring was continued for 2 hours at room temperature. The solvent was evaporated under a reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.44 g of 1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene from fractions of chloroform-methanol (30:1) elution. cooling and in an atmosphere of argon the stirring was continued for 2 hours at room temperature The solvent was evaporated under a reduced pressure

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

Procedure: 0.14 ml of N-(chlorocarbonyl) isocyanate was added dropwise at −50° C. to a 4 ml THF solution of 110 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(hydroxyamino)methyl]quinolin-4(1H)-one, followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 45 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}-1,2,4-oxadiazolidine-3,5-dione. followed by extraction with chloroform washing with aqueous saturated sodium chloride After drying over anhydrous sodium sulfate the solvent was evaporated under a reduced pressure the resulting residue was purified by silica gel column chromatography

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

Procedure: The compound 89 (245 mg, 0.6 mmol) was converted to the iminodicarboxylate with N-1-naphthyloxycarbonyl isocyanate prepared from 1-naphthol (158 mg, 1.1 mmol) and N-chlorocarbonylisocyanate (106 mg, 1 mmol) in the same manner as the example 82 to give the compound 104 (169 mg, 45%). Mp 166-167° C. Rf 0.38 (EtOAc). 1H-NMR (CDCl3): δH1.33 (6 H, d, J 6.8 Hz, (CH3)2CH), 3.21 (1 H, sep, J 6.9 Hz, (CH3)2CH), 5.33 (4 H, s, NCH2 and OCH2), 6.72 (2 H, d, J 1.6 Hz, arom 2- and 6-H), 6.78 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.05 (1 H, t, J 1.6 Hz, arom 4-H), 7.30 - 7.91 (7 H, m, 1-naphthyl), 8.04 (1 H, bs, NH), 8.45 (2 H, d-like, 4-pyridyl 3- and 5-H). IR(CHCl3)cm-1 : 3418 (NH), 1820 and 1748 (OOCNCOO). Elementary analysis (for C31H26N4O4SCl2) Calcd.: C, 59.91% H, 4.22% N, 9.01% S, 5.16% Cl, 11.41% Found: C, 59.34% H, 4.12% N, 9.27% S, 5.24% Cl, 11.16%

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

Procedure: The compound 89 (245 mg, 0.6 mmol) was converted to the iminodicarboxylate with N-4-biphenyloxycarbonyl isocyanate prepared from 4-phenylphenol (187 mg, 1.1 mmol) and N-chlorocarbonylisocyanate (106 mg, 1 mmol) in the same manner as the example 82 to give the compound 103 (215 mg, 55%). Mp 105-107° C. Rf 0.40 (EtOAc). 1H-NMR (CDCl3): δH1.32 (6 H, d, J 6.9 Hz, (CH3)2CH), 3.21 (1 H, sep, J 6.8 Hz, (CH3)2CH), 5.31 (2 H, s, NCH2), 5.33 (2 H, s, OCH2), 6.72 (2 H, d, J 1.5 Hz, arom 2- and 6-H), 6.78 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.06 (1 H, t, J 1.5 Hz, arom 4-H), 7.18 - 7.60 (9 H, m, 4-phenylphenyl), 7.82 (1 H, bs, NH), 8.46 (2 H, d-like, 4-pyridyl 3- and 5-H). IR(CHCl3)cm-1 : 3418 (NH), 1817 and 1747 (OOCNCOO). Elementary analysis (for C33H28N4O4SCl2) Calcd.: C, 61.21% H, 4.36% N, 8.65% S, 4.95% Cl, 10.95% Found: C, 61.06% H, 4.38% N, 8.64% S, 4.94% Cl, 10.78%

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

Procedure: The compound 89 (245 mg, 0.6 mmol) was converted to the iminodicarboxylate with N-4-biphenyloxycarbonyl isocyanate prepared from 4-phenylphenol (187 mg, 1.1 mmol) and N-chlorocarbonylisocyanate (106 mg, 1 mmol) in the same manner as the example 82 to give the compound 103 (215 mg, 55%). Mp 105-107° C. Rf 0.40 (EtOAc). 1H-NMR (CDCl3): δH1.32 (6 H, d, J 6.9 Hz, (CH3)2CH), 3.21 (1 H, sep, J 6.8 Hz, (CH3)2CH), 5.31 (2 H, s, NCH2), 5.33 (2 H, s, OCH2), 6.72 (2 H, d, J 1.5 Hz, arom 2- and 6-H), 6.78 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.06 (1 H, t, J 1.5 Hz, arom 4-H), 7.18 - 7.60 (9 H, m, 4-phenylphenyl), 7.82 (1 H, bs, NH), 8.46 (2 H, d-like, 4-pyridyl 3- and 5-H). IR(CHCl3)cm-1 : 3418 (NH), 1817 and 1747 (OOCNCOO). Elementary analysis (for C33H28N4O4SCl2) Calcd.: C, 61.21% H, 4.36% N, 8.65% S, 4.95% Cl, 10.95% Found: C, 61.06% H, 4.38% N, 8.64% S, 4.94% Cl, 10.78%

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

Procedure: The compound 89 (245 mg, 0.6 mmol) was converted to the iminodicarboxylate with N-decanyloxycarbonyl isocyanate prepared from 1-decanol (175 mg, 1.10mmol) and N-chlorocarbonylisocyanate (106 mg, 1 mmol) in the same manner as the example 82 to give the compound 99 (315 mg, 83%). Mp. 105-107° C. Rf 0.39 (EtOAc). 1H-NMR (CDCl3): δH0.88 (3 H, t like, CH3), 1.25-1.30 (14 H, m, --CH2 --), 1.31 (6 H, d, J 6.9 Hz, (CH3)2CH), 1.62 (2 H, m, --CH2 --), 3.18 (1 H, sep, J 6.9 Hz, (CH3)2CH), 4.14 (2 H, t, J 6.9 Hz, CH2O), 5.23 (2H, s, NCH2), 5.31 (2H, s, OCH2), 6.71 (2H, d, J 1.8 Hz, arom 2- and 6-H), 6.77 (2 H, d-like, 4-pyridyl 2- and 6-H), 6.99 (1 H, bs, NH), 7.06 (1 H, t, J 1.8 Hz, arom 4-H), 8.45 (2 H, d-like, 4-pyridyl 3- and 5-H). IR(CHCl3)cm-1 : 3424 (NH), 1807 and 1739 (OOCNCOO). Elementary analysis (for C31H40N4O4SCl2) Calcd. : C, 58.58% H, 6.34% N, 8.81% S, 5.04% Cl, 11.15% Found: C, 58.57% H, 6.37% N, 8.77% S, 5.02% Cl, 10.88%

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-bromo-1-propylamine hydrobromide (1.0 g, 4.56 mmol) in THF (20 mL) was added triethylamine (2.31 g, 22.8 mmol). The mixture was cooled to -78° C., triturated with N-(chlorocarbonyl)isocyanate (723 mg, 6.85 mmol) and stirred for 10 min. It was then concentrated, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated to give, in quantitative yield, the crude product which was used without purification. It was then concentrated the residue was partitioned between EtOAc and water The organic layer was dried over Na2SO4 filtered concentrated to give, in quantitative yield the crude product which was used without purification

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-bromo-1-propylamine hydrobromide (1.0 g, 4.56 mmol) in THF (20 mL) was added triethylamine (2.31 g, 22.8 mmol). The mixture was cooled to -78° C., triturated with N-(chlorocarbonyl)isocyanate (723 mg, 6.85 mmol) and stirred for 10 min. It was then concentrated, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated to give, in quantitative yield, the crude product which was used without purification. It was then concentrated the residue was partitioned between EtOAc and water The organic layer was dried over Na2SO4 filtered concentrated to give, in quantitative yield the crude product which was used without purification

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

Procedure: A mixture of 1-(5-acetamido-2-chloro-4-fluorophenyl)-3-(2-propynyl)urea (4.50 g, 15.9 mmol), and pyridine (2.56 mL, 31.8 retool) in methylene chloride is treated with N-(chlorocarbonyl) isocyanate (1.92 mL, 23.9 mmol), stirred at room temperature overnight, refluxed for 90 minutes, cooled to room temperature, treated with additional pyridine (1.30 mL) and N-(chlorocarbonyl) isocyanate (1.92 mL), stirred for 10 minutes, cooled to room temperature, and filtered to obtain a solid. The solid is washed sequentially with water and hexanes, and dried to give the title product as a tan solid. refluxed for 90 minutes cooled to room temperature stirred for 10 minutes cooled to room temperature filtered to obtain a solid The solid is washed sequentially with water and hexanes dried