acetic acid;hydrazine

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

Procedure: 2,2-Dimethylpropyl 4-(4-cyanopyridin-2-yl)piperazine-1-carboxylate (143 mg) obtained in Example 2 was dissolved in ethanol (5 mL), and hydrazine acetate (140 mg) and potassium carbonate (328 mg) were added thereto and heated under reflux for 5 hours, then the reaction liquid was evaporated. Acetic anhydride (3 mL) was added to the resulting residue, and heated under reflux for 2 hours, then the reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=9/1) to obtain 7.6 mg of the entitled compound as a colorless oil. heated under reflux for 5 hours the reaction liquid was evaporated Acetic anhydride (3 mL) was added to the resulting residue heated under reflux for 2 hours the reaction liquid washed with water and saturated saline water dried with anhydrous sodium sulfate The solvent was evaporated away the resulting residue was isolated purified through thin-layer silica gel chromatography (chloroform/methanol=9/1)

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

Procedure: 983 mg hydrazine acetate was added to 2 g 2,4-Dioxo-4-phenyl-butyric acid methyl ester in 10 mL concentrated acetic acid. The mixture was stirred over night at RT. Then water was added. The precipitate was filtered, stirred with diisopropylether and again filtered to give 1.3 g desired product. Rt: 1.39 min (method O), (M+H)+: 203 The precipitate was filtered stirred with diisopropylether again filtered

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

Procedure: A solution of acetyl 2,3-di-O-acetyl-4,6-dichloro-4,6-dideoxy-D-galactopyranose (compound 82) (2.24 g, 6.5 mmol) and hydrazine acetate (903 mg) in DMF (22 mL) was stirred for 2 hours at room temperature. The reaction mixture was then diluted with dichloromethane (250 mL) and washed 4 times with water (4×250 mL), dried over anhydrous sodium sulfate and evaporated. Flash chromatography using hexane-ethyl acetate (1:1) as an eluent gave 2,3-di-O-acetyl-4,6-dichloro-4,6-dideoxy-D-galactopyranose (~6.88 mmol). This compound was then dissolved in dichloromethane (20 mL) cooled to 0° C., and trichloroacetonitrile (3.35 mL, 34.4 mmol) was added. After stirring at 0° C. for 40 minutes, the solvent was evaporated and the residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate (5:1), to give imidate 83 (1.14 g, 39%) as a white solid. washed 4 times with water (4×250 mL) dried over anhydrous sodium sulfate evaporated

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

Procedure: A solution of acetyl 6-O-acetyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-D-galactopyranoside (68) (8.53 g, 17.4 mmol) and hydrazine acetate (2.4 g, 26.0 mmol, 1.5 eq) in 70 mL of DMF was stirred for 1 hour at room temperature. The reaction mixture was then evaporated, washed with water (5 times) and evaporated. The residue was chromatographed on a silica gel, eluting with hexane-ethyl acetate (2:1), to provide 6-O-acetyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-D-galactopyranose (7.44 g, 95.3%). This material was dissolved in dichloromethane (50 mL) and the resulting solution was cooled to 0° C. Trichloroacetonitrile (8.3 mL, 82.9 mmol) was added and the mixture was stirred for 2 hours. The solvent was then evaporated and the residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate (3:1), to give imidate 69 (6.3 g, 64%). The reaction mixture was then evaporated washed with water (5 times) evaporated The residue was chromatographed on a silica gel eluting with hexane-ethyl acetate (2:1)

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

Procedure: To a solution of tetra-O-acetyl-6-chloro-6-deoxy-D-galactopyranose (compound 54) (6.36 g, 17.3 mmol) in DMF (60 mL) was added hydrazine acetate (2.4 g, 26.0 mmol). The mixture was stirred for 1 hour at room temperature and then 1 L of dichloromethane was added and the resulting solution washed 4 times with water. The organic layer was dried over anhydrous sodium sulfate and evaporated. Flash column chromatography using hexane-ethyl acetate (1:1) as the eluent gave 2,3,4-tri-O-acetyl-6-chloro-6-deoxy-α-D-galactopyranose (5.79 g). This material was dissolved in 50 mL of dichloromethane and cooled to 0° C. Trichloroacetonitrile (8.93 mL, 89.2 mmol) was added followed by DBU (1.33 mL, 8.9 mmol). This solution was stirred for 1.5 hours and then evaporated. The residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate (2:1), to provide compound 55 (4.1 g, 51%) as a foam. the resulting solution washed 4 times with water The organic layer was dried over anhydrous sodium sulfate evaporated

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

Procedure: Compound 54 is then converted in two steps into O-(2,3,4-tri-O-acetyl-6-chloro-6-deoxy-α-D-glucopyranosyl) trichloroacetimidate (55). First, the anomeric acetate group of compound 54 is selectively removed by reaction with hydrazine acetate. Preferably, this reaction is conducted by contacting compound 54 with from about 1.1 to about 1.5 equivalents of hydrazine acetate (prepared by known procedures from hydrazine and acetic anhydride) at a temperature of from about 0° C. to about 20° C. for about 5 to about 10 hours. Typically, the reaction is conducted in an anhydrous solvent, such as dimethylformamide. Treatment of the resulting product with trichloroacetonitrile in the presence of an amine, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), provides compound 55. This reaction is typically conducted in an anhydrous inert organic solvent, such as dichloromethane, using an excess of trichloroacetonitrile. First, the anomeric acetate group of compound 54 is selectively removed by reaction with hydrazine acetate of from about 0° C. to about 20° C. for about 5 to about 10 hours

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-methyl-isonicotinamide (1.23 g) and N,N-dimethylformamide dimethyl acetal (1.05 ml) were dissolved in dry DMF (4 ml) under inert atmosphere and the resulting solution was heated to 90° C. and stirred for 1 h. The reaction mixture was cooled to room temperature and a solution of hydrazine acetate (3.32 g) in acetic acid (8 ml) was dropwise added. The mixture was heated to 90° C. and stirred for 1 h. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous solution of NaHCO3 and EtOAc. The organic phase was separated, washed with brine, dried under Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 1/1 to 3/7) affording 2-Chloro-6-methyl-4-(1H-[1,2,4]triazol-3-yl)-pyridine (0.92 g). GC (Rt)=13.21 min (method=3A) The reaction mixture was cooled to room temperature The mixture was heated to 90° C. stirred for 1 h The solvent was removed under reduced pressure the residue partitioned between saturated aqueous solution of NaHCO3 and EtOAc The organic phase was separated washed with brine dried under Na2SO4 filtered the solvent was evaporated under reduced pressure The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 1/1 to 3/7)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-methyl-isonicotinamide (1.23 g) and N,N-dimethylformamide dimethyl acetal (1.05 ml) were dissolved in dry DMF (4 ml) under inert atmosphere and the resulting solution was heated to 90° C. and stirred for 1 h. The reaction mixture was cooled to room temperature and a solution of hydrazine acetate (3.32 g) in acetic acid (8 ml) was dropwise added. The mixture was heated to 90° C. and stirred for 1 h. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous solution of NaHCO3 and EtOAc. The organic phase was separated, washed with brine, dried under Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 1/1 to 3/7) affording 2-Chloro-6-methyl-4-(1H-[1,2,4]triazol-3-yl)-pyridine (0.92 g). GC (Rt)=13.21 min (method=3A) The reaction mixture was cooled to room temperature The mixture was heated to 90° C. stirred for 1 h The solvent was removed under reduced pressure the residue partitioned between saturated aqueous solution of NaHCO3 and EtOAc The organic phase was separated washed with brine dried under Na2SO4 filtered the solvent was evaporated under reduced pressure The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 1/1 to 3/7)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOH (5 mL) and hydrazine acetate (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole as a solid. LRMS: calcd 399.3, found [M+1] 401.0. The volatile material is removed in vacuo The mixture is heated at 120° C. for 2 hours The solvent is removed NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue The organic layer is separated the aqueous layer is extracted with DCM (2×15 mL) The combined organic layers are dried the solvent removed The crude is purified by PTLC (ethyl acetate/Hexanes 1:1)

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

Procedure: To a solution of 3-acetylthio-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (530 mg, 1.08 mmol) (obtained as described in Reference Example 76) in dimethylformamide (27 ml) was added hydrazine acetate (120 mg, 1.30 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (642 mg, 1.08 mmol) in acetonitrile (32 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (753 μl, 4.32 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (95:5)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (652 mg, yield 76%) as a pale yellow solid. the completion of the reaction The mixture was stirred overnight were added to the reaction mixture The resulting mixture was shaken in a separatory funnel the ethyl acetate layer was separated washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (95:5))

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

Procedure: To a solution of 3-acetylthio-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (530 mg, 1.08 mmol) (obtained as described in Reference Example 76) in dimethylformamide (27 ml) was added hydrazine acetate (120 mg, 1.30 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (642 mg, 1.08 mmol) in acetonitrile (32 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (753 μl, 4.32 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (95:5)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (652 mg, yield 76%) as a pale yellow solid. the completion of the reaction The mixture was stirred overnight were added to the reaction mixture The resulting mixture was shaken in a separatory funnel the ethyl acetate layer was separated washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (95:5))

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

Procedure: To a solution of 3-acetylthio-1-{4-[3-(t-butyldiphenylsilyloxy)-azetidin-1-ylcarbonyl]-1,3-oxazol-2-yl}azetidine (860 mg, 1.61 mmol) (obtained as described in Reference Example 74) in dimethylformamide (43 ml) was added hydrazine acetate (178 mg, 1.93 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (957 mg, 1.61 mmol) in acetonitrile (48 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.12 ml, 6.44 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (95:5)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[3-(t-butyldiphenylsilyloxy)-azetidin-1-ylcarbonyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.20 g, yield 89%) as a pale yellow solid. the completion of the reaction The mixture was stirred overnight were added to the reaction mixture The resulting mixture was shaken in a separatory funnel the ethyl acetate layer was separated washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (95:5))