BETA-STYRENE SULFONYL CHLORIDE

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

Procedure: (E)-2-phenylethensulfonyl chloride (138 mg) and dimethylaminopyridine (40 mg) were added at room temperature under an atmosphere of nitrogen to a solution of 4-(1,3-benzodioxol-5-yl)-1-benzyl-3-methoxy-1H-pyrazol-5-amine (Preparation 58) (100 mg) in anhydrous pyridine (3 ml). After 24 h, another portion of (E)-2-phenylethensulfonyl chloride (32 mg) was added and the reaction was stirred for 48 h before the mixture was concentrated under reduced pressure. To the beige solid was added an aqueous solution of HCl (1N, 10 ml) and the mixture was extracted with dichloromethane (3×10 ml). The organic fractions were combined, dried on sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (5 ml) and an aqueous solution of sodium hydroxyde (2N, 2.25 ml) was added. The reaction was stirred overnight. The reaction mixture was then diluted with water (20 ml), acidified with an aqueous solution of HCl (2N) and the solution was extracted with ethyl acetate (3×15 ml). The combined organic fractions were washed with brine (15 ml), dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with hexane:ethyl acetate (2:1) to yield the title compound as colourless oil (109 mg) which crystallises in a mixture of ether and ethyl acetate. was concentrated under reduced pressure To the beige solid was added an aqueous solution of HCl (1N, 10 ml) the mixture was extracted with dichloromethane (3×10 ml) dried on sodium sulfate concentrated under reduced pressure The residue was dissolved in ethanol (5 ml) an aqueous solution of sodium hydroxyde (2N, 2.25 ml) was added The reaction was stirred overnight The reaction mixture was then diluted with water (20 ml) the solution was extracted with ethyl acetate (3×15 ml) The combined organic fractions were washed with brine (15 ml) dried on sodium sulfate concentrated under reduced pressure The residue was purified by column chromatography (silica, 10 g) eluted with hexane:ethyl acetate (2:1)

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

Procedure: (E)-2-phenylethensulfonyl chloride (381 mg) and dimethylaminopyridine (77 mg) were added at room temperature under an atmosphere of nitrogen to a solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-1-ethanol (200 mg) (Preparation 45) in anhydrous pyridine (6 ml). After 24 h, the mixture was concentrated under reduced pressure. To the yellow solid was added water (30 ml), an aqueous solution of HCl (1N) to acidify the solution and the mixture was extracted with dichloromethane (3×30 ml). The organic fractions were combined, dried on sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (6 ml) and dichloromethane (1 ml) and an excess of an aqueous solution of sodium hydroxyde (2N) was added. The reaction was stirred overnight. The reaction mixture was then diluted with dichloromethane (100 ml), acidified with an aqueous solution of HCl (1N). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic fractions were dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 20 g) eluted with dichloromethane:methanol (95:5) to yield the title compound as colourless solid (257 mg). the mixture was concentrated under reduced pressure To the yellow solid was added water (30 ml) the mixture was extracted with dichloromethane (3×30 ml) dried on sodium sulfate concentrated under reduced pressure The residue was dissolved in ethanol (6 ml) dichloromethane (1 ml) and an excess of an aqueous solution of sodium hydroxyde (2N) was added The reaction mixture was then diluted with dichloromethane (100 ml) The phases were separated the aqueous phase was extracted with dichloromethane (2×50 ml) The combined organic fractions were dried on sodium sulfate concentrated under reduced pressure The residue was purified by column chromatography (silica, 20 g) eluted with dichloromethane:methanol (95:5)

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

Procedure: To a solution of 5.33 g (18.24 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example 115, Step E) in DCM (45.0 mL) was added N,N-diisopropylethylamine (4.8 mL, 27.5 mmol), followed by trans-beta-styrenesulfonyl chloride (4.17 g, 20.58 mmol). The resulting solution was stirred at ambient temperature under an N2 atmosphere. After being stirred for 3.25 hours, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient) provided the title compound as a yellow solid. After being stirred for 3.25 hours extracted with DCM The combined organic layers were washed with sat. aq. NaCl solution dried over Na2SO4 filtered the filtrate was concentrated Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient)

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

Procedure: To a solution of 5.33 g (18.24 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example 115, Step E) in DCM (45.0 mL) was added N,N-diisopropylethylamine (4.8 mL, 27.5 mmol), followed by trans-beta-styrenesulfonyl chloride (4.17 g, 20.58 mmol). The resulting solution was stirred at ambient temperature under an N2 atmosphere. After being stirred for 3.25 hours, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient) provided the title compound as a yellow solid. After being stirred for 3.25 hours extracted with DCM The combined organic layers were washed with sat. aq. NaCl solution dried over Na2SO4 filtered the filtrate was concentrated Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient)

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

Procedure: To a solution of 5.33 g (18.24 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example 115, Step E) in DCM (45.0 mL) was added N,N-diisopropylethylamine (4.8 mL, 27.5 mmol), followed by trans-beta-styrenesulfonyl chloride (4.17 g, 20.58 mmol). The resulting solution was stirred at ambient temperature under an N2 atmosphere. After being stirred for 3.25 hours, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient) provided the title compound as a yellow solid. After being stirred for 3.25 hours extracted with DCM The combined organic layers were washed with sat. aq. NaCl solution dried over Na2SO4 filtered the filtrate was concentrated Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient)

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

Procedure: To a solution of 5.33 g (18.24 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example 115, Step E) in DCM (45.0 mL) was added N,N-diisopropylethylamine (4.8 mL, 27.5 mmol), followed by trans-beta-styrenesulfonyl chloride (4.17 g, 20.58 mmol). The resulting solution was stirred at ambient temperature under an N2 atmosphere. After being stirred for 3.25 hours, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient) provided the title compound as a yellow solid. After being stirred for 3.25 hours extracted with DCM The combined organic layers were washed with sat. aq. NaCl solution dried over Na2SO4 filtered the filtrate was concentrated Purification by flash chromatography on silica gel (0 to 40% EtOAc in hexanes gradient)

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

Procedure: To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg) and triethylamine (0.04 ml) in dichloromethane (2 ml) was added a solution of (E)-styrenesulfonyl chloride (48 mg) in dichloromethane (1 ml) in an ice-water bath. After being stirred for 30 minutes under ice-cooling, the reaction mixture was partitioned into dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-((E)-styrylsulfonylglycyl)amino]benzyloxy]-2-methylquinoline (78 mg) as an amorphous powder. cooling the reaction mixture was partitioned into dichloromethane and water The organic layer was dried over magnesium sulfate evaporated in vacuo The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol)

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

Procedure: To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg) and triethylamine (0.04 ml) in dichloromethane (2 ml) was added a solution of (E)-styrenesulfonyl chloride (48 mg) in dichloromethane (1 ml) in an ice-water bath. After being stirred for 30 minutes under ice-cooling, the reaction mixture was partitioned into dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-((E)-styrylsulfonylglycyl)amino]benzyloxy]-2-methylquinoline (78 mg) as an amorphous powder. cooling the reaction mixture was partitioned into dichloromethane and water The organic layer was dried over magnesium sulfate evaporated in vacuo The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol)

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

Procedure: To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg) and triethylamine (0.04 ml) in dichloromethane (2 ml) was added a solution of (E)-styrenesulfonyl chloride (48 mg) in dichloromethane (1 ml) in an ice-water bath. After being stirred for 30 minutes under ice-cooling, the reaction mixture was partitioned into dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-((E)-styrylsulfonylglycyl)amino]benzyloxy]-2-methylquinoline (78 mg) as an amorphous powder. cooling the reaction mixture was partitioned into dichloromethane and water The organic layer was dried over magnesium sulfate evaporated in vacuo The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol)

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

Procedure: The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using trans-b-styrenesulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated from 50% EtOAc/hexanes to give the title compound as a solid. The crude product is triturated from 50% EtOAc/hexanes

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3S,4S)-3-{N-benzyloxycarbonyl-β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one (237 mg, 0.5 mmol) obtained in example 8, was hydrogenated with 400 mg of 10% palladium on activated carbon in ethyl acetate (20 ml) and THF (10 ml) at 50 psi hydrogen pressure at room temperature for 2 hrs. After removal of catalyst by filtration, the desubstituted (3S,4S)-3{β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one was cooled to -15° C. Then triethylamine (50 mg, 0.5 mmol) and trans-2-phenyl-eth-1-ene sulfonyl chloride (101 mg, 0.5 mmol) were added at -15° C. Stirring was continued at a bath temperature of -10 to 0° C. for 1 hr and 5° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with cold saturated NaHCO3 solution, water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:1) as eluent and the title compound (30 mg) was obtained. After removal of catalyst by filtration was continued at a bath 5° C. overnight washed with cold saturated NaHCO3 solution, water, brine dried over sodium sulfate After removal of solvent the residue was purified by silica gel column chromatography

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

Procedure: To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg) and triethylamine (0.04 ml) in dichloromethane (2 ml) was added a solution of (E)-styrenesulfonyl chloride (48 mg) in dichloromethane (1 ml) in an ice-water bath. After being stirred for 30 minutes under ice-cooling, the reaction mixture was partitioned into dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated in vacua. The residue was purified by preparative thin-layer chromatography (dichloromethane--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-((E)-styrylsulfonylglycyl)amino]benzyloxy]-2-methylquinoline (78 mg) as an amorphous powder. cooling the reaction mixture was partitioned into dichloromethane and water The organic layer was dried over magnesium sulfate evaporated in vacua The residue was purified by preparative thin-layer chromatography (dichloromethane--methanol)