3,6,9-三氧杂十一烷-1,11-二胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phospine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixutre stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 nl) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixutre stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 nl) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phospine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixutre stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 nl) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixutre stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 nl) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound II in 250 ml pyridine was added 89 g of triphenyl phosphine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixture stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixture stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phosphine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixture stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixture stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phosphine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixture stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixture stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phospine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixutre stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 nl) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixutre stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 nl) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phosphine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixture stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixture stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phosphine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixture stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixture stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 200 mg, 324 μmol) and HATU (136 mg, 357 μmol) combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min at room temperature. The reaction mixture was slowly added dropwise to a solution of 1,11-diamino-3,6,9-trioxaundecane (312 mg, 304 μL, 1.62 mmol) in dry tetrahydrofuran (1.5 mL) at 0° C. The reaction was done after stirring at room temperature for 20 min. It was filtered and injected into Gilson reverse-phase high-performance liquid chromatography for purification. The desired fractions was converted to free base and lyophilized to afford (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide as a white solid (169 mg, 66% yield). LCMS (ES+) m/z calcd. for C39H47Cl2F2N5O6 [(M+H)+]: 790. found: 790. to give an off-white suspension at room temperature after stirring at room temperature for 20 min It was filtered injected into Gilson reverse-phase high-performance liquid chromatography for purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), HBTU (61.5 mg, 162 μmol) and Hunig's base (105 mg, 142 μL, 811 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred at room temperature for 30 min. 1,11-Diamino-3,6,9-trioxaundecane (15.6 mg, 15.2 μL, 81.1 μmol) was added. After stirring at room temperature overnight, the reaction mixture was absorbed on small amount of silica gel, loaded on a 24 g pre-packed silica gel column and eluted with ethyl acetate to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide, dimer as white solid (148 mg, 66% yield). LCMS (ES+) m/z calcd. for C70H74Cl4F4N8O9 [(M+H)+]: 1387. found: 1387. to give an off-white suspension at room temperature After stirring at room temperature overnight the reaction mixture was absorbed on small amount of silica gel eluted with ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), HBTU (61.5 mg, 162 μmol) and Hunig's base (105 mg, 142 μL, 811 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred at room temperature for 30 min. 1,11-Diamino-3,6,9-trioxaundecane (15.6 mg, 15.2 μL, 81.1 μmol) was added. After stirring at room temperature overnight, the reaction mixture was absorbed on small amount of silica gel, loaded on a 24 g pre-packed silica gel column and eluted with ethyl acetate to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide, dimer as white solid (148 mg, 66% yield). LCMS (ES+) m/z calcd. for C70H74Cl4F4N8O9 [(M+H)+]: 1387. found: 1387. to give an off-white suspension at room temperature After stirring at room temperature overnight the reaction mixture was absorbed on small amount of silica gel eluted with ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phosphine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixture stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum. the mixture stirred overnight The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml) The combined alcohol and dichloromethane extracts were concentrated under reduced pressure Concentrated hydrochloric acid (15 ml) was added the solvent removed under reduced pressure The residue was crystallized from ethanol/ether The hygroscopic crystals were dried under vacuum