乙基异噻唑烷-3-羧酸盐1,1-二氧化物

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

实验步骤: To a solution of crude 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (310 mg, approx. 0.61 mmol) in tetrahydrofuran (3.6 mL) was added lithium hydroxide hydrate (51 mg, 1.2 mmol) followed by water (910 μL). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The remaining solution was stirred and approximately 25 drops of 1 M hydrochloric acid were added to bring the pH to 4.5. The sample was stirred for 10 min and the aqueous solution was decanted away from the yellow gum. The gum was washed with water (2 mL). The combined aqueous layers were evaporated to dryness, and dried overnight to give 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid as a pale yellow residue (292 mg). the mixture was concentrated under reduced pressure to remove tetrahydrofuran The remaining solution was stirred approximately 25 drops of 1 M hydrochloric acid were added The sample was stirred for 10 min the aqueous solution was decanted away from the yellow gum The gum was washed with water (2 mL) The combined aqueous layers were evaporated to dryness dried overnight

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

实验步骤: Triethylamine (214 μL, 1.5 mmol) was added to a solution of (S)-3-(4-chloro-phenyl)-N1,N1-dimethyl-propane-1,2-diamine hydrochloride salt (Intermediate X; 182 mg, 0.73 mmol) in methanol (2 mL). The mixture was stirred for 10 min and then a solution of 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (Intermediate 8 Step 3; 190 mg, 0.61 mmol) in methanol (4 mL) was added under argon. The mixture was stirred at room temperature for 15 min and then cooled in an ice-bath. Solid sodium cyanoborohydride (57.5 mg, 0.9 mmol) and glacial acetic acid (540 μL) were added. The reaction mixture was allowed to warm to room temperature and stir. The progress of the reaction was monitored by LCMS. When the reaction was substantially complete, the solvents were evaporated and ethyl acetate (50 mL) was added. The solution was washed with washed with water (2×10 mL) and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give crude 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (390 mg) as a tacky yellow foam which was used directly in the next step without further purification. The mixture was stirred at room temperature for 15 min cooled in an ice-bath stir the solvents were evaporated ethyl acetate (50 mL) was added The solution was washed with washed with water (2×10 mL) the aqueous layer was extracted with ethyl acetate (50 mL) The combined organics were dried over sodium sulfate filtered concentrated

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

实验步骤: To a solution of crude 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (430 mg, approx. 0.96 mmol) in tetrahydrofuran (4 mL) was added lithium hydroxide hydrate (71 mg, 1.7 mmol) followed by water (1 mL). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The remaining solution was stirred and approximately 25 drops of 1 M hydrochloric acid were added to bring the pH to 4.5. The sample was stirred for 10 min and the aqueous solution was decanted away from the yellow gum. The gum was washed with water (2 mL). The combined aqueous layers were evaporated to dryness, and dried overnight to give 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid as a white residue (200 mg). the mixture was concentrated under reduced pressure to remove tetrahydrofuran The remaining solution was stirred approximately 25 drops of 1 M hydrochloric acid were added The sample was stirred for 10 min the aqueous solution was decanted away from the yellow gum The gum was washed with water (2 mL) The combined aqueous layers were evaporated to dryness dried overnight

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

实验步骤: Triethylamine (338 μL, 2.4 mmol) was added to a solution of (S)-3-(3-chloro-phenyl)-N1,N1-dimethyl-propane-1,2-diamine hydrochloride salt (264 mg, 1.06 mmol) in methanol (2 mL) under argon at room temperature. The mixture was stirred for 10 min and then a solution of 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (Intermediate 8 Step 3; 250 mg, 0.96 mmol) in methanol (4 mL) was added under argon. The mixture was stirred at room temperature for 15 min and then cooled in an ice-bath. Solid sodium cyanoborohydride (90.9 mg, 1.45 mmol) and glacial acetic acid (750 μL) were added. The reaction mixture was allowed to warm to room temperature and stir. The progress of the reaction was monitored by LCMS. When the reaction was substantially complete, the solvents were evaporated and ethyl acetate (50 mL) was added. The solution was washed with washed with water (2×10 mL) and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give crude 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (430 mg) as a yellow foam which was used directly in the next step without further purification. The mixture was stirred at room temperature for 15 min cooled in an ice-bath stir the solvents were evaporated ethyl acetate (50 mL) was added The solution was washed with washed with water (2×10 mL) the aqueous layer was extracted with ethyl acetate (50 mL) The combined organics were dried over sodium sulfate filtered concentrated

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

实验步骤: 3-Bromomethyl-benzaldehyde (2.44 g, 12.3 mmol) and cesium carbonate (9.08 g, 27.9 mmol) were added to a solution of a 4:3 mixture of 1,1-dioxo-isothiazolidine-3-carboxylic acid methyl ester and 1,1-dioxo-isothiazolidine-3-carboxylic acid ethyl ester (Intermediate 7 Step 2; 2.01 g, 10.8 mmol) in N,N-dimethylformamide (60 mL). The mixture was stirred at room temperature for 20 h and then dichloromethane (100 mL) was added. Saturated aqueous ammonium chloride solution (25 mL) was added followed by 1 M hydrochloric acid to bring the pH to 2-3. The two layers were separated and the organic layer was washed twice with brine. The solution was dried over sodium sulfate, and filtered. Celite was added and the solvents were evaporated under reduced pressure. The residue (containing the mixture of crude products coated onto Celite) was purified using flash chromatography (Analogix SF40-240 g Si), eluting with 30-70% ethyl acetate/hexanes to give 2-(3-formyl-benzyl)-1,1-dioxo-1λ6 isothiazolidine-3-carboxylic acid ethyl ester (first eluting peak; 1.26 g, 37%) and 2-(3-formyl-benzyl)-1,1-dioxo-1λ6 isothiazolidine-3-carboxylic acid methyl ester (second eluting peak; 1.69 g, 53%). The two layers were separated the organic layer was washed twice with brine The solution was dried over sodium sulfate filtered Celite was added the solvents were evaporated under reduced pressure The residue (containing the mixture of crude products coated onto Celite) was purified eluting with 30-70% ethyl acetate/hexanes