1,1-dioxo-1,4-thiazinane-4-carbonyl chloride

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (51.4 mg; 0.26 mmol) is added to a mixture of (S)-Azetidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (69 mg; 0.265 mmol) and N,N-diisopropylethylamine (0.141 mL; 0.81 mmol) in THF (2 mL). The reaction mixture is stirred at room temperature for 2 hours. After this time, the reaction mixture is diluted with dichloromethane and washed with water. The layers are separated and the aqueous layer is extracted with dichloromethane once. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 385 [M+H+]. washed with water The layers are separated the aqueous layer is extracted with dichloromethane once washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification by flash chromatography on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (0.30 g, 1.13 mmol), DIPEA (0.32 g, 2.48 mmol) and DMAP (16.0 mg, 0.13 mmol) is stirred at room temperature for 15 minutes. 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (0.27 g, 1.35 mmol) (prepared according to method M step 1) is added drop wise at 0° C. to the reaction mixture that is slowly warmed up to room temperature and stirred for 14 hours. The reaction mixture is diluted with EtOAc, washed with water and brine. After drying the organic phase over anhydrous Na2SO4, removal of the solvent under reduced pressured affords the crude product that is purified by prep TLC to afford the title product; m/z 427 [M+H+]. washed with water and brine After drying the organic phase over anhydrous Na2SO4, removal of the solvent affords the crude product that is purified by prep TLC

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thiomorpholine 1,1-dioxide (3 g; 22.192 mmol) is dissolved in THF (70 mL) and cooled to 0° C. Triethylamine (3.708 mL; 26.6 mmol) is added, followed by 20% phosgene in toluene (35.229 mL; 66.6 mmol). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is poured into ethyl ether (200 mL), then filtered through Celite®. The Celite® is washed with ethyl ether several times and the combined filtrates are concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, d-CDCl3): δ 3.1-3.2 (m; 4H), 4.1-4.3 (d, 4H). filtered through Celite® The Celite® is washed with ethyl ether several times the combined filtrates are concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide hydrochloride (150 mg; 0.521 mmol) in THF (6 mL) is added 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (102.97 mg; 0.521 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.07 mmol). The reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is quenched with water and extracted with methylene chloride twice. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 413 [M+H+]. The reaction mixture is quenched with water extracted with methylene chloride twice The combined organics were washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification by flash chromatography on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg; 0.347 mmol) in anhydrous THF (1 mL) is added triethylamine (0.098 mL; 0.7 mmol) and 1,1-dioxo-1λ6-thiomorpholine-4-carbonyl chloride (71.15 mg; 0.36 mmol). The reaction mixture is left stirring at room temperature overnight. The reaction mixture is diluted with water and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The reaction mixture is left extracted with ethyl acetate 3 times washed with brine dried over Na2SO4 filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thiomorpholine 1,1-dioxide (1 g; 7.397 mmolline) is dispersed in THF (50 mL). Triethylamine (1.238 mL; 8.88 mmol) is added, followed by 20% phosgene in toluene (11.743 mL; 22.2 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with diethyl ether and filtered through Celite®. The Celite® is washed with diethyl ether several times and the combined filtrates are concentrated in vacuo to afford the title compound. H NMR (400 MHz, CDCl3): δ 3.1-3.2 (m; 4H), 4.1-4.3 (d, 4H). filtered through Celite® The Celite® is washed with diethyl ether several times the combined filtrates are concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of [1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-methanone (0.2 g, 0.636 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0° C. To this reaction mixture was added 1,1-dioxo-thiomorpholine-4-carbonyl chloride slowly and stirred for 2 h at ambient temperature. The solvents were evaporated and the residue purified by preparative HPLC to afford 1,1-dioxo-thiomorpholine-4-carboxylic acid {2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide (0.007 g, 2.3%). MS-ESI m/z 476 (M+1); 1H-NMR (300 MHz, CD3OD) δ 1.5 (t, 1H), 1.8 (m, 4H), 2.1 (brs, 3H), 2.8 (s, 4H), 3.6 (t, 2H), 3.8 (s, 4H), 4.2 (m, 2H), 4.5 (t, 2H), 4.7 (s, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 7.85 (s, 1H), 8.3 (s, 1H). HPLC (VERYPOL.M): tr=6.24 min (97%). The solvents were evaporated the residue purified by preparative HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (0.092 g; 0.337 mmol) in tetrahydrofuran (2.5 mL) is added 1,1-dioxo-1λ6-thiomorpholine-4-carbonyl chloride (0.067 g; 0.337 mmol) and N,N-diisopropylethylamine (0.123 mL; 0.708 mmol). The mixture is stirred at room temperature for 3 hours before diluting with ethyl acetate and washing with 1N hydrochloric acid and brine. The organics are concentrated in vacuo and purified by preparatory HPLC. The product fractions are pooled and concentrated in vacuo to afford title compound. ESI m/z 399 [M+H]+/397 [M−H]− washing with 1N hydrochloric acid and brine The organics are concentrated in vacuo purified by preparatory HPLC concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thiomorpholine 1,1-dioxide (1 g; 7.397 mmol) is dispersed in tetrahydrofuran (50 mL) followed by the addition of triethylamine (1.238 mL; 8.88 mmol) and 20% phosgene in toluene (11.743 mL; 22.2 mmol). The reaction mixture is stirred at room temperature overnight. After this time, the mixture is diluted with ether and filtered through Celite®. The Celite® is washed with ether several times and the combined filtrates are concentrated in vacuo to afford title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 3.15 (4H, m), 4.13 (2H, s), 4.24 (2H, s). filtered through Celite® The Celite® is washed with ether several times the combined filtrates are concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thiomorpholine 1,1-dioxide (1 g; 7.397 mmol) is dispersed in tetrahydrofuran (50 mL) followed by the addition of triethylamine (1.238 mL; 8.88 mmol) and 20% phosgene in toluene (11.743 mL; 22.2 mmol). The reaction mixture is stirred at room temperature overnight. After this time, the mixture is diluted with ether and filtered through Celite®. The Celite® is washed with ether several times and the combined filtrates are concentrated in vacuo to afford title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 3.15 (4H, m), 4.13 (2H, s), 4.24 (2H, s). filtered through Celite® The Celite® is washed with ether several times the combined filtrates are concentrated in vacuo