1,2-thiazolidine 1,1-dioxide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reaction flask was charged with copper (I) iodide (8 mg, 0.042 mmol), sarcosine (N-methyl glycine) (9 mg, 0.1 mmol), isothiazolidine 1,1-dioxide (204 mg, 1.685 mmol), (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 100 mg, 0.168 mmol) and potassium phosphate (179 mg, 0.842 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous N,N-dimethylformamide (3 mL) was added. The resulting suspension was vigorously stirred at 100° C. for 17 h, and then allowed to cool to 25° C. The mixture was diluted with ethyl acetate (30 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×20 mL) and saturated aqueous brine solution (40 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 100% dichloromethane, 2nd column: 5% hexanes in dichloromethane) to afford the desired product. The crude product was triturated with absolute ethanol (3×) and dried in vacuo at 60° C. to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (70 mg, 0.119 mmol, 71%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.17-1.24 (2H, m), 1.40-1.61 (4H, m), 2.39-2.46 (2H, m), 2.51-2.54 (1H, m), 2.64-2.65 (1H, m), 3.03-3.05 (1H, m), 3.53-3.60 (3H, m), 3.83 (2H, t, J=6.3 Hz), 4.43 (1H, d, J=15.4 Hz), 4.97 (1H, d, J=15.6 Hz), 7.15 (2H, t, J=9.0 Hz), 7.32-7.35 (2H, m), 7.51-7.54 (2H, m), 7.62 (1H, d, J=8.5 Hz). LC-MS (ESI) calcd for C27H27FN4O6S2 586.14, found 587.4 [M+H+]. The flask was degassed anhydrous N,N-dimethylformamide (3 mL) was added to cool to 25° C The mixture was diluted with ethyl acetate (30 mL) washed with 1.0 M aqueous hydrochloric acid solution (2×20 mL) and saturated aqueous brine solution (40 mL) The organic layer was dried over magnesium sulfate filtered concentrated in vacuo Purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 100% dichloromethane, 2nd column: 5% hexanes in dichloromethane)

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

Procedure: To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl-methanesulfonate (360 mg, 0.75 mmol) and K2CO3 (207 mg, 1.5 mmol) in acetonitrile (10 mL) was added isothiazolidine 1,1-dioxide (121 mg, 4.6 mmol), and the mixture was refluxed overnight. The mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC to afford compound (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (2.43 mg, 1%). LC-MS Method 2 tR=1.37 min, m/z=509, 507. 1H NMR (CDCl3): 1.48 (t, 3H), 2.05-2.41 (m, 7H), 2.71-2.92 (m, 2H), 3.11 (m, 3H), 3.21 (m, 2H), 5.58 (m, 1H), 6.73 (d, 2H), 7.18 (m, 1H), 7.23 (m, 3H);7.35 (m, 3H). the mixture was refluxed overnight The mixture was filtered the filtrate was concentrated to give the crude product, which was purified by preparative HPLC

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

Procedure: A mixture of 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (15.9 mg, 47.2 μmol), 1,1-dioxo-isothiazolidine (11.4 mg, 94.4 μmol) and DBU (14.2 μL, 94.4 μmol) in DMF (250 μL) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 75:25% to 5:95%. WL: 230 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.10 mg, 16%). MS (m/e): 387.3 (MH+). The reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 75:25% to 5:95%. WL: 230 nm Flow: 30 mL/min.)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 40 mL scintillation vial was charged with 1,1-dioxo-isothiazolidine (115 mg, 0.949 mmol) and DMF (3 mL). The reaction mixture was cooled to 0° C. and sodium hydride (95 mg, 2.373 mmol) was added. The reaction was left to stir at room temperature for 20 min followed by the addition of 3-bromo-5-(chloromethyl)pyridine hydrochloride (277 mg, 1.139 mmol). The reaction was stirred at room temperature for 3 h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water twice, dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel flash chromatography using heptane-ethyl acetate (60-40, v/v) to afford 3-bromo-5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridine as a colorless oil. MS (ESI) m/z 292.9 (M+H)+ The reaction was left The reaction was stirred at room temperature for 3 h quenched with water extracted with ethyl acetate The organic layer was washed with water twice dried over sodium sulfate concentrated in vacuo The crude was purified by silica gel flash chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product from Example 26.1.2 (100 mg, 0.189 mmol), isothiazolidine 1,1-dioxide (46 mg, 0.378 mmol), copper(I) iodide (4 mg, 0.019 mmol), N,N-dimethylethyl diamine (3 mg, 0.039 mmol) and potassium carbonate (55 mg, 0.378 mmol) were mixed in DMF (4.0 mL) and heated to 80° C. After 2 h, TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature and poured into aqueous hydrochloric acid (1.0 M, 40 mL. The resulting solid was collected by filtration and washed with water, dried and subjected to column chromatography (dichloromethane/methanol 50:1) to afford the desired product (93 mg, 95%). The reaction mixture was cooled to room temperature The resulting solid was collected by filtration washed with water dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product from Example 26.1.2 (100 mg, 0.189 mmol), isothiazolidine 1,1-dioxide (46 mg, 0.378 mmol), copper(I) iodide (4 mg, 0.019 mmol), N,N-dimethylethyl diamine (3 mg, 0.039 mmol) and potassium carbonate (55 mg, 0.378 mmol) were mixed in DMF (4.0 mL) and heated to 80° C. After 2 h, TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature and poured into aqueous hydrochloric acid (1.0 M, 40 mL. The resulting solid was collected by filtration and washed with water, dried and subjected to column chromatography (dichloromethane/methanol 50:1) to afford the desired product (93 mg, 95%). The reaction mixture was cooled to room temperature The resulting solid was collected by filtration washed with water dried