1,2,3,4,4a,5,7,7a-octahydrothieno[3,4-b]pyrazine 6,6-dioxide

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

Procedure: This example illustrates the preparation of a typical diol of this invention using a reactive, watersoluble epoxide. (Water soluble epoxides have at most four carbon atoms). 2.5 ml. (0.05 mole) of ethylene oxide was condensed into a reaction flask and dissolved in 5 ml. of water. To this solution was added gradually at room temperature, a solution of 3.5 g. (0.02 mole) in 5 ml. of water of 1,2,3,4,4a,5,7,7a-octahydrothieno[3,4-b]pyrazine 6,6-dioxide, the diamine of Example 1. After the reaction was complete, the reaction mixture was allowed to cool to room temperature and the waterr and excess epoxide were removed under vacuum, leaving a white solid. Trituration with toluene gave a product, 1,2,3,4,4a,5,7,7a-octahydrothieno[3,4-b]pyrazine 1,4-diethanol 6,6-dioxide, M.P. 145°-147°C. IR spectrum showed bands at 3300 cm-1, broad (OH) at 1285 cm-1 and 1125 cm-1 (SO2) and at 1010 cm-1 (CO). condensed into a reaction flask dissolved in 5 ml To this solution was added gradually at room temperature the waterr and excess epoxide were removed under vacuum leaving a white solid

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Xylene (150 mL) was added to 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.73 g, 4.15 mmol; Intermediate 34), Pd2(dba)3 (0.08 g, 0.87 mmol), Xantphos (0.20 g, 0.35 mmol) and Cs2CO3 (1.59 g, 4.84 mmol). The resulting mixture was stirred at 120° C. overnight, filtered through Celite and the solvent was removed in vacuo. The crude product was purified by flash chromatography [eluent: DCM and DCM:MeOH (1:1)] and then recrystallized from MeOH to afford 0.354 g (8%) of the title product. HPLC 90%, RT: 1.390 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, CDCl3) δ ppm 2.85 (dd, J=12.62, 7.42 Hz, 1H) 3.16-3.49 (m, 6H) 3.71 (t, J=11.63 Hz, 1H) 4.02-4.05 (m, 1H) 5.17-5.25 (m, 1H) 6.93 (d, J=2.23 Hz, 1H) 7.62 (t, J=2.72 Hz, 1H) 7.77 (d, J=1.98 Hz, 1H) 8.19 (d, J=1.98 Hz, 1H). LC-MS 338 (M+H)+. filtered through Celite the solvent was removed in vacuo The crude product was purified by flash chromatography [eluent: DCM and DCM:MeOH (1:1)] recrystallized from MeOH

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

Procedure: cis-3,4-Dichlorotetrahydrothiophene 1,1-dioxide (5.0 g, 26.0 mmol) in dioxane (40 mL) was added dropwise to ethane-1,2-diamine (10.4 g, 173.0 mmol) in dioxane (25 mL) at 0° C. The mixture was heated at 100° C. for 3 h, followed by cooling to room temperature and continued stirring overnight. The two layers were separated and the bottom layer, containing ethylene diamine and amine salt, was washed twice with dioxane. The dioxane layers were combined and the solvent was removed in vacuo. The crude product was recrystallized from toluene to afford 2.7 g (59%) of the title compound as white crystals. HPLC 98%, RT: 0.292 (System B; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 2.67-2.76 (m, 2H) 2.86-2.96 (m, 2H) 3.13-3.20 (m, 2H) 3.33-3.44 (m, 2H) 3.63-3.70 (m, 2H). LC-MS 177 (M+H)+. *Previously described in U.S. Pat. No. 3,882,122. by cooling to room temperature The two layers were separated the bottom layer, containing ethylene diamine and amine salt was washed twice with dioxane the solvent was removed in vacuo The crude product was recrystallized from toluene