双氢克尿塞(氢氯噻嗪)

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: Treat 6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine with Cs2CO3 and substitute 1,2-dibromoethane for benzylbromoacetate in the procedure of Example 7, step A to obtain 2-(2-bromoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.

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

实验步骤: To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol) in DMF (50 mL) was added cesium carbonate (7.51 g, 23.0 mmol) and ethyl bromoacetate (7.69 g, 46.1 mmol) and the mixture was stirred for 18 hours at room temperature. The solids were removed via suction filtration, and the solvent was evaporated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/ether to give the title product (10.9 g, 61% yield) as white needles: mp 199-203° C.; 1H NMR (400 MHz, d6-DMSO) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.53 (s, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); Mass spectrum (API-TIS) m/z 384 (MH+), 401 (MNH4+), 784 (2MNH430). The solids were removed via suction filtration the solvent was evaporated under vacuum The resulting residue was partitioned between ethyl acetate and water the organic layer was washed with water and brine dried over magnesium sulfate After evaporation of the solvent the residue was recrystallized from ethyl acetate/ether

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

实验步骤: To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol) in DMF (50 mL) was added cesium carbonate (7.51 g, 23.0 mmol) and ethyl bromoacetate (7.69 g, 46.1 mmol) and the mixture was stirred for 18 hours at room temperature. The solids were removed via suction filtration, and the solvent was evaporated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/ether to give the title product (10.9 g, 61% yield) as white needles: mp 199-203° C.; 1H NMR (400 MHz, d6-DMSO) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.53 (s, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); Mass spectrum (API-TIS) m/z 384 (MH+), 401 (MNH4+), 784 (2MNH430). The solids were removed via suction filtration the solvent was evaporated under vacuum The resulting residue was partitioned between ethyl acetate and water the organic layer was washed with water and brine dried over magnesium sulfate After evaporation of the solvent the residue was recrystallized from ethyl acetate/ether

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

实验步骤: To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol) in DMF (50 mL) was added cesium carbonate (7.51 g, 23.0 mmol) and ethyl bromoacetate (7.69 g, 46.1 mmol) and the mixture was stirred for 18 hours at room temperature. The solids were removed via suction filtration, and the solvent was evaporated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/ether to give the title product (10.9 g, 61% yield) as white needles: mp 199-203° C.; 1H NMR (400 MHz, d6-DMSO) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.53 (s, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); Mass spectrum (API-TIS) m/z 384 (MH+), 401 (MNH4+), 784 (2MNH4+). The solids were removed via suction filtration the solvent was evaporated under vacuum The resulting residue was partitioned between ethyl acetate and water the organic layer was washed with water and brine dried over magnesium sulfate After evaporation of the solvent the residue was recrystallized from ethyl acetate/ether

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

实验步骤: To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol) in DMF (50 mL) was added cesium carbonate (7.51 g, 23.0 mmol) and ethyl bromoacetate (7.69 g, 46.1 mmol) and the mixture was stirred for 18 hours at room temperature. The solids were removed via suction filtration, and the solvent was evaporated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/ether to give the title product (10.9 g, 61% yield) as white needles: mp 199-203° C.; 1H NMR (400 MHz, d6-DMSO) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.53 (s, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); Mass spectrum (API-TIS) m/z 384 (MH+), 401 (MNH4+), 784 (2MNH4+). The solids were removed via suction filtration the solvent was evaporated under vacuum The resulting residue was partitioned between ethyl acetate and water the organic layer was washed with water and brine dried over magnesium sulfate After evaporation of the solvent the residue was recrystallized from ethyl acetate/ether

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

实验步骤: Treat 6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine with Cs2CO3 and substitute 1,2-dibromoethane for benzylbromoacetate in the procedure of Example 6, step A to obtain 2-(2-bromoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.

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

实验步骤: Treat 6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine with Cs2CO3 and substitute 1,2-dibromoethane for benzylbromoacetate in the procedure of Example 6, step A to obtain 2-(2-bromoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.

实验步骤: 投料: 12.30 9:40 将原料SM1（25g,84.1mmol,1eq)加入反应瓶中，DMF(150ml)溶解，再加入NCS（14g,105.1mmol,1.25eq)加入完毕升温至100℃反应2h. 11:40 TLC(DCM:MeOH=10:1)监测没有原料点，有较原料大一点的新点生成，停止反应。 LCMS(11775-1-2-2h)监测到产物峰 后处理 待体系冷却至室温，将反应液倒入搅拌的冰水混合物中，有米白色固体析出，过滤，滤饼用水洗涤，收集固体用EA打浆2遍，HPLC(C4X-11775)纯度在85%左右，将粗品（与上一批次总共20g)反相纯化，固体用DMSO（50ml)和甲醇（50ml)溶解，甲醇和水为洗脱剂，（120g柱子每针进样6ml),MeOH=40%出产物保持梯度冲洗大约10min,收集层析液浓缩，最终得11.35g白色固体。

实验步骤: 投料: 12.29 12:30 将原料SM1（5g,16.8mmol,1eq)加入反应瓶中，DMF溶解，再加入NCS（2.81g,21mmol,1.25eq)加入完毕升温至100℃反应2h. 14:30 TLC(DCM:MeOH=10:1)监测没有原料点，有较原料大一点的新点生成，停止反应。 LCMS(11775-1-1-2H)能监测到产物MS 后处理　待体系冷却至室温，将反应液倒入搅拌的冰水混合物中，有米黄色固体析出，过滤，滤饼用水洗涤，再用EA打浆，HPLC（C4X-11775)纯度在85％左右，与放大批次一起纯化。

实验步骤: 投料: 在500ml干燥单口瓶中，向SM1(15g，50.4mmol，1.0eq），加入水（15ml）和·醋酸（75ml），冷却至0℃，加入亚硝酸钠（5.22g，75.6mmol，1.5eq），升至室温搅拌反应2h. 16：00 送样LCMS（117722-TM1-1-2),仍有少量原料未反应完全，发现产物MS，有大量固体（黄色）析出。 16：15 停止反应，抽滤，收集滤饼。 12月4日 9：15 将粗品置于油泵干燥，送样核磁，HPLC（117722-TM1)确认产物，纯度未够（94). 12月5日 16：00 将粗品加入少量异丙醇打浆，异丙醇洗涤滤饼，将滤饼送样HPLC（117722-TM1-FD),纯度大于95。

实验步骤: 投料: 在100ml干燥单口瓶中，向SM1(500mg，1.7mmol，1.0eq），加入水（0.5ml）和·醋酸（2.5ml），冷却至0℃，加入亚硝酸钠（176mg，2.55mmol，1.5eq），升至室温搅拌反应2h. 13：00 送样LCMS（117722-TM1-1-1),仍有少量原料未反应完全，发现产物MS，有大量固体（黄色）析出。 16：00 停止反应，抽滤，收集滤饼，送样核磁，HPLC（117722-TM1-1-1)确认产物，纯度未够（92). 12月4日 12：15 将粗品加入少量异丙醚打浆，异丙醚洗涤滤饼，将滤饼送样HPLC和核磁（117722-TM1-CL)，纯度未发生变化。 12月5日 10：45 将粗品加入少量异丙醇打浆，异丙醇洗涤滤饼。 11：30 将滤饼送样HPLC（117722-TM1-YBC),纯度大于95。 12月6日 入库13.55g。