莫沙必利

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

实验步骤: 投料: 平行两份称取2.50g莫沙比利（1.0eq,5.92mmol)，加入11ml DCM（白浑），搅拌后冰浴再加入7.93ml 30%双氧水（白色奶油物），5min后撤冰浴，再加入1.7ml 甲酸，室温搅拌反应,溶液变黄。\n监测: TLC监测（DCM:MeOH=10:1），剩余少量原料未消耗完。 14:30 TLC监测（DCM:MeOH=10:1），原料消耗完。\n纯化: 加饱和碳酸氢钠调节PH后，加水、DCM萃（很黏，会粘壁），点板监测至水相无产物点，收集有机相旋干得橙色粗品约6g。 11/19 转交制备（燕云） 11/26 取样+水 LCMS（M-C4X-10441），为产物信号。 取样+水 HPLC（M-C4X-10441），纯度为97.8%。 取样+DMSO HNMR（M-C4X-10441）,与标谱一致。 送检KF：7%，上油泵继续拉。 11/29 送检KF：3.1255%。 入库1.6g。

实验步骤: 投料: 称取2.30g莫沙比利（1.0eq,5.45mmol)，加入5.45ml DCM（白浑），搅拌后冰浴再加入5.45ml 30%双氧水（白色奶油物），5min后撤冰浴，再加入1.1ml 甲酸，室温搅拌反应。类奶油物搅拌困难，再加5ml DCM，冰浴再加入2ml 30%双氧水、0.5ml 甲酸，继续搅拌，溶液变黄。\n监测: TLC监测（DCM:MeOH=10:1），原料未消耗完。 14:30 TLC监测（DCM:MeOH=10:1），原料消耗完。\n纯化: 加水、DCM萃（黄色泡沫状物，难以分层），加入饱和碳酸氢钠调节酸性后有利于分层，且有机相仍能萃取出目标产物，收集有机相旋干得橙色粗品约2.0g。 16:00 取197mg +0.5ml 水+0.1ml 甲醇溶解，过反相（213nm、274nm收集）乙腈-水 0%--10min；0%-20%--10min；20%-50%--10min。 换成甲醇--水走同样梯度也不行。 11/8 转交制备（燕云） 11/14 取样+水LCMS（C4X-10441-1-3），为产物信号。 取样+水 HPLC（C4X-10441-1-3），纯度为96.5%。 取样+DMSO HNMR（C4X-10441-1-3）,与标谱一致。 定量（三甲氧基苯），内标不合适。 11/15 定量（碳酸乙烯酯），内标不合适 送检TGA+残渣,10%。 11/18 挂冻干。 11/22 送检TGA+残渣,9%。 11/25 上油泵拉 11/26 送检KF：4%，上油泵继续拉。 11/28 送检KF：3.5468% 入库695mg。

实验步骤: 投料: 称取2.0g莫沙比利（1.0eq,4.74mmol)，加入4.74ml DCM（白浑），搅拌后冰浴再加入4.74ml 30%双氧水（白色奶油物），5min后撤冰浴，再加入0.95ml 甲酸，室温搅拌反应。类奶油物搅拌困难，再加5ml DCM仍搅不清，补加0.5ml 甲酸，黄色加深，继续搅拌，但仍有类奶油物。\n监测: TLC监测（DCM:MeOH=10:1），原料未消耗完。 14:00 TLC监测（DCM:MeOH=10:1），原料未消耗完。 14:20 补加2ml 30%双氧水 15:20 TLC监测（DCM:MeOH=10:1），原料基本消耗完。 \n纯化: 加水、DCM萃取，点板监测至水相无产物点，收集有机相旋干。 17:00 取样加甲醇LCMS监测(C4X-10441-1-2)，有目标产物分子量信号。 10/25 9:50 过柱（先DCM：MeOH=15:1冲至出现产物点后换DCM：MeOH=10:1，冲了较长一段时间发现产物点很淡换DCM：MeOH=5:1），收集含纯产物点的液体，旋干得产物。10:1（200mg）、5:1（80mg）。 17:30 取样加DMSO HNMR监测(C4X-10441-1-2-C)(10:1)，与标谱基本一致，怀疑核磁管不纯。 10/28 10:45取样加DMSO HNMR监测(C4X-10441-1-2-2)(5:1)，体系较杂。 14:10 取样加DMSO HNMR监测(C4X-10441-1-2-3)(10:1)，与标谱基本一致，与上次打谱一致，经过分析为多了DCM带入的杂峰。 10/29 取样加甲醇HPLC监测(C4X-10441-1-2)，纯度为97.8% 10/30 取20mg样品加甲基叔丁基醚打浆，吹干后取样加DMSO HNMR监测(C4X-10441-MTBE)，杂峰仍无法消除。

实验步骤: 投料: 称取211.4mg莫沙比利（1.0eq,0.5mmol)，加入0.5ml DCM，搅拌后冰浴再加入0.5ml 30%双氧水，2min后撤冰浴，室温反应。 12:00 补加0.5ml DCM搅拌。 13:50 补加0.5ml 30%双氧水搅拌。 16:40 转至50度反应。 17:05 补加1ml DCM搅拌。 17:25 补加1ml DCM搅拌，室温过夜。 10/15 17:26 补加0.2ml甲酸，室温继续搅拌，溶液变黄。\n监测: 取样加甲醇LCMS监测(C4X-10441-4)，有目标产物分子量信号。 TLC监测（DCM:MeOH=20:1），原料消耗完。\n纯化: 加水、DCM萃取，收集有机相旋干。 15:55 取样加甲醇LCMS监测(C4X-10441-5)，有目标产物分子量信号。 10/16 刮大板（DCM:MeOH=15:1），加DCM和适量MeOH溶解刮下来得硅胶，有三个色带，分别 取样加甲醇LCMS监测(C4X-10441-1-D1)，为峰杂，很少产物信号。 取样加甲醇LCMS监测(C4X-10441-1-D2)，有产物信号。 取样加甲醇LCMS监测(C4X-10441-1-D3)，有产物信号。 10/17 9:30 取D2、D3滤上清液后旋干有机相。 取样加DMSO HNMR监测(C4X-10441-1-1-D2）、(C4X-10441-1-1-D3），基本相同，与标谱基本相符，留样待放大。\n投料: 称取211.4mg莫沙比利（1.0eq,0.5mmol)，加入1ml DCM（白浑），搅拌后再加入173mg m-CPBA（2.0eq,1.0mmol)，室温反应。 17:00 补加1.5ml DCM搅拌。 10/22 m-CPBA（含量85%）故需补加，同时补加0.5eq，共补加80mg。\n监测: TLC监测（DCM:MeOH=10:1），原料未消耗完。 14:00 （1）取上述体系1ml，加入甲酸0.2ml，室温搅拌反应。 （2）取上述体系1ml，加入DMF 0.2ml，升温至50度搅拌反应。 （3）称取211.4mg莫沙比利（1.0eq,0.5mol)，加入1ml 乙酸，搅拌后冰浴再加入0.3ml 30%双氧水，2min后撤冰浴，室温反应。 10/23 9:00 TLC监测（DCM:MeOH=10:1），原料未消耗完。 10:00 (2)升温至80度搅拌反应。 10/24 9:00 TLC监测（DCM:MeOH=10:1），原仍未消耗完。

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Stannous chloride dihydrate (5.4 g) is added to a stirred mixture of 5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-4-nitrobenzamide (2.2 g), ethanol (30 ml), and ethyl acetate (30 ml). The reaction mixture is stirred at 70° C. for 2 hours and concentrated. The residue is basified with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is recrystallized from ethanol to give the title compound (1.1 g), mp 151°-153° C. concentrated extracted with ethyl acetate The organic layer is washed successively with water and saturated aqueous sodium chloride solution dried over magnesium sulfate evaporated The residue is recrystallized from ethanol

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

实验步骤: A mixture of 4-acetylamino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (2.0 g) and 10% hydrochloric acid (40 ml) is refluxed with stirring for 1 hour and cooled. The reaction mixture is neutralized with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is dried over magnesium sulfate and evaporated. The residue is recrystallized from ethanol to give the title compound (1.4 g), mp 151°-153° C. is refluxed cooled extracted with chloroform The organic layer is dried over magnesium sulfate evaporated The residue is recrystallized from ethanol

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred suspension of 4-amino-5-chloro-2-ethoxybenzoic acid (2.9 g) in dichloromethane (50 ml), triethylamine (1.6 g) is added at 25° C. The resulting mixture is cooled to -10° C., and isobutyl chloroformate (2.0 g) is added slowly. After the mixture is stirred at the same temperature for 1 hour, a solution of 2-aminomethyl-4-(4-fluorobenzyl)morpholine (3.0 g) in dichloromethane (10 ml) is added. The reaction mixture is stirred for 1 hour at a temperature of between -10° C. and -5° C. and then at 25° C. overnight. The mixture is washed successively with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recyrstallized from ethanol to give the title compound (4.1 g), mp 151°-153° C. is added at 25° C The reaction mixture is stirred for 1 hour at a temperature of between -10° C. and -5° C. at 25° C. overnight The mixture is washed successively with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution dried over magnesium sulfate evaporated under reduced pressure

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-aminomethyl-4-(4-fluorobenzyl)morpholine (2.5 g) in dichloromethane (50 ml), 4-amino-5-chloro-2-ethoxybenzoic acid (2.7 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 g) are added, and the mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title compound (3.0 g), mp 151°-153° C. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution dried over magnesium sulfate evaporated under reduced pressure The residue is recrystallized from ethanol