苯海拉明

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

实验步骤: A 500 ml round bottom flask equipped with a stirrer, thermometer and heating mantle was set up. The flask was charged with 176 g of a 10% aqueous sodium hydroxide solution. Thereafter, 118 g (0.40 mole) diphenhydramine hydrochloride was slowly added, with stirring, to the flask at room temperature. The reaction mixture was then stirred for 30 minutes at 45–50° C. The reaction mixture was allowed to settle for 15 minutes and the organic layer was separated (the pH of the layer was 12.8). The organic layer consisting of the diphenhydramine free base was washed by mixing it with 100 ml of purified water and maintaining a temperature of 70–75° C. for one hour, while stirring. Stirring was then discontinued and the phases were allowed to split over a period of one hour. The lower organic layer consisting of the diphenhydramine free base was then separated. The yield of the free base was found to be 104 g (about 99% of theory) and it had a moisture content of 2.18% as determined by Karl. Fischer (K. F.) analysis. A 500 ml round bottom flask equipped with a stirrer thermometer and heating mantle The reaction mixture was then stirred for 30 minutes at 45–50° C the organic layer was separated (the pH of the layer was washed by mixing it with 100 ml of purified water maintaining a temperature of 70–75° C. for one hour while stirring Stirring to split over a period of one hour was then separated

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

实验步骤: A 500 ml round bottom flask equipped with a stirrer, thermometer and heating mantle was set up. The flask was charged with 176 g of a 10% aqueous sodium hydroxide solution. Thereafter, 118 g (0.40 mole) diphenhydramine hydrochloride was slowly added, with stirring, to the flask at room temperature. The reaction mixture was then stirred for 30 minutes at 45–50° C. The reaction mixture was allowed to settle for 15 minutes and the organic layer was separated (the pH of the layer was 12.8). The organic layer consisting of the diphenhydramine free base was washed by mixing it with 100 ml of purified water and maintaining a temperature of 70–75° C. for one hour, while stirring. Stirring was then discontinued and the phases were allowed to split over a period of one hour. The lower organic layer consisting of the diphenhydramine free base was then separated. The yield of the free base was found to be 104 g (about 99% of theory) and it had a moisture content of 2.18% as determined by Karl. Fischer (K. F.) analysis. A 500 ml round bottom flask equipped with a stirrer thermometer and heating mantle The reaction mixture was then stirred for 30 minutes at 45–50° C the organic layer was separated (the pH of the layer was washed by mixing it with 100 ml of purified water maintaining a temperature of 70–75° C. for one hour while stirring Stirring to split over a period of one hour was then separated

实验步骤: 投料: 将M-C4X-14246-SM1(12g 41.12mmol 1eq)溶于DCM（120ml）中搅拌（体系溶清无色透明），降温加入m-CPBA（25.04g 123.36mmol 3eq）,加完，升至室温搅拌 监测：LCMS(取样加甲醇稀释)(14246-2-FD-FY)反应完全。 后处理：抽滤，滤液（LCMS:14246-2-CL-LY）,减压浓缩得淡黄色固体，将反应液用甲醇溶解，加入氢氧化钠水溶液调至碱性（PH=10~11）。 纯化：将产物经过反相（MEOH:H2O=1:1,50%，0.1%TEA)纯化，减压浓缩得9.5g棕色油状物。油状物经过(MTBE)打浆，抽滤得到白色固体4.3g。

实验步骤: 投料: 将M-C4X-14246-SM1(10g 34.27mmol 1eq)溶于DCM（100ml）中搅拌（体系溶清无色透明），降温加入m-CPBA（10.44g 51.4mmol 1.5eq）,加完，升至室温搅拌 监测：LCMS(取样加甲醇稀释)(14246-FD-FY-1)反应完全。 后处理：抽滤，滤液（LCMS:14246-CL-LY）,减压浓缩得淡黄色固体，将反应液用甲醇溶解，加入氢氧化钠水溶液调至中性。 纯化：将产物经过反相（H2O:ACN =75%:25%）纯化，减压浓缩得产品。产品经过氢氧化钠水溶液调至碱性（PH=10~11),经过反相（MEOH:H2O=1:1,50%)纯化，减压浓缩得2g棕色油状物，油状物经过甲基叔丁基醚（1ml)打浆，抽滤，冻干得到480mg白色固体。

实验步骤: 投料: 将M-C4X-14246-SM1(0.5g 1.71mmol 1eq)溶于DCM（5ml）中搅拌（体系溶清无色透明），降温加入m-CPBA（0.6g 2.57mmol 1.5eq）,加完，升至室温搅拌 监测：LCMS(取样加甲醇稀释)(14246-XS-FY)反应完全。 后处理：加水淬灭，分液一次，DCM萃取两次，合并有机相，用碳酸钠水溶液淬洗两次，调至PH至碱性，无水硫酸钠干燥，减压浓缩得淡黄色油状物

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

实验步骤: Another typical combination composition was formulated as follows. Diphenhydramine hydrochloride 58 g (0.2 mole) was dissolved in water 100 ml, and 5N NaOH 40 ml (0.2 mole) was added slowly with stirring. Diphenhydramine free base was formed as oily white precipitates. Without isolation of the free base, N-acetyl-L-proline 48 g (0.3 mole) and N-acetyl-D-glucosamine 44 g (0.2 mole) were added with stirring into the oily mixture, and the mixture became a clear solution. Propylene glycol 100 ml and water 50 ml were added to make total volume 400 ml (444 g). This formulation contained diphenhydramine 14.5%, N-acetyl-L-proline 12% and N-acetyl-D-glucosamine 11% in a propylene glycol/water solution. The above formulation 22 g and tribenzyl citrate 10 g were mixed with hydrophilic ointment or oil-in-water cream 68 g. The composition thus prepared had pH 3.8 and contained 10% tri-benzyl citrate, 3% diphenhydramine, 2.6% N-acetyl-L-proline and 2.4% N-acetyl-D-glucosamine in a water-washable cream.

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

实验步骤: Another typical combination composition was formulated as follows. Diphenhydramine hydrochloride 58 g (0.2 mole) was dissolved in water 100 ml, and 5N NaOH 40 ml (0.2 mole) was added slowly with stirring. Diphenhydramine free base was formed as oily white precipitates. Without isolation of the free base, N-acetyl-L-proline 48 g (0.3 mole) and N-acetyl-D-glucosamine 44 g (0.2 mole) were added with stirring into the oily mixture, and the mixture became a clear solution. Propylene glycol 100 ml and water 50 ml were added to make total volume 400 ml (444 g). This formulation contained diphenhydramine 14.5%, N-acetyl-L-proline 12% and N-acetyl-D-glucosamine 11% in a propylene glycol/water solution. The above formulation 22 g and tribenzyl citrate 10 g were mixed with hydrophilic ointment or oil-in-water cream 68 g. The composition thus prepared had pH 3.8 and contained 10% tri-benzyl citrate, 3% diphenhydramine, 2.6% N-acetyl-L-proline and 2.4% N-acetyl-D-glucosamine in a water-washable cream.

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

实验步骤: A 500 ml round bottom flask equipped with a stirrer, thermometer and heating mantle was set up. The flask was charged with 176 g of a 10% aqueous sodium hydroxide solution. Thereafter, 118 g (0.40 mole) diphenhydramine hydrochloride was slowly added, with stirring, to the flask at room temperature. The reaction mixture was then stirred for 30 minutes at 45–50° C. The reaction mixture was allowed to settle for 15 minutes and the organic layer was separated (the pH of the layer was 12.8). The organic layer consisting of the diphenhydramine free base was washed by mixing it with 100 ml of purified water and maintaining a temperature of 70–75° C. for one hour, while stirring. Stirring was then discontinued and the phases were allowed to split over a period of one hour. The lower organic layer consisting of the diphenhydramine free base was then separated. The yield of the free base was found to be 104 g (about 99% of theory) and it had a moisture content of 2.18% as determined by Karl. Fischer (K. F.) analysis. A 500 ml round bottom flask equipped with a stirrer thermometer and heating mantle The reaction mixture was then stirred for 30 minutes at 45–50° C the organic layer was separated (the pH of the layer was washed by mixing it with 100 ml of purified water maintaining a temperature of 70–75° C. for one hour while stirring Stirring to split over a period of one hour was then separated