盐酸卡替洛尔EP杂质 C

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

实验步骤: Ethyl 4-piperidylcarbamate (2 g), from Preparation 4, and 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (2.54 g), from Preparation 5, were dissolved in ethanol (50 mL) and the resulting solution was heated under reflux for 6 hours and then cooled to room temperature. Concentrated hydrochloric acid (1 mL) was added. A white product precipitated, which was collected by filtration. The crude product was recrystallized from ethanol to yield 2.8 g (56.5%) of 3,4-dihydro-5-[2-hydroxy-3-(4-(ethoxycarbonylamino)-1-piperidyl)propoxy]carbostyril hydrochloride, m.p. 232°-234° C. (dec.). from Preparation 5 the resulting solution was heated under reflux for 6 hours A white product precipitated which was collected by filtration The crude product was recrystallized from ethanol

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

实验步骤: Prepared analogous to Example 133 from 5-(2,3-epoxy-propoxy)-3,4-dihydro-carbostyril (m.p. 171°-173° C.) and tert. butyl mercaptan.

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

实验步骤: Prepared analogous to Example 59 from 5-(2,3-epoxy-propoxy)-3,4-dihydro-carbostyril and thiophenol.

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

实验步骤: 3.1 g of 6-[4-(2-amino-2-methylpropylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone obtained in Example 1, (3) and 2.2 g of 1-(3,4-dihydrocarbostyril-5-yloxy)-2,3-epoxypropane were dissolved in 30 ml of isopropyl alcohol and heated with stirring for 20 hours. After the end of the reaction, the reaction solution was concentrated under reduced pressure. The residue was separated by silica gel chromatography (chloroform-methanol=10:1). Recrystallization from dichloro-methane-isopropanol gave 2.4 g of 6-[4-[2-[3-(3,4-di hydrocarbostyril-5-yloxy)2-hydroxypropylamino]-2-methyl-propylamino]phenyl]-4,5-dihydro-3(2H)-pyridazinone. heated After the end of the reaction the reaction solution was concentrated under reduced pressure The residue was separated by silica gel chromatography (chloroform-methanol=10:1) Recrystallization from dichloro-methane-isopropanol

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

实验步骤: 4.4 grams of 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 3.4 g of 4-phenylpiperazine are dispersed in 60 ml of methanol and reacted at 50°-60° C. for 3 hours. After the reaction is completed, the reaction mixture is concentrated under a reduced pressure. To the residue thus obtained are added 5 ml of concentrated hydrochloric acid and 30 ml of ethanol to dissolve the residue uniformly and further 200 ml of acetone are added. The crystals precipitated are collected by filtration and dried. Recrystallization from water to obtain 6.5 g of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydro carbostyril monohydrochloride in the form of colorless needle-like crystals with a melting point of 239°-241° C. reacted at 50°-60° C. for 3 hours the reaction mixture is concentrated under a reduced pressure To the residue thus obtained to dissolve the residue uniformly The crystals precipitated are collected by filtration dried Recrystallization from water

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

实验步骤: 4.4 Grams of 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 3.4 g of 4-phenylpiperazine are dispersed in 60 ml of methanol and reacted at 50°-60° C. for 3 hours. After the reaction is completed, the reaction mixture is concentrated under a reduced pressure. To the residue thus obtained are added 5 ml of concentrated hydrochloric acid and 30 ml of ethanol to dissolve the residue uniformly and further 200 ml of acetone are added. The crystals precipitated are collected by filtration and dried. Recrystallization from water obtains 6.5 g of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril monohydrochloride in the form of colorless needle-like crystals with a melting point of 239°-241° C. reacted at 50°-60° C. for 3 hours the reaction mixture is concentrated under a reduced pressure To the residue thus obtained to dissolve the residue uniformly The crystals precipitated are collected by filtration dried Recrystallization from water

实验步骤: 投料: 在单口瓶中加入1.58g SM、30ml THF搅拌分散，配制稀硫酸用5ml H2O在冰浴下滴加入浓硫酸7滴，溶解均匀后取3ml 加入冰浴下的反应体系，后再补加2ml 纯水转至油浴中升温至45℃搅拌反应过夜，白色固体逐渐溶解。\n监测: LCMS（228713-2-3-R）监测反应已完全，停止反应。\n纯化: 粗品拌样后经硅胶柱层析纯化，流动相为DCM：MeOH，当MeOH=7%时过出产品点，收集浓缩得到0.8100g白色粉末。\n后处理: 向反应体系中滴加饱和NaHCO3水溶液，调节pH至6~7，随后旋干，用DCM溶解加入硅胶粉拌样。

实验步骤: 投料: 样品瓶中加入5ml THF、219mg SM（1mmol），冰浴下搅拌分散，后配制1ml 稀硫酸（1滴浓硫酸+1ml H2O）滴入反应体系使其pH=2~3，pH达标后反应液补足1ml H2O。5min后撤去冰浴，在室温下反应过夜。\n监测: LCMS（228713-2-1-R-2）监测未反应完全，且疑似有个小包杂质峰。 6-20 12:00: 228713反应液再分成两份（各3ml），①号补加5滴先前配制的稀硫酸，升温至45℃，②号不补加，升温至50℃。 6-20 14:30: 对两者不同条件进行观察，发现①号仍未浑浊液，②号已溶清，点板监测两者反应进程差不多。 6-21 17:00: LCMS2（228713-2-1）、（228713-2-2-50）为228713的①②号条件，已确定①号反应完全，②号未反应完全，①号送检HPLC（228713-2-1-R）确定无重叠的杂质峰，反应最佳为①号条件。

实验步骤: 投料: 在100ml 单口瓶中加入1.63g SM1，加入2.3ml DMF后溶解部分再加入3.6ml H2O，原料吸水后结块，再滴加1.85g SM2，搅拌分散5min，配制1ml 含0.8g NaOH的水溶液，缓慢滴加入反应体系，固体逐渐溶解，室温搅拌反应。 06-16 11:05: 反应液在搅拌中逐渐析出固体。\n监测: LCMS2（228718-1-1-R）监测有产物MS为主峰，原料还剩5-10%，TLC点板监测原料Rf=0.45，产物Rf=0.65，有少量杂质在原料点附近。\n后处理: 过滤反应液再用H2O洗涤滤饼3次，点板水相大部分为杂质和原料，固体基本为产物，直接投下一步。

实验步骤: 投料: 在100ml 单口瓶中称量2.20g SM，加入40ml无水甲醇在冰浴中搅拌分散后再倒入1.08g MeONa，转至油浴中升温至45℃搅拌反应过夜。\n监测: LCMS（228718-2-4-R）监测反应已完全，停止反应。\n纯化: 粗品直接拌样经硅胶柱层析纯化，流动相为DCM:MeOH，当MeOH=5%时过出产品点，收集得到2.3325g白色固体。

实验步骤: 投料: 在样品瓶中称量219mg SM（1mmol），加入5ml MeOH在冰浴下搅拌冷却15min，随后分别加入（0.1eq）氯化铁，搅拌反应过夜。\n监测: LCMS（228718-2-3-R-2）监测显示③号条件未反应完全，但反应体系较为干净，升温至45℃搅拌过夜后再观察。 06-21 17:00: LCMS2（228713-2-3）实际上为该228718的③号条件，监测反应仍未反应完全，停止反应。

实验步骤: 投料: 在样品瓶中称量219mg SM（1mmol），加入5ml MeOH在冰浴下搅拌冷却15min，随后分别加入（2eq）MeONa，搅拌反应过夜。\n监测: LCMS（228718-2-2-R-2）监测显示②号条件未反应完全，但反应体系较为干净，升温至45℃搅拌过夜后再观察。 06-21 17:00: LCMS2（228713-2-2）实际上为该228718的②号条件，监测反应已完全，送检HPLC确定无①号条件的杂质峰，效果最佳为②号条件。