雷尼替丁杂质25

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

实验步骤: (3) Hill and Barbaro, Experiments in Organic Chemistry. Contemporary Publishing Co. of Raleigh, Inc., Raleigh, 1996. 5 g of sodium hydroxide, dissolved in 25 ml of water and 25 ml of 95% ethanol, was cooled to 20 to 25° C. 2.9 g (50 mmol) of acetone and 10.6 g (100 mmol) of benzaldehyde were added, and a yellow precipitate formed. After 20 minutes the solution was filtered, and the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets: mp 111.9-112.5° C. (lit. mp 112° C., Hill and Barbaro, supra). 1H NMR (250 MHz) δ 7.79-7.73 (d, 1 H), 7.65-7.61 (m, 4 H), 7.44-7.41 (t, 6 H), 7.13-7.07 (d, 1 H) ppm. a yellow precipitate formed After 20 minutes the solution was filtered the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets

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

实验步骤: (3) Hill and Barbaro, Experiments in Organic Chemistry. Contemporary Publishing Co. of Raleigh, Inc., Raleigh, 1996. 5 g of sodium hydroxide, dissolved in 25 ml of water and 25 ml of 95% ethanol, was cooled to 20 to 25° C. 2.9 g (50 mmol) of acetone and 10.6 g (100 mmol) of benzaldehyde were added, and a yellow precipitate formed. After 20 minutes the solution was filtered, and the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets: mp 111.9-112.5° C. (lit. mp 112° C., Hill and Barbaro, supra). 1H NMR (250 MHz) δ 7.79-7.73 (d, 1 H), 7.65-7.61 (m, 4 H), 7.44-7.41 (t, 6 H), 7.13-7.07 (d, 1 H) ppm. a yellow precipitate formed After 20 minutes the solution was filtered the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets

反应条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 400 mg of 4-iodophenylacetic acid, 273 mg of 4-azabenzimidazole, 17.9 mg of trans,trans-dibenzylideneacetone, 303 mg of 1,10-phenanthroline, 19.2 mg of copper (I) trifluoromethanesulfonate benzene complex and 547 mg of Cs2CO3 in 1.5 ml of xylene is stirred for 80 hours at 125° C. The mixture obtained is allowed to cool to rt and concentrated in vacuo. The concentration residue obtained is dissolved in aqueous 1N NaOH solution and extracted with EtOAc. To the aqueous layer aqueous 1N HCl is added in order to obtain an acidic pH and the mixture obtained is extracted with CH2Cl2. The organic phase obtained is dried (Na2SO4), filtered and concentrated. The concentration residue obtained is subjected to reversed phase MPLC(CH3CN/H2O/TFA). (4-Imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid is obtained. The mixture obtained to cool to rt concentrated in vacuo The concentration residue obtained extracted with EtOAc To the aqueous layer aqueous 1N HCl is added in order to obtain an acidic pH the mixture obtained is extracted with CH2Cl2 The organic phase obtained is dried (Na2SO4) filtered concentrated The concentration residue obtained

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

实验步骤: (3) Hill and Barbaro, Experiments in Organic Chemistry. Contemporary Publishing Co. of Raleigh, Inc., Raleigh, 1996. 5 g of sodium hydroxide, dissolved in 25 ml of water and 25 ml of 95% ethanol, was cooled to 20 to 25° C. 2.9 g (50 mmol) of acetone and 10.6 g (100 mmol) of benzaldehyde were added, and a yellow precipitate formed. After 20 minutes the solution was filtered, and the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets: mp 111.9-112.5° C. (lit. mp 112° C., Hill and Barbaro, supra). 1H NMR (250 MHz) δ 7.79-7.73 (d, 1H), 7.65-7.61 (m, 4H), 7.44-7.41 (t, 6H), 7.13-7.07 (d, 1H) ppm. a yellow precipitate formed After 20 minutes the solution was filtered the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets

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

实验步骤: A solution of aq. NaOH solution (2 N, 125 mL) in EtOH (250 mL) was added to a mixture of benzaldehyde (26.5 g, 25 mmol) in acetone (9.2 mL, 13 mmol). The reaction mixture was stirred for 4 h at ambient temperature and the resulting yellow precipitate was filtered, washed with H2O, recrystallized from EtOAc and dried in vacuo to obtain NW275 as a yellow solid (23.1 g, 79%). mp: 106-107° C. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.78 (d, 3J=16.0 Hz, 2H, Hvin), 7.66-7.64 (m, 4H, HAr), 7.46-7.44 (m, 6H, HAr), 7.12 (d, 3J=16.0 Hz, 2H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 189.3 (C), 143.7 (CH), 135.2 (C), 130.9 (CH), 129.4 (CH), 128.8 (CH), 125.8 (CH). MS (EI) m/z: 234.2 (M+). Anal. calcd for C17H14O: C, 87.15; H, 6.02. Found: C, 87.03; H, 6.03%. the resulting yellow precipitate was filtered washed with H2O recrystallized from EtOAc dried in vacuo

实验步骤: 投料: 在250ml 三口瓶中加入1.57g SM1、60ml 甲苯搅拌溶解，加入1.90g（1.1eq）SM2、101mg（0.02eq）(DBA)3Pd2、124mg（0.04eq）DPPF、2.63g（5.10eq）t-BuONa、27mg（0.03eq）KI，随后置换N2，在N2保护下升温至105℃搅拌反应2.5h。\n监测: LCMS（293733-P4-2-1-R-1h）监测原料SM1: 产物=1: 9，继续反应。 06-11 13:30: LCMS（293733-P4-2-1-R-2.5h）监测原料占5%左右，体系杂质开始有增多的迹象，停止反应。\n后处理: 反应液直接过滤，用甲苯洗涤滤饼数次，抽干后刮下固体，母液送检LCMS（293733-P4-2-1-work-MY）确认杂质占大部分，固体用H2O、DCM萃取，点板确定水相无产物后收集有机相浓缩，分别送检LCMS（293733-P4-2-1-work-O, 293733-P4-2-1-work-W）确认有机相只有产物单峰，体系干净无杂质，到手2.0g红色固体直接投下一步。 06-12 12:00: 送检HNMR(CDCl3): 293733-P4-2-C。

实验步骤: 投料: 取500ml三口瓶，加入C4X-293715-SM1（9.8g 1eq）和甲苯（200ml），氮气置换，室温下加入C4X-293715-SM2（7.55g 2eq）、（DBA）3Pd2 （0.37g 0.02eq）、DPPF（0.45g 0.04eq）、叔丁醇钠（4.69g）、碘化钾（0.10g 0.03eq），添加完毕后，氮气置换，升至105℃下搅拌过夜 LCMS监测（293715-s1-2-n），结果显示，10%左右收率 后处理：反应液冷却至室温，加入水和乙酸乙酯萃取，取有机相，水相再用DCM萃取一次，水相TLC确认无产物。合并有机相并用无水硫酸钠干燥，抽滤，滤液减压浓缩得到棕黑色油状物，待用

实验步骤: 投料: 取500ml三口瓶，加入C4X-293715-SM1（4.3g 1eq）和甲苯（200ml），氮气置换，室温下加入C4X-293715-SM2（7.55g 2eq）、（DBA）3Pd2 （0.37g 0.02eq）、DPPF（0.45g 0.04eq）、叔丁醇钠（4.69g）、碘化钾（0.10g 0.03eq），添加完毕后，氮气置换，升至105℃下搅拌过夜 LCMS监测（293715-s1-2-n），结果显示，原料反应完全，几乎全为接一个的中间体 后处理：反应液冷却至室温，加入水和乙酸乙酯萃取，取有机相，水相再用DCM萃取一次，水相TLC确认无产物。合并有机相并用无水硫酸钠干燥，抽滤，滤液减压浓缩得到棕黑色油状物，粗品直接用于下一步

实验步骤: 投料: 取500ml三口瓶，加入C4X-293715-SM1和二氧六环（5ml），氮气置换，室温下加入C4X-293715-SM2、（DBA）3Pd2 、BINAP、DIPEA，添加完毕后，氮气置换，升至105℃下搅拌过夜 LCMS监测（293715-s1-dba-n），结果显示，无反应

实验步骤: 投料: 取500ml三口瓶，加入C4X-293715-SM1（3.4g 1eq）和甲苯（200ml），氮气置换，室温下加入C4X-293715-SM2（10g 2eq）、（DBA）3Pd2 （0.27g 0.02eq）、DPPF（0.34g 0.04eq）、叔丁醇钠（3.7g 2.5eq）、碘化钾（0.08g 0.03eq），添加完毕后，氮气置换，升至105℃下搅拌过夜 LCMS监测（293715-s1-n），结果显示，原料反应完全，有产物ms生成，大部分是接一个的，10%收率 后处理：反应液冷却至室温，加入水和乙酸乙酯萃取，取有机相，水相再用DCM萃取一次，水相TLC确认无产物。合并有机相并用无水硫酸钠干燥，抽滤，滤液减压浓缩得到棕黑色油状物，粗品直接用于下一步（纯化一针不加酸反相无法分离）

实验步骤: 投料: 取500ml三口瓶，加入C4X-293715-SM1（1eq）和甲苯（5ml），氮气置换，室温下加入C4X-293715-SM2（ 2eq）、（DBA）3Pd2 、DPPF、叔丁醇钠、碘化钾，添加完毕后，氮气置换，升至105℃下搅拌过夜 LCMS监测（293715-s1-dba-n），结果显示，原料反应完全，有产物ms生成，大部分是接一个的，15%收率

实验步骤: 投料: 取500ml三口瓶，加入C4X-293715-1（7.7g 1eq）和甲苯（200ml），氮气置换，室温下加入C4X-293715-SM2（8.33g 2eq）、（DBA）3Pd2 （0.27g 0.02eq）、DPPF（0.34g 0.04eq）、碘化钾（0.08g 0.03eq），添加完毕后，氮气置换，升至105℃下搅拌过夜 LCMS监测（293715-s1-2-n），结果显示，原料反应完全，有产物ms生成，22%左右收率 后处理：反应液冷却至室温，加入水和乙酸乙酯萃取，取有机相，水相再用DCM萃取一次，水相TLC确认无产物。合并有机相并用无水硫酸钠干燥，抽滤，滤液减压浓缩得到棕黑色油状物 纯化：粗品经自动过柱机分离纯化（ACN:H2O=30:70 0.1%甲酸）,得到黄色固体。经HPLC检测，纯度90%，有一杂质。粗品再经自动过柱机分离纯化（ACN:H2O=25%，0.1%甲酸 ，每次进样量200mg，用乙腈溶解后，先用纯水冲柱5min，升至25%乙腈等梯度冲柱，可得干净产物），得到黄色固体，HNMR检测，甲酸结合3个，将纯品用水溶解，用碳酸钠溶液调节PH至7-8，用DCM萃取，取有机相，水相再用EA萃取（DCM萃取效果没有EA好），合并有机相并用无水硫酸钠干燥，抽滤，滤液减压浓缩得到淡黄色油状物。纯品用少量乙腈溶解，加入甲酸（0.9eq），搅拌30min后，加入水冻干，得到淡黄色固体。