No. | Unit Operations | Process description in Chine | Process description in English | ||
1 | Instrument/Equipment preparation 仪器/设备准备 | 装有机械搅拌(或磁力搅拌)，加料漏斗，温度计(或分水器，干燥管)的3L三口瓶 | A 3L three-necked round bottom flask equipped with mechanical stirrer (or magnetic stirrer), addition funnel and thermometer (or Dean-Stock; drying tube) | ||
反应中所用的所有瓶子，真空条件下加热30min，氮气吹扫10min。 | All flasks ud in the reaction were heated under vacuum for 30 minutes and purged with nitrogen for 10 minutes. | ||||
将500L高压釜通氮气至0.4~0.5MPa。若0.5~1h内压力无变化，则气密性良好。 | A 500L autoclave reactor was filled with nitrogen to increase the pressure to 0.4~0.5MPa. If the pressure had no change within 0.5~1h, then the air-tightness of the autoclave reactor was good. | ||||
将500L搪瓷釜抽真空到<-0.08MPa，再通氮气至常压。重复进行3次。 | A 500L glass-lined reactor was evacuated to less than -0.08MPa, then filled with nitrogen to normal pressure. This was repeated for 3 times. | ||||
将1000L 钛钢釜于>60oC用氮气烘6~8h，然后降温到20~25oC。 | A 1000L titanium reactor was dried at >60oCwith hot nitrogen for 6~8h, then cooled to 20~25oC. | ||||
2 | Charging/ 投料 | Order/ 顺序 | 向瓶中加入A 10ml(1mol)，B (2 g, 2mol) and C (50 ml ) | The flask was charged with A (10 ml, 1 mol), B (2 g, 2mol) and C (50 ml ) | |
依次加入D (10 g, 1 mol) and E (20 ml) | D (10 g, 1 mol) and E (20 ml) were added in turn | ||||
向A(10ml, 1 mol)和B (2 g, mol)的C(50ml)溶液(体系或悬浮液)中，依次加入D (10 g, 1 mol) 和 E (20 ml) | D (10 g, 1 mol) and E (20 ml) were added into a solution (mixture or suspension) of A (10 ml, 1 mol) and B (2 g, mol) in C (50 ml) in turn | ||||
Way/ 方式 | 氮气保护下，控温20~30oC，通过固体加料漏斗一次性向100L搪瓷釜中加入A (40.0kg, 10.0mol) | Under the protection of nitrogen, A(40.0kg, 10.0mol) was added into a 100L glass-lined reactor in one portion via the solid additional funnel while maintaining the temperature at 20~30oC | |||
控温20~30oC， 向500L白钢釜中， 分四批加入A (10.0kg, 10.0mol)，每批2.5kg，间隔时间为5~10min | A(10.0kg, 10.0mol) was added to a 500L stainless steel reactor in four portions (2.5kg×4) at interval of 5~10min while maintaining the temperature at 20~30oC | ||||
将D (10 g, 1 mol) 分批加入，1h加完。 | D (10 g, 1 mol) was added in portions during a period of 1 h. | ||||
将D (10 g, 1 mol) 分批加入，1h内加完。 | D (10 g, 1 mol) was added in portions within 1 h. | ||||
2 | Charging/ 投料 | Way/ 方式 | 控温20~30oC， 用真空向干燥洁净的100L搪瓷釜中抽入114260的乙酸乙酯溶液(外标折算后为50.0kg 114260)。 | Maintaining the temperature at 20~30oC, solution of 114260 in ethyl acetate (50.0kg 114260 corrected by wt%) was added by vacuum to a clean and dried 100L glass-lined reactor | |
控温20~30oC，用氮气压入A(100kg, 101mol)，开动搅拌， | A(100kg,101mol) was added(charged) by nitrogen at 20~30oC and then the stirrer was started. | ||||
控温20~30oC，用真空抽入A(100kg, 101mol) | Maintaining the temperature at 20~30oC, A (100kg,101mol) was added(charged) by vacuum. | ||||
控温20~30oC，用泵打入A(100kg, 101mol) | A(100kg,101mol) was added(charged) by pump while maintaining the temperature at 20~30oC | ||||
将正丁基锂或硼烷/四氢呋喃溶液(10 ml, 1 mole, 2.5 M in 己烷)，通过管路导入滴加漏斗或A的B溶液中。 | A solution of BuLi or BH3/THF (10 ml, 1 mole, 2.5 M in hexane) was cannulated into addition funnel or into a solution A in solvent B | ||||
通过插管，滴加漏斗或针筒，将正丁基锂或硼烷/四氢呋喃溶液(10 ml, 1 mole, 2.5 M in 己烷)，通过管路导入滴加漏斗或A的B溶液中，5h加完。 | A solution of BuLi or BH3/THF (10 ml, 1 mole, 2.5 M in hexane) was added into a solution of A in solvent B via cannula, dropping funnel or syringe over a period of 5h | ||||
3 | Add dropwi 滴加 | 控温10~15oC，通过50L滴加罐(高位瓶或恒滴)向体系中滴加D (101kg, 10 mol)，滴速为15~20kg/h。 | D (101g, 10mol) was added dropwi into the mixture through (via) 50L additional vesl (or carboy or constant pressure funnel) at a rate of 15~20kg/h while maintaining the temperature at 10~15oC. | ||
控温10oC(或保持微回流或保持内温10~30oC)，氮气保护下，(通过加料漏斗或针筒)滴加D (10 g, 1 mol) 的 E (20 ml)溶液。 | a solution of D (10 g, 1 mol) in E (20 ml) was added dropwi (via addition funnel or syringe) at 10oC (or while maintaining gentle reflux; while keeping inner temperature between 10oC ~30oC) under nitrogen | ||||
4 | Heat 升温 | 将体系升温至15~20oC，升温速度5~10oC/h | The mixture was heated to 15~20oC at the rate of 5~10oC/h. | ||
用汽水混合器将体系升温至50~60oC。 | The mixture was heated to 50~60oC by the steam-water mixing heating. | ||||
5 | Cool 降温 | 将体系降温至15~20oC，降温速度5~10℃/h | The mixture was cooled to 15~20oC at the rate of 5~10oC/h. | ||
用外浴乙醇/液氮将体系降温至-70~-75oC | The mixture was cooled to -70~-75oC by ethanol/liquid nitrogen | ||||
6 | Maintain 保温 | 将体系于15~20oC保温搅拌0.5h。 | The mixture was stirred at 15~20oC for 0.5h。 | ||
7 | Reflux 回流 | 体系于78~82oC回流3h。 | The mixture was refluxed at 78~82oC for 3h. | ||
8 | Exchange/ 置换 | 控温20~30oC，将氮气通入液面下置换体系10次，每次通氮气至0.2MPa，然后排空至常压；再液面下通氢气置换体系5次，每次通氢气至0.2MPa，然后排空至常压。 （高压反应中用到） | The mixture was exchanged with nitrogen under liquid level for 10 times. The pressure was increased to 0.2MPa with nitrogen and pumped down to normal pressure each time. And then the mixture was exchanged with hydrogen under liquid level for 5 times. The pressure was increased to 0.2MPa with hydrogen and pumped down to normal pressure each time. During exchanging, the temperature of mixture was controlled at 20~30oC | ||
9 | React 反应 | Type/ 类型 | 无溶剂反应：将A (1 g, 1 mol) and B (1 g, 1 mol)溶于溶剂C中，蒸干后，于50oC加热2小时。 | A (1 g, 1 mol) and B (1 g, 1 mol) were dissolved in solvent C, evaporated to dryness and heated at 50oC for 2h。 | |
催化量的反应：于0oC，加入A (20 ml, 142 mmol)和催化量B（1微量或两滴），加入C(4.549 g, 46.4 mmol)的D (120ml)溶液中。 | A (20 ml, 142 mmol) and catalytic amount (a trace amount or two drops) of B were added into a solution of C (4.549 g, 46.4 mmol) in D (120mL) at 0oC | ||||
闷罐反应或封管反应：控温T=40oC，P=0.5MP ，A(1g, 1mol)的饱和氨水（或其他气体如：一氧化碳、二氧化碳、硫化氢）乙醇(1ml)溶液在50ml封管或闷罐/高压釜中搅拌5小时。 | A solution of A (1g, 1mol) in ethanol (x ml) saturated with NH3 (or other gas such as: CO,CO2, H2S) was stirred under 0.5MPa at 40oC for 5hrs in a 50 ml of aled tube or autoclave. | ||||
A(1g, 1mol) 的饱和氯化氢甲醇(1ml) 溶液在20oC搅拌。 | A solution of A (1g, 1mol) in methanol (1ml) saturated with HCl was stirred at 20oC. | ||||
控温20oC，向A(1g, 1mol)的甲醇(1ml)溶液中通臭氧15min。然后通氮气除臭氧，再于20oC加入Me2S (5ml)。 | Ozone was bubbled into a solution of A (1g, 1mol) in MeOH (1ml) at 20oC for 15minutes. After excess O3 was purged by N2, Me2S (5ml) was added at 20oC. | ||||
9 | React 反应 | Type/ 类型 | A(1g, 1mol)和B(1g, 1mol)的C(1ml)溶液在30oC下通气体0.5小时。 | Gas was bubbled into a solution of A (1g, 1mol) and B (1g, 1mol) in solvent C (1 ml) at 30oC for 0.5h. | |
控温10oC，D(1g, 1mol) 加入到A(1g, 1mol)的B(5ml)和C(10ml)溶剂混合液（或B和C的混合溶剂）中，反应体系搅拌（回流或加热）两小时。 | To a solution of A (1g, 1mol) in a mixture of solvent B (5ml) and solvent C (10ml) (or a mixed solvent of B and C) was added D (1g, 1mol) at 10oC, the reaction mixture was allowed to stir (reflux or heat) for 2h. | ||||
向A(1g, 1mol)的丙酮水溶液（丙酮:水=10：1）中加入B (1g, 1mol)，再加入C(1g, 1mol)，反应体系搅拌（回流或加热）五小时。 | To a solution of A (1g, 1mol) in 10: 1 aqueous acetone (1ml) was added B (1g, 1mol) followed by addition of C (1g, 1mol), the reaction mixture was allowed to stir (reflux or heat) for 5hrs. | ||||
将A和B溶于苯或甲苯，体系回流1h，共沸带水。 | A (x g, x mol) and B (x g, x mol) in benzene or toluene (x mL) were refluxed for x h with azeotropical removal of water. | ||||
将A、B和甲苯磺酸的甲苯溶液加热回流，用分水器除水。 | A mixture of A, B and TsOH.H2O (56.91 g, 0.3 mol) in toluene (400 mL) was heated to reflux and remove water by Dean-Stark trap. | ||||
氮气保护下，向A的乙醇溶液中加入Pd-C或Ra-Ni或Pd(OH)2/C。悬浮液真空下除氧，再通几次氢气。 | To a solution of A (x g, x mol) in EtOH (x mL) was added Pd-C or Ra-Ni or Pd(OH)2/C (10%,x g) under N2. The suspension was degasd under vacuum and purged with H2 veral times. | ||||
体系于5 psi ，20oC搅拌氢化1h。[氢化瓶或高压釜] | The mixture was stirred under H2 (5 psi) at 20oC for 1h. | ||||
体系于20oC搅拌氢化1h。[常压氢化如气球反应] | The mixture was stirred under H2 balloon at 20oC for 1h. | ||||
A和Ra-Ni的乙醇溶液在室温、50Psi氢气压力下氢化2h。 | A mixture of A (x g, x mol) and Ra-Ni (x g) in EtOH (x ml) was hydrogenated under 50 Psi of hydrogen pressure for 2h at room temperature. | ||||
Condition or process/ 条件或过程 | 反应体系(溶液或悬浮液)于5oC搅拌2hrs后，于室温保温2hrs(或过夜)。 | The reaction mixture (solution or suspension) was stirred at 5oC for 2h and then kept at room temperature (or ambient temperature) for another 2h (or overnight) | |||
反应体系(溶液或悬浮液)于60oC回流2hrs(或过夜)。 | The reaction mixture (solution or suspension) was refluxed at 60oC for 2h (or overnight) | ||||
9 | React 反应 | Condition or process/ 条件或过程 | 反应体系(溶液或悬浮液)容许回流2hrs(或过夜)。 | The reaction mixture (solution or suspension) was allowed to reflux (or heat to reflux) for 2h (or overnight) | |
反应体系(溶液或悬浮液)容许回温2hrs后， 回流2hrs(或过夜) | The reaction mixture (solution or suspension) was allowed to warm to temperature during 2h and reflux for 2h (or overnight) | ||||
State or Endpoint of reaction/ 反应状态或终点 | 反应通过TLC(石油醚：乙酸乙酯=4：1)，LC-MS，液相或核磁确认完成（为完成或杂乱的）。 | The reaction was complete (incomplete or messy) detected (determined or confirmed) by TLC (PE/EtOAc 4:1), LC-MS, HPLC or NMR | |||
TLC(石油醚：乙酸乙酯=1：1)或液相(107757-088-1)显示反应结束。 | TLC (PE:EtOAc=1:1) or HPLC (107757-088-1) showed or indicated that the reaction was complete. | ||||
TLC(石油醚：乙酸乙酯=1：1)或液相(107757-088-1)显示起始原料完全消耗。 | TLC (PE:EtOAc=1:1) or HPLC (107757-088-1) showed the starting material was consumed completely. | ||||
TLC(石油醚：乙酸乙酯=1：1)或液相(107757-088-1)显示根本没有反应或大部分原料剩余。 | TLC (PE: EtOAc =1:1) or HPLC (107757-088-1) showed the reaction didn’t work at all or most of starting material was still remained. | ||||
起始原料完全消耗，但经MS (106657-078-1) 或LC-MS (106657-078-1)检测，没有预期的产物。 | The starting material was consumed completely, but no desired compound was detected or determined by MS (106657-078-1) or LC-MS (106657-078-1). | ||||
TLC显示有几个点 | Several spots were shown on TLC. | ||||
经MS (106657-078-1) 或LC-MS (106657-078-1)或 HPLC (106657-078-1) 或TLC (石油醚：乙酸乙酯=1：1).检测，只有很少量的预期产物。 | Only a trace amount of desired compound was detected by MS (106657-078-1) or LC-MS (106657-078-1) or HPLC (106657-078-1) or TLC (PE:EtOAc=1:1). | ||||
由于收率低或溶解性不好，通过层析或制备的高效液相色谱仪，不能分离或纯化预期化合物，。 | The desired compound could not be isolated, parated or purified by chromatography or prep. HPLC due to poor yield or poor solubility. | ||||
通过1H NMR (106675-010-2) or MS确认，得到(或分离)的不是预期化合物，反应失败。 | 1H NMR (106675-010-2) or MS confirmed the obtained (or isolated) compound is not the desired compound. The reaction failed. | ||||
9 | React 反应 | Scaling up technic in Asymchem/ 放大工艺中 | 体系于50~55oC反应，12h后， 每1~2h取样一次HPLC跟踪，直至化合物A含量<1%且连续两次取样化合物A含量变化<0.5%。若连续两次取样化合物A含量变化<0.5%且化合物A含量≥1%，则补加化合物B | The mixture was stirred at 50~55oC. 12h later, the reaction was monitored by HPLC every 1~2h. The reaction was considered completion when the content of compound A was <1% and the change of compound A content between concutive samples was <0.5%. If change of compound A content between concutive samples was <0.5% and the content of compound A was still ≥1%, extra compound B was added. | |
体系于50~55oC搅拌反应，12h后， 每1~2h取样一次HPLC跟踪，直至113443相对于乙苯含量≤0.1% | The mixture was stirred at 50~55oC. 12h later, the reaction was monitored by HPLC every 1~2h. The reaction was considered as complete when the peak area of 113443 ≤0.1% relative to ethyl benzene | ||||
10 | Sampling method 取样方法 (由于终产品报告中，取样方法用一般现在时，故此处也用一般现在时) | 从反应体系(溶液或悬浮液)通过滴管或注射器取样。处理完毕后，通过TLC, LC-MS or HPLC检测反应 | Take sample from the reaction mixture (solution or suspension) by dropping tube or syringe. After workup, check the reaction via TLC, LC-MS or HPLC etc. | ||
用取样器取滤液5ml，直接送样检测液相外标 | Take 5ml filtrate with the sampler; nd to be analyzed wt% by HPLC directly. | ||||
用药勺取滤饼2g，直接送样检测液相纯度 | Take 2g filter cake with the medicinal ladle; nd to analyze its purity by HPLC directly. | ||||
用取样器取体系2~3ml，打入5ml纯净水中，用2ml乙酸乙酯萃取后，有机相送液相 | Take 2~3ml mixture with the sampler, add it into 5ml purified water. After extract with 2ml ethyl acetate, Send the organic pha to be analyzed by HPLC. | ||||
用取样器取体系5ml，静置后分液，有机相用TLC检测(乙酸乙酯:环己烷=3:7) | Take 5ml mixture with the sampler, hold and then parate. Send the organic pha to be analyzed by TLC (ethyl acetate: n-hexane=3:7) | ||||
11 | Quench 终止 | 当反应体系(溶液或悬浮液)回温至-5oC(或室温)，将A水溶液滴加到反应体系中。 | An aqueous solution of A (10 ml) was added dropwi into the reaction mixture once the reaction mixture (solution or suspension) was allowed to warm (or cool) to -5oC (or room temperature or ambient temperature) | ||
热的(或冷的)反应体系(溶液或悬浮液)倒入水(冰水)中或浇到冰上。 | The hot (or cold) reaction mixture (solution or suspension) was poured into water (ice water) or poured onto ice | ||||
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