11192的工艺路线评估.docx

临时编号：11192项目名称：N-(2-amino-4,6-dichloro-pyrimidin-5yl)-amineCAS NO.: 55583-59-0评估人：徐小平 审核人： 评估日期：2011-8-31 项目评估结论项目编号综合评估结论可以做该项目，决定采用路线1 公司不适宜做该项目人员配置本科及以下:_人 硕士:_1_人 博士:_人预计进度拉通工艺时间 _20-30_天20克样品时间 _天工艺优化时间30-35_天完成询盘生产时间_天成本情况（指研发阶段）原材料成本_元人工成本_元分析成本_元新增设备或仪器_元合 计_元不确定因素建议难度系数Synthetic RouteReference (参考文献)操作步骤1. 化合物A的合成2. 化合物B的合成3. 化合物D的合成Process StepQty (kg)Qty (lts)Stage 11.Vent R1 and H1 to a caustic scrubber2.Charge DMF to R16503.Charge DADHP to R13004.Agitate the contents of R1 for 10-15 minutes.5.Cool the contents of R1 to less than 5C.6.Charge Phosphorous oxychloride to H110307.Slowly add phosphorous oxylchloride to R1 maintaining the temperature below 25C.8.Maintain the contents at less than 30C for 30-45 minutes.9.Heat the contents to 70-75C over 2 hours.10.Agitate the contents of R1 for 48 hours at 70-75C.11.Charge toluene to R1 at 70-75C.110012.Cool the contents of R1 to less than 5C.13.Charge water to H230014.Cool the water in H2 to 2-5C15.Charge 25% of chilled water to R1, maintaining the temperature at less than 10C.75016.Transfer the contents of R1 to R217.Charge toluene R110018.Charge chilled water to R120019.Slowly transfer the contents of R1 to R2, maintaining the contents of R2 below 10C.20.Slowly charge the remaining chilled water to R2, maintaining the contents at less than 10C.21.Charge 47% caustic solution to H3220022.Adjust the pH of R2 to pH 7.0 to 7.5 using caustic solution, maintaining temperature at less than 10C.23.Agitate the contents of R2 for 10-15 minutes.24.Check the pH of aqueous layer is pH 7.0-7.5.25.Heat the contents to 60-65C.26.Stir the contents at 60-65C for 30-45 minutes.27.Settle the contents of R2 for at least 45 minutes.28.Separate the aqueous layer to R3.29.Transfer the organic layer to R4.30.Transfer the aqueous layer back to R2.31.Charge toluene to R2.45032.Heat the contents to 60-65C.33.Stir the contents at 60-65C for 15-30 minutes.34.Settle the contents of R2 for at least 45 minutes.35.Separate the aqueous layer to R3.36.Transfer the organic layer from R4 to R2.37.Charge water to R2150038.Heat the contents to 60-65C.39.Stir the contents at 60-65C for 15-30 minutes.40.Settle the contents of R2 for at least 45 minutes.41.Separate the aqueous layer to R3.42.Charge water to R2150043.Heat the contents to 60-65C.44.Stir the contents at 60-65C for 15-30 minutes.45.Settle the contents of R2 for at least 45 minutes.46.Separate the aqueous layer to R3.47.Transfer the organic layer from R2 to R5.48.Charge carbon to R5.1549.Heat the contents of R5 to 60-65C.50.Maintain the contents at 60-65C for 1 hour.51.Filter the contents of R5 through a 2kg bed of diatomaceous earth & a polishing filter to R6.52.Charge toluene line wash to R5 and transfer to R6.15053.Remove toluene from R6 by vacuum distillation at less than 40C, until as much toluene as possible is removed.54.Charge methanol to R6.160055.Heat the contents of R6 to about 40C and agitate until dissolution is achieved.56.Transfer the contents of R6 to R757.Charge methanol to R6.50058.Transfer the contents of R6 to R759.Cool the contents of R7 to 20-25C.60.Charge water to H3.23061.Charge concentrated HCl to H3 to make a 6N solution.27062.Adjust the pH in R7 to pH 1.4-1.6, maintain batch at 20-25C.63.Agitate the batch for 15 minutes & confirm pH is 1.4-1.664.Heat to 40-50C. 65.Maintain batch at 40-50C and a pH of 1.4-1.6 (adding HCl as required) for 4 hours66.Perform IPC for completion of reaction. (HPLC)67.When reaction complete cool the batch to 5-10C.68.Charge conc. Ammonia solution to H4.20069.Adjust R7 contents to pH 8.0-8.5 maintaining a temperature below 10C.70.Transfer the batch from R7 to R8.71.Remove methanol from R8 by vacuum distillation at less than 40C, to 4 volumes (1200l).72.Cool the contents of R8 to 0-5C.73.Charge water to H5 and slowly transfer to R8 maintaining a temperature less than 10C.74.Stir the contents of R8 for about 1 hour.75.Isolate the batch on a centrifuge.76.Wash the batch with water100077.Discharge the water damp batch (265kg, dry equivalent).4. 化合物TM的合成1.Charge damp batch to reactor RB12652.Charge 0.1M NaH2PO4 buffer, adjusted to pH3.0 with phosphoric acid20143.Charge methanol to RB149824.Heat the contents of RB1 to reflux5.Adjust the contents to pH 3.48 using phosphoric acid1536.Reflux the batch for 20 hours.7.Adjust the pH of RB1 to 1.49 using concentrated sulfuric acid818.Continue to reflux for a further 2 hours.9.Cool the contents of RB1 to 30-35C.10.Charge dichloromethane to RB1524711.Stir for 1 hour12.Settle the contents of RB1 for at least 20 minutes13.Transfer the lower organic layer to RB214.Charge dichloromethane to RB1265015.Stir for 1 hour16.Settle the contents of RB1 for at least 20 minutes17.Transfer the lower organic layer to RB218.Charge dichloromethane to RB1265019.Stir for 1 hour20.Settle the contents of RB1 for at least 20 minutes21.Transfer the lower organic layer to RB222.Charge dichloromethane to RB1265023.Stir for 1 hour24.Settle the contents of RB1 for at least 20 minutes25.Transfer the lower organic layer to RB226.Distill the contents of RB2 to a 7.6 volumes (2014lts).27.Charge IMS to RB2265028.Vacuum distill the contents of RB2 to a 7.6 volumes.29.Cool the contents of RB2 to about 0C.30.Isolate the batch on a centrifuge.31.Wash the batch with IMS at 0C39832.Dry the batch under vacuum at about 50C.33.Yield149.7成本估算评述1该项目来自GSK，客户要求价格低于80英镑/kg，询问订单量30吨/年；询价该化合物价格约3500-4500元/kg;2经过六步反应得到产物。客户技术包报道其起始原料化合物B有市场供应，但询价未能找到。文献报道合成化合物B参考JOC文献，关环合成嘧啶环问题不大，硝化还原也有报道，但资料中收率计算与实际结果有