CIESC Journal ›› 2021, Vol. 72 ›› Issue (3): 1465-1472.DOI: 10.11949/0438-1157.20201788

• Process system engineering • Previous Articles     Next Articles

Multi-objective solvent design considering selectivity and reaction rate for pharmaceutical reactions

ZHAO Hongqing(),LIU Qilei,ZHANG Lei(),DONG Yachao,DU Jian   

  1. Institute of Chemical Process Systems Engineering, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, Liaoning, China
  • Received:2020-12-05 Revised:2020-12-11 Online:2021-03-05 Published:2021-03-05
  • Contact: ZHANG Lei

考虑选择性和反应速率的多目标制药反应溶剂设计

赵红庆(),刘奇磊,张磊(),董亚超,都健   

  1. 大连理工大学化工学院,化工系统工程研究所,辽宁 大连 116024
  • 通讯作者: 张磊
  • 作者简介:赵红庆(1995—),男,硕士研究生,2262640461@qq.com
  • 基金资助:
    国家自然科学基金项目(22078041);中央高校基本科研业务费专项资金(DUT20JC41)

Abstract:

There are plenty of liquid-liquid homogeneous organic reactions in the drug research and development. A suitable reaction solvent can significantly increase the rate and selectivity for these reactions, thereby improve the synthesis efficiency and enhance the quality of drug synthesis. Taking the aromatic nucleophilic reaction (SNAr) of 2,4-dichloro-5-nitropyrimidine and p-aminobenzonitrile as the research object, the computer-aided molecular design (CAMD) method was used to design the reaction solvent. First, the reaction rate constants for a small number of solvents are obtained using quantum mechanics (QM) method. Then, the obtained reaction rate constants are used to build a surrogate reaction kinetic model which correlates the solvent properties. Afterward, a mixed integer nonlinear programming (MINLP) multi-objective optimization model considering both selectivity and reaction rate is established. Finally, a decomposed algorithm is used to solve the established model, which achieves the objective of reaction solvent design in pharmaceutical reactions.

Key words: systems engineering, solvent, optimization, reaction, selectivity

摘要:

药物研制过程存在着大量的液–液均相有机反应,合适的反应溶剂能够大幅提高此类反应的反应速率与选择性,从而提高合成效率,提升药物质量。以2,4-二氯-5-硝基嘧啶与对氨基苯腈的芳香亲核反应(SNAr)为研究对象,采用计算机辅助分子设计(computer-aided molecular design, CAMD)的方法进行反应溶剂设计。首先使用量子力学(quantum mechanics, QM)计算的方法获得少量溶剂中的反应速率常数并通过反应动力学模型与溶剂性质关联,然后构建同时考虑选择性和反应速率常数的混合整数非线性规划(mixed-integer nonlinear programming, MINLP)的多目标优化模型,最后采用分解式算法对模型优化求解,实现制药反应溶剂设计的目标。

关键词: 系统工程, 溶剂, 优化, 反应, 选择性

CLC Number: