考虑选择性和反应速率的多目标制药反应溶剂设计

doi:10.11949/0438-1157.20201788

摘要/Abstract

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（S_NAr）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

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 (S_NAr) 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

中图分类号:

赵红庆, 刘奇磊, 张磊, 董亚超, 都健. 考虑选择性和反应速率的多目标制药反应溶剂设计[J]. 化工学报, 2021, 72(3): 1465-1472.

ZHAO Hongqing, LIU Qilei, ZHANG Lei, DONG Yachao, DU Jian. Multi-objective solvent design considering selectivity and reaction rate for pharmaceutical reactions[J]. CIESC Journal, 2021, 72(3): 1465-1472.

图/表 9

图1 QM-CAMD设计方法

Fig.1 QM-CAMD design method

图2 2,4-二氯-5-硝基嘧啶与对氨基苯腈的化学反应方程式

Fig.2 Reaction of 2,4-dichloro-5-nitropyrimidine and 4-aminobenzonitrile

图3 分解式算法原理

Fig.3 Principle of decomposition-based algorithm

图4 真空中的反应过渡态结构

Fig.4 Transition state structure of reaction in vacuum

表1 真空中反应物、过渡态与产物的相对自由能

Table 1 Relative Gibbs free energies of reactants, transition states, and products in a vacuum

取代位置	相对Gibbs自由能/(kJ·mol^-1)
取代位置	反应物	过渡态	产物
4-位	0	100.90	-91.00
2-位	0	117.79	-77.39

图5 lgk量化计算结果与回归模型预测结果的比较

Fig.5 Comparison of regression model and DFT results for lgk

表2 MINLP模型中的结构和性质约束

Table 2 Structure and property constraints in MINLP

约束条件	基团总数	官能团数	苯环数	熔点/K	沸点/K	毒性/(mg·L^-1)	溶解度系数/MPa^1/2
上限	8	1	1	273.15	—	4.80	15.55
下限	3	0	0	—	273.15	—	23.39

图6 反应溶剂设计结果（×代表80种初始选取溶剂，■代表设计结果）

Fig.6 Reaction solvents design results(× are 80 initial solvents, ■ are design results)

表3 反应溶剂设计结果

Table 3 Reaction solvents design results

序号	lgk₄	lgk₂	lgk₄ – lgk₂
0	-4.921	-5.158	0.237
1	-5.476	-7.712	2.236
2	-4.709	-5.985	1.276
3	-4.276	-5.001	0.725
4	-3.590	-3.097	-0.493

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