Reaction Solvent Design Method For Pyrimidine Synthesis Based On Solvent Effect

The pyrimidine skeleton is an important six-membered heterocyclic compound.Because of its significant pharmacological activity,it has been the focus of pharmaceutical chemists.In the treatment of cancer,pyrimidine drugs play an important role.There are a large number of liquid-liquid homogeneous organic reactions in the synthesis of pyrimidine drugs.Among them,the reaction solvent plays an important role in whether the synthesis process is efficient and environmentally friendly.It can not only affect the synthesis rate and product quality of the reaction,but also determine the degree of environmental harm caused by waste water discharge.Therefore,a suitable reaction solvent is needed to achieve a clean and efficient drug synthesis process.Therefore,in this paper,computer-aided molecular design(CAMD)method was used to design the reaction solvent for the nucleophilic aromatic substitution reaction(S_NAr)between2,4-dichloro-5-nitropyrimidine and 4-Aminobenzonitrile.This paper mainly includes the following parts:(1)The reaction mechanism of aromatic nucleophilic substitution was studied and the reaction rate constant was obtained.Reaction rate constant is an important parameter in the study of reaction kinetics.Due to the lack of experimental data,quantum mechanics(QM)method is adopted in this paper.Two possible reaction mechanisms of the competitive reaction are explored.Finally,the reaction mechanism is determined as a concerted mechanisms.At the same time,the reaction energy barriers at different reaction sites were obtained,and then the performance of the reaction in different solvents was studied with the implicit solvent model,and the reaction rate constants at the two reaction sites were calculated.(2)A multi-objective solvent design model based on transition state theory is established.The reaction kinetics model is constructed by using the descriptors derived from the transition state theory.The mixed-Integer Non-Linear Programming(MINLP)model for the design of reaction solvent was constructed with the reaction rate constant and reaction selectivity as the objective functions,and the structural constraints and property constraints were combined.Among them,the structural constraint mainly considers the structural feasibility of solvent molecules.The property constraint includes the linear properties such as melting point or boiling point and toxicity calculated by Group contribution(GC)method and the nonlinear properties such as the infinite dilution activity coefficient calculated by Conductor-like Screen Model for Segment Activity Coefficient(COSMO-SAC)method.The MINLP model was optimized by the decomposition algorithm,and the optimal solvent that increased the reaction rate constant by 62.8%and selectivity by an order of magnitude was successfully obtained.(3)The reaction solvent design model based on Frontier molecular orbital energy was constructed.In order to solve the tedious calculation of the descriptors related to the transition state structure and to identify the solvation of isomers,the frontier molecular orbital energy which is easy to calculate based on the molecular structure of the reactants is selected as the descriptor.The artificial neural network(ANN)method is used to realize the rapid prediction of orbital energy,and then the reaction solvent design is integrated with the CAMD method.The method is verified in two case,S_NAr reaction based on QM calculation of reaction rate constants and Menshutkin reaction based on experimental reaction rate constants.Among them,Case 1 obtained the conclusion consistent with the descriptor based on the transition state theory,indicating that the simple descriptor can achieve similar results with the descriptor based on the transition state theory in such reactions;In case 2,the reaction kinetics model was constructed,and the solvent molecules with the reaction rate constant increased by 26%were obtained by CAMD.