DENSITY FUNCTIONAL THEORY (DFT) METHOD ON REACTION MECHANISM OF SHORT SYNTHESIS MOLNUPIRAVIR Aristia Pratiwi Meliawati (1,3*), Muhamad Abdulkadir Martoprawiro(1), Aminatus Arifah(1), Badra Sanditya Rattyananda(2), Merika Indri Widayanti(1), Nelly Safitri Anwari(1), Selvi Anasha(1)
1)Master^s Program in Chemistry, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology (Jl. Ganesha No.10, Bandung 40132, Indonesia)
2)National Research and Innovation Agency (Jl. Tamansari No.71, Bandung 40132, Indonesia)
3)State Vocational High School 6 Garut (Jl. Raya Nagreg-Limbangan KM. 01, Balubur Limbangan, Garut 44186, Indonesia)
* aristiapm[at]gmail.com
Abstract
Molnupiravir (MK-4482, EIDD-2801) was a prodrug recommended by the Emergency Use Authorization (EUA) from the Food and Drug Administration (FDA) to treat emergencies due to Covid-19. The synthetic route of molnupiravir involves transesterification and transamination from cytidine. Transesterification of cytidine is conducted by immobilized Candida antarctica lipase B and isobutyric oxime ester. Afterward, it was followed by a transamination reaction between hydroxylamine and intermediate. Transesterification uses 1,4-dioxane as a solvent, while transamination uses isopropyl alcohol as the solvent. The synthesis reaction experiment was carried out in two schemes. The first scheme was to carry out the transesterification reaction followed by the transamination reaction. The second scheme was the reverse reaction of the first one. In which transamination was followed by transesterification. The experimental results show that scheme-1 produces products as much as 75%, while scheme-2 has 37%. The study of the reaction mechanism for the synthesis of molnupiravir was carried out using the Density Functional Theory (DFT) method and the theoretical level of B3LYP that were calculations performed using the base set def2-SVP without involving a catalyst. From the computational result, the transesterification occurs concerted without going through an intermediate. The reaction needs activation energy of 128.09 kJ/mol for scheme-1 and 127.93 kJ/mol for scheme-2. It means that the transesterification reaction in both pathways can produce several products that are not much different. The transamination reaction passes through two intermediates. The first was a protonation reaction with an activation energy of 106.57 kJ/mol in scheme-1 and 165.06 kJ/mol for scheme-2. The following reaction is the substitution of ammonia with hydroxylamine. At this stage, scheme-1 requires activation energy of 146.84 kJ/mol, and scheme-2 requires an activation energy of 204.71 kJ/mol. The last rea
