Isomerization of dimethyl maleate to dimethyl fumarate

Isomerization of dimethyl maleate to dimethyl fumarate

Isomerism | isomerization | organic chemistry | class 12

The ratio of the second-order rate constants for these geometrical isomers, k′DMF/k′DMM, was greater in the cases with polymeric amine and diamine as catalyst than in the cases with low-molecular-weight monoamines when lauryl mercaptan (LSH) was added to dimethyl maleate (DMM) and dimethyl fumarate (DMF). Only the polymeric amine gave optically active product in the addition reaction catalyzed by optically active amines, and the absolute configuration of the product obtained from DMF was opposite that of the product obtained from DMM.

Experiment – 2 – recrystallization – diethyl ether

The present innovation describes an improved method for producing dimethyl fumarate on an industrial scale. In the presence of a Lewis acid, a one-pot ring opening reaction of maleic anhydride to monomethyl maleate is followed by isomerization into the corresponding monomethyl fumarate. Finally, an acid catalyzed esterification reaction was used to convert the monomethyl fumarate to dimethyl fumarate.
The chemical name for dimethyl fumarate, a dimethyl ester of fumaric acid, is dimethyl (E) butenedioate. It is an FDA-approved medication for the treatment of multiple sclerosis and is sold by Biogene under the brand name Tecfidera. Dimethyl fumarate has also been used in the treatment of organ transplant rejection to mitigate or prevent the recipient’s rejection.
The esterification of fumaric acid to the diester in the presence of an acid catalyst is the general synthetic approach stated for the development of dimethyl fumarate. The synthesis of dimethyl fumarate by sulphuric acid catalyzed fumaric acid esterification is defined in WO 2012/170923. However, when fumaric acid is esterified in the presence of sulphuric acid and methanol, a by-product called dimethyl sulphate is formed, which is a known genotoxic impurity.

Maleic acid vs fumaric acid

Maleic and fumaric acid diesters are common chemicals with a variety of uses[1-5] including monomers for polymer synthesis, chemical intermediate processing, pharmaceuticals, food additives, and biocide. Commercially, these diesters are made by esterifying maleic anhydride with petroleum-derived chemicals (Scheme 1) including n-butane and benzene as a raw material[6]. The energy crisis, on the other hand, prompted researchers to investigate a possible route for the direct synthesis of dicarboxylic acid ester to replace the petroleum-based route. Carbon monoxide is a desirable carbon source for use in chemical transformations[7-9]. Its use as the C1 building block in carbon-carbon bond formation reactions, in particular, will open up new pathways for the direct synthesis of carboxylic acids and their derivatives.
For dicarbonylation of acetylene, we used the PdCl2/KI/air catalytic method, which avoided the use of large quantities of acid and strong metallic salts. This catalytic system had a lot more catalytic activity than the others. Furthermore, orthogonal experiments revealed that the partial pressure of air and the sum of KI play critical roles in the reaction.

Experiment – 2- recrystallization – toluene

Using cyclic voltammetry (CV), rotating ring-disk electrode voltammetry (RRDE), and in situ FT-IR spectroelectrochemistry, the electrochemical reduction of dimethyl maleate (DMM) and dimethyl fumarate (DMF) in acetonitrile and methanol solutions was investigated. In both solvents, the electrochemically formed radical anion of DMM undergoes a rapid cis-trans isomerisation process, yielding the dimethyl fumarate radical anion (DMF.-), as well as a rapid radical anion dimerisation reaction, yielding the dimethyl fumarate radical anion (DMF.-). These species’ radical anion dimerization is fast, with second order rate constants of 1×107 mol dm-3 s-1. DMF and DMM are formed as a result of an autocatalytic electron cross-exchange reaction between the DMF.- and DMM species, resulting in a rapid build-up of the trans isomer in solution.