Scale-up synthesis of mesna using alkyl trithiocarbonate approach

Mesna (brand names: Mesnex, Uromitexan) is an important synthetic compound that protects the bladder from the urotoxic metabolites of oxazaphosphorine antineoplastics (ifosfamide, cyclophosphamide) by chemically interacting with them and their metabolites. In this connection, mesna binds to toxic acrolein within the urine1-3. The free sulfhydryl group combines directly with the double bond of acrolein as well as other urotoxic 4-hydroxyoxazaphosphorine metabolites. This medication is given as an infusion into a vein (intravenous) with or after chemotherapy. Mesna may also be given as a pill to be taken by mouth3. Chemically, this molecule has a fairly simple structure which consists of two groups: thiol (-SH) and sulfonate (-SO3Na) linked together via the ethylene bridge (-CH2-CH2-) (Figure 1.) The literature has shown that mesna can be synthesized by different pathways. The reported synthetic methods for preparing mesna consist of two main stages, namely the formation of -SO3 Na group (by the Strecker reaction of 1,2-halogenoethane and Na2SO3) and the building of -SH group (by hydrolysis or reduction various intermediate functionalities, such as thioester, thiouronium, alkyl-xanthate and Bunte salt)2, 4-8. Recently, we have found the novel approach to synthesis of this drug in the laboratory scale (~1 g/experiment) from 1,2 -dihalogenoethane by using alkyl trithiocarbonate intermediate. This new method has produced mesna to satisfy all the requirements of British Pharmacopoeia 2015 (BP 2015) in the total yield up to 44.44% and without using ion-exchange chromatography to purify, which is applied by necessity in the other routes9. Our method has strong potential for practical preparing of mesna