Short Communication SYNTHESIS OF DESGLYMIDODRINE FROM MIDODRINE BY CONVENTIONAL AMIDE HYDROLYSIS METHOD S. T. NARENDERAN 1,* , SRIKANTH JUPUDI 2 , P. VANAJA 2 , S. N. MEYYANATHAN 1 1 Department of Pharmaceutical Analysis, 2 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund, Jagadguru Sri Shivarathreeshwara University, Mysore 643001, India Email: mail2narederan@gmail.com Received: 23 Oct 2017 Revised and Accepted: 21 Dec 2017 ABSTRACT Objective: The term prodrug involves chemically modifying inert compound which upon administration releases the active parent drug to elicit its pharmacological response within the body. Acting as a α-adrenergic agonist, desglymidodrine an active metabolite of amide prodrug midodrine is used for the treatment of essential and orthostatic hypotension. In the present study synthesis of desglymidodrine from midodrine was reported. Methods: The synthesis was done by the conventional amide hydrolysis method. Results: A novel synthesis of desglymidodrine was successfully achieved and spectrally elucidated by infrared spectroscopy (IR), 1 H, 13 C nuclear magnetic resonance (NMR) and mass analysis. Conclusion: The acquired results were found to be accurate, the synthetic route appeared to be simple, cost-effective and time efficient. Hence the synthesized desglymidodrine can be as a reference standard for the estimation of the same. Keywords: Midodrine, Desglymidodrine, Amide hydrolysis. © 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijpps.2018v10i2.23251 Midodrine (N-glycyl derivative of Desglymidodrine), consisting of glycine promoiety linking to the amine group, undergoes enzymatic deglycination to give desglymidodrine. Desglymidodrine is α-adrenergic receptor agonist which increases the vascular tone and causes elevation of blood pressure [1]. Chemically midodrine is 2-amino-N-[2-(2, 5- dimethoxyphenyl)-2-hydroxyethyl] acetamide. It has an empirical formula of C12H18N2O4 and a molecular weight of 254.28 g/mol [2]. The literature survey revealed different simultaneous estimation techniques like HPLC [3-6], Spectrometric [7], HPTLC [8] and to the best of our knowledge, plasma estimation in healthy human volunteers by UPLC-MS/MS [9] and ascetic patients using liquid chromatography-tandem mass spectroscopy [10] have been reported earlier. However, despite the significance of these analytical efforts in the simultaneous estimation of both prodrug and its active metabolite no synthetic route has been reported in the literature for the synthesis of desglymidodrine. Midodrine is a glycinamide prodrug consisting of a secondary amide linkage between glycine and desglymidodrine. The possible mechanism involves attack of hydroxide anion towards positively charged carbonyl carbon causing localization of the pi bond to carbonyl oxygen. This leads to the formation of a tetrahedral intermediate which eventually generates neutral amine and glycine anion. Here the amide linkage was cleaved by approaching conventional amide hydrolysis method under basic conditions giving desglymidodrine. The midodrine hydrochloride reference standard was supplied by PAR formulations, Chennai synthetic work was done by procuring analytical grade solvents. TLC was performed to monitor the reaction and to determine the purity of the sample product. The melting point of the synthesized compounds was determined in open capillaries using veego VMP-1 apparatus and expressed in ˚C and are uncorrected. The IR spectrum of compounds was recorded on Shimadzu FT-IR spectrometer using KBr pellet technique and is expressed in cm -1 . 1 H-NMR and 13 C-NMR spectra were recorded on the Agilent (400MHz FT-NMR) using Vnmrj 3.2 V as processing software. Mass spectra were recorded with Shimadzu LC-MS/MS 8030 system using lab solution software. DSC analysis was carried out by DSC Q 200 system. To a solution of midodrine hydrochloride (3 g, 0.01M) in 1N NaOH solution (200 ml) was refluxed in a water bath for 30 h. The completion of the reaction was monitored by TLC (n-butanol: water, 4.5:0.5 v/v) and LC-MS/MS. White crystals of desglymidodrine were obtained upon the addition of sodium hydroxide (q. s) which was filtered, dried and recrystallized using acetonitrile as solvent (fig. 1). O O OH NH NH 2 CH 3 C H 3 O Reflux, 30 hrs 1N, NaOH O O OH NH 2 CH 3 C H 3 + O H NH 2 O Midodrine Desglymidodrine Glycine Fig. 1: Synthesis of desglymidodrine from midodrine International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 10, Issue 2, 2018