1775-IJBCS-Article-Odin Monday

Available online at http://ajol.info/index.php/ijbcs Int. J. Biol. Chem. Sci. 7(4): 1735-1744, August 2013 ISSN 1991-8631 Original Paper http://indexmedicus.afro.who.int Epoxidation of aminometradin (l-allyl-3-ethyl-6-amino uracil) using tetraoxochromate(VI) acid, trifloroperacetic acid and hydrogen peroxide as oxidants, catalyzed by dioxovanadium(V) ion E.M. ODIN *, P.K. ONOJA and B.O. AKABUEZE Department of Pure and Industrial Chemistry, Kogi State University, Anyigba, Nigeria. * Corresponding author, E-mail: [email protected]; Tel: +234 08138637104 ABSTRACT This paper compared the epoxidation of aminometradin (l-allyl-3-ethyl-6-amino uracil) (1) using tetraoxochromate(VI) acid, trifloroperacetic acid and hydrogen peroxide as oxidants. Tetraoxochromate(VI) and trifloroperacetic acids yielded epoxides in low yields and environmentally unfriendly products. Epoxidation with H 2O2 in the presence of dioxovanadium(V) ion as catalyst improved the yield. However, the presence of pyridine-N-Oxide as co-catalyst, increase in the amount of H 2O2 and temperature gave epoxidation reaction that proceeded to near completion. (9a-o), indicating that H 2O2 is a highly reactive oxidant for the epoxidation of aminometradin, and pyridine-N-Oxide catalyzed the formation of epoxides in quantitative yields. © 2013 International Formulae Group. All rights reserved. Keywords: Epoxidation, Aminometradin, Dioxo vanadium(V) ion, Pyridine N-oxide, Co-catalyst. INTRODUCTION The growth in the chemistry of aminouracil Epoxidation has advanced in ten years during the last decade is due to the search by from little more than a laboratory curiosity to chemists for new diuretic drugs. a commercial chemical process. Epoxidized Aminometradin is a diuretic drug which fatty esters derived from such natural oils as increases urine and solute excretion from the soybean and from such synthetic oils as butyl kidney. To be therapeutically useful, a oleate, are major products of epoxidation diuretic should increase the output of sodium technology (Latourette et al., 2012). These are as well as of water. Diuretics are normally principally used as secondary plasticizers for required to remove oedema fluid which is polyvinyl chloride and copolymers, to which composed of water and solutes, of which they impact a spectrum of properties including sodium is the most important (Abdillahi and heat and light stability, superior aging, and James, 2003; Gerd-Jan et al., 2007; Lawrence low-temperature flexibility (Gall and et al., 1998). Accumulation of sodium in the Greenspan, 2012). Aminometradin (1- allyl-3- kidney will normally lead to high blood ethyl-6-aminouracil) belongs to the pressure. Each day the body produces about pryimidine group of heterocyclic compounds. 180 litres of glomerular filterate which is © 2013 International Formulae Group. All rights reserved. DOI : http://dx.doi.org/10.4314/ijbcs.v7i4.29 E.M. ODIN et al. / Int. J. Biol. Chem. Sci. 7(4): 1735-1744, 2013 modified in its passage down the renal tubules 8:2, V/V ). The Infrared ( IR) spectra were to appear as 1.5 litres of urine. The diuretic recorded in cm -1 on a Bulk Scientific 500 drugs act on the tubule to alter body fluid and spectrophotometer.The mass spectra were electrolyte balance (Lawrence et al., 1998; recorded on a Shimadzu GCMS-QP-1000 EX Tayde et al., 2011). In this paper, we report mass spectrometer at 70 eV and elemental the synthesis of new aminometradin analysis for C, H, N on a Perkin-Elmer CHN derivatives for further assessment of their Analyzer 2400. therapeutic activities as diuretics. The main objective of this work is to establish an Epoxidations of aminometradin (1-allyl-3- oxidant that will give a green epoxidation of ethyl-6-aminouracil) aminometradin in quantitative yields. Their Oxidation using tetraoxochromate(VI) epoxidation was studied using three types of acid: 785 mg, 5 mmol of aminometradin (1) oxidants (Adolfson, 2004; Rao, 2012). The was dissolved in chloroform (20 ml). While expected epoxides can be transformed into a stirring, 100 ml of tetraoxochromate(VI) acid large variety of compounds via regio- and (0.090 mmol) was gradually added at 25 0C. stereoselective ring opening (Clementina et The mixture was separated using column al., 2006; Latourette et al., 2012). chromatography (eluent: n-hexene/ Tetraoxochromate(V1) acid, trifloroperacetic ethylacetate = 5:1.5, v/v). The yield was 25 acid and hydrogen peroxide were employed as mg (3.8%) epoxide (2). oxidants. The epoxidation reaction was catalysed by dioxovanadium(V) ion and Oxidation using trifluoroperacetic acid pyridine N-oxide acting as co-catalyst 90 ml of trifluoroperacetic acid (0.75 (Golchoubian and Nemati, 2005; Guodong mmol) was added to a solution of 500 g, 3.2 and Espensor, 2005; Petrovic et al., 2012). mmol aminometradin (1) in chloroform (15 The reaction was carried out at different ml). The addition was done while stirring temperatures and reaction conditions. continuously for 1 hr at 25 0C. The mixture was also separated using column MATERIALS AND METHODS chromatography (eluent: n-hexane/ All chemicals were obtained from ethylacetate 5:2, v/v). The yield was 28 mg different commercial sources (Lavans, (5.6%) epoxide (8). Aldrich, Merck) and were used without further purification. The melting points (m.p) Oxidation using hydrogenperoxide were determined on a SMP3 melting point Oxidation without pyridine-N-oxide apparatus and are reported in 0C uncorrected. (catalyst) Column chromatography was performed on Aminometradin (1) [500 mg, 3.2 1 Scharlau silica gel 60 (70-230 mesh). The H mmol] and vanadium reagent-VO (acac) 2 (3.2 and 13 C –NMR spectra were recorded on a mmol) were dissolved in a 1:1 mixture of Varian Germini 2000 spectrophotometer chloroform/methol (14 ml). This solution was operating 200 and 50 MHz respectively. added to 35% aqueous H 2O2 (0 .4 ml, 12 Chemical shifts were recorded as δ values in mmol). The reaction mixture was stirred at 25 ppm referenced to the solvent. HPLC 0C for 1 hr. The mixture was separated by separations were performed on a Bulk preparative silica gel thin layer Scientific 500 apparatus using a reverse phase chromatography (eluent: 40-60 petroleum Lichrospher 100RP-18 (5 µm) column, at ether/ethyl acetate (2:3, v/v) to give trace room temperature ( eluent: methanol / water - quality of epoxide (9a). The yield/effective 1736 E.M. ODIN et al. / Int. J. Biol. Chem. Sci. 7(4): 1735-1744, 2013 yield are 9a (0.60%, 11.5%) (Table 2, Entry intermediate (4) yielded the epoxide precursor 1). (5) by reductive elimination process which Oxidation using Pyridine-N-oxide (co- finally gave the cis – epoxide (2) (Goug et al., catalyst) 2006; Mungroo et al., 2008; Ojinaka, 2001) In the case of epoxide 9b-g (Table 2, (Scheme 2). Entries 2-7), the catalyst (3.2 mmol) was The result revealed low yield of added to a solution of the appropriate epoxide, accumulated byproducts and aminometradin (500 mg, 3.2 mmol) and unreacted starting material. The reaction did pyridine-N-oxide (0.64 mmol) in acetonitrile not show a “green” oxidation system. (10 ml). 35% aqueous H 2O2 (0.4 ml, 12 mmol) The epoxidation of aminometradin ( 1) was added and the mixture stirred at 25 0C for was equally tested with trifloroperacetic acid. a period ranging between 60 min to 300 min. (Table 1, Entry 2). The result gave cis- The mixture was separated by HPLC. The epoxide ( 8) in low yield and the reaction yields/effective yields of the epoxidation are occurred very slowly (Scheme 3). shown in Table 2, Entries 2-7 (9b-g epoxide). The epoxidation of aminometradin (1) Epoxide 9i-j (Table 2, Entries 9-10) was also investigated with alkaline hydrogen were prepared using an increased amount of peroxide with dioxovanadium(V) ion as H2O2. As described above, to the mixture catalyst in the presence of pyridine N –oxide containing the catalyst (3.2 mmol), as co-catalyst. The reaction was carried out at aminometradin (3.2 mmol) and pyridin-N- different temperatures, concentration of H 2O2 oxide (0.64 mmol) were added to 35% and reaction period. Scheme 4 showed that aqueous H 202 (16 mmol). The mixture was attack of hydrogen peroxide is stereo selective stirred at 50 0C for 60 min. The separation was and did not occur via a cyclic transition state done using HPLC as above .The as in trifloroperacetic acid. yields/effective yields are (50.2%, 70.9% and The aminometradine (1) was equally 60%, 75%) (Table 2, Entries 9-10). reacted with alkaline hydrogen peroxide in the Similarly, the remaining (Table 2, presence of dioxovanadium(V) ion as the Entries 11-15) epoxides 9k-n were prepared catalyst and at room temperature. The result while varying the quantity of H 2O2 with (Table 2, Entry 1) was trace quantity of reaction period. epoxide and a high amount of unreacted aminometradin (1) (Clementina et al., 2006; RESULTS Dinda et al., 2008). The substrate (1) was First, aminometradin (1) was further treated with alkaline hydrogen epoxidized with tetraoxochromate(VI) acid. peroxide using the catalyst and pyridine N- The acid condensed with the aminometradin Oxide as co-catalyst. Table 2 (Entries 2-7) (1) to give epoxide (2) in trace quantity (Table showed an appreciable amount of epoxide . It 1, Entry 1) Scheme 1. was also noted that the yield decreased with Another possible mechanism is given increase in the reaction period. (Table 2 in Scheme 2. The initial step was the Entries 2-7). formation of a tetraoxochromate(VI) acid - The aminometradin was later treated aminometradin π complex (3). This led to the with an increase amount of hydrogen formation of a four-centered cyclic organo- peroxide, at elevated temperature. Table 2, chromium intermediate (4) via a [2+2] Entries 8 and 9 revealed that the epoxidation interaction between the aminometradine and proceeded to near completion at elevated the oxo group on the chromium.

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