A Modified Method for the Synthesiss of Nitrofurazone
Mohammd Hassan Hoshdar Tehrani*a, Afshin Zarghi, Sara Fathali Department of Pharmaceutical Chemistry, School of pharmacy, Shaheed Beheshti University of Medical Sciences. Tehran, Iran. Abstract Nitrofurazone is one of theantibacterial nitrofuran agents used topically for skin infections. The drug is effective on the majority of infectious microorganisms. Because of the importance of this drug in clinic, in this study various methods of synthesis of nitrofurazone were examined and the most appropriate method, applicable to pharmaceutical industry was chosen and optimized from the points of quality and yield. Keywords:Nitrofurazone; Synthesis; Quality control.
Introduction Nitroheterocyclic drugs are used for the treatment of a wide range of bacterial and protozoal diseases. The Nitrofuran group of drugs is very large and displays a wide spectrum of clinical and nonclinical applications. Nitrofurans are known to produce DNA strand breaks as a consequence of reduction of their nitro group. One of thenitrofuran drugs is nitrofurazone. This drug is used primarily against gram-negative infections of skin injuries typified by Escherichia coli, Pseudomonas and Proteus (1). For the synthesis of nitrofurazone various methods have been used (2-10). The starting material used in the synthesis may be 5-nitrofurfural diacetate (2-6), 5-nitro-2-furaldehyde (7), 2-furaldehyde (8-9) or nitrofurfuraloxime (10).Since 2-furaldehyde is a cheap substance and could be used in an industrial scale production of nitrofurazone, in this study those methods in which 2-furaldehyde is used
1) HNO 3, H 2SO 4
as a starting material were chosen and applied with varying conditions of time, temperature, pH and changing catalysts to obtain a product with an appropriate quality and good enough yield, to be scaled up inindustry. Experimental Methods All chemical compounds were from Merck Co. and of analytical grades. IR spectra were recorded on Perkin-Elmer model 840. 1H-NMR spectra were recorded on varian-400 spectrometer. Quality controls of the products were carried out according to United States Pharmacopeia (11). Materials Synthesis of 5-nitrofurfural diacetate A mixture of concentrated nitric acid (4.3ml) and sulfuric acid (0.3 ml) was added dropwise to acetic anhydride (45 ml) at -5°C to 5°C. To this solution a double-distilled furfural
O O2N O CH NNHCNH2
CHO 2) (CH3CO) 2O
*Corresponding author: E-mail: firstname.lastname@example.org
M H Hoshdar Tehrani, A Zarghi, S Fathali / 2003, 2: 67- 69
(5.2 ml) was added, under the same condition.The mixture was stirred in ice bath for 1 h. Then water (40 ml) was added to the mixture at room temp. After 30 min and adjusting pH at 2.5-2.7, the mixture was warmed (55°C, 1 h) and then left overnight at room temperature. The precipitate thus formed was collected and recrystallized from ethanol. [m.p.: 90°C, yield: 52%. 1H-NMR (CDCl3, δ): 7.71 (s, 1H, C-H), 7.30 (d, 2H, H-C4 furan), 6.74 (d, 2H,H-C3 furan), 2.18 (s, 6H, CH3)]. Synthesis of Nitrofurazone Method 1: 5-niotrofurfural diacetate (4.86 g, 20 mmol) and semicarbazide Hydrochloride (2.56 g, 23 mmol) were dissolved in ethanolwater solvent (1:1, 20 ml) and refluxed (2 h). The precipitate thus formed was collected, washed with ethanol and water and then dried (1 h, 105°C) [m.p.: 240°C, yield: 82%. IR (KBr ν): 3430 (N-H), 1710 (C=O),1580 (C=N), 1520, 1350 (NO2)]. Method 2: 5-nitro furfural diacetate (20 mmol) in 50% sulfuric acid (50 ml) was boiled (1-2 min). The mixture was added dropwise to a solution of semicarbazide HCl (2.56 g, 23 mmol) in water (250 ml). After 20 min stirring the precipitate was collected, washed and dried. m.p.: [238ºC, yield: 80%]. Method 3: 5-nitrofurfural diacetate (20 mmol) and semicarbazide HCl...