Improved Convenient Synthesis of Benzoyl Metronidazole : A Nitroimidazole Antibiotics Zhi-zhongWang

Metronidazole (MTZ), 1-hydroxyethyl-2-methyl-5-nitroimidazole, is known to be a powerful antiprotozoal and antibacterial drug. It is clinically effective in trichomoniasis, amoebic colitis, and giardiasis [1]. However, it has a bitter taste, and it is not acceptable to some young patients. Benzoyl metronidazole, the benzoyl ester of metronidazole, is tasteless and has also been widely used because of its greater palatability [2]. e conventional routes for synthesis of benzoyl metronidazole were the two-step synthesis as shown in Scheme 1, which required the preparation of benzoyl chloride, the reaction required strict anhydrous conditions [3, 4], and the reactor should be corrosion resistant. In addition, in the combination of benzoyl chloride and metronidazole, the deacid reagent such as pyridine was needed to promote the reaction. NNNNN-carbonyldiimidazole (CDI) is one of several commonly used reagents for activating carboxyl groups. It is relatively cheap, and the only byproducts are carbon dioxide and imidazole which, being relatively benign, are unlikely to cause problems on scale up [5]. Herein, we report an improved procedure for the preparation of benzoyl metronidazole in one pot by using NNNNN-carbonyldiimidazole as a coupling reagent, and the byproduct imidazole as the catalyst can promote the reaction. ese processes are simple and suitable to large-scale manufactures (Scheme 2). 2. Experimental


Introduction
Metronidazole (MTZ), 1-hydroxyethyl-2-methyl-5-nitroimidazole, is known to be a powerful antiprotozoal and antibacterial drug.It is clinically effective in trichomoniasis, amoebic colitis, and giardiasis [1].However, it has a bitter taste, and it is not acceptable to some young patients.Benzoyl metronidazole, the benzoyl ester of metronidazole, is tasteless and has also been widely used because of its greater palatability [2].
e conventional routes for synthesis of benzoyl metronidazole were the two-step synthesis as shown in Scheme 1, which required the preparation of benzoyl chloride, the reaction required strict anhydrous conditions [3,4], and the reactor should be corrosion resistant.In addition, in the combination of benzoyl chloride and metronidazole, the deacid reagent such as pyridine was needed to promote the reaction.  � -carbonyldiimidazole (CDI) is one of several commonly used reagents for activating carboxyl groups.It is relatively cheap, and the only byproducts are carbon dioxide and imidazole which, being relatively benign, are unlikely to cause problems on scale up [5].Herein, we report an improved procedure for the preparation of benzoyl metronidazole in one pot by using   � -carbonyldiimidazole as a coupling reagent, and the byproduct imidazole as the catalyst can promote the reaction.ese processes are simple and suitable to large-scale manufactures (Scheme 2).

Experimental
e HPLC assays for the purity of benzoyl metronidazole were performed on a Perkin-Elmer Series 200 HPLC system using a Kromasil 100-10-C18 column (4.6 mm × 250 mm) at room temperature; �ow rate: 1.0 mL/min; detection wavelength: 310 nm; the mobile phase: 35 : 65 MeOH-KH 2 PO 4 (0.02 M). e melting point determinations were carried out on an XRC-1 melting point apparatus.e progresses of the reactions were monitored by TLC on 0.25 mm thick layers of silica gel GF 254 developed with solvent system, AcOEt: petroleum ether (1 : 1 v/v).Dichloromethane (DCM) was dried by CaCl 2 for 12 h and distilled prior to use.All other chemicals were of commercial grade and used without further puri�cation.

Results and Discussion
In our work, we found that simply mixing benzoyl imidazole (2) with metronidazole in DCM did not result in an obvious reaction in 24 h.Imidazole can efficiently promote the reaction.Furthermore, the stronger bases such as Na 2 CO 3 or Et 3 N did not distinctly enhance the reaction rate.
� -carbonyldiimidazole is a useful, general carboxylic acid activating reagent, and its byproduct imidazole can serve as the catalyst.erefore, benzoyl metronidazole (1) was prepared in a simple, two-step sequence in just one reactor.In the �rst step, based on TLC analysis, the reaction between benzoic acid and   � -carbonyldiimidazole was quantitative within 8 h at room temperature.In the second step, the coupling of metronidazole to the benzoyl group was accomplished in 16 h under re�ux in DCM.

Conclusions
An improved method for the preparation of benzoyl metronidazole via a one-pot reaction was developed by using   �carbonyldiimidazole as a coupling reagent, which do not require extra catalysts.Compared with routine synthetic methods, these procedures may become an efficient route for the synthesis of benzoyl metronidazole on a large scale.

S 2 :
e improved convenient procedures.