Improvement In The Synthesis Of2-amino-3-benzoyl-phenylacetamide

Nepafenac as a new generation of non steroid anti-inflammatory drugs （NSAID）precursor was approved by FDA, listed on the first eye ophthalmic NSAIDS precursorpharmaceutical preparations in2005; and its eye ophthalmic suspension liquid （commodityname Nevanac, Alcon Company）, mainly used in the treatment of cataract surgery pain andinflammation. European Medicines Agency （EMA） has approved the new indications ofnepafenac （developed by alcon）, which can be used to relieve pain and inflammation ofdiabetic patients after cataract surgery, and reduce the risk of diabetic macular edema aftercataract surgery. The pharmacology of nepafenac is after ocular drug delivery, rapidly passingthrough the cornea, transformed to Amfenac under the action of eye tissue hydrolase, and itcan quickly reach the targeted point and play a role. Nepafenac compared with the traditionalnon-steroidal anti-inflammatory drug, has the advantages of a stronger penetration, a strongertarget function, and a smaller side effects, etc. The People’s Republic of China has approvedthe application of Alcon （China） ophthalmic product co., about clinical registration ofnepafenac eye drops, and not yet on the market in domestic at present.Nepafenac is the international common accepted name for2-amino-3-benzoyl-phenylacetamide, and has empirical formula of C₁₅H₁₄N₂O₂, and amolecular weight of254.28g/mol, which is a new type of eye ophthalmic antipyreticanalgesic anti-inflammatory drug. This article is a study on the synthesis route and synthesisprocess, aimed at improving the production process which started from2-Aminobenzophenone for the synthesis of2-amino-3-benzoyl-phenylacetamide to enhancethe product’s yield. The cost of materials, catalyst, temperature, chloride reagent, purificationof solvent, reaction conditions and post-processing were determined for its industrialization.The improved synthetic methods of nepafenac were researched, and the procedure is morehelpful for the industrial production.The experiment results showed as the following: The foul smell of sodium thiophenolateis larger and the price of it is very higher, not using this route. The materials of methyl（methylthio） acetate or ethyl （methylthio） acetate can not be easy to buy in the domesticmarket. Although started from methanethiol sodium salt and methyl chloroacetate for the synthesis of methylthio acetamide has a low yield, the raw materials are easily available andcheap, and the quality of methylthio acetamide is more stable （>99.9%）, and the syntheticsmell of this reaction is bigger, suggesting small-scale production or purchase; There is not agreat deal of difference between the catalytic effect of tetrabutyl ammonium bromide andtetramethyl ammonium bromide. The chlorinating agent of tert-butyl hypochlorite hascomplex preparation, and the property is not stable, the detection results at any time to change,determining not to use this chlorinating agent; There are some great advantage of high processyield, stable quilty to use the chlorinating agent of N-Chlorosuccinimide; Compared withtert-butyl hypochlorite, the chlorinating agent of sulfochlorides has overcome the drawbacksof low yield and has not been easy to store; Compared with N-Chlorosuccinimide, thechlorinating agent of sulfochlorides has some merits and demerits, such as the merits of moreeconomic advantage, the demerits of the requirement of temperature in the process andleading to the increase of energy consumption, so the process of using sulfochlorides has yetto be further research. To ethanol was added the raw nepafenac （ethanol/nepafenac=40/1）,heated to completely dissolved by thermostat oil bath pot, decolorized by activated carbon,naturally cooled to0℃and stirred to separate out enough light yellow needle-likecrystal（HPLC showing the purity of product reached99.8%）, obtaining the yield of80%.The optimized synthesis route of nepafenac has the advantages of the following: mildreaction conditions, good reproducibility, and the quality of products are stable. The resultsfor the synthesis of nepafenac have an impotant guiding significance for industrial production,and the product yield has a substantial increace.