Study On The Synthesis Of Retigabine And Its Related Impurities

Epilepsy is a common neurological disorder. About 1% of people worldwide(65 million) have epilepsy, and nearly 80% of cases occur in developing countries. In 2013 it resulted in 116,000 deaths up from 111,000 deaths in 1990. Epilepsy becomes more common as people age. In the developed world, onset of new cases occurs most frequently in infants and the elderly. In our country epilepsy have become one of the main disease of the central nervous system.Retigabine or ezogabine, is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration(FDA),under the trade namePotiga, on June 10, 2010.Objective:To synthesize Retigabine(ethyl N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamate, compound 1) and its related impurities, including ethyl N-(2, 4-diaminophenyl) carbamate(compound a), ethyl N-(2-amino-4-benzylaminophenyl)carbamate(compound b) and ethyl N-[4-(4-fluorobenzyl-amino)-2-nitrophenyl]carbamate(compound c).Methods:1 Ethyl N-(4-nitrophenyl)carbamate(compound 2) was synthesized by nucleophilic substitution reaction of 4-nitroaniline and ethyl chlorocarbonate.The compound 2 was reduced to ethyl N-(4-aminophenyl)carbamate(compound3) by H2 over Pd/C catalyst. Ethyl N-[4-(1,3-dioxoisoindolin-2-yl)phenyl]carbamate(compound 4) was produced by the reaction of compound 3with phthalic anhydride to protect amino group in compound 3. Then, compound4 reacted with 69% nitric acid to form ethyl N-[4-(1,3-dioxoisoindolin-2-yl)-2-nitrophenyl]carbamate(compound 5). Ethyl N-(4-amino-2-nitrophenyl)carbamate(compound 6), a key intermediate, was obtained by the hydrazinolysis of compound 5 with 50% hydrazine hydrate. The nucleophilic addition reaction of compound 6 and 4-fluorobenzaldehyde to form imine,which was then reduced to ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl]carbamate(compound 8) by NaBH4. Finally, compound 8 was converted into target compound 1 using Raney Ni.2 The compound 6 was reduced to compound a with Pd/C catalyst.3 The nucleophilic addition reaction of compound 6 with benzaldehyde provided imine, which was then reduced to ethyl N-(4-benzylamino-2-nitrophenyl)carbamate(b2) by NaBH4. The intermediate(b2) was reduced to compound b by H2 over Raney Ni catalyst.4 Compound 8 was an key intermediate during the synthesis of Retigabine,it was also one of the related impurities, compound C.Results:1 Retigabine was synthesized from inexpensive 4-nitroaniline through seven steps, including acylation, reduction of nitro group, protection of amino group, nitration, deprotection of amino group, condensation/ hydrogenation and reduction of nitro group, with an overall yield of 25.3%.2 Compound a was produced by compound 6, with an yield of 92.3%.3 Compound b was produced by the condensation and hydrogenation of compound 6, with an yield of 63.5%.4 In the preparation of compound 2, acid-binding agent is needed. And N,N-diiso-propylethylamine was better than triethylamine and potassium carbonate.5 It was better to use hydrazine hydrate other than ammonia solution in the hydrazinolysis of compound 5 to compound 6.6 It was suggested to use isopropanol as the solvent, stirring at room temperature for 15 h, and then add methanol solution containing NaBH4 during the conversion of compound 6 to compound 8. By using this method, the conversion of material will be greatly improved, and simultaneously provides less by-products. The target product could be easily separated.7 The catalysis performance of Raney Ni was better than Pd/C in the reduction of compound 8 to compound 1, while stannous chloride was the worst.Conclusion: Retigabine and its related impurities were synthesized according to the designed routes. The chemical structures of important compounds were confirmed by 1H-NMR and electrospray ionization-mass spectrometry(ESI-MS). The influence of acid-binding agents, solvents and reduction catalysts on several intermediate steps in the synthesis of Retigabine was also studied.