Research On New Synthesis Of Guanethidine Sulfate

Guanethidine sulfate ( [2-(Octahydro-1-azocinyl)ethyl]guanidine sulfate), is found to have protracted antihypertensive properties.It is very effective and widely used today. An new process for the synthesis of the target drug was researched in this article. Sodium ethoxide was used as a condensation catalyzer for the reaction of cyclohexanone with nitromethane to give sodium salt of 1-(nitromethyl)cyclohexanol, then acidification of the above compound resulted in 1-(nitromethyl)cyclohexanol. In acidic medium hydrogenation was carried out to convert 1-(nitromethyl)cyclohexanol to 1-(aminomethyl) cyclohexanol. cycloheptanone are prepared more conveniently via diazotization and ring-enlargement by treatment 1-(aminomethyl) cyclohexanol with sodium nitrite. 2-ketoheptamethylenimine was prepared by one-pot reaction of cycloheptanone with concentrated sulfuric acid. In this step, oximation and rearrangement occurred .The key intermediate for synthesis of Guanethidine was Heptamethylenimine.we found a new method for the preparation of this intermediate in good yield compared with other known methods.The process was simple,safe and costed low,the synthetic conditions had also been optimized by orthogonal design method.We thougt it cound be used in manufacture of Guanethidine.As for our procedure , Heptamethylenimine was prepared directly by reduction of 2-ketoheptamethylenimine under mild conditions . In reaction above the reductant was cheap and safety to be treated,the solvent was also selected specially. Gabriel reaction was adopted to synthesis 2-(0ctahydro-1-azocinyl)ethylamine, N-(β-Heptamethyleniminoethy1)phthalimide was prepared by treating Heptamethylenimine with N - (β-bromoethy1) phthalimide. N - (β-bromoethy1) phthalimide was easily prepared from phthalic anhydride in two steps. Finally, Guanethidine sulfate was gaven in good yield by condensation of 2- (0ctahydro-1-azocinyl) ethylamine with 2-Methylthiopseudourea sulfate. In order to confirm with many countries's Pharmacopoeias ,Guanethidine monosulfate and Guanethidine hemisulfate were directly prepared in the last step under different synthetic conditions respectively. In conclusion, we had found a new process which was suitable for manufacture of Guanethidine sulfate with low product cost and safe operation procedure.In addition, pollution of the process were extremely reduced.