The Synthesis Of Flupirtine, Triamino Pyridine Compounds, And Study On Flupirtine Modification Transformation

Flupirtine is a centrally activing non-opioid analgesic made by Asta Medica, which is originally used for the surgery pain. Flupirtine, as an nonaddictive analgesic, has not been registered in domestic yet. However, it was found that Flupirtine also has action as anticonvulsant, Myorelaxant, Cellular protective effect, Reverses akinesia and rigidity in dopamine-deplete animals, anti-parkinsonian, anti-migraine, anti-inflammatory and antipyretic activity.The synthesis of Flupirtine maleate was studied. 3-nitro-2,6-diaminopiridine was chosen as start material,which was amined sperately at position 2 and 6, then catalystically hydrogenated and acylated with ethyl chloroformate, finally salted with maleic acid to get Flupirtine in a total yield 76.5%.A reactive selectivity was discovered between two amino at position 2 and 3 on the pyridine ring of the triaminopyridine compound in the synthesis of Flupirtine, based on the selectivity, 3-nitro-2,6-diaminopiridine as start material reacting with cyclopropyl amine, then followed by hydrogenation and acylation gave 2-chloro-N-(2-cyclopropyl amine-4-chloro-3-pyridyl)-3-pyridyl carboxamide. 2,3-diamino-4-methyl pyridine was obtained from 2-amino-4-methylpyridine by nitration and hydrogenation . The two intermediates lay a solid foundation for creating a new synthetic route of dipyridodiazepine compounds as non-nuclei reverse transcriptase inhibitors.There are three kinds of modification A, B, S for Flupirtine, which involves drug absorption difference. Transformation from Mod. B And S to Mod. A was going on by stirring in the isopropynol at 20 ℃. Various samples were examined by X-ray diffractometry and then the Transformation from Mod. A and S to Mod. B was monitored by DSC. From the DSC data it was discovered that there is a linear relation between the inversion temperature Tt and the content of Mod. A. The relation helps deducting the content of Mod. A from Tt. In the IR spectrum it was found three zone are responsible for the change in Mod.A content. With the increasing Mod.A content, In zone No.3, the ratio of peak height at 758 cm^-1 to that at 775 cm^-1 rises gradually. When the ratio is 1:1, it indicates Mod.A content is about 80%⁹0%, which is for clinic use.