Left Dropropizine Dropropizine Derivatives Synthesis

Levodropropizine—as an chiral antitussive drug that has been produced since 1988 by Dompe'FarmS.P.A corporation and used in clinic therapy in Japan and several western countries. Now it has been produced in domestic market by a few domestic drag company.The synthesize methods of this companys is usually get Levodropropizine by spliting dropropizine despinner, which only could get the half Levodropropizine from the dropropizine and has a high cost. According to our producing conditions , we adopted L-3-chloro-l,2-propanediol and phenylpiperazine as the raw materiral to synthesize Levodropropizine, which is more easy than normal methods, the rate of production is 80%. Then we improved traditional synthesize of phenylpiperazine which reaction temperature is 220℃so that disagree with the lab synthesis. We firstly adopt the diethanolamine and thionyl chloride as the raw material to synthesize bis(2-Chloroethyl)amine hydrochloride, which secondly used to synthesize phenylpiperazine hydrochloride with aniline at only 135℃by cyclization reaction.In order to improve the drug effect, we designed two derivatives of dropropizine, which the one is benzene ring replaced by o-chloroaniline, the other is terminal hydroxyl of dropropizine replaced by several different kinds of alcohol ether. The target molecules were identified by spectrum methods and the process of synthesizing was optimized:(1)Bis(2-Chloroethyl)amine hydrochloride is synthesizd at 50℃and the chloroform as the solvent, the rate of production is almost 90%.(2)Phenylpiperazine is synthesizd at 135℃and n-butyl alcohol as the solvent,catalyst is potassium carbonate.(3)Epoxyphetpiperazine is synthesizd at room temperature and NaHCO₃ as the catalyst, the rate of production is almost 65%.(4)Using derivatives of 1, 4, 7 as representative compounds, with the results for compound 1 (dropropizine substituted by Ethylene glycol monomethyl ether): raw materials'molar ratio 1.4:1, reaction time 5h, reaction temperature 60℃; for 04(dropropizine substituted by diethylene glycol diethyl ether): raw materials' molar ratio 1.6:1, reaction time 2h, reaction temperature 40℃;for 07(dropropizine substituted by dipropylene glyeol methyl ether): raw materials' molar ratio 1.2:1, reaction time 2h, reaction temperature 30℃obtained and lay a good foundation for such compounds' yields and purification increase.