The Research On Synthesis Of Mirtazapine And Its Intermediates

Mirtazapine 1,2,3,4,10,14b-hexhydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c][2]benzazepine had been approved, under the trademarkRemenon,for the treatment of depression. As a novel medicine fordepressant, it had been researched and developed by OrganonCompany in Holland. With high price, Mirtazapine is still under theage of patents by now. So it is necessary for us to exploit aneconomical and practical route, which would do much benefit to thehealth of our people and bring good economical and research value,as well. Mirtazapine had been synthesized in high purity (99%) by eightsteps from styrene oxide, N-methylethylenediamine and 2-chloro-3-pyridine nitrile with a yield of 3% ,in contrast with 13.3% accordingto literature. The synthesis of 1-methyl-3-phenylpiperazine had been modifiedby aminating in lower temperature, and ring closing in highertemperature. This modification was advantageous over prior artprocesses, with higher yield (19.4%) and better purity (>99%). A new process had been provided for making 1-methyl-3-phenylpiperazine by attaching a large group to the nucleophilicreagent, which enhanced selectivity of the styrene oxide. So1-methyl-3-phenylpiperazine could be synthesized with a good yieldof 30% and a better purity of 99%, by a series of steps such as amino-protection, nuclear addition, chloration-deprotection and ring closing.The prior difficulty in isomer separation had resolved by the entirelynew route. A series of 2,3-pyridine derivatives had been synthesized. Amongthem, 2-chloro-3-pyridine nitrile had been purified by recrystalizationin petroleum, avoiding operation in vacuum, according to modifiedliterature. A new process had also provided for making the Mirtazapineintermediate, 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazinedirectly from 2-chloro-3-pyridine carboxylic acid and 1-methyl-3-phenylpiperazine. With moderate reaction conditions, this newprocess was advantageous over prior art processes, which necessitatedlonger reaction time and large volumes of concentrated base and acidsolutions. However, much effort should be made to improve its yield. Mirtazapine had been prepared by ring closing of theintermediate, 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-Piperazinecomprising two steps of Fried-Crafts reaction and Ming long-Huangreduction. This method could avoid the use of reducing reagentLiAlH4 and would be widely used in the future as well.