METHOD FOR THE PREPARATION OF AN ENANTIOMER OF A TETRACYCLIC BENZAZEPINE
The present invention relates to a method for the preparation of mirtazapine and tetracyclic analogous compounds having substantial enantiomeric excess of the R or S form. The invention further relates to a novel intermediate and its use for the preparation of mirtazapine having a substantial enantiomeric excess of the R or S form. The method comprising the steps of a: providing a carboxylic acid compound according to Formula I having a substantial enantiomeric excess of the R or S form, b: converting the carboxylic acid group of compound I into a ketone group, producing a ketone compound of Formula II, c: optionally reducing ketone compound II with a mild reduction agent to form the intermediate hydroxy compound of Formula III and d: forming the mirtazapine of Formula IV by reduction of the ketone compound II or of the hydroxy compound III using a strong reduction agent.
1 . A method for the preparation of mirtazapine (formula IV) having a substantial enantiomeric excess of the R or S form, the method comprising the steps of
a: providing a carboxylic acid compound according to Formula I having a substantial enantiomeric excess of the R or S form,
b: converting the carboxylic acid group of compound I into a ketone group, producing a ketone compound of Formula II,
c: optionally reducing ketone compound II to form the intermediate hydroxy compound of Formula III,
d: forming the mirtazapine of Formula IV by reduction of the ketone compound II or of the hydroxy compound III.
2 . The method according to claim 1 , wherein the formed mirtazapine has an enantiomeric excess of the R or S form of at least 80% and the obtained mirtazapine product comprises side products in an amount below 10 wt % (wt % expressed as the total weight of side products divided by the total weight of the obtained reaction product×100%).
3 . The method according to claim 2 , wherein the enantiomeric excess is at least 95% and the amount of side products is below 2 wt %.
4 . The method according to claim 1 , wherein the reduction step (c) is done with a hydride as reduction agent.
5 . The method according to claim 1 , wherein the reduction step is done with a mixture of a metal hydride reduction agent and a metal halogenide as reduction agent.
6 . The method according to claim 4 , wherein the hydride is a metal hydride.
7 . The method according to claim 1 , wherein the strong reduction agent is a mixture of a borohydride and a strong acid.
8 . The method according to claim 1 , wherein in step (b) the carboxylic acid group is first activated with an activator and subsequently reacted with a Lewis acid.
9 . The method according to claim 8 , wherein the activator is a chlorinating agent.
10 . A compound according to formula II in a mixture having an enantiomeric excess of the R or S form or in enantiopure pure R or S form.
11 . A compound according to formula III in racemic form, in a mixture having a substantial enantiomeric excess of the R or S form or in enantiopure pure R or S form.
12 . The compound according to claim 10 having enantiomeric excess of the R or S form of at least 80%, and comprising side products in an amount below 10 wt %.