Methods for the preparation of mirtazapine intermediates

Details Methods for the preparation of mirtazapine intermediates Methods for the preparation of mirtazapine intermediates

2002-02-14

2004-08-10

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C544S365000

Reexamination Certificate

active

06774230

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to the preparation of certain piperazine ring-containing compounds. More particularly, the invention relates to 1-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine dihydrate, methods for its preparation, and methods for its use in the preparation of mirtazapine.
BACKGROUND OF THE INVENTION
Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c][2]benzazepine, is the first agent in a new class of antidepressant compounds called piperazinoazepine-derivatives. Mirtazapine is the active ingredient in REMERON, manufactured by Organon, and is approved by the United States Food and Drug Administration for the treatment of depression. Conventional therapeutics for treating depression include selective serotonin reuptake inhibitors (e.g., fluoxetine), monoamine oxidase inhibitors (e.g. phenelzine), and tricyclic antidepressant agents (e.g. doxepin).
Evidence suggests that mirtazapine acts as an antagonist at central presynaptic &agr;
2
-adrenergic autoreceptors and heteroreceptors, thereby possibly resulting in increased central noradrenergic and serotonergic neurotransmission. Mirtazapine is a potent antagonist of serotonin type 2 (5-HT
2
) and type 3 (5-HT
3
) receptors, but the drug does not exhibit any significant affinity for serotonin type 1A (5-HT
1A
) or type 1B (5-HT
1B
) receptors. Mirtazapine is a potent antagonist of histamine (H
1
) receptors, is a moderate antagonist at muscarinic receptors, and exhibits moderate peripheral &agr;
2
-adrenergic blocking activity. Because of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated antidepressant agent that has demonstrated important anxiolytic and sleep-improving effects.
As a tetracyclic agent, mirtazapine differs structurally from conventional therapeutics. Mirtazapine has the following chemical structure I:
Mirtazapine can be prepared as shown in scheme 1, below.
Example 1 of U.S. Pat. No. 4,062,848 (“the '848 patent”) describes a conventional manner for sequentially preparing each of the four compounds shown in scheme 1. For example, 1-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine (“cyano-NMPP”) is converted into the 1-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine intermediate (“carboxy-NMPP”) by the hydrolysis of the nitrile under highly basic conditions (potassium hydroxide) at high temperatures (100° C.) for a long time (24 h).
A need remains, however, for methods for preparing carboxy-NMPP dihydrate and other mirtazapine intermediates, which are useful, for example, in preparing mirtazapine.


REFERENCES:
patent: 4062848 (1977-12-01), van der Burg
patent: 6376668 (2002-04-01), Iishi et al.

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