Mirtazapine

Preparation

Under a nitrogen atmosphere and at 30–40°C, 147.4 g (0.52 mol) of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol was added in portions over approximately 3 hours to 530 g (5.4 mol) of 98% sulfuric acid. The mixture was stirred at 30–40°C for approximately 6 hours. The disappearance of the starting material was confirmed by HPLC, yielding 677 g of the reaction solution. 260 g of this reaction solution was diluted by adding dropwise to 408 g of water at 5–26°C. The container containing the reaction solution was washed with 25.5 g of 98% sulfuric acid, and the washed solution was added to the diluent. 635.8 g of 25% sodium hydroxide aqueous solution was added dropwise to the diluent at 13–30°C to adjust the pH to 1.5. 21 g of decolorizing carbon was added, and the mixture was stirred at 30–33°C for 45 minutes. The mixture was filtered, washed with 108 g of water, and the filtrate was divided into two portions.

Add 51g of 2-propanol to 699g of the separated filtrate, and adjust the pH to 11.2 by adding 25% sodium hydroxide aqueous solution dropwise at 30-33°C (using 53.4g). Separate the solution at approximately 76°C. Add 255g of 2-propanol to the organic layer, then add 4.8g of alumina A-11 (Sumitomo Chemical), stir at approximately 28°C for 15 minutes, and then add 1.4g of decolorizing carbon and stir for another 15 minutes. Filter the decolorizing agent and wash with 14.2g of 2-propanol. Concentrate the filtrate under reduced pressure, and distill to remove 2-propanol until the concentrated residue is 38.5g. Add 7.5g of 2-propanol and heat to 66°C, then add 15g of heptane. Add a small amount of mirtazapine seed crystals at approximately 53°C, mature at 50°C for 1 hour, and cool to 1°C over 6 hours. Filter to crystallize, and wash the crystals with 14g of heptane. The solution was dried under reduced pressure at approximately 60°C to obtain 21.2 g of white crystalline mirtazapine. The yield was 80%, and the HPLC purity was 99.98%.

Description

Mirtazapine is an antidepressant launched in the Netherlands. Mirtazapine is a potent antagonist of presynaptic α2 receptors as well as a moderately potent 5-HT antagonist. Studies suggested that blockade of α2-adrenoceptors, but not inhibition of noradrenaline uptake, is involved in the mechanism of the antidepressant action of mirtazapine. Mirtazapine has demonstrated efficacy in various studies in depressed patients, being equal or more potent than mianserin, amitriptyline, etc. and exhibiting less anticholinergic and gastrointestinal side effects and low cardiovascular toxicity. In addition to its antidepressant effects, studies in animals indicated that mirtazapine has anxiolytic andor hypnotic activity.

Chemical Properties

White Crystalline Solid

Originator

Organon (Netherlands)

Uses

antidepressant;antagonist at the H1, 5-HT2A, 5-HT2C, 5-HT3, and a2-adrenergic receptors, in that order of potency

Uses

An a 2-Adrenergic blocker. An analogue of Mianserin. Antidepressant

Definition

ChEBI: Mirtazapine is a benzazepine and a tetracyclic antidepressant. It has a role as an alpha-adrenergic antagonist, a serotonergic antagonist, a histamine antagonist, an anxiolytic drug, a H1-receptor antagonist and a oneirogen.

Manufacturing Process

1) 1-(3-Cyanopyridyl-2)-2-phenyl-4-methylpiperazine
17.43 g (0.3 mol) potassium fluoride is added to a solution of 13.85 g (0.1mol) 2-chloronicotinonitrile and 17.62 g (0.1 mol) 1-methyl-3-phenylpiperazine in 250 ml dry DMF and the suspension is heated at 140°Cunder a nitrogen atmosphere for 20 hours. After cooling, the reaction mixtureis poured into 1,250 ml water. The aqueous phase is extracted four times withethyl acetate the combined organic extracts are washed with 100 ml water.After drying, the extracts are evaporated. The crude oil may be used as suchfor the following step. The nitrile obtained may however also be purified bycolumn chromatography on SiO2, with hexane-acetone (95:5). In this way,21.9 g (79%) pure 1-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine isobtained; the substance crystallizes from petroleum ether; melting point 66.5-67.5°C.
2) 1-(3-Carboxypyridyl-2)-2-phenyl-4-methylpiperazine
The solution of 19.5 g (0.07 mol) 1-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine in 390 ml of a solution of 25 g KOH/ 100 ml ethanol isheated at 100°C for 24 hours. After cooling, water (390 ml) is added. Thealcohol is evaporated under vacuum and the cloudy solution remaining isextracted twice with 100 ml methylene chloride. The residual aqueous phaseis cooled and the pH is adjusted to 7 with 2 N HCl, after which it is extractedwith chloroform. After drying the chloroform extract, it is evaporated and 16.2g 1-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine is obtained as acolourless oil. Crystallization from ethanol gives a crystalline substance with amelting point of 161-162°C.
3) 1-(3-Hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine
20.4 g (0.07 mol) 1-(3-carboxypyridyl-2)-2-phenyl-4-methylpiperazine isdissolved in 300 ml dry THF and gradually added to a boiling suspension of20.4 g LiAlH4in 600 ml dry THF under a nitrogen atmosphere. The mixture isboiled for 4 hours, after which it is cooled in an ice-bath and decomposed byadding 81.6 ml water. The inorganic salts are filtered off. The filtrate is driedand solvent is removed by evaporation, giving a yield of 18.39 g (93%) 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine. Recrystallization fromether gives a crystalline product (white needles) of melting point 124-126°C.
4)2-Methyl-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino-[1,2-a]-pyrido[2,3-c]azepine(Mirtazapine)
6.5 ml concentrated sulfuric acid is added dropwise at room temperature to3.25 g of 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine. Duringthe addition, the temperature rises to 35°C. The whole is subsequently stirredfor a few hours, after which 60 g ice is added and the mixture is madealkaline with concentrated ammonia (22 ml). The reaction mixture is thenextracted with chloroform. The chloroform extracts are dried andconcentrated. The crude reaction product crystallizes when ether is added,and the solid obtained is recrystallized from petroleum ether. Yield of 2-methyl-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino-[1,2-a]-pyrido[2,3-c]azepine 2.43 g; melting point: 114-116°C.

brand name

Remeron (Organon).

Therapeutic Function

Antidepressant, Antihistaminic, Antidiuretic

Biological Functions

Mirtazapine (Remeron) enhances both serotonergic and noradrenergic neurotransmission. By blocking presynaptic α₂-adrenoceptors, mirtazapine causes release of norepinephrine. Indirectly, through noradrenergic modulation of serotonin systems, mirtazapine also causes increased release of serotonin. It is an antagonist at the 5-HT_2A, 5HT_2C, 5-HT₃, and histamine receptors but has minimal affinity for muscarinic or α₁-receptors. Mirtazapine does not inhibit neuronal reuptake of serotonin or norepinephrine.Weight gain and sedation are common side effects; sedation necessitates dosing at bedtime. Mirtazapine does not have significant effects on cytochrome P450 isoenzymes.

General Description

Mirtazapine (Remeron) was recently introduced for clinicaluse in the United States; its parent mianserin (pyridyl N replacedwith C-H) was long known to be an antidepressant.It is reported to be faster acting and more potent than certainSSRIs. The mode of action gives increased NE release viaα2-NE receptor antagonism and increased 5-HT release viaantagonism of NE α2 heteroreceptors located on serotoninergicneurons.

General Description

Mirtazapine (Remeron) is another example of tetracyclicα2-blockers that shows selectivity for α2-receptorsversus 1-receptors. Blockade of central α2-receptors resultsin an increased release of NE and serotonin. This hasprompted its use as an antidepressant. This agent also hasactivity at nonadrenergic receptors. It is a potent blockerof 5-HT2 and 5-HT3 serotonin receptors and at histamineH1-receptors.

Mechanism of action

Animal studies indicate that the efficacy of mirtazapine as an antidepressant results from enhancing central noradrenergic and serotonergic activity, possibly through blocking central presynaptic α2-adrenergic receptors. Blocking these receptors inhibits the negative feedback loop, which increases the release of NE into the synapse. Mirtazapine also is a potent antagonist at 5-HT2 and 5-HT3 receptors, and it shows no significant affinity for 5-HT1A or 5-HT1B receptors. Additionally, it displays some anticholinergic properties, and it produces sedative effects (because of potent histamine H1 receptor antagonism) and orthostatic hypotension (because of moderate antagonism at peripheral α1-adrenergic receptors). Its antidepressant effect is comparable to the TCAs and may be better than some SSRIs, especially in patients with depression of the melancholic type, but at higher doses, it may cause drowsiness and weight gain. The drug generally is well tolerated, producing no more adverse events (including anticholinergic events) than the SSRIs and fewer adverse events than the TCAs.
Mirtazapine absorption is rapid and complete, with a bioavailability of approximately 50% as a result of first-pass metabolism. The rate and extent of mirtazapine absorption are minimally affected by food. Dose and plasma levels are linearly related over a dose range of 15 to 80 mg. The elimination half-life of the (–)-enantiomer is approximately twice that of the (+)-enantiomer. In females of all ages, the elimination half-life is significantly longer than in males (mean half-life, 37 versus 26 hours).

Clinical Use

Mirtazapine is a piperazinodibenzoazepine antidepressant that is an isostere of the antidepressant mianserin. A seemingly simple isosteric replacement of an aromatic methine group (CH) in mianserin with a nitrogen to give a pyridine ring (mirtazapine) has profound effects on the physicochemical properties, pharmacokinetics, mechanisms of action, and antidepressant activities. Profound differences between receptor affinity and transporter affinity, pharmacokinetics, regioselectivity in the formation of metabolites, and toxicity are observed for mianserin and mirtazapine and their antidepressant mechanisms of action. The pyridine ring increases the polarity of the molecule and decreases the measured partition coefficient and the basicity. Mianserin is a potent inhibitor of NET , whereas mirtazapine has negligible effects on the inhibition of NET (pKi = 7.1 vs. 5.8 respectively).