61337-67-5

Basic information

• Product Name: Mirtazapine
• Synonyms: 1,2,3,4,10,14B-HEXAHYDRO-2-METHYLPYRAZINO[2,1-A]PYRIDO[2,3-C][2]BENZAZEPINE;ORG-3770;MIRTAZANINE;MIRTAZEPINE;REMERON;1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine;1-a)pyrido(2,3-c)(2)benzazepine,1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino(;2-Methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine
• CAS NO: 61337-67-5
• Molecular Formula: C17H19N3
• Molecular Weight: 265.35
• EINECS: 288-060-6
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Serotonin;Pharmaceutical raw material
• Mol File: 61337-67-5.mol

Chemical Properties

• Melting Point: 114-116°C
• Boiling Point: 432.4 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: white/solid
• Density: 1.22 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: DMSO: ~8 mg/mL, soluble
• PKA: pKa 7.1(47% MeOH in H2O,t =25,I=0.15(KCl)) (Uncertain)
• CAS DataBase Reference: Mirtazapine(CAS DataBase Reference)
• NIST Chemistry Reference: Mirtazapine(61337-67-5)
• EPA Substance Registry System: Mirtazapine(61337-67-5)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-39/23/24/25
• Safety Statements: 22-24/25-45-36/37-16-7
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 3
• Hazardous Substances Data: 61337-67-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Mirtazapine is used as an antidepressant for treating major depressive disorder. It is considered effective, with equal or greater potency than other antidepressants such as mianserin and amitriptyline, while exhibiting fewer anticholinergic and gastrointestinal side effects and lower cardiovascular toxicity.
Mirtazapine is used as an antagonist at the H1, 5-HT2A, 5-HT2C, 5-HT3, and α2-adrenergic receptors for its anxiolytic and hypnotic effects, making it beneficial in managing anxiety and sleep disorders.
Used in Research and Development:
Mirtazapine serves as a potent blocker of 5-HT2 and 5-HT3 serotonin receptors and histamine H1 receptors, making it a valuable compound for studying the interactions and effects of these receptors in various conditions and potential therapeutic applications.

Manufacturing Process

1) 1-(3-Cyanopyridyl-2)-2-phenyl-4-methylpiperazine17.43 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-methylpiperazineThe 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.

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-HT2A, 5HT2C, 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.

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).

InChI:InChI=1/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3/p+2/t16-/m0/s1

Upstream product

• 61337-89-1 2-(4-methyl-2-phenylpiperazin-1-yl)-pyridine-3-methanol 
• 5271-27-2 1-methyl-3-phenylpiperazine 
• 1071838-96-4 rac-1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-10-ol 
• 191546-96-0 3,4,10,14b-tetrahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-1(2H)-one 
• 1071504-86-3 (10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepin-10-ylmethyl)(2-chloro-ethyl)-methylamine 
• 75-75-2 methanesulfonic acid 
• 10366-35-5 2-chloronicotinamide 
• 1071546-33-2 (14bS)-1,3,4,14b-tetrahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-10(2H)-one 
• 1071546-36-5 (14bS)-1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-10-ol 
• 824954-89-4 2-[(2S)-4-methyl-2-phenyl-1-piperazinyl]-3-pyridinemethanol 
• 85650-52-8 Mirtazapine 
• 130277-16-6 2-amino-3-benzylpyridine 
• 1071504-90-9 ((R)-10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepin-10-ylmethyl)-(2-hydroxyethyl)-methylamine 
• 1071504-78-3 (R)-(-)-10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-N-methylcarboxamide 

Downstream Products

• 61337-86-8 1,2,3,4,10,14b-hexahydro-8-bromo-2-methyl-pyrazino<2,1-a>pyrido<2,3-c><2>benzazepine 
• 61337-67-5 (-)-Mirtazapine 
• 680993-85-5 S-mirtazapine malonate 

Relevant articles and documents

METHOD FOR PRODUCING PHENYLPIPERAZINE PYRIDINE METHYL ACETATE

PROBLEM TO BE SOLVED: To provide a method for producing [2-(4-methyl-2-phenylpiperazin-1-yl)pyridin-3-yl] methyl acetate capable of improving the quality of mirtazapine and improving the efficiency of workability in an industrial scale. SOLUTION: There is provided a method for producing pyridine methyl acetate, in which a mixture of [2-(4-methyl-2-phenylpiperazine-1-yl)pyridin-3-yl] methyl acetate produced through a reaction between 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinemethanol and acetic anhydride in an organic solvent is crystallized in a mixed solvent or a single solvent. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT

Preparation method and intermediate product of mirtazapine

The invention discloses a preparation method and an intermediate product of mirtazapine. The preparation method comprises the following steps: in an organic solvent, carrying out a cyclization reaction on a compound represented by a formula I and/or an inorganic acid salt thereof in the presence of a sulfonic acid resin, and separating to obtain a solid, ie., the mirtazapine intermediate product;and carrying out an ion exchange reaction on the mirtazapine intermediate product and an alkali to obtain mirtazapine. The preparation method has the advantages of simplicity and convenience in operation, easiness in product separation, small pollution, suitability for industrial production and the like.

Simultaneous enantioselective determination of seven psychoactive drugs enantiomers in multi-specie animal tissues with chiral liquid chromatography coupled with tandem mass spectrometry

In stock farming, illegal use of antipsychotics has caused the food safety problem. This paper presents for the first time, a multi-residues method for the simultaneous enantioselective determination of seven antipsychotics in pork, beef and lamb muscles. The behaviors of Chiralpak AGP toward changes in pH and organic modifier in mobile phase were studied, and all analytes were rapidly separated within 30 min. The calibration curves of all enantiomers were linear in the range of 1–250 ng g?1, with correlation coefficient above 0.9931. The recoveries of the targeted compounds were higher than 82.1%, with repeatability and intermediate precision lower than 18.2% and 17.4%, respectively. In three matrices, the limit of detection and limit of quantification ranged from 0.20 to 0.65 ng g?1 and from 0.40 to 1.00 ng g?1, respectively. The proposed method can be used to provide additional information for the reliable risk assessment of chiral antipsychotics.

A synthesis method of midanping

The invention discloses a method for synthesizing mirtazapine. According to the method, 2-halogenated nicotinonitrile is used as an initial compound, and 2-chloronicotinamide, 2-(4-methyl-2phenyl-1-piperazinyl)nicotinamide, 2-(4-methyl-2phenyl-1-piperazinyl)nicotinic acid, 1-(3-hydroxymethylpyridyl-2-)-4-methyl-2-phenylpiperazine and other intermediate products are sequentially synthesized to prepare the mirtazapine. Against the defects in a current mirtazapine synthesizing method, the process is improved, a new synthesizing route is designed, and a preparation method which is economical and is easy for practical operation is provided to mirtazapine synthesis. The method is suitable for large-scale industrial production.

MANUFACTURING METHOD OF PYRIDINEMETHANOL COMPOUND AND MANUFACTURING METHOD OF MIRTAZAPINE

PROBLEM TO BE SOLVED: To provide a method capable of manufacturing a manufacturing intermediate of mirtazapine which is useful as an antidepressant at high yield and manufacturing high purity mirtazapine. SOLUTION: In a method for reacting 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinecarboxylic acid and hydrogenated bis(2-methoxyethoxy)aluminum sodium, manufacturing yield of 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridine methanol is improved by washing a reaction mixture with alkali metal halide. Also in the method, by-production amount of dimer impurities during reaction can be suppressed and high quality mirtazapine can be manufactured in a method for reaction 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridine methanol and sulfuric acid. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT

1-(3-CARBOXYPYRIDYL-2-)-2-PHENYL-4-METHYLPIPERAZINE HAVING CRYSTAL STRUCTURE AND METHOD FOR PRODUCING THE SAME

PROBLEM TO BE SOLVED: To provide a novel crystal form of pyridinecarboxylic acid compound having high solubility in an ether solvent, such as THF, which can be used in an industrial scale, and a method for producing a high-purity pyridinemethanol compound. SOLUTION: The present invention provides a 1-(3-carboxypyridyl-2-)-2-phenyl-4-methylpiperazine (pyridinecarboxylic acid compound) of novel crystalline form having a characteristic peak at least at 10.1°±0.2° and 13.9°±0.2° in 2θ, in X-ray diffraction using Cu-Kα rays, by crystallization in acetate ester and methanol solvent systems. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2018,JPO&INPIT

METHOD FOR PRODUCING 1-(3-HYDROXYMETHYLPYRIDYL-2-)-2-PHENYL-4-METHYLPIPERAZINE

PROBLEM TO BE SOLVED: To provide a method for producing a pyridinemethanol compound. SOLUTION: The present invention provides a method for producing a pyridinemethanol compound represented by formula (1). In the method, a pyridinecarboxylic acid compound represented by formula (3) is reduced with an aluminum metal reductant, and a reaction solution after the reduction is added to an aqueous solution comprising a compound that forms a complex with aluminum. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT

METHOD FOR PRODUCING MIRTAZAPINE

PROBLEM TO BE SOLVED: To provide a method in which mirtazapine useful as an antidepressant can be produced at high quality as well as at high production yield. SOLUTION: In a method for producing mirtazapine by reacting 2-(4-methyl-2-phenylpiperazin-1-yl)-3-pyridinemethanol with sulfuric acid, when an alcohol solution of crude mirtazapine obtained as a concentrated residue of a toluene extraction liquid is subjected to activated carbon treatment, the amount of toluene is made 15 g or less with respect to 100 g of the alcohol solution, whereby the reduction efficiency of specific impurities during the activated carbon treatment can be improved, and as a result, mirtazapine with high quality can be produced. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT

MANUFACTURING METHOD OF MIRTAZAPINE

PROBLEM TO BE SOLVED: To provide a method for manufacturing mirtazapine useful as an antidepressant at high quality and high manufacturing yield. SOLUTION: Mirtazapine with reduced impurities is manufactured by crystallizing mirtazapine by using a mixed solvent of a good solvent selected from ethanol, propanol, isopropanol, acetone, tetrahydrofuran and dioxane and a poor solvent which is water, or a mixed solvent of a good solvent selected from propanol and isopropanol and a poor solvent which is heptane in a method of manufacturing mirtazapine by reacting 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinemethanol and sulfuric acid. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT

MANUFACTURING METHOD OF MIRTAZAPINE

PROBLEM TO BE SOLVED: To provide a method for manufacturing mirtazapine useful as an antidepressant at high quality and high manufacturing yield. SOLUTION: Mirtazapine with reduced impurities is manufactured by crystallizing mirtazapine by using a mixed solvent of a good solvent selected from an alcohol solvent, a ketone solvent, an ether solvent and an ester solvent and a poor solvent selected from heptane and hexane, or a mixed solvent of a good solvent and a poor solvent in which a good solvent which is acetonitrile and a poor solvent which is water in a method of manufacturing mirtazapine by reacting 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinemethanol and sulfuric acid. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT