85650-52-8

Hazards Identification

Pictogram(s):

Signal:

Warning

GHS Hazard Statements:

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H336 (100%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]
H361 (30.51%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]
H373 (59.32%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]
H411 (33.9%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes:

P203, P260, P261, P264, P270, P271, P273, P280, P301+P317, P304+P340, P318, P319, P330, P391, P403+P233, P405, and P501

Hazard Classes and Categories:

Acute Tox. 4 (100%)
STOT SE 3 (100%)
Repr. 2 (30.51%)
STOT RE 2 (59.32%)
Aquatic Chronic 2 (33.9%)
Acute Tox. 4 (16.67%)
Carc. 2 (66.67%)
Aquatic Chronic 2 (66.67%)

Usage

Biological Activity

Antidepressant agent; potent 5-HT 2 , 5-HT 3 and histamine H 1 receptor antagonist and moderately potent α 2 -adrenoceptor antagonist (pK i values are 8.05, ~ 8.1, 9.3 and 6.95 respectively). Enhances noradrenalin (NA) release in rat brain via inhibition of α 2 -adrenergic autoreceptors and displays only weak affinity for monoamine transporters (pK i values are 5.6, < 5 and < 5.1 for inhibition of NA, dopamine and 5-HT uptake respectively). Increases hippocampal NA and 5-HT levels in rats following systemic administration in vivo .

Biochem/physiol Actions

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). Mirtazapine agonizes selective adrenergic and serotonergic receptors so that both NE release and 5-HT1A mediated serotonergic signaling are increased.

Veterinary Drugs and Treatments

Currently, the only FDA approved indication for mirtazapine is depression in humans. Reported veterinary uses include treatment of chemotherapy-induced nausea and vomiting (CINV); anorexia associated with renal failure (azotemia), congestive heart failure, gastro-intestinal disorders, liver disease, or neoplasia. Other uses suggested include stress induced diseases; insomnia; post-pyometra symptoms; and post-operative inappetance. Studies have shown that mirtazapine also alleviated sleep apnea in rats and humans. There are case reports published in human literature of mirtazapine use as treatment for non-mechanical vomiting after gastric bypass, CINV, obsessive-compulsive disorder, nocioception and chronic pain, migraine headache prophylaxis, anti-psychotic induced akathisia, idiopathic nausea and vomiting, serotonin syndrome induced nausea, anorexia, irritable bowel syndrome, resistant hyperemesis gravidarum, and for the treatment of negative symptoms of schizophrenia. Studies in rats have also shown that mirtazapine significantly improves memory.

Drug interactions

Potentially hazardous interactions with other drugs Alcohol: increased sedative effect. Antidepressants: possibly increased risk of serotonergic effects with fluoxetine, fluvoxamine or venlafaxine; CNS excitation and hypertension with MAOI and moclobemide - avoid. Antimalarials: avoid with artemether and lumefantrine and piperaquine with artenimol. Methylthioninium: risk of CNS toxicity - avoid if possible.

Metabolism

Extensively metabolised in the liver via CYP2D6, CYP1A2, and CYP3A4. The major biotransformation pathways are demethylation and oxidation followed by glucuronide conjugation. The N-desmethyl metabolite is pharmacologically active. Elimination is via urine and faeces (15%).

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 
• 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 
• 130277-16-6 2-amino-3-benzylpyridine 
• 1071504-87-4 N-(2-chloro-ethyl)-N-methyl-2-(10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepin-10-yl)-carboxamide 
• 1071504-81-8 N-(2-hydroxyethyl)-N-methyl-10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-carboxamide 
• 1071504-84-1 (10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepin-10-ylmethyl)(2-hydroxyethyl)-methylamine 
• 1071504-65-8 10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-N-methylcarboxamide 
• 1071504-64-7 (10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepin-10-ylmethyl)-methyl-amine 
• 1071504-75-0 10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-carboxylic acid ethyl ester 
• 1071504-70-5 10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine-10-carboxylic acid methyl ester 
• 1071504-67-0 10-bromomethyl-10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine 
• 10366-35-5 2-chloronicotinamide 

Downstream Products

• 61337-87-9 (+)-Mirtazapine 
• 61337-67-5 (-)-Mirtazapine 
• 85650-53-9 mirtazapinium hydrogenmaleate 
• 102335-57-9 1,2,3,4,10,14b-hexahydro-2-methylpyrazino<2,1-a>pyrido<2,3-c><2>benzazepin-8-ol 
• 61337-86-8 1,2,3,4,10,14b-hexahydro-8-bromo-2-methyl-pyrazino<2,1-a>pyrido<2,3-c><2>benzazepine 

Relevant academic research and scientific papers

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.

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

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.

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

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 MIRTAZAPINE

PROBLEM TO BE SOLVED: To provide a method by which mirtazapine useful as an antidepressant drug can be produced with high quality and high production yield in the present invention. SOLUTION: A method for producing mirtazapine includes allowing 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinemethanol and sulfuric acid to react with each other by stirring and mixing in a reaction vessel including a stirring body. In the method for producing mirtazapine, the stirring and mixing are performed by setting a tip rate which is the rate of a tip of the stirring body in the stirring at 1.0 m/s or more. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2018,JPOandINPIT

MANUFACTURING METHOD OF MIRTAZAPINE

PROBLEM TO BE SOLVED: To provide a method capable of manufacturing mirtazapine useful as antidepressant at high quality and high manufacturing yield without needs for complicated purification operation. SOLUTION: Mirtazapine with largely suppressed by-production amount of impurities during reaction can be manufactured by reacting with use of sulfuric acid with concentration of 85.0% or more and less than 96.0% in a method for manufacturing mirtazapine by reacting 2-(4-methyl-2-phenyl)-1-piperazinyl)-3-pyridinemethanol and sulfuric acid. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPO&INPIT

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