- 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
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Paragraph 0043-0048
(2020/03/04)
-
- 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.
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-
Paragraph 0033; 0035-0043
(2020/06/09)
-
- 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.
- Zhu,Li, Shuang,Zhou, Li,Li, Qing,Guo, Xingjie
-
-
- 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.
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-
-
- 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
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-
Paragraph 0055-0059; 0064; 0065
(2017/10/27)
-
- 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
- -
-
Paragraph 0058-0060
(2017/08/08)
-
- 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
- -
-
Paragraph 0062; 0063; 0064
(2017/07/14)
-
- 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
- -
-
Paragraph 0006; 0105-0107
(2018/01/11)
-
- 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
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-
Paragraph 0005; 0055-0061
(2018/04/14)
-
- 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
- -
-
Paragraph 0050-0052
(2017/06/19)
-
- 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
- -
-
Paragraph 0064; 0065
(2017/08/18)
-
- 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
- -
-
Paragraph 0051; 0052; 0053; 0055; 0056
(2017/11/03)
-
- PRODUCTION METHOD OF 2-(4-METHYL-2-PHENYLPIPERAZIN-1-YL)PYRIDINE-3-METHANOL
-
PROBLEM TO BE SOLVED: To provide a method of producing high-purity 2-(4-methyl-2-phenylpyperadin-1-yl)pyridine-3-methanol efficiently with a content of a specified impurity reduced. SOLUTION: In reducing 2-(4-methyl-2-phenylpyperadin-1-yl)pyridine-3-carboxylic acid or its salt, a solution or suspension of a metal hydride is added to 2-(4-methyl-2-phenylpyperadin-1-yl)pyridine-3-carboxylic acid or its salt. COPYRIGHT: (C)2016,JPO&INPIT
- -
-
-
- A SYNTHETIC METHOD OF HIGH PURITY MIRTAZAPINE
-
The present invention relates to a method for manufacturing Mirtazapine that is useful as an antidepressant and, more specifically, to an improved method for synthesizing high purity Mirtazapine by cyclizing 2-(4-methyl-2-phenylpiperazine-1-yl)pyridine-3-methanol under a toluene solvent and mixed acid of polyphosphoric acid and methanesulfonic acid. The present invention uses polyphosphoric acid and methane sulfonic acid instead of using concentrated sulfuric acid when manufacturing the Mirtazapine, thereby being able to solve a heating problem which is caused when divided adding the 2-(4-methyl-2-phenylpiperazine-1-yl)pyridine-3-methanol for 10-30 times at room temperature; and a remaining problem of starting materials caused by high viscosity agitation. The present invention uses toluene as a reaction media, thereby being able to prevent formation of tar formed during a reaction in highly concentrated acid; and not requiring additional solvents and being economical. Also, the present invention makes a reactive mixture into alkaline under the toluene solvent, thereby being easier to control temperature than methylene chloride; and being able to solve a problem in which the Mirtazapine is precipitated. The reactive mixture used in the manufacturing method of the present invention is easy to use in industrial fields and has a mild reaction condition, thereby being useful for mass production of the Mirtazapine.
- -
-
Paragraph 0058; 0060
(2016/12/16)
-
- PROCESS FOR THE PREPARATION OF 1- ( 3-HYDROXYMETHYLPYRID-2 -YL ) -2 -PHENYL-4-METHYLPIPERAZINE AND MIRTAZAPINE
-
Disclosed herein is a process for the manufacture of mirtazapine and intermediates useful in preparing mirtazapine which includes the reduction of 1-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine with an organoaluminum hydride.
- -
-
Page/Page column 4
(2011/09/14)
-
- PROCESS FOR THE PREPARATION OF 1- ( 3-HYDROXYMETHYLPYRID-2 -YL ) -2 -PHENYL-4-METHYLPIPERAZINE AND MIRTAZAPINE
-
Disclosed herein is a process for the manufacture of mirtazapine and intermediates useful in preparing mirtazapine which includes the reduction of 1-(3-carboxypyridyl-2)- 4-methyl-2-phenylpiperazine with an organoaluminum hydride.
- -
-
Page/Page column 14-15
(2010/05/13)
-
- PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE MIRTAZAPINE
-
The invention provides a process for efficiently producing optically active mirtazapine. Specifically, a process for production of optically active mirtazapine wherein an RS mixture of mirtazapine is optically resolved with optically active tartaric acid in the presence of a solvent. More specifically, a process for production of optically active mirtazapine, characterized by making an RS mixture of mirtazapine contact with optically active tartaric acid in the presence of a solvent, and preferentially crystallizing the optically active mirtazapine salt. The solvent is preferably a mixed solvent consisting of a water-soluble organic solvent and water, and more preferably a mixed solvent consisting of a C1-3 alcohol and water.
- -
-
Page/Page column 4-5
(2010/04/30)
-
- PAINKILLING ASSOCIATION COMPRISING A DIHYDROIMIDAZOPYRAZINE DERIVATIVE
-
The invention relates to a product comprising (1R)-1-[(({2R)-2-amino-3-[(8S)-8-(cyclohexylmethyl) -2-phenyl-5,6-dihydroimidazo [1,2-a]pyrazin-7(8H)-yl]-3-oxopropyl}dithio)methyl]-2-[(8S)-8-(cyclohexylmethyl) -2-phenyl-5,6-dihydrolmidazo[1,2-a]pyrazin-7(8H)-yl]-2-oxoethylamine in association with an analgesic agent selected from morphine, the similar or a morphine derivative, sodium channel inhibitors, non-steroidal antiflammatory agents (AINS), glutamatergic system inhibitors, tricycle antidepressants and gabaergic derivatives for simultaneous therapeutic use which is separated or out over the time for pain treatment or prevention.
- -
-
-
- A METHOD FOR THE PREPARATION OF AN ENANTIOMERICALLY PURE BENZAZEPINE
-
The invention relates to a method for the preparation of a cyclic compound according to formula (III) comprising reacting a compound according to Formula (I) and a compound according to formula (II), wherein in Formula (I), R1, R2, R3 and R4 may be hydrogen or substituent groups comprising one or more carbon atoms and/or hetero-atoms, wherein R1, R2, R3 and R4 can be combined in aromatic or aliphatic ring structures, -Y is a ring element comprising 1-3 substituted or unsubstituted carbon atoms and/or heteroatoms in the ring and -R5 is hydrogen or a hydrocarbon substituent group comprising one or more carbon atoms and optionally one or more hetero atoms, and wherein in Formula (II), Z1 and Z2 are, leaving groups, X is a reactive functional hydrocarbon group for subsequent ring closure, comprising one or more carbon atoms and a reactive functional group and having a chain of between 1 to 6 atoms between the carbon atom attached to the central carbon atom of formula (II) and the reactive functional group and R8 is hydrogen or a hydrocarbon substituent different from X making the central carbon atom of formula II a chiral centre in Formula (III) and wherein reactive functional group X can be or can be extended to be compound of formula (IV) which can be ring closed to produce the polycyclic component of formula (V). More in particular, the invention relates to the preparation of mirtazapine precursors and mirtazapine preferably having a substantial enantiomeric excess.
- -
-
-
- METHOD FOR THE PREPARATION OF AN ENANTIOMERICALLY PURE BENZAZEPINE
-
The invention relates to a method for the preparation of a cyclic compound according to formula III comprising reacting a compound according to Formula I and a compound according to formula II, wherein in Formula I, R1, R2, R3 and R4 may be hydrogen or substituent groups comprising one or more carbon atoms and/or hetero-atoms, wherein R1, R2, R3 and R4 can be combined in aromatic or aliphatic ring structures, —Y is a ring element comprising 1-3 substituted or unsubstituted carbon atoms and/or heteroatoms in the ring and —R5 is hydrogen or a hydrocarbon substituent group comprising one or more carbon atoms and optionally one or more hetero atoms, and wherein in Formula II, Z1 and Z2 are, leaving groups, X is a reactive functional hydrocarbon group for subsequent ring closure, comprising one or more carbon atoms and a reactive functional group and having a chain of between 1 to 6 atoms between the carbon atom attached to the central carbon atom of formula II and the reactive functional group and R8 is hydrogen or a hydrocarbon substituent different from X making the central carbon atom of formula II a chiral centre in Formula III and wherein reactive functional group X can be or can be extended to be compound of formula IV which can be ring closed to produce the polycyclic component of formula V. More in particular, the invention relates to the preparation of mirtazapine precursors and mirtazapine preferably having a substantial enantiomeric excess.
- -
-
Page/Page column 10
(2008/12/04)
-
- 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.
- -
-
Page/Page column 6
(2008/12/04)
-
- A 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.
- -
-
Page/Page column 14-15
(2008/12/08)
-
- Process For the Manufacture of Mirtazapine
-
Improved process for manufacturing mirtazapine. A process is described for preparing mirtazapine starting from a compound of formula (II), which is subjected to a ring cyclization, obtaining mirtazapine for pharmaceutical use in crystalline and anhydrous form.
- -
-
Page/Page column 4-5
(2008/12/08)
-
- Asymmetric synthesis of (S)-mirtazapine: Unexpected racemization through an aromatic ipso-attack mechanism
-
An asymmetric synthesis of (S)-mirtazapine has been achieved from the synthesis of the racemate by using (S)-1-methyl-3-phenylpiperazine as the starting material. Unfortunately, significant racemization was encountered in the final step, which involved an electrophilic aromatic ring closure of a alcohol by concentrated sulfuric acid. A significantly higher ee was observed when polyphosphoric acid (PPA) was used instead. A remarkable correlation between the amount of PPA used and the ee of the product was revealed, namely, an increase in the ee upon decreasing the amount of PPA. This trend was paralleled by the formation of an increasing amount of a side-product upon lowering the amount of PPA. The racemization and formation of a side-product can be explained by an ipso-attack mechanism during the electrophilic aromatic ring-closure reaction. This mechanism was supported by a mechanistic study using a deuterium-labeled substrate. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Van Der Linden, Marco,Borsboom, Judith,Kaspersen, Frans,Kemperman, Gerjan
-
experimental part
p. 2989 - 2997
(2009/04/07)
-
- PROCESS FOR PRODUCING OPTICALLY ACTIVE PIPERAZINE COMPOUND
-
Provided is a method of producing optically active 1-methyl-3-phenylpiperazine of the formula (11) or salt thereof, comprising the following steps 1 to 4, or steps 5 to 7 and step 4, and a method of producing optically active mirtazapine via this method.
- -
-
Page/Page column 25
(2008/12/06)
-
- IMPROVED PROCESS FOR THE MANUFACTURE OF MIRTAZAPINE
-
Improved process for manufacturing mirtazapine. A process is described for preparing mirtazapine starting from a compound of formula (II), which is subjected to a ring cyclization, obtaining mirtazapine for pharmaceutical use in crystalline and anhydrous form.
- -
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Page/Page column 9-15
(2008/06/13)
-
- A METHOD FOR THE PREPARATION OF ENANTIOMERICALLY PURE MIRTAZAPINE
-
The invention provides a method for the preparation of enantiomerically pure mirtazapine, said method comprising a step of ring closure of a compound of formula (II) wherein X is a leaving group, said step comprising treatment with an acid, whereby mirlazapine with enantiomeric excess is formed by the ring closure of the compound of formula (II) with enantiomeric excess by treatment with a suitable acid in the absence of a solvent or a suitable combination of an acid and an organic solvent.
- -
-
-
- Novel synthesis and crystallization of piperazine ring-containing compounds
-
The present invention is directed to methods for the preparation of piperazine ring-containing compounds, particularly mirtazapine. According to the present invention, the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base where the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine. The mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made of hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with potassium hydroxide at a temperature of at least about 130° C. The method of the present invention also includes reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2′-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-phenyl-4-methylpiperazine to form mirtazapine. The present invention a recrystallization of mirtazapine from crude mirtazapine. The present invention also relates to crystalline adducts of mirtazapine and water, preferably containing up to about 3.5% by weight water, pharmaceutical compositions containing the crystalline adducts, and methods of treating depression by administering such compositions.
- -
-
-
- DRUG COMBINATION FOR THE TREATMENT OF HEADACHE COMPRISING MIRTAZAPINE AND PARACETAMOL OR A NON-STEROIDAL ANTI-INFLAMMATORY DRUG
-
The invention relates to a combination comprising paracetamol or a non-steroidal anti-inflammatory drug (NSAID), or a pharmaceutically acceptable salt or solvate thereof, and another drug, in which combination the other drug is mirtazapine, or a pharmaceutically acceptable salt or solvate thereof, optionally in association with one or more pharmaceutically acceptable carriers, whereby paracetamol or an NSAID and mirtazapine are present in the combination in such amounts that the effect of the composition is more favourable than the added effects of the amounts of each drug separately. This combination can be used in the treatment of headache, whereby the invention also provides for a new method of treatment of headache.
- -
-
-
- Anhydrous mirtazapine crystals and process for preparing the same
-
Low-hygroscopic anhydrous mirtazapine crystals having a hygroscopic degree of not more than 0.6% by weight when the crystals are stored in the air having a relative humidity of 75% at 25° C. under atmospheric pressure for 500 hours; a process for preparing anhydrous mirtazapine crystals having a hygroscopic degree of not more than 0.6% by weight when the crystals are stored in the air having a relative humidity of 75% at 25° C. under atmospheric pressure for 500 hours, comprising drying crystals of mirtazapine hydrate; a crystal of a mirtazapine hydrate represented by the formula (I): wherein n is an integer of 1 to 5; and a process for preparing crystals of a mirtazapine hydrate, comprising crystallizing a crude mirtazapine using a water-soluble organic solvent and water. The anhydrous mirtazapine crystals can be suitably used, for instance, as an antidepressant.
- -
-
-
- Synthesis of piperazine ring
-
A novel process for preparing a compound of the formula I: whereinR1 denotes substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy or arylalkoxy; R2 denotes substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, arylalkoxy, tosyl, formyl, acetyl or amine; and R3 denotes substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy or arylalkoxy is disclosed. These compounds are useful in the synthesis of the antidepressant mirtazapine and other tetracyclic compounds.
- -
-
Page column 5-6
(2008/06/13)
-
- Determination of the absolute configuration of (-)-mirtazapine by vibrational circular dichroism
-
The absolute configuration of the (-)-enantiomer of mirtazapine was determined by means of vibrational circular dichroism (VCD). The observed VCD of (-)-mirtazapine showed excellent correlation with the calculated VCD of the (R)-enantiomer. This is in agr
- Freedman, Teresa B.,Dukor, Rina K.,Van Hoof, Peter J. C. M.,Kellenbach, Edwin R.,Nafie, Laurence A.
-
p. 1160 - 1165
(2007/10/03)
-
- Anhydrous mirtazapine and process for preparing the same
-
Methods for producing anhydrous mirtazapine crystals that are either (1) substantially free of lower alcohol insolubles or (2) substantially free of residual solvent and have an average particle diameter of from 10 to 50 μm, are provided, and the resulting anhydrous mirtazapine crystals produced thereby, which are useful in pharmaceuticals.
- -
-
-
- Anhydrous mirtazapine and process for preparing the same
-
Methods for producing anhydrous mirtazapine crystals that are either (1) substantially free of lower alcohol insolubles or (2) substantially free of residual solvent and have an average particle diameter of from 10 to 50 μm, are provided, and the resulting anhydrous mirtazapine crystals produced thereby, which are useful in pharmaceuticals.
- -
-
-
- Novel method for the preparation of piperazine and its derivatives
-
A novel method for the synthesis of piperazine and its derivatives of formula 1, 1wherein R is selected from hydrogen, or a lower alkyl group having 1 to 6 carbon atoms or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms; R1 is selected from hydrogen, a methyl group, a phenyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms; and R2 is selected from hydrogen, or a methyl group, or a fluoromethyl group; 2comprising the steps: a. reacting an ester of formula 11 with substituted or unsubstituted ethylenediamine of formula 7 to give 3,4-dehydropiperazine-2-one and its derivatives of formula 12, wherein R, R1, R2 are as defined above and R6 is a C1 to C4 linear or branched alkyl group; and b. reacting the 3,4-dehydro-piperazine-2-one and its derivatives of formula 12 with a reducing agent to yield the piperazine and its derivatives of formula 1.
- -
-
-
- Process for preparing pyridinemethanol compounds
-
A pyridinemethanol compound is an important intermediate for a mirtazapine which is useful as an antidepressant. The pyridinemethanol compound is obtained by reducing potassium pyridinecarboxylate represented by the formula (I): with a metal hydride.
- -
-
-
- Novel synthesis and crystallization of piperazine ring-containing compounds
-
The present invention is directed to methods for the preparation of piperazine ring-containing compounds, particularly mirtazapine. According to the present invention, the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base where the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine. The mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with potassium hydroxide at a temperature of at least about 130° C. The method of the present invention also includes reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2′-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-phenyl-4-methylpiperazine to form mirtazapine. The present invention also relates to new processes for recrystallization of mirtazapine from crude mirtazapine.
- -
-
-
- Tetracyclic compounds
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The invention relates to compounds of the general formula I: STR1 or a salt thereof, in which A represents a pyridine ring or a halogen substituted pyridine ring, R1 represents hydrogen, alkyl (1-6 C), alkoxy (1-6 C), alkylthio (1-6 C), halogen, OH, SH or CF3 R2 represents hydrogen or a lower alkyl or aralkyl group and n and m may each be 1, 2 or 3 with the proviso that the sum of m and n must be 2, 3 or 4, having CNS activity, a pronounced antihistamine activity and little or no antiserotonin activity.
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