- MANUFACTURING METHOD OF MIRTAZAPINE
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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
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Paragraph 0048-0049
(2017/06/19)
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- MANUFACTURING METHOD OF MIRTAZAPINE
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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
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Paragraph 0060; 0061
(2017/07/14)
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- MANUFACTURING METHOD OF MIRTAZAPINE
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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
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Paragraph 0056; 0057
(2017/08/08)
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- METHOD FOR PRODUCING MIRTAZAPINE
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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 0053; 0054
(2017/10/27)
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- A synthesis method of midanping
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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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Paragraph 0020; 0043; 0044
(2017/12/27)
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- METHOD FOR PRODUCING MIRTAZAPINE
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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 0053; 0054
(2018/04/14)
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- METHOD FOR PRODUCING 1-(3-HYDROXYMETHYL-PYRIDYL-2-)-2-PHENYL-4-METHYLPIPERAZINE
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PROBLEM TO BE SOLVED: To provide a method in which a pyridine methanol compound (1-(3-hydroxymethyl-pyridyl-2-)-2-phenyl-4-methylpiperazine) represented by formula (1) which is a useful intermediate for mirtazapine used as an antipsychotic agent, can be produced with high purity and with high yield. SOLUTION: Provided is a method for producing pyridine methanol compound by reducing a pyridine carboxylic acid compound represented by formula (3) to produce a pyridine methanol compound represented by formula (1), followed by crystallizing the pyridine methanol compound using an ester-based solvent. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0063-0066
(2017/08/30)
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- MANUFACTURING METHOD OF PYRIDINEMETHANOL COMPOUND AND MANUFACTURING METHOD OF MIRTAZAPINE
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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
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Paragraph 0055
(2017/08/18)
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- 1-(3-CARBOXYPYRIDYL-2-)-2-PHENYL-4-METHYLPIPERAZINE HAVING CRYSTAL STRUCTURE AND METHOD FOR PRODUCING THE SAME
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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
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Paragraph 0006; 0102-0104
(2018/01/11)
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- A rice the nitrogen is mellow synthetic method
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The invention discloses a 1-(3-hydroxymethylpyridine-2-yl)-4-methyl-2-phenylpiperazine synthesis method. The method includes: dissolving N-(2-chloroethyl)-N-methyl-alpha-chlorine-beta phenethylamine in mixed solution of water and a nonpolar solvent to obtain solution A, and dissolving 2-amino-3-hydroxymethylpyridine into a nonpolar solvent containing a small quantity of low carbon alcohols to obtain solution B; dripping the solution B into the solution A to obtain an intermediate by reaction, dissolving the intermediate into an anhydrous high-boiling-point polar solvent, and dripping into an anhydrous high-boiling-point polar solvent of inorganic iodides under inert gas shielding to realize reaction for obtaining 1-(3-hydroxymethylpyridine-2-yl)-4-methyl-2-phenylpiperazine. By two steps for synthesis of 1-(3-hydroxymethylpyridine-2-yl)-4-methyl-2-phenylpiperazine, oxidization of the intermediate due to direct high-temperature reaction can be avoided by specific solvent systems, and reaction stability and yield are improved.
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- PRODUCTION METHOD OF 2-(4-METHYL-2-PHENYLPIPERAZIN-1-YL)PYRIDINE-3-METHANOL
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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
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Paragraph 0039; 0040; 0042
(2018/11/22)
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- PROCESS FOR THE PREPARATION OF 1- ( 3-HYDROXYMETHYLPYRID-2 -YL ) -2 -PHENYL-4-METHYLPIPERAZINE AND MIRTAZAPINE
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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.
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Page/Page column 4
(2011/09/14)
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- PROCESS FOR THE PREPARATION OF 1- ( 3-HYDROXYMETHYLPYRID-2 -YL ) -2 -PHENYL-4-METHYLPIPERAZINE AND MIRTAZAPINE
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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.
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Page/Page column 13-14
(2010/05/13)
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- PROCESS FOR PRODUCTION OF 2-(4-METHYL-2-PHENYLPIPERAZIN- 1-YL)PYRIDINE-3-METHANOL
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The present invention provides a method for producing 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol, and this method includes the step of catalytically reducing 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine in the presence of a partially deactivated palladium catalyst in an aqueous acid solution.
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Page/Page column 3-4
(2008/12/07)
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- Process for preparing pyridinemethanol compounds
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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.
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- Novel method for the preparation of piperazine and its derivatives
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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.
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- Synthesis of piperazine ring
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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.
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Page column 6
(2008/06/13)
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- 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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