JP2017039659A - Manufacturing method of mirtazapine - Google Patents

Abstract

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

Description

  The present invention relates to a novel method for producing mirtazapine useful as an active pharmaceutical ingredient.

  1,2,3,4,10,14b-Hexahydro-2-methyl-pyrazino [2,1-a] pyrido [2,3-c] [2] benzazepine represented by the following formula (1) It is a drug substance compound called mirtazapine by name, and is used as an extremely useful antidepressant prescribed for patients with depression and depression.

  As a method for producing this mirtazapine, a method of reacting 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol (hereinafter also referred to as “pyridinemethanol compound”) with concentrated sulfuric acid, It is widely used because it is the simplest and most efficient (Patent Documents 1 and 2). As the reaction mechanism, as shown by the following formula (2), 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridine is accompanied by dehydration by the reaction of pyridinemethanol compound and sulfuric acid. Methanol hydrogen sulfate (hereinafter also referred to as “sulfate adduct”) is produced as a reaction intermediate, and then mirtazapine is produced by intramolecular cyclization of the sulfate adduct.

  In Patent Document 1, a specific method of the above method is disclosed. A pyridinemethanol compound is added to concentrated sulfuric acid, and the mixture is stirred at 30 to 40 ° C. for 8 hours to be reacted. The reaction mixture is added dropwise to water, neutralized with an aqueous sodium hydroxide solution, and mirtazapine is extracted with toluene. Mirtazapine coarse body is obtained by crystallizing mirtazapine with this toluene solution and heptane. The crude mirtazapine is purified by recrystallization or the like to obtain mirtazapine.

  Also in Patent Document 2, a post-reaction operation after reaction is different from Patent Document 1, but a method substantially similar to Patent Document 1 is disclosed for the reaction conditions. Patent Document 2 describes that the concentration of sulfuric acid used is preferably 97 to 99%.

Japanese Patent No. 3699680 Japanese Patent No. 5192707

  However, in the methods described in Patent Documents 1 and 2, a plurality of impurities are by-produced during the reaction, and those impurity groups are difficult to remove by post-reaction and purification operations after the reaction. In order to achieve acceptable quality, it has been found that purification at a low yield or multiple purifications are required. Among the impurity groups, in the high performance liquid chromatography (HPLC) described in the examples, the impurities whose retention time is around 20.3 minutes and the impurities which are around 26.6 minutes are compared in by-products during the reaction. It is an impurity with very low removal efficiency in post-treatment and purification operations. Since these two types of impurities had a molecular weight of 530 in the liquid chromatograph mass spectrometry (LC-MS) shown below, the two impurities of mirtazapine represented by the following formula (3) or the following formula (4) were used. It is presumed that it is a structural isomer of a dimer structure (hereinafter, “dimer 1” is an impurity showing a retention time of around 20.3 minutes, and “dimer 2” is an impurity showing a vicinity of 26.6 minutes) Say.).

(Measurement conditions for LC-MS)
Apparatus: Liquid chromatograph and mass spectrometer (Waters Corporation)
Made)
Detector: UV absorptiometer (manufactured by Waters Corporation)
Measurement wavelength: 240 nm
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Mobile phase a: a mixed solution in which 0.39 g of ammonium acetate was added to 1000 mL of water and dissolved.
Mobile phase b: acetonitrile.
Transfer of mobile phase: Concentration control is performed by changing the mixing ratio of mobile phases A and B as shown in Table 1.

Flow rate: 0.3 mL per minute.
Column temperature: constant temperature around 40 ° C.
Ionization method: Electrospray ionization method (ESI).
Detection mode: positive ion mode.

  Therefore, there is a demand for a method for producing mirtazapine having a quality acceptable as a drug substance without requiring an inefficient purification operation.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors greatly reduced the amount of by-products generated during the reaction by using sulfuric acid in a specific concentration range in the above reaction. In particular, it has been found that the amount of by-products of dimers 1 and 2 is remarkably suppressed.

  That is, the present invention provides a process for producing mirtazapine by reacting a pyridinemethanol compound and sulfuric acid, wherein the reaction is carried out using sulfuric acid having a concentration of 85.0% or more and less than 96.0%. Is the method.

  Specifically, in the analysis by HPLC, dimers 1 and 2 are by-produced by 0.12% or more in the conventional method, whereas in the method of the present invention, each is suppressed to 0.10% or less. Here, the concentration of sulfuric acid is a percentage (pure) of the weight of sulfuric acid contained in the sample with respect to the total amount of the sulfuric acid sample, and the other main component is water. Normally, the concentration of commercially available concentrated sulfuric acid is 96.0% or more. On the other hand, the sulfuric acid used in the present invention is similarly a mixture mainly composed of sulfuric acid and water, and the concentration thereof is 85.0% or more and less than 96.0%.

  It is surprising that the amount of by-products is greatly suppressed by such a difference in concentration. As described above, in this reaction, the pyridinemethanol compound and sulfuric acid react with each other to once form a sulfuric acid adduct, but the use of sulfuric acid in the concentration range of the present invention slows the progress of the reaction. As a result, the amount of the sulfate adduct present in the reaction system is reduced as compared with the conventional method, and as a result, the amount of dimer by-product is suppressed. The reason why the reaction proceeds slowly is not clear, but the sulfuric acid concentration is lowered, that is, the amount of water in the system is relatively increased, or the acidity function indicating the acidity is lowered. Is presumed to have an effect.

  According to the present invention, compared to the conventional method using concentrated sulfuric acid having a concentration of 96.0% or more, the amount of impurities by-produced during the reaction, particularly the amount of by-products of dimers 1 and 2 is suppressed. As a result, a high-quality mirtazapine that can be suitably used as an active pharmaceutical ingredient can be produced without the need for complicated purification operations. That is, the present invention is excellent in terms of the quality and production yield of mirtazapine and operability.

  The present invention is a method for producing mirtazapine, comprising reacting a pyridinemethanol compound with sulfuric acid having a concentration of 85.0% or more and less than 96.0%. After the reaction, post-treatment operations and purification operations can be performed to produce high-quality mirtazapine. In addition, when the reaction is carried out at 25 ° C. or higher and 80 ° C. or lower, the reaction can be completed, and by-product generation of impurities other than dimers 1 and 2 can be suppressed.

(Pyridine methanol compound)
The pyridinemethanol compound used in the present invention is not particularly limited and can be produced by a known method. As an example of a known method, 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinecarboxylic acid (hereinafter referred to as “pyridinecarboxylic acid” as described in JP-B-59-042678, etc.). And an acid compound ") in an organic solvent by reaction with a metal hydride. Specifically, a solution of a pyridinecarboxylic acid compound and tetrahydrofuran is obtained. Next, the solution is gradually added to a suspension of lithium aluminum hydride and tetrahydrofuran under a nitrogen atmosphere. The mixture is heated to the reflux temperature and reacted until the disappearance of the pyridinecarboxylic acid compound is confirmed by HPLC or the like. After completion of the reaction, water is added and the precipitated solid is filtered off to obtain a solution containing a pyridinemethanol compound. The pyridinemethanol compound can be isolated by concentrating the solution or purifying the concentrated residue by recrystallization with a solvent such as ether. By drying after isolation, the remaining organic solvent, water and the like can be removed, and a high-purity pyridinemethanol compound can be produced.

  In addition to lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, diisobutylaluminum hydride, or the like can also be used as the metal hydride in the above method. The reaction temperature may be appropriately determined depending on the type and amount of the metal hydride to be used, but is usually from −30 ° C. to 80 ° C. Further, the reaction solvent and the recrystallization solvent are not limited to the above, and may be determined from the viewpoint of not inhibiting the reaction, being able to dissolve the pyridinecarboxylic acid compound or pyridinemethanol compound, and aromatic carbonization such as toluene. Hydrogen esters and acetates such as isopropyl acetate can also be used.

  The purity of the pyridinemethanol compound thus produced is usually 97.0% or more and 100.0% or less. However, when purification by recrystallization is performed, 98.5% or more and 100.0% It can be used more suitably. The water content of the pyridinemethanol compound is usually 1 ppm or more and 1000 ppm or less. Here, the water content is a mass percentage of water contained in the pyridinemethanol compound sample. Therefore, the amount of water contained in the pyridinemethanol compound is extremely small relative to the amount of water contained in the sulfuric acid used, and need not be considered in the present invention.

(Sulfuric acid)
In the present invention, the most important requirement is to use sulfuric acid having a concentration of 85.0% or more and less than 96.0% (hereinafter sometimes referred to simply as sulfuric acid). The concentration of sulfuric acid can be calculated by neutralization titration using sodium hydroxide or the like as described in the examples.

  When the concentration of sulfuric acid is less than 85.0%, the reaction rate is greatly reduced, the reaction does not proceed sufficiently, or a long reaction time is required. On the other hand, in the case of 96.0% or more, the by-product amount of the impurity group including dimers 1 and 2 is significantly increased. Among the above ranges, when considering the reaction time and the amount of by-produced impurities, 87.0% or more and 95.5% or less are preferable, 90.0% or more and 95.0% or less are more preferable, and 92.0% or more 95.0% or less is most preferable.

  Any sulfuric acid within the above-mentioned concentration range can be used without any particular limitation, and can be particularly used without requiring a concentration adjusting operation or the like. On the other hand, if the sulfuric acid is out of the concentration range, it is necessary to adjust the concentration so as to be in the concentration range.

  First, concentrated sulfuric acid that is generally commercially available usually has a concentration of 96.0% or more. In this case, concentrated sulfuric acid and a predetermined amount of water may be mixed so as to be within the range of the present invention to prepare sulfuric acid in the concentration range. The mixing order of concentrated sulfuric acid and water is not particularly limited. In addition, since the mixing operation involves heat generation, it is preferable to carry out the cooling so that the temperature of sulfuric acid is 0 ° C. or higher and 50 ° C. or lower. Furthermore, the mixing operation is preferably carried out while stirring with a mechanical stirrer, a magnetic stirrer, or the like, so that uniform sulfuric acid can be prepared. On the other hand, if the sulfuric acid has a concentration of less than 85.0%, water may be removed by distillation or the like until it falls within the scope of the present invention. Distillation can be carried out under normal pressure or under reduced pressure, and the distillation temperature may be appropriately determined according to pressure or the like. However, in consideration of operability and accuracy of concentration adjustment, it is more preferable to prepare by mixing concentrated sulfuric acid and water.

  The usage-amount of the sulfuric acid prepared as mentioned above is 5.0 mol or more and 30.0 mol or less with respect to 1.0 mol of pyridinemethanol compounds. Here, the amount used is the pure content of sulfuric acid calculated from the sulfuric acid concentration. Among the above ranges, 7.5 mol or more and 20.0 mol or less is preferable, and 7.5 mol or more and 15.0 mol or less is preferable because the operability of the post-treatment operation is simple or the reaction can be completed in a short time. The following is more preferable.

(Reaction conditions)
In the present invention, after the pyridinemethanol compound and sulfuric acid are mixed, the resulting mixture is reacted in a predetermined temperature range. The mixing operation may be performed in a glass container, a stainless steel container, a Teflon (registered trademark) container, a glass lining container, or the like, and may be performed with stirring using a mechanical stirrer, a magnetic stirrer, or the like. From the viewpoint of operability and uniformity. Moreover, in order to prevent mixing of the water from air | atmosphere, it is preferable to implement not in air | atmosphere but in atmospheres, such as nitrogen and argon. By doing so, the sulfuric acid concentration does not change during the reaction, and the reproducibility of each production such as by-products and reaction time of the dimers 1 and 2 is increased.

  When the pyridinemethanol compound and sulfuric acid are mixed, the pyridinemethanol compound is not dissolved and a solid-liquid mixture is obtained. As the reaction proceeds, the pyridinemethanol compound dissolves, but the pyridinemethanol compound may form a lump in some cases during the mixing, and the reaction time may become longer. Further, since heat is generated during mixing, it is preferable to add the pyridinemethanol compound to the sulfuric acid little by little while confirming the lump formation status and the temperature of the mixture.

  Since the temperature of the mixing operation is accompanied by heat generation as described above, the mixing operation is preferably performed under cooling so that the temperature of the mixture is 0 ° C. or higher and 40 ° C. or lower. Moreover, since the time of the said operation changes with manufacturing scales etc., it cannot unconditionally specify, However, Usually, it is 10 minutes or more and 3 hours or less.

  The mixture obtained as described above is preferably reacted at a temperature of the mixture of 25 ° C. or higher and 80 ° C. or lower. By setting the temperature to 25 ° C. or higher, the reaction proceeds sufficiently, and a high production yield of mirtazapine can be obtained. On the other hand, the amount of by-products of impurities other than dimer can be suppressed by setting it to 80 ° C. or lower. Among the above ranges, from the viewpoint of reactivity and by-product amount of impurities, 30 ° C. or higher and 75 ° C. or lower is preferable, and 35 ° C. or higher and 70 ° C. or lower is more preferable.

  The reaction time is that the reaction conversion rate is 90.0% or more and 100.0% or less while confirming the residual amount of the raw material pyridinemethanol compound and the intermediate sulfuric acid adduct by HPLC or the like. Confirm and decide. Here, the reaction conversion rate is expressed as a percentage of the HPLC area value of the produced mirtazapine relative to the total value of the HPLC area values of the pyridinemethanol compound, the sulfate adduct, and mirtazapine. When the reaction conversion rate is higher, the production yield of mirtazapine is improved, and if it is 90.0% or more, a sufficient production yield can be obtained. On the other hand, as the reaction proceeds, the amount of by-produced impurities including dimer increases, and therefore, within the above range, 92.0% or more and 99.9% or less are preferable, and 94.0% or more and 99.8% or less. % Or less is more preferable.

  By performing the reaction as described above, the amount of by-products of the dimers 1 and 2 during the reaction can be reduced as compared with the conventional method. Specifically, in the conventional method, dimers 1 and 2 are each by-produced in an amount of 0.12% or more, whereas in the method of the present invention, each is 0.10% or less. This difference in the amount of by-product shows a dominant difference in the following post-treatment and purification operations.

(Post-processing operation)
In the present invention, a crude mirtazapine can be obtained by performing a post-treatment operation by a known method from the reaction mixture obtained as described above. For example, as in Patent Document 1, the reaction mixture after completion of the reaction is cooled, diluted with water and then neutralized with sodium hydroxide. Further, toluene is added, and the precipitated mirtazapine is dissolved and extracted in toluene. The toluene layer is separated from the aqueous layer, crystallized by adding heptane, and the crystal is isolated by solid-liquid separation to obtain a crude mirtazapine.

  As each operation method in the above method, a general known method may be adopted. In addition, the type of organic solvent such as sodium hydroxide and toluene is not limited to those described above. For example, sodium hydroxide used for neutralization includes hydroxides of alkali metals such as potassium hydroxide and lithium hydroxide, Potassium tertiary butoxide, sodium methoxide and the like may be used instead. However, the amount used is 1.5 mol or more and 5.0 mol or less with respect to 1.0 mol of sulfuric acid used. By using the said range, it can fully neutralize and, as a result, mirtazapine can fully be extracted to an organic solvent. Among these, considering the extraction efficiency into an organic solvent and the operability of the neutralization operation, 1.7 mol or more and 4.0 mol or less are preferable, and 1.8 mol or less and 3.5 mol or less are preferable. Moreover, since the temperature at the time of neutralization is accompanied by heat generation, it is preferable to carry out so that the temperature of the neutralized mixture is 0 ° C. or higher and 40 ° C. or lower. However, when the organic solvent layer and the aqueous layer are separated The temperature is preferably 30 ° C. or higher and 80 ° C. or lower. The reason is that the tar component by-produced by the reaction can be dissolved, and the operability of the layer separation is more preferable.

  In Patent Document 1, the effect of reducing dimers 1 and 2 in the post-processing operation is hardly obtained regardless of the method. Therefore, the amount of dimers 1 and 2 contained in the crude mirtazapine is 0.12% or more in the case of post-treatment operation after producing mirtazapine by the conventional method, whereas mirtazapine is used in the present invention. When the post-treatment operation is performed after the production, each is 0.08 or less.

(Purification operation)
In the present invention, mirtazapine can be obtained by subjecting the crude mirtazapine obtained as described above to purification by a known method. For example, as in Patent Literature 1, crude mirtazapine is dissolved in methanol, decolorized with activated carbon, crystallized by adding water, isolated by solid-liquid separation, and dried to obtain mirtazapine. be able to.

  As each operation method in the above method, a general known method may be adopted. As the methanol, lower alcohols such as ethanol, ethers such as dioxane and tetrahydrofuran, ketones such as acetone and the like may be used instead. From the viewpoint of purification efficiency, it is preferable to purify crude mirtazapine using such a mixed solvent of a water-soluble organic solvent and water. The amount used may be appropriately determined depending on the type of organic solvent used. In addition, since the reduction effect of the dimers 1 and 2 cannot be obtained by the above-mentioned activated carbon operation, it may be omitted, but it is preferable to carry out it in consideration of the color tone of the obtained mirtazapine. Regarding the final drying operation, mirtazapine having various hydration numbers can be obtained by changing the drying temperature, pressure, time and the like. For example, in the case of 5 g scale of pyridinemethanol compound, mirtazapine 0.5 hydrate having a water content of about 3.3% is obtained by drying at 60 ° C. under reduced pressure of 0.1 to 5.0 kPa for 4 hours. Can be obtained. Also, mirtazapine anhydride having a water content of about 0.2% can be obtained by drying for 15 hours at 90 ° C. under reduced pressure of 0.1 to 5.0 kPa at a similar scale. Therefore, drying conditions may be set as appropriate according to the desired hydrate, and drying may be performed while measuring the water content of mirtazapine with a Karl Fischer or the like.

  Although mirtazapine can be produced as described above, it is difficult to reduce dimers 1 and 2 regardless of the conditions employed in the purification operation. The reason is presumed that since the molecular skeleton constituting mirtazapine is similar, physical properties such as solubility in a purification solvent are equivalent to mirtazapine. Here, when used as an active pharmaceutical ingredient, referring to ICH guidelines, etc., which are guidelines on the quality of pharmaceuticals, the amount of individual impurities contained in the active pharmaceutical ingredient is desirably 0.05% or less. Referring to the guideline values, when methanol was used as the purification solvent and the crude mirtazapine obtained by the above conventional method was purified, dimers 1 and 2 were 0.08% or more each, and further purification An operation is required. On the other hand, in the case of the crude mirtazapine obtained by the method of the present invention, the amount of dimers 1 and 2 produced during the reaction is small. Therefore, mirtazapine of a quality that can be suitably used as an active pharmaceutical ingredient can be obtained without requiring further purification operation.

  Thus, by the method of the present invention, the amount of dimers 1 and 2 produced during the reaction can be reduced as compared with the conventional method. As a result, high-quality mirtazapine can be obtained without requiring complicated purification operations such as multiple purifications. Moreover, a high production yield of mirtazapine can be obtained due to a decrease in the number of purifications.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples. The various measurements and evaluation methods in the examples and comparative examples are as follows.

(Evaluation of mirtazapine purity and dimer impurity content)
The purity of mirtazapine and the content of dimer impurities by HPLC were measured by the following apparatus and conditions. In HPLC analysis under these conditions, the retention time of mirtazapine was around 14.0 minutes, dimer 1 was around 20.3 minutes, dimer 2 was around 26.6 minutes, pyridinemethanol compound was around 5.5 minutes, and the sulfate adduct was It is around 2.8 minutes. The purity of mirtazapine is a value expressed as a percentage of the peak area value of mirtazapine in the obtained chromatogram with respect to the sum of the area values of all peaks. The contents of dimers 1 and 2 are values expressed as percentages of the peak area value of each impurity with respect to the sum of the area values of all peaks.

Apparatus: 2695 manufactured by Waters
Detector: UV spectrophotometer (Waters 2489)
Detection wavelength: 240 nm
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm packed with 5 μm of octadecyl silica gel for liquid chromatography.
Mobile phase and liquid feeding method: Using the mobile phases A and B shown below, the mixture ratio was controlled as shown in Table 2 below according to the elapsed time after sample injection, and the liquid was fed.
Mobile phase A: 7.2 g of disodium hydrogenphosphate dodecahydrate was dissolved in 1000 mL of water, and phosphoric acid was added to adjust the pH to 7.4.
Mobile phase B: acetonitrile flow rate: 1.0 mL / min
Column temperature: constant temperature around 40 ° C

(Measurement of sulfuric acid concentration)
The sulfuric acid concentration by the automatic titrator was measured by the following apparatus and conditions. The concentration of sulfuric acid is a value expressed as a percentage of the weight of sulfuric acid in the sample calculated by the titration with respect to the weight of the sample.

Equipment: COM-2000 manufactured by Hiranuma Sangyo Co., Ltd.
Method: neutralization titration method Titration reagent: 0.5 mol / L sodium hydroxide aqueous solution Solvent: water

Production Example 1 (Production of pyridinemethanol compound)
To a 2 L four-necked flask equipped with a stirring blade and a thermometer, 1618 mL (1618 mmol) of a 1 mol / L lithium aluminum hydride / tetrahydrofuran solution was added, and a solution of 120 g (404 mmol) of a pyridinecarboxylic acid compound in 1800 mL of tetrahydrofuran was added. The mixture was added dropwise over 30 minutes while maintaining the temperature at around 25 ° C, and then stirred at 25 ° C for 3 hours. 70 mL of water was added and stirred while cooling the reaction solution, and then the organic layer and the aqueous layer were separated. The obtained organic layer was washed with 70 mL of 15 wt% aqueous sodium hydroxide solution and then with 200 mL of water and separated. . The obtained organic layer was concentrated under reduced pressure to obtain a crude pyridinemethanol compound.

  To the crude pyridinemethanol compound, 840 mL of isopropyl acetate was added and heated to 60 ° C. to dissolve the crude, and then 840 mL of heptane was added dropwise at an internal temperature of 50 ° C. or higher. The solution was cooled to 5 ° C. and the slurry solution of pyridinemethanol compound was aged at around 5 ° C. for 2 hours, and then the slurry solution was filtered by vacuum filtration. The crystals separated by filtration were washed with a mixed solution of 60 mL of isopropyl acetate and 60 mL of heptane, and then the obtained white crystals were dried under reduced pressure at 40 ° C. for 5 hours, and 102 g (363 mol, production yield: 89. 9%) (purity: 99.53%, water content: 320 ppm).

Example 1 (Production of mirtazapine)
A 100 mL four-necked flask equipped with a stirring blade and a thermometer was charged with 17.59 g (176.4 mmol) of concentrated sulfuric acid having a concentration of 98.4% under a nitrogen atmosphere and cooled to around 15 ° C. 1.02 g of water was added little by little, and the mixture was stirred at the same temperature for 10 minutes to prepare sulfuric acid having a concentration of 93.0%. Subsequently, 5.0 g (17.64 mmol) of the pyridinemethanol compound obtained in Production Example 1 was added little by little at 35 ° C. or lower over 20 minutes. The obtained mixture was heated to 55 ° C. and reacted for 7 hours (reaction conversion: 99.7%, dimer 1: 0.05%, dimer 2: 0.04%).

  After completion of the reaction, the reaction mixture was cooled to around 5 ° C., and 35 mL of water was added little by little at 35 ° C. or less. Then, 41.2 g of a 23 wt% aqueous sodium hydroxide solution was added little by little at 35 ° C. or lower, and 18 mL of toluene was added. Further, 12.2 g of a 23 wt% sodium hydroxide aqueous solution was added for neutralization (pH 14). After stirring at around 60 ° C. for 15 minutes, the aqueous layer was separated. After adding 10 mL of water to the organic layer and stirring for 15 minutes at around 60 ° C., the aqueous layer was separated to obtain an organic layer as a toluene solution of mirtazapine. The organic layer was crystallized by adding 25 mL of heptane at around 55 ° C. and aged at around 55 ° C. for 1 hour. Furthermore, after cooling to around 5 ° C. and aging at around 5 ° C. for 1 hour, the slurry solution was filtered by vacuum filtration. The crystals separated by filtration were washed with a mixture of 2.5 mL of toluene and 2.5 mL of heptane, and the obtained brown crystals were dried at 60 ° C. under reduced pressure for 15 hours to give 4.07 g of crude mirtazapine as brown crystals ( 15.33 mmol) was obtained (purity: 99.23%, dimer 1: 0.05%, dimer 2: 0.04%).

  To a 100 mL four-necked flask equipped with a stirring blade and a thermometer, 4.07 g of the obtained crude mirtazapine and 12 mL of methanol were added and dissolved. After cooling to around 5 ° C., 0.75 g of activated carbon was added, and the mixture was stirred at around 5 ° C. for 30 minutes. Activated carbon was separated by filtration under reduced pressure, and 44 mL of water was added little by little at around 25 ° C. to crystallize the resulting solution, followed by stirring at around 25 ° C. for 1 hour. Furthermore, after cooling to around 5 ° C. and aging at around 5 ° C. for 1 hour, the slurry solution was filtered by vacuum filtration. The crystals separated by filtration were washed with a mixed solution of 1.5 mL of methanol and 5 mL of water, and then the obtained white crystals were dried at 60 ° C. under reduced pressure for 15 hours to obtain 3.88 g (14.61 mmol, production of mirtazapine as white crystals). (Yield: 82.8%) was obtained (purity: 99.92%, dimer 1: 0.02%, dimer 2: 0.02%).

Examples 2-12
The same method as in Example 1 except that the amount of concentrated sulfuric acid and water added thereto was changed, that is, the concentration of sulfuric acid used in the reaction was changed, and / or the reaction temperature and time were changed. Mirtazapine was obtained. The production conditions are shown in Table 3, and the production results are shown in Table 4.

Comparative Examples 1-5
Same as Example 1 except that no water was added to the concentrated sulfuric acid, or that the amount of water was changed, that different concentrated sulfuric acid was used, and / or that the reaction temperature and time were changed. Mirtazapine was obtained by the method. The production conditions are shown in Table 3, and the production results are shown in Table 4.

Claims (2)

  2- (4-Methyl-2-phenyl-1-piperazinyl) -3-pyridine In a method for producing mirtazapine by reacting methanol with sulfuric acid, sulfuric acid having a concentration of 85.0% or more and less than 96.0% is used. A method for producing mirtazapine, characterized by reacting.   The method for producing mirtazapine according to claim 1, wherein the temperature at which 2- (4-methyl-2-phenyl-1-piperazinyl) -3-pyridinemethanol is reacted with sulfuric acid is 25 ° C or higher and 80 ° C or lower.