JP6622634B2 - Manufacturing method of mirtazapine - Google Patents

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 mirtazapine, in Patent Document 1, 2- (4-methyl-2-phenylpiperazin-1-yl) -3-pyridinemethanol (hereinafter also referred to as “pyridinemethanol compound”) represented by the following formula (2): .) And sulfuric acid are disclosed.

  This method is widely used because it is simple and has high conversion efficiency of pyridinemethanol compound to mirtazapine. Specifically, a pyridinemethanol compound and sulfuric acid are mixed and reacted under heating, and then neutralized by adding water and a base, followed by post-treatment. Next, the product mirtazapine is extracted with toluene, and another organic solvent such as heptane is added from the toluene solvent of the obtained mirtazapine to crystallize mirtazapine to produce a crude mirtazapine.

  The crude mirtazapine thus produced must be highly purified by purification. This is because a plurality of impurities are by-produced during the reaction of the pyridinemethanol compound and sulfuric acid and remain in the crude mirtazapine. One of the purification methods is a method of treating with activated carbon. According to this method, it is possible to reduce a plurality of impurities by-produced during the reaction and to improve the color tone of mirtazapine. In Patent Document 1, crude mirtazapine is dissolved in methanol, and the solution is treated with activated carbon. After the treatment, purification by recrystallization is performed to produce the final mirtazapine. .

Japanese Patent No. 3699680

  According to the study by the present inventors, as a method for obtaining crude mirtazapine, as in Patent Document 1, the method of crystallizing crude mirtazapine from the toluene solution after the reaction and post-treatment, the yield of mirtazapine in the crystallization operation is as follows. It was found that about 10% was lost, and the effect of reducing impurities was hardly obtained, and the impurities were reduced by the subsequent treatment with activated carbon and recrystallization. Therefore, a more preferable method includes a method of distilling toluene from the above toluene solution and obtaining crude mirtazapine as a concentrated residue. According to this method, the production yield of crude mirtazapine can be improved, and as a result, the production yield of mirtazapine can be improved.

  However, the crude mirtazapine obtained as a concentrated residue is subjected to activated carbon treatment and recrystallization in the same manner as in the conventional method, and the produced mirtazapine has a large amount of specific impurities remaining compared to the conventional method. There was found. Further, it has been found that this difference in the residual amount is due to the fact that the effect of reducing specific impurities in the activated carbon treatment is significantly lower than that of the conventional method.

  The specific impurity is an impurity having a retention time of around 4.4 minutes in the analysis by high performance liquid chromatography (HPLC) described in Examples. The impurity is contained in about 2% of crude mirtazapine (concentrated residue), but about 0.3% remains after the activated carbon treatment, and the impurity cannot be sufficiently reduced even in the subsequent purification by recrystallization. About 0.1% remained in the final mirtazapine. On the other hand, in the conventional method described in Patent Document 1, the amount of the specific impurity contained in the crude mirtazapine (crystal) is about 2%, which is equivalent to about 0.1% after the activated carbon treatment. In typical mirtazapine, it is reduced to about 0.05% or less.

  Therefore, a method for producing mirtazapine in high yield while maintaining high quality acceptable as a drug substance is desired.

  As a result of intensive studies to solve the above problems, the present inventors have reduced the specific impurities by reducing the amount of toluene in the treatment solution in the activated carbon treatment of crude mirtazapine as a concentrated residue. It has been found that can be significantly improved.

  That is, the present invention relates to a method in which a crude mirtazapine produced by reacting a pyridinemethanol compound and sulfuric acid, extracting with toluene, and concentrating the resultant is treated with activated carbon in an alcohol. A method for producing mirtazapine, wherein the amount of toluene is 15 g or less with respect to 100 g of a solution.

  When concentrating a toluene solution of mirtazapine, toluene tends to remain in the crude mirtazapine, which is a concentrated residue. About 25 g of toluene remains with respect to 100 g of the solution. By setting the residual amount of toluene to 15 g or less, the effect of reducing the specific impurities in the activated carbon treatment of crude mirtazapine as a concentrated residue is remarkably improved. As described above, when the residual amount of toluene is about 25 g, the specific impurity amount after the activated carbon treatment is about 0.3%, whereas when it is 15 g or less, it is reduced to 0.1% or less. The

  It is surprising that the reduction efficiency for specific impurities can be greatly improved by the difference in the residual amount of toluene as described above. The reason for this is not clear, but it is presumed that the difference in the polarity of the treatment solution due to the difference in the amount of toluene affects the amount of adsorption of the specific impurity on the activated carbon, and as a result, the reduction efficiency of the specific impurity is improved.

  According to the present invention, the production yield of mirtazapine can be improved as compared with the conventional method. Furthermore, the specific impurities are highly reduced in the activated carbon treatment of crude mirtazapine, which is a concentrated residue, and as a result, mirtazapine can be manufactured with high quality that can be suitably used as a drug substance.

  The present invention relates to a method for subjecting a crude mirtazapine obtained by extraction from a reaction solution obtained by reacting a pyridinemethanol compound and sulfuric acid using toluene and then concentrating to an activated carbon treatment in alcohol. A method for producing mirtazapine, wherein a residual amount of toluene is 15 g or less with respect to 100 g of an alcohol solution of mirtazapine. Moreover, when the alcohol is methanol, the effect of reducing specific impurities in the activated carbon treatment is more significantly improved.

(Pyridinemethanol compound)
The pyridinemethanol compound used in the present invention is not particularly limited and can be produced by a known method. Moreover, you may use what is marketed. In the case of production, an example of the method is a method described in JP-B-59-042678. In this method, 2- (4-methyl-2-phenylpiperazin-1-yl) -3-pyridinecarboxylic acid (hereinafter also referred to as “pyridinecarboxylic acid compound”) is reacted with a metal hydride in an organic solvent. This is a method of reducing. Specifically, a solution of a pyridinecarboxylic acid compound and tetrahydrofuran is obtained, and then 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. A highly purified pyridinemethanol compound can be produced by drying after isolation.

(Sulfuric acid)
The sulfuric acid used in the present invention is not particularly limited, and those commercially available as industrial products or reagents can be used. However, the concentration is preferably 85.0% or more. By using 85.0% or more sulfuric acid, the reaction can be completed. Among the above ranges, 87.0% to 98.0% is preferable, 90.0% to 96.5% is more preferable, and 92.0% to 95.0% is most preferable. This is because when the concentration of sulfuric acid is higher, the reaction rate is improved and the time required for the reaction can be shortened. On the other hand, when the concentration of sulfuric acid is lower, the amount of impurities during the reaction can be further suppressed. However, the by-product amount of the specific impurity does not change depending on the concentration of sulfuric acid.

  The usage-amount of a sulfuric acid is 5.0 mol or more and 30.0 mol or less with respect to 1.0 mol of pyridine methanol compounds. 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 are preferable, and 7.5 mol or more and 15.0 mol or less are preferable because the operability of the post-treatment is simple or the reaction can be completed in a short time. Is more preferable.

(Reaction operation)
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 container such as a glass container, a stainless steel container, a Teflon (registered trademark) container, or a glass lining container, and may be performed with stirring using a mechanical stirrer, a magnetic stirrer, or the like. From the viewpoint of operability and uniformity. The order of mixing is not particularly limited, but it is preferable to add the pyridinemethanol compound to sulfuric acid, and more preferably sequentially. This is because heat generation during mixing can be further suppressed and operability can be improved, and the pyridinemethanol compound is easily dispersed in sulfuric acid, and the reaction time is shortened.

  The mixture thus obtained is preferably reacted at a temperature of 25 ° C. or higher and 80 ° C. or lower. When the temperature is 25 ° C. or higher, the reaction proceeds sufficiently, and a high production yield of mirtazapine (yield based on pyridinemethanol compound) can be obtained. On the other hand, the amount of by-produced impurities can be suppressed by setting the temperature 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 may be appropriately determined by confirming the disappearance of the starting pyridinemethanol compound by HPLC or the like. Depending on the amount and concentration of sulfuric acid used, the pyridinemethanol compound usually disappears in 1 hour to 40 hours.

  In the reaction, a plurality of impurities are by-produced. Among them, specific impurities are produced as the most by-product, and the amount of by-products is usually 1.8% to 3.5% regardless of reaction conditions such as temperature and time. %.

(Post-processing operation)
In the present invention, a post-treatment is performed from the mixture obtained after completion of the reaction as described above to obtain a crude mirtazapine toluene solution. Specifically, after completion of the reaction, the reaction mixture is cooled. Next, the reaction mixture and water are mixed and diluted, and then neutralized by adding a base. Furthermore, toluene is added, and mirtazapine precipitated by neutralization is dissolved in toluene and extracted. A toluene solution of crude mirtazapine can be obtained by separating the obtained toluene layer and aqueous layer.

  Water can be used without particular limitation, such as tap water, ion exchange water, and pure water. It is preferable that the usage-amount is 1 mL or more and 20 mL or less with respect to 1 g of pyridine methanol compounds. Moreover, since the mixing operation of the reaction mixture and water is accompanied by heat generation, it is preferably carried out under cooling. The order of mixing is not particularly limited, but it is preferable to sequentially add the reaction mixture to water because heat generation can be further suppressed.

  As the base, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide, potassium tertiary butoxide, sodium methoxide and the like can be used. The form of solid or aqueous solution is not limited, but an aqueous solution is preferable from the viewpoint of operability. Moreover, the usage-amount is 1.5 mol or more and 5.0 mol or less with respect to 1.0 mol of sulfuric acid to be used. By using the said range, it can fully neutralize and, as a result, mirtazapine can fully be extracted to an organic solvent. The neutralization operation with the base is also preferably carried out under cooling because it generates heat similarly to the mixing operation with water. Moreover, after adding a part of said usage-amount, other operations, such as activated carbon treatment and addition of toluene, may be implemented, for example, and the remaining amount may be added after the said operation.

  Toluene can be used without particular limitation for industrial use or reagents. The usage-amount is 2 mL or more and 20 mL or less with respect to 1 g of pyridine methanol compounds. If it is the said range, mirtazapine can fully be extracted in toluene. Among these, 2.5 mL to 18 mL is preferable, and 4 mL to 15 mL is more preferable, because the operability at the time of liquid separation is preferable and the concentration operation which is a subsequent process is simple.

  The temperature at which mirtazapine is extracted by adding toluene is preferably 0 ° C. or more and 80 ° C. If it is the said range, the whole quantity of the mirtazapine produced | generated by reaction can be extracted in toluene. Among these, from the point that the tar component generated by the reaction can be dissolved and the operability at the time of liquid separation can be improved, and the extraction speed of mirtazapine is fast, 10 ° C to 75 ° C is preferable, and 20 ° C to 65 ° C is preferable. Is more preferable. Further, although the extraction time depends on the extraction temperature, it is usually sufficient that it is 1 minute to 2 hours.

  A toluene solution of crude mirtazapine can be obtained as a toluene layer by separating the toluene layer and the aqueous layer thus obtained. The operation method may be a known method. Moreover, it is preferable that the temperature at the said operation is 0 degreeC or more and 80 degrees C or less similarly to the extraction temperature to toluene. The amount of the specific impurity contained in the solution is 1.8% to 3.5% as in the case after the reaction.

(Concentration operation)
In the present invention, the toluene solution of crude mirtazapine is concentrated by distilling off toluene, and crude mirtazapine is obtained as a concentrated residue.

  The concentration temperature is preferably 20 ° C. or higher and 120 ° C. or lower. Among these, considering the concentration efficiency and the stability of mirtazapine, the temperature is preferably 30 ° C. or higher and 100 ° C. or lower, and more preferably 40 ° C. or higher and 80 ° C. or lower. Moreover, although it can carry out under normal pressure, pressure reduction, or gas, such as nitrogen and argon, ventilation | gas_flowing, the point of pressure reduction is more preferable from the point which can suppress byproducts, such as concentration efficiency and an oxide. The end point of concentration may be determined as appropriate after confirming that toluene is no longer distilled.

  After completion of the concentration operation, crude mirtazapine is obtained as a concentration residue, but mirtazapine is hard to solidify and is obtained as a viscous oil. For this reason, toluene tends to remain in the crude mirtazapine.

(Preparation of alcohol solution)
In the present invention, crude mirtazapine is dissolved in 1 mL or more and 20 mL or less of alcohol with respect to 1 g of pyridinemethanol compound, and then an alcohol solution of crude mirtazapine for treatment with activated carbon is prepared. The alcohol to be used is a liquid having 1 to 10 carbon atoms and having one or more hydroxyl groups. Specifically, methanol, ethanol, propanol and its isomer, butanol and its isomer, pentanol and its isomer, hexanol and its isomer, phenol, ethylene glycol and the like. Among these, methanol, ethanol, propanol and isomers thereof, butanol and isomers thereof are preferable because mirtazapine has high solubility and can be used in a small amount. Further, methanol is most preferable because the efficiency of reducing specific impurities in the activated carbon treatment is high, and the improvement in the reduction efficiency, which is the effect of the present invention, is more remarkably exhibited.

  The usage-amount of alcohol is 1 mL or more and 20 mL or less with respect to 1 g of pyridine methanol compounds. If it is less than 1 mL, depending on the type of alcohol, the total amount of crude mirtazapine does not dissolve, and operability is not preferred. On the other hand, when it exceeds 20 mL, the decoloring effect due to the activated carbon treatment decreases, and in the subsequent isolation operation, the yield decreases, or the concentration operation or the use of a poor solvent such as water is remarkably large. Necessary. Among the above ranges, in consideration of operability, 2 mL to 18 mL is preferable, and 3 mL to 15 mL is more preferable.

  The temperature at which the crude mirtazapine is dissolved in alcohol is -20 ° C or higher and 70 ° C or lower. Among these, from the point that the effect of the activated carbon treatment is high and the time required for dissolution can be shortened, −10 ° C. or higher and 60 ° C. or lower is preferable, and 0 ° C. or higher and 60 ° C. or lower is more preferable.

  In the present invention, it is essential that the amount of toluene contained in the crude mirtazapine alcohol solution obtained as described above is 15 g or less with respect to 100 g of the alcohol solution. By setting it as these ranges, the reduction efficiency of the specific impurity in activated carbon treatment can be improved.

  First, the amount of toluene contained in the alcohol solution is measured by a method using gas chromatography described in Examples. If the amount of toluene is within the range, the activated carbon treatment operation may be performed. However, as described above, since toluene tends to remain in the crude mirtazapine as a concentrated residue as described above, when 5 mL of alcohol is used with respect to 1 g of pyridinemethanol compound, about 25 g of alcohol solution with respect to 100 g of alcohol solution is used. Toluene remains. Therefore, it is necessary to reduce the amount of toluene and adjust it to be within a predetermined range.

  The operation of reducing toluene includes a method of concentrating the alcohol solution and again forming a crude mirtazapine alcohol solution in which the crude mirtazapine is dissolved in 1 mL or more and 20 mL or less of alcohol with respect to 1 g of pyridinemethanol compound. Concentration conditions such as temperature are the same as in the above concentration operation. The concentrated amount may be the total amount of alcohol or a part thereof. Moreover, you may concentrate after adding alcohol before concentration. In the case of concentrating without adding alcohol, alcohol may be added as needed after concentration to obtain a crude mirtazapine alcohol solution in which crude mirtazapine is dissolved in 1 mL to 20 mL of alcohol with respect to 1 g of pyridinemethanol compound. . Moreover, when alcohol is added, it is good also as an alcohol solution of the crude mirtazapine which the crude mirtazapine melt | dissolved in 1 mL or more and 20 mL or less of alcohol with respect to 1 g of pyridine methanol compounds by concentrating, and adding alcohol after further concentration. The crude mirtazapine may be an alcohol solution of crude mirtazapine in which 1 mL to 20 mL of alcohol is dissolved in 1 g of pyridine methanol compound.

  In any case, the amount of toluene is 15 g or less with respect to 100 g of the crude mirtazapine alcohol solution. Among these, 10 g or less is preferable, 7.5 g or less is more preferable, and 5 g or less is the most preferable from the viewpoint of higher specific impurity reduction efficiency.

(Activated carbon treatment)
In the present invention, an alcohol solution of crude mirtazapine and activated carbon are mixed and activated carbon treatment is performed. The activated carbon used in the present invention is a porous, carbon-based material, which is made of wood, coal, or the like and subjected to activation treatment. The raw material is not particularly limited, such as sawdust, coconut shell, charcoal, coal, and the activation treatment method is not particularly limited, such as treatment with a gas such as water vapor or treatment with a chemical such as zinc chloride. The amount used is preferably 2.5 g or more and 30 g or less with respect to 100 g of the pyridinemethanol compound. This is because the impurity reduction efficiency is high and the decolorization effect is high regardless of the specific impurity. From the viewpoint that these effects are higher and the loss of mirtazapine is less, 5 g or more and 25 g or less are more preferable, and 7.5 g or more and 20 g or less are more preferable.

  The temperature of the activated carbon treatment is the same as the preparation temperature of the alcohol solution, may be the same as the temperature, or may be different within the range. Further, the treatment time is usually sufficient for 30 minutes or more. After the treatment, it is necessary to remove the activated carbon by a filtration operation or the like. The operation may be appropriately selected from known methods such as decantation, vacuum filtration, pressure filtration, and centrifugal separation. In the said operation, the separation efficiency of activated carbon can be improved more by using filter aids, such as a radiolite.

(Isolation of mirtazapine)
In the present invention, mirtazapine is isolated from the solution after the activated carbon treatment. As the method, a recrystallization operation is preferable because it has a purification effect. The recrystallization operation is not particularly limited and may be performed by a known method. For example, crystallization is performed by adding a solvent having low solubility of mirtazapine such as water to the alcohol solution after the activated carbon treatment. Or after distilling alcohol off and concentrating, other solvent, such as acetone, is added and recrystallization operation is implemented. After crystallization, mirtazapine can be isolated by solid-liquid separation and drying by a known method.

  Thus, mirtazapine can be produced with a high production yield by the method of the present invention. Moreover, the reduction efficiency of the specific impurity at the time of activated carbon processing is high, As a result, the quality of the manufactured mirtazapine is high and can be used conveniently as a pharmaceutical active ingredient.

  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 purity of mirtazapine and content of specific impurities)
The purity of mirtazapine and the content of dimer impurities by HPLC were measured by the following apparatus and conditions. In the HPLC analysis under these conditions, the retention time of mirtazapine is around 14.0 minutes, the specific impurity is around 4.4 minutes, and the pyridinemethanol compound is around 5.5 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. Moreover, content of a specific impurity is the value shown with the percentage with respect to the sum total of the area value of all the peaks of the peak area value of each impurity.

Equipment: High performance liquid chromatograph (Waters 2695)
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

(Evaluation of the amount of toluene in the alcohol solution of crude mirtazapine)
The amount of toluene in the crude mirtazapine alcohol solution by GC was measured by the following apparatus and conditions.

  In the following examples and comparative examples, the amount of toluene in the alcohol solution of crude mirtazapine was calculated from the peak area value of toluene obtained by the measurement by the calibration curve method to calculate the ratio of the mass of toluene to the mass of the alcohol solution. . Moreover, the detection limit in the measurement was less than 25 ppm.

Apparatus: Gas chromatograph apparatus (Agilent Technologies, Inc.)
Detector: Hydrogen flame ionization detector (manufactured by Agilent Technologies, Inc.)
Column: A capillary column in which the inner surface of a fused silica tube having an inner diameter of 0.32 mm and a length of 30 m is coated with polyethylene glycol for gas chromatography at a thickness of 1.8 μm.
Column temperature: Injected at a constant temperature around 40 ° C. and maintained at around 40 ° C. for 4 minutes, then heated to 220 ° C. at 10 ° C. per minute and maintained for 8 minutes.
Inlet temperature: 200 ° C
Detector temperature: 220 ° C
Carrier gas: Helium column pressure: 50 kPa

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 obtained by dissolving 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 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, and the resulting 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 a 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%).

Example 1 (Production of mirtazapine)
A 100 mL four-necked flask equipped with a stirring blade and a thermometer was charged with 17.97 g (176.4 mmol) of concentrated sulfuric acid having a concentration of 96.3% under a nitrogen atmosphere, and cooled to around 15 ° C. 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 5 hours (mirtazapine purity: 92.45%, specific impurities: 2.34%).

  After completion of the reaction, the reaction mixture was cooled to around 5 ° C., and the reaction mixture was added little by little to 35 mL of water at 35 ° C. or less. Next, 61.4 g (352.9 mmol) of a 23 wt% aqueous sodium hydroxide solution was added little by little at 35 ° C. or lower. Furthermore, after adding toluene 50mL and stirring for 15 minutes at 60 degreeC vicinity, the water layer was liquid-separated and the toluene solution of mirtazapine was obtained as an organic layer. This solution was concentrated under reduced pressure at 50 ° C. to obtain 12.44 g of crude mirtazapine (including 7.40 g of toluene) as a yellow oily substance (including mirtazapine purity: 93.78%, specific impurities: 2.31%). The production yield of crude mirtazapine based on the pyridinemethanol compound was 97.1%.

  The obtained crude mirtazapine 12.44 g and methanol 25 mL (19.78 g) were placed in a 100 mL four-necked flask equipped with a stirring blade and a thermometer, and stirred at 25 ° C. for 15 minutes to obtain a solution. The amount of toluene in the solution was 24.5 g with respect to 100 g of the solution. The solution was concentrated under reduced pressure at 50 ° C., 13 mL (10.28 g) of methanol was distilled off, and 13 mL (10.28 g) of methanol was added. The amount of toluene in the solution was 14.3 g with respect to 100 g of the solution. After cooling the obtained solution to around 5 ° C, 0.75 g of activated carbon was added and stirred at around 5 ° C for 30 minutes. The activated carbon was separated by filtration under reduced pressure to obtain a solution (mirtazapine purity: 96.31%, specific impurities: 0.09%).

  The resulting solution was crystallized by adding 50 mL of water little by little at around 55 ° C., and stirred at around 25 ° C. for 1 hour. Further, 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 give 4.20 g (15.83 mmol) of mirtazapine as white crystals. Obtained (purity of mirtazapine: 99.80%, specific impurity: 0.05%). The production yield of mirtazapine based on the pyridinemethanol compound was 89.7%.

Examples 2-6
Mirtazapine was obtained in the same manner as in Example 1 except that the concentration of alcohol in the solution before the activated carbon treatment was changed and that the type and amount of alcohol were changed. The production conditions are shown in Table 2, and the production results are shown in Table 3.

Comparative Example 1
In the same manner as in Example 1, a toluene solution of mirtazapine was obtained. The solution was crystallized by adding 30 mL of heptane at around 55 ° C. and aged at around 55 ° C. for 1 hour. Further, after cooling to around 5 ° C. and aging at around 5 ° C. for 1 hour, the slurry solution was filtered by vacuum filtration. The filtered crystals 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 (15.33 mmol) of crude mirtazapine as brown crystals. (Mirtazapine purity: 94.43%, specific impurities: 2.29%). The production yield of crude mirtazapine based on the pyridinemethanol compound was 86.9%.

  The obtained crude mirtazapine 4.00 g and methanol 25 mL (19.78 g) were placed in a 100 mL four-necked flask equipped with a stirring blade and a thermometer, and stirred at 25 ° C. for 15 minutes to obtain a solution. The amount of toluene in the solution was 0.9 g with respect to 100 g of the solution. After cooling this solution to around 5 ° C., 0.75 g of activated carbon was added and stirred at around 5 ° C. for 30 minutes. The activated carbon was separated by filtration under reduced pressure to obtain a solution (mirtazapine purity: 96.74%, specific impurities: 0.02%).

  The resulting solution was crystallized by adding 50 mL of water little by little at around 55 ° C., and stirred at around 25 ° C. for 1 hour. Further, 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 3.75 g (14.13 mmol) of mirtazapine as white crystals. Obtained (mirtazapine purity: 99.82%, specific impurities: 0.01%). The production yield of mirtazapine based on the pyridinemethanol compound was 80.1%.

Comparative Examples 2-4
Mirtazapine was obtained in the same manner as in Example 1 except that the alcohol in the solution before the activated carbon treatment was not concentrated and that the type and amount of the alcohol were changed. The production conditions are shown in Table 2, and the production results are shown in Table 3.

Claims (2)

  2- (4-Methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol and sulfuric acid were used to extract mirtazapine using toluene, and then the crude mirtazapine was extracted from the toluene extract. Then, in the method for producing mirtazapine, which comprises subjecting the crude mirtazapine to an alcohol solution of the crude mirtazapine and treating with activated carbon, the toluene extract is concentrated to obtain the crude mirtazapine as a concentrated residue, and the crude mirtazapine is 2- ( 4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol dissolved in 1 mL to 20 mL of alcohol to form a crude mirtazapine alcohol solution, and in 100 g of the alcohol solution during activated carbon treatment The toluene content of is 15 g or less, Mirtazapine method for producing the symptoms.   The method for producing mirtazapine according to claim 1, wherein the alcohol is methanol.