JP2002220390A - Anhydrous mirtazapine and its manufacturing method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method by which anhydrous mirtazapine crystal containing substantially no lower alcohol-insoluble substance is manufactured from crude mirtazapine and anhydrous mirtazapine with an average particle size of 10 to 50 μm containing substantially no residual solvent is manufactured, efficiently and industrially. SOLUTION: The manufacturing method for anhydrous mirtazapine crystal containing substantially no lower alcohol-insoluble substance is characterized in that crude mirtazapine is dissolved in a lower alcohol and the crude mirtazapine lower alcohol solution thus obtained is filtrated, and then the filtrate is condensed and anhydrous mirtazapine is crystallized with a separating solvent selected from the group consisting of heptane and petroleum ether. Anhydrous mirtazapine with a average particle size of 10 to 50 μm containing substantially no residual solvent. The manufacturing method of anhydrous mirtazapine with a average particle size of 10 to 50 μm containing substantially no residual solvent is characterized in that the crystal of anhydrous mirtazapine is ground to get an average particle size of 10 to 50 μm.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to anhydrous mirtazapine and a method for producing the same. More specifically, the present invention relates to anhydrous mirtazapine useful as an antidepressant and a method for producing the same.

[0002]

2. Description of the Related Art As a method for increasing the purity of mirtazapine, a method of recrystallizing mirtazapine from petroleum ether or the like has been proposed (US Pat. No. 4,062,848).

However, this method has a purity of 95-99%.
When a coarse degree of mirtazapine is used, impurities are precipitated as oil and the crystallization of mirtazapine is inhibited, so that it is difficult to obtain mirtazapine having high purity.

[0004] Therefore, development of a process for efficiently producing anhydrous mirtazapine having high purity from crude mirtazapine is desired.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and is an efficient method of preparing crude mirtazapine from crude mirtazapine, which contains substantially no lower alcohol insolubles and has an average particle size of 10%. ~ 50μ
m, and an object of the present invention is to provide a method capable of industrially producing anhydrous mirtazapine containing substantially no residual solvent.

[0006]

The present invention provides (1) an anhydrous mirtazapine crystal substantially containing no lower alcohol insolubles, and (2) a crude mirtazapine obtained by dissolving a crude mirtazapine in a lower alcohol. After the solution is filtered, the filtrate is concentrated, and anhydrous mirtazapine is crystallized using a precipitation solvent selected from the group consisting of heptane and petroleum ether. A method for producing mirtazapine crystals, (3) the average particle size is 10 to 50 μm,
An anhydrous mirtazapine containing substantially no residual solvent and (4) an anhydrous mirtazapine crystal having an average particle diameter of 10 to 5
The present invention relates to a method for producing anhydrous mirtazapine having an average particle diameter of 10 to 50 μm, which is characterized by being pulverized to 0 μm, and containing substantially no residual solvent.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The anhydrous mirtazapine crystal of the present invention is substantially free of lower alcohol insolubles.

The lower alcohol includes, for example, methanol, ethanol, propanol, isopropanol and the like. Among these lower alcohols,
Methanol is preferred from the viewpoints of removing lower alcohol insolubles and economical efficiency. The lower alcohol may contain about 1 to 5% by weight of water.

The phrase "substantially free from lower alcohol insolubles" as used herein means that anhydrous mirtazapine crystals are added to 10 times the volume of methanol, and 20 to 30 volumes of methanol are added.
Dissolving anhydrous mirtazapine crystals at a temperature in the range of
When the absorbance of the solution is measured at a wavelength of 600 nm, the absorbance is 0.1 or less.

[0010] Crude mirtazapine is used as a starting material for the anhydrous mirtazapine crystals of the present invention.

[0011] Crude mirtazapine is disclosed, for example, in US Pat.
It can be prepared by the method described in 4,062,848.

More specifically, the crude mirtazapine comprises 2
-(4-methyl-2-phenylpiperazin-1-yl)
It can be obtained by subjecting pyridine-3-methanol (hereinafter, referred to as a pyridinemethanol compound) to dehydration and ring closure using concentrated sulfuric acid.

As the concentrated sulfuric acid, a concentrated sulfuric acid having a concentration of 97 to 99% can be suitably used. The temperature of the concentrated sulfuric acid at the time of adding the pyridinemethanol compound is from 0 to 40 from the viewpoint of suppressing heat generation and suppressing the generation of tar-like impurities.
C, preferably 5 to 35C.

When the pyridinemethanol compound is added to concentrated sulfuric acid, it is preferable to divide the pyridinemethanol compound and add it to concentrated sulfuric acid from the viewpoint of efficiently proceeding the reaction. For example, if a pyridinemethanol compound is
It is preferable to add to concentrated sulfuric acid by dividing into 20 parts.

The amount of concentrated sulfuric acid is usually 300 to 400 parts by weight, based on 100 parts by weight of the pyridinemethanol compound.
Preferably, the amount is 350 to 400 parts by weight.

After the pyridinemethanol compound is added to the concentrated sulfuric acid, the reaction is carried out at 20 to 50 ° C. to promote the reaction.
It is desirable to stir at a temperature of about 30 to 40 ° C. for about 7 to 10 hours.

Thus, the pyridine methanol compound is subjected to dehydration ring closure, and the end point of the ring closure reaction is determined by HPLC.
(High performance liquid chromatography).

Next, it is preferable to lower the concentration of sulfuric acid by a method such as dropping the obtained reaction solution into water. From the viewpoint of operability, the amount of water is preferably about 100 to 200 parts by weight based on 100 parts by weight of the reaction solution. Further, the liquid temperature of the reaction solution at the time of addition is preferably about 0 to 30 ° C. from the viewpoint of suppressing heat generation and the generation of impurities (tar).

Next, it is preferable to add an aqueous alkali solution to the reaction solution for neutralization. Examples of the alkali include sodium hydroxide, potassium hydroxide, sodium carbonate and the like. Of these, sodium hydroxide is preferred. The concentration of the alkali hydroxide in the aqueous alkali solution is desirably 20 to 30% by weight, preferably 20 to 25% by weight, from the viewpoint of operability. It is desirable to adjust the amount of the aqueous alkali hydroxide solution so that the pH of the solution becomes 1 to 3, preferably 1 to 2, so as not to precipitate crystals.

After the pH is adjusted, it is preferable to add a decolorizing carbon to the solution for decolorization.

Next, the solution is filtered as required, and crude mirtazapine can be extracted by adding toluene to the filtrate.

Toluene is used to remove fat-soluble impurities contained in the filtrate. The amount of toluene is
80 parts per 100 parts by weight of the pyridinemethanol compound
It is desirably from 200 to 200 parts by weight, preferably from 100 to 150 parts by weight. The temperature of the solution obtained by adding toluene to the filtrate is preferably 15 to 35 ° C, and more preferably 20 to 30 ° C. The solution is preferably stirred for 15 minutes or more, preferably 30 minutes to 1 hour.

Next, the solution is allowed to stand for at least 30 minutes, preferably for about 1 to 2 hours, to be separated into two liquids, an organic layer and an aqueous layer.

Of the two liquids separated, toluene is added to the aqueous layer. The amount of toluene is 150 to 300 parts by weight, preferably 170 parts by weight, per 100 parts by weight of the pyridinemethanol compound in order to efficiently extract crude mirtazapine.
Desirably, the amount is up to 250 parts by weight. After the addition of toluene, the pH of the aqueous layer should be at least 8, preferably at least 8.
It is desirable to adjust to 10 to 10. The pH of the aqueous layer can be adjusted using an alkali. Examples of the alkali include an aqueous sodium hydroxide solution.

Next, this solution is desirably heated to a temperature of 70 to 85 ° C., preferably 75 to 80 ° C. in order to dissolve the crude mirtazapine and to improve the liquid separating property.

When this solution is allowed to stand, it is separated into two solutions.
Among them, a dehydrating agent is preferably added to the organic layer in order to remove moisture.

Examples of the dehydrating agent include anhydrous magnesium sulfate and anhydrous sodium sulfate. Of these, anhydrous magnesium sulfate is preferred from the viewpoint of dehydration efficiency.

The amount of the dehydrating agent is 5 to 50 parts by weight, preferably 1 to 100 parts by weight of the pyridinemethanol compound.
Desirably, the amount is 0 to 20 parts by weight.

The dehydrating agent may be used by pre-coating on a filter used when filtering an organic layer.

From the viewpoint of improving the hue and the purity of the obtained anhydrous mirtazapine crystal, it is preferable to add a decolorizing agent to the organic layer.

Examples of the decolorizing agent include activated alumina,
Decolorizing carbon and the like. Of these, activated alumina is preferred. Since the amount of the decolorizing agent varies depending on the type thereof, it cannot be determined unconditionally, but is usually 5 to 50 parts by weight, preferably 10 to 20 parts by weight based on 100 parts by weight of the pyridine methanol compound. .

The temperature at which the decolorization is performed is not particularly limited, but is usually from room temperature to 85 ° C., preferably from 30 to 80 ° C. The time required for decolorization may be about 15 to 30 minutes.

Next, it is preferable to remove toluene from the organic layer. The amount of toluene to be distilled off may be about 50 to 80% by weight, preferably about 60 to 70% by weight of the toluene used. The distillation of toluene can be performed by distillation under reduced pressure. The degree of pressure reduction at that time is desirably 0.6 to 40 kPa, preferably 4 to 30 kPa, from the viewpoint of improving the concentration rate. Further, the distillation temperature is desirably 30 to 85 ° C, preferably 60 to 75 ° C, from the viewpoint of improving the concentration rate and preventing the obtained anhydrous mirtazapine crystal from being colored.

Heptane is preferably added to the obtained concentrated liquid in order to crystallize crude mirtazapine. From the viewpoint of improving the yield, the amount of heptane is 450 to 100 parts by weight of the pyridinemethanol compound.
700 parts by weight, preferably 500 to 600 parts by weight. The temperature at the time of adding heptane is preferably 75 to 85 ° C from the viewpoint of improving the filterability. In addition, when adding heptane, it is preferable that heptane is dripped.

Next, the obtained solution is used for 1 to 5 hours, preferably 2 to 3 hours, in order to make the crystal diameter uniform and improve the yield.
It is desirable to gradually cool to a temperature of -10 to 5C over time.

Thus, the crude mirtazapine can be crystallized. The crystals may be washed with, for example, heptane or a solvent obtained by cooling a mixed solvent of toluene and heptane to 0 to 5 ° C. In this case, the ratio of toluene and heptane may be about 70 to 100 parts by weight of heptane per 100 parts by weight of toluene.

Next, if necessary, the crystals may be 45 to 6
It may be dried under reduced pressure at a temperature of 5 ° C., preferably about 50 to 60 ° C. Thus, crude mirtazapine can be obtained.

Next, anhydrous mirtazapine crystals are obtained from the crude mirtazapine. The anhydrous mirtazapine crystals are obtained by dissolving the crude mirtazapine in a lower alcohol, filtering the lower alcohol solution of the obtained crude mirtazapine, concentrating the filtrate, and crystallizing using a solvent selected from the group consisting of heptane and petroleum ether. Can be obtained. The anhydrous mirtazapine crystals are substantially free of lower alcohol insolubles. less than,
The method for producing anhydrous mirtazapine crystals will be described in detail.

First, the crude mirtazapine is dissolved in a lower alcohol. Examples of the lower alcohol include methanol, ethanol, propanol, isopropanol and the like. Among these lower alcohols, methanol is preferable from the viewpoints of removability of lower alcohol insolubles and economical efficiency. The amount of lower alcohol is
From the viewpoint of sufficiently dissolving the crude mirtazapine and not dissolving the impurities contained in the crude mirtazapine, 300 to 5 parts by weight based on 100 parts by weight of the crude mirtazapine.
00 parts by weight, preferably 350 to 450 parts by weight.

The temperature at which the crude mirtazapine is dissolved in the lower alcohol is -5 to 10 ° C., preferably from -5 to 10 ° C., from the viewpoint of shortening the time required for dissolving the crude mirtazapine and not dissolving the impurities contained in the crude mirtazapine. Desirably, the temperature is 0 to 5 ° C.

After dissolving the crude mirtazapine in a lower alcohol, the solution is preferably brought into contact with a decolorizing agent in order to decolor the crude mirtazapine. Examples of the method of bringing the solution into contact with the decolorizing agent include a method of adding the decolorizing agent to the solution, a method of placing the decolorizing agent on the filter surface of the filter, and then pouring the solution into the filter. The invention is not limited by such a method.

Examples of the decolorizing agent include activated carbon, activated alumina and activated clay. Among these,
It is preferable to use activated carbon and activated clay in combination from the viewpoint of decolorization.

The amount of the decolorizing agent is from 0.1 to 30 parts by weight, preferably from 0.5 to 25 parts by weight, per 100 parts by weight of the crude mirtazapine, from the viewpoint of sufficiently decolorizing the crude mirtazapine and improving the purity. Part is desirable. When using activated carbon and activated clay together, from the viewpoint of decolorization, use 0.1 to 0.5 parts by weight of activated carbon and 10 to 25 parts by weight of activated clay with respect to 100 parts by weight of crude mirtazapine. Is preferred.

Next, the lower alcohol solution of the crude mirtazapine is filtered. The filtration method is not particularly limited, and for example, a commonly used filtration method such as a reduced pressure filtration method and a pressure filtration method can be employed. As a result, the lower alcohol insolubles contained in this solution are separated and removed.

The temperature for the filtration is preferably -5 to 10 ° C, more preferably 0 to 5 ° C, from the viewpoint of the solubility of the lower alcohol insolubles and the solubility of the crude mirtazapine.

The filtrate obtained was free of lower alcohol impurities and the crude mirtazapine was dissolved. This filtrate is preferably concentrated under reduced pressure. From the viewpoint of stability of anhydrous mirtazapine and avoiding coloring of anhydrous mirtazapine, the temperature of the filtrate at the time of concentration is from 0 to 0.
Preferably it is 50 ° C. Concentration is performed when the internal temperature is 5
It is preferable to carry out until the temperature reaches 0 ° C.

Next, in order to precipitate anhydrous mirtazapine contained in the concentrate, a precipitation solvent selected from the group consisting of heptane and petroleum ether is added to the filtrate.
Among these deposition solvents, heptane is preferred from the viewpoint of crystallization of anhydrous mirtazapine. From the viewpoint of preventing anhydrous mirtazapine from being precipitated as an oil and improving the yield of anhydrous mirtazapine, 100 to 10 parts by weight of the used crude mirtazapine is used.
00 parts by weight, preferably 130 to 800 parts by weight, more preferably 130 to 700 parts by weight.

Next, the solvent contained in the solution obtained by adding the precipitation solvent to the concentrated solution is distilled off at normal pressure, whereby the dissolved anhydrous mirtazapine can be crystallized. At that time, the solution temperature of the solution is preferably from 50 to 60 ° C from the viewpoint of distilling off methanol, and methanol is finally added until the internal temperature becomes 65 to 80 ° C, preferably 75 to 80 ° C. It is desirable to distill off.

After distilling off the solvent from the solution, the solution is cooled to -10 to 5 ° C. to precipitate anhydrous mirtazapine crystals. The solution after cooling is preferably stirred at a temperature of -10 to 5C for about 1 to 5 hours from the viewpoint of improving the yield of anhydrous mirtazapine crystals.

[0050] The anhydrous mirtazapine crystals can be recovered by filtration. The recovered anhydrous mirtazapine crystals can be dried under reduced pressure. In this case, the drying temperature is desirably 20 to 60 ° C, preferably 40 to 60 ° C, from the viewpoint of reducing the amount of residual solvent in the anhydrous mirtazapine crystals and preventing the coloring of the anhydrous mirtazapine crystals. Further, the degree of reduced pressure is from 0.1 to 40 kPa, preferably from 0.1 to 4 kP, from the viewpoint of reducing the amount of residual solvent in the anhydrous mirtazapine crystal and improving the drying rate.
a is desirable.

In order to obtain anhydrous mirtazapine crystals having higher purity, purification with a lower alcohol represented by methanol and recrystallization with the above-mentioned precipitation solvent may be repeated.

The anhydrous mirtazapine crystals thus obtained are substantially free of lower alcohol insolubles. This anhydrous mirtazapine crystal has a particle size so large that it cannot be measured by a laser diffraction particle size distribution analyzer.
It is about 0 to 300 μm.

By grinding the crystals of anhydrous mirtazapine, anhydrous mirtazapine containing substantially no residual solvent can be obtained. Thus, when the anhydrous mirtazapine crystals are milled, it is surprisingly possible to obtain anhydrous mirtazapine substantially free of residual solvent.

The term "anhydrous mirtazapine containing substantially no residual solvent" as used herein means that the amount of the residual solvent contained in anhydrous mirtazapine is 200 ppm or less.

For the pulverization of the anhydrous mirtazapine crystal, for example, a pulverizer such as a cutter mill, a hammer mill and an atomizer can be used.

The average particle size of the anhydrous mirtazapine after pulverization is preferably 1 from the viewpoint of easy preparation and easy handling.
0 to 50 μm. In this specification, the average particle size of anhydrous mirtazapine is measured by a laser diffraction particle size distribution analyzer [manufactured by Shimadzu Corporation, trade name: SALD20].
00, medium: water].

The anhydrous mirtazapine crystals of the present invention substantially free of lower alcohol insolubles and the anhydrous mirtazapine having an average particle diameter of 10 to 50 μm and containing substantially no residual solvent are all useful as antidepressants. It is.

[0058]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to only these examples.

Production Example 1 [Production of crude mirtazapine] After charging 6202 g of concentrated sulfuric acid into a 10 L flask, 2- (4-methyl-2-phenylpiperazine-1-yl) was added.
Il) 5723 g of pyridine-3-methanol (1723 g)
C. and the mixture was stirred at 30 to 40.degree. C. for 8 hours.

11. The obtained reaction mixture is treated with water at 0 to 5 ° C.
The solution was dropped into 4 kg and hydrolyzed. Place the flask in concentrated sulfuric acid 770
g, and the obtained washing liquid was mixed with the hydrolyzate obtained above.

Next, the pH of this mixed solution was adjusted to about 1.6 with a 25% by weight aqueous solution of sodium hydroxide, and 164 g of decolorizing carbon was used.
Was added to the reaction mixture, stirred for 1 hour and filtered. The decolorized carbon was washed with 1.6 kg of water, and the washing was mixed with the filtrate.

To the filtrate were added 2988 g of toluene, and 25
The impurities were removed by extraction at ~ 35 ° C.

The aqueous layer and the organic layer were separated at 20 to 30 ° C. To the aqueous layer was added 2988 g of toluene, and 2
The pH of the aqueous layer was adjusted to 8.5 with a 5% by weight aqueous sodium hydroxide solution.
Was adjusted. After stirring at 75 to 80 ° C, the mixture was separated into an aqueous layer and an organic layer.

After 288 g of anhydrous magnesium sulfate and 288 g of activated alumina were added to the organic layer, and the mixture was stirred at 75 to 80 ° C. for 15 minutes, the anhydrous magnesium sulfate and activated alumina were separated by filtration and washed with 1120 g of toluene.

Next, 3000 mL of toluene (about 2601
g) was distilled off under reduced pressure, and heptane (9817 g) was added.
After cooling to ５5 ° C. and stirring at the same temperature for 1 hour, the mixture was filtered. The obtained crystals were washed with 1355 g of heptane.

Next, the crystals were subjected to 50 kPa at a reduced pressure of 4 kPa.
By drying at a temperature of ６０60 ° C., 1291 g of crude mirtazapine having an HCLP purity of 99.8% was obtained.

Production Example 2 [Production of crude mirtazapine] Under a nitrogen stream, 270 kg of concentrated sulfuric acid was charged into a reaction vessel.
75 kg of (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol was added in portions at 0 to 30 ° C, and the mixture was stirred at 30 to 40 ° C for 8 hours.

The obtained reaction solution was cooled at a temperature of 0 to 30 ° C.
The reaction vessel was washed with 34 kg of concentrated sulfuric acid dropwise, and the obtained washing liquid was mixed with the hydrolyzate obtained above.

Next, the pH of this mixed solution was adjusted to 1 to 2 with a 25% by weight aqueous sodium hydroxide solution, and
g (50% wet) was added to the reaction mixture, stirred for 1 hour and filtered. The decolorized carbon was washed with 143 kg of water, and the washing was mixed with the filtrate. 98 kg of toluene was added to the filtrate and washed at 25 to 35 ° C.

The aqueous layer and the organic layer were separated at 25 to 35 ° C. 130 kg of toluene was added to the aqueous layer, and the pH of the aqueous layer was adjusted to 9 by further adding a 25% by weight aqueous sodium hydroxide solution. After stirring at 75 to 80 ° C, the mixture was separated into an aqueous layer and an organic layer.

351 kg of toluene was added to the organic layer, and 3
13 kg of anhydrous magnesium sulfate and activated alumina [manufactured by Sumitomo Chemical Co., Ltd., trade name: A-11] 13 at 0 to 40 ° C.
kg was added and stirred for 1 hour. The organic layer was filtered at 30 to 40 ° C, and the filtrate was washed with 43 kg of toluene. The washing liquid is mixed with the filtrate, and under reduced pressure of 5 to 40 kPa, 30 to 40 kPa.
At 80 ° C., the toluene was distilled off. The amount of toluene distilled off was 530 L. Heptane 427 at 60-80 ° C
kg at a temperature of about 50 ° C.
Cooled to ° C. The mixture was stirred at the same temperature for 1 hour and filtered. -1
The crystals were washed with 76 kg heptane cooled to 0-5 ° C. The resultant was washed at 40 to 50 ° C. under reduced pressure to obtain 56 kg of crude mirtazapine. The yield was 79.7%.

Example 1 129.1 g of the crude mirtazapine obtained in Production Example 1 was
Dissolved in 510.6 g of methanol at ５5 ° C.
At 5 ° C., 1.3 g of decolorizing carbon was added and stirred for 15 minutes. This solution was filtered at 0 to 5 ° C to remove lower alcohol insolubles, and methanol was distilled off from the obtained filtrate under reduced pressure of 40 to 50 kPa until the internal temperature became 50 ° C. The amount of methanol distilled off was 490 g.

Next, heptane (582.8 g) was added to the filtrate from which methanol was distilled off, and methanol was azeotropically distilled off until the internal temperature reached 73 ° C., whereby 270 g of heptane containing methanol was distilled off.

Next, this concentrated solution was cooled to -10 to 5 ° C., stirred at the same temperature for 1 hour, filtered, and the obtained crystals were washed with 176.6 g of heptane. After that, the crystal
It was dried at 60 ° C. under reduced pressure of kPa to obtain 103.3 g of anhydrous mirtazapine crystals. The yield was 80. The obtained anhydrous mirtazapine crystal had a particle diameter so large that it could not be measured by a laser diffraction particle size distribution analyzer, and the particle diameter was about 200 to 300 μm.
Heptane is 1010 ppm in anhydrous mirtazapine crystals.
It remained.

Next, a part of the obtained anhydrous mirtazapine crystal was taken, the anhydrous mirtazapine crystal was added to 10 times the volume of methanol, and anhydrous mirtazapine was dissolved at a temperature in the range of 20 to 30 ° C. Solution wavelength 6
When the absorbance at 00 nm was measured, the absorbance was 0.1 or less. From this, it was confirmed that the anhydrous mirtazapine crystals did not substantially contain the lower alcohol insolubles.

Next, the anhydrous mirtazapine crystals were crushed using a pulverizer (using an atomizer (pulverizer), 12 hammers, and a screen with an opening of 1 mm) at a rotation speed of 5175.
The mixture was pulverized at rpm to obtain an average particle size of about 20 μm to obtain 100 g of white anhydrous mirtazapine crystal powder (anhydro mirtazapine) (pulverization yield: 97%). A micrograph of the obtained anhydrous mirtazapine is shown in FIG. In FIG. 1, the magnification of the photograph is 500 times.

When the residual solvent of the obtained anhydrous mirtazapine was examined, the content of heptane as the residual solvent was 180.
ppm. From this, it was confirmed that anhydrous mirtazapine contained substantially no residual solvent.

The physical properties of the obtained anhydrous mirtazapine were as follows. (1) HPLC purity: 99.9% (2) Melting point: 114-116 ° C (3) Bulk density: 0.3 g / mL

Example 2 50 kg of the crude mirtazapine obtained in Production Example 2 was
The mixture was added to 198 kg of methanol at 0 ° C and stirred, and 0.5 kg of decolorizing carbon was added at 0 to 5 ° C and stirred for 1 hour. Activated clay was added to the filter [Mizusawa Chemical Co., Ltd. product name: V2, particle size: 5
６０60 mesh, specific surface area: 150 to 300 m ² / g]
After pre-coating 11.5 kg, the resulting solution was
The solution was filtered at 5 ° C, and the filtrate was washed with 24 kg of methanol at 0 to 5 ° C. The filtrate was reduced under reduced pressure of 4 to 55 kPa and the internal temperature was 5
Methanol was distilled off until the temperature reached 0 ° C. The amount of methanol distilled off was 161 L.

Next, 306 kg of heptane was added to the filtrate from which methanol was distilled off, and methanol was azeotropically distilled off until the internal temperature reached 75 ° C., whereby 230 L of heptane containing methanol was distilled off.

Next, when the concentrated liquid was gradually cooled, crystallization occurred at about 58 ° C. After stirring at the same temperature for 1 hour, then cooling to -10 to 5 ° C and stirring at the same temperature for 1 hour, the obtained anhydrous mirtazapine crystal was filtered, and then 0 to 5 ° C.
Was washed with 137 kg of heptane.

Under reduced pressure, this anhydrous mirtazapine crystal was
It dried at 90 degreeC, and after drying at 90 degreeC and internal temperature became constant temperature. The anhydrous mirtazapine crystal has a particle size so large that it cannot be measured by a laser diffraction particle size distribution analyzer, and the particle size was about 200 to 300 μm. The yield of anhydrous mirtazapine crystals was 38 kg.

Next, a part of the obtained anhydrous mirtazapine crystal was taken, the anhydrous mirtazapine crystal was added to 10 times the volume of methanol, and the anhydrous mirtazapine was dissolved at a temperature in the range of 20 to 30 ° C. Solution wavelength 6
When the absorbance at 00 nm was measured, the absorbance was 0.1 or less. From this, it was confirmed that the anhydrous mirtazapine crystals did not substantially contain the lower alcohol insolubles.

Next, the anhydrous mirtazapine crystals were crushed using a pulverizer (using an atomizer (pulverizer), 12 hammers, and a screen with an opening of 1 mm) at a rotation speed of 5175.
Milled at rpm. When the average particle size of the obtained anhydrous mirtazapine was examined, it was about 20 μm.

When the residual solvent of the obtained anhydrous mirtazapine was examined, the content of heptane as the residual solvent was found to be 92 p.
pm. From this, it was confirmed that anhydrous mirtazapine contained substantially no residual solvent.

The physical properties of the obtained anhydrous mirtazapine were as follows. (1) HPLC purity: 99.9% (2) Melting point: 114 to 116 ° C. (3) Bulk density (static): 0.17 g / mL Bulk density (dynamic): 0.45 g / mL

Comparative Example 1 10 g of the crude mirtazapine obtained in Production Example 1 was heated and dissolved in 13 g of petroleum ether, decolorized with 500 mg of decolorizing carbon, filtered, cooled, cooled to 0 to 5 ° C., and crystallized. Thereafter, the crystals were collected by filtration, dried, and mirtazapine.
1 g was obtained. Since the hue was pale yellow and the absorbance was 1.6, it was confirmed that insolubles insoluble in methanol were contained. The HPLC purity of this mirtazapine was 99.8%.

Next, when the amount of residual solvent in the obtained mirtazapine was examined, the heptane content was 1100 ppm. Also, the average particle size of mirtazapine was investigated,
It was too large to measure.

Comparative Example 2 10 g of the crude mirtazapine obtained in Production Example 1 was dissolved by heating in 15 g of tert-butyl methyl ether.
mg, filtered, cooled to 0-5 ° C and crystallized.

The obtained mirtazapine crystals were filtered and dried to obtain 8.6 g of mirtazapine crystals. The color of the obtained mirtazapine crystal was pale yellow, and the absorbance was 2.42. Therefore, it was confirmed that insolubles insoluble in methanol were contained. The HPLC purity of this mirtazapine was 99.8%.

Further, the obtained mirtazapine crystals are
-Butyl methyl ether had a strong odor and was not practical.

[0092]

The anhydrous mirtazapine crystal of the present invention substantially free of lower alcohol insolubles and the anhydrous mirtazapine having an average particle diameter of 10 to 50 μm and substantially containing no residual solvent are suitably used for pharmaceuticals and the like. It is possible.

Further, according to the production method of the present invention, there is an effect that anhydrous mirtazapine having high purity can be efficiently and industrially produced from crude mirtazapine.

[Brief description of the drawings]

FIG. 1 is a micrograph (magnification: 500 times) showing the anhydrous mirtazapine crystal obtained in Example 1.

Continued on the front page (72) Inventor Eiichi Iishi 3-1-1, Utajima, Nishiyodogawa-ku, Osaka-shi F-term in Sumika Finechem Co., Ltd. 4C065 AA04 AA18 BB10 CC07 DD03 EE03 HH01 JJ01 KK09 PP01 QQ07 4C086 AA04 CB11 NA20 ZA12

Claims (8)

[Claims] 1. An anhydrous mirtazapine crystal substantially containing no lower alcohol insolubles. 2. A crude mirtazapine is dissolved in a lower alcohol, a lower alcohol solution of the obtained crude mirtazapine is filtered, and the filtrate is concentrated. A method for producing anhydrous mirtazapine crystals substantially free of lower alcohol insolubles, characterized by crystallizing anhydrous mirtazapine. 3. The method according to claim 2, wherein the temperature of the lower alcohol is from -5 to 10 ° C. 4. The method according to claim 2, wherein the amount of the lower alcohol is 300 to 500 parts by weight based on 100 parts by weight of the crude mirtazapine. 5. The method according to claim 2, wherein the lower alcohol is methanol. 6. The method according to claim 1, wherein the amount of the precipitation solvent is crude mirtazapine 100.
3 to 600 parts by weight based on parts by weight.
5. The method according to any one of the above items. 7. An anhydrous mirtazapine having an average particle size of 10 to 50 μm and containing substantially no residual solvent. 8. An anhydrous mirtazapine crystal having an average particle size of 1
A method for producing anhydrous mirtazapine having an average particle diameter of 10 to 50 μm and substantially containing no residual solvent, which is pulverized to have a particle diameter of 0 to 50 μm.