JP2016069349A - Production process for aripiprazole anhydride b-type crystal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a process for industrially producing a B-type crystal of aripiprazole anhydride by an easy and safe operation and yet without using a highly toxic solvent, and without forming a mixed crystal with other crystal forms, at high purity and in high yield.SOLUTION: Provided is a production process for aripiprazole anhydride B-type crystal comprising dissolving an aripiprazole anhydride crystal having a powder X-ray diffraction spectrum exhibiting peaks at 2θ=16.3°, 21.8°, 22.2°, 23.3° and 24.5°, a melting point of 148±3°C, and a moisture content of 0.05 to 0.30%, into a mixed solvent of benzyl alcohol and amyl acetate to thereby recrystallize the same.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a method capable of industrially easily and safely producing aripiprazole anhydride crystals B used for the treatment of schizophrenia and the like in a high yield with high purity.

Aripiprazole (7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril) is a useful drug for psychiatric schizophrenia.
Crystals of the anhydride (hereinafter also referred to as “aripiprazole anhydride”) exhibit various crystal habits depending on the solvent used, reaction conditions thereof, and the like. For example, Patent Documents 1 and 2 include Forms I, II, B-type, C-type, D-type, E-type, F-type, and G-type are disclosed.

Above all, with respect to the B-form crystals of aripiprazole anhydride, the production method is described in Patent Document 1 described above.
In this production method, “aripiprazole hydrate A” obtained by pulverizing aripiprazole hydrate exhibiting the physicochemical properties described in [Claim 1] to a particle size of 50 μm or less is heated at a high temperature (90%). 3 to 50 hours at ˜125 ° C. Specifically, if the heating temperature is 100 ° C., the heating time is about 24 hours; if the heating temperature is 120 ° C., the heating time is about 3 hours; By gently dehydrating, agglomeration phenomenon caused by rapid dehydration is avoided.
However, the manufacturing method for heating the “aripiprazole hydrate A having a particle size of 50 μm or less” involves not only a complicated process for obtaining the hydrate A, but also a heating operation at a high temperature is dangerous. There were problems such as a large amount of energy required and a long time required for production.

On the other hand, Patent Document 3 discloses a mixture of aripiprazole crystalline form II having a specific XRD pattern and other aripiprazole crystalline forms.
However, as described in paragraph [0008] of Patent Document 1 described above, the type II crystal is reproduced on an industrial scale, as well as the possibility of using such a mixed crystal as a pharmaceutical is extremely low. It was difficult to isolate it with good quality and high purity.

Japanese Patent No. 3760264 Japanese Patent No. 3750023 JP 2013-237682 A

  In view of the above situation, the present invention is a mixed crystal with other crystal forms of aripiprazole anhydride B-type crystals industrially easy and safe operation without using a toxic solvent. It is an object of the present invention to provide a method for manufacturing with high purity without any problems.

  In order to solve the above-mentioned problems, the present inventors have made various studies. As a result, if an anhydrous crystal of aripiprazole is crystallized with a mixed solvent of benzyl alcohol and amyl acetate, it can be easily recrystallized. In this way, it was found that anhydrous B-form crystals can be obtained independently without mixing with other crystal forms, and that the B-form crystals are difficult to change into hydrates over a long period of time. It came to do.

That is, the present invention provides an aripiprazole anhydride B-type crystal having a powder X-ray diffraction spectrum having peaks at 2θ = 11.0 °, 16.6 °, 19.3 °, 20.3 °, and 22.1 °. A method of manufacturing comprising:
Having a powder X-ray diffraction spectrum showing peaks at 2θ = 16.3 °, 21.8 °, 22.2 °, 23.3 ° and 24.5 °;
Melting point is 148 ± 3 ° C,
An anhydrous aripiprazole crystal having a water content of 0.05 to 0.30% measured by Karl Fischer volumetric titration method,
The gist of the present invention is a method for producing an aripiprazole anhydride B-type crystal comprising dissolving in a mixed solvent of benzyl alcohol and amyl acetate and recrystallizing.

Benzyl alcohol and amyl acetate are organic solvents that are hardly volatile, have low toxicity, are inexpensive, and are easy to obtain and handle.
In the production of an aripiprazole anhydride B-type crystal having excellent properties such as low hygroscopicity by selecting such benzyl alcohol and amyl acetate from infinitely existing organic solvents, This achieves lowering and shortening of drying without requiring complicated operations.
In the present invention, the mixing ratio (weight ratio) of the mixed solvent of benzyl alcohol and amyl acetate is preferably benzyl alcohol: amyl acetate = 1: 10 to 1:30, and after dissolution in this mixed solvent More preferably, the precipitated crystals are dried at 50 to 110 ° C.

The aripiprazole anhydride B-form crystal obtained by the production method of the present invention can be dried more easily (low temperature and in a short time) compared to the conventionally known production methods, and has low hygroscopicity over a long period of time. Therefore, it can be suitably used as a medicine such as an antipsychotic drug for the treatment of schizophrenia and autism in autistic patients.
In addition, according to the present invention, this B-form crystal is obtained by a unique crystallization method using a mixed solvent of benzyl alcohol and amyl acetate, with high purity and high yield as compared with the conventional production method. It can be manufactured industrially easily and safely.

2 is a powder X-ray diffraction pattern of anhydrous aripiprazole Form II crystal obtained in Reference Example 1. FIG. 2 is a powder X-ray diffraction pattern of anhydrous aripiprazole Form B crystal obtained in Example 1. FIG. FIG. 4 is a diagram showing IR analysis results of an aripiprazole anhydride crystal B obtained in Example 1. 2 is a powder X-ray diffraction pattern of anhydrous aripiprazole Form B crystal obtained in Example 2. FIG. 4 is a powder X-ray diffraction pattern of anhydrous aripiprazole Form B crystal obtained in Example 3. FIG.

  The production method of the present invention comprises recrystallizing an anhydrous crystal of aripiprazole in a mixed solvent of benzyl alcohol and amyl acetate (hereinafter also referred to as “mixed solvent”).

As the aripiprazole anhydride crystals, powder X showing characteristic peaks at 2θ = 16.3 °, 21.8 °, 22.2 °, 23.3 ° and 24.5 ° as shown in FIG. It has a line diffraction spectrum, a melting point of 148 ± 3 ° C., and a water content measured by Karl Fischer volumetric titration method of 0.05 to 0.30% (preferably 0.05 to 0.25%). Use things. For example, an aripiprazole anhydride type II crystal is suitable.
An aripiprazole anhydride type II crystal may be synthesized by a conventional method, or a commercially available product may be used as it is. In the present invention, unlike the above-described conventional technique (the method for producing a B-type crystal described in Patent Document 1), a pulverizing step for reducing the particle size of the II-type crystal is not required.

The amount of the mixed solvent used at this time is not particularly limited, but is 12 to 35 times the volume (milliliter) of the aripiprazole anhydride type II crystal weight (g) (hereinafter, milliliter is referred to as mL) (for example, aripiprazole The mixed solvent is preferably 12 to 35 mL), more preferably 18 to 19 times the volume (mL) with respect to 1 g of anhydrous form II crystals.
In order to completely dissolve the aripiprazole anhydride type II crystals in the mixed solvent, the solution is heated to 70 to 90 ° C., preferably about 80 ° C., and then the solution is cooled to 0 to 30 ° C. to precipitate the crystals.
At this time, in the stage heated to 70-90 degreeC, it is preferable to add and stir after adding activated carbon, and to filter when warm. Moreover, you may add a seed crystal in a solution in the stage cooled to 30-50 degreeC.

The mixing ratio of benzyl alcohol and amyl acetate in the mixed solvent is preferably 10 to 30 parts by weight, more preferably 15 to 18 parts by weight with respect to 1 part by weight of benzyl alcohol.
If the ratio of amyl acetate to benzyl alcohol is too large, the yield of B-form crystals obtained may be reduced. If it is too small, other crystal forms may be mixed.

The precipitated crystals are separated by filtration and dried under normal pressure or reduced pressure (about 30 to 60 Pa) at 50 to 110 ° C. for 2 to 24 hours to obtain aripiprazole anhydride B-form crystals. Since benzyl alcohol and amyl acetate are relatively high boiling point solvents, preferable drying conditions are 80 to 90 ° C. for 2 to 10 hours.
At this time, prior to drying, the object of the present invention (such as obtaining B-form crystals with high purity and high yield) can be satisfactorily achieved, and mixed crystals (mixing of crystal forms other than B-form) can be avoided. For this purpose, it is preferable to wash the collected crystals with a lower alcohol such as methanol.
As described above, the present invention does not require a high-temperature and long-time drying step as well as a raw material pulverization step as in the above-described prior art, which is extremely useful for industrial production.

The shape of the B-type crystal obtained by the production method of the present invention is a white powder and is 2θ = 11.0 °, 16.6 °, 19.3 °, 20.3 ° and 22.1 °. It has a powder X-ray diffraction spectrum showing a peak.
The melting point of the B-form crystal is preferably 140.5 ± 2 ° C., and the water content measured by Karl Fischer volumetric titration is preferably 0.05 to 0.30%.

As described above, in the present invention, an aripiprazole anhydrous crystal is dissolved industrially in a mixed solvent of benzyl alcohol and amyl acetate and recrystallized to easily (in a short time) and safely industrially aripiprazole. Anhydrous Form B crystals can be produced.
The production method according to the present invention can be applied to an aripiprazole anhydride crystal produced by any method. Desirably, the crude crystals of aripiprazole anhydride are dissolved in N, N-dimethylformamide and then applied to aripiprazole anhydride type II crystals obtained by precipitation by adding ethanol.

[Reference Example 1]
An aripiprazole anhydride used in the production method of the present invention << 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril anhydride >> The synthesis was performed as follows.

First step:
Synthesis of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril;
To 82 g (0.5 mol) of 7-hydroxy-3,4-dihydrocarbostyril was added 408 g of acetonitrile, and an aqueous potassium carbonate solution (a solution of 69 g of potassium carbonate (0.5 mol) dissolved in 204 g of water) was added thereto. Thereafter, 324 g (1.5 mol) of 1,4-dibromobutane was further added, and the mixture was refluxed for 6 hours.
The reaction solution was concentrated under reduced pressure, 408 g of 2-propanol was added to the residue, and the mixture was stirred at 10 ° C. or lower for 1 hour. Then, 204 g of water was added, stirred at 10 ° C. or lower for 1 hour, crystallized and filtered.
The obtained crystal was dried at 80 ° C. to obtain 109 g of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril (yield: 73.3%).

Second step:
Synthesis of crude crystals of aripiprazole anhydride <7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril>
To 109 g (0.37 mol) of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril obtained in the first step, 82 g (0.55 mol) of sodium iodide and 1088 g of acetonitrile were added and stirred. Warmed to 70 ° C.
Next, 92 g (0.33 mol) of 1- (2,3-dichlorophenyl) piperazine hydrochloride, 816 g of acetonitrile, and 185 g (1.83 mol) of triethylamine were added, and the mixture was refluxed for 30 minutes.
The reaction solution was concentrated under reduced pressure, 2177 g of water was added to the residue, cooled, and the precipitated crystals were collected by filtration and dried to obtain 149 g of crystals.
Among these crystals, 1110 g of dichloromethane was added to 148 g, and the mixture was stirred at room temperature for 1 hour, and then impurities were separated by filtration. The filtrate was concentrated under reduced pressure, 2590 g of methanol was added to the residue, and the suspension was washed under reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration.
The obtained crystals were dried at 80 ° C. to obtain 80 g of crude aripiprazole anhydride (yield: 54.5%, water content: 0.14%).

Third step:
Synthesis of Form II crystals of aripiprazole anhydride << 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril}
150 g of N, N-dimethylformamide was added to 80 g (0.18 mol) of crude aripiprazole anhydride obtained in the second step, and the mixture was dissolved by heating to 50 to 60 ° C.
Next, 8 g of activated carbon and 128 g of ethanol heated to 50 to 60 ° C. were added, and the mixture was stirred for 30 minutes while maintaining 50 to 60 ° C., and then filtered while warm.
The filtrate was cooled to 5 ° C., and the precipitated crystals were collected by filtration and washed with 128 g of methanol.
The crystal obtained by repeating the operation of the third step once more was dried under reduced pressure at 80 ° C. for 5 hours to give 50 g of light yellowish white to white aripiprazole anhydride crystal (yield: 62. 5%, purity: 99.85% (HPLC, area percentage)).
The obtained type II crystal was subjected to X-ray diffraction, melting point measurement, and moisture content measurement. Results are shown below.

X-ray diffraction Using an X-ray measuring apparatus (trade name “Mini Flxe II” manufactured by Rigaku Corporation), measurement was performed with a Ni filter at a scan speed of 4 ° / min.
As shown in FIG. 1, this result showed characteristic peaks at 2θ = 16.3 °, 21.8 °, 22.2 °, 23.3 ° and 24.5 °.

-Melting | fusing point measurement It carried out using melting | fusing point measuring device (BUCHI brand name "B-545"). The results were as follows:
Melting point: 148.5 ° C

-Moisture content measurement In accordance with the volumetric titration method of the Karl Fischer method, an automatic moisture measuring device (trade name "787 KF Titrino" manufactured by Metrohm) was used. The results were as follows:
Water content: 0.18%

[Example 1]
To 50 g of aripiprazole anhydride crystal II obtained in the third step of Reference Example 1, 52 g of benzyl alcohol and 874 g of amyl acetate were added, heated to 80 ° C., 2.5 g of activated carbon was added, and the mixture was stirred for 15 minutes. Thereafter, it was filtered while warm.
The filtrate was cooled to 20 ° C., and the precipitated crystals were collected by filtration and washed with 200 g of methanol.
The crystals after washing were dried at 80 ° C. under atmospheric pressure for 3 hours to obtain 36 g of white aripiprazole anhydride crystals B (yield: 72%, purity: 99.91% (HPLC, area percentage)). Obtained.
The obtained crystal was subjected to X-ray diffraction, melting point measurement, moisture content measurement, and IR analysis. Results are shown below.

-X-ray diffraction It carried out similarly to the case of the reference example 1.
As shown in FIG. 2, this result showed characteristic peaks at 2θ = 11.0 °, 16.6 °, 19.3 °, 20.3 °, and 22.1 °.
-Melting | fusing point measurement It carried out similarly to the case of the reference example 1. The results were as follows:
Melting point: 139.9 ° C
-Moisture content measurement It carried out similarly to the case of the reference example 1. The results were as follows:
Water content: 0.10%

IR analysis Measurement was performed by the KBr method using an infrared spectroscopic analyzer (trade name “NICOLET 380” manufactured by Thermo Corporation).
This result, as FIG. ^{3, 2945cm -1, 2812cm -1,} 1678cm -1, 1627cm -1, 1448cm -1, 1377cm -1, 1173cm -1, characteristic absorption in 960 cm ^-1, and 779cm ^-1 Was recognized.

[Examples 2 to 4]
Except that the mixing ratio of the mixed solvent of benzyl alcohol and amyl acetate in Example 1 was changed as shown in Table 1, it was carried out in the same manner as in Example 1 to obtain a white B crystal of aripiprazole anhydride. . Table 1 shows the weight (g) and yield (%) of each B-form crystal obtained.
In Examples 2 and 3 in which precipitation of 30 g or more of crystals was confirmed in the above experiment, X-ray diffraction and melting point measurement of each crystal were performed in the same manner as in Example 1 (note that only a very small amount of crystals was observed). Regarding Example 4 which was not obtained, X-ray diffraction and melting point could not be measured substantially). The results of X-ray diffraction are shown in FIGS. 4 and 5, and the results of melting points are shown in Table 1.

[Examples 5 and 6]
Except for drying the washed crystals in Example 1 at 105 ° C. (Example 6) or 50 ° C. (Example 7), the same procedure as in Example 1 was conducted to obtain white aripiprazole anhydride. B-form crystals were obtained. Table 1 shows the weight (g) and yield (%) of each obtained B-form crystal.
X-ray diffraction and melting point measurement of the crystals obtained in Examples 6 and 7 were performed in the same manner as in Example 1.
The X-ray diffraction of Examples 6 and 7 was the same as that shown in FIG. The melting point results are also shown in Table 1.

[Comparative Examples 1-8]
Except having replaced the mixed solvent of benzyl alcohol and amyl acetate in Example 1 with the solvent shown in Table 2, it carried out similarly to the case of Example 1, and obtained the white crystal | crystallization of Comparative Examples 1-8. Table 2 shows the weight (g) and yield (%) of each white crystal obtained.
In Comparative Examples 2 to 8 in which precipitation of 30 g or more of crystals was confirmed in the above experiment, the melting point of each crystal was measured in the same manner as in Example 1 (note that only a trace amount of crystals was obtained). For Comparative Example 1, the melting point could not be measured substantially).
The results are as shown in Table 2, and no B-form crystals were obtained.

According to the present invention, B-type crystals of aripiprazole anhydride can be produced by an industrially easier operation and without using a highly toxic solvent as compared with conventionally known production methods.
And the aripiprazole anhydride B-form crystal obtained by the production method of the present invention is a crystal that can be dried quickly and has a low hygroscopic property over a long period of time. Therefore, it can be suitably used as a therapeutic agent for schizophrenia and autism patients with autism.

Claims (3)

A method for producing an aripiprazole anhydrous form B crystal having a powder X-ray diffraction spectrum having peaks at 2θ = 11.0 °, 16.6 °, 19.3 °, 20.3 ° and 22.1 °. ,
Having a powder X-ray diffraction spectrum showing peaks at 2θ = 16.3 °, 21.8 °, 22.2 °, 23.3 ° and 24.5 °;
Melting point is 148 ± 3 ° C,
An anhydrous aripiprazole crystal having a water content of 0.05 to 0.30% measured by Karl Fischer volumetric titration method,
A method for producing aripiprazole anhydrous crystals B, which comprises dissolving in a mixed solvent of benzyl alcohol and amyl acetate and recrystallizing.   The method for producing an aripiprazole anhydride B-type crystal according to claim 1, wherein the mixing ratio of the mixed solvent is benzyl alcohol: amyl acetate = 1: 10 to 1:30.   The method for producing an aripiprazole anhydride B-type crystal according to claim 1 or 2, wherein the precipitated crystal is dried at 50 to 110 ° C after dissolution in the mixed solvent.