JP2010229098A - Method for producing type a crystal form of isoindoline derivative and type a crystal form of isoindoline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an isoindoline derivative having a fixed crystal form, especially a method for selectively producing type A crystal form of isoindoline derivative. <P>SOLUTION: The method for producing type A crystal of isoindoline derivative represented by formula (1) includes: (a) a step for dissolving a crude body of the isoindoline derivative in at least one organic solvent selected from the group consisting of a 1-4C alcohol, a 2-6C ketone and others, and preparing a solution containing the isoindoline derivative and (b) a step for recrystallizing type A crystal form of the isoindoline derivative from the solution in the presence of type A seed crystal of the isoindoline derivative. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to a method for producing an A type crystal form of an isoindoline derivative and an A type crystal form of the isoindoline derivative.

Many compounds having an isoindoline skeleton have been known as drugs acting on the central nervous system. Especially, as a compound which can be used as a water-soluble anesthetic, especially a intravenous anesthetic, as shown to following formula (1) shown by patent document 1, (-)-2- (2- Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclopenta [f] isoindoline-1 (2H) -one (hereinafter referred to as iso An indoline derivative) and a synthesis method thereof are known.

JP 2004-189733 A

The substance obtained by synthesizing and recovering the isoindoline derivative represented by the above formula (1) by the synthesis method described in Patent Document 1 was amorphous.
The present inventors have found that when the obtained amorphous is purified by recrystallization, two types of crystal forms, an A-type crystal form and a B-type crystal form, are obtained.
That is, the present inventors have found that a crystal polymorph exists in the isoindoline derivative represented by the above formula (1).

Furthermore, the present inventors only need to purify the amorphous obtained by the synthesis method described in Patent Document 1 by recrystallization, and either of the A-type crystal form or the B-type crystal form. It has been found that crystal forms can be obtained randomly, or crystals in which A-type and B-type crystal forms are mixed. That is, it has been found that the reproducibility of the obtained crystal form cannot be obtained by the synthesis method described in Patent Document 1, and it is difficult to selectively produce only a specific type of crystal form.

In general, it is known that substances having crystal polymorphs have different properties such as solubility, dissolution rate, stability, and absorbability depending on the crystal form. Therefore, even if it is the same compound, a completely different effect may be shown.
Since it is desired that a compound used as a pharmaceutical is of the same quality that can always be expected to have a certain effect, when using a compound with a crystalline polymorph as a drug, uniform quality and a certain effect Therefore, it is necessary to stably provide a compound having a uniform crystal form.

As found by the present inventors, the isoindoline derivative represented by the above formula (1) has at least two different crystal forms as described above. Therefore, in order to ensure the quality as a pharmaceutical product, it was necessary to establish a method for producing an isoindoline derivative by controlling the crystal form to be constant.

An object of the present invention is to provide a method for producing an isoindoline derivative having a certain crystal form, and in particular, a method for selectively producing an A-type crystal form of an isoindoline derivative. Another object of the present invention is to provide an A-type crystal form of an isoindoline derivative.

The present inventors examined a method for producing an isoindoline derivative while controlling the crystal form to be constant. As a result, a crude form of isoindoline derivative whose crystal form is not controlled is dissolved in a solvent, and recrystallization is performed in the presence of an A type seed crystal of the isoindoline derivative, thereby obtaining an A type crystal of the isoindoline derivative. The inventors have found that only the shape can be selectively produced, and reached the present invention.

のＡ型の結晶形の製造方法であって、
（ａ）上記イソインドリン誘導体の粗体を、炭素数１〜４のアルコール、炭素数２〜６のケトン、炭素数１〜４の脂肪族ニトリル、炭素数１〜４のカルボン酸のエステル、炭素数２〜６の鎖状または環状エーテル、炭素数１〜４のクロロアルカンからなる群より選ばれる少なくとも１種の有機溶媒を含む溶剤に溶解し、上記イソインドリン誘導体を含有する溶液を調製する工程、および、
（ｂ）上記イソインドリン誘導体のＡ型の種結晶の共存下、上記イソインドリン誘導体を含有する溶液から、上記イソインドリン誘導体のＡ型の結晶形を再結晶せしめる工程、
を含むことを特徴とする。 That is, the present invention
(1) (−)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3, 5, 6, 7 represented by the formula (1) -Isoindoline derivatives having the chemical structure of tetrahydrocyclopenta [f] isoindoline-1 (2H) -one

A method for producing a crystal form of A
(A) A crude product of the above isoindoline derivative is obtained by converting an alcohol having 1 to 4 carbon atoms, a ketone having 2 to 6 carbon atoms, an aliphatic nitrile having 1 to 4 carbon atoms, an ester of a carboxylic acid having 1 to 4 carbon atoms, carbon A step of preparing a solution containing the isoindoline derivative by dissolving in a solvent containing at least one organic solvent selected from the group consisting of a chain or cyclic ether having 2 to 6 carbon atoms and a chloroalkane having 1 to 4 carbon atoms. ,and,
(B) a step of recrystallizing the A-type crystal form of the isoindoline derivative from a solution containing the isoindoline derivative in the presence of the A-type seed crystal of the isoindoline derivative;
It is characterized by including.

Alternatively, the present invention
(2) A method for producing the A-type crystal form of the isoindoline derivative according to (1) above,
The organic solvent used in the step (a) is at least one selected from the group consisting of ethanol, acetone, acetonitrile, methyl acetate, ethyl acetate, diethyl ether, tetrahydrofuran, methylene chloride, and chloroform.

Alternatively, the present invention
(3) A method for producing the A-type crystal form of the isoindoline derivative according to (1) above,
The organic solvent used in the step (a) is at least one selected from the group consisting of ethanol, acetone, and ethyl acetate.

Alternatively, the present invention
(4) A method for producing an A-type crystal form of the isoindoline derivative according to (3) above,
The solvent is substantially composed of only an organic solvent selected from the group consisting of ethanol, acetone, and ethyl acetate.

Alternatively, the present invention
(5) A method for producing an A-type crystal form of the isoindoline derivative according to any one of (1) to (3) above,
In addition to the organic solvent, the solvent further contains water.

Alternatively, the present invention
(6) A method for producing the A-type crystal form of the isoindoline derivative according to any one of (1) to (5) above,
0.01 to 2 g of the A-type seed crystal of the isoindoline derivative coexists with 100 g of the crude isoindoline derivative.

Alternatively, the present invention
(7) A method for producing an A-type crystal form of the isoindoline derivative according to any one of (1) to (6) above,
In the recrystallization in the step (b), the solution containing the isoindoline derivative is heated to a temperature of 50 ° C. or higher or the boiling point of the organic solvent, and then cooled to 0 to 30 ° C. during the cooling or cooling. After completion, it is characterized in that it is made by casting a seed crystal of type A of the isoindoline derivative into a solution.

Alternatively, the present invention
(8) A method for producing the A-type crystal form of the isoindoline derivative according to any one of (1) to (7) above,
The chemical purity of the crude isoindoline derivative calculated by high performance liquid chromatography is 95% or more.

Alternatively, the present invention
(9) A method for producing an A-type crystal form of the isoindoline derivative according to any one of (1) to (7) above,
The chemical purity of the crude isoindoline derivative calculated by high performance liquid chromatography is 98% or more.

Alternatively, the present invention
(10) A method for producing an A-type crystal form of the isoindoline derivative according to any one of (1) to (9) above,
Before performing the step (a), a step of recrystallizing the crude isoindoline derivative using a solvent is further performed.

Alternatively, the present invention
(11) A method for producing an A-type crystal form of the isoindoline derivative according to any one of (1) to (10) above,
The A-type crystal form of the isoindoline derivative has physical property data represented by the following (i).
(I): It has the powder X-ray diffraction spectrum data represented by FIG.

Alternatively, the present invention
(12) A method for producing an A-type crystal form of the isoindoline derivative according to any one of (1) to (10) above,
The A-type crystal form of the isoindoline derivative is characterized by having powder X-ray diffraction spectrum data having peaks at diffraction angles (2θ) of 5.1, 10.2, and 22.5.

Alternatively, the present invention
(13) A method for producing an A-type crystal form of the isoindoline derivative according to any one of (1) to (10) above,
The crystal form of the isoindoline derivative has powder X-ray diffraction spectrum data showing diffraction angles and relative intensities shown in Table 1 below.

のＡ型の結晶形である。 Alternatively, the present invention
(14) (-)-2- (2-phenyl) -3- [2- (4) represented by the formula (1) obtained by the method according to any one of (1) to (13) above. -Mind-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclopenta [f] isoindoline-1 (2H) -one isoindoline derivative

A-type crystal form.

のＡ型の結晶形であって、
下記の（ｉ）で表される物性データを有することを特徴とする。
（ｉ）：図１で表される粉末Ｘ線回折スペクトルデータを有する。 Alternatively, the present invention
(15) (-)-2- (2-phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3, 5, 6, 7 represented by the formula (1) -Isoindoline derivatives having the chemical structure of tetrahydrocyclopenta [f] isoindoline-1 (2H) -one

A type crystal form of
It has the physical property data represented by the following (i).
(I): It has the powder X-ray diffraction spectrum data represented by FIG.

のＡ型の結晶形であって、
５．１、１０．２、及び、２２．５の回折角（２θ）にピークを有する粉末Ｘ線回折スペクトルデータを有することを特徴とする。 Alternatively, the present invention
(16) (−)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3, 5, 6, 7 represented by the formula (1) -Isoindoline derivatives having the chemical structure of tetrahydrocyclopenta [f] isoindoline-1 (2H) -one

A type crystal form of
It has powder X-ray diffraction spectrum data having peaks at diffraction angles (2θ) of 5.1, 10.2, and 22.5.

のＡ型の結晶形であって、
上記表１に示す回折角度及び相対強度を示す粉末Ｘ線回折スペクトルデータを有することを特徴とする。 Alternatively, the present invention
(17) (-)-2- (2-phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3, 5, 6, 7 represented by the formula (1) -Isoindoline derivatives having the chemical structure of tetrahydrocyclopenta [f] isoindoline-1 (2H) -one

A type crystal form of
It has powder X-ray diffraction spectrum data showing the diffraction angle and relative intensity shown in Table 1 above.

According to the method for producing the A-type crystal form of the isoindoline derivative of the present invention, the A-type crystal form of the isoindoline derivative can be selectively produced by controlling the crystal form to be always constant.
In addition, the A-type crystal form of the isoindoline derivative can be suitably used for pharmaceutical applications, particularly as a intravenous anesthetic.

FIG. 1 is a powder X-ray diffraction chart of an A-type crystal form of the isoindoline derivative represented by the formula (1). FIG. 2 is a powder X-ray diffraction chart of the B-type crystal form of the isoindoline derivative represented by the formula (1). FIG. 3 is an example of a powder X-ray diffraction chart of the crude isoindoline derivative obtained in Example 2.

まず、各結晶形について説明する。 In the isoindoline derivative represented by the following formula (1), there are at least two crystal forms of an A-type crystal form and a B-type crystal form.

First, each crystal form will be described.

Identification of each crystal form can be performed using powder X-ray measurement.
In this specification, the conditions of the powder X-ray measurement used for specifying each crystal form are as follows.
Equipment: Rigaku RINT2000
X-ray: Cu-Kα ray apparatus control: Parallel method Measurement angle: 3-50 deg
Voltage: 40kV
Current: 40 mA

The form A crystal form of the isoindoline derivative is a crystal form characterized by peaks at diffraction angles (2θ) of 5.1, 10.2 and 22.5 in the chart obtained in the powder X-ray measurement. .

An example of a powder X-ray diffraction chart of an A-type crystal form of an isoindoline derivative is shown in FIG.

Table 1 shows an example of the diffraction angle and the relative intensity obtained in the powder X-ray measurement of the A-type crystal form of the isoindoline derivative.

The B-type crystal form of the isoindoline derivative is, for example, a crystal form showing a powder X-ray diffraction chart as shown in FIG.
When the powder X-ray diffraction chart shown in FIG. 1 and the powder X-ray diffraction chart shown in FIG. 2 are compared, it can be seen that the peak positions shown in each chart are different. Therefore, it is possible to specify the crystal form of the isoindoline derivative by performing powder X-ray diffraction measurement.

Hereinafter, an embodiment of the method for producing the A-type crystal form of the isoindoline derivative of the present invention will be described.
First, a crude isoindoline derivative represented by the formula (1) is obtained. A crude product of an isoindoline derivative is obtained by synthesizing a derivative of an isoindoline derivative represented by the formula (1) by a conventionally known method. The “crude body” refers to a crystal whose crystal form is not controlled, and the form (crystal form) is not particularly limited, but is often amorphous.

The crude isoindoline derivative may be purified by dissolving it in a solvent and recrystallizing it to increase its chemical purity (chemical purity measured by high performance liquid chromatography).
The chemical purity of the crude isoindoline derivative obtained is desirably 95% or more, and more desirably 98% or more.
The optical purity of the crude isoindoline derivative obtained was 90% e.e. e. Desirably, it is 96% e.e. e. More preferably, it is 99% e. e. More preferably, it is more than that.

The type of solvent used for recrystallization to increase the chemical purity of the isoindoline derivative is not particularly limited, but from ethanol, acetone, acetonitrile, methyl acetate, ethyl acetate, diethyl ether, tetrahydrofuran, methylene chloride, chloroform The organic solvent which consists of at least 1 sort (s) chosen from the group which consists of, or the solvent which added water in an appropriate amount to these organic solvents can be used suitably.

As preferable conditions for recrystallization performed to increase the chemical purity of the isoindoline derivative, for example, acetone / water = 9/1 (volume ratio) is used as a solvent, and the solvent is heated to 55 to 65 ° C. 111.0 g of a crude isoindoline derivative per liter of solvent is dissolved by stirring, and the solution is gradually cooled to 0 to 10 ° C. over 10 to 20 hours.
By setting it as such conditions, the impurity can be removed and the crude body of an isoindoline derivative with high chemical purity can be obtained. In addition, the yield of the crude isoindoline derivative can be increased to 60 to 70%.

In addition, since the obtained crude isoindoline derivative is dissolved again in a solvent containing an organic solvent in the subsequent step, the crystal form is not particularly limited, and the A-type crystal form and the B-type crystal are not particularly limited. Any crystal form can be used. Further, a crystal in which an A-type crystal form and a B-type crystal form are mixed may be used. Further, it may be amorphous.

In this production method, “recrystallization” refers to adding a solvent that reduces the solubility of the isoindoline derivative to the solution containing the isoindoline derivative, in addition to refining in a narrow sense using a temperature difference. A method (crystallization) for precipitating crystals of an isoindoline derivative is also included.

Next, the crude isoindoline derivative is dissolved in a solvent containing an organic solvent to prepare a solution containing the isoindoline derivative.
Examples of the organic solvent include alcohol having 1 to 4 carbon atoms, ketone having 2 to 6 carbon atoms, aliphatic nitrile having 1 to 4 carbon atoms, ester of carboxylic acid having 1 to 4 carbon atoms, and chain having 2 to 6 carbon atoms. Alternatively, at least one organic solvent selected from the group consisting of cyclic ethers and chloroalkanes having 1 to 4 carbon atoms can be suitably used.

In particular, the organic solvent is preferably at least one selected from the group consisting of ethanol, acetone, acetonitrile, methyl acetate, ethyl acetate, diethyl ether, tetrahydrofuran, methylene chloride, and chloroform, and the organic solvent is ethanol, acetone, More preferably, it is at least one selected from the group consisting of ethyl acetate. It is further desirable that the solvent consists essentially of an organic solvent selected from the group consisting of ethanol, acetone, and ethyl acetate.
The solvent may contain water in addition to the organic solvent.
Further, when the solvent contains water in addition to the organic solvent, the solubility is improved and the amount of the solvent to be used can be reduced.

Next, in the presence of the A-type seed crystal of the isoindoline derivative, the A-type crystal form of the isoindoline derivative is recrystallized from the solution containing the isoindoline derivative.
By performing recrystallization in the presence of the A-type seed crystal of the isoindoline derivative, the A-type crystal form of the isoindoline derivative can be selectively obtained.

The type A seed crystal of the isoindoline derivative used here is a crystal of the isoindoline derivative obtained by removing impurities and the chart obtained by powder X-ray diffraction shows the characteristics of the type A crystal form. It is obtained by sorting.

The amount of the isoindoline derivative A-type seed crystal that coexists when recrystallization is not particularly limited, but is 0.01 to 100 g of the crude isoindoline derivative contained in the solution. It is desirable that 2 g of isoindoline derivative type A seed crystal coexist.

When a B-type seed crystal is used instead of an A-type seed crystal during recrystallization, the obtained crystal forms are only the A-type crystal form, the B-type crystal form, and the A-type seed crystal. It is either a crystal in which a crystal form and a B-type crystal form are mixed. That is, when a B-type seed crystal is introduced, a specific crystal form cannot be selectively obtained.

The method for performing recrystallization is not particularly limited, and a method using a temperature difference, crystallization, or the like can be used as described above.
As a desirable method, a solution containing an isoindoline derivative is heated to a temperature of 50 ° C. or higher or lower than the boiling point of an organic solvent, and then cooled to 0 to 30 ° C. There is a method in which seed A crystals of the derivative are poured into the solution.

In particular, it is desirable that the cooling time is 10 to 20 hours and the cooling rate is 1 to 5 ° C./hour.
In addition, when the temperature of the solution is 65 to 75 ° C., it is desirable to throw an A-type seed crystal of the isoindoline derivative into the solution.
By satisfying such conditions, the A-type crystal form of the isoindoline derivative can be obtained more stably.
Moreover, it may heat to the temperature below the boiling point of an organic solvent, and may implement filter filtration before starting cooling.

Then, by filtering and drying the crystals deposited by the recrystallization, an A-type crystal form of the isoindoline derivative can be obtained.
As drying conditions, it is desirable to use a vacuum dryer, set the drying temperature to 50 to 60 ° C., and adjust the drying time so that the content of the remaining organic solvent is 0.5% by weight or less.
For example, it can be set as the conditions dried for 5 to 15 hours with a vacuum degree of 20 mmHg or less using a commercially available vacuum dryer.

Hereinafter, the A-type crystal form of the isoindoline derivative of the present invention will be described.
The form A crystal form of the isoindoline derivative of the present invention is a crystal form obtained by the method for producing the form A crystal form of the isoindoline derivative of the present invention.
In addition, the A-type crystal form of the isoindoline derivative of the present invention has powder X-ray diffraction spectrum data having peaks at diffraction angles (2θ) of 5.1, 10.2, and 22.5.

Examples of the A-type crystal form of the isoindoline derivative of the present invention include those having the powder X-ray diffraction spectrum data shown in FIG. 1, and powders having the diffraction angles and relative intensities shown in Table 1 above. Those having X-ray diffraction spectrum data may be mentioned.

Since the A-type crystal form of the isoindoline derivative of the present invention is controlled so that the crystal form becomes the A-type crystal form, it can be suitably used as a pharmaceutical application, particularly as a intravenous anesthetic. it can.

Examples in which the present invention is disclosed more specifically are shown below, but the present invention is not limited to these examples.

Example 1
(−)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclopenta [f] isoindoline-1 Preparation of (2H) -one A-type crystal form

(A) Step: (−)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclopenta [f 351 g (901 mmol) of a crude product of isoindoline-1 (2H) -one was dissolved by heating in 2.84 L of acetone and 316 mL of water (solvent ratio acetone / water = 9/1). The solution was completely dissolved at an internal temperature of 60 ° C. and stirred overnight. The mixture was further cooled with ice, and the slurry was filtered and dried. (-)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7 -227 g of a crude product of tetrahydrocyclopenta [f] isoindoline-1 (2H) -one was obtained as white crystals (yield 65%, chemical purity 99.9%, optical purity 100% ee). When the powder X-ray diffraction measurement was performed on the crystal, it was confirmed that the obtained crystal was a B-type crystal form. The measurement conditions for powder X-ray diffraction are as described above.
Subsequently, 10 g (25.7 mmol, crystal form B, chemical purity 99.9%, optical purity 100% ee) of the crude isoindoline derivative obtained was heated to 70 mL of ethanol at an internal temperature of 70 ° C. It melt | dissolved and the solution containing this isoindoline derivative was prepared.

Step (b): 0.05 g of an isoindoline derivative type A seed crystal was added to the solution containing the isoindoline derivative obtained in step (a) and stirred overnight while the temperature was lowered to room temperature. Further, the crystals were precipitated by cooling with ice, and the precipitated crystals were filtered and dried (9 g, chemical purity 100%). When powder X-ray diffraction measurement was performed on the crystal, it was confirmed that the obtained crystal was an A-type crystal form.

In the recrystallization performed in the above-described step (a), a B-type crystal form was obtained as a crude isoindoline derivative, but the crystal obtained when recrystallization was performed a plurality of times in step (a). The shape is not limited to the B-type crystal form, and depending on the lot, an A-type crystal form may be obtained, or a mixed crystal of the A-type crystal form and the B-type crystal form may be obtained.
The type A seed crystal of the isoindoline derivative used in step (b) is obtained by selecting the crystal form of type A obtained as a crude isoindoline derivative in step (a) of another lot. It is what was done.

(Example 2)
Step (a): A crude isoindoline derivative was obtained as white crystals in the same manner as in step (a) of Example 1. When the powder X-ray diffraction measurement was performed on the crystal, the obtained crystal was a mixed crystal of an A-type crystal form and a B-type crystal form mainly composed of an A-type crystal form.

FIG. 3 is a powder X-ray diffraction chart of the crude isoindoline derivative obtained in Example 2.
The powder X-ray diffraction chart shown in FIG. 3 is a chart obtained by synthesizing a powder X-ray diffraction chart of the A-type crystal form and a powder X-ray diffraction chart of the B-type crystal form, and is characterized by the A-type crystal form. The typical peak is shown more strongly. That is, the crude product of the isoindoline derivative was a mixed crystal of an A-type crystal form and a B-type crystal form mainly composed of an A-type crystal form.

Subsequently, the isoindoline derivative was prepared in the same manner as in Example 1 except that 100 g of a crude isoindoline derivative (mixed crystal of A-type crystal form and B-type crystal form) was used and 700 mL of ethanol was used as a solvent. A containing solution was prepared.

(B) Process: In the same manner as in Example 1, addition of A-type seed crystals, recrystallization, and powder X-ray diffraction measurement were performed. The precipitated crystal was filtered and dried (87 g, chemical purity 100%), and powder X-ray diffraction measurement was performed on the crystal. As a result, it was confirmed that the obtained crystal was an A-type crystal form.
In this example, 0.5 g of A-type seed crystal was added.

Example 3
Step (a): A crude isoindoline derivative (B-type crystal form) was obtained in the same manner as in Step (a) of Example 1.
Subsequently, a solution containing an isoindoline derivative was prepared in the same manner as in Example 1 except that a mixed solvent of 45 mL of ethanol and 45 mL of water was used as a solvent for dissolving the isoindoline derivative.

(B) Step: In the same manner as in Example 1, addition of A-type seed crystals, recrystallization, and powder X-ray diffraction measurement were performed. The precipitated crystal was filtered and dried (8.0 g, chemical purity 100%), and powder X-ray diffraction measurement was performed on the crystal. As a result, it was confirmed that the obtained crystal was an A-type crystal form. .

Example 4
Step (a): A crude isoindoline derivative (B-type crystal form) was obtained in the same manner as in Step (a) of Example 1. In addition, the isoindoline derivative crude body (B-type crystal form) of 300 g or more was obtained by increasing the amount of acetone / water as the solvent and the first isoindoline derivative crude body used in this step.
Subsequently, a solution containing the isoindoline derivative was prepared in the same manner as in Example 1 except that 300 g of the obtained crude isoindoline derivative (B-type crystal form) was used and 2.1 L of ethanol was used as a solvent. Prepared.

(B) Process: In the same manner as in Example 1, addition of A-type seed crystals, recrystallization, and powder X-ray diffraction measurement were performed. The precipitated crystal was filtered and dried (273 g, chemical purity 100%), and powder X-ray diffraction measurement was performed on the crystal. As a result, it was confirmed that the obtained crystal was an A-type crystal form.
In this example, 1.5 g of A-type seed crystal was added.

(Examples 5 to 12)
In the step (a), the production of the isoindoline derivative and the powder X-ray diffraction measurement were performed in the same manner as in Example 1 except that each organic solvent shown in Table 2 was used as a solvent for dissolving the isoindoline derivative.
When the powder X-ray diffraction measurement was performed with respect to the crystal obtained in each Example, it was confirmed that the obtained crystal was an A-type crystal form.

About each said Example, the same operation was repeated 5 times by another lot, and reproducibility was confirmed. As a result, an A-type crystal form was selectively obtained in all lots of each example.

(Comparative Example 1)
Production of an isoindoline derivative and powder X-ray diffraction measurement were carried out in the same manner as in Example 1 except that the type of seed crystal added in the step (b) of Example 1 was changed to a B-type seed crystal.
As a result of repeating this operation five times, when an A-type crystal form is obtained, or when a B-type crystal form is obtained, a crystal in which the A-type crystal form and the B-type crystal form are mixed is obtained. In some cases, specific crystal forms could not be selectively obtained.

(Comparative Example 2)
Production of an isoindoline derivative and powder X-ray diffraction measurement were performed in the same manner as in Example 1 except that recrystallization was performed without adding a seed crystal in the step (b) of Example 1.
As a result of repeating this operation five times, when an A-type crystal form is obtained, or when a B-type crystal form is obtained, a crystal in which the A-type crystal form and the B-type crystal form are mixed is obtained. In some cases, specific crystal forms could not be selectively obtained.

Table 2 summarizes the production conditions and analysis results of powder X-ray diffraction measurement in each Example and Comparative Example. In addition, in the item of “analysis result” in Table 2, A-type crystal form, B-type crystal form, and crystals in which A-type crystal form and B-type crystal form coexist are obtained in 5 iterations. Indicates the number of times received.

As is clear from the results shown in Table 2, in each Example using an A-type crystal form as a seed crystal, an A-type crystal form was selectively obtained. On the other hand, in Comparative Example 1 using the B-type crystal form as the seed crystal and Comparative Example 2 not using the seed crystal, the A-type crystal form, the B-type crystal form, the A-type crystal form, and the B-type crystal There were cases where crystals with mixed shapes were obtained, and specific crystal forms could not be selectively obtained.
From this, it was clarified that the method for producing the A-type crystal form of the isoindoline derivative of the present invention is an excellent production method in that the A-type crystal form can be selectively obtained.

Claims (17)

(-)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclo represented by the formula (1) Isoindoline derivative having chemical structure of penta [f] isoindoline-1 (2H) -one

A method for producing a crystal form of A
(A) A crude product of the isoindoline derivative is made of an alcohol having 1 to 4 carbon atoms, a ketone having 2 to 6 carbon atoms, an aliphatic nitrile having 1 to 4 carbon atoms, an ester of a carboxylic acid having 1 to 4 carbon atoms, carbon A step of preparing a solution containing the isoindoline derivative by dissolving in a solvent containing at least one organic solvent selected from the group consisting of a linear or cyclic ether having 2 to 6 carbon atoms and a chloroalkane having 1 to 4 carbon atoms. ,and,
(B) a step of recrystallizing the A-type crystal form of the isoindoline derivative from a solution containing the isoindoline derivative in the presence of the A-type seed crystal of the isoindoline derivative;
A process for producing an A-type crystal form of an isoindoline derivative, characterized by comprising: The organic solvent used in the step (a) is at least one selected from the group consisting of ethanol, acetone, acetonitrile, methyl acetate, ethyl acetate, diethyl ether, tetrahydrofuran, methylene chloride, and chloroform. A method for producing an A-type crystal form of an indoline derivative. The method for producing an A-type crystal form of an isoindoline derivative according to claim 1, wherein the organic solvent used in the step (a) is at least one selected from the group consisting of ethanol, acetone, and ethyl acetate. The method for producing an A-type crystal form of an isoindoline derivative according to claim 3, wherein the solvent consists essentially of an organic solvent selected from the group consisting of ethanol, acetone, and ethyl acetate. The method for producing an A-type crystal form of an isoindoline derivative according to any one of claims 1 to 3, wherein the solvent further contains water in addition to the organic solvent. The isoindoline according to any one of claims 1 to 5, wherein 0.01 g to 2 g of the A-type seed crystal of the isoindoline derivative coexists with 100 g of the crude isoindoline derivative. A process for producing the crystalline form of derivative A. In the recrystallization in the step (b), the solution containing the isoindoline derivative is heated to a temperature of 50 ° C. or higher or the boiling point of the organic solvent, and then cooled to 0 to 30 ° C. during the cooling or cooling. The method for producing an A-type crystal form of an isoindoline derivative according to any one of claims 1 to 6, which is performed by pouring the A-type seed crystal of the isoindoline derivative into a solution after completion. The method for producing an A-type crystal form of an isoindoline derivative according to any one of claims 1 to 7, wherein the crude product of the isoindoline derivative has a chemical purity calculated by high performance liquid chromatography of 95% or more. The method for producing an A-type crystal form of an isoindoline derivative according to any one of claims 1 to 7, wherein the crude product of the isoindoline derivative has a chemical purity calculated by high performance liquid chromatography of 98% or more. The step of recrystallizing the crude isoindoline derivative using a solvent before the step (a) is further performed. Production method. The method for producing an A-type crystal form of an isoindoline derivative according to any one of claims 1 to 10, wherein the A-type crystal form of the isoindoline derivative has physical property data represented by the following (i).
(I): It has the powder X-ray diffraction spectrum data represented by FIG. The form A crystal form of the isoindoline derivative has powder X-ray diffraction spectrum data having peaks at diffraction angles (2θ) of 5.1, 10.2, and 22.5. A process for producing the crystal form of the isoindoline derivative of type A. The method for producing an A-type crystal form of an isoindoline derivative according to any one of claims 1 to 10, wherein the crystal form of the isoindoline derivative has powder X-ray diffraction spectrum data showing the following diffraction angle and relative intensity.

A (-)-2- (2-phenyl) -3- [2- (4-methyl-1-piperazyl) represented by the formula (1) obtained by the method according to any one of claims 1 to 13. ) -2-oxoethyl] -3,5,6,7-tetrahydrocyclopenta [f] isoindoline-1 (2H) -one isoindoline derivative

A-type crystal form. (-)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclo represented by the formula (1) Isoindoline derivative having chemical structure of penta [f] isoindoline-1 (2H) -one

A type crystal form of
A type A crystal form of the isoindoline derivative having physical property data represented by the following (i).
(I): It has the powder X-ray diffraction spectrum data represented by FIG. (-)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclo represented by the formula (1) Isoindoline derivative having chemical structure of penta [f] isoindoline-1 (2H) -one

A type crystal form of
Form A crystal form of the isoindoline derivative having powder X-ray diffraction spectrum data having peaks at diffraction angles (2θ) of 5.1, 10.2, and 22.5. (-)-2- (2-Phenyl) -3- [2- (4-methyl-1-piperazyl) -2-oxoethyl] -3,5,6,7-tetrahydrocyclo represented by the formula (1) Isoindoline derivative having chemical structure of penta [f] isoindoline-1 (2H) -one

A type crystal form of
A type A crystal form of the isoindoline derivative having powder X-ray diffraction spectrum data showing the following diffraction angle and relative intensity.

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