JP2010208957A - 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2-imino-4-thiazolidinone having crystal structure and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone having high solubility in an organic solvent.
When producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone, the temperature of the reaction solution is maintained at 30 ° C. or lower. Crystals are precipitated to produce 5- {4- [2- (5-(-2-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone having a novel crystal form.
[Selection figure] None

Description

  The present invention relates to 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone having a novel crystal structure and a method for producing the same.

  Following formula (1)

5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione hydrochloride (hereinafter sometimes referred to as pioglitazone hydrochloride) is an excellent blood sugar. Since it exhibits a lowering action and has low toxicity, it is practically used as a therapeutic agent for diabetes. The pioglitazone hydrochloride has the following formula (3)

5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-2-thiazolidinone (hereinafter sometimes referred to as imino form) and hydrogen chloride (hydrochloric acid) Can be produced by reacting (see, for example, Patent Document 1). Since this pioglitazone hydrochloride is used as a therapeutic agent as described above, a high-purity one is required, but it is difficult to purify because it is difficult to dissolve in a solvent. For example, in Patent Document 1, the following method is employed to produce high-purity pioglitazone and, by extension, high-purity pioglitazone hydrochloride.

Specifically, first, methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate represented by the above formula (2) (hereinafter referred to as bromo compound) In some cases) and thiourea are reacted to obtain an imino form represented by the above formula (3). Next, the imino form and hydrochloric acid are reacted to obtain pioglitazone hydrochloride represented by the above formula (1). Further, the pioglitazone hydrochloride is reacted with a base such as sodium hydrogen carbonate to obtain pioglitazone represented by the above formula (4). And the method of recrystallizing and refine | purifying this pioglitazone in a dimethylformamide-water mixed solvent is employ | adopted. According to this method, highly pure pioglitazone can be produced.

  However, according to the above method, it was necessary to react the pioglitazone with hydrochloric acid again in order to obtain a highly pure pioglitazone hydrochloride. In addition, since pioglitazone itself is difficult to dissolve in a solvent, it was necessary to use a solvent having a high dissolving power such as dimethylformamide in the above method.

  On the other hand, in the method described in Patent Document 1, if the purity of the imino compound represented by the above formula (3) can be increased, highly pure pioglitazone hydrochloride can be produced simply by reacting with hydrochloric acid. In this method, the production method of the imino form will be described in detail as follows. First, thiourea and sodium acetate are added to an ethanol solution containing the bromo compound represented by the above formula (2) and refluxed for 3 hours. Then, the solution is concentrated under reduced pressure, and the residue is neutralized with a saturated aqueous sodium hydrogen carbonate solution. Water and ether are added and mixed for 10 minutes, and the resulting imino form is further purified by recrystallization from methanol.

  However, according to the study by the present inventors, it has been found that there is room for improvement in the following points when an imino compound having a higher purity is produced by the above method. That is, since the imino form represented by the above formula (3) has low solubility in methanol, it is necessary to use a large amount of methanol, and purification by recrystallization using methanol is disadvantageous in industrial production. I understood.

  In addition, if the bromo compound represented by the above formula (2), which is the precursor of the imino compound, can be purified, it is considered that a high-purity imino compound can be produced. Since it is a stable and oily compound, it is not suitable for purification.

Japanese Patent Publication No. 5-66956

  According to the method described in Patent Document 1, purification of the imino form represented by the above formula (3) is industrially disadvantageous, but if a highly pure imino form can be obtained by a simple method, High purity pioglitazone hydrochloride can be produced. For example, if the solubility of the imino form in a solvent can be increased, it is considered that the imino form can be easily purified, and thus highly pure pioglitazone hydrochloride can be easily produced.

  Accordingly, an object of the present invention is to provide a novel crystalline form of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino having high purity and high solubility in a solvent. It is to provide -4-thiazolidinone (imino form) and to provide a method for producing the imino form. Furthermore, it is providing the method which can manufacture highly purified pioglitazone hydrochloride easily by using the obtained imino body.

  The inventors of the present invention have intensively studied the above problems. Specifically, 5- {4- [2] obtained by reacting methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate with thiourea. A method for synthesizing an imino compound having a crystal structure with high purity and high solubility in a solvent in-(5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (imino compound) investigated. As a result, when synthesizing the imino form, it was found that the imino form that is precipitated while maintaining the temperature of the reaction solution at a specific temperature or less is highly pure and highly soluble in a solvent. The invention has been completed.

  That is, the present invention has a crystal structure that gives characteristic peaks at least at 2θ = 14.9 °, 16.9 °, 22.5 °, and 23.4 ° by X-ray diffraction using Cu—Kα rays. 5- {4- [2- (5-Ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. Hereinafter, 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (imino form) having the above crystal structure is referred to as a type II crystalline imino form. In some cases.

  The present invention also provides a reaction solution obtained by reacting methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate with thiourea in an organic solvent. From this, 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone is precipitated while keeping the temperature of the reaction solution at 30 ° C. or lower. 5- {4 having a crystal structure giving characteristic peaks at least at 2θ = 14.9 °, 16.9 °, 22.5 °, 23.4 ° by X-ray diffraction using Cu—Kα ray This is a method for producing-[2- (5-ethyl-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (type II crystalline imino form).

  Furthermore, the present invention is characterized by at least 2θ = 14.9 °, 16.9 °, 22.5 °, 23.4 ° by X-ray diffraction using the Cu—Kα ray obtained by the above production method. 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (type II crystalline imino form) having a crystal structure giving a peak is reacted with hydrogen chloride It is the manufacturing method of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione hydrochloride characterized by the above-mentioned.

  5- {4- [2- (5-Ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (imino form) of the present invention has a novel crystal structure and has a high purity. It is. This imino form has better solubility in an organic solvent than a conventional crystal form, and can be dissolved in a small amount of an organic solvent, so that it can be easily purified. Therefore, it is optimal for intermediates such as pharmaceuticals that require particularly high purity raw materials.

  Moreover, according to the method of the present invention, the above-described novel crystalline imino form having high solubility in an organic solvent can be easily produced. Therefore, by reacting 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone obtained by the method of the present invention with hydrogen chloride, high purity is obtained. Of pioglitazone hydrochloride can be obtained.

2 is an X-ray diffraction chart of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone of the present invention produced in Example 1. FIG. 2 is an infrared absorption spectrum of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone of the present invention produced in Example 1. 2 is a 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone DSC curve of the present invention produced in Example 1. 2 is an X-ray diffraction chart of Form I 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone produced in Comparative Example 1. 2 is an infrared absorption spectrum of Form I 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone produced in Comparative Example 1. 2 is a DSC curve of Form I 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone produced in Comparative Example 1.

  The present invention will be described in detail below.

(Type II crystalline imino form)
The crystalline compound of the present invention, 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (imino form), has a predetermined crystal structure. That is, the imino compound is a compound (II) having characteristic peaks at least at 2θ = 14.9 °, 16.9 °, 22.5 °, and 23.4 ° by X-ray diffraction using Cu—Kα ray. Type crystal imino form). In this case, the measurement error of the X-ray diffraction angle is allowed up to about 0.2 °. The X-ray diffraction measurement result of this type II crystalline imino form is shown in FIG. FIG. 2 shows an infrared absorption spectrum of a type II crystalline imino compound, and FIG. 3 shows the results of DSC (differential scanning calorimetry).

  The above-mentioned type II crystalline imino form will be described in detail in the following Examples. 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2 obtained by the method of Patent Document 1 Compared with -imino-4-thiazolidinone (hereinafter, this imino form may be referred to as a type I crystalline imino form), the solubility in organic solvents is dramatically improved. Specifically, at room temperature, the type II crystalline imino form can be dissolved in about 1/9 of the amount of methanol than the type I crystalline imino form. Therefore, since it can be recrystallized with a small amount of solvent and the purity can be easily increased, it can be effectively used as a raw material for pioglitazone hydrochloride as a drug substance.

(Method for producing type II crystalline imino compound)
The type II crystalline imino form is not particularly limited, but is preferably produced by the following method. Specifically, it is obtained by reacting methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate (bromo compound) with thiourea in an organic solvent. From the resulting reaction solution, 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (imino form) was reduced to 30 ° C. or lower. By precipitating while maintaining, a type II crystalline imino form can be produced. The imino form obtained by precipitating the reaction solution at the above temperature is the type II crystalline imino form. In the following, description will be given in order.

  In the method for producing a type II crystalline imino compound of the present invention, a bromo compound used as a starting material can be produced by a known method, for example, a method described in Patent Document 1. Specifically, 4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} aniline is diazotized in the presence of hydrobromic acid, and further reacted in the presence of a copper catalyst and methyl acrylate (Meerwein Array). ).

  The purity of high-performance liquid chromatography (HPLC) of the bromo compound obtained by the above method is generally about 40 to 80%, and this purity can be used for the reaction as it is. In the present invention, the product obtained by multiplying the bromo compound and all the products containing impurities by the purity of HPLC is regarded as the pure component equivalent amount (yield) of the bromo compound, and is distinguished from the yield of all products. . In addition, in the imino form described in detail below, the pure component equivalent amount of the imino form is determined to determine the yield.

  In the method for producing a type II crystalline imino compound of the present invention, the organic solvent used as a reaction solvent is usually an alcohol (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol). , 2-methoxyethanol, etc.), dimethyl sulfoxide, dimethylformamide, dimethylacetamide and other highly polar solvents can be used. Among these, methanol and ethanol are preferable in view of the fact that toxicity and boiling point are low and the salt generated by the reaction hardly remains in the imino form.

  The amount of these organic solvents to be used varies somewhat depending on the type of organic solvent to be used. Usually, the amount used is 3 ml to 20 ml with respect to 1 g of the pure bromo compound, and 5 to 10 ml is more preferable in view of the batch yield. preferable.

  The bromo compound and thiourea react almost quantitatively. In general, the reaction rate increases as the amount of thiourea used increases. However, when the amount of thiourea remaining in the obtained imino derivative is reduced and the yield and purity of the imino derivative are taken into consideration, The amount of urea used is preferably 0.8 to 5.0 mol, particularly preferably 1.0 to 3.0 mol, per 1 mol of pure bromo compound.

  In addition, the reaction between the bromo compound and thiourea can be performed in the presence of sodium acetate, potassium acetate or the like in order to capture hydrobromic acid by-produced as the reaction proceeds. The amount of these used is preferably 0.8 to 5.0 mol, particularly preferably 1.0 to 3.0 mol, per 1 mol of the pure bromo compound.

  In the present invention, the temperature (reaction temperature) when the bromo compound and thiourea are reacted in an organic solvent is not particularly limited, but may be 20 ° C. or higher and the boiling point of the organic solvent to be used. It is particularly preferable that the temperature be 60 ° C. or higher and the boiling point of the organic solvent or lower. The reaction between the bromo compound and thiourea is preferably carried out with stirring by a known means. Furthermore, the reaction time may be appropriately determined by confirming the production status of the imino form from the reaction solution by HPLC, but is usually about 30 minutes to 5 hours according to the above conditions.

  In the production method of the present invention, the greatest feature is that after the above reaction (after reacting the bromo compound and thiourea in an organic solvent), the temperature of the resulting reaction solution is maintained at 30 ° C. or lower and directly It is to deposit an imino form. The imino form precipitated under these conditions becomes the type II crystal imino form. If the imino form is precipitated at a temperature exceeding 30 ° C., an imino form having the same crystal structure as that of a conventional type I crystalline imino form is produced, which is not preferable. On the other hand, the lower limit of the temperature of the reaction solution when precipitating the type II crystalline imino compound is preferably lower, but it is preferably 0 ° C. in view of industrial production. Considering industrial production and production efficiency of type II crystalline imino compound, the temperature of the reaction solution is preferably maintained at 10 ° C. or more and 25 ° C. or less.

  By maintaining the reaction solution at 30 ° C. or lower and directly depositing imino crystals, an imino form (type II crystal imino form) different from the conventional method can be produced. The reason why this type II crystalline imino compound can be produced is not clear, but the precipitation of the imino compound directly from the reaction solution maintained at a temperature of 30 ° C. or less has a great influence on the determination of the crystal structure. It is thought that there is. That is, it is considered that other components contained in the reaction solution and the temperature of the reaction solution influence the production of the type II crystal imino form.

  In the present invention, the type II crystalline imino form precipitated by the above method can be separated by a known method or a solid-liquid separation method such as filtration or centrifugation. Moreover, it can also dry by natural drying, ventilation drying, vacuum drying, etc. as needed.

  The type II crystalline imino form produced and isolated as described above has higher purity and higher solubility in organic solvents than the type I crystalline imino form produced by the conventional method. Therefore, purification becomes easier and it can be suitably used as a raw material for pioglitazone hydrochloride.

(Method for producing pioglitazone hydrochloride)
The type II crystal imino obtained by the above method is only different in crystal structure from the conventional type I crystal imino. Therefore, pioglitazone hydrochloride can be obtained by reacting with hydrogen chloride as in the case of type I crystalline imino form. Specifically, crystals of pioglitazone hydrochloride can be produced by precipitating the type II crystalline imino form by cooling a reaction solution obtained in water or an organic solvent.

  The reaction solvent for the type II crystalline imino compound and hydrogen chloride is not particularly limited, and may be reacted in a polar solvent or water. In consideration of handling, it is preferable to use hydrogen chloride dissolved in the polar solvent and water. At this time, the hydrogen chloride solution having a hydrogen chloride concentration of 0.1N to 6.0N is generally used.

  The reaction between the protector and hydrogen chloride can be carried out by mixing the two. However, as other reaction conditions, the reaction is usually performed at a reaction temperature of 50 to 100 ° C. for 3 to 20 hours with stirring. That's fine. The completion of the reaction can be confirmed by high performance liquid chromatography.

  Since pioglitazone hydrochloride obtained by reacting an imino form with hydrogen chloride under the above conditions has low solubility in a solvent, the compound is easily separated and isolated from the reaction solution by an operation such as filtration. can do. The obtained pioglitazone hydrochloride has a very high purity. If necessary, it can be washed with water, ethanol or the like, and further purified by recrystallization or the like.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

  First, an evaluation method, an analysis method, and a purity measurement method for a type II crystal imino compound will be described.

(1) Solubility Evaluation of Type II Crystalline Imino Form 100 mg of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone crystal (imino form crystal) The mixture was placed in an eggplant flask and an appropriate amount of methanol was added at room temperature, followed by stirring for 5 minutes. When insolubles existed, methanol was further added and the same operation was performed, and the amount of methanol when the entire amount was visually dissolved was used as a simple solubility index.

(2) Crystal analysis method (2) -1 X-ray powder diffraction analysis (XRD measurement)
X-ray powder diffraction analysis was performed on a Rigaku RINT1200 X-ray powder diffractometer using CuKα radiation having a wavelength of 1.5406 Å. The voltage was set to 40 kV and the current was set to 40 mA. The sampling width was set to 0.020, and the scan speed was set to 1.0 ° / min. Measurement was performed in the range of a start angle of 10 ° and an end angle of 50 °. The sample was prepared for analysis by pressing it uniformly into the holder.

(2) -2 Differential scanning calorimetry (DSC measurement)
DSC measurement was performed using EXSTAR6000 manufactured by Seiko Instruments Inc. Approximately 10 mg of sample was accurately weighed and inserted into the furnace. Each sample was heated at a rate of 10 ° C / min from 20 ° C to a final temperature of 250 ° C to obtain a DSC curve.

(2) -3 Infrared spectroscopic analysis Infrared spectroscopic analysis was performed in SpectrumOneFT-IR Spectrometer manufactured by PerkinElmer. Each spectrum in the range of 4000 to 400 ^-1, 4 times the number of scans was measured under the conditions of the spectrometer resolution 4.00 cm ^-1.

(2) -4 Purity measurement of imino form The measurement of the purity of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (imino form) is a liquid. Chromatography, column: ODS-A manufactured by YMC (inner diameter: 4.6 mm, length: 150 mm), detection wavelength: 269 nm.

Production example
Method for producing methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate (bromo compound) 4- [2- (5-ethyl-2-pyridyl) ethoxy Nitrobenzene (180.0 g) and 1500 mL of methanol were charged into a 2 L flask, and catalytic reduction was performed at room temperature and 1 atm in the presence of 10% Pd-C (50% wet, 18.0 g). Filtration was performed, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in acetone (1500 mL) -methanol (600 mL), and 47% aqueous HBr solution (456 g) was added. Then, it was cooled and 90 mL of an aqueous solution of NaNO ₃ was added dropwise at 5 ° C. or lower. After stirring at 5 ° C. for 30 minutes, methyl acrylate (336 g) was added and heated to 38 ° C., and cuprous oxide (6.0 g) was added little by little while continuing vigorous stirring. After confirming the completion of the generation of nitrogen gas, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and 20% aqueous ammonia were added to the residue, and the organic layer was extracted. After drying over magnesium sulfate, the solvent was distilled off to obtain 222.0 g of a bromo oil (pure 113.2 g).

Example 1
(Method for producing type II crystalline imino compound)
Methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate obtained in Production Example 186.3 g (pure amount 95.0 g), thiourea 36.9 g , 39.7 g of sodium acetate and 650 mL of methanol were charged into a 1 L flask and refluxed at 65 ° C. for 3 hours. After the reaction, the reaction solution is rapidly cooled until the temperature of the reaction solution reaches 25 ° C., maintained at 25 ° C. for 1 hour, and 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2. -Crystals of imino-4-thiazolidinone were precipitated. The reaction solution was filtered to obtain white 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone crystals. The purity was 98.5% and the yield was 82.5%.

  When powder X-ray diffraction (hereinafter referred to as XRD) is measured using this crystal as a sample, the X-ray diffraction chart shown in FIG. 1 is obtained. This crystal has 2θ = 14.9 °, 16.9 °, 22. It was found to be a compound having a crystal structure giving characteristic peaks at 5 ° and 23.4 °. Further, FIG. 2 shows an infrared absorption spectrum (IR spectrum), and FIG. 3 shows a differential scanning calorimetry (DSC). From these results, this crystal has a novel crystal form of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone (type II crystalline imino form) It turns out that.

(Solubility evaluation)
When the solubility of the obtained crystals in methanol was confirmed by the above method, 100 mg of the crystals could be dissolved in 10 mL of methanol.

(Recrystallization operation)
10 g of the crystals obtained were dissolved when refluxed with 50 mL of methanol. Upon cooling, it was crystallized at 50 ° C., and it was possible to obtain a type I crystalline imino compound having a purity of 99.3% and a yield of 90.3%. When the obtained crystal is used as a raw material of pioglitazone hydrochloride, it is clear that the purity of pioglitazone hydrochloride can be further increased.

Example 2
(Method for producing pioglitazone hydrochloride)
Crystal of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone obtained in Example 1 (type II crystal purity 98.5%) 65. 0 g, 500 g of purified water and 5.7 g of concentrated hydrochloric acid were charged into a 1 L flask and refluxed for 4 hours. The resulting reaction solution was cooled to room temperature and stirred overnight. The reaction solution was filtered to obtain 65.5 g of white crystals of pioglitazone hydrochloride. The purity was 98.7% and the yield was 91.2%.

Example 3
(Method for producing type II crystalline imino compound)
180.5 g of methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate obtained in the production example (pure amount 95.0 g), 55.2 g of thiourea , 59.6 g of sodium acetate and 650 mL of ethanol were charged into a 1 L flask and refluxed for 2.5 hours. After the reaction, the reaction solution is rapidly cooled until the temperature of the reaction solution reaches 25 ° C., maintained at 25 ° C. for 1 hour, and 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2. -Crystals of imino-4-thiazolidinone were precipitated. The reaction solution was filtered to obtain white 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone crystals. The purity was 98.2% and the yield was 79.7%.

  When XRD is measured using this crystal as a sample, this crystal is a compound having a crystal structure that gives characteristic peaks at 2θ = 14.9 °, 16.9 °, 22.5 °, and 23.4 °. I understood. From these results, this crystal was found to be a type II crystal imino form of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone.

  Further, as in Example 1, the solubility was evaluated, and as a result, 100 mg of crystals could be dissolved in 10 ml of methanol.

Example 4
(Method for producing type II crystalline imino compound)
2-Bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} methyl propionate 180.5 g (pure amount 95.0 g), thiourea 36.9 g, sodium acetate 39.7 g Then, 650 mL of ethanol was charged into a 1 L flask and refluxed for 2.5 hours. When the reaction solution was rapidly cooled after the reaction, crystals of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone were obtained at a temperature of 15 ° C. Precipitated in large quantities. After cooling to 5 ° C., the mixture was kept at 5 ° C. for 1 hour, and the reaction solution was filtered to obtain white 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino. Crystals of -4-thiazolidinone were obtained. The purity was 97.6% and the yield was 79.7%.

  When XRD is measured using this crystal as a sample, this crystal is a compound having a crystal structure that gives characteristic peaks at 2θ = 14.9 °, 16.9 °, 22.5 °, and 23.4 °. I understood. From these results, this crystal was found to be a type II crystal imino form of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone.

  Further, as in Example 1, the solubility was evaluated, and as a result, 100 mg of crystals could be dissolved in 10 ml of methanol.

Comparative Example 1
(Production of type I crystal by the method described in Patent Document 1)
Methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate obtained in Preparation Example 73.0 g (pure amount 37.2 g), thiourea 14.2 g Sodium acetate (15.3 g) and ethanol (500 mL) were charged into a 1 L flask and refluxed for 3 hours. After the reaction, the reaction solution was air-cooled, and crystals were precipitated at a reaction solution temperature of 55 ° C. The reaction solution was concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous sodium hydrogen carbonate solution. Water and ether were added and the mixture was stirred for 10 minutes to obtain precipitated crystals of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. After refluxing with 2.5 L of methanol, recrystallization is performed to give yellow crystals of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. Got. The purity was 96.1% and the yield was 80.3%.

  When XRD was measured using the obtained crystal as a sample, an X-ray diffraction chart shown in FIG. 4 was obtained. From this result, it was found that this crystal was a compound having a crystal structure giving characteristic peaks at 2θ = 13.20 °, 19.28 °, and 21.94 °. FIG. 5 shows an infrared absorption spectrum (IR spectrum), and FIG. 6 shows a DSC. From these results, it was found that this crystal was an imino form (type I crystal imino form) different from those in Examples 1-3.

  As in Example 1, when the solubility of this crystal in methanol was confirmed, 100 mg of this crystal could be dissolved in 90 ml of methanol.

Comparative Example 2
(Method for producing pioglitazone hydrochloride)
65.0 g of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone crystals (type I crystalline imino form) obtained in Comparative Example 1, purified water 500 g and 5.7 g of concentrated hydrochloric acid were charged into a 1 L flask and refluxed for 4 hours. The resulting reaction solution was cooled to room temperature and stirred overnight. The resulting crystals were filtered to obtain 65.6 g of white crystals of pioglitazone hydrochloride. The purity was 97.0% and the yield was 91.3%.

Comparative Example 3
Methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate obtained in Production Example 186.3 g (pure amount 95.0 g), thiourea 36.9 g Then, 39.7 g of sodium acetate and 650 mL of methanol were charged into a 1 L flask and refluxed for 3 hours. After the reaction, the reaction solution was air-cooled, and crystals were precipitated at a reaction solution temperature of 55 ° C. The reaction solution was concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous sodium hydrogen carbonate solution. Water and ether were added and the mixture was stirred for 10 minutes to obtain precipitated crystals of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. Reslurry was performed using 1 L of methanol to obtain yellow crystals of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. The purity was 96.6% and the yield was 88.2%.

  When XRD was measured using the obtained crystal as a sample, an X-ray diffraction chart shown in FIG. 4 was obtained. From this result, it was found that this crystal was a compound having a crystal structure giving characteristic peaks at 2θ = 13.20 °, 19.28 °, and 21.94 °. FIG. 5 shows an infrared absorption spectrum (IR spectrum), and FIG. 6 shows a DSC. From these results, it was found that this crystal was an imino form (type I crystal imino form) different from those in Examples 1 to 3 above.

As in Example 1, the solubility of this crystal in methanol was confirmed, and 100 mg of this crystal could be dissolved in 90 ml of methanol. Comparative Example 4
Methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate obtained in Production Example 158.3 g (pure amount 95.0 g), thiourea 55.2 g , 59.6 g of sodium acetate and 650 mL of ethanol were charged into a 1 L flask and refluxed for 2.5 hours. After the reaction, the temperature of the reaction solution is maintained at 40 ° C. for 1 hour to precipitate 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone crystals. It was. The reaction solution is cooled to room temperature and then filtered to obtain yellowish white 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone crystals. It was. The purity was 95.5% and the yield was 90.1%.

  When XRD is measured using this crystal as a sample, this crystal is a compound having a crystal structure giving characteristic peaks at 2θ = 13.20 °, 19.28 °, and 21.94 °, which is the same as Comparative Example 1. It was found to be a type I crystal.

  As in Example 1, when the solubility of this crystal in methanol was confirmed, 100 mg of this crystal could be dissolved in 90 ml of methanol.

Claims (3)

  5- {4- [having a crystal structure giving characteristic peaks at least at 2θ = 14.9 °, 16.9 °, 22.5 °, 23.4 ° by X-ray diffraction using Cu—Kα rays. 2- (5-Ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone.   From a reaction solution obtained by reacting methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate with thiourea in an organic solvent, 5- {4 Cu-Kα radiation characterized by precipitating-[2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone while keeping the temperature of the reaction solution at 30 ° C. or lower 5- {4- [2- (5) having a crystal structure giving characteristic peaks at least 2θ = 14.9 °, 16.9 °, 22.5 °, 23.4 ° by X-ray diffraction using -Ethyl-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone.   5- {4- [having a crystal structure giving characteristic peaks at least at 2θ = 14.9 °, 16.9 °, 22.5 °, 23.4 ° by X-ray diffraction using Cu—Kα rays. 2- {5- [2- (5-ethyl-2-pyridyl), characterized by reacting 2- (5-ethyl-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone with hydrogen chloride Ethoxy] benzyl} -2,4-thiazolidinedione hydrochloride.