JP2013203685A - Method of producing 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of lowering N, N'-dimethyl-4-nitroaniline with high efficiency in 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene serving as an important intermediate of electronic material and the like.SOLUTION: A method of producing PI-03 or a salt thereof includes: a reaction process of producing PI-03 by reacting 2-(5-ethyl-2-pyridyl)ethanol with 4-fluoronitrobenzene in a reaction solvent formed of N,N'-dimethylformamide in the presence of a base; a separation process of separating a crude PI-03 containing N,N'-dimethyl-4-nitroaniline as impurities from a reaction mixture obtained in the reaction process; and a back extraction process of bringing a solution obtained by dissolving the crude PI-03 in a water-insoluble or hardly water-soluble organic solvent into contact with an acid aqueous solution to form a salt of PI-03, and extracting the formed salt into an aqueous phase.

Description

  The present invention relates to a novel process for producing 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene or a salt thereof.

  4- [2- (5-Ethyl-2-pyridyl) ethoxy] nitrobenzene (hereinafter also referred to as “PI-03”) or a salt thereof represented by the following formula (1) is used as an intermediate for medical and agricultural chemicals, electronic materials, etc. It is an important intermediate.

  In particular, pioglitazone used as a therapeutic agent for diabetes, that is, (±) -5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2 represented by the following formula (2) , 4-dione hydrochloride (hereinafter also referred to as “PIO”).

  Conventionally, 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene (PI-03) includes 2- (5-ethyl-2-pyridyl) ethanol represented by the following formula (3) and the following formula ( The 4-fluoronitrobenzene represented by 4) is reacted in the presence of a base, followed by a post-treatment operation, and then purified by a recrystallization operation.

  For example, 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene are reacted in the presence of sodium hydride in a N, N′-dimethylformamide solvent, followed by a post-treatment operation. It is purified and produced by recrystallization using a mixed solvent of ether and hexane (Patent Document 1). In another method, 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene are reacted in an acetone solvent in the presence of an alkali metal hydroxide, and then a post-treatment operation is performed. Next, a method for purification by crystallization from a mixed solvent of water and methanol (Patent Document 2) and 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene are combined with dimethyl sulfoxide and water. It is produced by a method of performing a post-treatment operation after reacting with sodium hydride in a mixed solvent in the presence of a phase transfer catalyst, and then purifying by recrystallization using diisopropyl ether (Patent Document 3).

Japanese Patent No. 1855588 International Publication No. 2009/133576 Pamphlet International Publication No. 2006/035459 Pamphlet

  However, when the inventors conducted a follow-up experiment on the methods described in these patent documents, it was found that there were the following problems. That is, it has been clarified that the methods described in Patent Documents 2 and 3 have extremely low reactivity and require a long time to complete the reaction. In contrast, the method described in Patent Document 1 does not have such a problem and can obtain PI-03, which is the target product, in a high yield, but the obtained PI-03 includes the PI-3. It has been found that about several percent of specific impurities that are by-products when PIO is produced using -03 and that cause impurities (raw materials) that are difficult to remove by purification are included.

  Here, the specific impurity is N represented by the following formula (5), which is considered to be produced by the reaction of dimethylamine, which is a decomposition product of N, N′-dimethylformamide, which is a reaction solvent, and 4-fluoronitrobenzene. , N′-dimethyl-4-nitroaniline (hereinafter also referred to as “specific impurity”). And when PIO was synthesized using PI-03 containing several percent of the specific impurity as a raw material, it was found that the product contained about 0.2% of impurities derived from the specific impurity. Impurities could not be removed sufficiently even after purification such as recrystallization.

  Pharmaceutical drug substances such as PIO are generally very expensive. In addition, the demand for the purity of the drug substance is severe, and in order to satisfy such a requirement, it is necessary to repeat a purification process such as recrystallization, and the presence of impurities that are difficult to remove increases the number of purification cycles. Connected. For these reasons, reducing the amount of impurities that are difficult to remove has a significant industrial significance. Therefore, the present invention provides a highly low content of the specific impurity when producing PI-03 by reacting 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene in the presence of a base. It aims at providing the method of manufacturing PI-03 of purity efficiently.

  Based on the mechanism for producing the specific impurity, the inventors of the present invention are reaction solvents other than N, N′-dimethylformamide, which have a reaction rate equal to or higher than that when N, N′-dimethylformamide is used ( It was thought that the above-mentioned problem could be solved if a reaction solvent that gave (reactivity) could be found, and such a reaction solvent was searched. However, the reactivity is particularly high when N, N′-dimethylformamide is used as a solvent, and is about the same as or higher than when N, N′-dimethylformamide is used when other reaction solvents are used. It was not possible to find a solvent that gave reactivity. As a result, it was found that N, N'-dimethylformamide had to be used as a reaction solvent in order to obtain high reactivity. Therefore, the present inventors have further studied a method for efficiently removing the specific impurities once generated. Specifically, paying attention to the difference in the base dissociation constant between PI-03 and specific impurities, various studies were conducted. As a result, it was found that PI-03 tends to form a salt with an acid as compared with a specific impurity. Therefore, PI-03 containing a specific impurity (also referred to as a crude product of PI-03) is dissolved in a water-insoluble or poorly water-soluble organic solvent to form a solution, and the resulting solution is brought into contact with an aqueous acid solution. Thus, when PI-03 was selectively extracted into the aqueous layer as a water-soluble salt, it was found that PI-03 and specific impurities can be efficiently separated, and the present invention has been completed.

  That is, in the present invention, 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene are reacted in a reaction solvent consisting of N, N′-dimethylformamide in the presence of a base. 2- (5-Ethyl-2-pyridyl) ethoxy] nitrobenzene, 4- [2- containing N, N′-dimethyl-4-nitroaniline as an impurity from the reaction mixture obtained in the reaction step (5-Ethyl-2-pyridyl) ethoxy] separation step for separating a crude product of nitrobenzene, and contacting a solution obtained by dissolving the crude product in a water-insoluble or poorly water-soluble organic solvent with an aqueous acid solution Forming a salt of 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene by extraction and extracting the formed salt into an aqueous phase. 4 is a [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene or a salt thereof.

  According to the present invention, 4- ± useful as a raw material for (±) -5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride (PIO). [2- (5-Ethyl-2-pyridyl) ethoxy] nitrobenzene (PI-03) can be produced with high purity.

  Furthermore, according to the present invention, N, N′-dimethyl-4-nitroaniline (specific impurity) contained as an impurity can be particularly reduced. As a result, when PIO is produced from PI-03 produced according to the present invention, it is possible to obtain high-purity PIO with a low content of “impurities derived from specific impurities” that are difficult to remove by purification. it can.

  In the method of the present invention, when reacting 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene in the presence of a base to produce PI-03, N is obtained that is highly reactive as a reaction solvent. , N′-dimethylformamide (reaction step), and the crude product containing specific impurities inevitably generated when the reaction solvent is used is separated from the resulting reaction mixture (separation step). The target salt, PI-03, is converted into a water-soluble salt and selectively extracted into an aqueous phase (back extraction step) to separate the target salt from the specific impurity, and further, if necessary, It is characterized in that the salt is returned to PI-03 to be highly purified (purified). Hereinafter, the method of the present invention will be described in detail.

(Reaction process)
In the reaction step in the present invention, 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene are reacted in N, N′-dimethylformamide in the presence of a base to produce PI-03.

  The reaction step is not particularly different from the conventional method for producing PI-03. For example, as described in Patent Document 1, 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene are used. What is necessary is just to add a base to the solution obtained by making it melt | dissolve in N, N'- dimethylformamide, and to make it react.

  The base used in the reaction step can be used without particular limitation as long as it allows the target reaction to proceed and does not react with 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene. it can. For example, sodium hydride used in Patent Document 1, and alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, and barium hydroxide used in Patent Documents 2 and 3. A hydroxide is mentioned. In addition, potassium tertiary butoxide, sodium methoxide, and the like can be used. Among these, it is preferable to use sodium hydroxide, potassium hydroxide, or lithium hydroxide from the viewpoint of high reactivity and low risk of ignition and the like.

  The amount of each reaction reagent and solvent used in the reaction step is not particularly different from the conventional one. That is, 0.8 to 1.5 mol of 4-fluoronitrobenzene is usually used for 1 mol of 2- (5-ethyl-2-pyridyl) ethanol.

  The base is usually 0.8 to 5.0 equivalents, preferably 0.85 to 3.0 equivalents, more preferably 1 mol of 2- (5-ethyl-2-pyridyl) ethanol. Is 0.9 to 2.5 equivalents.

  The amount of N, N'-dimethylformamide used is usually 0.5 to 20.0 milliliters per gram of 2- (5-ethyl-2-pyridyl) ethanol. Considering the reactivity, the amount of specific impurities and other impurities produced, the complexity of post-treatment operations, etc., it is preferably 1.0 to 10.0 ml, more preferably 2.0 to 7.5 ml.

  The reaction temperature is preferably 30 ° C. or higher and 70 ° C. or lower, more preferably 0 ° C. or higher and 40 ° C. or lower, from the viewpoint of reaction rate and prevention of decomposition of N, N′-dimethylformamide.

  The reaction time may be appropriately determined by confirming the consumption of 2- (5-ethyl-2-pyridyl) ethanol or 4-fluoronitrobenzene by high performance liquid chromatography, thin layer chromatography or the like. Since the reactivity varies depending on the type and amount of the base used in the reaction, it cannot be generally stated, but if about 200 mmol of 2- (5-ethyl-2-pyridyl) ethanol is reacted, 0.1% The reaction proceeds sufficiently in the period of 48 hours.

(Separation process)
In the separation step, a crude product of PI-03 containing specific impurities is separated from the reaction mixture obtained in the reaction step. In the separation step, it is only necessary to roughly separate the solvent, the remaining reaction reagent and the reactive organism PI-03. For example, an organic solvent and water are added to the reaction solution after the reaction, and PI-03 is extracted into the organic solvent. Then, the organic layer and the aqueous layer are separated, and the resulting organic layer is concentrated to produce a crude product, or the reaction solution after the reaction has low solubility in PI-03, water, etc. The method of adding the solvent and crystallizing PI-03 can be suitably employed. In the former method, an emulsion is easily formed due to the influence of N, N′-dimethylformamide, and it may be difficult to separate the organic layer and the aqueous layer. Therefore, the latter method may be adopted. More preferred.

  The crude product of PI-03, separated by the above method, was produced by reacting N, N′-dimethylformamide, which is a reaction solvent, with dimethylamine and 4-fluoronitrobenzene. N'-dimethyl-4-nitroaniline (specific impurity) is usually contained in an amount of about 0.1 to 10%, preferably about 0.1 to 3%.

  The concentration of the specific impurity is a value represented by the ratio of the peak area value of the specific impurity to the total area value of all the peaks when measured by high performance liquid chromatography (HPLC) under the conditions described in the following examples. It is. The purity of PI-03 can also be expressed as the ratio of the peak area value of PI-03 to the total area value of all peaks when measured by HPLC in the same manner as described above.

(Back extraction process)
In the back extraction step, a solution obtained by dissolving the crude product separated in the separation step in a water-insoluble or poorly water-soluble organic solvent (hereinafter also referred to as a crude product solution) and an acid aqueous solution are contacted. To form a salt of 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene, and the salt formed is extracted into the aqueous phase.

  At the time of preparing the crude solution in the back extraction step, a water-insoluble or poorly water-soluble organic solvent is used as the organic solvent in which PI-03 is dissolved. Examples of the organic solvent include esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate, ethers such as dimethyl ether, diethyl ether, ethyl methyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, and dioxane. Aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and pentane, halogenated aliphatic hydrocarbons such as dichloromethane and chloroform, and the like. These solvents may be used alone or in combination of two or more.

  Among these, ethyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, and toluene are preferable from the viewpoint of high solubility in PI-03 and relatively low boiling point and easy removal in subsequent steps. Particularly preferred are ethyl acetate, diethyl ether and diisopropyl ether.

  In this invention, the usage-amount of the said organic solvent is not restrict | limited in particular, What is necessary is just a solvent amount in which PI-03 melt | dissolves, and what is necessary is just to determine suitably according to the kind of organic solvent to be used. The amount of the solvent used is usually 1.0 to 20.0 ml with respect to 1 gram of PI-03, but preferably 1.5 to 10.0 in view of the extraction efficiency into the aqueous layer. More preferably, it is 2.0 to 7.5 milliliters.

  The aqueous acid solution used in the present invention is prepared by mixing an acid and water, but the preparation method is not particularly limited and can be appropriately carried out by a known method. What is marketed as aqueous solution, such as hydrochloric acid and hydrobromic acid, may be used as it is. In addition, when the acid aqueous solution is brought into contact with the PI-03 solution, the acid aqueous solution may be prepared in advance. Alternatively, after adding water to the PI-03 solution, the acid is then added in the system. It may be prepared. The order of adding the acid and water is not limited and may be determined appropriately.

  Any acid can be used without particular limitation as long as it forms an acid salt with PI-03. Specifically, hydrochloric acid, hydrogen chloride, hydrobromic acid, hydrogen bromide, sulfuric acid, sulfurous acid, fuming sulfuric acid, nitric acid, fuming nitric acid, nitrous acid, phosphoric acid, boric acid, borofluoric acid, carbonic acid, silicic acid, etc. Inorganic acids including mineral acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid, lauric acid, lactic acid, cyclohexanecarboxylic acid, oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, Fumaric acid, maleic acid, malic acid, citric acid, aconitic acid, benzoic acid, phthalic acid, mellitic acid, cinnamic acid and other carboxylic acids, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid And sulfonic acids such as camphorsulfonic acid. These acids can be used alone or in combination of two or more.

  Among these, considering the ease of forming an acid salt with PI-03, inorganic acids including mineral acids such as hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, boric acid, formic acid, acetic acid, It is preferable to use carboxylic acids such as fluoroacetic acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc., and 4- [2- (5-ethyl- Considering the separation efficiency between 2-pyridyl) ethoxy] nitrobenzene and specific impurities and the extraction efficiency into the aqueous layer, it is particularly preferable to use hydrochloric acid, sulfuric acid, or hydrobromic acid.

  In this invention, if the usage-amount of an acid is a monovalent acid with respect to PI-03: 1mol, it will be 0.5-1.8 mol. However, the range of the amount of acid used varies depending on the valence of the acid used, and in the case of divalent and higher polyvalent acids, it is a value obtained by dividing the number of moles by the valence of the acid (ie, equivalent) . Specifically, if it is a divalent acid, it will be 0.25-0.9 mol. Among these ranges, when less than 1.2 equivalents of acid are used, the entire amount of PI-03 does not become an acid salt, but partially forms an acid salt and is extracted into the aqueous layer. And the specific salt is reduced in this extracted salt of PI-03. In the present invention, considering extraction efficiency and separation efficiency, 0.6 to 1.7 equivalents are preferable, and 0.7 to 1.6 equivalents of acid are more preferable.

  In this invention, the usage-amount of the said acid aqueous solution uses 1.0-30.0 milliliter normally with respect to 1 gram of PI-03. Among these, considering the extraction efficiency into the aqueous layer, it is preferably 1.5 to 20.0 ml, more preferably 2.0 to 10.0 ml.

  The contact between the crude solution and the acid aqueous solution in the back extraction step can be suitably performed by mixing and stirring both in a container. Usually, when stirring is continued for about 0.1 minute to 24 hours, PI-03 and the acid in the crude solution spontaneously form a salt, and the formed salt moves from the organic layer to the aqueous layer (back extraction). )

  As a container to be used, a glass container, a stainless steel container, a fluororesin container, a glass lining container, or the like can be used. The container is preferably equipped with a thermometer or a temperature sensor. Extraction is preferably performed by stirring with a mechanical stirrer, magnetic stirrer, or the like in such a container, and stirring is preferably performed with a stirring blade or the like for large-scale production. This is because, in the present invention, the organic layer containing PI-03 and the aqueous layer containing acid are in contact with each other, so that PI-03 is efficiently back-extracted into the aqueous layer by stirring and contacting. This is because it is effective to improve the efficiency.

  At this time, the temperature at which the crude solution and the acid aqueous solution are charged into the container, and further the temperature at the time of mixing the both are not higher than the boiling point of the solvent of the crude solution and the formed salt does not precipitate. What is necessary is just to determine suitably from the inside according to the property, quantity, etc. of the acid to be used or the acid salt to produce | generate. Considering the extraction efficiency into the aqueous layer and the separation efficiency with specific impurities, it is preferable to set the temperature within the temperature range of 10 ° C. to 80 ° C., particularly 20 ° C. to 50 ° C. and satisfying the above conditions. It is.

  The contact can be carried out under atmospheric pressure, under pressure, or under reduced pressure, but it is preferably carried out under atmospheric pressure in consideration of the load on the reaction vessel, apparatus and the like. In addition, the contact can be performed in the air or an inert gas such as nitrogen, argon, helium, or the like, and is preferably performed in the air in consideration of simplification of the apparatus.

  As described above, after bringing the crude product solution into contact with the acid aqueous solution and back-extracting the salt of PI-03 into the aqueous layer, the organic layer and the aqueous layer are separated, and the obtained aqueous layer is separated from the PI layer. What is necessary is just to take out -03 or its acid salt. Examples of the method for recovering as a salt include a method in which the separated aqueous layer is cooled or concentrated to precipitate salt crystals, or the aqueous layer is concentrated to dry the salt. In addition, as a method for recovering as PI-03, a base is introduced into the aqueous layer and neutralized to remove the acid radical to obtain free PI-03, which is precipitated as crystals, and the precipitated PI-03 And a method for obtaining PI-03 from which an organic solvent and a base have been removed in an aqueous layer and acid radicals have been extracted, and then concentrating and obtaining the organic solvent. By purifying PI-03 in this way, it is possible to produce high-purity PI-03 with reduced N, N′-dimethyl-4-nitroaniline (specific impurities).

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples. The various measurements and evaluation methods in the examples and comparative examples are as follows.

1. PI-03 purity and concentration evaluation of specific impurities The obtained PI-03 crude product or purified product thereof is dissolved in acetonitrile to prepare a sample solution, and the sample solution is subjected to high performance liquid chromatography (HPLC) measurement. Based on the results, the purity and specific impurity concentration of PI-03 were determined. Specifically, based on the chromatogram (chart) obtained by HPLC measurement, the ratio expressed as a percentage of the peak area derived from each substance with respect to the total area of all peaks derived from the measurement sample appearing in the chromatogram These values were determined as (HPLC area%). The apparatus and measurement conditions used for HPLC measurement are shown below.
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 269 nm
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 25 ° C. Mobile phase flow rate: 1.0 mL / min
Mobile phase and liquid delivery method: Using mobile phases A and B shown below, the concentration of the mobile phase is changed by changing the mixing ratio of both to the mixing ratio shown in Table 1 below according to the elapsed time after sample injection. The solution was fed under gradient control.
Mobile phase A: A mixed solution in which 2.3 g of sodium acetate was added to 1500 mL of water and dissolved, and then 1500 mL of acetonitrile and 60 mL of acetic acid were added.
Mobile phase B: A mixed solution in which 1.8 g of sodium acetate was added to 1200 mL of water and dissolved, and then 1800 mL of acetonitrile and 60 mL of acetic acid were added.

2. Extraction efficiency of PI-03 into the aqueous layer The extraction efficiency of PI-03 into the aqueous layer is determined by the amount of PI-03 contained in the whole aqueous layer obtained by liquid separation and the PI contained in the whole organic layer. It was evaluated as a ratio to the amount of -03 (water layer / organic layer). In addition, water layer / organic layer measured each sample solution prepared similarly from the water layer and the organic layer by HPLC similarly, and computed from the HPLC area value of obtained PI-03, and a following formula. Here, “S _O ” and “S _w ” in the following formulas mean the peak area of PIO-03 in the chromatogram obtained when HPLC measurement was performed on the sample solution prepared from the organic layer and the aqueous layer, respectively. , “V _O ” and “V _w ” mean the total volume (mL) of the organic layer and the total volume (mL) of the aqueous layer obtained when the liquids are separated, respectively.
Water layer / organic layer = (S _w × V _w ) / (S _O × V _O ).

3. PIO Purity and Evaluation of Concentration of Impurities Derived from Specific Impurities The purity of PIO and the amount of impurities derived from N, N′-dimethyl-4-nitroaniline (specific impurities) were measured by high performance liquid chromatography (HPLC). The following apparatus and conditions were employed as the apparatus used for HPLC measurement and the measurement conditions. In the HPLC analysis under these conditions, the retention time of PIO is around 5.0 minutes, and the retention time of impurities derived from the specific impurities is around 4.5 minutes.

Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 269 nm
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Mobile phase: A mixed solution in which 2.3 g of sodium acetate was added and dissolved in 1500 mL of water, and then 1500 mL of acetonitrile and 60 mL of acetic acid were added.
Flow rate: 1.0 mL per minute
Column temperature: constant temperature around 25 ° C

Example 1 (Production Example of PI-03)
(Production of crude 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene)
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 30.0 g (198.4 mmol) of 2- (5-ethyl-2-pyridyl) ethanol and 29.4 g (208.4 mmol) of 4-fluoronitrobenzene Was dissolved in 100 mL of N, N′-dimethylformamide and cooled to 0 ° C. Next, 11.9 g (297.5 mmol) of sodium hydroxide was added little by little so that the temperature of the reaction solution was 0 to 5 ° C., and the mixture was reacted at 0 to 5 ° C. for 9 hours. After completion of the reaction, 360 mL of cooled water was added, and the precipitated crystals were separated by filtration. The obtained tan crystals were dried at 40 ° C. for 12 hours under reduced pressure to obtain 50.9 g (186.9 mmol) of a crude product of PI-03 as tan crystals. (Yield: 94.2%, HPLC purity: 89.52%, specific impurities: 2.33%)
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 5.0 g (18.4 mmol) of a crude product of PI-03 containing 2.33% of specific impurities and 20 mL of diisopropyl ether obtained as tan crystals. The mixture was stirred and heated to 40 ° C. for dissolution. Subsequently, an acid aqueous solution prepared by separately mixing 10 mL of water and 9.4 g (25.7 mmol, 1.4 equivalents) of 10% hydrochloric acid was added and stirred for 1 hour. After completion of stirring, the organic layer and the aqueous layer were separated. When the obtained aqueous layer was measured by HPLC, the purity of PI-03 was 97.03% and the specific impurity was 0.43%. Moreover, the ratio of PI-03 contained in each layer was water layer / organic layer = 1.0 / 0.0.

Examples 2 to 13 (Production Examples of PI-03)
The same procedure as in Example 1 was conducted except that the type and amount of acid in Example 1, the type and amount of organic solvent, and the temperature were changed as shown in Table 2. The results are shown in Table 2.

Example 14 (PIO production example)
To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, the aqueous layer containing PI-03 hydrochloride obtained in Example 1 and 20 mL of diisopropyl ether were added and stirred, and the mixture was heated to 40 ° C. Subsequently, 11.0 g (27.5 mmol) of 10% sodium hydroxide was added and stirred at 40 ° C. for 30 minutes. After completion of the stirring, the organic layer and the aqueous layer were separated. The obtained organic layer was concentrated under reduced pressure to obtain PI-034.8 g (17.7 mmol).

  To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, PI-034.8 g (17.7 mmol), methanol 40 mL, and 10% Pd—C 0.5 g were added, and the mixture was stirred at 25 ° C. for 1 hour. After completion of stirring, the insoluble solid was filtered off and the resulting solution was concentrated. To the remaining oily substance, 20 mL of methanol and 20 mL of acetone were added and stirred, and then cooled to −8 ° C. After adding 9.5 g (55.2 mmol) of 47% hydrobromic acid, an aqueous solution prepared from 1.4 g (20.8 mmol) of sodium nitrite and 2.5 mL of water was added dropwise little by little. After the entire amount was dropped, the mixture was stirred at around −5 ° C. for 30 minutes, and then 18.3 g (212.2 mmol) of methyl acrylate was added. The resulting mixture was heated to 50 ° C., 0.32 g (2.3 mmol) of cuprous oxide was added, and the mixture was stirred at around 50 ° C. for 3 hours. After the stirring, the mixture was cooled to 20 ° C. and concentrated. After adding 20 mL of ethyl acetate and 10 mL of water to the obtained residue, it cooled to 5 degrees C or less. 5 mL of 20% aqueous ammonia was added at 5 ° C. or lower. After stirring for 15 minutes, the organic layer and the aqueous layer were separated, 10 mL of 20% sodium chloride aqueous solution was added to the obtained organic layer, and after stirring for 15 minutes, the organic layer and the aqueous layer were separated. 1 g of magnesium sulfate was added to the obtained organic layer, and after stirring, the insoluble solid was filtered off and the resulting solution was concentrated to obtain 5.2 g of a black oily substance.

  To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 5.2 g of the above black oil and 25 mL of methanol were added and stirred to obtain a black solution. Subsequently, 1.2 g (15.8 mmol) of thiourea and 1.2 g (15.0 mmol) of sodium acetate were added and heated to 70 ° C. After stirring at about 70 ° C. for 4 hours, the mixture was cooled to about 25 ° C. The precipitated solid was separated by filtration to obtain 1.8 g of a brown solid. To the obtained brown solid, 5 mL of dimethylacetamide and 1 mL of ethanol were added and heated to 115 ° C. Then, it cooled to 25 degreeC vicinity, the depositing solid was separated by filtration, and 1.3g of brown solid was obtained.

  To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 1.3 g of the above brown solid, 15 mL of water, and 1.5 g of concentrated hydrochloric acid were added and stirred. The resulting mixture was warmed to 110 ° C. and stirred at around 110 ° C. for 4 hours. After stirring, the mixture was cooled to around 25 ° C. The precipitated solid was separated by filtration to obtain 1.9 g of a crude PIO as a light brown solid.

  In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, the above (±) -5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione was added. The crude hydrochloride salt (1.9 g), methanol (5 mL), and concentrated hydrochloric acid (0.25 g) were added and stirred. The resulting mixture was warmed to 70 ° C. and then cooled to 25 ° C. Subsequently, the mixture was stirred at around 25 ° C. for 3 hours, and the precipitated solid was filtered off and dried at 40 ° C. to obtain 1.2 g of PIO as a white solid.

  When the obtained PIO was measured by HPLC, the purity of PIO was 99.64% and the impurity derived from the specific impurity was 0.02%.

Comparative Example 1 (Production Comparative Example of PI-03: Corresponds to the method described in Patent Document 1)
In a 50 mL three-necked flask equipped with a stirring blade and a thermometer, 5.0 g (18.4 mmol) of a crude product of PI-03 containing 2.33% of the specific impurity obtained in Example 1 and 10 mL of diethyl ether were obtained. Then, 25 mL of hexane was added and stirred, and heated to 50 ° C. to dissolve. After confirming that all of 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene was dissolved, it was gradually cooled to 5 ° C. or lower and held for 2 hours. The precipitated solid was filtered off and the cake was washed twice with 5 mL of hexane. The obtained yellow crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain PI-032.5 g (9.2 mmol) as yellow crystals. (Recovery rate: 50.0%, HPLC purity: 96.57%, specific impurities: 2.58%)

Comparative Example 2 (Production Comparative Example of PI-03: Corresponds to the method described in Patent Document 2)
In a 50 mL three-necked flask equipped with a stirring blade and a thermometer, 5.0 g (18.4 mmol) of a crude product of PI-03 containing 2.33% of the specific impurity obtained in Example 1 and 10 mL of methanol, 10 mL of water was added and stirred, and heated to 50 ° C. to dissolve. After confirming that all of PI-03 was dissolved, it was gradually cooled to 5 ° C. or lower and held for 2 hours. The precipitated solid was filtered off and the cake was washed twice with 5 mL of water. The obtained yellow crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain PI-032.8 g (10.3 mmol) as yellow crystals. (Recovery: 56.0%, HPLC purity: 96.77%, specific impurities: 2.67%)

Comparative Example 3 (Production Comparative Example of PI-03: Corresponds to the method described in Patent Document 3)
In a 50 mL three-necked flask equipped with a stirring blade and a thermometer, 10.0 g (36.4 mmol) of a crude product of PI-03 containing 2.33% of the specific impurity obtained in Example 1 and 20 mL of diisopropyl ether were obtained. The mixture was stirred and heated to 50 ° C. to dissolve. After confirming that all of PI-03 was dissolved, it was gradually cooled to 5 ° C. or lower and held for 2 hours. The precipitated solid was filtered off, and the cake was washed twice with 10 mL of diisopropyl ether. The obtained yellow crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain PI-037.4 g (27.2 mmol) as yellow crystals. (Recovery rate: 73.9%, HPLC purity: 97.00%, specific impurities: 2.64%)

Comparative Example 4 (Production Comparative Example of PI-03)
In a 100 mL three-neck flask equipped with a stirring blade and a thermometer, 5.0 g (18.4 mmol) of a crude product of PI-03 containing 2.33% of the specific impurity obtained in Example 1 and 20 mL of diisopropyl ether were obtained. The mixture was stirred and heated to 40 ° C. for dissolution. Subsequently, an acid aqueous solution prepared by separately mixing 10 mL of water and 13.2 g (36.8 mmol, 2.0 equivalents) of 10% hydrochloric acid was added and stirred for 1 hour. After completion of the stirring, the organic layer and the aqueous layer were separated. When the obtained aqueous layer was measured by HPLC, the purity of 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene was 77.72% and the specific impurity was 2.90%. Moreover, the organic layer was also measured by HPLC in the same manner as the aqueous layer. From the area value of PI-03 obtained in the measurement of each layer, the ratio of PI-03 contained in each layer was water layer / organic layer = 1.0 / 0.0.

Comparative Example 5 (Production Comparative Example of PI-03)
In a 100 mL three-neck flask equipped with a stirring blade and a thermometer, 5.0 g (18.4 mmol) of a crude product of PI-03 containing 2.33% of the specific impurity obtained in Example 1 and 20 mL of diisopropyl ether were obtained. The mixture was stirred and heated to 40 ° C. for dissolution. Subsequently, separately, an acid aqueous solution prepared by mixing 10 mL of water and 2.0 g (5.5 mmol, 0.3 equivalent) of 10% hydrochloric acid was added and stirred for 1 hour. After completion of the stirring, the organic layer and the aqueous layer were separated. When the obtained aqueous layer was measured by HPLC, the purity of PI-03 was 94.11% and the specific impurity was 2.48%. Moreover, the organic layer was also measured by HPLC in the same manner as the aqueous layer. From the area value of PI-03 obtained in the measurement of each layer, the ratio of PI-03 contained in each layer was water layer / organic layer = 1.0 / 7.7.

Comparative Example 6 (PIO production comparative example)
A method similar to Example 14 was used except for the step of returning PI-03 hydrochloride to PI-03 using 4.8 g of a crude product of PI-03, to obtain 1.1 g of PIO. When the obtained PIO was measured by HPLC, the purity of PIO was 99.02% and the impurity derived from a specific impurity was 0.21%.

Claims (3)

2- (5-ethyl-2-pyridyl) ethanol and 4-fluoronitrobenzene are reacted in the presence of a base in a reaction solvent consisting of N, N′-dimethylformamide to give 4- [2- (5-ethyl). 2-Pyridyl) ethoxy] nitrobenzene, and 4- [2- (5-ethyl-2-ethyl-2-phenyl-2-nitro-2-aniline) as an impurity from the reaction mixture obtained in the reaction step. A separation step of separating a crude product of pyridyl) ethoxy] nitrobenzene, and a solution obtained by dissolving the crude product in a water-insoluble or sparingly water-soluble organic solvent and an acid aqueous solution to bring about 4- It includes a back extraction step of forming a salt of [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene and extracting the formed salt into an aqueous phase. Chill-2-pyridyl) ethoxy] nitrobenzene or a salt thereof. In the back extraction step, an acid aqueous solution containing 0.5 to 1.8 equivalents of acid per 1 mol of 4- [2- (5-ethyl-2-pyridyl) ethoxy] nitrobenzene is brought into contact with the solution as the acid aqueous solution. The method according to claim 1, wherein: 3. The method according to claim 1, wherein an aqueous solution of hydrochloric acid, sulfuric acid or hydrobromic acid is used as the aqueous acid solution in the back extraction step.