JP5441913B2 - Method for producing carbonyloxy compound - Google Patents

Description

  The present invention relates to a novel method for producing a carbonyloxy compound produced using an aniline compound and an α, β-unsaturated carbonium compound as raw materials. In particular, the present invention relates to a novel method for producing a carbonyloxy compound that is useful as a raw material for producing a drug substance or an intermediate used in the treatment of type 2 diabetes caused by insufficient insulin action.

  A therapeutic agent that exhibits an excellent effect on type 2 diabetes caused by insufficient action of insulin, such as pioglitazone, ciglitazone, and rosiglitazone (formula (10) shows the basic skeleton of the therapeutic agent) has conventionally been represented by the following formula: It is produced by a method via a carbonyloxy compound represented by (8).

The carbonyloxy compound represented by the formula (8) is produced by the Meerwein arylation reaction using the aniline compound represented by the formula (7). (For example, refer nonpatent literature 1 and patent literature 1). This reaction is a reaction in which a diazonium salt produced by reacting a nitrite with an aniline compound represented by the formula (7) in the presence of hydrogen bromide and a carbonyl compound are reacted in the presence of a copper catalyst. It is.
Journal of Medicinal Chemistry 35, 14, 2617-2626 (1992) Japanese Patent Publication No. 5-66956

  As described above, according to the methods described in Non-Patent Document 1 and Patent Document 1, a carbonyloxy compound represented by Formula (8) can be produced.

  However, in the Meerwein arylation reaction, various side reactions proceed simultaneously. Therefore, when producing a carbonyloxy compound by the above reaction, there is room for further improvement in terms of yield and purity. In particular, when the carbonyloxy compound represented by formula (8), which is an intermediate of the drug substance, contains impurities, it is difficult to obtain a high-purity drug substance in a high yield. Therefore, in the reaction for producing the carbonyloxy compound, it is particularly desired to suppress the generation of impurities.

  An object of the present invention is to provide a method for producing a carbonyloxy compound having a high yield and a high purity.

  In order to solve the above problems, the present inventor has conducted earnest research. As a result, a diazonium salt is synthesized by reacting an aniline compound and nitrite in the presence of an acid, and then Meerwein arylation using the diazonium salt and an α, β-unsaturated carbonyloxy compound in the presence of a copper catalyst. It has been found that, when a reaction is carried out, if a base having a specific acid dissociation index is present in the reaction system, side reactions are suppressed and a high-purity carbonyloxy compound can be produced in a high yield. The present invention has been completed based on the above discovery.

That is, the present invention
In the presence of hydrogen chloride or hydrogen bromide,
Following formula (1)

(Where
R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or an organic group. n is an integer of 1-5. When n is 2 or more, R ¹ may be the same group or different groups. )
A diazonium salt synthesis step of synthesizing a diazonium salt by reacting an aniline compound represented by formula (II) with a nitrite, and a diazonium salt obtained in the diazonium salt synthesis step in the presence of a copper catalyst;

(Where
R ² is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group.

R ³ is a hydrogen atom, an alkyl group, or an aryl group. )
Is reacted with an α, β-unsaturated carbonyloxy compound represented by the following formula (3):

(Where
R ¹ and n have the same meaning as in formula (1),
R ² and R ³ have the same meaning as in the formula (2),
X is a chlorine atom or a bromine atom. )
A carbonyloxy compound synthesis step for synthesizing a carbonyloxy compound represented by:
A method for producing a carbonyloxy compound comprising:
In the carbonyloxy compound synthesis step, when the diazonium salt and the α, β-unsaturated carbonyloxy compound are reacted, a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present in the reaction system. And a method for producing a carbonyloxy compound.

  In the carbonyloxy compound synthesis step, it is preferable that 0.05 to 10 mol of the base is present per 1 mol of the diazonium salt.

    The base is preferably a nitrogen-containing heterocyclic compound having an acid dissociation index (pKa) at 25 ° C. of 4 to 7.

  The production method of the present invention includes a method for producing methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate, which is an intermediate of pioglitazone hydrochloride. This production method can effectively reduce side reactions.

  In addition, the production method of the present invention comprises methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate produced according to the above production method in the presence of an alkali. A method for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone, characterized by reacting with urea.

  Furthermore, the present invention is characterized in that 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone produced according to the above method is reacted with hydrogen chloride. And 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride.

  According to the present invention, a high purity carbonyloxy compound can be produced in high yield by the presence of a predetermined base in the Meerwein arylation reaction. Since the carbonyloxy compound produced by the high-yield production method of the present invention has a high purity, it is particularly useful as a raw material or intermediate for a drug substance. Therefore, this manufacturing method has very high industrial utility value.

  In particular, according to the present invention, 2-bromo-3- {useful as a raw material for 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride. Methyl 4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate can be produced in high yield and purity.

    Since methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate produced by the production method of the present invention has high purity, By reacting with thiourea, high-purity 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone can be produced in high yield.

    Further, by reacting high purity 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone obtained by the above method with hydrogen chloride, Pure 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride can be produced in high yield.

  The method for producing a carbonyloxy compound represented by formula (3) of the present invention comprises reacting an aniline compound represented by formula (1) with a nitrite in the presence of hydrogen chloride or hydrogen bromide to form a diazonium salt. In the presence of a copper catalyst, the diazonium salt produced in the diazonium salt synthesis step and the α, β-unsaturated carbonyloxy compound represented by the formula (2) are reacted in the presence of a copper catalyst, A carbonyloxy compound synthesis step for synthesizing the carbonyloxy compound represented by the formula (3) is included.

    Furthermore, the method for producing the carbonyloxy compound represented by the formula (3) includes an acid dissociation index at 25 ° C. when the diazonium salt and the α, β-unsaturated carbonyloxy compound are reacted in the carbonyloxy compound synthesis step. A base having (pKa) of 7 or less is present in the reaction system.

    Hereinafter, the present invention will be described step by step.

Diazonium salt synthesis step In the diazonium salt synthesis step, a diazonium salt derived from the aniline compound is synthesized by reacting the aniline compound represented by the formula (1) with nitrite in the presence of hydrogen chloride or hydrogen bromide. It is a process to do.

(Aniline compound)
In the diazonium salt synthesis step, the aniline compound used as a raw material is represented by the following formula (1):

(Where
R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or an organic group. n is an integer of 1-5. When n is 2 or more, R ¹ may be the same group or different groups. )
It is a compound shown by these.

  As the aniline compound, a reagent or an industrial raw material can be used without any limitation.

In the production method of the present invention, the aniline compound represented by the formula (1) is a functional group such as a hydroxyl group or a cyano group even if R ¹ is an atom such as a hydrogen atom or a halogen atom. May be. Furthermore, R ¹ may be an organic group.

When R1 is an organic group, the organic group is not particularly limited. However, in view of the usefulness of the finally obtained carbonyloxy compound and the purity and yield of the obtained carbonyloxy compound, the organic group of R ¹ is represented by an alkyl group or the following formula (4). A group having an ether bond is preferred.

Where
R ⁴ is preferably an alkyl group, an aryl group, or a group represented by the following formula (5) or the following formula (6).

(In Formula (5),
R ⁵ and R ⁶ are each a hydrogen atom or an alkyl group. m is an integer of 1-3. )

(In Formula (6),
R ⁷ and R ⁸ are each a hydrogen atom or an alkyl group. )
When the group R ¹ in the aniline compound represented by the formula (1) is an alkyl group, considering the reactivity and the usefulness of the resulting carbonyloxy compound, the group R ¹ is an alkyl having 1 to 6 carbon atoms. It is preferably a group. When the group R ¹ is an alkyl group, specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, and a hexyl group. Group or a cyclohexyl group.

When the group R ¹ in the aniline compound represented by the formula (1) is a group represented by the formula (4) and R ⁴ is an alkyl group, the alkyl group has 1 to 6 carbon atoms. Alkyl groups are preferred. Specific examples of the alkyl group include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, isopentyl group, hexyl group, or cyclohexyl group.

When the group R ¹ in the aniline compound represented by the formula (1) is a group represented by the formula (4) and R ⁴ is an aryl group, examples of the aryl group include a phenyl group or benzyl Groups and the like.

When the group R ¹ in the aniline compound represented by the formula (1) is a group represented by the formula (4) and R ⁴ is a group represented by the formula (5), the group R ⁵ , and The groups R ⁶ are each a hydrogen atom or an alkyl group. m is an integer of 1-3. In the case where the group R ⁵ and the group R ⁶ are alkyl groups, the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and specific examples thereof include the same groups as the alkyl groups described for the group R ^1. .

When the group R ¹ in the aniline compound represented by the formula (1) is a group represented by the above formula (4) and R ⁴ is a group represented by the above formula (6), the group R ⁷ , and the group R ⁸ is each a hydrogen atom or an alkyl group. The alkyl group, an alkyl group having 1 to 6 carbon atoms preferably, and specific examples thereof include the same groups as the alkyl group described for radicals R ^1.

In the formula (1), n in an integer of 1 to 5, indicating the number of groups ^{R 1.} When n is an integer of 2 or more, each group R ¹ may be a different group or the same group. Considering the usefulness of the obtained carbonyloxy compound and the purity and yield of the obtained carbonyloxy compound, n is preferably 1 to 2.

  Specific examples of the aniline compound represented by the formula (1) are shown below. However, the present invention is not limited to the case where these aniline compounds are used as raw materials.

    According to the present invention, the above aniline compound is employed, and in the carbonyloxy compound synthesis step, the presence of a specific amine in the reaction system suppresses the formation of by-products, and the high purity and high purity carbonyloxy compound is obtained. Can be obtained. As a result, the production method of the present invention can be suitably employed for the production of a carbonyloxy compound that is an intermediate of a drug substance. When the aniline compound is 4- [2- (5-ethyl-2-pyridyl) ethoxy] aniline, the drug substance can be produced more efficiently.

(Hydrogen chloride, hydrogen bromide)
In the diazonium salt synthesis step, the aniline compound and nitrite are reacted in the presence of hydrogen chloride or hydrogen bromide to synthesize a diazonium salt derived from the aniline compound.

  As hydrogen bromide or hydrogen chloride, reagents or industrial raw materials can be used without any limitation. Hydrogen chloride or hydrogen bromide is preferably hydrochloric acid or hydrobromic acid in an aqueous solution from the viewpoint of easy handling (hereinafter, hydrochloric acid and hydrobromic acid are collectively referred to as “acid”. May be displayed.) The higher the acid concentration, the higher the reaction rate, and the generation of impurities is suppressed. Therefore, in the case of hydrochloric acid, it is preferable to use general-purpose concentrated hydrochloric acid having a hydrogen chloride concentration of about 35% by mass. In the case of hydrobromic acid, it is preferable to use general-purpose hydrobromic acid having a hydrogen bromide concentration of about 47% by mass.

Stoichiometrically, the amount of acid used is twice the molar amount of the aniline compound. Therefore, the amount of acid used is preferably 2 mol or more of hydrogen chloride or hydrogen bromide with respect to 1 mol of the aniline compound. When the group R ¹ of the aniline compound of the formula (1) is a functional group that forms a salt with an acid, it is preferable to increase the amount of acid used in consideration of the amount of the salt. For example, when the group R ¹ is a basic group such as a pyridyl group and forms a salt with an acid, the amount of acid used is increased according to the number of groups R ¹ . For example, when one basic group R ¹ is bonded to an aniline compound (when n = 1), the preferred amount of hydrogen chloride or hydrogen bromide to be used is 3 to 1 mol per aniline compound. 5 moles.

  As described above, the production method of the present invention can be suitably applied to a method for producing a carbonyloxy compound that is an intermediate of a drug substance. When 4- [2- (5-ethyl-2-pyridyl) ethoxy] aniline is used as the aniline compound, the acid used is an odor in consideration of the good yield of the carbonyloxy compound obtained. Hydrohydric acid is preferred.

(Nitrite)
As the nitrite used in the present invention, reagents or industrial raw materials can be used without any limitation. Examples of the nitrite include sodium nitrite and potassium nitrite.

  From the viewpoint of increasing the yield of the diazonium salt, the amount of nitrite used is preferably 1 mol or more per 1 mol of the aniline compound. In view of economy, the amount of nitrite used is more preferably 1 to 5 mol, further preferably 1 to 3 mol, and more preferably 1 to 2 mol, relative to 1 mol of the aniline compound. It is particularly preferable that

    Nitrite may be added directly to the reaction solution as it is in the solid state. However, in general, it is preferable to add an aqueous solution of nitrite dropwise to the reaction solution. In this case, considering the solubility and economical efficiency of nitrite, the amount of water for dissolving nitrite is preferably 1 to 3 ml, more preferably 1.2 to 2.5 ml, with respect to 1 g of nitrite.

(Other reaction conditions)
The conditions for synthesizing the diazonium salt in the diazonium salt synthesis step are determined in consideration of improvement of the reaction rate, adjustment of the reaction temperature, reduction of side reaction products, and the like. The synthesis reaction is preferably carried out in an organic solvent. The organic solvent is preferably compatible with water. Specific examples include ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, and nitriles such as acetonitrile. As these organic solvents, reagents or solvents for industrial raw materials can be used without any limitation. A solvent can also be used individually or in mixture of 2 or more types. As the solvent for increasing the reaction rate, the solubility of the raw material, the solubility of the obtained diazonium salt, and the selectivity of the obtained diazonium salt, ketones and alcohols are preferable. Moreover, these mixed solvents are also preferable.

    The amount of the organic solvent or the mixed solvent used is preferably 5 to 25 ml, more preferably 7 to 20 ml, with respect to 1 g of the aniline compound to be used in consideration of economy and reduction of side reaction products.

  In the synthesis reaction of the diazonium salt synthesis step, there are no particular limitations on the method of mixing and adding hydrogen chloride or hydrogen bromide, the aniline compound represented by the formula (1), and the nitrite. For example, the acid, aniline compound, and nitrite may be simultaneously introduced into the reaction vessel and mixed. Alternatively, there is a method in which two components are mixed in advance, and other components are added to the mixed solution and mixed.

    In order to suppress side reactions, the following mixing method is preferred. That is, it is a method in which nitrite is added to a mixed solution obtained by mixing the aniline compound and acid dissolved or dispersed in an organic solvent as necessary. Nitrite is preferably added in the form of an aqueous solution.

  In the reaction for synthesizing the diazonium salt, the reaction temperature is preferably 0 to 15 ° C, more preferably 0 to 10 ° C. When the reaction temperature exceeds 15 ° C., side reactions tend to occur. During the reaction, the reaction solution is preferably stirred. The reaction time is not particularly limited. The reaction time is preferably 0.01 to 10 hours with stirring, and more preferably 0.1 to 5 hours.

  In the diazonium salt synthesis step, a diazonium salt corresponding to the raw material aniline compound is generated by performing the reaction according to the above reaction conditions. The resulting diazonium salt is reacted with an α, β-unsaturated carbonyloxy compound in the subsequent carbonyloxy compound synthesis step.

    The resulting diazonium salt may be purified before reacting with the α, β-unsaturated carbonyloxy compound in the next step. However, the diazonium salt is an unstable compound. Therefore, it is preferable to use the obtained diazonium salt as it is for the next carbonyloxy compound synthesis step without purifying the diazonium compound. For the above reasons, in the next carbonyloxy compound synthesizing step, it is preferable to directly use the solution (reaction product solution) containing the diazonium salt produced according to the above-mentioned method without purification. In the case of using an organic solvent in the reaction of the diazonium salt synthesis step, the solution (reaction product liquid) contains an organic solvent.

Carbonyloxy compound synthesis step In the carbonyloxy compound synthesis step, the diazonium salt obtained in the diazonium salt synthesis step is reacted with the α, β-unsaturated carbonyloxy compound represented by the formula (2) in the presence of a copper catalyst. In this step, the carbonyloxy compound represented by the formula (3) is synthesized. The greatest feature of the present invention, which will be described in detail below, is that, in this step, a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present in the reaction system.

(Α, β-unsaturated carbonyloxy compounds)
In the present invention, the α, β-unsaturated carbonyloxy compound to be reacted with the diazonium salt is represented by the following formula (2):

(Where
R ² is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group.

R ³ is a hydrogen atom, an alkyl group, or an aryl group. )
Indicated by

When the group R ² is an alkyl group, the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms. When the alkyl group has 1 to 6 carbon atoms, the reactivity is high, and the usefulness of the resulting carbonyloxy compound is high. Specific examples of the preferred alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, a hexyl group, and a cyclohexyl group. .

When group R ² is an alkenyl group, examples of the alkenyl group include an allyl group having 2 to 6 carbon atoms and a vinyl group.

When group R ² is an aryl group, examples of the aryl group include a phenyl group having 6 to 12 carbon atoms, a benzyl group, and the like.

When the group R ³ is an alkyl group or an aryl group, examples of the alkyl group or aryl group include the same groups as those exemplified for the group R ² .

  As the α, β-unsaturated carbonyloxy compound represented by the formula (2), any reagent or industrial raw material can be used without any limitation. The α, β-unsaturated carbonyloxy compound is determined according to the carbonyloxy compound to be synthesized.

    When emphasizing the production of the carbonyloxy compound represented by the formula (3), which is highly useful and reactive, the α, β-unsaturated carbonyloxy compound includes acrylic acid, methyl acrylate, acrylic acid Ethyl, butyl acrylate, isobutyl acrylate, t-butyl acrylate, methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, t-butyl methacrylate, allyl methacrylate, vinyl methacrylate, methacryl Preference is given to benzyl acid, cinnamic acid, methyl cinnamate, ethyl cinnamate, benzyl cinnamate, vinyl cinnamate and the like.

    When especially considering the usefulness of the obtained carbonyloxy compound, as the α, β-unsaturated carbonyloxy compound, methyl acrylate or ethyl acrylate is preferable. Furthermore, when importance is attached to the ease of purification of the resulting carbonyloxy compound, methyl acrylate is preferred as the α, β-unsaturated carbonyloxy compound.

  The amount of the α, β-unsaturated carbonyloxy compound represented by the formula (2) is preferably 1 mol or more and more preferably 2 mol or more with respect to 1 mol of the diazonium salt used in the reaction. When the amount is less than 1 mol, the yield decreases. The upper limit of the amount of α, β-unsaturated carbonyloxy compound used is not particularly limited, but in consideration of the operability and economics of post-treatment after the reaction, a diazonium salt derived from an aniline compound 50 mol is preferable with respect to 1 mol, and 40 mol is more preferable.

(Copper catalyst)
As the copper catalyst used in the carbonyloxy compound synthesis step, any reagent or industrial raw material can be used without any limitation. Examples of the copper catalyst that can be used include copper (I) oxide, copper (II) oxide, copper (I) bromide, copper (II) bromide and the like. The amount of copper catalyst used is the same as the usual amount of catalyst. Specifically, 0.01 to 0.2 mol is preferable and 0.02 to 0.1 mol is more preferable with respect to 1 mol of the diazonium salt derived from the aniline compound. When the amount is less than 0.01 mol, the reaction time tends to be long. When it exceeds 0.2 mol, it becomes difficult to shorten the reaction time in proportion to the amount of copper catalyst used.

(Base having an acid dissociation index (pKa) at 25 ° C. of 7 or less)
The greatest feature of the present invention is that in this carbonyloxy compound synthesis step, a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present in the reaction system. Even when a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is not present in the reaction system, the reaction for synthesizing the carbonyloxy compound proceeds. However, when a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present, a high-purity carbonyloxy compound represented by the formula (3) can be obtained in a high yield.

  When a base having an acid dissociation index (pKa) at 25 ° C. of more than 7 is present, the purity and yield of the obtained carbonyloxy compound are lowered. The lower limit of the acid dissociation index (pKa) at 25 ° C. of the base that can be used is 4 considering the availability of the base.

  As the base having an acid dissociation index (pKa) at 25 ° C. of 7 or less used in the present invention, a reagent or a base for industrial raw materials can be used without any limitation. Examples of the base that can be used include pyridine (5.42), 2-methylpyridine (5.95), 3-methylpyridine (5.76), 4-methylpyridine (6.04), 2,4-dimethylpyridine ( 6.63), 2,6-dimethylpyridine (6.90), 2,2′-bipyridyl (pKa2 = 4.42), 4,4′-bipyridyl (pKa2 = 4.77), 1,10-phenanthroline (PKa2 = 4.98), o-phenylenediamine (pKa2 = 4.63), quinoline (4.97), 1-methylimidazole (6.95) and the like. In addition, the value described in parentheses indicates an acid dissociation index at 25 ° C.

    Among these bases, nitrogen-containing heterocyclic compounds are particularly preferable. By making these bases exist in the reaction system, a high-purity carbonyloxy compound can be obtained in a high yield. That is, in the carbonyloxy compound synthesis step, the base to be present in the reaction system is particularly preferably a nitrogen-containing heterocyclic compound having an acid dissociation index (pKa) at 25 ° C. of 4 or more and 7 or less. Here, the nitrogen-containing heterocyclic compound refers to a heterocyclic compound containing at least one nitrogen atom in the heterocyclic ring.

    Examples of preferred nitrogen-containing heterocyclic compounds include pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,6-dimethylpyridine, 2,2′-bipyridyl, 4 , 4′-bipyridyl, 1,10-phenanthroline, 1-methylimidazole and the like. Among these nitrogen-containing heterocyclic compounds, a compound having a pyridine ring is particularly preferable in view of the selectivity of the reaction and ease of operability. Specific examples include pyridine compounds such as pyridine and 2-methylpyridine, and bipyridyl compounds such as 2,2'-bipyridyl and 4,4'-bipyridyl.

  0.05-10 mol is preferable with respect to 1 mol of diazonium salt derived from an aniline compound, and, as for the usage-amount of this base, 0.1-5 mol is more preferable. Within the range of the use amount of the base, preferable effects such as reaction selectivity, yield, purity improvement, operability improvement, economy and the like are exhibited.

  In the present invention, the above effect is exhibited by the presence of a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less. The reason for this has not been elucidated.

    The present inventors considered that a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less interacts with a copper catalyst to suppress the Sandmeyer reaction, which is a side reaction of the Meerwein arylation reaction. Yes.

(Other reaction conditions)
In the carbonyloxy compound synthesis step, the reaction conditions other than the above are not particularly limited. There are no particular limitations on the method of adding each component and the method of mixing in the carbonyloxy compound synthesis step.

    The following methods can be illustrated as a method for adding each component and a mixing method. That is, the reaction proceeds by mixing the α, β-unsaturated carbonyloxy compound and the base with the solution containing the diazonium salt, and further adding and mixing the copper catalyst. Alternatively, the reaction proceeds by adding a solution containing a diazonium salt dropwise to the mixture of the α, β-unsaturated carbonyloxy compound and the base in the presence of a copper catalyst and mixing them.

    In the above case, the copper catalyst can be added to the mixture of the α, β-unsaturated carbonyloxy compound and the base simultaneously with the solution containing the diazonium salt. Furthermore, a copper catalyst can be added to the mixture in advance. In consideration of ease of reaction control, simplification of the apparatus, etc., it is preferable to previously mix a copper catalyst with the mixture of the α, β-unsaturated carbonyloxy compound and the base.

    When the α, β-unsaturated carbonyloxy compound is in a solid state at the reaction temperature, the reaction is performed in the state of a mixture (mixture) of the α, β-unsaturated carbonyloxy compound and the base using an organic solvent. It is preferable to make it. On the other hand, when the α, β-unsaturated carbonyloxy compound is in a liquid state at the reaction temperature, the mixture is in the form of a mixture (mixture) of the α, β-unsaturated carbonyloxy compound and the base without using an organic solvent. You may make it react.

  If the reaction temperature is excessively high, side reactions tend to occur. On the other hand, when it is too low, the reaction rate decreases. Therefore, 10-60 degreeC is preferable and, as for reaction temperature, 15-50 degreeC is more preferable.

    The reaction time is not particularly limited. What is necessary is just to determine suitably, confirming the progress of reaction. Generally, when controlling reaction time within the said temperature range, 0.1 to 10 hours are preferable and 0.5 to 5 hours are more preferable. It is preferable to stir during the reaction.

  By reacting under the reaction conditions of the carbonyloxy compound synthesis step, a reaction product solution is obtained. The resulting reaction product solution is neutralized with an alkaline aqueous solution such as aqueous ammonia according to a conventional method, and then subjected to an extraction treatment using a solvent such as ethyl acetate. Next, the extraction solvent is separated from the reaction product solution. Then, the carbonyloxy compound shown by following formula (3) can be obtained by distilling an extraction solvent off.

  The carbonyloxy compound represented by the formula (3) thus obtained may be further purified by a known method such as crystallization, distillation, column purification, etc., depending on the intended use.

(Carbonyloxy compound)
In the present invention, a carbonyloxy compound represented by the following formula (3) can be synthesized by performing each reaction of the diazonium salt synthesis step and the carbonyloxy compound synthesis step.

(Where
R ¹ and n have the same meaning as in formula (1),
R ² and R ³ have the same meaning as in the formula (2),
X is a chlorine atom or a bromine atom. )

In the formula (3), the groups R ¹ , R ² , and R ³ are functional groups determined according to the aniline compound and the α, β-unsaturated carbonyloxy compound to be used.

    The group X is a functional group determined according to the acid used (hydrogen chloride (hydrochloric acid) or hydrogen bromide (hydrobromic acid)).

    Therefore, hydrogen bromide is used as the acid, 4- [2- (5-ethyl-2-pyridyl) ethoxy] aniline is used as the aniline compound, and methyl acrylate is used as the α, β-unsaturated carbonyloxy compound. Is used, methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate useful as an intermediate of the drug substance is produced.

Production of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone According to the production method of the present invention, a high-purity carbonyloxy compound is obtained in a high yield. Can be manufactured. According to the production method of the present invention, as the carbonyloxy compound represented by the formula (3), 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] represented by the following formula (11): In the case of producing methyl phenyl} propionate, the compound represented by the formula (11) can be obtained with high purity and high yield.

    Therefore, by using this compound, 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino represented by the formula (12) which is a useful intermediate of the drug substance -4-thiazolidinone and 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride represented by formula (13) as a useful drug substance It can be manufactured efficiently.

  Hereinafter, methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate represented by the formula (11) produced by the present production method is used. A method for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone represented by 12) will be described.

  The production method itself of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone represented by the formula (12) is a known method. For example, the method described in Patent Document 1 can be used.

    Specifically, by using an organic solvent such as ethanol as a reaction solvent and reacting a compound represented by the formula (11) with thiourea in the presence of an alkali, 5- { 4- [2- (5-Ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone can be efficiently produced.

    Examples of the alkali include lithium acetate, sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy potassium, sodium hydride, sodium methoxide, sodium ethoxide, Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like are preferable.

    As for the usage-amount of an alkali, 1-3 mol is preferable with respect to 1 mol of compounds shown by Formula (11). As for the usage-amount of thiourea, 1-3 mol is preferable with respect to 1 mol of compounds shown by Formula (11). The reaction temperature is preferably 25 to 120 ° C., and the reaction time is preferably 1 to 50 hours. The addition method of alkali and thiourea is not particularly limited, and all components may be mixed and reacted at the reaction temperature for the above time.

  After reacting under the conditions as described above, the reaction solution is cooled to give 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl}-represented by the formula (12). Crystals of 2-imino-4-thiazolidinone are precipitated. Furthermore, in order to improve the yield, the reaction solution is concentrated under reduced pressure, and the resulting residue is neutralized with a saturated aqueous sodium carbonate solution, and then added with water and ether, and cooled to obtain the formula (12). Crystals of the compound shown are obtained. This crystal can be purified by a usual method. For example, it can be purified by a method of washing with water and drying. The resulting compound represented by the formula (12) can be used in the next reaction.

  The compound of the formula (11) obtained by the production method of the present invention has a high purity and a high yield. Therefore, in comparison with the conventional method, when the compound of the formula (11) obtained by the method of the present invention is used, the compound represented by the formula (12) can be obtained in a high yield.

  Next, a method for converting the compound of the formula (12) produced by the above production method into its hydrochloride will be described.

Production of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride As described above, a method for producing a compound represented by the formula (12) of the present invention Has a high yield and a low impurity content. As a result, by using the compound of formula (12) as a raw material, 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2 represented by formula (13) 4-dione hydrochloride can be obtained in high yield.

  Hereinafter, a method for producing the compound represented by the formula (13) will be exemplified.

    First, 1 mol of the compound represented by the formula (12) obtained by the above method is dissolved in an aqueous solution containing 3 to 20 mol of hydrogen chloride, and then heated at reflux temperature for 0.5 to 10 hours for hydrolysis. Do. Subsequently, the compound shown by Formula (13) precipitates by cooling the obtained aqueous solution. This crystal can be purified by a known method.

  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.

Example 1
(Diazonium salt synthesis process)
0.47 g (5 mmol) of aniline was dissolved in 4.6 ml of methanol and 5.7 ml of acetone, cooled to 10 ° C., and 1.76 g of 47% by mass of hydrobromic acid (10.2 mmol of hydrogen bromide) was added. The solution containing aniline and hydrobromic acid was cooled to 2 ° C. While keeping the solution containing aniline and hydrobromic acid not exceeding 5 ° C., an aqueous nitrous acid solution was added dropwise to the stirring solution. The aqueous nitrous acid solution was prepared by dissolving 0.35 g (5.7 mmol) of sodium nitrite in 0.7 ml of water. A nitrous acid aqueous solution was added dropwise, and the mixture was stirred at 3 ° C. for 20 minutes to synthesize a diazonium salt.

    This diazonium salt was subjected to the next reaction without being purified and contained in the solution. In addition, when the purity of the diazonium salt was confirmed by HPLC (high performance liquid chromatography), the purity was 99.0% by mass, and the diazonium salt was quantitatively synthesized. That is, almost the entire amount of aniline was a diazonium salt.

(Carbonyloxy compound synthesis process)
In a separate container, 5.14 g (10 mmol) of methyl acrylate, 1.19 g of pyridine (15 mmol, acid dissociation index at 25 ° C. (pKa) = 5.42), 0.091 g (0.63 mmol) of copper (I) bromide ) And the temperature was raised to 47 ° C. Then, stirring the mixed solution containing methyl acrylate, pyridine, and copper (I) bromide heated to 47 ° C., the solution containing the diazonium salt produced in the diazonium salt synthesis step was added to the mixed solution. It was added dropwise over 30 minutes. After the dropwise addition, the reaction solution was further stirred at 47 ° C. for 2 hours, and then the solvent was distilled off. To the obtained residue, 20 ml of ethyl acetate and 10 ml of 28% by mass ammonia water were added. The separated organic layer was washed with water and dried. Then, the solvent of the organic layer was distilled off. As a result, 1.08 g of methyl 2-bromo-3-phenylpropionate was obtained as a carbonyloxy compound. When purity was confirmed by HPLC, purity was 81.2 mass%. Therefore, the yield of methyl 2-bromo-3-phenylpropionate was 72.3%.

Examples 2-6
In the diazonium salt synthesis step of Example 1, the same operation as in Example 1 was performed except that the aniline compound shown in Table 1 was used instead of aniline. The results are shown in Table 1. The diazonium salt obtained in the diazonium salt synthesis step of each example had a purity of 99.0% by mass or more. Therefore, the diazonium salt has been synthesized quantitatively.

Examples 7-11
In the carbonyloxy compound synthesis step of Example 1, 2,2′-bipyridyl (acid dissociation index at 25 ° C. (pKa) = 4.42) in place of pyridine was 1.5 with respect to the aniline compounds shown in Table 2. The same operation as in Example 1 was carried out except that a double molar equivalent (an amount corresponding to 1.5 mol of 2,2′-bipyridyl relative to 1 mol of the diazonium salt) was used. The results are shown in Table 2.

Examples 12-14
In the carbonyloxy compound synthesis step of Example 1, an experiment similar to Example 1 was performed, except that the compound shown in Table 3 (α, β-unsaturated carbonyloxy compound) was used instead of methyl acrylate. . The results are shown in Table 3.

Comparative Example 1
The same operation as in Example 1 was performed except that pyridine was not added in Example 1. As a result, 1.07 g (yield 52.8%) of methyl 2-bromo-3-phenylpropionate having an HPLC purity of 60.0% by mass was obtained.

Comparative Examples 2-6
In Examples 2 to 6, the same operations as in Examples 2 to 6 were performed except that pyridine was not added. The results are shown in Table 4.

Comparative Example 7
In Example 5, the same operation as in Example 5 was performed except that triethylamine (acid dissociation index (pKa) at 25 ° C. = 10.72) was used instead of pyridine. As a result, 1.68 g of methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate having an HPLC purity of 12.7% by mass (yield 10.9%) )Obtained.

Examples 15-19
In the carbonyloxy compound synthesis step of Example 1, 1-methylimidazole (acid dissociation index at 25 ° C. (pKa) = 6.95) was used for the aniline compounds shown in Table 5 instead of pyridine. The same operation as in Example 1 was performed. The results are shown in Table 5.

Example 20 (Production of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone)
1.73 g (purity 82.1%) of methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate obtained in Example 5 was added to a Dimroth reflux tube. A three-necked flask equipped with a thermometer was charged. Next, 9 ml of ethanol and 0.55 g of thiourea were added to dissolve methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate. Sodium acetate 0.59g was added and it recirculate | refluxed for 4 hours. After refluxing, the crystals were precipitated by cooling. The precipitated crystals are filtered, washed with water, and dried to give slightly yellow crystals of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. 16 g (90.1% yield, 65.2% overall yield from aniline compound) was obtained. When purity was confirmed by HPLC, purity was 99.01 mass%.

Example 21 (Production of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride)
A 3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone 1.16 g obtained in Example 20 was equipped with a Dimroth reflux tube and a thermometer 3 9.8 mL of 1.0 mol / L hydrochloric acid aqueous solution was added to the necked flask and dissolved at room temperature. Stirring was performed for 4 hours while the solvent was refluxed to hydrolyze 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. After the reaction, when the obtained reaction solution was cooled to 5 ° C. over 1.5 hours, crystals were precipitated. The obtained crystals were filtered and dried under vacuum for 12 hours to obtain white crystals of (5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride. 1.16 g (yield 90.2%, total yield 58.8% from the aniline compound) was obtained, and the purity was confirmed to be 99.1% by mass.

Comparative Example 8 (Production of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone)
1.67 g (purity 59.6%) of methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate obtained in Comparative Example 5 was added to a Dimroth reflux tube. A three-necked flask equipped with a thermometer was charged. Next, 9 ml of ethanol and 0.34 g of thiourea were added to dissolve methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate. Sodium acetate 0.37g was added and it recirculate | refluxed for 4 hours. After refluxing, the crystals were precipitated by cooling. The precipitated crystals were filtered, washed with water, and dried to obtain 0.80 g (yield) of a slightly yellow crystal of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. The rate was 88.7%, and the overall yield from the aniline compound was 45.0%). When purity was confirmed by HPLC, purity was 98.98 mass%.

  In Comparative Example 8, since no base was present in the carbonyloxy compound synthesis step, the purity of the carbonyloxy compound was as low as 59.6%. Since this low-purity carbonyloxy compound was used to synthesize 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone, The overall yield was as low as 45.0%.

Comparative Example 9 (Production of 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride)
A 3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone 0.80 g obtained in Comparative Example 8 was equipped with a Dimroth reflux tube and a thermometer 3 The mixture was charged into a one-necked flask, and 6.7 mL of a 1.0 mol / L hydrochloric acid aqueous solution was added and dissolved at room temperature. Stirring was performed for 4 hours while the solvent was refluxed to hydrolyze 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone. After the reaction, when the obtained reaction solution was cooled to 5 ° C. over 1.5 hours, crystals were precipitated. The obtained crystals were filtered and dried under vacuum for 12 hours to obtain white crystals of (5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride. 0.80 g (90.5% yield, 40.7% overall yield from the aniline compound) was obtained, and the purity was confirmed by HPLC to be 99.12% by mass.

Claims (7)

In the presence of hydrogen chloride or hydrogen bromide,
Following formula (1)

(Where
R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or an organic group. n is an integer of 1-5. When n is 2 or more, R ¹ may be the same group or different groups. )
A diazonium salt synthesis step of synthesizing a diazonium salt by reacting the aniline compound represented by formula (2) with a nitrite, and a diazonium salt obtained in the diazonium salt synthesis step in the presence of a copper catalyst and the following formula (2):

(Where
R ² is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group.
R ³ is a hydrogen atom, an alkyl group, or an aryl group. )
Is reacted with an α, β-unsaturated carbonyloxy compound represented by the following formula (3):

(Where
R ¹ and n have the same meaning as in Formula (1).
R ² and R ³ have the same meanings as in the formula (2).
X is a chlorine atom or a bromine atom. )
A carbonyloxy compound synthesis step for synthesizing a carbonyloxy compound represented by:
A method for producing a carbonyloxy compound comprising:
In the carbonyloxy compound synthesis step, when the diazonium salt and the α, β-unsaturated carbonyloxy compound are reacted, a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present in the reaction system. A method for producing a carbonyloxy compound. The group R ^{1 in the} formula (1) is an alkyl group, or the following formula (4)

{Wherein R ⁴ is
An alkyl group,
An aryl group,
Following formula (5)

(Where
R ⁵ and R ⁶ are each a hydrogen atom or an alkyl group, and m is an integer of 1 to 3. Or a group represented by the following formula (6)

(Where
R ⁷ and R ⁸ are each a hydrogen atom or an alkyl group. ). }
The manufacturing method of the carbonyloxy compound of Claim 1 using the aniline compound which is group shown by these.   2. The production of a carbonyloxy compound according to claim 1, wherein in the carbonyloxy compound synthesis step, 0.05 to 10 mol of a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is used per 1 mol of the diazonium salt. Method.   The nitrogen-containing heterocyclic compound having an acid dissociation index (pKa) at 25 ° C of 4 to 7 is used as the base having an acid dissociation index (pKa) at 25 ° C of 7 or less in the carbonyloxy compound synthesis step. The manufacturing method of the carbonyloxy compound as described in 2.   In the diazonium salt synthesis step, hydrogen bromide is used, 4- [2- (5-ethyl-2-pyridyl) ethoxy] aniline is used as the aniline compound represented by the formula (1), and the carbonyl In the oxy compound synthesis step, by using methyl acrylate as the α, β-unsaturated carbonyloxy compound represented by the formula (2), 2-bromo-3- {4- [2- (5-ethyl- The method for producing a carbonyloxy compound according to claim 1, wherein methyl 2-pyridyl) ethoxy] phenyl} propionate is produced.   After producing methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate by the method for producing a carbonyloxy compound according to claim 5, in the presence of an alkali. 5-methyl-4- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate methyl obtained and thiourea are reacted. A process for producing 2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone.   After preparing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone by the method according to claim 6, the obtained 5- {4 5- {4- [2- (5-ethyl--), characterized by reacting-[2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone and hydrogen chloride 2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride production method.