JP2021104940A - Method for producing iguratimod derivative or salt thereof - Google Patents

Abstract

To provide a method for producing an iguratimod derivative or a salt thereof, in which the production of a by-product UK-3 derivative can be suppressed.SOLUTION: By subjecting an iguratimod derivative precursor represented by the following formula (2) or a salt thereof to a cyclization reaction using a cyclization agent in the presence of an organic base, the iguratimod derivative represented by the following formula (3) or a salt thereof is produced. (In formulas (2) and (3), R1 is a phenyl group which may be substituted with a substituent, R2 is an alkyl group having 1 to 10 carbon atoms which may be substituted with a substituent.).SELECTED DRAWING: None

Description

The present invention refers to 3-formylamino-6-phenyloxy-7-methylsulfonylamino-4H-1-benzopyran-4-one (hereinafter referred to as iguratimod) and its derivatives (hereinafter, also referred to as iguratimod derivatives together with iguratimod). ) Or the method of producing the salt thereof. More specifically, it is a novel method for producing an iguratimod derivative or a salt thereof, in which the formation of a specific by-product is suppressed by adding an additive and reacting.

The iguratimod derivative or a salt thereof has an anti-inflammatory effect, an antipyretic analgesic effect, an anti-arthritis effect and an anti-allergic effect, and is useful as an anti-inflammatory agent. As shown below, an industrial production method for obtaining an iguratimod derivative or a salt thereof from an iguratimod derivative precursor or a salt thereof using a cyclizing agent (N, N-dimethylformamide dimethylacetal, etc.) has already been reported (Patent). Document 1).

According to the study by the present inventors, the following formula (1) is used as a by-product in the above cyclization reaction.

N- [3-formylamino-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] -N-methyl-alkylsulfonamide (hereinafter, also referred to as UK-3 derivative) represented by N- [3-formylamino-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] -N-methyl-alkylsulfonamide (hereinafter, also referred to as UK-3 derivative) is by-produced. (Note that the UK-3 derivative corresponding to the case where the iguratimod derivative precursor is an iguratimod precursor is also hereinafter referred to as UK-3). The production of the UK-3 derivative not only causes a decrease in the production rate of the iguratimod derivative or its salt, but also requires an additional purification step in purifying the obtained iguratimod derivative or its salt in order to reduce the UK-3 derivative. It becomes.

Patent Document 1 states that an additive may be added in order to suppress a side reaction. Specifically, there is a description that glacial acetic acid may be added as an additive. However, a specific side reaction has not been identified in Patent Document 1, and no by-product has been reported.

Japanese Unexamined Patent Publication No. 05-125072

As described above, in the conventional production method, the production of the by-product UK-3 derivative cannot be suppressed, which not only causes a decrease in the production rate of the iguratimod derivative or a salt thereof, but also reduces the UK-3 derivative. In addition, an additional purification step is required, extra labor (time) is required, and the yield of the finally obtained iguratimod derivative is also reduced. Therefore, an object of the present invention is to provide a method for producing an iguratimod derivative or a salt thereof capable of suppressing the production of a UK-3 derivative.

The present inventors have made extensive studies to solve the above problems. As a result of examining the addition of various additives in the above cyclization reaction, the addition of an organic base as an additive does not cause a significant decrease in the production rate of the iguratimod derivative or its salt, and the UK-3 derivative We have found that the cyclization reaction proceeds while suppressing the formation, and have completed the present invention.

That is, the present invention has the following equation (2).

(In the formula, R ¹ is a phenyl group which may be ^{substituted with a substituent, and R 2} is an alkyl group having 1 to 10 carbon atoms which may be substituted with a substituent.)
The iguratimod derivative precursor represented by (3) or a salt thereof is subjected to a cyclization reaction in the presence of an organic base using a cyclizing agent according to the following formula (3).

（式中、Ｒ^１、Ｒ^２は前記式（２）におけるものと同義である。）
で表わされるイグラチモド誘導体またはその塩の製造方法である。

(In the formula, R ¹ and R ² are synonymous with those in the above formula (2).)
It is a method for producing an iguratimod derivative represented by (1) or a salt thereof.

In the present invention, the organic base is represented by the following formulas (4-1), (4-2), (4-3) or (4-4).

（式（４−１）中、Ｒ^３〜Ｒ^５は、置換基で置換されていてもよいアルキル基、置換基で置換されていてもよいアラルキル基、又は水素原子であり、それぞれ同一の基であっても、異なる基であってもよく、Ｒ^３〜Ｒ^５の全てが水素原子であることはない。

(In the formula (4-1), R ^{3 to} R ⁵ are an alkyl group which may be substituted with a substituent, an aralkyl group which may be substituted with a substituent, or a hydrogen atom, which are the same group, respectively. However, it may be a different group, and ^{not all of R 3 to} R ⁵ are hydrogen atoms.

In formula (4-2), R ⁶ is an alkyl group optionally substituted with a substituent, an aralkyl group optionally substituted with a substituent, or a hydrogen atom. Also, X is _{-CH 2 -, - NH -,} - NMe -, - O -, - S -, - S (= O) - or -SO ₂ - is a group selected from. l and m are integers independently selected from 0 to 10.

In formula (4-3), R ⁷ is a substituent selected from a halogen atom, an ester group, a carboxyl group, an amide group, a nitrile group, a nitro group, an aldehyde group, a ketone group, an alkyl group or an aralkyl group. n is an integer selected from 0 to 5, and when n is 2 or more, R ⁷ may be the same group or different groups.

In formula (4-4), Y is _{a group selected from -CH 2-} , -NH- or -NMe-. In the case of a nitrogen atom, it may be substituted with an alkyl group. o is an integer selected from 1 to 5).
It is preferable that it is at least one organic base selected from the organic bases represented by, and the cyclizing agent is preferably N, N-dimethylformamide dimethylacetal.

By carrying out the cyclization reaction under appropriate temperature conditions, the production of the UK-3 derivative can be further reduced in addition to the above-mentioned effect of adding the organic base. The cyclization reaction is preferably carried out at −10 to 20 ° C. until the conversion is 50% or more.

According to the method for producing an iguratimod derivative of the present invention, the formation of a UK-3 derivative can be effectively suppressed in the cyclization reaction of an iguratimod derivative precursor or a salt thereof to an iguratimod derivative or a salt thereof. Therefore, it is possible to suppress a decrease in the production rate of iguratimod derivative due to the production of UK-3 derivative, further, it is possible to avoid an additional purification step, and the present invention is an industrial technique for producing iguratimod and its derivative or a salt thereof. Is very useful. By avoiding the additional purification step, it is possible to efficiently produce the product without labor, and it is possible to suppress a decrease in the yield of the iguratimod derivative or a salt thereof due to the additional purification step.

The method for producing an igratimod derivative or a salt thereof of the present invention produces an igratimod derivative or a salt thereof by carrying out a cyclization reaction of the igratimod derivative precursor or a salt thereof in the presence of an organic base using a cyclizing agent. The method. Hereinafter, the present invention will be described in detail.

(Iguratimod derivative precursor)
In the present invention, the iguratimod derivative precursor or a salt thereof is represented by the following formula (2).

で表わされる化合物またはその塩である。

A compound represented by or a salt thereof.

In the formula, R ¹ is a phenyl group which may be substituted with a substituent. Examples of the substituent include at least one group selected from a halogen atom, an ester group, a carboxyl group, an amide group, a nitrile group, a nitro group, an aldehyde group, a ketone group, an alkyl group or an aralkyl group. When the phenyl group is substituted with a plurality of substituents and at least two of the substituents are an alkyl group or an aralkyl group, they may be bonded to each other to form a ring. Preferably, R ¹ is a phenyl group.

R ² is an alkyl group having 1 to 10 carbon atoms which may be substituted with a substituent. Examples of the substituent include at least one group selected from a halogen atom, an ester group, a carboxyl group, an amide group, a nitrile group, a nitro group, an aldehyde group, a ketone group, an alkyl group or an aralkyl group. R ² is preferably a lower alkyl group having 1 to 5 carbon atoms having no substituent, and more preferably a methyl group.

The iguratimod derivative precursor or a salt thereof is an iguratimod precursor or a salt thereof when R ¹ is a phenyl group and R ² is a methyl group. The iguratimod derivative precursor or a salt thereof is preferably an iguratimod precursor. The cyclization reaction can produce iguratimod, a therapeutic agent for rheumatoid arthritis. By producing an iglatimod derivative or a salt thereof in which the by-product UK-3 derivative is reduced from the igratimod derivative precursor or a salt thereof by the production method of the present invention, an additional purification step can be avoided, and the igratimod derivative or a salt thereof can be produced. It can be manufactured efficiently.

(Organic base)
In the present invention, the cyclization reaction for producing the igratimod derivative represented by the formula (3) or the salt thereof from the igratimod derivative precursor represented by the formula (2) or the salt thereof is a sub-representation represented by the formula (1). The product is carried out in the presence of an organic base to suppress the formation of the UK-3 derivative.

The organic base is not particularly limited as long as it does not inhibit the reaction, but the following formulas (4-1), (4-2), (4-3) or (4-4)

（式（４−１）中、Ｒ^３〜Ｒ^５は、置換基で置換されていてもよいアルキル基、置換基で置換されていてもよいアラルキル基、又は水素原子であり、それぞれ同一の基であっても、異なる基であってもよく、Ｒ^３〜Ｒ^５の全てが水素原子であることはない。

(In the formula (4-1), R ^{3 to} R ⁵ are an alkyl group which may be substituted with a substituent, an aralkyl group which may be substituted with a substituent, or a hydrogen atom, which are the same group, respectively. However, it may be a different group, and ^{not all of R 3 to} R ⁵ are hydrogen atoms.

In formula (4-2), R ⁶ is an alkyl group optionally substituted with a substituent, an aralkyl group optionally substituted with a substituent, or a hydrogen atom. Also, X is _{-CH 2 -, - NH -,} - NMe -, - O -, - S -, - S (= O) - or -SO ₂ - is a group selected from. l and m are integers independently selected from 0 to 5, respectively.

In formula (4-3), R ⁷ is a substituent selected from a halogen atom, an ester group, a carboxyl group, an amide group, a nitrile group, a nitro group, an aldehyde group, a ketone group, an alkyl group or an aralkyl group. n is an integer selected from 0 to 5, and when n is 2 or more, R ⁷ may be the same group or different groups.

In formula (4-4), Y is _{a group selected from -CH 2-} , -NH- or -NMe-. o is an integer selected from 1 to 5. )
It is preferable that it is at least one organic base selected from the organic bases represented by.

In the formula (4-1), the alkyl group preferably has 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. The aralkyl group preferably has 7 to 12 carbon atoms, and more preferably 7 or 8 carbon atoms. When the alkyl or aralkyl group is substituted with a substituent, the substituent is selected from a halogen atom, an ester group, a carboxyl group, an amide group, a nitrile group, a nitro group, an aldehyde group, a ketone group, an alkyl group or an aralkyl group. At least one substituent.

R ^{3 to} R ⁵ are alkyl groups or hydrogen atoms, and it is preferable that at least two are alkyl groups.

Examples of the organic base represented by the formula (4-1) include organic bases having a chain alkyl group such as diethylamine, trimethylamine, diisopropylethylamine, triethylamine, tributylamine, dimethylamine and dibutylamine, and triethylamine and diethylamine. Is preferable.

In the formula (4-2), the alkyl group optionally substituted with a substituent and the aralkyl group optionally substituted with a substituent may be an alkyl substituted with a substituent in the formula (4-1). It is synonymous with an aralkyl group which may be substituted with a group and a substituent.

R ⁶ is preferably an alkyl group or a hydrogen atom.

X is preferably −CH _2- , −NH−, −NMe−, −O−.

l and m are integers independently selected from 0 to 7, and are preferably 0 to 4.

Examples of the organic base represented by the formula (4-2) include aliphatic heterocyclic organic bases such as pyrrolidine, piperidine, piperazine, morpholine, and N-methylmorpholine. Pyrrolidine, piperidine and morpholine are preferred.

In the formula (4-3), the alkyl group optionally substituted with a substituent and the aralkyl group optionally substituted with a substituent may be an alkyl substituted with a substituent in the formula (4-1). It is synonymous with an aralkyl group which may be substituted with a group and a substituent.

R ⁷ is preferably an alkyl group.

n is an integer selected from 0 to 5, preferably 0 to 3. When n is 2 or more, R ⁷ may be the same group or different groups.

Examples of the organic base represented by the formula (4-3) include pyridine, picoline and lutidine. Pyridine is preferred.

In formula (4-4), Y is -CH2-, -NH-, -NMe-.

o is an integer selected from 1 to 5, preferably 1-3.

Examples of the organic base represented by the formula (4-4) include DBU (diazabicycloundecene), DBN (diazabicyclononene), and TBD (1,5,7-triazabicyclo [4.4.0] deca-5. -En), MTBD (7-methyl-1,5,7-triazabicyclo [4.4.0] deca-5-ene) and other aliphatic heterocyclic organic bases can be mentioned.

Among the above-mentioned organic bases, particularly preferable compounds are triethylamine and morpholine.

The amount of the organic base used is not particularly limited. Since the formation of the UK-3 derivative, which is a by-product, can be effectively suppressed, it is preferable to use 1 to 10 mol with respect to 1 mol of the iguratimod derivative precursor represented by the formula (2) or a salt thereof. , 2-5 mol is more preferred.

(Rating agent)
In the present invention, for example, the cyclizing agent used in the cyclization reaction for producing the igratimode derivative represented by the formula (3) or the salt thereof from the igratimodo derivative precursor represented by the formula (2) or a salt thereof is, for example,. Examples thereof include N, N-dimethylformamide dilower alkyl acetals such as N, N-dimethylformamide dimethylacetal or N, N-dimethylformamide diethylacetals, N, N-dimethylformamide dicyclohexylacetals and the like. Preferably, it is N, N-dimethylformamide dimethylacetal.

The amount of the cyclizing agent used is not particularly limited. It is preferable to use 1 to 10 mol, and more preferably 2 to 5 mol, with respect to 1 mol of the iguratimod derivative precursor represented by the formula (2) or a salt thereof.

(Iguratimod derivative)
In the present invention, the iguratimod derivative or a salt thereof obtained by the cyclization reaction has the following formula (3).

で表わされる化合物またはその塩である。

A compound represented by or a salt thereof.

In the formula, R ¹ and R ² are synonymous with those in the above formula (2). When R ¹ is a phenyl group and R ² is a methyl group, the cyclization reaction gives iguratimod or a salt thereof.

(Manufacturing of iguratimod derivative)
In the present invention, the iguratimod derivative precursor represented by the formula (2) or a salt thereof is subjected to a cyclization reaction using a cyclizing agent in the presence of an organic base, and the iguratimod derivative represented by the formula (3) or a salt thereof is subjected to a cyclization reaction. Produce the salt. The cyclization reaction can be carried out in an organic solvent.

(Organic solvent)
The organic solvent is not particularly limited as long as it does not inhibit the reaction, but a highly polar organic solvent is preferable.

Examples of the organic solvent include esters such as ethyl acetate, methyl acetate, butyl acetate and isopropyl acetate; nitriles such as acetonitrile and propionitrile; tetrahydrofuran (THF), 2-methyl THF, 1,4-dioxane and tert-butyl. Ethers such as methyl ether, cyclopentylmethyl ether, dimethoxyethane, diglime; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene; aromatic hydrocarbons such as toluene and xylene Aliphatic hydrocarbons such as hexane and heptane; amides such as dimethylformamide and dimethylimidazolinone; sulfoxides such as dimethylsulfoxide can be mentioned. Preferred is dimethylformamide, which is a polar solvent. These organic solvents can be used alone or as a mixed solvent thereof.

The amount of the organic solvent used is not particularly limited. It is preferable to use 1 to 100 times the volume of the organic solvent, and more preferably 2 to 10 times the volume of the iguratimod derivative precursor represented by the formula (2) or a salt thereof. When a mixed solvent is used as the reaction solvent, the total amount of the mixed solvent may satisfy the above range.

The cyclization reaction can be carried out by mixing each component. The method of mixing each component is not particularly limited, and can be carried out in a reaction vessel equipped with a stirrer. The reaction atmosphere is not particularly limited, but it is preferably under an inert gas atmosphere or an air atmosphere. Further, the inside of the reaction system may be under atmospheric pressure, pressurization, or depressurization. Above all, it is preferable to carry out under atmospheric pressure.

In the present invention, the order in which each component is charged into the reaction vessel is not limited, but it is preferable to charge the iguratimod derivative precursor or a salt thereof, or a cyclizing agent last to start the cyclization reaction. That is, the igratimod derivative precursor or a salt thereof, an organic base and an organic solvent are charged in the reaction vessel, and finally a cyclizing agent is charged, or a cyclizing agent, an organic base and an organic solvent are charged in the reaction vessel, and finally igratimod. It is preferable to charge a derivative precursor or a salt thereof to initiate a cyclization reaction. At this time, for example, when the cyclizing agent is finally charged, the order in which the iguratimod derivative precursor other than the cyclizing agent or a salt thereof, an organic base and an organic solvent are charged into the reaction vessel is not particularly limited. Finally, when the iguratimod derivative precursor or a salt thereof is charged, the order in which the components other than the iguratimod derivative precursor or the salt thereof are charged into the reaction vessel is not particularly limited. By finally charging the igratimod derivative precursor or its salt or the cyclizing agent, the cyclizing agent and the igratimod derivative precursor or its salt do not come into contact with each other in the absence of an organic base to initiate the cyclization reaction. , The effect of suppressing the production of the by-product UK-3 derivative represented by the formula (1) is fully exhibited. For example, the iguratimod derivative precursor represented by the formula (2) or a salt thereof and an organic solvent may be charged in advance into the reaction vessel with stirring, then an organic base may be added, and then a cyclizing agent may be added. The reaction temperature is not particularly limited and can be carried out in the range of 0 ° C. to 100 ° C. The reaction time is not particularly limited and may be appropriately determined while confirming the conversion rate to the product iguratimod derivative, but usually it may be 1 hour or more and 24 hours or less, preferably 2 hours. More than 10 hours or less.

In order to further suppress the formation of the UK-3 derivative during the cyclization reaction, it is more preferable to carry out the reaction at a low temperature at the initial stage of the reaction. Specifically, when each component is charged, it is preferable to add the iguratimod derivative precursor or a salt thereof or a cyclizing agent at the end in the range of −10 to 20 ° C., more preferably 0 to 10 ° C. After adding the iguratimod derivative precursor or a salt thereof or a cyclizing agent, it is possible to react to the end point of the cyclization reaction in the same temperature range, but the reaction time is shortened while further suppressing the formation of the UK-3 derivative. Therefore, it is preferable to allow the reaction to proceed for a while in the same temperature range and then raise the temperature to complete the reaction. Specifically, the reaction is carried out at −10 to 20 ° C. until the conversion rate of the iguratimod derivative precursor or its salt to the iguratimod derivative becomes 50% or more, and then the temperature is raised to 30 to 70 ° C. for the cyclization reaction. It is more preferable to react to the end point of. The conversion rate and the end point of the cyclization reaction can be confirmed by high performance liquid chromatography (HPLC). The reaction time until the conversion rate reaches 50% or more at −10 to 20 ° C. may be determined by confirming the conversion rate by HPLC analysis in advance, but is usually 1 hour or more and 5 hours or less. The reaction time from the temperature rise to the end point at 30 to 70 ° C. may be determined by confirming the conversion rate of the reaction in advance, but is usually 0.5 hours or more and 5 hours or less.

According to the detailed reaction analysis of the present inventors, more UK-3 derivatives are produced at the initial stage of the reaction. Therefore, after adding the cyclizing agent, the reaction at a low temperature for a while (until the conversion rate becomes 50% or more) suppresses the formation of the UK-3 derivative at the initial stage of the reaction, and then the temperature is raised to make the UK. It is presumed that the reaction could be completed in a short time while the production of the -3 derivative was suppressed.

(Post-treatment of reaction)
In the present invention, after carrying out the above reaction, the iguratimod derivative or a salt thereof can be separated by the following method. For example, when a 10% aqueous hydrogen chloride solution is added until the inside of the reaction system becomes acidic, a solid precipitates. The precipitated solid may be collected by filtration, washed with hydrous acetone, and dried under reduced pressure.

When the UK-3 derivative is contained in the iguratimod derivative or a salt thereof, the UK-3 derivative can be removed and further purified by applying a known method such as column separation or recrystallization. It is possible. However, when the extracted iguratimod derivative contains a large amount of the UK-3 derivative, it is necessary to repeat the purification step and the yield is lowered.

The obtained iguratimod derivative or a salt thereof can be suitably used as various physiologically active compounds including pharmaceuticals.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto. The conversion rate of the iguratimod derivative precursor or its salt to the iguratimod derivative or its salt and the production rate of the iguratimod derivative and the UK-3 derivative were measured under the following conditions.

<HPLC conditions>
Equipment: Liquid chromatograph equipment (manufactured by Waters Corporation)
Detector: Ultraviolet absorptiometer Measurement wavelength: 240 nm
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 250 mm filled with octadecylsilylated silica gel for liquid chromatography having a particle size of 5 μm.

Mobile layer A: A mixed solution prepared by adding 8.16 g of potassium dihydrogen phosphate to 3000 mL of water and dissolving it, and then adding phosphoric acid to pH 2.5. Mobile layer B: acetonitrile Transfer of mobile layer: Mobile layer A And the concentration gradient is controlled by changing the mixing ratio of the moving layer B as follows.

Flow rate: 0.8 mL / min
Column temperature: Constant temperature around 30 ° C Measurement time: 50 minutes Holding time: Iguratimod: 8.11 minutes (RRT1.00)
UK-3: 10.36 minutes (RRT1.28)
Iguratimod precursor: 5.53 minutes (RRT 0.68)

The production rate (%) of iguratimod and the production rate (%) of UK-3 are the ratios of the respective area values to the total area values of all peaks (excluding the solvent peak) measured under the above conditions. The conversion rate (%) from the iguratimod precursor to iguratimod is the ratio of the peak area value of iguratimod to the total area value of the peaks of iguratimod and the iguratimod precursor.

Example 1
9. N, N-dimethylformamide dimethylacetal in a mixture of 30 mL of N, N-dimethylformamide, 10 g (27.45 mmol) of iguratimod precursor, and 8.33 g (82.33 mmol) of triethylamine at a temperature of 0-10 ° C. 81 g (82.33 mmol) was added. The mixture was stirred at 0-10 ° C. for 3 hours (conversion rate: 64.3%). After that, the reaction mixture was heated to 35 ° C. and stirred for 1.5 hours (conversion rate: 99.9%). The reaction mixture was cooled to 0-10 ° C. and 90 mL of acetone was added. 50.0 g of a 10% hydrogen chloride aqueous solution was added to make it acidic, and the precipitated solid was collected by filtration. The mixture was washed twice with 10 mL of 50% hydrous acetone and dried at 50 ° C. under reduced pressure to obtain 8.21 g (yield 82%, HPLC purity 99.76%) of iguratimod as a white solid. Table 2 shows the production rates of iguratimod and UK-3 in the reaction system after the cyclization reaction.

Example 2
N, N-dimethylformamide dimethylacetal 0 in a mixture of 3 mL of N, N-dimethylformamide, 1.0 g (2.74 mmol) of iguratimod precursor, 0.83 g (8.23 mmol) of triethylamine at a temperature of 0-10 ° C. .98 g (8.23 mmol) was added. The mixture was stirred at 40 ° C. for 3 hours to give iguratimod (conversion rate: 99.9%). Table 2 shows the production rates of iguratimod and UK-3 in the reaction system after the cyclization reaction.

Example 3
A mixture of 0.45 mL of N, N-dimethylformamide with 0.15 g (0.412 mmol) of iguratimod precursor and 97.7 mg (1.24 mmol) of pyridine was added to the ringing agent N, N-dimethyl at 0-10 ° C. 0.15 g (1.24 mmol) of formamide dimethylacetal was added. The mixture was stirred at 0-10 ° C. for 2 hours (conversion rate: 91.6%). Then, the reaction mixture was heated to 40 ° C. and stirred for 1 hour to obtain iguratimod (conversion rate: 99.9%). Table 2 shows the production rates of iguratimod and UK-3 in the reaction system after the cyclization reaction.

Comparative Example 1
To a mixture of 0.45 mL of N, N-dimethylformamide and 0.15 g (0.412 mmol) of iguratimod precursor, 0.15 g (1) of the cyclizing agent N, N-dimethylformamide dimethylacetal at a temperature of 0 to 10 ° C. .24 mmol) was added. The mixture was stirred at 0-10 ° C. within the same temperature range for 2 hours (conversion rate 94.0%). The reaction mixture was heated to 40 ° C. and stirred for 1 hour to obtain iguratimod (conversion rate: 99.9%). Table 2 shows the production rate of iguratimod and the production rate of UK-3 in the reaction system after the cyclization reaction.

Comparative Example 2
To a mixture of 3 mL of N, N-dimethylformamide and 1.0 g (2.74 mmol) of iguratimod precursor, 0.82 g (6.86 mmol) of N, N-dimethylformamide dimethylacetal as a cyclizing agent at a temperature of 0 to 10 ° C. ) And 165 mg (2.74 mmol) of glacial acetic acid were added sequentially. The mixture was stirred at 17.5 ° C. for 4 hours (conversion rate 90.0%). Table 2 shows the production rate of iguratimod and the production rate of UK-3 in the reaction system after the cyclization reaction.

Examples 4-6
The cyclization reaction was carried out in the same manner as in Example 3 except that the organic base or acid shown in Table 2 was used to obtain iguratimod. Table 2 shows the production rate of iguratimod and the production rate of UK-3 in the reaction system after the cyclization reaction.

Comparative Example 3
The cyclization reaction was carried out in the same manner as in Example 2 except that the organic base or acid shown in Table 2 was used to obtain iguratimod. Table 2 shows the production rate of iguratimod and the production rate of UK-3 in the reaction system after the cyclization reaction.

Claims (4)

The following formula (2)

(In the formula, R ¹ is a phenyl group which may be ^{substituted with a substituent, and R 2} is an alkyl group having 1 to 10 carbon atoms which may be substituted with a substituent.)
The iguratimod derivative precursor represented by (3) or a salt thereof is subjected to a cyclization reaction in the presence of an organic base using a cyclizing agent according to the following formula (3).

(In the formula, R ¹ and R ² are synonymous with those in the above formula (2).)
A method for producing an iguratimod derivative or a salt thereof represented by. The organic base is the following formula (4-1), (4-2), (4-3) or (4-4).

(In the formula (4-1), R ^{3 to} R ⁵ are an alkyl group which may be substituted with a substituent, an aralkyl group which may be substituted with a substituent, or a hydrogen atom, which are the same group, respectively. However, it may be a different group, and ^{not all of R 3 to} R ⁵ are hydrogen atoms.
In formula (4-2), R ⁶ is an alkyl group optionally substituted with a substituent, an aralkyl group optionally substituted with a substituent, or a hydrogen atom. Further, X is a group selected from -CH2-, -NH-, -NMe-, -O-, -S-, -S (= O)-or -SO2-. l and m are integers independently selected from 0 to 10.
In formula (4-3), R ⁷ is a substituent selected from a halogen atom, an ester group, a carboxyl group, an amide group, a nitrile group, a nitro group, an aldehyde group, a ketone group, an alkyl group or an aralkyl group. n is an integer selected from 0 to 5, and when n is 2 or more, R ⁷ may be the same group or different groups.
In formula (4-4), Y is a group selected from -CH2-, -NH- or -NMe-. o is an integer selected from 1 to 5).
The method for producing an iguratimod derivative or a salt thereof according to claim 1, which is at least one organic base selected from the organic bases represented by. The method for producing an iguratimod derivative or a salt thereof according to claim 1, wherein the cyclizing agent is N, N-dimethylformamide dimethylacetal. The method for producing an iguratimod derivative or a salt thereof according to claim 1, wherein the cyclization reaction is carried out at −10 to 20 ° C. until the conversion rate becomes 50% or more.