Composition, method for producing fluticasone furancarboxylic acid ester, method for purifying fluticasone furancarboxylic acid ester, and method for producing labeled compound

Abstract

This composition comprises a compound represented by formula (A) and impurities represented by formula (X1). The composition contains the compound at 99.2% or more and impurities at more than 0% but less than 0.05% with respect to the total composition.

Description

Composition, method for producing fluticasone furoate, method for purifying fluticasone furoate, and method for producing labeled compound

[0001] The present invention relates to a composition, a method for producing fluticasone furoate, a method for purifying fluticasone furoate, and a method for producing a labeled compound. This application claims priority to Japanese Patent Application No. 2023-195247, filed November 16, 2023, the contents of which are incorporated herein by reference.

[0002] Fluticasone furoate is known as a synthetic corticosteroid used as a therapeutic drug, and various methods for synthesizing it have been investigated (see, for example, Patent Document 1).

[0003] Patent No. 5568299

[0004] Meanwhile, European and American regulatory authorities have issued instructions to pharmaceutical manufacturers regarding risk assessments of impurity contamination, urging them to minimize impurity contamination. However, in general, separation is difficult when the target product and impurities are structurally similar. Furthermore, complex purification processes are sometimes required to reduce the impurity content, but these complex purification processes lead to reduced production efficiency. Therefore, there is room for improvement in terms of obtaining high-quality fluticasone furoate.

[0005] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a composition containing fluticasone furoate at a high content. Another object of the present invention is to provide a method for producing fluticasone furoate that enables easy production of high-quality fluticasone furoate, a method for purifying fluticasone furoate that enables easy purification of fluticasone furoate, and a method for producing a labeled compound (impurity) contained in the product of the method for producing fluticasone furoate.

[0006] The present inventors have investigated the above-mentioned problem and have noticed that the following compound (X1) produced by the synthesis of fluticasone furoate is difficult to separate from fluticasone furoate.

[0007] According to the studies of the inventors, compound (X1) is more difficult to separate than other impurities generated in the synthesis of fluticasone furoate. Therefore, in a composition containing fluticasone furoate, if the content of compound (X1) is sufficiently low, the contents of other impurities will be lower than that of compound (X1). Based on the above findings, the inventors conducted extensive studies treating compound (X1) as a label compound indicating the purity of fluticasone furoate, and completed the present invention.

[0008]

[0009] That is, in order to solve the above problems, one aspect of the present invention includes the following aspects.

[0010] [1] A composition containing a compound represented by the following formula (A) and an impurity represented by the following formula (X1), wherein the composition contains the compound in an amount of 99.2% or more and the impurity in an amount of more than 0% and less than 0.05% based on the total amount of the composition.

[0011] [2] A method for producing fluticasone furoate, comprising the steps of: obtaining a reaction mixture containing a compound represented by the following formula (A) and an impurity having a skeleton represented by the following formula (X); and purifying the compound represented by the following formula (A) by crystallizing it from the reaction mixture using a mixed solution of methyl ethyl ketone:acetone:water in a volume ratio of 1:1 to 4:1 to 6: (wherein X is a hydrogen atom or a fluorine atom)

[0012] [3] The method for producing fluticasone furoate according to [2], wherein the step of obtaining a reaction mixture comprises the steps of reacting a compound represented by the following formula (1), furoic anhydride, and an inorganic salt, and fluoromethylating the product of the reaction step, wherein the inorganic salt is at least one selected from the group consisting of alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal hydroxides, and alkali metal bicarbonates:

[0013] [4] The method for producing fluticasone furoate according to [3], wherein the fluoromethylation step is carried out after the step of reacting with an inorganic salt without isolating the product.

[0014] [5] The inorganic salt is Li ２ CO ３ , LiOH, CsCO ３ , KOH, NaOH, Na ２ CO ３ , NaHCO ３ , KHCO ３ , K ２ CO ３ , CaCO ３ and Ca(OH) ２ The method for producing fluticasone furoate according to [3] or [4], wherein the compound is at least one selected from the group consisting of:

[0015] [6] The method for producing fluticasone furoate according to any one of [3] to [5], wherein the fluoromethylation step comprises reacting the product with either or both of fluoroiodomethane and fluoromethyl p-toluenesulfonate.

[0016] [7] The fluoromethylation step is carried out using a solvent selected from DMF, CH ３ The method for producing fluticasone furoate according to any one of [3] to [6], which is carried out in a mixed solvent of water and two solvents selected from the group consisting of CN, THF, methyl ethyl ketone and acetone.

[0017] [8] The method for producing fluticasone furoate according to [7], wherein the mixed solvent is a mixed solvent of methyl ethyl ketone, acetone, and water, and the purifying step comprises, after the fluoromethylation step, a step of adjusting the mixing ratio of the mixed solvent contained in the reaction mixture of the fluoromethylation step to a volume ratio of methyl ethyl ketone:acetone:water=1:1 to 4:1 to 6, and a step of filtering the reaction mixture after the adjusted mixing ratio of the mixed solvent.

[0018] [9] A method for purifying fluticasone furoate, comprising mixing a mixture of a compound represented by the following formula (A) and an impurity having a skeleton represented by the following formula (X) with a mixed solution of methyl ethyl ketone:acetone:water in a volume ratio of 1:1 to 4:1 to 6, followed by filtration: (wherein X is a hydrogen atom or a fluorine atom)

[0019]

[10] A method for producing a labeled compound, comprising a step of heating a compound represented by the following formula (1) in DMF in the presence of imidazole:

[0020]

[11] The method for producing a labeled compound according to

[10] , further comprising a step of fluoromethylating the reaction product obtained in the heating step.

[0021] The present invention aims to provide a composition containing fluticasone furoate at a high content. It also provides a method for easily producing high-quality fluticasone furoate, a method for easily purifying fluticasone furoate, and a method for producing a labeled compound (impurity) contained in the product of the method for producing fluticasone furoate.

[0022] <Method for producing fluticasone furoate and method for purifying fluticasone furoate> The method for producing fluticasone furoate of this embodiment includes the steps of obtaining a reaction mixture containing a compound represented by formula (A) below and an impurity having a skeleton represented by formula (X) below, and purifying the compound represented by formula (A) below by crystallizing it from the reaction mixture in a mixed solution having a volume ratio of methyl ethyl ketone:acetone:water=1:1 to 4:1 to 6:

[0023] (wherein X is a hydrogen atom or a fluorine atom)

[0024] Fluticasone furoate represented by formula (A) may be referred to as "compound (A)" in the following description.

[0025] The inventors' investigations have revealed that, among various impurities generated in the synthesis of compound (A), compound (X1) is particularly difficult to separate from compound (A). Therefore, if the content of compound (X1) can be sufficiently removed from the reaction mixture (composition containing fluticasone furoate) obtained by the above reaction formula (I), it is expected that the contents of other impurities will also be reduced at the same time.

[0026] Furthermore, in order to produce a large amount of high-quality compound (A), the purification method is preferably a simple process that allows treatment of a large amount of the reaction mixture.

[0027] In the course of investigating purification methods from these perspectives, the inventors confirmed that impurities contained in the reaction mixture are easily soluble in the mixed solvent having the above ratio, while compound (A) is less soluble in the mixed solvent and is more likely to precipitate as crystals. Based on this finding, the inventors discovered that the content of impurities can be sufficiently reduced by crystallizing a composition containing compound (A) using a mixed solvent having the above ratio. Surprisingly, crystallization using the above mixed solvent enables separation of compound (A) and impurities having a skeleton represented by formula (X), including compound (X1), which has been difficult to separate using conventional methods.

[0028] Hereinafter, the method for producing fluticasone furoate of this embodiment will be described in order of synthesis of compound (A) and purification of compound (A).

[0029] [Synthesis of fluticasone furoate] In this embodiment, the step of obtaining a reaction mixture includes a step (Step 1) of reacting a compound represented by the following formula (1) with furoic anhydride and an inorganic salt, and a step (Step 2) of fluoromethylating the product of the reaction step, and the inorganic salt is preferably at least one selected from the group consisting of alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal hydroxides, and alkali metal hydrogencarbonates.

[0030]

[0031] The compound represented by formula (1) is 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid. In the following description, the compound represented by formula (1) is referred to as compound (1).

[0032] [Step 1] The inorganic salt used in step 1 is specifically Li ２ CO ３ , LiOH, CsCO ３ , KOH, NaOH, Na ２ CO ３ , NaHCO ３ , KHCO ３ , K ２ CO ３ , CaCO ３ and Ca(OH) ２ The inorganic salt used in the reaction is at least one selected from the group consisting of carbonate (Li ２ CO ３ , CsCO ３ , Na ２ CO ３ , K ２ CO ３ , CaCO ３ ) is preferred, and Na ２ CO ３ and K. ２ CO ３It is more preferable that either one or both of K ２ CO ３ It is more preferable that:

[0033] The amount of the inorganic salt in step 1 is preferably in the range of 0.5 to 2 equivalents relative to compound (1).

[0034] The amount of furancarboxylic anhydride in step 1 is preferably in the range of 0.9 to 1.2 equivalents relative to compound (1).

[0035] The reaction in step 1 can be carried out at a temperature ranging from -20°C to 60°C, preferably from 0°C to 40°C.

[0036] The reaction solvent in step 1 is DMF, THF, CH ３ At least one solvent selected from the group consisting of CN, acetone, methyl ethyl ketone (MEK), and alcohol-based solvents, such as methanol, ethanol, propanol, isopropanol, n-butanol, and t-butanol, can be used.

[0037] In addition, the reaction solvent in step 1 contains water.

[0038] The reaction solvent in step 1 is DMF, THF, CH ３ It is preferable to use a mixed solvent of at least one solvent selected from the group consisting of CN and acetone with water, and it is more preferable to use a mixed solvent of acetone and water.

[0039] The amount of the solvent in step 1 is preferably 5 to 40 times (by mass) the amount of compound (1).

[0040] [Step 2] In step 2, a fluoromethylating agent is used as a reaction substrate. The fluoromethylating agent can be represented by the following formula (B). Step 2 is preferably carried out after step 1 above without isolating the product of step 1. In other words, steps 1 and 2 are preferably carried out as a continuous operation. Note that "continuous operation" means "carrying out the next step without isolating the product of the previous step."

[0041] (In the formula, X ａrepresents a leaving group containing halogen, Cl, Br, I, or OTs)

[0042] The fluoromethylating agent is fluoroiodomethane (X ａ = I) and fluoromethyl p-toluenesulfonate (fluoromethyl-4-methylbenzenesulfonate, X ａ =OTs) or both thereof are preferred.

[0043] In step 2, the amount of the fluoromethylating agent is preferably in the range of 1.0 to 2.0 equivalents (by mass) relative to compound (1), more preferably in the range of 1.1 to 1.3 equivalents.

[0044] The reaction in step 2 can be carried out at a temperature ranging from -20°C to 30°C, preferably from 0°C to 10°C.

[0045] Step 2 is DMF, CH ３ It is preferable that the step 2 is carried out in a mixed solvent of water and two solvents selected from the group consisting of CN, THF, methyl ethyl ketone (MEK), and acetone. It is preferable that the step 2 contains the solvent used in the step 1. It is also preferable that the step 2 is carried out in a mixed solvent of water and two solvents selected from the group consisting of DMF, CH ３ It is more preferable that the step 2 be performed in a mixed solvent of one solvent selected from the group consisting of CN, THF, and MEK, acetone, and water, and it is even more preferable that the step 2 be performed in a mixed solvent of MEK, acetone, and water. By performing the step 2 in a mixed solvent of MEK, acetone, and water, the yield of the step 2 can be easily increased.

[0046] The amount of the solvent in step 2 is preferably 5 to 30 times (by mass), more preferably 10 to 15 times, the amount of compound (1).

[0047] The method for producing fluticasone furoate of this embodiment can be represented by the following reaction scheme (I): In the following chemical scheme, fluoroiodomethane is used as a reaction substrate for the fluoromethylation reaction.

[0048]

[0049] According to the production method of this embodiment, the target compound, fluticasone furoate (compound (A)), can be produced without isolating the intermediate (Xa).

[0050] The compound represented by the formula (A) is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester. In the following description, the compound represented by the formula (A) is referred to as compound (A).

[0051] Specifically, as shown in the following reaction formula (I)-1, it is believed that the reaction between the added inorganic salt and compound (1) generates an anion at the thiocarboxylic acid group of compound (1), and the generated anion reacts with furancarboxylic anhydride to undergo intramolecular rearrangement to produce a furancarboxylic acid ester group. In formula (I)-1, the compound represented by formula (Xb) is a synthetic equivalent of the above formula (Xa). Furthermore, it is believed that the anion on the thiocarboxylic acid group of the compound represented by formula (Xb) (reaction intermediate) is fluoromethylated to produce the target compound (A).

[0052]

[0053] The compound represented by formula (Xb) is the potassium salt of 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-17α-(2-furoyloxy)-3-oxo-androsta-1,4-diene-17β-carbothioic acid. In the following description, the compound represented by formula (Xb) is referred to as compound (Xb).

[0054] It is thought that compound (Xb) reacts with furancarboxylic anhydride in the system to produce a by-product (difuroate (Xc)) in which a furancarboxylic acid group is also bonded to the thiocarboxylic acid group. However, since the reaction solvent contains water, hydrolysis occurs at the thiocarboxylic acid group of the resulting difuroate (Xc), and compound (Xb) is again produced. Therefore, it is thought that the equilibrium shifts in the direction of producing compound (Xb) as a whole, and the reaction proceeds, as shown in the following reaction formula (I)-2.

[0055]

[0056] As described above, in Step 1, the inclusion of water in the reaction solvent makes it easier to produce compound (Xb), and Step 2, which directly produces compound (A), can also be carried out. On the other hand, in order to reduce impurities, it is preferable to carry out a separation operation after Step 1 and before Step 2. Prior to the separation operation, it is advisable to add water to the reaction mixture to promote the reaction represented by Reaction Scheme (I)-2.

[0057] In the separation operation, for example, methyl acetate, ethyl acetate, isopropyl acetate, toluene, xylene, methylene chloride, and chloroform can be used as a solvent for the organic layer, with methyl acetate, ethyl acetate, isopropyl acetate, and toluene being preferred.

[0058] In the method for producing compound (A) according to the present invention, compound (A) may be synthesized by a reaction using an amine as in Patent Document 1. However, in this case, the presence of amines in the reaction system may result in the generation of nitrosamines as reaction impurities.

[0059] In pharmaceuticals, regulatory authorities in Europe and the United States have issued instructions to pharmaceutical manufacturers regarding risk assessment of nitrosamine contamination, and the contamination of pharmaceuticals with nitrosamines can pose a quality risk. Therefore, when synthesizing compound (A), the formation of nitrosamines can be suppressed by using inorganic salts instead of amines, as in the above-mentioned steps 1 and 2.

[0060] [Purification of fluticasone furoate] The reaction mixture obtained in reaction formula (I) contains, in addition to the target compound (A), the starting material compound (1) and an impurity having the same skeleton as the target compound (A) (an impurity having a skeleton represented by the following formula (X)).

[0061] (wherein X is a hydrogen atom or a fluorine atom)

[0062] Impurities contained in the reaction mixture include, for example, compounds (X1) to (X6) represented by the following formulae.

[0063]

[0064]

[0065]

[0066] As described above, in the production method of this embodiment, a compound represented by the following formula (A) is crystallized from the obtained reaction mixture using a mixed solution having a volume ratio of methyl ethyl ketone:acetone:water=1:1 to 4:1 to 6. The reaction mixture (a mixture of compound (A) and an impurity having a skeleton represented by formula (X)) may be in the form of a solution or a solid (crude crystals).

[0067] In this embodiment, it is preferable to use a mixed solution of MEK, acetone, and water as the mixed solvent used in step 2, and then, after step 2, to include a step of adjusting the mixing ratio of the mixed solvent (mixed solution) contained in the reaction mixture of step 2 to MEK:acetone:water=1:1 to 4:1 to 6 by volume, and a step of filtering the reaction mixture with the adjusted mixed solvent ratio, thereby enabling compound (A) to be suitably filtered out from the reaction mixture.

[0068] The above purification method does not have to be based on the above-mentioned method for producing compound (A) and can be carried out alone. The purification method not based on the method for producing compound (A) corresponds to the "method for purifying fluticasone furoate" in the present invention.

[0069] When the reaction mixture is not subjected to the method for producing fluticasone furoate of the present embodiment, impurities contained therein before purification include, for example, compounds (X7) to (X9) represented by the following formulae. Because compounds (X7) to (X9) have similar chemical structures to the above-mentioned compounds (X1) to (X6), it is believed that compounds (X7) to (X9) can also be purified by the method for purifying fluticasone furoate of the present embodiment.

[0070]

[0071] That is, the method for purifying fluticasone furoate of the present embodiment is a method of mixing a mixture of compound (A) and an impurity having a skeleton represented by the following formula (X) with a mixed liquid of MEK:acetone:water=1:1 to 4:1 to 6 by volume, followed by filtration.

[0072] (wherein X is a hydrogen atom or a fluorine atom)

[0073] The mixture of compound (A) and the impurity having a skeleton represented by formula (X) may be in the form of a solution or a solid (crude crystals).

[0074] In the method for producing compound (A) of this embodiment, when the ratio of the mixed solvent is changed in a mixture (reaction solution) containing the target compound (A) and the above-mentioned impurities, fine crystals of compound (A) are formed in the system. Furthermore, by filtering the reaction solution, high-purity compound (A) can be easily obtained.

[0075] In the method for producing compound (A) of this embodiment, it is preferable to perform step 1, step 2, and the above-mentioned purification (the step of adjusting the mixing ratio of the mixed solvents and the step of filtering the reaction mixture with the adjusted mixing ratio) continuously. That is, in the method for producing compound (A) of this embodiment, it is preferable to obtain the final target compound (A) without isolating the intermediate product in any of the steps. This reduces the loss that would occur if a step of isolating the intermediate product were performed, and enables high-purity fluticasone furoate to be easily produced.

[0076] <Method for Producing Composition and Compound> Compound (A) produced by the method described above is obtained as a composition of such high purity that, in addition to the target compound (A), compound (X1), which is particularly difficult to separate from compound (A) among the above-mentioned impurities, can be detected in trace amounts. In this embodiment, compound (X1) is used as a labeled compound and can be used as an index of the purity of compound (A).

[0077] That is, the composition of the present embodiment is a composition containing a compound represented by the following formula (A) and an impurity represented by the following formula (X1), and the composition contains the compound in an amount of 99.8% or more and the impurity in an amount of more than 0% and less than 0.05% based on the total amount of the composition.

[0078]

[0079] In this embodiment, the purity of the composition was determined by performing HPLC analysis on the composition and calculating the area ratio of compound (A) to the total peak area (HPLC area ratio (Area%)) from the peak area values ​​of the obtained chromatogram. The same analytical method can also be used to confirm the progress of the synthesis reaction. The conditions for HPLC analysis are as follows:

[0080] <Analysis conditions> Column: L-Column ODS (4.6 x 250 mm, 5 µm) Column temperature: 40°C Mobile phase A: 0.01% by volume trifluoroacetic acid aqueous solution Mobile phase B: acetonitrile Gradient (volume ratio): Condition 1 (0 → 15 min) Mobile phase A:mobile phase B = 55:45 Condition 2 (15 → ​​25 min) Mobile phase A:mobile phase B = 50:50 Condition 3 (25 → 45 min) Mobile phase A:mobile phase B = 10:90 Condition 4 (45 → 55 min) Mobile phase A:mobile phase B = 55:45 Detector: UV 239 nm

[0081] The mobile phase concentrations were changed continuously at a constant rate, as described above under "Gradient." Under condition 1, the volume ratio of mobile phase A:mobile phase B was set to a constant value of 55:45. Under condition 2, the ratio was changed continuously at a constant rate from 55:45 to 50:50. Conditions 3 and 4 can be understood in the same way as condition 2.

[0082] <Method for producing labeled compound> In investigating the above-mentioned method for producing fluticasone furoate, compound (X1) was needed as a reference substance in order to remove impurities, particularly compound (X1), from compound (A) to obtain a highly pure compound (A). Therefore, the inventors investigated a method for synthesizing compound (X1) and completed a new method for producing a precursor of compound (X1) (compound (X1-1)) and a method for producing compound (X1).

[0083] That is, the method for producing a labeled compound in this embodiment includes a step of heating a compound represented by the following formula (1) in DMF in the presence of imidazole.

[0084]

[0085] By the above production method, a precursor of the compound (X1) (represented by the following formula (X1-1)) can be produced.

[0086]

[0087] The method for producing a labeled compound of this embodiment is characterized by heating in the presence of imidazole.

[0088] The mechanism of production of compound (X1-1) has not been reported so far. Furthermore, the inventors have investigated the production method and found that compound (1) can be produced by reacting compound (1) with an alkali metal carbonate (K ２ CO ３ ) in DMF, the reaction did not proceed. ４ When heated in DMF, the reaction did not proceed.

[0089] On the other hand, when compound (I) was treated with carbonyldiimidazole in DMF, an increase in the production of compound (X1-1) was observed. Based on this result, the inventors conducted extensive studies and found that when imidazole produced in a reaction system using carbonyldiimidazole was added and the mixture was heated in DMF, the reaction proceeded and compound (X1-1) was obtained.

[0090] In the method for producing the compound (X1-1), the amount of imidazole is preferably 1.0 equivalent or more and 2.0 equivalents or less relative to the starting compound (1).

[0091] The reaction time in the method for producing the compound (X1-1) is preferably 3 hours or more and 8 hours or less.

[0092] The reaction temperature in the method for producing the compound (X1-1) is preferably 90°C or higher and 100°C or lower.

[0093] Furthermore, the method for producing a labeled compound includes a step of fluoromethylating the reaction product obtained in the heating step, thereby producing compound (X1). In the following reaction formula, compound (X1-1), which corresponds to a reaction intermediate, is omitted.

[0094]

[0095] The reaction conditions such as the solvent used in the heating step and the reaction temperature can be the same as those in Step 1 of the production method of Compound (A) described above.

[0096] The reaction conditions for the fluoromethylation step can be the same as those for step 2 in the above-mentioned method for producing compound (A).

[0097] In the method for producing compound (X1), when fluoromethylation is carried out using fluoroiodomethane, the amount of fluoroiodomethane is preferably 1.0 equivalent or more and 3.0 equivalents or less relative to the starting compound (1).

[0098] As described above, in the method for producing a labeled compound, it was found that compound (X1-1) is produced by heating compound (1) in DMF together with imidazole, an amine, but compound (X1-1) is not produced by heating compound (1) together with an alkali metal carbonate instead of imidazole. That is, in the above-mentioned method for producing fluticasone furoate, imidazole (amine) is not used in step 1, but an alkali metal carbonate or alkaline earth metal carbonate is used, which makes it difficult to produce compound (X1-1), an impurity, in step 1, and makes it easier to obtain a highly pure target product.

[0099] By using the compound (X1-1) and the compound (X1) obtained by the above method, the purification of the compound (A) can be easily investigated.

[0100] As described above, in the method for producing and purifying compound (A) of this embodiment, the target product can be obtained without using amines. Furthermore, the target product can be obtained with high purity by a simple method in which the reaction mixture for synthesizing compound (A) is mixed with a mixture in a specific ratio, followed by filtration.

[0101] Therefore, the process for producing fluticasone furoate having the above-described configuration makes it possible to easily produce high-quality (high-purity) fluticasone furoate.Furthermore, the process for purifying fluticasone furoate having the above-described configuration makes it easy to purify fluticasone furoate.

[0102] The resulting composition contains a high content of fluticasone furoate. Furthermore, the method for producing the labeled compound allows for easy production of trace amounts of the labeled compound (X1-1) (X1), which is an impurity, for further purification studies of fluticasone furoate.

[0103] Although the preferred embodiment of the present invention has been described above, the present invention is not limited to these examples. The shapes and combinations of the components shown in the above examples are merely examples, and various modifications can be made based on the design, specifications, etc., without departing from the spirit of the present invention.

[0104] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0105] (Abbreviations) DMF: N,N-dimethylformamide, THF: tetrahydrofuran, MEK: methyl ethyl ketone, HPLC: high performance liquid chromatography

[0106] In the following description, the starting materials for the reactions and the compounds to be synthesized are appropriately designated by names such as compound (A) as in the above-described embodiment.

[0107] In the following examples, HPLC analysis was carried out under the following analytical conditions. <Analysis conditions> Column: L-Column ODS (4.6 × 250 mm, 5 μm) Column temperature: 40°C Mobile phase A: 0.01% by volume trifluoroacetic acid aqueous solution Mobile phase B: acetonitrile Gradient (volume ratio): Condition 1 (0 → 15 min) Mobile phase A:mobile phase B = 55:45 Condition 2 (15 → ​​25 min) Mobile phase A:mobile phase B = 50:50 Condition 3 (25 → 45 min) Mobile phase A:mobile phase B = 10:90 Condition 4 (45 → 55 min) Mobile phase A:mobile phase B = 55:45 Detector: UV 239 nm

[0108] Example 1: Comparison with known manufacturing method The difference in effect between the present invention and a known manufacturing method was examined in Example 1. In the comparative example, the method described in Japanese Patent No. 5,568,299 was used as the known method.

[0109] Example 1-1 (Step 1) K was dissolved in acetone (8 mL) and water (5.5 mL) under nitrogen. ２ CO ３ Compound (1) (1 g) and furancarboxylic anhydride (0.60 g, 1.2 equivalents relative to compound (1)) were then added, and the mixture was stirred at 25° C. for 22 hours.

[0110] Toluene (5 mL) was added to the resulting reaction solution, and the aqueous layer was separated. A mixture of acetone (5 mL) and toluene (5 mL) was then added to the aqueous layer, followed by separation to separate the aqueous layer. Acetone (5 mL) was added to the resulting aqueous layer, and separation was performed to obtain an aqueous solution of compound (Xb) as the aqueous layer.

[0111] HPLC analysis at the end of the reaction revealed that the content (purity) of compound (Xb) in the product was 94.5%, and the content of compound (X1-1) in the product was 0.08%.

[0112] (Step 2) Fluoroiodomethane (0.47 g, 1.2 equivalents relative to compound (1)) was added to MEK (10 mL) at 25°C, and the mixture was cooled to 0°C.

[0113] On the other hand, water (3 mL) was added to the aqueous solution of compound (Xb) prepared by the above method, and then K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)) was added.

[0114] The aqueous solution of compound (Xb) was added dropwise to the fluoroiodomethane solution over 15 minutes while maintaining the internal temperature at 0 to 5° C. or less, and then the mixture was stirred for 2 hours or more while maintaining the internal temperature at 0 to 5° C. or less to obtain compound (A). HPLC analysis at the end of the reaction showed that the purity of compound (A) was 93.3% and the proportion of compound X1 was 0.23%.

[0115] Water (10 mL) was added to the resulting reaction liquid, and the temperature was raised to around 10 to 15° C., after which acetone (15 mL) was added. The resulting mixed solvent had a volume ratio of MEK:acetone:water=1:1.5:1.85.

[0116] After standing at 0°C for 1 hour, compound (A) was obtained as a fine white solid by filtration (dry yield: 1.07 g, 82% theoretical yield, purity 99.9%, each impurity less than 0.05%).

[0117] [Example 1-2] (Step 1) Compound (1) (20 g), K ２ CO ３(9.38 g, 1.4 equivalents relative to compound (1)) and furancarboxylic acid anhydride (10.5 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 6 hours.

[0118] Water (160 mL) was added to the resulting reaction solution, and the mixture was stirred for 1 hour. Toluene (100 mL) was added to separate the aqueous layer. Toluene (100 mL) was further added to the aqueous layer, and a separation operation was performed to obtain an aqueous solution of compound (Xb) as the aqueous layer.

[0119] (Step 2) Tetrabutylammonium iodide (7.61 g, 0.43 equivalents relative to compound (1)) and sodium iodide (21.8 g, 3 equivalents relative to compound (1)) were suspended in MEK (100 mL), and a MEK solution (100 mL) of fluoromethyl-4-methylbenzenesulfonate (14.8 g, 1.5 equivalents relative to compound (1)) was added at 25°C, followed by heating at 79°C for 2 hours to prepare fluoroiodomethane.

[0120] The resulting fluoroiodomethane solution was cooled to an internal temperature of 0°C, and the aqueous solution of compound (Xb) prepared by the method described above was added dropwise to the fluoroiodomethane solution over 15 minutes. During the dropwise addition, the internal temperature was maintained at 0°C or higher and 5°C or lower. After the dropwise addition of the aqueous solution of compound (Xb), the mixture was stirred for 1 hour while maintaining the internal temperature at 5°C or lower to allow the reaction to proceed. HPLC analysis at the end of the reaction showed that the content of compound (X1) in the product was 0.28%.

[0121] Water (400 mL) was added to the organic layer (MEK solution), which was the reaction mixture, and the mixture was stirred for 1 hour while being heated to 30° C. or higher and 35° C. or lower. Acetone (200 mL) was then added, and the mixture ratio of the mixed solvents in the reaction mixture was adjusted to MEK:acetone:water=1:2:4 by volume.

[0122] The reaction mixture with the adjusted mixing ratio was cooled to 0° C. or higher and 5° C. or lower, stirred for 1 hour, and then filtered to obtain compound (A) in a crude yield of 95.7%.

[0123] The content (purity) of compound (A) in the obtained product was 99.2% by HPLC analysis, and the product also contained 0.03% of compound (X1) by HPLC analysis.

[0124] [Comparative Example 1-1] Compound (1) (3 g) and DMAP (0.09 g, 0.1 equivalents relative to compound (1)) were added to MEK (36 mL), and the mixture was stirred at 20 to 22°C under nitrogen for 10 minutes to prepare an MEK solution.

[0125] Next, tripropylamine (4.32 mL, 3.1 equivalents relative to compound (1)) was added to the obtained MEK solution, and the obtained solution was cooled to −8° C. to −5° C. Next, furoyl chloride (solvent-free) (1.5 g, 1.5 equivalents relative to compound (1)) was added dropwise to the obtained solution at −5° C. to 0° C. over 2 to 3 minutes. The reaction mixture was stirred at −5° C. to 0° C. for 15 minutes.

[0126] Next, to the resulting reaction mixture was added dropwise an aqueous solution (1.45 mL) of N-methylpiperazine (0.49 mL, 0.6 equivalents relative to compound (1)) over 2 to 3 minutes at −5° C. to 0° C. The reaction mixture was stirred at −5° C. to 0° C. for a total of 10 minutes.

[0127] Next, fluoroiodomethane (1.36 g, 1.2 equivalents relative to compound (1)) was quickly added to the resulting reaction mixture at 0° C. Thereafter, the reaction mixture was rapidly warmed to 20-22° C. and stirred at 20-22° C. for 5 hours.

[0128] The content (purity) of compound (A) in the obtained product was about 65% by HPLC analysis, and the product also contained 0.41% of compound (X1) by HPLC analysis.

[0129] Next, the product containing compound (A) was diluted with MIBK (69 mL) and then washed by a separation operation twice with a 2 mol / L aqueous hydrochloric acid solution (15 mL), once with water (15 mL), once with a 4% aqueous potassium carbonate solution (10 mL), and subsequently once with water (15 mL).

[0130] The organic phase was concentrated under reduced pressure to obtain compound (A) (3.9 g, 100% theoretical yield, purity 83.4%). In addition to compound (A), the product contained impurities such as compound (X1) 0.12%, compound (X4) 10.5%, impurities derived from other reagents 2.4%, and related impurities ranging from 0.02 to 0.5% for a total of 5.99%.

[0131] From the above results, it was found that the purification method of Comparative Example 1 (washing by separation) was insufficient for the purpose of obtaining a highly pure compound (A).

[0132] Comparative Example 1-2: Under nitrogen, in acetone (10 mL), K ２ CO ３ Compound (1) (0.44 g, 1.3 equivalents relative to compound (1)) was suspended in the suspension, and then compound (1) (1 g) was added and cooled to 0° C. After cooling, 2-furoyl chloride (0.53 g, 1.05 equivalents relative to compound (1)) was added dropwise to the mixed suspension, and the mixture was stirred at room temperature for 24 hours.

[0133] Water (8 mL) and toluene (5 mL) were added to the resulting reaction mixture, and the mixture was separated to obtain an aqueous solution of compound (Xb) as the aqueous layer.

[0134] The content (purity) of compound (Xb) in the obtained product was 95.6% by HPLC analysis, and the product also contained 1.7% of compound (X1-1) and 0.7% of the above-mentioned difuroate (Xc) by HPLC analysis.

[0135] Acetone (7 mL) was added to the prepared aqueous solution of compound (Xb), and then fluoroiodomethane (1.62 g, 1.2 equivalents relative to compound (1)) was added at 0° C. and stirred for 1 hour. At the end of the reaction, 1.64% of compound (Xb) remained.

[0136] Water (7 mL) was added to the reaction mixture, which was then diluted with isopropyl acetate (60 mL), and the organic layer was washed with basic water. The organic layer was separated and concentrated to obtain compound (A). The theoretical yield was 80%.

[0137] The obtained product was a white fine solid. The content (purity) of compound (A) in the product was 92.3% by HPLC analysis. The product also contained 2.17% of compound (X1) by HPLC analysis.

[0138] From the above results, it was found that the purification method of Comparative Example 2 (washing by separation) was insufficient for the purpose of obtaining a highly pure compound (A).

[0139] Example 2: Examination of volume ratio of mixed solvent In Example 2, a suitable volume ratio of mixed solvents for purifying compound (A) was examined.

[0140] [Example 2-1] (Step 1) Compound (1) (2 g), K ２ CO ３ (0.94 g, 1.4 equivalents relative to compound (1)), furancarboxylic anhydride (1.05 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25°C for 6 hours. Water (16 mL) was added to the resulting reaction solution, and the mixture was stirred for 1 hour. Toluene (10 mL) was then added to separate the aqueous layer. Toluene (10 mL) was then added to the aqueous layer, and a separation operation was performed to obtain an aqueous solution of compound (Xb) as the aqueous layer.

[0141] (Step 2) Fluoroiodomethane (0.93 g, 1.2 equivalents relative to compound (1)) was added to MEK (20 mL) at 25°C, and the mixture was cooled to 0°C.

[0142] Next, the aqueous solution of compound (Xb) obtained in step 1 was added dropwise to the fluoroiodomethane solution over 15 minutes. During the dropwise addition, the internal temperature was maintained at 5°C or below. The mixture was stirred and reacted for 2 hours while maintaining the internal temperature at 5°C or below to obtain compound (A). HPLC analysis at the end of the reaction showed that the purity of compound (A) in the product was 97.1% and the content of compound (X1) was 0.15%.

[0143] Water (40 mL) was added to the organic layer (MEK solution, MEK 20 mL), which was the reaction mixture, and the temperature was raised to 24° C. Acetone (40 mL) was further added, and the mixing ratio of the mixed solvents in the reaction mixture was adjusted to MEK:acetone:water=1:2:2 by volume.

[0144] By filtering the reaction mixture with the adjusted mixing ratio, compound (A) was obtained in a theoretical yield of 107% (undried). The content (purity) of compound (A) in the obtained product was 99.7% by HPLC analysis. Furthermore, the product contained 0.01% of compound (X1) by HPLC analysis.

[0145] [Example 2-2] Compound (A) was obtained in the same manner as in [Example 2-1]. HPLC analysis at the end of the reaction revealed that the purity of compound (A) in the product was 97.7%, and the content of compound (X1) was 0.2%.

[0146] Water (20 mL) was added to the organic layer (MEK solution, MEK 20 mL), which was the reaction mixture, and the mixture was cooled to 0° C. or higher and 10° C. or lower. Acetone (20 mL) was further added, and the mixing ratio of the mixed solvents in the reaction mixture was adjusted to MEK:acetone:water=1:1:1 by volume.

[0147] By filtering the reaction mixture with the adjusted mixing ratio, compound (A) was obtained in a theoretical yield of 111% (undried). The content (purity) of compound (A) in the obtained product was 99.7% by HPLC analysis. Furthermore, the product contained 0.01% of compound (X1) by HPLC analysis.

[0148] [Example 2-3] Compound (A) was obtained in the same manner as in [Example 2-1], except that the amount of MEK used in step 2 was 40 mL. HPLC analysis at the end of the reaction revealed that the purity of compound (A) in the product was 97.1%, and the content of compound (X1) was 0.16%.

[0149] Water (80 mL) was added to the organic layer (MEK solution, MEK 40 mL), which was the reaction mixture, and the mixture was cooled to 0° C. or higher and 10° C. or lower. Acetone (60 mL) was further added, and the mixing ratio of the mixed solvents in the reaction mixture was adjusted to MEK:acetone:water=1:1.5:2 by volume.

[0150] The reaction mixture was filtered to obtain compound (A) in a theoretical yield of 69%. The content (purity) of compound (A) in the resulting product was 99.7% by HPLC analysis. Furthermore, the product contained 0.02% of compound (X1) by HPLC analysis.

[0151] [Comparative Example 2-1] Compound (A) was obtained in the same manner as in [Example 2-1]. HPLC analysis at the end of the reaction revealed that the purity of compound (A) in the product was 96.6% and the content of compound (X1) was 0.14%.

[0152] Water (40 mL) was added to the organic layer (MEK solution, MEK 20 mL), which was the reaction mixture, and the mixture was cooled to 0° C. or higher and 10° C. or lower. Acetone (15 mL) was further added, and the mixing ratio of the mixed solvents in the reaction mixture was adjusted to MEK:acetone:water=1:0.75:2 by volume.

[0153] The content (purity) of compound (A) in the obtained product was 99.6% by HPLC analysis, and the product also contained 0.08% of compound (X1) by HPLC analysis.

[0154] As a result of the above investigation, it was found that when the volume ratio of the mixed solvent during crystallization is outside the range of MEK:acetone:water=1:1 to 4:1 to 6, it tends to be difficult to remove compound (X1) in particular.

[0155] [Example 2-4] (Step 1) Compound (1) (1 g), K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)) and furancarboxylic acid anhydride (0.53 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 6 hours.

[0156] Water (8 mL) was added to the resulting reaction solution, and the mixture was stirred for 1 hour. Toluene (5 mL) was added to separate the aqueous layer. Toluene (5 mL) was further added to the aqueous layer, and a separation operation was performed to obtain an aqueous solution of compound (Xb) as the aqueous layer.

[0157] HPLC analysis at the end of the reaction showed that the content of compound (Xb) in the product was 97.2%.Similarly, the content of compound (X1-1) in the product was 0.04%.

[0158] (Step 2) Acetone (7 mL) was added to the aqueous solution of compound (Xb) obtained in step 1, and the mixture was cooled to 0°C. Fluoroiodomethane (1.49 g, 1.1 equivalents relative to compound (1)) was added to the cooled solution, and the mixture was stirred for 1 hour. Water (10 mL) was added to the organic layer (acetone solution), which was the reaction mixture, and the mixture was filtered to obtain a mixture containing compound (A).

[0159] HPLC analysis at the end of the reaction showed that the content of compound (A) in the mixture was 97.51%, the content of compound (X1) was 0.31%, and the content of compound (X9) was 0.05%.

[0160] 2 g of the obtained mixture was dissolved in MEK (40 mL) at 40° C. To the obtained solution, acetone (40 mL) was added, and water (90 mL) was added dropwise so as not to lower the internal temperature. The obtained mixed solvent had a volume ratio of MEK:acetone:water=1:1:2.25.

[0161] After cooling to 0°C, the resulting crystals were filtered to obtain a composition containing 99.74% of compound (A), 0% of compound (X7), 0.02% of compound (X1), and 0.04% of compound (X9) (yield: 104%).

[0162] [Example 2-5] To an aqueous solution of compound (Xb) obtained according to (Step 1) of [Example 2-4], acetone (6 mL), tetrabutylammonium bromide (1.1 g, 1.8 equivalents relative to compound (1)), and fluoromethyl-4-methylbenzenesulfonate (0.43 g, 1.1 equivalents relative to compound (1)) were added at 25°C, and the temperature was raised to 55°C or higher and 60°C or lower, followed by stirring for 45 hours.

[0163] Water (5 mL) was added to the organic layer (acetone solution) of the reaction mixture, and the mixture was diluted with ethyl acetate (5 mL). The organic layer was then separated and concentrated to obtain a mixture containing compound (A).

[0164] HPLC analysis at the end of the reaction showed that the contents of compound (A), compound (X7), compound (X1), and compound (X9) in the mixture were 97.04%, 0.47%, 0.35%, and 0.05%, respectively.

[0165] 2 g of the obtained mixture was dissolved in MEK (40 mL) at 30° C. To the obtained solution, acetone (40 mL) was added, and water (60 mL) was added dropwise so as not to lower the internal temperature. The obtained mixed solvent had a volume ratio of MEK:acetone:water=1:1:1.5.

[0166] After cooling to 0°C, the resulting crystals were filtered to obtain a composition containing 99.7% of compound (A), 0.03% of compound (X7), 0.03% of compound (X1), and 0.03% of compound (X9) (yield: 75%).

[0167] [Example 2-6] A mixture containing compound (A) was obtained in the same manner as in [Example 2-4]. HPLC analysis at the end of the reaction revealed that the content of compound (A) in the mixture was 99.09%, the content of compound (X7), the content of compound (X1), and the content of compound (X9) were 0.06%.

[0168] 2 g of the above mixture was dissolved in MEK (40 mL) at 30° C. To the resulting solution, acetone (40 mL) was added, and water (100 mL) was added dropwise so as not to lower the internal temperature. The resulting mixed solvent had a volume ratio of MEK:acetone:water=1:1:2.5.

[0169] After cooling to 0°C, the resulting crystals were filtered to obtain a composition containing 99.6% of compound (A), 0% of compound (X7), 0.04% of compound (X1), and 0.04% of compound (X9) (yield: 101%).

[0170] In Examples 2-4 to 2-6, the volume ratio of the mixed solvent during crystallization was MEK:acetone:water=1:1 to 4:1 to 6, so that Compound (A) of high purity was suitably obtained.

[0171] Example 3: Examination of differences in synthesis methods of compound (A) In Example 3, the influence of differences in synthesis methods of compound (A) was confirmed.

[0172] Example 3-1 (Step 1) Under nitrogen, in acetone (10 mL), K ２ CO ３ Compound (1) (0.44 g, 1.3 equivalents relative to compound (1)) was suspended in the suspension, and then compound (1) (1 g) was added and cooled to 0° C. After cooling, 2-furoyl chloride (0.53 g, 1.05 equivalents relative to compound (1)) was added dropwise to the mixed suspension at 0 to 5° C. or below, and the mixture was stirred at room temperature for 24 hours.

[0173] Water (8 mL) and ethyl acetate (5 mL) were added to the resulting reaction solution, and the mixture was separated to obtain an aqueous solution of compound (Xb) as the aqueous layer. HPLC analysis at the end of the reaction revealed that the content of compound (Xb) in the product was 94.6%. Similarly, the content of compound (X1-1) in the product was 0.5%.

[0174] (Step 2) Tetrabutylammonium iodide (0.74 g, 0.43 equivalents relative to compound (1)) and sodium iodide (1.1 g, 3 equivalents relative to compound (1)) were suspended in MEK (5 mL), and a MEK solution (5 mL) of fluoromethyl-4-methylbenzenesulfonate (0.74 g, 1.5 equivalents relative to compound (1)) was added at 25° C. The mixture was heated at 79° C. for 2 hours to prepare a fluoroiodomethane solution.

[0175] The obtained fluoroiodomethane solution was added to MEK (10 mL) and the temperature was adjusted to 0 to 5°C. The aqueous solution of compound (Xb) prepared in step 1 was added to the fluoroiodomethane solution, and the mixture was stirred for 1 hour at 0 to 5°C. At the end of the reaction, 0.12% of compound (Xb) remained. At the end of the reaction, the purity of compound A by HPLC analysis was 89.7%, and the content of compound (X1) was 1.02%.

[0176] Water (15 mL) was added to the reaction solution, and the temperature was raised to 25 to 30° C., followed by the addition of acetone (20 mL). The resulting mixed solvent had a volume ratio of MEK:acetone:water=1:1:1.15.

[0177] The reaction mixture with the adjusted mixing ratio was cooled to 0° C. or higher and 5° C. or lower and stirred for 1 hour. The reaction mixture was filtered to obtain Compound A with a purity of 99.53% and containing 0.04% of Compound (X1) in a yield of 80.4%.

[0178] [Example 3-2] (Step 1) Compound (1) (1 g), K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)) and furancarboxylic acid anhydride (0.53 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 6 hours.

[0179] Water (8 mL) was added to the resulting reaction solution, and the mixture was stirred for 1 hour. Toluene (5 mL) was added to separate the aqueous layer. Toluene (5 mL) was further added to the aqueous layer, and a separation operation was performed to obtain an aqueous solution of compound (Xb) as the aqueous layer.

[0180] HPLC analysis at the end of the reaction showed that the content of compound (Xb) in the product was 97.2%.Similarly, the content of compound (X1-1) in the product was 0.04%.

[0181] (Step 2) Fluoroiodomethane (0.47 g, 1.2 equivalents relative to compound (1)) was added to acetone (5 mL) at 25° C. and cooled to 0° C. Water (3 mL) was added to the aqueous solution of compound (Xb) prepared in step 1, and then K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)) was added. That is, in this example, the reaction solvent during fluoromethylation was a mixed solvent of acetone and water.

[0182] While maintaining the internal temperature at 0 to 5° C. or lower, the aqueous solution of compound (Xb) was added dropwise to the fluoroiodomethane solution over 15 minutes, and the mixture was stirred for 1 hour while maintaining the internal temperature at 0 to 5° C. or lower to obtain compound (A). HPLC analysis at the end of the reaction showed that 2.2% of compound (Xb) remained after 1 hour.

[0183] To the resulting reaction mixture, MEK (10 mL) and water (10 mL) were added while maintaining the temperature at 0 to 5° C., and after the temperature was raised to around 10 to 15° C., acetone (15 mL) was added. The resulting mixed solvent had a volume ratio of MEK:acetone:water=1:2:2.1.

[0184] After standing at 0 to 5°C for 1 hour, filtration was carried out to obtain compound (A) as a white fine solid (dry yield: 1.07 g, 82% theoretical yield, purity 99.8%, each impurity content less than 0.05% (compound (X1) content 0.04%)).

[0185] From the above investigations, it was found that compound (A) obtained by various synthesis methods can be easily purified to a high purity by crystallization using a mixed solvent of MEK, acetone, and water.

[0186] On the other hand, a comparison of Example 3-2 with the above-mentioned Example 1-1 revealed that in Example 3-2, in which MEK was not contained in the system in Step 2, compound (Xb) was more likely to remain at the end of the reaction and the reaction addition rate tended to be lower than in Example 1-1, in which MEK was contained.

[0187] [Example 4: Confirmation of effect of repeated purification procedure] A mixture containing compound (A) was obtained according to the description in [Comparative Example 1-1]. HPLC analysis at the end of the reaction showed that the content of compound (A) in the mixture was 83.4%, the content of compound (X1) was 0.11%, the content of compound (X4) was 10.5%, and the content of other related impurities was 5.99%.

[0188] 1 g of the obtained mixture was dissolved in MEK (10 mL) at 50° C. To the obtained solution, acetone (20 mL) was added, and water (15 mL) was added dropwise so as not to lower the internal temperature, followed by cooling to 0 to 5° C. The obtained mixed solvent had a volume ratio of MEK:acetone:water=1:2:1.5.

[0189] The resulting crystals were filtered to obtain a composition containing 98.63% of compound (A), 0.01% of compound (X1), and 0.48% of compound (X4) (yield: 86%).

[0190] The obtained crystals were then dissolved in MEK (8.6 mL) at 40° C. Acetone (17.2 mL) was added to the obtained MEK solution, and water (12.6 mL) was added dropwise so that the internal temperature did not fall below 30° C., followed by cooling to 0-5° C. and stirring for 1 hour. The obtained mixed solvent had a volume ratio of MEK:acetone:water=1:2:1.47.

[0191] The resulting crystals were filtered to obtain a composition containing 99.5% of compound (A), 0.01% of compound (X1), and 0.04% of compound (X4) (yield: 87%).

[0192] From the above investigation, it was confirmed that the purity of compound (A) can be improved by repeating the purification method of the present invention using a mixed solvent of MEK, acetone, and water.

[0193] [Example 5: Detailed study of impurity removal] (Step 1) Compound (1) (10 g), K ２ CO ３ (4.69 g, 1.4 equivalents relative to compound (1)) and furancarboxylic acid anhydride (5.25 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 6 hours.

[0194] Water (80 mL) was added to the resulting reaction solution, and the mixture was stirred for 1 hour. Toluene (50 mL) was then added to separate the aqueous layer. Toluene (50 mL) was then added to the aqueous layer, and the layers were separated to obtain an aqueous solution of compound (Xb) as the aqueous layer.

[0195] HPLC analysis at the end of the reaction showed that the content of compound (Xb) in the product was 97.3%.Similarly, the content of compound (X1-1) in the product was 0.18%.

[0196] (Step 2) Fluoroiodomethane (4.65 g, 1.2 equivalents relative to compound (1)) was added to MEK (100 mL) at 25°C, and the mixture was cooled to 0°C.

[0197] Next, the aqueous solution of compound (Xb) obtained in step 1 was added dropwise to the fluoroiodomethane solution over 15 minutes. During the addition, the internal temperature was maintained at 5°C or below. The reaction was carried out with stirring for 2 hours while maintaining the internal temperature at 5°C or below. HPLC analysis at the end of the reaction showed that the purity of compound (A) in the product was 95.1% and the content of compound (X1) was 0.26%.

[0198] Water (100 mL) was added to the organic layer (MEK solution) of the reaction mixture, and the temperature was raised to 10 to 15°C. Acetone (150 mL) was further added, and the mixing ratio of the mixed solvents in the reaction mixture was adjusted to MEK:acetone:water = 1:1.5:1 by volume. The reaction mixture with the adjusted mixing ratio was filtered, and compound (A) was obtained in a theoretical yield of 74.1%.

[0199] The content (purity) of compound (A) in the obtained product was 99.79% by HPLC analysis. The product also contained less than 0.05% of each impurity (0.02% of compound (X1)) by HPLC analysis.

[0200] The removal rate of each impurity (compounds other than compound (A)) in Example 5 is shown in Table 1. The removal rate was calculated using the following formula: Removal rate (%) = {([content A] - [content B]) / [content A]} x 100 (content A: content in the product at the end of the reaction, content B: content in the product after filtration).

[0201] In Table 1, the HPLC peaks are numbered in order of elution time (RT), and each peak is treated as representing the corresponding compound, not as noise.

[0202] In the tables of this example, the content (%) of each compound is shown as determined from the HPLC peak area. Each value is calculated by calculating each peak area to three decimal places and then rounding to two decimal places. Therefore, the total content may exceed 100% or may be less than 100%.

[0203]

[0204] In the table, "-" indicates that the value was below the detection limit by HPLC. In calculating the removal rate, "-" is considered to be 0%. In addition, for No. 11, the value was below the detection limit in the product at the end of the reaction, but was detected in the product after filtration. Because the removal rate cannot be calculated due to the definition of the removal rate above, the removal rate for No. 11 is listed as "N / A" in Table 1. The same applies to the following tables.

[0205] As a result of the investigation, it was confirmed that the content of impurities having a skeleton represented by the following formula (X) (compounds (X1) to (X6)) was reduced by the purification method (production method) of the present invention using a mixed solvent of MEK, acetone, and water.

[0206] (wherein X is a hydrogen atom or a fluorine atom)

[0207] [Example 6: Examination of scale-up] [Example 6-1] Compound (A) was obtained in the same manner as in Example 5, except that 30 g of compound (1) as a starting material was used, and the amounts of other reagents, reaction solvents, and solvents used in the separation operation were three times those in Example 5.

[0208] Example 6-2 Compound (A) was obtained in the same manner as in Example 5, except that 100 g of compound (1) as a starting material was used, and the amounts of other reagents, reaction solvents, and solvents used in the separation operation were 10 times those in Example 5.

[0209] Regarding the removal rate of each impurity in Example 6, the results of Example 6-1 are shown in Table 2, and the results of Example 6-2 are shown in Table 3.

[0210]

[0211]

[0212] As a result of the investigation, it was found that according to the production method (purification method) of the present embodiment, it is possible to easily produce a large amount of highly pure compound (A) by crystallization using a mixed solvent of MEK, acetone, and water.

[0213] Example 7: Examination of inorganic salts In Example 7, the inorganic salt used in the synthesis of compound (Xb) was changed, and the influence thereof was examined.

[0214] [Example 7-1] (Step 1) Compound (1) (0.5 g), Li ２ CO ３ (0.13 g, 1.4 equivalents relative to compound (1)) and furancarboxylic acid anhydride (0.26 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 4 hours.

[0215] Water (4 mL) was added to the resulting reaction solution, and the mixture was stirred at 40°C for 2 hours. Toluene (2.5 mL) was then added, and the mixture was stirred and allowed to stand, and the aqueous layer was separated. Furthermore, acetone (2.5 mL) and toluene (2.5 mL) were added to the aqueous layer, and the mixture was stirred and allowed to stand, and the aqueous layer was separated. Acetone (2.5 mL) was added to the aqueous layer, and the mixture was stirred, to obtain an aqueous solution of compound (Xb).

[0216] (Step 2) Fluoroiodomethane (0.23 g, 1.2 equivalents relative to compound (1)) was added to methyl ethyl ketone (5 mL) and cooled to 0° C. Water (1.5 mL) was added to the aqueous solution of compound (Xb) prepared in step 1, and then Li ２ CO ３ (0.13 g, 1.4 equivalents relative to compound (1)) was added.

[0217] While maintaining the temperature at 0 to 5°C, the aqueous solution of compound (Xb) was added dropwise to the fluoroiodomethane solution, and the mixture was stirred for 3 hours to obtain compound (A).

[0218] To the resulting reaction mixture, water (5 mL) and acetone (7.5 mL) were added while maintaining the temperature at 0 to 5°C, and the mixture was allowed to stand for 1 hour and then filtered to obtain compound (A) with a purity of 99.4% and a theoretical yield of 100%.

[0219] [Example 7-2] In (Step 1), Li ２ CO ３ Instead of Na ２ CO ３ (0.18 g, 1.4 equivalents relative to compound (1)) was added, and in (step 2), Li ２ CO ３ Instead of Na ２ CO ３ A reaction mixture containing compound (A) was obtained in the same manner as in Example 7-1, except that 0.18 g (1.4 equivalents relative to compound (1)) was added.

[0220] To the resulting reaction mixture, water (5 mL) and acetone (7.5 mL) were added while maintaining the temperature at 0 to 5°C, and the mixture was allowed to stand for 1 hour and then filtered to obtain compound (A) with a purity of 99.6% and a theoretical yield of 100%.

[0221] [Example 7-3] In (Step 1), Li ２ CO ３ Instead of Cs ２ CO ３ (0.55 g, 1.4 equivalents relative to compound (1)) was added, and in (step 2), Li ２ CO ３ Instead of Cs ２ CO ３ A reaction mixture containing compound (A) was obtained in the same manner as in Example 7-1, except that 0.55 g (1.4 equivalents relative to compound (1)) was added.

[0222] To the resulting reaction mixture, water (5 mL) and acetone (7.5 mL) were added while maintaining the temperature at 0 to 5°C, and the mixture was allowed to stand for 1 hour and then filtered to obtain compound (A) with a purity of 99.6% and a theoretical yield of 93%.

[0223] Regarding the removal rate of each impurity in Example 7, the results of Example 7-1 are shown in Table 4, the results of Example 7-2 are shown in Table 5, and the results of Example 7-3 are shown in Table 6.

[0224]

[0225]

[0226]

[0227] As a result of the investigation, it was found that, regardless of which inorganic salt was used, it was possible to easily produce a highly pure compound (A).

[0228] Example 8: Examination of solvent type In Example 8, the solvent used in the synthesis of compound (A) was changed, and the influence thereof was examined.

[0229] [Example 8-1] (Step 1) Compound (1) (1 g), K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)), and furancarboxylic acid anhydride (0.52 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 5 hours.

[0230] Water (8 mL) was added to the resulting reaction solution, and the mixture was stirred at 40°C for 2 hours. The mixture was cooled to 30°C, toluene (5 mL) was added, and the mixture was stirred and allowed to stand, and the aqueous layer was separated. Further, acetone (5 mL) and toluene (5 mL) were added to the aqueous layer, and the mixture was separated. Acetone (5 mL) was added and the mixture was stirred, and an aqueous solution of compound (Xb) was obtained as the aqueous layer.

[0231] (Step 2) Fluoroiodomethane (0.47 g, 1.2 equivalents relative to compound (1)) was added to DMF (10 mL) at 28° C. and cooled to 0° C. Water (3 mL) was added to the aqueous solution of compound (Xb) prepared in step 1, and then K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)) was added.

[0232] While maintaining the internal temperature at 0 to 5°C or below, the aqueous solution of compound (Xb) was added dropwise to the fluoroiodomethane solution, and the mixture was stirred for 3 hours while maintaining the internal temperature at 0 to 5°C or below to obtain compound (A).

[0233] To the resulting reaction mixture, water (10 mL) and acetone (15 mL) were added while maintaining the temperature at 0 to 5°C, and the mixture was allowed to stand for 1 hour and then filtered to obtain Compound (A) (dry yield: 1.21 g, 93% theoretical yield, purity 96.9%) as a white fine solid.

[0234] [Example 8-2] (Step 1) Compound (1) (1 g), K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)), and furancarboxylic acid anhydride (0.52 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 4 hours.

[0235] Water (8 mL) was added to the resulting reaction solution, and the mixture was stirred for 2 hours at 40° C. The mixture was cooled to 28° C., and the subsequent procedures were carried out in the same manner as in Example 8-1 to obtain an aqueous solution of compound (Xb).

[0236] (Step 2) Compound (A) was obtained as a white fine solid (dry yield: 1.21 g, 93% theoretical yield, purity 99.4%) in the same manner as in Example 8-1, except that THF (10 mL) was used instead of DMF.

[0237] [Example 8-3] (Step 1) Compound (1) (1 g), K ２ CO ３ (0.47 g, 1.4 equivalents relative to compound (1)), furancarboxylic acid anhydride (0.52 g, 1.05 equivalents relative to compound (1)) were added, and the mixture was stirred at 25° C. for 3 hours.

[0238] Water (8 mL) was added to the resulting reaction solution, and the mixture was stirred for 3 hours at 40° C. The mixture was cooled to 28° C., and the subsequent procedures were carried out in the same manner as in Example 8-1 to obtain an aqueous solution of compound (Xb).

[0239] (Step 2) CH instead of DMF ３ The procedure of Example 8-1 was repeated except that CN (10 mL) was used, to obtain Compound (A) (dry yield: 1.22 g, 94% theoretical yield, purity 98.6%) as a white fine solid.

[0240] Regarding the removal rate of each impurity in Example 8, the results of Example 8-1 are shown in Table 7, the results of Example 8-2 are shown in Table 8, and the results of Example 8-3 are shown in Table 9.

[0241]

[0242]

[0243]

[0244] As a result of the investigation, it was found that, regardless of which solvent was used, it was possible to easily produce a highly pure compound (A).

[0245] Example 9: Production of compound (X1-1) In the following examples, HPLC analysis was carried out using the analytical method described below.

[0246] <Analysis method> Column: Thermo Hypersil BDS C18 (4.6 x 250 mm, 5 μm) Column temperature: 30°C Mobile phase A: pH 3H ３ P.O. ４ Aqueous solution Mobile phase B: acetonitrile Gradient: A / B = 45 / 65 to A / B = 5 / 95, 70 min Detector: UV 239 nm

[0247] Compound (X1-1) was produced according to the following scheme.

[0248]

[0249] 1 g of compound (1) was dissolved in DMF (12 mL), and imidazole (1 g, 3 equivalents) was added, followed by heating at 90° C. for 3 hours.

[0250] After cooling to room temperature, the solvent was evaporated under reduced pressure, and 5% aqueous potassium carbonate solution (10 mL), toluene (10 mL), and acetone (10 mL) were added and stirred, and the aqueous layer was separated. Toluene (10 mL) was added to the resulting aqueous layer, and the mixture was stirred, and the aqueous layer was separated.

[0251] To the aqueous layer, 29% aqueous ammonium chloride solution (7.5 mL) and acetone (10 mL) were added and stirred, and then the organic layer was separated.

[0252] The solvent was distilled off under reduced pressure to give compound (X1-1) with a purity of 81.8% as determined by HPLC analysis, in a theoretical yield of 27%.

[0253] Example 10: Preparation 1 of compound (X1) Compound (X1) was prepared according to the following scheme.

[0254]

[0255] 500 mg of compound (1) was dissolved in DMF (5 mL), and imidazole (82 mg, 1 equivalent relative to compound 1) was added, followed by heating at 100° C. for 5 hours.

[0256] After cooling to room temperature, 5% aqueous potassium carbonate solution (20 mL) and toluene (20 mL) were added, and the aqueous layer was separated. The separated aqueous layer was slowly added dropwise to a solution of fluoroiodomethane in MEK (380 mg, 2 equivalents relative to compound (1)) cooled to 0°C, and the mixture was stirred at 0°C for 1 hour.

[0257] Ethyl acetate (200 mL) was added to the stirred reaction solution, and the organic layer was separated and washed with a 5% aqueous potassium carbonate solution (20 mL) and a 0.25 N aqueous hydrochloric acid solution (50 mL) in that order. The organic layer was then concentrated under reduced pressure to obtain a reaction mixture containing compound (X1).

[0258] The reaction mixture was separated by silica gel flash chromatography to obtain compound (X1) with a purity of 92.7% as determined by HPLC analysis, in a theoretical yield of 21%. １ H-NMR (400 MHz, solvent: deuterated DMSO) and １３ The product was confirmed by C-NMR (100 MHz, solvent: deuterated DMSO). The spectral data of each NMR is shown in Table 4. The numbers of hydrogen and carbon atoms shown in Table 4 correspond to the numbers in formula (X1) below.

[0259]

[0260]

[0261] Example 11: Preparation 2 of compound (X1) Compound (1) (5 g), DMF (60 mL), and imidazole (830 mg, 1 equivalent relative to compound (1)) were placed in a flask and heated at 100° C. for 8 hours. After cooling in air, the DMF was removed using an evaporator.

[0262] Acetone (60 mL), water (50 mL), toluene (50 mL), and potassium carbonate (5 g, 3 equivalents relative to compound (1)) were added to the resulting reaction solution, followed by separation, and the organic layer was removed. Toluene (50 mL) was added again, followed by separation, to obtain an aqueous layer.

[0263] The resulting aqueous layer was mixed with an aqueous solution of potassium carbonate (3.4 g, 2 equivalents relative to compound (1)) dissolved in water (15 mL) to obtain a mixed solution, which was then added dropwise to a MEK solution (50 mL) of fluoroiodomethane (2 g, 2.4 equivalents relative to compound (1)) cooled to 0°C, and the mixture was stirred at 0°C for 5.5 hours.

[0264] After stirring, ethyl acetate (100 mL) was added to the reaction mixture, followed by separation of the organic layer. Water (100 mL) was added to the organic layer, and the mixture was again separated.

[0265] The obtained crystals (reaction mixture) were separated using a column to obtain compound (X1). The compound obtained was identified as compound (X1) by the following: １ H-NMR (400 MHz, solvent: deuterated DMSO) and １３ The product was confirmed by C-NMR (100 MHz, solvent: deuterated DMSO).

[0266] From the above results, it was confirmed that the present invention is useful.

Claims

1. A composition comprising a compound represented by the following formula (A) and an impurity represented by the following formula (X1), wherein the composition contains 99.2% or more of the compound and more than 0% and less than 0.05% of the impurity relative to the entire composition.

2. A method for producing fluticasone furoate, comprising the steps of: obtaining a reaction mixture containing a compound represented by the following formula (A) and an impurity having a skeleton represented by the following formula (X); and purifying the compound represented by the following formula (A) by crystallizing it from the reaction mixture in a mixed liquid having a volume ratio of methyl ethyl ketone:acetone:water=1:1-4:1-6. (wherein X is a hydrogen atom or a fluorine atom).

3. The method for producing fluticasone furoate according to claim 2, wherein the step of obtaining a reaction mixture comprises the steps of reacting a compound represented by the following formula (1), furoic anhydride, and an inorganic salt, and fluoromethylating the product of the reaction step, wherein the inorganic salt is at least one selected from the group consisting of alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal hydroxides, and alkali metal hydrogen carbonates.

4. The process for preparing fluticasone furoate according to claim 3, wherein the fluoromethylation step is carried out after the step of reacting with an inorganic salt without isolating the product.

5. The inorganic salt is Li ２ CO ３ , LiOH, CsCO ３ , KOH, NaOH, Na ２ CO ３ , NaHCO ３ , KHCO ３ , K ２ CO ３ , CaCO ３ and Ca(OH) ２ The method for producing fluticasone furoate according to claim 3 or 4, wherein the compound is at least one selected from the group consisting of:

6. The method for producing fluticasone furoate according to claim 3 or 4, wherein in the fluoromethylation step, the product is reacted with either or both of fluoroiodomethane and fluoromethyl p-toluenesulfonate.

7. The fluoromethylation step is carried out using DMF, CH ３ 5. The process for preparing fluticasone furoate according to claim 3 or 4, which is carried out in a mixed solvent of water and two solvents selected from the group consisting of CN, THF, methyl ethyl ketone and acetone.

8. The method for producing fluticasone furoate according to claim 7, wherein the mixed solvent is a mixed solvent of methyl ethyl ketone, acetone and water, and the purifying step comprises the steps of: adjusting, after the fluoromethylation step, a mixing ratio of the mixed solvent contained in the reaction mixture of the fluoromethylation step to a volume ratio of methyl ethyl ketone:acetone:water=1:1 to 4:1 to 6; and filtering the reaction mixture having the mixed solvent ratio adjusted.

9. A method for purifying fluticasone furoate, comprising mixing a mixture of a compound represented by the following formula (A) and an impurity having a skeleton represented by the following formula (X) with a mixed liquid having a volume ratio of methyl ethyl ketone:acetone:water=1:1-4:1-6, followed by filtering. (wherein X is a hydrogen atom or a fluorine atom).

10. A method for producing a labeled compound, comprising the step of heating a compound represented by the following formula (1) in DMF in the presence of imidazole:

11. The method for producing a labeled compound according to claim 10, further comprising a step of fluoromethylating the reaction product obtained in the heating step.

Images