Method for producing compound

Abstract

This method for producing a compound represented by formula (3) includes a step in which a compound represented by formula (1) is reacted with an organolithium compound, and subsequently reacted with a compound represented by formula (2) (in the formula, X is a halogen atom, and Pro is a protecting group) in the presence of a coordinating additive, thereby obtaining a compound represented by the aforementioned formula (3) (in the formula, Pro is the same as defined for the aforementioned formula (2)).

Description

Compound manufacturing method

[0001] The present disclosure relates to methods for making compounds.

[0002] The present disclosure relates to a method for producing 3-[5-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-2-thienyl]-2,2-dimethylpropanoic acid or an intermediate thereof. This application claims priority to Japanese Patent Application No. 2023-173845, filed October 5, 2023, the contents of which are incorporated herein by reference.

[0003] Patent Document 1 discloses a method for synthesizing the hydrochloride salt of 3-[5-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-2-thienyl]-2,2-dimethylpropanoic acid represented by the following formula:

[0004] Specifically, in Patent Document 1, in the synthesis process of the above compound, 5-methylthiophene-2-carboxylic acid is reacted with NaH, then with lithium diisopropylamide (LDA), and further with 2-bromoisobutyric acid tert-butyl ester to synthesize 5-(2-tert-butoxycarbonyl-2-methylpropyl)thiophene-2-carboxylic acid as an intermediate.

[0005] International Publication No. 2015 / 137408

[0006] The present disclosure relates to a novel method for producing 3-[5-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-2-thienyl]-2,2-dimethylpropanoic acid (also referred to as "compound represented by formula (6)" or "compound (6)") or an intermediate thereof.

[0007] In the present disclosure, a coordinating additive is used in the synthesis of an intermediate of compound (6). Examples of new methods for producing compound (6) or its intermediate include the following embodiments:

[0008] [1] Formula (1): is reacted with an organolithium compound, followed by reaction of a compound represented by formula (2): [wherein X is a halogen atom and Pro is a protecting group] in the presence of a coordinating additive to obtain a compound represented by formula (3): [wherein Pro is as defined in formula (2)]. [2] A method for producing a compound represented by formula (3), comprising the step of obtaining a compound represented by formula (3). [2] The method for producing a compound represented by formula (3), wherein the coordinating additive comprises at least one structure selected from the group consisting of a tertiary amine structure, an amide structure, a urea structure, a phosphoramide structure, and a sulfoxide structure. [3] The method for producing a compound represented by formula (1) or (2), wherein the coordinating additive comprises a urea structure or an amide structure. [4] The method for producing a compound represented by formula (1) to (3), wherein the coordinating additive comprises a cyclic urea structure. [5] The method for producing a compound represented by formula (1) to (4), wherein the coordinating additive comprises 1,3-dimethyl-2-imidazolidinone or N,N'-dimethylpropyleneurea. [6] The method for producing a compound represented by formula (2), wherein Pro is a tert-butyl group. [7] A step of obtaining a compound represented by formula (3) according to the production method according to any one of [1] to [6], and a step of reacting the compound represented by formula (3) with a compound represented by formula (4): or a salt thereof to form a compound represented by formula (5): [wherein Pro is as defined in formula (2)] or a salt thereof, and a method for producing a compound represented by formula (5) or a salt thereof, the method comprising the steps of: [8] obtaining a compound represented by formula (5) or a salt thereof according to the production method described in [7]; and deprotecting the compound represented by formula (5) or a salt thereof to obtain a compound represented by formula (6): [9] A method for producing a compound represented by formula (6) or a salt thereof, comprising the steps of: obtaining a compound represented by formula (6) or a salt thereof; and

[10] The method for producing a compound represented by formula (6) or a salt thereof, further comprising the step of crystallizing the compound represented by formula (6) or a salt thereof to increase its purity.

[11] The method for producing a compound represented by formula (6) or a salt thereof, comprising the steps of: obtaining a compound represented by formula (6) or a salt thereof;

[12] The method for producing a compound represented by formula (6) or a salt thereof,

[0009] A new method for producing compound (6) or an intermediate thereof is provided.

[0010] Hereinafter, embodiments of the method for producing compound (6) or an intermediate thereof will be specifically described, but various modifications are possible without departing from the spirit of the invention. Hereinafter, the compounds represented by formulas (1) to (5) will also be referred to as compounds (1) to (5), respectively.

[0011] <Synthetic Route> The synthetic route for compound (6) according to the present disclosure is outlined below. Each step will be specifically described below. According to the production method of the present disclosure, the use of flammable reagents (e.g., NaH) can be avoided, and the production of by-products can be suppressed, thereby improving the yield of compound (6). Furthermore, according to the production method of the present disclosure, reproducibility is good even when compound (6) is synthesized in large quantities.

[0012] <Method of Producing Compound (3)> One embodiment is a method of producing a compound (3) by a method according to formula (1): is reacted with an organolithium compound, followed by reaction of a compound represented by formula (2): [wherein X is a halogen atom and Pro is a protecting group] in the presence of a coordinating additive to obtain a compound represented by formula (3): [wherein Pro is as defined in formula (2)].

[0013] [Step 1] In this embodiment, first, compound (1) is reacted with an organolithium compound. By this reaction, compound (1) is lithiated. "Lithiation" means substituting a hydrogen atom of compound (1) with a lithium atom.

[0014] The organolithium compound may be any compound capable of lithiating compound (1). Examples of the organolithium compound include lithium amide and alkyllithium. Examples of the lithium amide include lithium diisopropylamide, lithium-2,2,6,6-tetramethylpiperidide, and lithium hexamethyldisilazide. Examples of the alkyllithium include n-butyllithium, sec-butyllithium, tert-butyllithium, and methyllithium.

[0015] The molar ratio of the organolithium compound to the compound (1) is preferably 2.0 to 3.0, more preferably 2.0 to 2.2.

[0016] The reaction of compound (1) with an organolithium compound is preferably carried out in a solvent. The solvent is preferably one that does not inhibit the lithiation of compound (1). Examples of the solvent include ether solvents, hydrocarbon solvents, and mixed solvents thereof. Examples of the ether solvent include tetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether. Examples of the hydrocarbon solvent include cyclohexane and hexane.

[0017] The reaction temperature of the compound (1) with the organolithium compound is preferably -80 to 0°C, more preferably -50 to -10°C, and even more preferably -30 to -20°C.

[0018] [Second Step] In the present embodiment, secondly, compound (1) that has been reacted with an organolithium compound is reacted with compound (2) in the presence of a coordinating additive to obtain compound (3).

[0019] X in the formula (2) of the compound (2) is a halogen atom, preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and more preferably a bromine atom.

[0020] Pro in formula (2) of compound (2) is a protecting group. The protecting group is preferably stable under basic conditions and can be deprotected under acidic conditions. Examples of the protecting group include an alkyl group. Although not particularly limited, the protecting group is preferably an alkyl group having 1 to 4 carbon atoms, more preferably a tert-butyl group.

[0021] The molar ratio of compound (2) to compound (1) is preferably 1.0 to 3.0, more preferably 1.2 to 2.0.

[0022] The coordinating additive is preferably an additive capable of coordinating to a lithium atom. The reason why the yield of compound (3) is improved by using a coordinating additive is assumed to be that the lithiated compound (1) exists in an associated state with itself, but the addition of a coordinating additive breaks the associated state, thereby improving the reactivity of the lithiated compound (1). However, the present embodiment is not limited by the assumed reason.

[0023] Examples of the partial structure of the coordinating additive include a tertiary amine structure, an amide structure, a urea structure, a phosphoramide structure, and a sulfoxide structure.

[0024] The coordinating additive can be appropriately selected from those having a preferred partial structure suitable for commercial mass production of compound (6) based on various viewpoints. From such viewpoints, for example, from the viewpoint of increasing the production amount of compound (3), the coordinating additive preferably contains at least one structure selected from the group consisting of an amide structure, a urea structure, a phosphoramide structure, and a sulfoxide structure, more preferably contains at least one structure selected from the group consisting of an amide structure, a urea structure, and a phosphoramide structure, further preferably contains a urea structure, and particularly preferably contains a cyclic urea structure.

[0025] From another viewpoint, for example, from the viewpoint of reducing the remaining amount of compound (1), the coordinating additive preferably contains at least one structure selected from the group consisting of a tertiary amine structure, an amide structure, a urea structure, and a phosphoramide structure, and more preferably contains at least one structure selected from the group consisting of a tertiary amine structure, a urea structure, and a phosphoramide structure.

[0026] Furthermore, from another viewpoint, for example, from the viewpoint of reducing the amount of by-products produced, the coordinating additive preferably contains at least one structure selected from the group consisting of an amide structure, a urea structure, a phosphoramide structure, and a sulfoxide structure, more preferably contains at least one structure selected from the group consisting of an amide structure, a urea structure, and a sulfoxide structure, and even more preferably contains at least one structure selected from the group consisting of an amide structure and a sulfoxide structure.

[0027] More specific examples of the coordinating additive include 1,3-dimethyl-2-imidazolidinone (DMI), N,N'-dimethylpropyleneurea (DMPU), tetramethylurea (TMU), N-methyl-2-pyrrolidone (NMP), hexamethylphosphoric triamide (HMPA), tetramethylethylenediamine (TMEDA), dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO).

[0028] The coordinating additive can be appropriately selected from various viewpoints, and is suitable for commercial mass production of compound (6). From such viewpoints, for example, from the viewpoint of increasing the production amount of compound (3), the coordinating additive preferably contains at least one selected from the group consisting of DMI, DMPU, TMU, NMP, HMPA, DMAC, and DMSO, more preferably contains at least one selected from the group consisting of DMI, DMPU, NMP, HMPA, and DMAC, and even more preferably contains at least one selected from the group consisting of DMI and DMPU.

[0029] From another viewpoint, for example, from the viewpoint of reducing the remaining amount of compound (1), the coordinating additive preferably contains at least one selected from the group consisting of DMI, DMPU, TMU, NMP, HMPA, TMEDA, and DMAC, more preferably contains at least one selected from the group consisting of DMI, DMPU, NMP, HMPA, TMEDA, and DMAC, and further preferably contains at least one selected from the group consisting of DMI, DMPU, HMPA, and TMEDA.

[0030] From another viewpoint, for example, from the viewpoint of reducing the amount of by-products produced, the coordinating additive preferably contains at least one selected from the group consisting of DMI, DMPU, TMU, NMP, HMPA, DMAC, and DMSO, and more preferably contains at least one selected from the group consisting of DMI, DMPU, TMU, NMP, DMAC, and DMSO.

[0031] The coordinating additive is preferably selected based on one or more of the above viewpoints, more preferably selected based on at least one viewpoint including either the viewpoint of increasing the amount of compound (3) produced or the viewpoint of reducing the amount of compound (1) remaining, and even more preferably selected based on at least two viewpoints including the viewpoint of increasing the amount of compound (3) produced and the viewpoint of reducing the amount of compound (1) remaining.

[0032] The molar ratio of the coordinating additive to the compound (1) is preferably 1.0 to 20, more preferably 4.0 to 8.0.

[0033] The reaction of compound (1) reacted with an organolithium compound with compound (2) is preferably carried out in a solvent, such as the solvents exemplified in the above [Step 1].

[0034] The reaction temperature of compound (1) reacted with an organolithium compound and compound (2) is preferably −80 to 0° C., more preferably −50 to −10° C., and even more preferably −30 to −20° C.

[0035] Compound (3) may be produced by a batch process or a flow process (including, but not limited to, continuous synthesis, flow chemistry, etc.). Flow chemistry is a continuous synthesis method using a reaction apparatus in which two or more different solutions (e.g., raw materials and solvent, reagents and solvent, etc.) are transferred from a container to a reaction container and then to a recovery container (recovery device) through a piping (flow path) at a constant flow rate using a transport device (which may also be referred to as a liquid infusion device, liquid delivery device, etc.).

[0036] In one embodiment, the flow method preferably includes mixing a solution stream of compound (1) with a solution stream of an organolithium compound to obtain a first mixed stream; and mixing the first mixed stream with a solution stream of compound (2) and a coordinating additive to obtain a second mixed stream containing compound (3). The solution stream of compound (2) and the coordinating additive may be a single solution stream in which compound (2) and the coordinating additive are mixed, or may be two different solution streams, one for compound (2) and the other for the coordinating additive. The present disclosure does not particularly limit the definition of the "mixed stream" in the flow method. Those skilled in the art may appropriately mix solution streams containing any compound, organolithium compound, coordinating additive, and / or optional reagents other than those described above, as long as the mixture does not violate the production method described in the present disclosure, and refer to the resulting mixture as a "mixed stream." For example, a solution flow of an organolithium compound and a solution flow of any reagent may be mixed to form a first mixed flow, a mixed flow of the first mixed flow and a solution flow of compound (1) may be formed as a second mixed flow, or a mixed flow of the second mixed flow and a solution flow of compound (2) may be formed as a third mixed flow.

[0037] The use of the flow method can suppress decomposition of an unstable intermediate produced by the reaction of compound (1) with an organolithium compound, thereby improving the yield of compound (3). Furthermore, the use of the flow method allows for a higher reaction temperature to be employed compared to the batch method, thereby reducing costs in terms of energy consumption.

[0038] <Method for producing compound (5) or a salt thereof> One embodiment includes the steps of obtaining a compound represented by formula (3) according to the above-mentioned production method (<Method for producing compound (3)>), and reacting the compound represented by formula (3) with a compound represented by formula (4): or a salt thereof to form a compound represented by formula (5): [wherein Pro is as defined in formula (2)] or a salt thereof; and

[0039] [Activation of Compound (3)] This embodiment also encompasses an embodiment in which compound (3) is activated before being reacted with compound (4) or a salt thereof. Examples of activation of compound (3) include reacting compound (3) with an acid halide agent to form an acid halide. Examples of acid halide agents include thionyl chloride and oxalyl chloride.

[0040] The molar ratio of the acid halogenating agent to the compound (3) is preferably 1.0 to 5.0, more preferably 1.0 to 1.5.

[0041] The reaction of compound (3) with an acid halogenating agent is preferably carried out in the presence of a catalytic amount of an additive, such as DMF or pyridine.

[0042] The reaction of compound (3) with an acid halogenating agent is preferably carried out in a solvent. Examples of the solvent include ether solvents, nitrile solvents, ester solvents, and mixtures thereof. Examples of the ether solvent include methyl tert-butyl ether, cyclopentyl methyl ether, and tetrahydrofuran. Examples of the nitrile solvent include acetonitrile and propionitrile. Examples of the ester solvent include methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and n-propyl acetate.

[0043] The reaction temperature of the compound (3) with the acid halogenating agent is preferably 0 to 50°C, more preferably 0 to 25°C, and even more preferably 0 to 10°C.

[0044] [Reaction with Compound (4) or a Salt Thereof] Examples of salts of compound (4) include hydrochloride, ammonium salt, and mixed salts thereof.

[0045] The molar ratio of compound (4) or a salt thereof to compound (3) is preferably 1.0 to 2.0, more preferably 1.0 to 1.5.

[0046] The reaction of compound (3) with compound (4) or a salt thereof is preferably carried out in the presence of a base, such as pyridine.

[0047] The reaction of compound (3) with compound (4) or a salt thereof is preferably carried out in a solvent, such as the solvents exemplified above in [Activation of compound (3)].

[0048] The reaction temperature of the compound (3) and the compound (4) or a salt thereof is preferably -20 to 20°C, more preferably -10 to 0°C.

[0049] Examples of salts of compound (5) include trifluoroacetate, hydrochloride, formate, oxalate, fumarate, maleate, and tosylate. Compound (5) can be converted into a trifluoroacetate to facilitate isolation and purification by crystallization.

[0050] <Method for producing compound (6) or a salt thereof> One embodiment includes the steps of obtaining a compound represented by formula (5) or a salt thereof according to the above-mentioned production method (<Method for producing compound (5)>), and deprotecting the compound represented by formula (5) or a salt thereof to obtain a compound represented by formula (6): and a process for producing a compound represented by formula (6) or a salt thereof.

[0051] For deprotection of compound (5) or a salt thereof, appropriate conditions may be selected depending on the type of protecting group. For example, when the protecting group is a tert-butyl group, deprotection is preferably carried out with an acid (preferably hydrochloric acid).

[0052] The deprotection of compound (5) or a salt thereof is preferably carried out in a solvent. Examples of the solvent include ether solvents, ester solvents, nitrile solvents, halogenated solvents, aromatic hydrocarbon solvents, water, and mixed solvents thereof. Examples of the ether solvent include cyclopentyl methyl ether, diethyl ether, and dioxane. Examples of the ester solvent include methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and n-propyl acetate. Examples of the nitrile solvent include acetonitrile and propionitrile. Examples of the halogenated solvent include dichloromethane, trichloroethylene, perchloroethylene, and 1,2-dichlorobenzene. Examples of the aromatic hydrocarbon solvent include benzene, toluene, and xylene.

[0053] The salt of compound (6) is preferably the hydrochloride salt.

[0054] (Purification Step) This embodiment may further include a step of crystallizing compound (6) or a salt thereof to increase its purity. Examples of crystallization solvents include water, alcoholic solvents, and mixed solvents thereof. Examples of alcoholic solvents include 2-propanol and ethanol. Although not particularly limited, the crystallization solvent is preferably a mixed solvent of water and 2-propanol.

[0055] Example 1 [Step 1] Under a nitrogen flow, tetrahydrofuran (2.2 L) and diisopropylamine (220 mL) were added to the reaction vessel. After cooling the reaction solution to -30°C, a 2.66 M hexane solution (600 mL) of n-butyllithium was added dropwise at 0°C or below. After stirring for 30 minutes, a solution of compound 1 (5-methyl-2-thiophenecarboxylic acid, 110.3 g) in tetrahydrofuran (495 mL) was added dropwise at -25°C or below, and the dropping funnel was washed with tetrahydrofuran (110 mL). After stirring for 30 minutes, a mixed solution of compound 2 (tert-butyl 2-bromoisobutyrate, 259.0 g) and 1,3-dimethyl-2-imidazolidinone (529.4 g) was added dropwise at -20°C or below. After stirring for 30 minutes, 2.0 M hydrochloric acid (1.2 L) was added dropwise while the temperature was raised to 0°C. The reaction solution was warmed to room temperature and then concentrated under reduced pressure, and ethyl acetate (1.1 L) was added. After separation into an aqueous layer and an organic layer, the aqueous layer was further extracted with ethyl acetate (1.1 L), and the resulting organic layers were mixed. The combined organic layers were washed with 20% aqueous sodium chloride solution (1.1 L), followed by washing three times with 1.0 M hydrochloric acid (1.7 L) and once with 20% aqueous sodium chloride solution (1.1 L), sequentially. After concentrating the organic layer under reduced pressure, ethyl acetate (77 mL) and heptane (1.5 L) were added, and the mixture was heated to 60°C. Activated carbon (11.3 g) was added and stirred for 1 hour. Insoluble matter was removed by filtration through Celite, and then washed with a mixed solution of ethyl acetate (33 mL) and heptane (626 mL). The filtrate was concentrated under reduced pressure to 660 mL, heated to 55°C, cooled to -15°C, and stirred. The precipitated crystals were washed with heptane and dried under reduced pressure to obtain compound 3 (158.2 g). １ H-NMR (500MHz, CDCl ３ ) δ: 7.72 (d, J=3.8Hz, 1H), 6.83 (d, J=3.7Hz, 1H), 3.06 (s, 2H), 1.46 (s, 9H), 1.19 (s, 6H). １３ C-NMR (126MHz, CDCl ３ ) δ: 175.92, 167.45, 150.41, 134.84, 130.97, 128.22, 80.83, 43.98, 40.63, 27.98, 25.23. LC-MS (ESI, m / z): 283 [M-H] -

[0056] [Step 2] Under an argon atmosphere, compound 3 (17.50 g) was dissolved in MTBE (35 mL), MeCN (17.5 mL), and pyridine (1.0 mL) and cooled to 10°C. Thionyl chloride (5.4 mL) was added dropwise at an internal temperature of 15°C or below, and the mixture was stirred at the same temperature for 1 hour to prepare an acid chloride. Under an argon atmosphere, compound 4 (12.78 g) and MeCN (130 mL) were added to a separate container and cooled to -5°C. The MTBE / MeCN solution of the acid chloride obtained above was added dropwise to the MeCN solution of compound 4 at an internal temperature of 0°C or below, and the mixture was washed in with MeCN (10 mL). Pyridine (14.9 mL) was added at an internal temperature of 0°C or below, and the mixture was stirred for 3 hours. TFA (15.1 mL) was added at an internal temperature of 0°C or below, followed by stirring at an internal temperature of 10°C for 16 hours, and then water (315 mL) was added dropwise at an internal temperature of 15°C or below. After stirring at 10°C for 3.5 hours, the reaction mixture was filtered and washed with cold 40% MeCN aq. (70 mL). The resulting wet crystals were dried under reduced pressure at 50°C for 19 hours to obtain crude crystals of compound 5 (31.86 g). The resulting crude crystals (10.0 g) were suspended in MeCN (50 mL) and stirred at 50°C for 2 hours, then cooled to -5°C over 1 hour and stirred at the same temperature for 1 hour. The mixture was filtered and washed with water (40 mL). The resulting wet crystals were dried under reduced pressure at 50°C for 15 hours to obtain compound 5 (7.77 g). １ H-NMR (500MHz, DMSO) δ: 9.43 (s, 2H), 9.29 (s, 2H), 7.99 to 7.90 (m, 2H), 7.81 to 7.72 (m, 2H), 7.09 (d, J = 3.8Hz, 1H), 3.13 (s, 2H), 1.42 (s, 9H), 1.15 (s, 6H) LC-MS (ESI, m / z): 421 [M+H] ＋

[0057] [Step 3] Cyclopentyl methyl ether (100 mL) and compound 5 (20.00 g) were added to a reaction vessel and stirred, and then a 4 M cyclopentyl methyl ether hydrochloride solution (60 mL) and water (0.6 mL) were added at room temperature, and the mixture was stirred at 65°C for 6 hours. After the reaction was completed, the mixture was cooled to 20°C and stirred for 1 hour. The precipitate was filtered, washed with cyclopentyl methyl ether (40 mL), and dried in vacuo at 50°C to obtain crude crystals of compound 6 as a white to pale yellow powder (15.0 g).１ H-NMR (500MHz, DMSO) δ: 12.57 (s, 1H), 9.55 (s, 2H), 9.37 (s, 2H), 8.02 to 7.95 (m, 2H), 7.82 to 7.73 (m, 2H), 7.09 (d, J = 3.8Hz, 1H), 3.14 (s, 2H), 1.16 (s, 6H) LC-MS (ESI, m / z): 365 [M+H] ＋

[0058] [Step 4] 2-Propanol (60 mL), water (30 mL), and crude crystals of compound 6 (12.02 g) were added to a reaction vessel and cooled to 5°C. 1N aqueous sodium hydroxide solution (28.7 mL) was slowly added until the pH reached approximately 7.0, and the mixture was stirred at the same temperature for 1 hour. The precipitate was then filtered and washed with water (36 mL), and the wet crystals were transferred to another reaction vessel. 2-Propanol (60 mL) and water (30 mL) were then added, and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered, washed with water (36 mL), and vacuum dried at 50°C to obtain compound 6 (free form) as a white to pale yellow powder (10.8 g). 2-Propanol (20 mL), water (22 mL), and compound 6 (free form) (10.01 g) were added to a reaction vessel and stirred, and 6N aqueous hydrochloric acid solution (4.32 mL) was added at room temperature. The mixture was then stirred at 60°C, activated carbon (800 mg) was added, and the mixture was stirred for 1 hour. The mixture was cooled to 50°C and filtered, and the residue was washed with a hot mixed solvent (2-propanol (2.5 mL) and water (3.0 mL)) at 50°C. The filtrate was cooled to 45°C, and a solution prepared by diluting 6N aqueous hydrochloric acid (10 mL) with water (57 mL) was added, followed by stirring at the same temperature for 30 minutes. The precipitate was slowly cooled to 5°C and aged at the same temperature for 3 hours. The precipitate was filtered, washed with water (30 mL), and then vacuum dried at 50°C to obtain compound 6 as a white powder (9.69 g). １ H-NMR (500MHz, DMSO) δ: 12.57 (s, 1H), 9.55 (s, 2H), 9.37 (s, 2H), 8.02 to 7.95 (m, 2H), 7.82 to 7.73 (m, 2H), 7.09 (d, J = 3.8Hz, 1H), 3.14 (s, 2H), 1.16 (s, 6H) LC-MS (ESI, m / z): 365 [M+H] ＋

[0059] Examples 2 to 8 Compound 3 was synthesized in the same manner as in Example 1, except that various coordinating additives (6 molar equivalents relative to Compound 1) listed in Table 2 below were used instead of 1,3-dimethyl-2-imidazolidinone in Step 1 of Example 1.

[0060] Comparative Example 1 Compound 3 was synthesized in the same manner as in Example 1, except that 1,3-dimethyl-2-imidazolidinone was not used in Step 1 of Example 1.

[0061] The proportion of the product in each example and comparative example was measured by HPLC. The HPLC conditions were as follows: Column: InertSustain C18 φ4.6 mm × 150 mm, Particle size: 3 μm (GL-Sciences) Column temperature: constant temperature around 40°C Mobile phase A: water / TFA = 1000 / 1 (v / v) Mobile phase B: MeCN / TFA = 1000 / 1 (v / v) Flow rate: 1.0 ml / min Detection wavelength: 254 nm Gradient conditions: as shown in Table 1

[0062]

[0063] The results are shown in Table 2. In Table 2, the area percentage (area%) of Compound 3 is represented as "A" when it is 75% or more, "B" when it is 60% or more but less than 75%, and "C" when it is less than 60%. Furthermore, the area percentage (area%) of Compound 1 is represented as "A" when it is less than 10%, "B" when it is 10% or more but less than 20%, and "C" when it is 20% or more. Furthermore, the area percentage (area%) of By-Product 1 is represented as "A" when it is less than 15%, and "B" when it is 15% or more.

[0064]

[0065]

[0066]

[0067] <Method for synthesizing compound 3 (alternative method: flow method)> Compound 1 (5-methyl-2-thiophenecarboxylic acid, 0.889 g) was dissolved in tetrahydrofuran to prepare 25 mL of solution A. Diisopropylamine (1.265 g) was dissolved in tetrahydrofuran to prepare 50 mL of solution B. Compound 2 (tert-butyl 2-bromoisobutyrate, 2.092 g) and 1,3-dimethyl-2-imidazolidinone (4.281 g) were dissolved in tetrahydrofuran to prepare 25 mL of solution C. Solution B and a 2.66 M hexane solution of n-butyllithium were pumped separately, cooled to 0°C in a reaction tube, and then mixed to obtain a first mixed stream. Next, solution A was pumped and cooled to -20°C in a reaction tube, and then mixed with the first mixed stream to obtain a second mixed stream. Furthermore, solution C was pumped and cooled to 20°C in the reaction tube, and then mixed with the second mixed stream to obtain a third mixed stream. The third mixed stream (reaction solution) was collected in a receiver containing 2.0 M hydrochloric acid (9.46 g) cooled to 0°C. The reaction solution was warmed to room temperature, concentrated under reduced pressure, and ethyl acetate (8.89 mL) was added. After separation into aqueous and organic layers, the aqueous layer was further extracted twice with ethyl acetate (8.89 mL), and the resulting organic layers were mixed. The combined organic layer was washed with 20% aqueous sodium chloride solution (8.89 g), followed by washing three times with 1.0 M hydrochloric acid (13.3 g) and once with 20% aqueous sodium chloride solution (8.89 g). The organic layer was concentrated under reduced pressure, and ethyl acetate (0.70 mL) and heptane (12.4 mL) were added. The mixture was heated to 60°C, activated carbon (0.089 g) was added, and the mixture was stirred for 1 hour. After removing insoluble matter by filtration through Celite, the mixture was washed with a mixed solution of ethyl acetate (0.27 mL) and heptane (5.00 mL). The filtrate was concentrated under reduced pressure to 5.3 mL, cooled to -15°C, and stirred. The precipitated crystals were washed with heptane and dried under reduced pressure to obtain Compound 3 (1.16 g).

Claims

1. Formula (1): with an organolithium compound, followed by reaction of a compound represented by formula (2): [wherein X is a halogen atom and Pro is a protecting group] in the presence of a coordinating additive to obtain a compound represented by formula (3): [wherein Pro is as defined in formula (2)].

2. The method according to claim 1, wherein the coordinating additive comprises at least one structure selected from the group consisting of a tertiary amine structure, an amide structure, a urea structure, a phosphoramide structure, and a sulfoxide structure.

3. The method according to claim 1, wherein the coordinating additive comprises a urea structure or an amide structure.

4. The method according to claim 1, wherein the coordinating additive comprises a cyclic urea structure.

5. The method of claim 1, wherein the coordinating additive comprises 1,3-dimethyl-2-imidazolidinone or N,N'-dimethylpropylene urea.

6. The method according to claim 1, wherein Pro in the formula (2) is a tert-butyl group.

7. A process for obtaining a compound represented by formula (3) according to the process for producing a compound represented by formula (4): or a salt thereof to obtain a compound represented by the formula (5): [wherein Pro is as defined in formula (2)] or a salt thereof; and 8. A process for producing a compound represented by formula (5) or a salt thereof according to the process for producing a compound represented by formula (5) or a salt thereof, and a process for producing a compound represented by formula (6): or a salt thereof, 9. The method according to claim 8, further comprising a step of crystallizing the compound represented by formula (6) or a salt thereof to increase its purity.

10. The method according to claim 8, wherein the compound represented by formula (6) or a salt thereof is a hydrochloride salt of the compound represented by formula (6).

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