Method for producing acylthiourea compound

Abstract

The present invention relates to a method for producing 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, the method comprising a step for linking 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide and 2-phenylacetyl isothiocyanate.

Description

Method for producing acylthiourea compounds

[0001] The present invention relates to a method for producing an acylthiourea compound, and more particularly to a method for producing an acylthiourea compound that can be mass-produced.

[0002] When active pharmaceutical ingredients (APIs) are industrially produced, the process of producing APIs from raw materials requires a small number of steps and a high yield. Furthermore, because APIs must be mass-produced, procedures that are not suitable for mass production cannot be used. The quality of APIs produced by such processes must meet standards set by the International Council on Harmonization (ICH), including impurities, residual solvents, and residual metals contained in the APIs.

[0003] Patent Document 1 discloses that 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (hereinafter also referred to as Compound 1) is a compound having an antitumor effect. Patent Documents 2 and 3 disclose that Compound 1 exhibits therapeutic effects on osteoporosis and fibrosis. Patent Document 4 discloses that Compound 1 is administered to humans after forming a mesylate salt, and Patent Document 5 discloses an example of a pharmaceutical formulation of Compound 1.

[0004] Patent Document 1 describes the derivation of tert-butyl 4-chloro-7-methoxyquinoline-6-carboxylate from 4-hydroxy-7-methoxyquinoline-6-carboxylic acid. Compound 1 is then synthesized through the sequential steps of introducing nitrophenol into the tert-butyl 4-chloro-7-methoxyquinoline-6-carboxylate, reducing the nitro group, converting the aniline into an acylthiourea, deprotecting the carboxylic acid, and introducing methylamine.

[0005] Furthermore, Patent Document 1 discloses 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (hereinafter also referred to as analogue 1) as one of the precursors of acylthiourea derivatives.

[0006] International Publication No. WO 2009 / 125597 International Publication No. WO 2015 / 046484 International Publication No. WO 2016 / 208744 International Publication No. WO 2016 / 175305 International Publication No. WO 2018 / 151177

[0007] When manufacturing an API, a manufacturing method is required that consists of a small number of steps and that can obtain intermediates and API in high yields. Furthermore, these steps must include only simple operations and must not include operations that are not feasible for large-scale production. Furthermore, the manufactured API must meet the high quality required for pharmaceuticals.

[0008] In contrast, according to Patent Document 1, the production of Compound 1 includes steps of protecting and deprotecting the carboxylic acid with tert-butyl, and a production method with fewer steps is desired. However, a synthesis method for Compound 1 that does not include steps of protecting and deprotecting with tert-butyl has not been found. Furthermore, the process for producing Compound 1 described in Patent Document 1 includes purification by column chromatography, which is not suitable for mass production.

[0009] Furthermore, Patent Document 1 describes 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (hereinafter also referred to as Analog 1), but there is no example of directly deriving Compound 1 from Analog 1 by introducing an acylthiourea group, which is a partial structure of Compound 1. Furthermore, there is no description that such Analog 1 can be included in an API.

[0010] In view of the above circumstances, an object of the present invention is to provide a method for producing an acylthiourea compound having a specific structure that can be mass-produced when producing a mesylate salt of Compound 1 as an API.

[0011] As a result of intensive research into the above-mentioned problems, the present inventors have found a new method for producing Compound 1, which is useful as an API that can be mass-produced, and have further found that this production method can produce a mesylate salt of Compound 1, which is an API of a quality suitable for use as a pharmaceutical.

[0012] That is, the present invention provides the following [1] to [5]. [1] A method for producing 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, which comprises a step of linking 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide with 2-phenylacetyl isothiocyanate. [2] The production method according to [1] above, which comprises a step of obtaining the 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide by aminolysis of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate. [3] The production method according to [1] or [2] above, which comprises a step of obtaining the 2-phenylacetyl isothiocyanate by derivatization from 2-phenylacetyl chloride. [4] The method for producing a mesylate salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, comprising a step of producing a mesylate salt from 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide obtained by the method for producing a mesylate salt of ...

[0013] According to the present invention, the free form of Compound 1 can be synthesized from Analog 1 in one step, enabling mass production of API of a quality suitable for pharmaceutical use.

[0014] <<Method for Producing Compound 1>> One embodiment of the present invention relates to a method for producing 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide from 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, which involves the following reaction. That is, by employing a step of linking 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide with 2-phenylacetylisothiocyanate, compound 1 can be produced from analog 1. Note that in the structural formulae herein, Me represents a methyl group.

[0015]

[0016] 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide produced in this embodiment is an acylthiourea compound having the following structure, and is referred to as "Compound 1" in this specification.

[0017]

[0018] The free form of Compound 1 in this embodiment is a compound described in Patent Document 1 and can be produced by a commonly known method. Compound 1 or a pharmaceutically acceptable salt thereof is useful as an antitumor agent, a therapeutic agent for osteoporosis, and a therapeutic agent for fibrosis. Compound 1 is then converted from the free form to a mesylate salt, which is used as an API. The API is not administered to a patient as is, but rather a formulation is appropriately produced by a commonly known method, and the formulation is administered to a patient.

[0019] When Compound 1 in this embodiment is used as an API, it is preferably in the form of a salt, and mesylate is preferred for the reasons described above, but this does not exclude other salts, such as salts of inorganic bases, salts of organic bases, salts with inorganic acids, salts with organic acids, salts with acidic amino acids, and salts with basic amino acids, as shown below.

[0020] ​Examples of salts of inorganic bases include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium salts and calcium salts. Examples of salts of organic bases include trimethylamine, triethylamine, pyridine, N-methylpyridine, N-methylpyrrolidine, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, etc.

[0021] Examples of inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, etc. Examples of organic acids include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, ascorbic acid, isoascorbic acid, mandelic acid, glutaric acid, adipic acid, fumaric acid, aspartic acid, maleic acid, lactic acid, malic acid, hippuric acid, citric acid, tartaric acid, carbonic acid, picric acid, mesylic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0022] Examples of acidic amino acids include glutamic acid, aspartic acid, etc. Examples of basic amino acids include lysine, asparagine, ornithine, etc.

[0023] 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide in this embodiment is a compound having the following structure, and is referred to as "analog 1" in this specification.

[0024]

[0025] In this embodiment, analog 1 is a starting material that is derived into compound 1 by introducing acylthiourea.

[0026] Batch production, used in the manufacture of products or compounds, is a method in which a certain amount of raw materials is charged and each process is carried out sequentially to produce a certain fixed amount of product or compound at one time.

[0027] In batch production, the term "mass production" used in this embodiment refers to a case where the amount of raw materials charged in one production run, called one batch, is, for example, 1 kg or more. In other words, the amount of raw materials used in one production run of a desired compound is, for example, 1 kg or more. The desired compound includes not only the API but also intermediates used in the production of the API.

[0028] In this embodiment, when producing compound 1 from analog 1, the reagent used for introducing the acylthiourea group is not particularly limited as long as it is a commonly known reagent, and examples thereof include 2-phenylacetylisothiocyanate. Among these, it is preferable to link analog 1 with 2-phenylacetylisothiocyanate.

[0029] 2-Phenylacetyl isothiocyanate has the following structure and is preferably obtained by derivatization from 2-phenylacetyl chloride. Specifically, it can be produced by reacting 2-phenylacetyl chloride with potassium thiocyanate. 2-Phenylacetyl isothiocyanate may also be produced by other methods or may be a commercially available product.

[0030]

[0031] In this embodiment, 2-phenylacetylisothiocyanate can be used in an amount of 1.0 to 100 molar equivalents, preferably 1.2 molar equivalents or more, and particularly preferably 1.5 molar equivalents or more, relative to the starting analog 1. The number of equivalents is preferably 20 molar equivalents or less, more preferably 10 molar equivalents or less, even more preferably 5.0 molar equivalents or less, still more preferably 3.0 molar equivalents or less, particularly preferably 2.5 molar equivalents or less, and particularly preferably 2.2 molar equivalents or less.

[0032] In this embodiment, the reaction time is not particularly limited, and may be, for example, 0.5 to 500 hours, but is preferably 6 hours or more and preferably 20 hours or less.

[0033] In the present embodiment, the reaction temperature is not particularly limited as long as it is equal to or lower than the boiling point of the solvent used, and may be, for example, 0 to 100°C. However, the reaction temperature is preferably 15°C or higher, more preferably 20°C or higher, and is preferably 50°C or lower, more preferably 30°C or lower.

[0034] In this embodiment, the solvent used is not particularly limited as long as it does not significantly decompose Related Substance 1, Compound 1, and 2-phenylacetylisothiocyanate. Examples of the solvent include water, C5 to C10 hydrocarbons, C6 to C14 aromatic hydrocarbons, C1 to C6 alcohols, C3 to C10 aliphatic carboxylic acid esters, C3 to C10 ketones, C4 to C10 ethers, C3 to C5 aprotic polar organic solvents, and mixed solvents thereof. In this specification, the term "C" refers to the number of carbon atoms, and refers to the total number of carbon atoms contained in the compound.

[0035] C5 to C10 hydrocarbons are hydrocarbons having 5 to 10 carbon atoms, and examples thereof include pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.

[0036] The C6 to C14 aromatic hydrocarbons are aromatic hydrocarbons having 6 to 14 carbon atoms, and examples thereof include benzene, naphthalene, anthracene, toluene, xylene, cumene, styrene, and phenanthrene.

[0037] The C1 to C6 alcohol is an alcohol having 1 to 6 carbon atoms, and examples thereof include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, and n-hexanol.

[0038] The C3 to C10 aliphatic carboxylic acid ester is an aliphatic carboxylic acid ester having 3 to 10 carbon atoms, and examples thereof include propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, propyl propionate, methyl butanoate, and ethyl butanoate.

[0039] The C3 to C10 ketones are ketones having 3 to 10 carbon atoms, and examples thereof include acetone, ethyl methyl ketone, diethyl ketone, isopropyl methyl ketone, and cyclohexanone.

[0040] The C4 to C10 ether is an ether having 4 to 10 carbon atoms, and examples thereof include diethyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane.

[0041] The C3 to C5 aprotic polar organic solvent is an aprotic polar organic solvent having 3 to 5 carbon atoms, and examples thereof include N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0042] In this embodiment, the solvent to be used is preferably a C6 to C14 aromatic hydrocarbon, a C1 to C6 alcohol, or a mixed solvent thereof, and particularly preferably toluene, ethanol, or a mixed solvent thereof.

[0043] When a solvent containing toluene and ethanol (mixed solvent) is used as the solvent in this embodiment, the amount of toluene can be 0.01 to 100 times the amount of ethanol by volume, but is preferably 0.1 times or more, more preferably 0.5 times or more, even more preferably 1.0 times or more, still more preferably 2.0 times or more, especially preferably 3.0 times or more, and particularly preferably 4.0 times or more. The amount of toluene is preferably 50 times or less, more preferably 25 times or less, even more preferably 10 times or less, still more preferably 8.0 times or less, especially preferably 7.0 times or less, and particularly preferably 6.0 times or less by volume relative to the amount of ethanol.

[0044] The method for producing Compound 1 according to this embodiment is characterized by including a step of linking Analog 1 and 2-phenylacetyl isothiocyanate. Preferably, the method for producing Compound 1 is characterized by including a step of linking Analog 1 and 2-phenylacetyl isothiocyanate, and includes a step of obtaining 2-phenylacetyl isothiocyanate by derivatization from 2-phenylacetyl chloride. More preferably, the method for producing Compound 1 is characterized by including a step of linking Analog 1 and 2-phenylacetyl isothiocyanate in a solvent containing toluene and ethanol, and includes a step of obtaining 2-phenylacetyl isothiocyanate by derivatization from 2-phenylacetyl chloride. Even more preferably, the method for producing Compound 1 is characterized by including a step of linking Analog 1 and 2-phenylacetyl isothiocyanate in a solvent containing toluene and ethanol, in which the amount of toluene is 0.01 to 100 times the volume ratio of the amount of ethanol, and includes a step of obtaining 2-phenylacetyl isothiocyanate by derivatization from 2-phenylacetyl chloride. Particularly preferred is a method for producing Compound 1, which is characterized by including a step of linking Analog 1 with 2-phenylacetyl isothiocyanate in a solvent containing toluene and ethanol, where the amount of toluene is 0.01 to 100 times the amount of ethanol by volume, and the amount of 2-phenylacetyl isothiocyanate used in this step is 1.0 to 5.0 molar equivalents of Analog 1, and which includes a step of obtaining 2-phenylacetyl isothiocyanate by derivatization from 2-phenylacetyl chloride.

[0045] In the method for producing Compound 1 according to this embodiment, it is preferable that Analog 1 is obtained by aminolysis of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate. That is, it is preferable that the method further includes a step of obtaining Analog 1 by aminolysis from methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate. Aminolysis is a method for constructing an amide from an ester, and includes a step of reacting an ester with an amine.

[0046] In the production of analogue 1, methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate and 4-(4-nitro-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide are considered as starting materials. However, the inventors' investigations suggested that aminolysis of methyl 4-(4-nitro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate to obtain 4-(4-nitro-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide would result in elimination of fluoronitrophenol. As a result, it was suggested that the route to produce compound 1 by obtaining analogue 1 from 4-(4-nitro-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide would result in a low yield and would not be suitable for mass production.

[0047] In addition to the above, the present inventors also investigated a route to obtain compound 1 by first converting the amino group of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate to acylthiourea to synthesize methyl 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxyquinoline-6-carboxylate, and then performing aminolysis. However, the acylthiourea moiety was decomposed during aminolysis, and compound 1 could not be obtained in high yield.

[0048] In contrast, it has been found that aminolysis of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate does not result in the elimination of fluoronitrophenol as described above, and allows the production of related substance 1 in high yield. Therefore, the production method according to this embodiment is characterized by obtaining compound 1 from related substance 1, but is preferably a method in which compound 1 is obtained from related substance 1, and related substance 1 is obtained from methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate. More preferably, compound 1 is obtained from related substance 1, and related substance 1 is obtained from methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate, and methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate is obtained from methyl 4-(4-nitro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate. The aminolysis here can be carried out under known conditions. For example, in a method in which a high concentration of methylamine is reacted in a mixed solvent of N-methyl-2-pyrrolidone and water, the analogue 1 was obtained in a yield of 80% or more.

[0049] Furthermore, methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate can be obtained by reducing the nitro group of methyl 4-(4-nitro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate. This reduction reaction can also be carried out under known conditions. For example, a method using iron and a mixed solvent of hydrochloric acid and methanol has produced the reduced product in a yield of 90-98%. For example, catalytic reduction using carbon-supported platinum and hydrogen has produced the reduced product in a yield of almost 100%.

[0050] From the above results, it was found that the production of compound 1 preferably includes a step of obtaining analog 1 by aminolysis from methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate. Furthermore, for the mass production of compound 1, a production method including a step of linking 2-phenylacetylisothiocyanate to analog 1 is preferred because it requires fewer steps. Furthermore, the absence of column chromatography makes this method suitable for mass production. In addition, this method is suitable for mass production because the yield and quality of the resulting compound 1 are highly reproducible, it can be produced even when the stirring capacity during the reaction is reduced compared to small-scale synthesis, it can be produced even when the time required for adding raw materials and reagents is longer than in small-scale synthesis, and production costs can be reduced.

[0051] <Method for producing mesylate of compound 1>

[0052] Compound 1 thus obtained is purified as necessary, and then converted into a mesylate salt by, for example, the method described in Patent Document 4, and used as an API. The solvent used when converting Compound 1 into a mesylate salt of Compound 1 is not particularly limited, but preferred examples include water, alcohols, aliphatic carboxylic acid esters, ketones, ethers, hydrocarbons, and aprotic polar solvents, and mixed solvents of these can also be used.

[0053] Examples of alcohols include methanol, ethanol, n-propanol, and isopropanol, with ethanol and isopropanol being preferred. Examples of aliphatic carboxylic acid esters include methyl formate, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate, with ethyl acetate being preferred. Examples of ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and cyclohexanone, with acetone, methyl ethyl ketone, or methyl isobutyl ketone being preferred. Examples of ethers include diethyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane. Examples of hydrocarbons include n-hexane, n-pentane, n-heptane, cyclohexane, cyclopentane, and petroleum ether. Examples of aprotic polar solvents include acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0054] The solvent is preferably water, alcohol, aliphatic carboxylic acid ester, ketone, or a mixed solvent thereof, more preferably ethanol, isopropanol, ethyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, or an acetone-water mixed solvent, and particularly preferably an acetone-water mixed solvent.

[0055] The ratio of each solvent in the acetone-water mixed solvent is preferably 0.1 to 100 volumes of acetone per volume of water, more preferably 0.5 volumes or more, even more preferably 1 volume or more, still more preferably 5 volumes or more, and more preferably 20 volumes or less, even more preferably 10 volumes or less, still more preferably 5 volumes or less.

[0056] The amount of solvent that can be used in the method for producing the mesylate salt of this embodiment is 0.1 to 100 (volume / weight) times the amount of Compound 1, preferably 1 to 50 (volume / weight), and more preferably 5 to 30 (volume / weight).

[0057] The temperature in the step of precipitating the mesylate salt of this embodiment is appropriately set depending on the solvent used, and is set between 0° C. and the boiling point of the solvent. The temperature in the step of precipitating does not need to be constant, and heating or cooling can be performed between 0° C. and the boiling point of the solvent.

[0058] Stirring in the step of precipitating the mesylate salt of this embodiment is carried out using a stirrer, stirring blade, magnetic stirrer, or the like, as appropriate depending on the amount of solvent and the size of the reaction vessel. The stirring speed is 1 to 600 rpm, preferably 10 to 300 rpm. Generally, if the stirring time for salt precipitation is too short, precipitation does not proceed sufficiently, and salt or crystals cannot be obtained in high yield. On the other hand, if the stirring time is too long, decomposition of the active ingredient occurs, resulting in a decrease in yield; therefore, an appropriate time is set. The stirring time in the step of precipitating the mesylate salt of this embodiment can be 1 minute to 120 hours, preferably 1 hour to 72 hours, and more preferably 3 hours to 48 hours.

[0059] In the step of precipitating the mesylate salt of this embodiment, seed crystals of the mesylate salt of Compound 1 may be added in an amount of 0.1 to 10% by weight, preferably 1 to 3% by weight, of the theoretical yield of the mesylate salt of Compound 1 in the crystallization.

[0060] The mesylate salt according to the present embodiment precipitated in the solvent can be isolated and purified by known separation and purification means, such as filtration, washing with an organic solvent, drying under reduced pressure, etc. Examples of organic solvents used for washing include the same solvents as those usable in the above production.

[0061] <<Method for Purifying Compound 1>> In the present invention, in order to improve the chemical purity of Compound 1, purification may be performed in each step in the production of Compound 1, or purification may be performed on Compound 1 after production. The purification method is not particularly limited, and various purification methods used in the relevant field can be used. Specifically, in one embodiment of the present invention, a purification step is performed in which related substances are removed from the free form of Compound 1.

[0062] In this embodiment, the free form of Compound 1 used for purification may be one produced by a commonly known method or one derived from Analog 1 and 2-phenylacetylisothiocyanate, but is preferably one derived from Analog 1 and 2-phenylacetylisothiocyanate. Note that the term "one derived from Analog 1 and phenylacetylisothiocyanate" has the same meaning as the one obtained by the step of linking Analog 1 and phenylacetylisothiocyanate described above in "Method for producing Compound 1," and preferred embodiments thereof are also the same as those described therein.

[0063] In this embodiment, the purpose of the purification step is to improve the chemical purity of Compound 1 after purification. The chemical purity here refers to the purity calculated by high performance liquid chromatography. In this embodiment, the purification step may be a step using a method such as recrystallization or heating and suspending, and preferably includes a recrystallization step.

[0064] In this embodiment, the impurities to be removed by purification are not particularly limited as long as they are compounds other than Compound 1, but are preferably Related Substances 1 to 5 and salts thereof, and more preferably Related Substances 1 to 3 and 5 and salts thereof.

[0065] In this embodiment, the solvent used for purification is not particularly limited, but a solvent containing N,N-dimethylacetamide (hereinafter also referred to as DMA) and a protic polar solvent is preferred. Examples of protic polar solvents include methanol, ethanol, and propanol. More preferred are solvents containing DMA and ethanol, or solvents containing DMA and 2-propanol, and even more preferred are solvents containing DMA and ethanol. When using a solvent containing DMA and a protic polar solvent, a mixed solvent obtained by mixing them in advance may be used, but the solvents may also be mixed as a result of using DMA and a protic polar solvent in that order.

[0066] In this embodiment, the amount of solvent used for purification refers to the amount of solvent in which Compound 1 is dispersed when Compound 1 is collected by filtration, and does not include the solvent used for washing after collection by filtration. The amount of solvent used for purification is not particularly limited as long as purification is possible, but is preferably 0.5 to 100 times (volume / weight) the amount of Compound 1 to be purified, more preferably 2 to 50 times (volume / weight), and even more preferably 5 to 20 times (volume / weight) the amount of Compound 1 to be purified.

[0067] In this embodiment, when recrystallization is employed for purification, it is required that compound 1 be dissolved in a solvent. The solvent employed is not particularly limited, but is preferably DMA alone or a solvent containing DMA and a protic polar solvent, more preferably a solvent containing DMA and a protic polar solvent, and even more preferably a solvent containing DMA and ethanol. A mixed solvent in which DMA and a protic polar solvent are mixed in advance may be used, or compound 1 may be dissolved in DMA and then mixed with a protic polar solvent, resulting in a mixed solvent. In particular, from the viewpoint of obtaining high-purity compound 1, it is preferable to carry out a step of adding a protic polar solvent after the step of dissolving compound 1 in DMA, and it is more preferable to carry out a step of adding ethanol after the step of dissolving compound 1 in DMA.

[0068] The present inventors have also investigated various solvents other than DMA for recrystallization. For example, dissolving Compound 1 using dimethyl sulfoxide (DMSO) is considered. However, it has been suggested that when DMSO is used for dissolution by heating, the thioketone (C=S) moiety in the acylthiourea structure of Compound 1 becomes a ketone (C=O), causing the structure to collapse. In contrast, it has been found that DMA can be successfully heated to dissolve Compound 1 while maintaining its structure, suggesting that it is a preferable solvent for use in the dissolving step.

[0069] In this embodiment, when recrystallization is employed for purification, the temperature at which Compound 1 dissolves in a solvent is not particularly limited, but is preferably 40 to 100° C., and more preferably 50 to 80° C. Furthermore, when dissolving in DMA, the dissolution temperature is more preferably 70 to 80° C.

[0070] In this embodiment, after dissolving Compound 1 in a solvent, the temperature at which the dissolved Compound 1 is precipitated is not particularly limited, but when precipitation is performed by adding ethanol, for example, the temperature at which ethanol is added is preferably 50 to 80° C. The temperature at which subsequent precipitation (crystallization) is performed is preferably 45 to 55° C.

[0071] In the present embodiment, when recrystallization is employed for purification, the time from dissolving Compound 1 in a solvent until it is precipitated and collected by filtration is not particularly limited as long as the amount of precipitated Compound 1 becomes constant, but is preferably 1 hour or more, more preferably 1 to 100 hours, and even more preferably 1 to 72 hours.

[0072] In the present embodiment, when recrystallization is employed for purification, the temperature at which Compound 1 is collected by filtration is not particularly limited as long as it is equal to or higher than the melting point of the solvent used, but is preferably −10 to 50° C., and more preferably 0 to 30° C.

[0073] In this embodiment, when a solvent containing DMA and ethanol is used as the recrystallization solvent, the mixing ratio (volume ratio) of DMA to ethanol is preferably DMA:ethanol=1:0.01 to 1:100, more preferably 1:0.01 to 1:10 or 1:0.1 to 1:100, even more preferably 1:0.1 to 1:10, and even more preferably 1:1 to 1:10.

[0074] The recrystallization step includes a step of dissolving Compound 1 in a solvent and a step of crystallizing (precipitating) the dissolved Compound 1. In this embodiment, when a solvent containing DMA and ethanol is used as the recrystallization solvent, the solvent used in the step of dissolving the free form of Compound 1 is preferably DMA or a mixed solvent of DMA and a protic polar solvent, more preferably DMA. To dissolve the free form of Compound 1, the amount of solvent and temperature can be set as described above.

[0075] In the subsequent step of precipitating the dissolved Compound 1, Compound 1 is dissolved in the solvent, and then, for example, a protic polar solvent is added, or the temperature is lowered in addition to or instead of the addition, thereby precipitating the free form of Compound 1. The protic polar solvent is preferably ethanol.

[0076] Whether the free form of Compound 1 thus obtained satisfies the quality requirements for API is determined by analyzing the mesylate of Compound 1. This determination is made in accordance with the standards set forth in ICH, and the chemical purity used as the standard is calculated by measurement using high performance liquid chromatography or the like.

[0077] Therefore, the step of purifying Compound 1 in this embodiment particularly relates to a purification method for removing related substances from the free form of Compound 1, preferably a purification method for removing related substances from the free form of Compound 1, more preferably a purification method including a recrystallization step. Even more preferably, the purification method for removing related substances from the free form of Compound 1 includes a recrystallization step using a solvent containing N,N-dimethylacetamide and ethanol.

[0078] In another embodiment, the purification step of removing related substances from the free form of Compound 1 is more preferably a purification method comprising the steps of dissolving Compound 1 in DMA at 75±5°C (70-80°C), subsequently adding ethanol at 65±15°C (50-80°C), and subsequently crystallizing at 50±5°C (45-55°C). Even more preferably, the purification method of removing related substances from the free form of Compound 1 is a purification method comprising the steps of dissolving Compound 1 in DMA at 75±5°C (70-80°C) so that the volume ratio of DMA:ethanol is 1:1 to 1:10 (0.1 to 1 volume), subsequently adding ethanol at 65±15°C (50-80°C), and subsequently crystallizing at 50±5°C (45-55°C).

[0079] <<Related Substances of Compound 1>> The produced Compound 1 is decomposed to produce Related Substance 1 and compounds such as Related Substances 2 and 3 shown below. Furthermore, Compound 1 produced by a method including specific steps may contain Related Substances 4 and 5 shown below.

[0080] Analog 2 is N-((3-fluoro-4-hydroxyphenyl)carbamothionyl)-2-phenylacetamide and has the following structure:

[0081]

[0082] Analog 3 is 4-hydroxy-7-methoxy-N-methylquinoline-6-carboxamide and has the following structure:

[0083]

[0084] Analog 4 is 7-methoxy-N-methyl-4-(4-(3-(2-phenylacetyl)thioureido)phenoxy)quinoline-6-carboxamide and has the following structure:

[0085]

[0086] Analog 5 is 4-(2-fluoro-4-(2-phenylacetamido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide and has the following structure:

[0087]

[0088] As described above, all of the analogs 1 to 3 are compounds generated by decomposition of Compound 1. Therefore, the analogs 1 to 3 and their salts can be considered impurities that may be contained in the API and formulations of Compound 1.

[0089] Analog 4 is a compound that can be included in Compound 1 and is produced by a method including the following steps.

[0090]

[0091] That is, the compound is derived from 4-nitrophenol contained in 2-fluoro-4-nitrophenol in the linkage of methyl 4-chloro-7-methoxyquinoline-6-carboxylate and 2-fluoro-4-nitrophenol (described in Example 39a of Patent Document 1), which is a step for obtaining methyl 4-(4-nitro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate.

[0092] Analog 5 is a by-product of Compound 1 obtained in the step of linking the above-mentioned Analog 1 with 2-phenylacetylisothiocyanate.

[0093] Both analogs 4 and 5 are compounds that are produced during the manufacturing process of compound 1. Therefore, analogs 4 and 5 and their salts can be considered impurities that may be contained in the API and formulations of compound 1.

[0094] Analogs 1 to 5 or salts thereof may be solvates (e.g., hydrates) or non-solvates, and in this embodiment, both are encompassed by the term "compounds or salts thereof." Analogs 1 to 5 also include their tautomers.

[0095] The salt of the compound is not particularly limited, and examples thereof include mesylate salts, as well as addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and sulfuric acid; alkylsulfuric acids such as methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid; and organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid; salts with alkali metals such as potassium and sodium; salts with alkaline earth metals such as calcium and magnesium; and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts.

[0096] In this specification, the terms "analog 1," "analog 2," "analog 3," "analog 4," and "analog 5" may be intended to include "salts" and "solvates" of the analogs in question.

[0097] Combinations of the above-mentioned analogs 1 to 5 or salts thereof may also be included in APIs and formulations of Compound 1. The combinations contain two or more of the above-mentioned analogs 1 to 5 or salts thereof. The combinations may include all of the following: all of the analogs 1 to 5, a portion of the analogs 1 to 5 and the rest being salts of one or more of the above-mentioned analogs 1 to 5, and all of the analogs 1 to 5 being salts. The combinations may include one of the above-mentioned analogs 1 to 5 and a salt of that analog.

[0098] The present invention also includes Compound 1 or a salt thereof as an API, wherein the content of each of Related Substances 1 to 5 and their salts is less than 0.2% by mass of the total API.

[0099] Examples of methods for producing Compound 1 or a salt thereof in which the respective contents of Related Substances 1 to 5 and their salts are less than 0.2% by mass of the total API include the above-described methods for producing Compound 1 or a salt thereof derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate. Furthermore, when the respective contents of Related Substances 1 to 5 and their salts are derived from starting materials, reagents, solvents, etc., the respective contents of Related Substances 1 to 5 and their salts can be reduced to less than 0.2% by mass of the total API by controlling the starting materials, etc. used in the above-described production methods. The respective contents of Related Substances 1 to 5 and their salts can be determined, for example, by the above-described methods for analyzing related substances.

[0100] The above embodiment is preferably Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and in which the contents of Related Substances 1 to 5 and their salts are each less than 0.2% by mass of the total API. More preferably, Compound 1 or a salt thereof is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, and in which the contents of Related Substances 1 to 5 and their salts are each less than 0.2% by mass of the total API. Even more preferably, Compound 1 mesylate is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, in which the amount of Related Substance 1 charged per production run is 1 kg or more, and in which the contents of Related Substances 1 to 5 and their salts are each less than 0.2% by mass of the total API.

[0101] In another embodiment, the present invention relates to Compound 1 or a salt thereof, wherein the content of Related Substance 1 and its salt is each less than 0.2% by mass of the total API. Preferably, the present invention relates to Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the content of Related Substance 1 and its salt is each less than 0.2% by mass of the total API. More preferably, the present invention relates to Compound 1 or a salt thereof, which is produced by a production method including a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, and wherein the content of Related Substance 1 and its salt is each less than 0.2% by mass of the total API. Even more preferably, the present invention relates to the mesylate salt of Compound 1, which is produced by a production method including a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, and wherein the amount of Related Substance 1 charged per production run is 1 kg or more, and wherein the content of Related Substance 1 and its salt is each less than 0.2% by mass of the total API.

[0102] In another embodiment, the present invention relates to Compound 1 or a salt thereof, wherein the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API. Preferably, Compound 1 or a salt thereof is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API. More preferably, Compound 1 or a salt thereof is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, and wherein the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API. Even more preferably, Compound 1 mesylate is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of Related Substance 1 charged per production run is 1 kg or more, and the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API.

[0103] In another embodiment, the present invention relates to Compound 1 or a salt thereof, wherein the content of Related Substance 3 and its salt is each less than 0.2% by mass of the total API. Preferably, Compound 1 or a salt thereof is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and the content of Related Substance 3 and its salt is each less than 0.2% by mass of the total API. More preferably, Compound 1 or a salt thereof is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, and wherein the content of Related Substance 3 and its salt is each less than 0.2% by mass of the total API. Even more preferably, Compound 1 mesylate is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of Related Substance 1 charged per production run is 1 kg or more, and the content of Related Substance 3 and its salt is each less than 0.2% by mass of the total API.

[0104] In another embodiment, the present invention relates to Compound 1 or a salt thereof, wherein the content of related substance 4 and its salt is each less than 0.2% by mass of the total API. Preferably, the present invention relates to Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the content of related substance 4 and its salt is each less than 0.2% by mass of the total API. More preferably, the present invention relates to Compound 1 or a salt thereof, which is produced by a production method including a step of linking related substance 1 and 2-phenylacetylisothiocyanate, and wherein the content of related substance 4 and its salt is each less than 0.2% by mass of the total API. Even more preferably, the present invention relates to the mesylate salt of Compound 1, which is produced by a production method including a step of linking related substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of related substance 1 charged per production run is 1 kg or more, and the content of related substance 4 and its salt is each less than 0.2% by mass of the total API.

[0105] In another embodiment, the present invention relates to Compound 1 or a salt thereof, wherein the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API. Preferably, Compound 1 or a salt thereof is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API. More preferably, Compound 1 or a salt thereof is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, and wherein the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API. Even more preferably, Compound 1 mesylate is produced by a production method including a linking step of Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of Related Substance 1 charged per production run is 1 kg or more, and the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API.

[0106] In another embodiment, the present invention is a method for producing Compound 1 or a salt thereof, wherein the contents of Related Substances 1 to 5 and their salts are each less than 0.2% by mass of the total API. Preferably, the method is for producing Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the contents of Related Substances 1 to 5 and their salts are each less than 0.2% by mass of the total API. More preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the contents of Related Substances 1 to 5 and their salts are each less than 0.2% by mass of the total API. Even more preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of Related Substance 1 charged per production run is 1 kg or more, and the contents of Related Substances 1 to 5 and their salts are each less than 0.2% by mass of the total API.

[0107] In another embodiment, the present invention is a method for producing Compound 1 or a salt thereof, wherein the content of each of related substance 1 and its salt is less than 0.2% by mass of the total API. Preferably, the method is for producing Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the content of each of related substance 1 and its salt is less than 0.2% by mass of the total API. More preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking related substance 1 and 2-phenylacetylisothiocyanate, wherein the content of each of related substance 1 and its salt is less than 0.2% by mass of the total API. Even more preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking related substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of related substance 1 charged per production run is 1 kg or more, and the content of each of related substance 1 and its salt is less than 0.2% by mass of the total API.

[0108] In another embodiment, the present invention is a method for producing Compound 1 or a salt thereof, wherein the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API. Preferably, the method is for producing Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API. More preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API. Even more preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of Related Substance 1 charged per production run is 1 kg or more, and the content of Related Substance 2 and its salt is each less than 0.2% by mass of the total API.

[0109] In another embodiment, the present invention is a method for producing Compound 1 or a salt thereof, wherein the content of each of related substance 3 and its salt is less than 0.2% by mass of the total API. Preferably, the method is for producing Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the content of each of related substance 3 and its salt is less than 0.2% by mass of the total API. More preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking related substance 1 and 2-phenylacetylisothiocyanate, wherein the content of each of related substance 3 and its salt is less than 0.2% by mass of the total API. Even more preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking related substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of related substance 1 charged per production run is 1 kg or more, and the content of each of related substance 3 and its salt is less than 0.2% by mass of the total API.

[0110] In another embodiment, the present invention is a method for producing Compound 1 or a salt thereof, wherein the content of each of related substance 4 and its salt is less than 0.2% by mass of the total API. Preferably, the method is for producing Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the content of each of related substance 4 and its salt is less than 0.2% by mass of the total API. More preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking related substance 1 and 2-phenylacetylisothiocyanate, wherein the content of each of related substance 4 and its salt is less than 0.2% by mass of the total API. Even more preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking related substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of related substance 1 charged per production run is 1 kg or more, and the content of each of related substance 4 and its salt is less than 0.2% by mass of the total API.

[0111] In another embodiment, the present invention is a method for producing Compound 1 or a salt thereof, wherein the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API. Preferably, the method is for producing Compound 1 or a salt thereof, which is derived from methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 2-fluoro-4-nitrophenol, and 2-phenylacetylisothiocyanate, and wherein the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API. More preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API. Even more preferably, the method is for producing a mesylate of Compound 1, which includes a step of linking Related Substance 1 and 2-phenylacetylisothiocyanate, wherein the amount of Related Substance 1 charged per production run is 1 kg or more, and the content of Related Substance 5 and its salt is each less than 0.2% by mass of the total API.

[0112] One embodiment of the present invention is a method for producing a mesylate of compound 1, comprising the steps of: linking analog 1 with 2-phenylacetylisothiocyanate to produce compound 1; and producing a mesylate of compound 1 from the compound 1 obtained in the step.

[0113] Another embodiment of the present invention is a method for producing a mesylate salt of compound 1, comprising the steps of: preparing analog 1 from methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate by aminolysis; preparing compound 1 by linking analog 1 obtained in the above step with 2-phenylacetylisothiocyanate; and preparing a mesylate salt of compound 1 from the compound obtained in the above step.

[0114] Another embodiment of the present invention is a method for producing a mesylate salt of compound 1, comprising the steps of: linking analog 1 with 2-phenylacetylisothiocyanate to produce compound 1; purifying compound 1 obtained in the above step; and producing a mesylate salt of compound 1 from the purified compound 1.

[0115] Another embodiment of the present invention is a method for producing a mesylate salt of compound 1, comprising the steps of: producing analog 1 from methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate by aminolysis; producing compound 1 by linking analog 1 obtained in the above step with 2-phenylacetylisothiocyanate; purifying compound 1 obtained in the above step; and producing a mesylate salt of compound 1 from compound 1 purified in the above step.

[0116] A further embodiment of the present invention is a method for purifying Compound 1, comprising the step of recrystallizing Compound 1.

[0117] A further embodiment of the present invention is a method for purifying Compound 1, comprising the step of recrystallizing Compound 1 using a solvent containing N,N-dimethylacetamide and ethanol.

[0118] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples. Unless otherwise specified, commercially available products were used for the various reagents used in the examples and comparative examples. The content of related substance 1 contained in the free form or mesylate of compound 1 was determined using high-performance liquid chromatography.

[0119] Reference Example 1 Synthesis of Analogous Substance 1 Analogous substance 1 (compound 46a of Patent Document 1) was synthesized with reference to Example 46 of Patent Document 1.

[0120] Example 1 Synthesis of the free form of Compound 1 from Related Substance 1: Under a nitrogen atmosphere, ethanol (114.6 mL) and Related Substance 1 (27.50 g) were added to toluene (571.6 mL) and stirred. 2-Phenylacetylisothiocyanate (21.42 g) was added dropwise thereto, and the mixture was stirred at an internal temperature of 20 to 30°C (target 25°C) for 20 hours. After confirming the completion of the reaction, the precipitate was collected by filtration and washed with toluene. This was dried under reduced pressure at 40 to 50°C to obtain the free form of Compound 1 (yield: 39.40 g, 94.8%).

[0121] Comparative Example 1 Aminolysis of methyl 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxyquinoline-6-carboxylate:

[0122]

[0123] In order to search for a suitable substrate for constructing a methylamide from a carboxylic acid or ester at the 6-position of quinoline, we attempted aminolysis of methyl 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxyquinoline-6-carboxylate (hereinafter also referred to as Compound 2) with methylamine, as shown in the above scheme.

[0124] Compound 2 was synthesized under the same conditions as in Example 1, except that Compound 39b of Patent Document 1 was used instead of Analogue 1. However, compound 1 could not be obtained by aminolysis of compound 2 using methylamine. A method was also investigated in which compound 2 was hydrolyzed to obtain a carboxylic acid, and then condensed with methylamine. However, the desired carboxylic acid was not obtained during hydrolysis. Therefore, it was determined that obtaining compound 1 after constructing a methylamide from compound 2 was inappropriate.

[0125] Example 2 Recrystallization of Compound 1 in a Solvent Containing N,N-Dimethylacetamide and Ethanol (Purification Step 1) and Preparation of Mesylate (Step 2): (Step 1) The free form of Compound 1 obtained in Example 1 (3 g) was added to N,N-dimethylacetamide (12 mL), and the mixture was heated to 75°C to dissolve Compound 1. Ethanol (24 mL) was added dropwise thereto, and the mixture was stirred at 50°C for 30 minutes, then cooled to 5°C and stirred for 1 hour to allow crystallization. The precipitate was then filtered to obtain the free form of Compound 1 (2.5 g). (Step 2) With reference to Example 1 of Patent Document 4, the mesylate of Compound 1 was obtained from the free form of Compound 1. The total content of Related Substance 1 and its salt contained in the mesylate of Compound 1 was measured, and it was found to have decreased to less than 0.05% by mass of the total mesylate of Compound 1. Therefore, it was determined that purifying Compound 1 by recrystallization (Step 1) shown in Example 1 is suitable for purifying API.

[0126] Reference Example 2 Recrystallization of the Free Form of Compound 1 with Dimethyl Sulfoxide (Purification Step): The free form of Compound 1 obtained in Example 1 was added to dimethyl sulfoxide and heated at 85°C, but Compound 1 tended to decompose, making purification by recrystallization difficult.

[0127] [Example 3] Preparation of the free form of Compound 1: (Step 1) Synthesis of methyl 4-(4-nitro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate Methyl 4-(4-nitro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate was obtained from methyl 4-chloro-7-methoxyquinoline-6-carboxylate and 2-fluoro-4-nitrophenol according to the method described in Example 39 (Compound 39a) of Patent Document 1. (Step 2) Synthesis of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate Methyl 4-(4-nitro-2-fluorophenoxy)-7-methoxyquinoline-N-methylquinoline-6-carboxylate (7.00 g) obtained in Step 1 and 1% platinum on carbon (Pt / C; 0.7 g) were added to dimethoxyethane (DME; 70 mL) and stirred. The pressure was increased to 0.2-0.3 MPa with nitrogen gas and then released three times, followed by another operation of increasing the pressure to 0.2-0.3 MPa with hydrogen gas and then releasing the pressure three times. The mixture was pressurized to 0.2-0.3 MPa with hydrogen gas, heated to an internal temperature of 70±5°C, and stirred at the same temperature for at least 2 hours. After confirming the completion of the reaction, the mixture was cooled to an internal temperature of 40±5°C. The reaction solution was filtered at the same temperature and washed with DME. The filtrate was concentrated under reduced pressure to 70 mL, and the internal temperature was adjusted to 25±5°C. Water (105 mL) was added dropwise over at least 30 minutes. After the dropwise addition was completed, the mixture was stirred at the same temperature for at least 2 hours. The crystals were collected by filtration and washed with DME / water (1 / 4) (35 mL). The resulting crystals were dried under reduced pressure at an external temperature of 45±5°C to obtain methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate (6.53 g, yield 101.5%). (Step 3) Synthesis of Related Substance 1 According to the method described in Example 46 (46a) of Patent Document 1, Related Substance 1 was obtained from methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate obtained in Step 2. (Step 4) Under a nitrogen atmosphere, ethanol (95.75 L) and Related Substance 1 (22.96 kg) were added to toluene (477.1 L) and stirred. 2-Phenylacetylisothiocyanate (pure amount 17.88 kg) was added dropwise thereto, and the mixture was stirred at an internal temperature of 20 to 30°C (target 25°C) for 6 hours.After confirming the completion of the reaction, the mixture was stirred at the same temperature for an additional hour, and the precipitate was collected by filtration and washed with toluene. This was dried under reduced pressure at 40-50°C to obtain the free form of Compound 1 (yield: 34.22 kg, 98.1%). This production method requires fewer steps and can produce Compound 1 with a low impurity content without the need for purification by silica gel column chromatography. Therefore, it was determined that this method can maintain the quality of pharmaceutical products and is suitable for mass production.

[0128] Example 4: Mass production of mesylate of compound 1: With reference to Example 1 of Patent Document 4, mesylate of compound 1 was obtained from the free form of compound 1 (11.95 kg) obtained in Example 3 (yield: 11.50 kg, yield: 81.2%). The content of each of the related substances 1 to 5 or salts thereof relative to the mesylate of compound 1 was less than 0.2 mass%. This production method, like Example 3, has a small number of steps and can obtain mesylate of compound 1 with a low impurity content without purification by silica gel column chromatography. Therefore, it was determined that this method can maintain the quality of pharmaceuticals and is suitable for mass production.

[0129] Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention. This application is based on Japanese patent applications filed on February 14, 2020 (Patent Application No. 2020-023754), May 18, 2020 (Patent Application No. 2020-086940), September 18, 2020 (Patent Application No. 2020-157815), and September 18, 2020 (Patent Application No. 2020-157816), the contents of which are incorporated herein by reference.

Claims

1. A method for producing 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, comprising the step of coupling 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide with 2-phenylacetylisothiocyanate.

2. The process according to claim 1, comprising the step of obtaining said 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide by aminolysis of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylate.

3. The process according to claim 1 or 2, which comprises the step of obtaining said 2-phenylacetyl isothiocyanate by derivatization from 2-phenylacetyl chloride.

4. The method according to any one of claims 1 to 3, wherein a solvent containing toluene and ethanol is used in the linking step.

5. A method for producing a mesylate salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, comprising a step of producing a mesylate salt from 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide obtained by the method according to any one of claims 1 to 4.