Method for producing heterocyclic compounds

Abstract

A method for producing a compound that is represented by formula (X) and has a MALT1 inhibitory action or a salt thereof, said method involving a step for producing a compound represented by formula (B-2) or a salt thereof and being characterized by comprising crystallizing a salt of a compound represented by formula (B-1) and an optically active organic acid. (In the formulae, each symbol is as defied in the description.)

Description

[Technical field]

[0001] The present invention relates to an efficient method for producing novel heterocyclic compounds that have MALT1 (Mucosa associated lymphoid tissue protein 1) inhibitory activity and are expected to be useful as preventive or therapeutic drugs for cancer and the like. [Background technology]

[0002] Inhibitors that block MALT1 activity are expected to be able to correct increased MALT1 activity caused by abnormalities in T cell receptor signaling and B cell receptor signaling, and are thought to be useful as preventive or therapeutic agents for cancer, inflammatory diseases, and other conditions caused by MALT1 activity. Research into MALT1 inhibitors has been conducted in the art. For example, Patent Document 1 discloses compounds having MALT1 inhibitory activity and useful for treating autoimmune disorders and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and vasculitic conditions, hematopoietic cancers or solid tumors including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas, and Patent Document 2 discloses compounds having MALT1 inhibitory activity and useful for treating autoimmune disorders and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome, systemic lupus erythematosus, and vasculitic conditions, hematopoietic cancers or solid tumors including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas. Patent Documents 3, 4, and 5 also disclose compounds having MALT1 inhibitory activity. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2015 / 181747 [Patent Document 2] International Publication No. 2017 / 081641 [Patent Document 3] International Publication No. 2018 / 020474 [Patent Document 4] International Publication No. 2018 / 085247 [Patent Document 5] International Publication No. 2021 / 000855 Summary of the Invention [Problem to be solved by the invention]

[0004] In this context, a novel compound represented by the following formula (X) or a salt thereof has been found to have excellent MALT1 inhibitory activity (International Application No. PCT / JP2019 / 046261 (International Filing Date: November 27, 2019); International Publication No. WO2020 / 111087 (International Publication Date: June 4, 2020)).

[0005] [ka]

[0006] (In the formula, R 1 is a methyl group, R 2 is C 1-6 an alkyl group or a halogen atom, R 3 is C 1-6 Alkyl groups, and R 4 C which may be substituted with a halogen atom 1-6 It indicates an alkyl group.

[0007] More specifically, novel compounds represented by the following formulae (X1) and (X2) have been found (hereinafter sometimes abbreviated as compound (X1) and compound (X2)).

[0008] [ka]

[0009] Chemical name: (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea (compound of Example 2 of the above international application)

[0010] [ka]

[0011] Chemical name: (S)-N-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea (compound of Example 3 of the above international application)

[0012] The excellent MALT1 inhibitory activity of compounds (X1) and (X2) and the production method thereof will be described in detail in the section [Examples] below, but they are produced according to the following synthesis scheme.

[0013] [ka]

[0014] [ka]

[0015] In order to produce the compound (X1) or (X2) having high optical purity, the above-mentioned production methods use chiral column purification in the process or in the final process. However, the chiral column purification method is complicated and not suitable for mass synthesis of compounds having high optical purity. Therefore, the above synthesis scheme is not necessarily sufficient as a method for industrially producing compound (X) with high optical purity, and there is a need for the development of a production method more suitable for industrial production. [Means for solving the problem]

[0016] As a result of intensive research to solve the above problems, the present inventors have found that compound (B-2) with high optical purity can be efficiently produced by using an optical resolution method utilizing the formation of a diastereomeric salt of compound (B-1) with an optically active organic acid instead of chiral column purification. Furthermore, the inventors have made improvements to the synthesis scheme leading to compound 7, such as producing compound (B-1) by asymmetric reduction of compound (A), and have found a new production method and a new intermediate suitable for industrial production of compound (X), thereby completing the present invention. The present invention makes it possible to efficiently produce novel compound (X), which has excellent MALT1 inhibitory activity and is expected to be developed and marketed as a pharmaceutical in the future. The preparation method of the present invention is illustrated by the following synthesis scheme.

[0017] [ka]

[0018] (In the formula, R 1 ~R 4 are the same as defined above, R 5 and R 6 each independently represents a hydrogen atom or an amino protecting group, and R 7 C may be substituted with a hydrogen atom or a halogen atom 1-6 an aryloxycarbonyl group optionally substituted with an alkoxy group, or an aryloxycarbonyl group optionally substituted with a nitro group,

[0019] Each of the above steps is important as constituting the production method of the present invention. Among them, step (1) is a production step of compound (B-2) characterized by crystallizing a diastereomeric salt of a compound represented by formula (B-1) (hereinafter, sometimes abbreviated as compound (B-1). The same applies to compounds represented by other formulas.) with an optically active organic acid, and is the core step of the present invention. This step makes it possible to obtain compound (B-2) having high optical purity, and by carrying out the subsequent steps (2) and (3) using the obtained compound (B-2) or a salt thereof, compound (X) or a salt thereof, which is an excellent MALT1 inhibitor, can be produced. Therefore, the production method of compound (X) or a salt thereof, which includes carrying out step (1), is one of the preferred embodiments of the present invention. The compound (C) or a salt thereof obtained in step (2) is a novel compound. Therefore, the present invention is also useful as a method for producing a novel compound (C) which is useful for producing compound (X).

[0020] In addition, the compound (B-1) used as a raw material in step (1) may be a racemate, but may also be an optically active form, which is a mixture containing one optical isomer in a larger amount than the other optical isomer. Such an "optically active form" compound (B-1) can be obtained by subjecting compound (A) to asymmetric reduction (step (A)). Therefore, step (A) is also another core step of the present invention. A method for producing compound (X) or a salt thereof, which comprises carrying out step (A) in combination with step (1), is another preferred embodiment of the present invention.

[0021] Although not limited thereto, preferred embodiments of the present invention will be specifically shown below. [1] Formula (B-1):

[0022] [ka]

[0023] (In the formula, R 1 and R 2have the same meanings as above.) The present invention relates to a method for producing a crystallized salt of a compound represented by the formula (B-2):

[0024] [ka]

[0025] (In the formula, R 1 and R 2 have the same meanings as above.) A method for producing a compound represented by the following formula (compound (B-2)) or a salt thereof: [2]1) Formula (B-1):

[0026] [ka]

[0027] (In the formula, R 1 and R 2 have the same meanings as above.) and an optically active organic acid, to obtain a compound represented by the formula (B-2):

[0028] [ka]

[0029] (In the formula, R 1 and R 2 have the same meanings as above.) or a salt thereof, 2) The obtained compound (B-2) or a salt thereof is subjected to an alkylation reaction to obtain a compound represented by the formula (C):

[0030] [ka]

[0031] (In the formula, R 1 ~R 3have the same meanings as above.) A method for producing a compound represented by the following formula (compound (C)) or a salt thereof: [3]1) Formula (B-1):

[0032] [ka]

[0033] (In the formula, R 1 and R 2 have the same meanings as above.) and an optically active organic acid, to obtain a compound represented by the formula (B-2):

[0034] [ka]

[0035] (In the formula, R 1 and R 2 have the same meanings as above.) or a salt thereof, 2) The obtained compound (B-2) or a salt thereof is subjected to an alkylation reaction to obtain a compound of the formula (C):

[0036] [ka]

[0037] (In the formula, R 1 ~R 3 have the same meanings as above.) or a salt thereof, 3) The obtained compound (C) or a salt thereof is reacted with a compound of the formula (D):

[0038] [ka]

[0039] (In the formula, R 4 is as defined above, and R 7 C may be substituted with a hydrogen atom or a halogen atom 1-6 represents an aryloxycarbonyl group which may be substituted with an alkoxy group or a nitro group. or a salt thereof,

[0040] [ka]

[0041] (In the formula, R 1 ~R 4 have the same meanings as above.) A method for producing a compound represented by the following formula (compound (X)) or a salt thereof: [4]1) Formula (A):

[0042] [ka]

[0043] (In the formula, R 1 and R 2 are as defined above, R 5 and R 6 each independently represents a hydrogen atom or an amino-protecting group. or a salt thereof is subjected to 1) an asymmetric reduction reaction of a carbonyl group, or 2) an asymmetric reduction reaction of a carbonyl group and an elimination reaction of an amino-protecting group, to obtain a compound represented by the formula (B-1):

[0044] [ka]

[0045] (In the formula, R 1 and R 2 are the same as above.) or a salt thereof, 2) Crystallizing the salt of the obtained compound (B-1) with an optically active organic acid, to obtain a compound represented by the formula (B-2):

[0046] [ka] (In the formula, R 1 and R 2 are the same as above.) A method for producing a compound represented by the formula: [5]1) Formula (A):

[0047] [ka]

[0048] (In the formula, R 1 , R 2 , R 5 and R 6 have the same meanings as above.) or a salt thereof is subjected to 1) asymmetric reduction of a carbonyl group, or 2) asymmetric reduction of a carbonyl group and elimination of an amino-protecting group to obtain a compound represented by the formula (B-1):

[0049] [ka]

[0050] (In the formula, R 1 and R 2 are the same as above.) or a salt thereof, 2) The salt of the obtained compound (B-1) with an optically active organic acid is crystallized to obtain a compound of the formula (B-2):

[0051] [ka]

[0052] (In the formula, R 1 and R 2are the same as above.) or a salt thereof, 3) The obtained compound (B-2) or a salt thereof is subjected to an alkylation reaction to obtain a compound of the formula (C):

[0053] [ka]

[0054] (In the formula, R 1 ~R 3 have the same meanings as above.) or a salt thereof, 4) The obtained compound (C) or a salt thereof is reacted with a compound of the formula (D):

[0055] [ka]

[0056] (In the formula, R 4 and R 7 have the same meanings as above.) or a salt thereof,

[0057] [ka]

[0058] (In the formula, R 1 ~R 4 have the same meanings as above.) A method for producing a compound represented by the formula: [6] Optically active organic acids include D-(-)-tartaric acid, L-(+)-tartaric acid, (S)-(-)-2-pyridone-5-carboxylic acid, (R)-(+)-2-pyridone-5-carboxylic acid, L-malic acid, D-malic acid, (S)-(+)-camphor-10-sulfonic acid, (R)-(-)-camphor-10-sulfonic acid, (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid, (R)-(-)-2-(6-methoxy-2-naphthyl)propionic acid. The method for producing quinic acid according to any one of the above [1] to [5], wherein the quinic acid is selected from the group consisting of quinic acid, (+)-cis-2-benzamidocyclohexanecarboxylic acid, (-)-cis-2-benzamidocyclohexanecarboxylic acid, dehydroabietic acid, (R)-(-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, (S)-(+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, D-(-)-quinic acid and L-(+)-quinic acid. [7] The method according to any one of the above [1] to [5], wherein the optically active organic acid is D-(-)-tartaric acid. [8] Formula (C):

[0059] [ka]

[0060] (In the formula, R 1 ~R 3 have the same meanings as above.) or a salt thereof,

[0061] [ka]

[0062] (In the formula, R 4 and R 7 have the same meanings as above.) or a salt thereof,

[0063] [ka]

[0064] (In the formula, R 1 ~R 4 have the same meanings as above.) A method for producing a compound represented by the formula: [9]1) Formula (B-2):

[0065] [ka]

[0066] (In the formula, R 1 and R 2 have the same meanings as above.) or a salt thereof is subjected to an alkylation reaction to obtain a compound represented by the formula (C):

[0067] [ka]

[0068] (In the formula, R 1 ~R 3 have the same meanings as above.) or a salt thereof, 2) The obtained compound (C) or a salt thereof is reacted with a compound of the formula (D):

[0069] [ka]

[0070] (In the formula, R 4 and R 7 have the same meanings as above.) or a salt thereof,

[0071] [ka]

[0072] (In the formula, R 1 ~R 4 have the same meanings as above.) A method for producing a compound represented by the following formula (compound (X)) or a salt thereof:

[10] Formula (C):

[0073] [ka]

[0074] (In the formula, R 1 ~R 3 have the same meanings as above.) A compound represented by the formula: Effect of the Invention

[0075] The present invention provides an industrial production method for efficiently and mass-synthesizing compound (X), a novel MALT1 inhibitor, or a salt thereof, which has a high optical purity and involves a shorter number of steps and does not require a complicated procedure such as chiral column purification. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] The salt of compound (X) is preferably a pharmacologically acceptable salt, and examples of such salts include salts with inorganic acids, salts with organic acids, and salts with acidic amino acids. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[0077] The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. In this specification, "C 1-6 Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. In the present specification, "C optionally substituted with a halogen atom" 1-6 The alkyl group may, for example, be a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkyl group include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl. As used herein, the term "aryloxycarbonyl group" refers to, for example, C aryloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc. 6-14 The aryl part of the "aryloxycarbonyl group" may have 1 to 3 nitro groups. As used herein, the term "amino protecting group" refers to an amino protecting group commonly used in the art, for example, C 1-6 Preferred examples include alkoxy-carbonyl groups (eg, tert-butoxycarbonyl).

[0078] In this specification, formulas, chemical structures or compound names expressed without specifying stereochemistry refer to mixtures of isomers that may exist (including mixtures of equal amounts) unless otherwise specified.

[0079] [ka]

[0080] For example, the compound (B-1) has the following formula:

[0081] [ka]

[0082] This refers to a mixture of two optical isomers represented by the formula:

[0083] The production method of the present invention will be described below. The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Such salts are not particularly limited as long as the reaction proceeds, but examples thereof include the same salts as those of compound (X) (e.g., salts with inorganic acids).

[0084] When the compound obtained in each step is a free compound, it can be converted to the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or another type of desired salt by a method known per se. Such salts are not particularly limited as long as the reaction proceeds, but examples include the same salts as compound (X) (e.g., salts with inorganic acids). Such salt conversion can be carried out for the purpose of improving the operability of the reaction or improving the efficiency of the reaction. In addition, such conversion can be carried out at a stage prior to carrying out the reaction in each step. If necessary, it can also be reconverted to a free form.

[0085] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. in accordance with a conventional method.

[0086] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0087] Unless otherwise specified, the reactions in each step are carried out without a solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include those described in the Examples below and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, 1-propanol, 2-propanol, t-amyl alcohol, etc.; Ethers: diethyl ether, diisopropyl ether, cyclopentyl methyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Organic bases: pyridine, triethylamine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used as a mixture of two or more kinds in an appropriate ratio.

[0088] Each step of the present invention will be described in detail below along with its embodiment.

[0089] Regarding embodiment [1] The embodiment [1] of the present invention is a production method characterized by obtaining a compound (B-2) or a salt thereof having a high optical purity by optical resolution including crystallization of a salt of compound (B-1) with an optically active organic acid (step (1)). The optical resolution is carried out by mixing compound (B-1) with an optically active organic acid in a solvent and filtering the precipitated crystals. When compound (B-1) forms a salt in the step (1), it is converted into a free form (compound (B-1)) using a base, and then mixed with an optically active organic acid. The "optically active organic acid" used in step (1) refers to an optically active organic acid having high optical purity, which is substantially composed of only one optical isomer (e.g., optical purity of 95% or more), and a commercially available product can be used if available.

[0090] Examples of the optically active organic acid used in step (1) include D-(-)-tartaric acid, L-(+)-tartaric acid, (S)-(-)-2-pyridone-5-carboxylic acid, (R)-(+)-2-pyridone-5-carboxylic acid, L-malic acid, D-malic acid, (S)-(+)-camphor-10-sulfonic acid, (R)-(-)-camphor-10-sulfonic acid, (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid, (R)-(-)- These include 2-(6-methoxy-2-naphthyl)propionic acid, (+)-cis-2-benzamidocyclohexanecarboxylic acid, (-)-cis-2-benzamidocyclohexanecarboxylic acid, dehydroabietic acid, (R)-(-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, (S)-(+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, D-(-)-quinic acid and L-(+)-quinic acid. A person skilled in the art can carry out step (1) by appropriately selecting an optically active organic acid, and preferred examples include D-(-)-tartaric acid, (R)-(-)-camphor-10-sulfonic acid, and (R)-(-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, and particularly preferred example is D-(-)-tartaric acid. The amount of the optically active organic acid used is usually 0.3 to 1.2 mol, and preferably 0.4 to 1.0 mol, per 1 mol of compound (B-1). Examples of the solvent for mixing with the optically active organic acid include esters, nitriles, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, water, and the like. The mixing is usually carried out at 0 to 100° C., preferably 25 to 60° C. The reaction time is usually about 10 minutes to about 96 hours, preferably about 0.5 to about 80 hours. In this step (1), the compound (B-1) used as the raw material may be a racemate, or may be a mixture containing one optical isomer more than the other optical isomer ("optically active form"). The compound (B-1) which is an "optically active form" can be obtained, for example, by subjecting the compound (A) to asymmetric reduction (step (A)), but those skilled in the art can obtain the "optically active form" by other appropriate methods. In carrying out this step, the "optically active form" is not limited, but for example, it is preferably one which contains the desired optical isomer (optical isomer represented by formula (B-2)) in 70 to 99% (molar ratio), more preferably one which contains 80 to 99% (molar ratio), and most preferably one which contains 85 to 98% (molar ratio).

[0091] Regarding embodiment [2] The embodiment [2] of the present invention is an embodiment in which the steps (1) and (2) are carried out continuously, and is a production method characterized by obtaining a compound (B-2) or a salt thereof having a high optical purity by optical resolution characterized by crystallizing a salt of compound (B-1) with an optically active organic acid (step (1)), and by subjecting the obtained compound (B-2) or a salt thereof to an alkylation reaction to obtain compound (C) or a salt thereof (step (2)).

[0092] (1) Process (1) In this embodiment, step (1) can be carried out according to the method described in the above embodiment [1].

[0093] (2) Process (2) In step (2), the reaction is carried out by reacting compound (B-2) or a salt thereof with an alkylating agent in a solvent. Examples of the alkylating agent include alkyl halides (e.g., methyl iodide), methyl p-toluenesulfonate, trimethyloxonium tetrafluoroborate, etc. The amount of the alkylating agent used is usually 0.8 to 1.5 mol, preferably 0.9 to 1.2 mol, per 1 mol of compound (B-2). When an alkyl halide or methyl p-toluenesulfonate is used, it is preferable to carry out the reaction in the presence of a base. Examples of the base include sodium hydride, sodium tert-butoxide, potassium tert-butoxide, silver(I) carbonate, potassium carbonate, sodium carbonate, triethylamine, isopropylethylamine, etc. The amount of the base used is usually 0.9 to 4 mol, preferably 1.0 to 3.5 mol, per mol of compound (B-2). Examples of the solvent include ethers, alcohols, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, esters, ketones, and nitriles. The reaction is usually carried out at −30 to 50° C., preferably −10 to 25° C. The reaction time is usually about 10 minutes to about 24 hours, preferably about 1 hour to about 8 hours.

[0094] Regarding embodiment [3] The embodiment [3] of the present invention is an embodiment in which steps (1), (2) and (3) are carried out continuously, and is a production method characterized by obtaining a compound (B-2) or a salt thereof having a high optical purity by optical resolution characterized by crystallizing a salt of compound (B-1) with an optically active organic acid (step (1)), subjecting the obtained compound (B-2) or a salt thereof to an alkylation reaction to obtain compound (C) or a salt thereof (step (2)), and further reacting the obtained compound (C) or a salt thereof with compound (D) or a salt thereof to obtain compound (X) or a salt thereof (step (3)).

[0095] (1) Step (1) and Step (2) In this embodiment, step (1) can be carried out according to the method described in the above embodiment [1], and step (2) can be carried out according to the method described in the above embodiment [2].

[0096] (2) Process (3) In step (3), the reaction is carried out by urea formation in the presence of compound (C) or a salt thereof and compound (D) or a salt thereof, and optionally an activator and a base. The amount of compound (D) used is usually 0.7 to 2.0 mol, preferably 0.9 to 1.5 mol, per 1 mol of compound (C). Examples of the activating agent include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, or p-nitrophenyl chloroformate, triphosgene, phosgene, N,N'-carbonyldiimidazole, or N,N'-disuccinimidyl carbonate, with triphosgene and 2,2,2-trichloroethyl chloroformate being preferred. The amount of the activating agent used is usually 0.3 to 1.5 mol, preferably 0.4 to 1.0 mol, per mol of compound (C). The base is preferably an organic base such as triethylamine or diisopropylethylamine. The amount of the base used is usually 0.8 to 5.0 mol, preferably 1.0 to 3.5 mol, per 1 mol of compound (C). Examples of the solvent include ethers, nitriles, amides, and sulfoxides. The reaction is usually carried out at 0 to 150° C., preferably 10 to 120° C. The reaction time is usually about 1 hour to about 48 hours, preferably about 2 to about 24 hours.

[0097] Regarding embodiment [4] The embodiment [4] of the present invention is an embodiment in which step (A) and step (1) are carried out consecutively, and is a production method characterized in that compound (A) or a salt thereof is subjected to 1) an asymmetric reduction reaction of a carbonyl group, or 2) an asymmetric reduction reaction of a carbonyl group and a elimination reaction of an amino-protecting group to obtain compound (B-1) or a salt thereof (step (A)), and compound (B-2) or a salt thereof having high optical purity is obtained by optical resolution including crystallization of a salt of the obtained compound (B-1) with an optically active organic acid (step (1)).

[0098] (1) Process (A) Step (A) comprises carrying out an asymmetric reduction step and, if desired, a deprotection step of the amino-protecting group. (Asymmetric reduction step) This step involves subjecting compound (A) or a salt thereof to an asymmetric reduction reaction to obtain compound (B-1) or a salt thereof. The reaction is carried out by reacting compound (A) or a salt thereof with a hydrogen source in a solvent in the presence of an asymmetric catalyst or a catalyst and a chiral ligand. Examples of the hydrogen source include ammonium formate, isopropyl alcohol, formic acid, hydrogen, etc. The amount of the hydrogen source used is usually 1 to 100 moles, preferably 5 to 20 moles, per mole of compound (A). When hydrogen gas is used, it is used in large excess under normal pressure or increased pressure. The asymmetric catalyst is chloro((1S,2S)-N-(benzylsulfonyl)-1,2-diphenylethanediamine)(mesitylene)ruthenium(II) (RuCl((S,S)-BnSO 2dpen)(mesitylene)), chloro((1S,2S)-N-(2',6'-dimethylbenzylsulfonyl)-1,2-diphenylethanediamine)(mesitylene)ruthenium(II) (RuCl((S,S)-2',6'-(CH 3 ) 2 BnSO 2 dpen)((mesitylene)), chloro((1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine)(mesitylene)ruthenium(II)(RuCl((S,S)-TsDPEN)(mesitylene)), chloro((1S,2S)-N-(isobutanesulfonyl)-1,2-diphenylethanediamine)(mesitylene)ruthenium(II)(RuCl((S,S)-i-BuSO 2 The amount of the asymmetric catalyst used is usually 0.001 to 0.2 mol, and preferably 0.005 to 0.1 mol, per 1 mol of compound (A). The catalyst used was dichloro(benzene)ruthenium(II) dimer ([RuCl 2 (benzene)] 2 ), bis(norbornadiene)rhodium(I) tetrafluoroborate ([Rh(NBD) 2 BF 4 ]), chloronorbornadiene rhodium(I) dimer ([RhCl(NBD)] 2 The amount of the catalyst used is usually 0.001 to 0.2 mol, and preferably 0.005 to 0.1 mol, per 1 mol of compound (A). Chiral ligands include (R)-(-)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane ((R)-PHANEPHOS), (R)-1-[(S)-2-diphenylphosphinoferrocenyl]ethyl-di-tert.-butylphosphine ((R,S)-PPF-PtBu 2 The amount of the asymmetric ligand used is usually 0.001 to 0.2 mol, and preferably 0.005 to 0.1 mol, per 1 mol of compound (A). This reaction may be carried out in the presence of a base, if desired. Examples of the base include organic bases such as diethylamine and cyclohexylamine. The amount of the base used is usually 0.1 to 5 mol, preferably 0.2 to 1.0 mol, per mol of compound (A). Examples of the solvent include nitriles, alcohols, amides, aromatic hydrocarbons, organic bases, and water. The reaction is usually carried out at −10 to 100° C., preferably 50 to 80° C. The reaction time is usually about 1 to about 72 hours, preferably about 2 to about 48 hours. After the reaction is completed, compound (A) or a salt thereof is isolated. purification The reaction mixture may be directly subjected to the next step (1) without carrying out any post-treatment or after a conventional work-up treatment. (Deprotection step) This step can be carried out as necessary, and can be carried out by a person skilled in the art using an amino-protecting group elimination reaction (removal reaction) known in the art.

[0099] (2) Process (1) In this embodiment, step (1) can be carried out according to the method described in the above embodiment [1].

[0100] Regarding embodiment [5] The embodiment [5] of the present invention is an embodiment in which steps (A), (1), (2) and (3) are carried out successively, and is a production method characterized in that compound (A) or a salt thereof is subjected to 1) asymmetric reduction reaction of a carbonyl group, or 2) asymmetric reduction reaction of a carbonyl group and elimination reaction of an amino protecting group to obtain compound (B-1) or a salt thereof (step (A)), compound (B-2) or a salt thereof having high optical purity is obtained by optical resolution including crystallization of a salt of the obtained compound (B-1) with an optically active organic acid (step (1)), compound (B-2) or a salt thereof having high optical purity is obtained by subjecting the obtained compound (B-2) or a salt thereof to an alkylation reaction to obtain compound (C) or a salt thereof (step (2)), and further compound (C) or a salt thereof is reacted with compound (D) or a salt thereof to obtain compound (X) or a salt thereof (step (3)). In this embodiment, each of the steps (A) and (1) to (3) can be carried out according to the method described in the above embodiments [1] to [4].

[0101] Regarding embodiment [8] The embodiment [8] of the present invention is a production method characterized by reacting compound (C) or a salt thereof obtained by carrying out an appropriate combination of steps (A), (1), and (2) of the present invention with compound (D) or a salt thereof to obtain compound (X) or a salt thereof (step (3)). In this embodiment, step (3) can be carried out according to the method described in the above embodiment [3].

[0102] Regarding embodiment [9] The embodiment [9] of the present invention is a production method characterized in that, for example, compound (B-2) or a salt thereof obtained by carrying out an appropriate combination of step (A) and step (1) of the present invention is subjected to an alkylation reaction to obtain compound (C) or a salt thereof (step (2)), and further compound (C) or a salt thereof is reacted with compound (D) or a salt thereof to obtain compound (X) or a salt thereof (step (3)). In this embodiment, steps (2) and (3) can be carried out according to the methods described in the above embodiments [2] and [3]. EXAMPLES

[0103] The present invention will be further explained in detail by the following examples, formulation examples and test examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified. In silica gel column chromatography, NH indicates aminopropylsilane-bonded silica gel, Diol indicates 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel, and DiNH indicates N-(2-aminoethyl)-3-aminopropylsilane-bonded silica gel. In HPLC (high performance liquid chromatography), C18 indicates octadecyl-bonded silica gel. The ratio of elution solvents is by volume unless otherwise specified. The following abbreviations are used in the following examples: Boc 2 O: Di-tert-butyl dicarbonate CDCl 3 : deuterated chloroform 13 C NMR: Carbon nuclear magnetic resonance DMSO-d 6 : Deuterated dimethyl sulfoxide 1 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DIEA: Diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide mp: melting point DPPA: Diphenylphosphoryl azide MS: Mass spectrum [M+H] + , [MH] - : Molecular ion peak M: Molar concentration N: Regulation Pd(OAc) 2 :Palladium(II) acetate SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran 1 H and 13 C NMR was measured by Fourier transform NMR. ACD / SpecManager (trade name) was used for analysis. Very gentle peaks of protons such as hydroxyl and amino groups are not recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. The data shown are the actual measurements (found). Usually, the molecular ion peak ([M+H] + , [MH] - In the case of compounds with a tert-butoxycarbonyl group, the fragment ion peaks due to the elimination of the tert-butoxycarbonyl group or the tert-butyl group may be observed. In the case of compounds with a hydroxyl group, the fragment ion peaks due to the elimination of the tert-butoxycarbonyl group or the tert-butyl group may be observed. 2 Peaks due to the loss of O may also be observed. In the case of salts, the free molecular ion peak or fragment ion peak is usually observed.

[0104] [Method for producing compound (X) described in International Application No. PCT / JP2019 / 046261] Reference example 1 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine A) 5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (3.0 g) and THF (15 mL), 2H-1,2,3-triazole (0.921 mL) was added at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.75 g). MS: [M+H]+ 259.9.

[0105] B) 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine To a mixture of 5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine (3.54 g), 10% hydrochloric acid / methanol solution (101 mL) and methanol (100 mL), tin(II) chloride (12.95 g) was added at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was neutralized by adding 2N aqueous sodium hydroxide solution. The precipitate was filtered, and the aqueous layer of the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.95 g). MS: [M+H] + 229.9.

[0106] Reference example 2 (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0107] [ka]

[0108] A) tert-Butyl (6-chloro-2-(2-methoxypropanoyl)pyridin-3-yl)carbamate To a mixture of tert-butyl (2-bromo-6-chloropyridin-3-yl)carbamate (20.0 g) and THF (160 mL), 1.08 M methyllithium / diethyl ether solution (72.3 mL) was added at -78°C, and the reaction mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, 1.6 M n-butyllithium / hexane solution (52.8 mL) was added at -78°C, and the reaction mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, a solution of 2-methoxy-1-morpholinopropan-1-one (16.9 g) in THF (60 mL) was added at -78°C, and the reaction mixture was stirred for 2 hours while warming to room temperature. To the reaction mixture, a solution of acetic acid (15 mL) in water (150 mL) was added at room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (15.81 g). MS: [M+H-tBu] + 258.9.

[0109] B) 1-(6-chloro-3-((2-nitrovinyl)amino)pyridin-2-yl)-2-methoxypropan-1-one To a mixture of tert-butyl (6-chloro-2-(2-methoxypropanoyl)pyridin-3-yl)carbamate (15.7 g) and ethyl acetate (100 mL), 4N hydrogen chloride cyclopentyl methyl ether solution (200 mL) was added at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. To the reaction mixture, 4N hydrogen chloride cyclopentyl methyl ether solution (100 mL) was further added at room temperature, and the mixture was stirred at the same temperature overnight, and the solvent was distilled off under reduced pressure. A mixture of the obtained residue, (E)-4-(2-nitrovinyl)morpholine (9.47 g), 6N hydrochloric acid (36 mL), and acetone (120 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (240 mL) and stirred at 0° C. for 1 hour. The precipitate was collected by filtration and washed with water, and the obtained solid was dried under reduced pressure to obtain the title compound (12.55 g). MS: [M+H] + 286.0.

[0110] C) 2-Chloro-8-(1-methoxyethyl)-7-nitro-1,5-naphthyridine A solution of 1-(6-chloro-3-((2-nitrovinyl)amino)pyridin-2-yl)-2-methoxypropan-1-one (12.55 g) in THF (280 mL) was added to a mixture of DBU (6.62 mL) and THF (120 mL) at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was added with 2N hydrochloric acid to adjust the pH to weak acidity, then diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (9.82 g). MS: [M+H] + 267.9.

[0111] D) 6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine A mixture of 2-chloro-8-(1-methoxyethyl)-7-nitro-1,5-naphthyridine (5.00 g), tin(II) chloride dihydrate (21.1 g) and ethyl acetate (150 mL) was stirred at 60° C. for 2 hours, and then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the mixture was neutralized with 2M aqueous potassium carbonate solution. The precipitate was filtered, and the aqueous layer of the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (3.91 g). MS: [M+H] + 238.0.

[0112] E) (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine 6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (3.84 g) was separated by HPLC (CHIRALPAK IG (VJ003), 20 mmID x 250 mmL, mobile phase: hexane / ethanol = 900 / 100), and the fraction with a longer retention time containing the target substance was concentrated under reduced pressure to obtain the title compound (1865 mg). Optical purity: 99.9% ee, retention time: 7.359 min (CHIRALPAK AD-H (VJ019), 4.6 mm ID x 250 mmL, mobile phase: hexane / 2-propanol = 850 / 150) MS: [M+H] + 238.0. The absolute configuration was determined by single crystal X-ray diffraction.

[0113] F) (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea The reaction was carried out in four batches as shown below. Reaction mixture 1: To a mixture of triphosgene (62 mg) and THF (5 mL), (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (100 mg) and DIEA (0.220 mL) in THF (2 mL) were added at 0° C., and the reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (106 mg) obtained in Reference Example 1 was added at 0° C., and the reaction mixture was stirred at 60° C. overnight. Reaction mixture 2: To a mixture of triphosgene (187 mg) and THF (12 mL), (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (300 mg) and DIEA (0.660 mL) in THF (6 mL) were added at 0° C., and the reaction mixture was stirred at the same temperature for 1 hour. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (318 mg) obtained in Reference Example 1 was added to the reaction mixture at 0° C., and the reaction mixture was stirred at 60° C. for 2 hours. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (29 mg) was added to the reaction mixture at the same temperature, and the reaction mixture was stirred overnight. Reaction mixture 3: To a mixture of triphosgene (375 mg) and THF (24 mL), (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (600 mg) and DIEA (1.32 mL) in THF (12 mL) were added at 0° C., and the reaction mixture was stirred at the same temperature for 1 hour. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (636 mg) obtained in Reference Example 1 was added to the reaction mixture at 0° C., and the reaction mixture was stirred at 60° C. for 2 hours. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (116 mg) was added to the reaction mixture at the same temperature, and the reaction mixture was stirred overnight. Reaction mixture 4: To a mixture of triphosgene (531 mg) and THF (34 mL), (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (850 mg) and DIEA (1.87 mL) in THF (17 mL) were added at 0° C., and the reaction mixture was stirred at the same temperature for 1 hour. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (901 mg) obtained in Reference Example 1 was added to the reaction mixture at 0° C., and the reaction mixture was stirred at 60° C. for 2 hours. 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (164 mg) was added to the reaction mixture at the same temperature, and the reaction mixture was stirred overnight. The reaction mixtures 1-4 were combined, the mixture was diluted with saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. THF and ethyl acetate were added to the residue, insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain crude crystals (3.46 g). The obtained crude crystals were dissolved in ethyl acetate (20 mL) at 80°C, and n-heptane (180 mL) was added dropwise to the mixed solution at the same temperature. The mixed solution was stirred at the same temperature for 1 hour, then cooled to room temperature, and stirred at the same temperature overnight. The precipitate was collected by filtration, washed with a mixed solution of ethyl acetate and n-heptane, and dried under reduced pressure to obtain the title compound (3.35 g). 1 H NMR (300MHz, DMSO-d 6 )δ1.56(3H,d,J=6.4Hz),3.36(3H,s),5.85(1H,q,J=6.7Hz),7.77(1H,d,J=8.7Hz),8.18(2H,s),8.46( 1H,d,J=9.1Hz),8.74(1H,d,J=2.6Hz),8.89(1H,d,J=2.3Hz),9.24(1H,s),9.68(1H,s),10.89(1H,s). MS: [M+H] + 491.1. The absolute configuration was determined by single crystal X-ray diffraction.

[0114] Reference example 3 (S)-N-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0115] [ka]

[0116] A) 8-(1-methoxyethyl)-2-methyl-7-nitro-1,5-naphthyridine 2-Chloro-8-(1-methoxyethyl)-7-nitro-1,5-naphthyridine (500 mg), 2,4,6-trimethylboroxine (0.39 mL), Pd(dppf)Cl 2 ·CH 2 Cl 2 A mixture of (153 mg), tripotassium phosphate (793 mg) and 1,2-dimethoxyethane (20 mL) was heated at 100° C. for 1.5 hours under microwave irradiation. The reaction mixture was diluted with ethyl acetate. Insoluble matter was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (439 mg). MS: [M+H] + 247.9.

[0117] B) 4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-amine A mixture of 8-(1-methoxyethyl)-2-methyl-7-nitro-1,5-naphthyridine (470 mg), tin(II) chloride dihydrate (2.57 g), THF (3 mL) and ethanol (12 mL) was stirred at room temperature overnight and at 60° C. for 7 hours. The reaction mixture was diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. Insoluble matter was filtered and washed with ethyl acetate. The filtrate was extracted twice with ethyl acetate. The organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (306 mg). MS: [M+H] + 217.9.

[0118] C) N-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea A solution of triphosgene (54.6 mg) in THF (1 mL) was added at 0° C. to a solution of 4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-amine (80 mg), 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (101 mg) obtained in Reference Example 1, and pyridine (0.089 mL) in THF (5 mL). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. Pyridine (0.089 mL) was added at 0° C., and then a solution of triphosgene (54.6 mg) in THF (1 mL) was added. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 4 hours. The mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (127 mg). MS: [M+H] + 473.1.

[0119] D) (S)-N-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea N-(4-(1-methoxyethyl)-6-methyl-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea (119.8 mg) was separated by HPLC (CHIRALPAK AD-H (VA001), 20 mmID x 250 mmL, mobile phase: hexane / ethanol = 700 / 300), and the fraction with a shorter retention time containing the target substance was concentrated under reduced pressure to obtain the title compound (55.6 mg). MS: [M+H] + 473.1.

[0120] [Method for producing compound (X) according to the present invention] Manufacturing Example 1 Phenyl 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-aminocarbamate A) 5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (30 g) in 2-propanol (150 mL), 1H-1,2,3-triazole (8.44 mL), potassium carbonate (27.45 g), and 2-propanol (210 mL) were added at room temperature, and the reaction mixture was stirred at the same temperature for 7 hours. Water (270 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 16 hours. The obtained solid was collected by filtration, washed with water (150 mL), and then dried at 55° C. overnight to obtain the title compound (26.43 g). 1 H NMR (500 MHz, CDCl 3 )δ8.06(2H,s),9.06(1H,s),9.59(1H,s).

[0121] A-1) 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (7.98 kg) and 2-propanol (75.0 kg) were mixed together, to which 1H-1,2,3-triazole (2.90 kg) and potassium carbonate (7.30 kg) were added at room temperature, and the reaction mixture was stirred at the same temperature for 12 hours. Water (72.0 kg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 3 hours. The resulting solid was collected by filtration, washed with water (39.9 kg), and then dried at 55°C overnight to obtain the title compound (7.23 kg).

[0122] B) 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine A mixture of 5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine (25 g), 10% palladium-carbon (K type) (2.5 g) and methanol (625 mL) was added to an autoclave and stirred at 55° C. for 8 hours under a hydrogen pressure of 0.5 MPa. The mixture was filtered and washed with methanol (50 mL). The filtrate was concentrated to 50 mL, and then water (110 mL), seed crystals, and water (115 mL) were added in that order at 5° C. and stirred at the same temperature for 3 hours. The obtained solid was filtered, washed with water (100 mL), and then dried at 55° C. overnight to obtain the title compound (20.16 g). 1 H NMR (500 MHz, CDCl 3 )δ4.56(2H,br s),7.30(1H,s),7.87(2H,s),8.03(1H,br s).

[0123] B-1) A mixture of 5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine (7.14 kg), 10% palladium-carbon (K type) (0.72 kg) and methanol (142.6 kg) was added to an autoclave, and after nitrogen replacement, the mixture was stirred at 55°C for 8 hours under a hydrogen pressure of 0.5 MPa. The mixture was filtered and washed with methanol (11.4 kg). The filtrate was concentrated under reduced pressure to about 14 L, and then water (32.0 kg), seed crystals, and water (32.8 kg) were added in that order at 5°C and stirred at the same temperature for 3 hours. The obtained solid was filtered, washed with water (28.8 kg), and then dried at 55°C overnight to obtain the title compound (5.55 kg).

[0124] C) Phenyl 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-aminocarbamate Under a nitrogen atmosphere, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (15 g), acetonitrile (45 mL) and pyridine (10.35 g) were mixed at 5° C., and chlorophenyl carbonate (11.27 g) was added, followed by stirring at the same temperature for 1 hour. Ethanol (15 mL), water (105 mL) and seed crystals were added, and the mixture was further stirred at the same temperature for 3 hours. The obtained solid was collected by filtration, washed with ethanol / water (1 / 1, 45 mL), and then dried at 55° C. overnight to obtain the title compound (21.47 g). 1 H NMR (500 MHz, CDCl 3 )δ7.14-7.19(2H,m),7.25-7.30(1H,m),7.37-7.45(2H,m),7.94(2H,s),8.61(1H,br s),8.69(1H,d,J=2.52Hz).

[0125] C-1) Under a nitrogen atmosphere, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (5.01 kg), acetonitrile (11.8 kg) and pyridine (3.49 kg) were mixed at 5°C and chlorophenyl carbonate (3.80 kg) was added, and the mixture was stirred at the same temperature for 1 hour. Phenyl chlorocarbonate (0.30 kg) was added at the same temperature and stirred at the same temperature for 1 hour. Phenyl chlorocarbonate (0.29 kg) was added at the same temperature and stirred at the same temperature for 1 hour. Ethanol (3.90 kg), water (35.00 kg) and seed crystals (5 g) were added at the same temperature and stirred at the same temperature for 3 hours. The obtained solid was filtered, washed with a mixed solution of ethanol (5.90 kg) and water (7.55 kg), and then dried at 55°C overnight to obtain the title compound (7.22 kg).

[0126] Manufacturing Example 2 4-Acetyl-6-chloro-1,5-naphthyridin-3-amine A) (E)-4-(2-nitrovinyl)morpholine A mixture of nitromethane (461 mL), triethyl orthoformate (510 mL), p-toluenesulfonic acid monohydrate (9.83 g), and morpholine (150 g) was stirred at 80° C. for 4 hours under a nitrogen atmosphere. After cooling to 50° C., the mixture was concentrated under reduced pressure to about 300 mL. Ethanol (150 mL) was added, and the mixture was concentrated under reduced pressure again to about 300 mL. A mixed solvent of methyl tert-butyl ether (600 mL) and ethanol (60 mL) was added to the concentrated liquid, and the mixture was suspended and stirred at room temperature for 2 hours. The obtained solid was collected by filtration, washed with a mixed solvent of methyl tert-butyl ether / ethanol (10 / 1,300 mL), and then dried under reduced pressure at 35° C. to obtain the title compound (242 g). 1 H NMR (500 MHz, CDCl 3 )δ3.20-3.50(4H,br s),3.73-3.84(4H,m),6.74(1H,d,J=10.72Hz),8.10(1H,d,J=11.03Hz).

[0127] B) 3-(2-(E)-nitrovinylamino)-6-chloropyridine-2-carboxylic acid 6M hydrochloric acid (483mL) was added to a mixture of 3-amino-6-chloropyridine-2-carboxylic acid (100g), (E)-4-(2-nitrovinyl)morpholine (110g), and acetone (900mL) at 20-28℃, and the mixture was stirred at room temperature for 3.5 hours. 4M aqueous sodium hydroxide solution (670mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The obtained solid was collected by filtration, washed with acetone / water (1 / 4,500mL), and then dried under reduced pressure at 60℃ to obtain the title compound (162.3g). 1 H NMR (500MHz, DMSO-d 6 )δ(E / Z mixture) (main product) 6.69(1H,d,J=6.31Hz),7.54(1H,d,J=8.51Hz),8.01-8.10(1H,m),8.15(1H,d,J=8.51Hz) ,14.61(1H,d,J=15.00Hz).(Byproduct)7.37(1H,d,J=10.72Hz),7.47(1H,d,J=8.83Hz),8.72(1H,d,J=10.72Hz).

[0128] C) 6-chloro-3-nitro-1,5-naphthyridin-4-ol A mixture of 3-(2-(E)-nitrovinylamino)-6-chloropyridine-2-carboxylic acid (160 g), potassium acetate (79.93 g), and acetic anhydride (800 mL) was stirred at 80° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to 50° C., and water (800 mL) was added at a temperature between 45 and 62° C. The mixture was stirred at 50° C. for 1 hour and at room temperature for 1.5 hours, and the resulting solid was collected by filtration, washed with acetone / water (1 / 4, 800 mL), and dried at 60° C. to give the title compound (105.2 g). 1 H NMR (500MHz, DMSO-d 6 )δ7.88(1H,d,J=8.51Hz),8.20(1H,d,J=8.83Hz),9.28(1H,s),12.17-13.95(1H,m).

[0129] D) 8-Bromo-2-chloro-7-nitro-1,5-naphthyridine Phosphorus tribromide (63.1 g) was added to a suspension of 6-chloro-3-nitro-1,5-naphthyridin-4-ol (35.0 g) in DMF (345 mL) under nitrogen atmosphere at 5 ± 5 ° C. The reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was added to water (630 mL) cooled to 5 ± 5 ° C., and 8 M aqueous sodium hydroxide solution (69.8 mL) was further added. The resulting suspension was stirred at 25 ± 5 ° C. for 15 hours, and the resulting solid was collected by filtration, washed with water (175 mL), and then dried by blowing nitrogen. The resulting solid was suspended in ethanol (175 mL), water (350 mL) was added, and the mixture was stirred at 25 ± 5 ° C. for 1 hour. The resulting solid was collected by filtration, washed with ethanol (175 mL), and then dried by blowing nitrogen for 1 hour to obtain the title compound (42.52 g). 1 H NMR (500MHz, DMSO-d 6 )δ8.11(1H,d,J=8.51Hz),8.66(1H,d,J=8.83Hz),9.41(1H,s).

[0130] E) 2-chloro-8-(1-ethoxyvinyl)-7-nitro-1,5-naphthyridine A solution of 8-bromo-2-chloro-7-nitro-1,5-naphthyridine (24.5 g) and tributyl(1-ethoxyvinyl)tin (33.7 g) in DME (245 mL) was degassed and replaced with nitrogen, and then PdCl 2 (Amphos) 2 (1.2g) was added and the mixture was stirred at 80°C for 2 hours. A solution of potassium fluoride (49.3g) in water (245mL) was added to the reaction mixture at room temperature and stirred at room temperature for 1 hour. After filtering the reaction mixture, the obtained insoluble matter was washed with toluene (108mL) and the filtrate was concentrated under reduced pressure to about 370mL. Toluene (245mL) was added, the organic layer was separated, and the obtained organic layer was washed twice with 10% saline. The organic layer was passed through silica gel (Wakogel (registered trademark) FC-40, 25g) and eluted with toluene (50mL). The eluate was concentrated under reduced pressure and then diluted with acetone (135mL). Activated carbon Shirasagi A (registered trademark) (4.9g) was added and stirred at room temperature for 20 minutes. The activated carbon was filtered and then concentrated under reduced pressure. The obtained residue was suspended in 2-propanol (49mL) and stirred for 1 hour. The resulting solid was collected by filtration, washed with 2-propanol (24.5 mL), and then dried under reduced pressure at 60° C. to obtain the title compound (17.14 g). 1 H NMR (500MHz, DMSO-d 6 )δ1.27(1H,t,J=6.94Hz),3.98(2H,q,J=6.94Hz),4.73(1H,d,J=3.15Hz),4.98 (1H,d,J=3.15Hz),8.05(1H,d,J=8.83Hz),8.61(1H,d,J=8.83Hz),9.44(1H,s).

[0131] F) 8-Acetyl-2-chloro-7-nitro-1,5-naphthyridine 6M hydrochloric acid (11mL) was added to a solution of 2-chloro-8-(1-ethoxyvinyl)-7-nitro-1,5-naphthyridine (15g) in acetone (60mL) at 22 to 26°C, and the mixture was stirred at room temperature for 4 hours. 1M aqueous sodium hydroxide solution (70mL) and water (99mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration, washed with acetone / water (1 / 3, 75mL), and then dried under reduced pressure at 60°C to 13.06g. A mixture of the resulting solid and ethyl acetate (45mL) was heated to 60°C. Heptane (75mL) was added, and the mixture was stirred at 5°C for 1.5 hours. The resulting solid was collected by filtration, washed with heptane (75mL), and then dried under reduced pressure at 60°C to obtain the title compound (11.21g). 1 H NMR (500MHz, DMSO-d 6 )δ2.72(3H,s),8.14(1H,d,J=8.83Hz),8.70(1H,d,J=8.83Hz),9.70(1H,s).

[0132] G) 4-Acetyl-6-chloro-1,5-naphthyridin-3-amine 8-Acetyl-2-chloro-7-nitro-1,5-naphthyridine (13.0 g), 5% palladium-carbon (PE type 1.30 g) and methanol (221 mL) were placed in an autoclave, cooled to 15°C, and stirred at 0.20 MPa hydrogen pressure for 6 hours. After releasing the hydrogen pressure, tetrahydrofuran (130 mL) was added and heated to 50°C. The resulting solution was stirred at 50°C for 20 minutes, after which the catalyst was filtered and washed with tetrahydrofuran (52 mL). The filtrate was concentrated under reduced pressure to about 52 mL, and methanol (130 mL) was added. This operation was repeated. The filtrate was concentrated under reduced pressure to about 65 mL, and heated to 60°C. Water (130 mL) was added at 60°C, and stirred at the same temperature for 1 hour. After stirring at room temperature for 12 hours, the resulting solid was filtered and washed with methanol / water (1 / 2, 39 mL). The solid was dried under reduced pressure at 60° C. to give the title compound (9.91 g). 1 H NMR (500MHz, DMSO-d 6)δ2.82(3H,s),7.44(1H,d,J=8.51Hz),7.94(2H,s),8.21(1H,d,J=8.51Hz),8.70(1H,s).

[0133] H) Di-tert-butyl 4-acetyl-6-chloro-1,5-naphthyridine-3-aminodicarbamate A solution of 4-acetyl-6-chloro-1,5-naphthyridin-3-amine (27 g) in THF (270 mL) was treated with Boc 2 O (57.96 g), triethylamine (50.48 mL), and DMAP (147.48 mg) were added at 0-5°C. The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate / hexane to obtain the title compound (35 g). MS: [M+H] + 422.1.

[0134] Example 1 (S)-6-Chloro-4-(1-phenyl) Doro (Xyethyl)-1,5-naphthyridin-3-amine

[0135] [ka]

[0136] A mixture of di-tert-butyl 4-acetyl-6-chloro-1,5-naphthyridine-3-aminodicarbamate (10 g), potassium formate (19.96 g), chloro((1S,2S)-N-(benzylsulfonyl)-1,2-diphenylethanediamine)(mesitylene)ruthenium(II) (294.96 mg), tert-amyl alcohol (50 mL) and water (25 mL) was degassed with argon and stirred at 50° C. for 48 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed with water and then with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in toluene, filtered through silica gel, and concentrated under reduced pressure. The residue was dissolved in cyclopentyl methyl ether (50 mL), and a 4M solution of hydrogen chloride in cyclopentyl methyl ether (100 mL) was added at 0°C. The reaction mixture was stirred overnight at room temperature, and the resulting solid was collected by filtration. The resulting solid was neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate / THF. The organic layer was washed with water and then with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in isopropyl acetate (150 mL) at 50° C. A solution of D-(-)-tartaric acid (1.6 g) in ethanol (20 mL) was added to the resulting solution at 50° C., and the mixture was stirred at the same temperature for 1 hour. Isopropyl acetate was added, and the mixture was stirred at room temperature overnight. The resulting solid was collected by filtration and washed with isopropyl acetate to obtain the hemi-D-(-)-tartrate salt of the title compound (4.4 g, 97.2% ee). The resulting hemi-D-(-)-tartrate salt was neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate / THF. The organic layer was washed with water, then saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.27 g). MS: [M+H] + 224.1.

[0137] Example 2 (S)-6-Chloro-4-(1-phenyl) Doro (xyethyl)-1,5-naphthyridin-3-amine hemi-D-(-)-tartrate

[0138] [ka]

[0139] (1) [RuCl 2 (benzene)] 2(214.4 mg), (R)-PHANEPHOS (593.2 mg), and 4-acetyl-6-chloro-1,5-naphthyridin-3-amine (9.50 g) were charged into an autoclave, and after replacing with nitrogen, a mixture of cyclohexylamine (2.443 mL) and deoxygenated ethanol (380 mL) was added. After the hydrogen pressure was adjusted to 0.5 MPa, the mixture was heated to 60°C. After the hydrogen pressure was adjusted to 0.95 MPa, the mixture was stirred at 60°C for 16 hours. After cooling to 50°C, the hydrogen was released and the mixture was concentrated under reduced pressure to approximately 143 mL. To the residue was added 4M hydrochloric acid (16.1mL), and the mixture was stirred at room temperature for 3 hours. The obtained solid was collected by filtration and washed with cold ethanol (66.5mL). The solid was dried under reduced pressure at 60°C to obtain 3.76g of a solid. A mixture of the obtained solid (3.50g) and water (122.5mL) was stirred for 20 minutes. The solid was filtered off and washed with water (17.5mL). Isopropyl acetate (35mL) and 8M aqueous sodium hydroxide solution (1.682mL) were added to the filtrate at room temperature, and the mixture was stirred. The organic layer was separated and warmed to 40°C, and then a solution of D-(-)-tartaric acid (1.21g) in hot ethanol (8.8mL) was added. Heptane (26.3mL) was added, and the mixture was stirred at 40°C for 3.5 hours and at room temperature for 66 hours. The resulting solid was collected by filtration and washed with isopropyl acetate / heptane / ethanol (4 / 2 / 1, 24.5 mL), and dried under reduced pressure at 60° C. to obtain the title compound (2.80 g, >99.9% ee). 1 H NMR (500MHz, DMSO-d 6 )δ1.40(3H,d,J=6.62Hz),4.33(1H,s),5.73(1H,br s),5.97(1H,q,J=6.62Hz),6.29(2H,br s),7.37(1H,d,J=8.51Hz),8.17(1H,d,J=8.83Hz),8.54(1H,s).

[0140] (2) [RuCl 2 (benzene)] 2(338.5g), (R)-PHANEPHOS (936.6g), and 4-acetyl-6-chloro-1,5-naphthyridin-3-amine (15.0kg) were charged into a 500L pressure reactor, and after replacing with nitrogen, a mixture of cyclohexylamine (3.36kg) and deoxygenated ethanol (474kg) was added. After the hydrogen pressure was adjusted to 0.5MPa, the mixture was heated to 60°C. After the hydrogen pressure was adjusted to 0.95MPa, the mixture was stirred at 60°C for 23 hours. After cooling to 30°C, the hydrogen was released and the mixture was concentrated under reduced pressure to approximately 150L. To the residue, 4M hydrochloric acid (23.7 kg) was added, and the mixture was stirred at room temperature for 3 hours. The obtained solid was collected by filtration and washed with ethanol (83.0 kg). The solid was dried under reduced pressure at 60°C to obtain 14.0 kg of solid. A mixture of the obtained solid and water (490 kg) was stirred for 35 minutes. The solid was filtered off and washed with water (70 L). Isopropyl acetate (122.2 kg) and 8M aqueous sodium hydroxide solution (7.0 kg) were added to the filtrate at room temperature, and the mixture was stirred. The organic layer was separated and heated to 40°C, after which a solution of D-(-)-tartaric acid (4.85 kg) in ethanol (27.7 kg) was added. Heptane (71.8 kg) was added, and the mixture was stirred at 40°C for 3 hours and at room temperature for 61 hours. The obtained solid was collected by filtration and washed with isopropyl acetate / heptane / ethanol (4 / 2 / 1, 79.1 kg). Drying under reduced pressure at 60°C yielded 9.5 kg of solid. 9.3 kg of the obtained solid and ethanol (82.5 kg) were heated to 70°C and dissolved. Heptane (122.0 kg) was added at the same temperature, and the mixture was aged at around 60°C for 8 hours, and then cooled to 20°C over 13 hours. The obtained solid was collected by filtration and washed with heptane / ethanol (3 / 1, 26.4 kg). Drying under reduced pressure at 60°C yielded the title compound (6.0 kg, >99.9% ee).

[0141] Example 3 (S)-6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine

[0142] [ka]

[0143] (S)-6-Chloro-4-(1-phenyl) Doro 60% sodium hydride (613.8 mg) was added to a solution of (oxyethyl)-1,5-naphthyridin-3-amine (3.27 g) in THF (33 mL) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (2.39 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The combined residue was dissolved in methyl tert-butyl ether at 50° C., hexane was added at the same temperature, and the mixture was stirred for 1 hour. After further stirring at room temperature overnight, the obtained solid was filtered and washed with hexane to obtain the title compound (1.69 g, 99.9% ee). MS: [M+H] + 238.0.

[0144] Example 4 (S)-6-Chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine

[0145] [ka]

[0146] (1)(S)-6-chloro-4-(1-phenyl) Doro A mixture of hemi(D)-(-)-tartrate (1.0 g) and acetonitrile (20 mL) was cooled to 5° C., and sodium tert-butoxide (965.2 mg) was added. After 10 minutes, methyl p-toluenesulfonate (0.507 mL) was added and stirred for 3 hours. Sodium tert-butoxide (64.3 mg) was added and stirred for 1 hour. Water (5 mL) was added, and the mixture was concentrated under reduced pressure to 10 mL, and then water (15 mL) was added. The resulting suspension was stirred at room temperature, and the solid was collected by filtration. The resulting solid was washed with water (5 mL) and dried under reduced pressure at 60° C. to give the title compound (584.8 mg). 1 H NMR (500MHz, DMSO-d 6)δ1.42(3H,d,J=6.94Hz),3.21(3H,s),5.62(1H,d,J=6.62Hz),6.20(2H,s),7.38(1H,d,J=8.51 Hz),8.18(1H,d,J=8.51Hz),8.56(1H,s).

[0147] (2)(S)-6-chloro-4-(1-phenyl) Doro A mixture of hemi(D)-(-)-tartrate (5.8 kg), acetonitrile (91.0 kg) and DMF (27.4 kg) was heated to 50°C and stirred for 50 minutes. The mixture was cooled to 5°C, sodium tert-butoxide (4.7 kg) was added, methyl p-toluenesulfonate (3.7 kg) was added and stirred for 4 hours. Sodium tert-butoxide (0.2 kg) was added and stirred for 2 hours. The mixture was warmed to 25°C and stirred for 2 hours, after which water (29.0 kg) was added. The mixture was concentrated under reduced pressure to 30 L, and water (128 kg) was added. 6M aqueous hydrochloric acid was added to adjust the pH to 5. The mixture was stirred for 4 hours, and the solid was collected by filtration. The obtained solid was washed with water (58 kg) and dried under reduced pressure at 60°C to obtain the title compound (3.68 kg).

[0148] Example 5 (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0149] [ka]

[0150] To a solution of triphosgene (17.48 g) in THF (280 mL), (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (28 g) and DIEA (61.56 mL) were added at 0° C., and the reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (29.7 g) was added at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous layer was extracted with ethyl acetate / THF. The organic layer was washed with water and then with saturated saline, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate at 70° C., and the insoluble matter was filtered through Celite. NH silica gel was added to the filtrate, and the mixture was stirred at 70° C. for 1 hour, after which the insoluble matter was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate at 70°C, and n-heptane was added dropwise to the mixed solution at the same temperature. The mixed solution was stirred at the same temperature for 1 hour, then cooled to room temperature and stirred at the same temperature overnight. The precipitate was collected by filtration and washed with n-heptane to obtain the title compound (41.3 g, 99.5% ee). 1 H NMR (300MHz, DMSO-d 6 )δ1.56(3H,d,J=6.8Hz),3.36(3H,s),5.75-5.94(1H,m),7.77(1H,d,J=8.7Hz),8.18(2H,s),8.46(1 H,d,J=8.7Hz),8.74(1H,d,J=2.6Hz),8.89(1H,d,J=2.3Hz),9.24(1H,s),9.69(1H,s),10.89(1H,br s). MS: [M+H] + 493.2.

[0151] Example 6 (S)-N-(6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-yl)-N'-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)urea

[0152] [ka]

[0153] (1) Under a nitrogen atmosphere, (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (3.00 g) and phenyl 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-aminocarbamate (5.29 g) were dissolved in DMF (15 mL) at 100°C, and the resulting mixture was stirred at the same temperature for 4 hours. The mixture was cooled to room temperature, and ethanol (9 mL) and water (51 mL) were added. The resulting suspension was stirred at room temperature for 2 hours. The resulting solid was collected by filtration, washed with ethanol / water (1 / 1, 15 mL), and dried by blowing nitrogen. The resulting solid was dissolved in ethyl acetate (45 mL) at 70°C. The insoluble matter was filtered off at the same temperature, and the filtrate was concentrated to 21 mL. The residue was warmed to 70°C, heptane (60 mL) was added, and the mixture was stirred at 5°C for 2 hours. The resulting solid was collected by filtration and washed with ethyl acetate / heptane (1 / 1, 24 mL). The solid was dried under reduced pressure at 60°C to give the title compound (4.63 g, 99.1% ee). 1 H NMR (500MHz, DMSO-d 6 )δ1.57(3H,d,J=6.62Hz),3.38(3H,s),5.86(1H,q,J=6.62Hz),7.76(1H,d,J=8.83Hz),8.20( 2H,s),8.45(1H,d,J=8.83Hz),8.75(1H,s),8.90(1H,s),9.26(1H,s),9.70(1H,s),10.91(1H, br s). 13 C NMR (126 MHz, DMSO-d 6 )δ19.76,57.28,73.66,120.91,121.17,121.47,123.64,124.78,125.40,125.45,131.89, 134.43,136.94,138.17,138.64,141.19,141.60,141.65,142.10,148.05,150.37,152.60.

[0154] (2) Under a nitrogen atmosphere, (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine (3.6 kg) and phenyl 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-aminocarbamate (6.6 kg) were dissolved in DMF (17.0 kg) at 100°C, and the resulting mixture was stirred at the same temperature for 9 hours and 20 minutes. The mixture was cooled to room temperature, and ethanol (8.5 kg) and water (61.0 kg) were added. The resulting suspension was stirred at room temperature for 3 hours and 20 minutes. The resulting solid was filtered, washed with ethanol / water (1 / 1, 14.1 kg), and dried under reduced pressure at 60°C. The resulting solid (7.6 kg) was added to ethyl acetate (48.0 kg) and stirred at 70°C for 3 hours. The insoluble matter was filtered at the same temperature and washed with ethyl acetate (180.0 kg). The filtrate and washings were concentrated under reduced pressure to 72 L. The mixture was heated to 70°C, heptane (72.0 kg) was added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 5°C and stirred for 5 hours. The obtained solid was collected by filtration and washed with ethyl acetate / heptane (1 / 1, 24.0 kg). The solid was dried under reduced pressure at 60°C to obtain the title compound (4.20 kg). The obtained solid (4.1 kg) was added to ethyl acetate (32.2 kg), and the mixture was stirred at 70°C for 15 minutes. The insoluble matter was filtered at the same temperature and washed with ethyl acetate (8.0 kg). The filtrate and washings were heated to 70°C, heptane (47.0 kg) was added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 5°C and stirred for 5 hours. The obtained solid was collected by filtration and washed with ethyl acetate / heptane (1 / 1, 13.0 kg). The solid was dried under reduced pressure at 60° C. to give the title compound (3.32 kg, >99.9% ee).

[0155] [MALT1 inhibitory activity of compound (X)] Test Example 1 (1) Preparation of recombinant human MALT1 protein Human MALT1 gene was generated by PCR using GC-030-D09 (pENTR221 / MALT1, GeneCopoeia) as a template with primers with BamH I restriction enzymes at the N-terminus and Not I restriction enzymes at the C-terminus to obtain human MALT1 (340-789aa), and yeast GCN4 leucine zipper gene was generated by PCR using yeast DNA as a template with primers with Nde I restriction enzymes at the N-terminus and a linker sequence (GGAAGTGGCTCAGGTAGC: SEQ ID NO: 1) and BamH I restriction enzymes at the C-terminus to form a dimer, to obtain yeast GCN4 (251-281aa). Both fragments obtained were treated with restriction enzymes and inserted between Nde I and Not I of pET28a (Novagen) vector to obtain recombinant human MALT1 protein expression vector pET28a / His-LZ-hMALT1v1(340-789)-His. The recombinant human MALT1 protein was prepared by transforming the expression plasmid prepared above into ECOS Competent E. coli BL21(DE3) (Nippon Gene Co., Ltd.). The transformed E. coli was inoculated into 300 mL of LB medium (1% tryptone, 0.5% yeast extract, 0.5% sodium chloride, 0.01% ampicillin) and cultured at 30°C for 16 hours. The resulting culture was transferred to a jar culture tank containing 6 L of main fermentation medium (0.3% potassium dihydrogen phosphate, 0.6% disodium hydrogen phosphate, 0.1% ammonium chloride, 0.05% sodium chloride, 0.024% magnesium sulfate, 0.01% Antifoam PE-L, 1.5% sorbitol, 1.5% casamino acids, 0.5% yeast extract, 0.01% ampicillin), and culture was started at 37°C, aeration rate of 5 L / min, and agitation speed of 400 rpm. When the turbidity of the culture solution reached approximately 500 Klett units, the culture temperature was lowered to 16°C, isopropyl-β-D-thiogalactopyranoside (IPTG) was added to a final concentration of 0.1 mM, and the culture was continued for another 16 hours to induce expression of human MALT1 protein. After the culture was completed, the culture solution was centrifuged at 5,000 rpm for 10 min, and the resulting human MALT1 protein-expressing E. coli was suspended in a buffer containing 50 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 5 U / ml Benzonase, 20 mM Imidazole, 10% glycerol, and 0.1% NP-40, and then sonicated using a sonifier (Branson). The homogenate was centrifuged (15,300×G, 30 min, TOMY MX-301), and the resulting supernatant was passed through a Ni-NTA Superflow (QIAGEN) column previously equilibrated with 50 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, and 10% glycerol for adsorption, and then eluted with a buffer containing 50 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 10% glycerol, and 250 mM imidazole.The fraction of interest was collected by gel filtration using a Superdex 200 pg column equilibrated with a buffer solution containing 50 mM Tris-HCl pH 8.0, 150 mM NaCl, 5 mM DTT, and 10% glycerol, and an equal volume of 50 mM Tris-HCl pH 8.0, 150 mM NaCl, 5 mM DTT, and 90% glycerol was added to obtain purified human MALT1 protein. The prepared protein was stored at -30°C, and the protein concentration was measured using a BCA Protein Assay Kit (PIERCE) with BSA as a standard.

[0156] (2) Measurement of MALT1 enzyme inhibitory activity Assay buffer (20 mM HEPES (Dojindo Chemical Industries, Ltd.), 10 mM KCl (Wako Pure Chemical Industries, Ltd.), 1.5 mM MgCl 2 Compound solution (2 μL) diluted with 1 mM EDTA (pH 8.0) (Nippon Gene), 0.01% TritonX-100 (Sigma-Aldrich), 1 mM DTT (Wako Pure Chemical Industries) was added. Then, purified recombinant human MALT1 enzyme solution (2 μL) was added and incubated at room temperature for 60 minutes. Substrate solution (75 μM Ac-LRSR-AFC (SM Biochemicals), 20 mM HEPES (Dojindo Chemical Industries), 10 mM KCl (Wako Pure Chemical Industries), 1.5 mM MgCl 2 (Sigma-Aldrich), 1 mM EDTA (pH 8.0) (Nippon Gene), 0.01% TritonX-100 (Sigma-Aldrich), 1 mM DTT (Wako Pure Chemical Industries)) 2 μL was added and incubated at room temperature for 60 minutes. The fluorescence values ​​at Excitation 400 nm and Emission 485 nm immediately after the addition of the substrate and after the enzyme reaction were measured using a plate reader Envision (PerkinElmer), and the increase in fluorescence due to the enzyme reaction was used to calculate the inhibition rate (%). The inhibition rate (%) was calculated by setting the value without the addition of enzyme as 100% and the value without the addition of compound as 0%. The results of measuring MALT1 enzyme inhibitory activity are shown below.

[0157] [Table 1]

[0158] This result demonstrated that compound (X) has MALT1 enzyme inhibitory activity.

[0159] Test Example 2 Growth inhibition assay using OCI-Ly3 cells 1.25x10 in 96-well plate 3 OCI-Ly3 cells were seeded in cell culture medium IMDM (Fujifilm Wako Pure Chemical) containing 20% ​​FCS (fetal calf serum, Thermo Fisher Scientific) and monothioglycerol (Fujifilm Wako Pure Chemical) so that the cells were 100 cells / well. Cell Titer-Glo solution (Promega) was added to cells without the test compound, and the cells were stirred at room temperature for 15 minutes, after which the luminescence intensity was measured using Envision (PerkinElmer) on the day of seeding. Cells with the test compound dissolved in dimethyl sulfoxide (Fujifilm Wako Pure Chemical) added were incubated with CO 2 After leaving the cells in an incubator (37°C) for 6 days, the luminescence intensity was measured in the same manner. The inhibition rate (%) of the test compound against the proliferation of OCI-Ly3 cells was calculated according to the following formula. Cell proliferation inhibition rate (%)=(1-(luminescence value on the 6th day after treatment with test compound-luminescence value before treatment with test compound)÷(luminescence value on the 6th day after no compound was added-luminescence value before treatment with compound))×100 The results of measuring the cell proliferation inhibition rate are shown below.

[0160] [Table 2]

[0161] The results demonstrated that compound (X) inhibits cell proliferation.

[0162] Test Example 3 Antitumor effect on OCI-Ly3 cell tumor-bearing model Human diffuse large B-cell lymphoma cells OCI-Ly3 (DSMZ, German Collection of Microorganisms and Cell Cultures) were suspended in a 1:1 solution of Matrigel (BD Biosciences):HBSS (Thermo Fisher Scientific) and injected subcutaneously at 1x10 into the abdominal cavity of female NOG mice (CLEA Japan). 7 The diameter of the engrafted tumor was measured, and the tumor volume was calculated using the following formula. Tumor volume = major axis × minor axis × minor axis × (1 / 2) Tumor volume is 120mm 3 Animals with tumors of similar size were selected, and six animals per group were used in the experiment. A suspension of the test compound in 0.5% methylcellulose solution (Fujifilm Wako Pure Chemical Industries) was orally administered at a dose of 10 mg / kg (10 mL / kg) twice a day for three weeks. Tumor volume was measured over time on the day before administration began and every three to four days, and the tumor diameter was finally measured the day after the end of the 21-day administration, and tumor volume was calculated. The tumor growth in the test compound administration group compared to the control administration group was calculated as the average tumor volume increase ratio T / C using the following formula. T / C=((tumor volume after administration of the test compound group-tumor volume on the day before administration of the test compound group) / (tumor volume after administration of the control group-tumor volume on the day before administration of the control group))×100 The T / C of the test compounds is shown below.

[0163] [Table 3]

[0164] These results demonstrated that compound (X) has an antitumor effect in a subcutaneously transplanted model of human diffuse large B-cell lymphoma cells OCI-Ly3. [Industrial Applicability]

[0165] The present invention provides an industrial production method for efficiently and mass-synthesizing compound (X), a novel MALT1 inhibitor, or a salt thereof, which has high optical purity, with a shorter number of steps and without the need for complicated procedures such as chiral column purification, and is useful in the field of the pharmaceutical industry.

[0166] This application is based on patent application No. 2020-092687 filed in Japan (filing date: May 27, 2020), the contents of which are incorporated in their entirety herein.

Claims

1. The following formula (X1): 【Chemistry 1】 or a salt thereof, comprising a step of isolating and / or purifying a compound represented by the following formula (compound (X1)):

2. The method for producing compound (X1) or a salt thereof according to claim 1, wherein the isolation and / or purification comprises isolation and / or purification by one or more separation means selected from concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, and chromatography.

3. The optical purity is 99% ee or more. The following formula (X1): 【Chemistry 2】 or a salt thereof, comprising a step of obtaining a compound represented by the following formula (compound (X1)):

4. The method for producing compound (X1) or a salt thereof according to claim 3, wherein the optical purity is 99.1% ee or more.

5. The method for producing compound (X1) or a salt thereof according to claim 4, wherein the optical purity is 99.5% ee or more.

6. A method for producing a compound according to the present invention, comprising reacting (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine or a salt thereof with 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine or a salt thereof, The following formula (X1): 【Chemistry 3】 A method for producing a compound represented by the following formula (compound (X1)) or a salt thereof:

7. A method for producing a compound according to the present invention, comprising reacting (S)-6-chloro-4-(1-methoxyethyl)-1,5-naphthyridin-3-amine or a salt thereof with phenyl 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridine-3-aminocarbamate or a salt thereof, The following formula (X1): 【Chemistry 4】 A method for producing a compound represented by the following formula (compound (X1)) or a salt thereof:

8. Formula (B-1): 【Chemistry 5】 (In the formula, R １ is a methyl group, and R ２ is C １－６ It represents an alkyl group or a halogen atom. The present invention relates to a method for producing a crystallized salt of a compound represented by the formula (B-2): 【Chemistry 6】 (In the formula, R １ and R ２ are the same as defined above.) A method for producing a compound represented by the formula:

9. 1) Formula (B-1): 【Chemistry 7】 (In the formula, R １ is a methyl group, and R ２ is C １－６ It represents an alkyl group or a halogen atom. The compound represented by the formula (B-2): 【Chemistry 8】 (In the formula, R １ and R ２ are the same as defined above.) or a salt thereof, 2) The compound (B-2) or a salt thereof obtained is subjected to an alkylation reaction, to obtain a compound represented by the formula (C): 【Chemistry 9】 (In the formula, R １ and R ２ are as defined above, and R ３ is C １－６ It indicates an alkyl group. A method for producing a compound represented by the formula (compound (C)) or a salt thereof.

10. 1) Formula (B-1): 【Chemistry 10】 (In the formula, R １ is a methyl group, and R ２ is C １－６ It represents an alkyl group or a halogen atom. The compound represented by the formula (B-2): 【Chemistry 11】 (In the formula, R １ and R ２ are the same as defined above.) or a salt thereof, 2) The obtained compound (B-2) or a salt thereof is subjected to an alkylation reaction to obtain a compound of the formula (C): 【Chemistry 12】 (In the formula, R １ and R ２ are as defined above, and R ３ is C １－６ It indicates an alkyl group. or a salt thereof, 3) The obtained compound (C) or a salt thereof is reacted with a compound of the formula (D): 【Chemistry 13】 (In the formula, R ４ is C which may be substituted with a halogen atom １－６ Alkyl groups, and R ７ is a C group optionally substituted with a hydrogen atom or a halogen atom １－６ represents an aryloxycarbonyl group which may be substituted with an alkoxy group or a nitro group. or a salt thereof, 【Chemistry 14】 (In the formula, R １ ~R ４ are the same as defined above.) A method for producing a compound represented by the following formula (compound (X)) or a salt thereof:

11. 1) Formula (A): 【Chemistry 15】 (In the formula, R １ is a methyl group, R ２ is C １－６ an alkyl group or a halogen atom, R ５ and R ６ each independently represents a hydrogen atom or an amino-protecting group. or a salt thereof is subjected to 1) an asymmetric reduction reaction of a carbonyl group, or 2) an asymmetric reduction reaction of a carbonyl group and an elimination reaction of an amino-protecting group, to obtain a compound represented by the formula (B-1): 【Chemistry 16】 (In the formula, R １ and R ２ are the same as defined above.) or a salt thereof, 2) Crystallizing a salt of the obtained compound (B-1) with an optically active organic acid, 【Chemistry 17】 (In the formula, R １ and R ２ are the same as defined above.) A method for producing a compound represented by the following formula (compound (B-2)) or a salt thereof:

12. 1) Formula (A): 【Chemistry 18】 (In the formula, R １ is a methyl group, R ２ is C １－６ an alkyl group or a halogen atom, R ５ and R ６ each independently represents a hydrogen atom or an amino-protecting group. or a salt thereof is subjected to 1) an asymmetric reduction reaction of a carbonyl group, or 2) an asymmetric reduction reaction of a carbonyl group and an elimination reaction of an amino-protecting group, to obtain a compound represented by the formula (B-1): 【Chemistry 19】 (In the formula, R １ and R ２ are the same as defined above.) or a salt thereof, 2) The salt of the obtained compound (B-1) with an optically active organic acid is crystallized to obtain a compound of the formula (B-2): 【Chemistry 20】 (In the formula, R １ and R ２ are the same as defined above.) or a salt thereof, 3) The obtained compound (B-2) or a salt thereof is subjected to an alkylation reaction to obtain a compound of the formula (C): 【Chemistry 21】 (In the formula, R １ and R ２ are as defined above, and R ３ is C １－６ It indicates an alkyl group. or a salt thereof, 4) The obtained compound (C) or a salt thereof is reacted with a compound of the formula (D): 【Chemical 22】 (In the formula, R ４ is C which may be substituted with a halogen atom １－６ Alkyl groups, and R ７ is a C group optionally substituted with a hydrogen atom or a halogen atom １－６ represents an aryloxycarbonyl group which may be substituted with an alkoxy group or a nitro group. or a salt thereof, 【Chemistry 23】 (In the formula, R １ ~R ４ are the same as defined above.) A method for producing a compound represented by the following formula (compound (X)) or a salt thereof:

13. Optically active organic acids include D-(-)-tartaric acid, L-(+)-tartaric acid, (S)-(-)-2-pyridone-5-carboxylic acid, (R)-(+)-2-pyridone-5-carboxylic acid, L-malic acid, D-malic acid, (S)-(+)-camphor-10-sulfonic acid, (R)-(-)-camphor-10-sulfonic acid, (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid, (R)-(-)-2-(6-methoxy-2-naphthyl)propionic acid, 13. The method according to any one of claims 8 to 12, wherein the quinic acid is selected from the group consisting of quinic acid, (+)-cis-2-benzamidocyclohexanecarboxylic acid, (-)-cis-2-benzamidocyclohexanecarboxylic acid, dehydroabietic acid, (R)-(-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, (S)-(+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine, D-(-)-quinic acid and L-(+)-quinic acid.

14. The method according to any one of claims 8 to 12, wherein the optically active organic acid is D-(-)-tartaric acid.

15. Formula (C): 【Chemistry 24】 (In the formula, R １ is a methyl group, R ２ is C １－６ an alkyl group or a halogen atom, and R ３ is C １－６ It indicates an alkyl group. or a salt thereof, 【Chemistry 25】 (In the formula, R ４ is C which may be substituted with a halogen atom １－６ Alkyl groups, and R ７ is a C group optionally substituted with a hydrogen atom or a halogen atom １－６ represents an aryloxycarbonyl group which may be substituted with an alkoxy group or a nitro group. or a salt thereof, 【Chemistry 26】 (In the formula, R １ ~R ４ are the same as defined above.) A method for producing a compound represented by the following formula (compound (X)) or a salt thereof:

16. 1) Formula (B-2): 【Chemistry 27】 (In the formula, R １ is a methyl group, and R ２ is C １－６ It represents an alkyl group or a halogen atom. or a salt thereof is subjected to an alkylation reaction to obtain a compound represented by the formula (C): 【Chemistry 28】 (In the formula, R １ and R ２ are as defined above, and R ３ is C １－６ It indicates an alkyl group. or a salt thereof, 2) The obtained compound (C) or a salt thereof is reacted with a compound of the formula (D): 【Chemical 29】 (In the formula, R ４ is C which may be substituted with a halogen atom １－６ Alkyl groups, and R ７ is a C group optionally substituted with a hydrogen atom or a halogen atom １－６ represents an aryloxycarbonyl group which may be substituted with an alkoxy group or a nitro group. or a salt thereof, 【Chemistry 30】 (In the formula, R １ ~R ４ are the same as defined above.) A method for producing a compound represented by the following formula (compound (X)) or a salt thereof:

17. Formula (C): 【Chemistry 31】 (In the formula, R １ is a methyl group, R ２ is C １－６ an alkyl group or a halogen atom, and R ３ is C １－６ It indicates an alkyl group. A compound represented by the formula (compound (C)) or a salt thereof.

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