Method for producing uracil derivative

Abstract

Provided is a novel method for producing a uracil derivative. A method for producing a compound represented by formula (III) (in the formula, R1 represents a halogen or the like, each R2 is independently a halogen or the like, Z is CH or the like, and n is an integer of 1-5), or a salt thereof, characterized by reacting a compound represented by formula (I) (symbols in the formula are as defined above), or a salt thereof, with a compound represented by formula (II) (symbols in the formula are as defined above), or a salt thereof, in the presence or absence of a base and in the presence of a condensing agent selected from the group consisting of T3P (registered trademark) and the like.

Description

Method for producing uracil derivatives

[0001] The present invention relates to a novel compound exhibiting inhibitory activity against coronavirus 3CL protease, a novel synthetic intermediate thereof, or a salt thereof, and a method for producing the same.

[0002] Coronaviruses, which belong to the Orthocoronavirus subfamily of the Coronaviridae family of the Nidovirales order, have a genome size of approximately 30 kilobases and are among the largest single-stranded positive-strand RNA viruses known. Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Seven types of coronaviruses that infect humans are known: two types in the Alphacoronavirus genus (HCoV-229E and HCoV-NL63) and five types in the Betacoronavirus genus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2). Of these, four (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens that cause the common cold, while the remaining three are severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and novel coronavirus (SARS-CoV-2), which cause severe pneumonia.

[0003] The novel coronavirus disease (COVID-19) that emerged in December 2019 rapidly spread internationally, and on March 11, 2020, the WHO declared it a pandemic. The main routes of SARS-CoV-2 transmission have been reported to be droplet, contact, and aerosol transmission, and it has been confirmed that SARS-CoV-2 remains airborne with aerosols for approximately three hours, maintaining its infectiousness (Non-Patent Document 1). The incubation period is approximately two to 14 days, and typical symptoms include cold-like fever (87.9%), dry cough (67.7%), fatigue (38.1%), and phlegm (33.4%) (Non-Patent Document 2). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, and interstitial pneumonia occurs. Multiple organ failure, including renal and liver failure, has also been reported.

[0004] In Japan, through drug repositioning of existing drugs, the antiviral drug remdesivir, the anti-inflammatory drug dexamethasone, and the rheumatism drug baricitinib have been approved as treatments for COVID-19, with the anti-IL-6 receptor antibody tocilizumab receiving additional approval in January 2022. Furthermore, the antibody cocktail therapy Lonaprive (casirivimab / imdevimab) received special approval in July 2021, sotrovimab in September 2021, and molnupiravir in December 2021. There is insufficient evidence regarding the efficacy and safety of these drugs. Therefore, there is an urgent need to develop treatments for COVID-19.

[0005] When coronaviruses infect cells, they synthesize two polyproteins. These polyproteins contain the replication complex that creates the viral genome and two proteases. Proteases cleave the polyproteins synthesized by the virus, playing an essential role in enabling each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 3). In June 2021, the completion of Phase 1b trials of Pfizer's Lufotrelvir (PF-07304814), a prodrug of PF-00835231, a COVID-19 treatment targeting 3CL protease, was published in ClinicalTrials.gov (NCT04535167). Additionally, in March 2021, Pfizer announced the initiation of Phase 1 trials for PF-07321332, a therapeutic drug for COVID-19. The structural formulae of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, and have different chemical structures from the compounds produced by the production method of the present invention (Non-Patent Documents 4, 8, and 9, and Patent Documents 1 and 2). PF-00835231: Lufotrelvir (PF-07304814): PF-07321332: In December 2021, PAXLOVID™ was granted emergency use authorization in the United States, and on February 10, 2022, PAXLOVID® Pak was granted special approval in Japan.

[0006] Furthermore, in August 2021, the start of Phase 1 trials of PBI-0451 by Pardes Biosciences, a COVID-19 treatment targeting 3CL protease, was published in ClinicalTrials.gov (NCT05011812). The structural formula of PBI-0451 is shown below, and its chemical structure differs from that of the compound produced by the production method of the present invention (Non-Patent Document 11).

[0007] Furthermore, Zocova (registered trademark) was approved in Japan on November 22, 2022, as a COVID-19 treatment targeting 3CL protease (Non-Patent Document 16). The active ingredient of Zocova is ensitrevir fumarate, and its structural formula is shown below, and its chemical structure is different from that of the compound produced by the production method of the present invention (Patent Documents 10 and 11).

[0008] On the other hand, there is insufficient evidence regarding resistance mutations to COVID-19 drugs targeting 3CL proteases.

[0009] Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 4 to 7 and 12 to 15, but none of these documents describe or suggest compounds produced by the production method of the present invention. Furthermore, although the compounds of the present invention are described in Patent Documents 12 and 13, they do not describe or suggest the production method of the present invention. ３ and / or P2X ２／３ Compounds having receptor inhibitory activity are disclosed in Patent Documents 3 to 9, but none of these documents describe or suggest 3CL protease inhibitory activity or antiviral effects. Non-Patent Document 10 describes a compound having HIV-1 reverse transcriptase inhibitory activity, but none of these documents describe or suggest 3CL protease inhibitory activity or anti-coronavirus effects.

[0010] International Publication No. 2021 / 205298 International Publication No. 2021 / 250648 International Publication No. 2012 / 020742 International Publication No. 2013 / 118855 Chinese Patent Application Publication No. 113620888 Chinese Patent Application Publication No. 113666914 Chinese Patent Application Publication No. 113735838 Chinese Patent Application Publication No. 113773300 Chinese Patent Application Publication No. 113801097 International Publication No. 2022 / 138987 International Publication No. 2022 / 138988 International Publication No. 2023 / 195529 International Publication No. 2023 / 195530

[0011] The New England Journal of Medicine (2020), Vol. 382, ​​pp. 1564-1567, "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [Retrieved March 16, 2023], Internet <URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-final-report.pdf> Science (2003), Vol. 300, pp. 1763-1767 "A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19", Journal of Virology, 2021 Mar 10; 95(7), e01819-20 Cell Research (2020), Vol. 30, pp. 678-692 Science (2020), Vol. 368, pp. 409-412 ACS Central Science (2021), Vol. 7, No. 3, pp. 467-475 261st Am Chem Soc (ACS) Natl Meet ・ 2021-04-05 / 2021-04-16 ・ Virtual, N / A ・ Abst 243Science (2021), Vol. 374, pp. 1586-1593 Synthetic Communications (2006), Vol. 36, No. 19, pp. 2913-2920 "Discovery and Development of PBI-0451", [online], March 24, 2022, 35th International Conference on Antiviral Research (ICAR), [Retrieved March 16, 2023], Internet <URL: https: / / ir.pardesbio.com / static-files / fc7c4f8c-e0bd-4b97-8c9c-eff09bafd4db>Molecules (2020), Vol. 25, p. 3193Molecules (2020), Vol. 25, p. 3920European Journal of Medicinal Chemistry (2020), Vol. 206, p. 112711Journal of the American Chemical Society (2022), Vol. 144, p. 2905-2920Shionogi & Co., Ltd. Press Release (November 22, 2022).

[0012] An object of the present invention is to provide a novel compound having coronavirus 3CL protease inhibitory activity, a novel synthetic intermediate thereof, or a salt thereof, and a method for producing the same.

[0013] The present invention relates to the following: (1) A compound of formula (I): (In the formula, R １ is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, and Z is CH or N.) or a salt thereof with a compound represented by formula (II): (In the formula, R ２ are each independently halogen, haloC1-C4 alkyl, or cyano, and n is an integer of 1 to 5. A compound represented by the formula (I) or a salt thereof is reacted with T3P (registered trademark), ethylphosphonic anhydride, n-butylphosphonic anhydride, PyBOP (registered trademark), HATU, WSCD, WSCD.HCl, MsCl, and ClP(O)(OPh) in the presence or absence of a base. ２ The compound of formula (III): (The symbols in the formula have the same meanings as above.) or a salt thereof. (2) The production method according to the above item (1), wherein the condensing agent is T3P (registered trademark). (3) The production method according to the above item (1) or (2), characterized in that the production is carried out in the presence of triethylamine. (4) The compound represented by formula (III) is produced by condensing a compound represented by formula (IV): (5) The method for producing a compound represented by formula (III): (In the formula, R １ is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, Z is CH or N, R ２ are each independently halogen, haloC1-C4 alkyl or cyano, and n is an integer of 1 to 5, and a compound represented by formula (V): (The symbols in the formula have the same meanings as above.) or a salt thereof, or a solvate thereof. (6) The production method according to the above item (5), wherein the base is DBU, LDA, or potassium t-butoxide. (7) The production method according to the above item (5), wherein the base is DBU. (8) A method for producing a compound represented by formula (V) represented by formula (VI): (9) The method for producing a compound represented by formula (V): (In the formula, R １ is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, Z is CH or N, R ２ are each independently halogen, haloC1-C4 alkyl, or cyano, and n is an integer of 1 to 5.) or a salt thereof, or a solvate thereof, is reacted with a chlorinating agent selected from the group consisting of phosphorus oxychloride, phenyl dichlorophosphate, and phenylphosphonic acid dichloride in the presence or absence of one or more additives selected from the group consisting of water, sulfolane, n-butanol, DMF, and tetrabutylammonium chloride, and in the presence or absence of a solvent, to produce a compound represented by formula (VII): (wherein the symbols have the same meanings as above) or a salt thereof. (10) The production method according to the above item (9), wherein the chlorinating agent is phosphorus oxychloride or phenyl dichlorophosphate. (11) The production method according to the above item (9) or (10), characterized in that the production is carried out in the presence of water. (12) The production method according to the above item (11), characterized in that the production is carried out in the presence of sulfolane. (13) The production method according to the above item (VII), wherein the compound represented by formula (VII) is a compound represented by formula (VIII): (14) The method for producing a compound represented by formula (IV): or a salt thereof, comprising the step of obtaining a compound represented by formula (IX): (15) A method for producing a compound represented by formula (VI): or a salt thereof, by the production method described in the above item (8). or a salt thereof, or a solvate thereof, (16) A method for producing a compound represented by formula (VIII): or a salt thereof, by the production method described in the above item (13). or a salt thereof, comprising the step of obtaining a compound represented by formula (IX): (17) A method for producing a compound represented by formula (IV): or a salt thereof, by the method described in the above item (4). or a salt thereof, by the method described in the above item (8), or a salt thereof, or a solvate thereof, and a process for producing a compound represented by formula (VIII): or a salt thereof, comprising a step of producing a compound represented by formula (IX): (18) A method for producing a compound represented by formula (IV): or a salt thereof. (19) A compound represented by formula (VI): or a salt thereof. (20) A compound represented by formula (VIII): (21) A compound represented by formula (X): or a salt thereof. or a salt thereof.

[0014] The compound represented by formula (IX) produced by the production method of the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and / or preventive agent for coronavirus infection. The compound represented by formula (IX) produced by the production method of the present invention is also useful as a pharmaceutical ingredient. Furthermore, a pharmaceutical composition containing the compound represented by formula (IX) produced by the production method of the present invention is highly useful as a therapeutic and / or preventive agent for novel coronavirus disease (COVID-19). The production method of the present invention is a method that enables the compound represented by formula (IX) to be produced in high yield.

[0015]

[0033] Figure 1 shows the powder X-ray diffraction pattern of compound 6. The horizontal axis represents 2θ (deg), and the vertical axis represents intensity (cps). Figure 1 shows a peak list for the powder X-ray diffraction pattern. In this peak list, height represents intensity. The parenthesized values ​​for each measurement value represent standard deviation. Figure 1 shows the powder X-ray diffraction pattern of an anhydrous crystal of the compound represented by formula (IX). The horizontal axis represents 2θ (°), and the vertical axis represents intensity. Figure 3 shows a peak list for the powder X-ray diffraction pattern. In the table, Position represents 2θ (°), and Intensity represents intensity. Figure 1 shows the crystal structure (structure in the asymmetric unit) of an anhydrous crystal of the compound represented by formula (IX). Figure 1 shows the results of differential scanning calorimetry (DSC) of an anhydrous crystal of the compound represented by formula (IX). The horizontal axis represents temperature (°C), and the vertical axis represents heat (W / g). The figure shows the results of simultaneous differential thermal analysis and thermogravimetry (TG / DTA) of the anhydrous crystal of the compound represented by formula (IX). The vertical axis shows the amount of heat (μV) or the weight change (%), and the horizontal axis shows the temperature (°C). Cel in the figure means degrees Celsius (°C). The figure shows the Raman spectrum of the anhydrous crystal of the compound represented by formula (IX). The horizontal axis shows the Raman shift (cm －１ ) and the vertical axis represents peak intensity. This shows the powder X-ray diffraction pattern of Compound 6 obtained in Step 3 of Example 1A. The horizontal axis represents 2θ (deg) and the vertical axis represents intensity (cps). Figure 9 shows a peak list of the powder X-ray diffraction pattern. In this peak list, height represents intensity. The parenthesized values ​​for each measurement value indicate the standard deviation.

[0016] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The terms "comprise" and "include" mean that the term is not limited to the constituent elements and does not exclude unrecited elements. The present invention will be described below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0017] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, fluorine and chlorine atoms are preferred.

[0018] The term "alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl. "C1-C4 alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Preferred embodiments of "C1-C4 alkyl" include methyl, ethyl, n-propyl, and isopropyl. "Halo C1-C4 alkyl" refers to a group in which one or more of the above-mentioned "halogens" are bonded to the above-mentioned "C1-C4 alkyl." When substituted with two or more halogens, the halogens may be the same or different. Examples include monofluoromethyl, difluoromethyl, 2-monofluoroethyl, 3-monofluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2-difluoroethyl, 1,1,1-trifluoropropan-2-yl, 4,4,4-trifluorobutyl, and 3,3,4,4,4-pentafluorobutyl. Preferred embodiments of "halo C1-C4 alkyl" include trifluoromethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

[0019] The compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) are not limited to specific isomers, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates or mixtures thereof. For example, the compound represented by formula (V) includes the following tautomers: For example, the compound represented by formula (VI) includes the following tautomers.

[0020] One or more hydrogen, carbon and / or other atoms in the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include: ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. １２３ I and ３６The isotopes of the compounds represented by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X) include isotope-substituted compounds. The isotope-substituted compounds are also useful as pharmaceuticals. The compounds represented by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X) include all radiolabeled compounds substituted with radioactive isotopes contained in the isotopes. The present invention also encompasses "radiolabeling methods" for producing the "radiolabeled compounds," which are useful as research and / or diagnostic tools in metabolism, pharmacokinetic studies, and binding assays.

[0021] Radiolabeled compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) can be prepared by introducing tritium into specific compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) by catalytic dehalogenation reaction using tritium. This method involves reacting an appropriately halogen-substituted precursor of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0022] The compound of formula (IX) used herein may form a prodrug. A prodrug is a derivative of a compound produced by the production method of the present invention having a chemically or metabolically decomposable group, and is a compound that is pharmaceutically active in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to a compound of formula (IX) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to a compound of formula (IX) by hydrolysis with gastric acid, etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." A prodrug may itself have activity.

[0023] As used herein, the "compound represented by formula (IX)" may form a salt, a co-crystal, or a solvate thereof. As used herein, the "compound represented by formula (IX) or a salt thereof" also encompasses such various salts, co-crystals, and solvates thereof.

[0024] As used herein, the term "salt" refers to a compound represented by, for example, formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), or formula (X) and a counter molecule arranged regularly in the same crystal lattice, and may contain any number of counter molecules. This refers to a compound formed via an ionic bond by proton transfer between the compound and the counter molecule in the crystal lattice.

[0025] Examples of salts of the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) include salts of the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) with an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metal (e.g., zinc, iron, etc.), ammonia, organic base (e.g., trimethylamine, triethylamine, dicyclohexylamine, , ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[0026] The compounds of the present invention represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X), or salts thereof, may form solvates (e.g., hydrates, etc.), co-crystals, and / or crystalline polymorphs, and the present invention also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) with any number of solvent molecules (e.g., water molecules, etc.). When the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VII), formula (VIII), formula (IX), and formula (X), or salts thereof, or solvates thereof, are left in the atmosphere, they may absorb moisture, resulting in the adhesion of adsorbed water or the formation of hydrates. Furthermore, when the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X), or salts thereof, or solvates thereof are recrystallized, a crystalline polymorph may be formed. "Cocrystal" means that the compound represented by formula (I) or salt and a counter molecule exist in the same crystal lattice, and any number of counter molecules may be included.

[0027] As used herein, the term "cocrystal" refers to a compound in which counter molecules (co-former molecules) are regularly arranged within the same crystal lattice, and may contain any number of counter molecules (co-former molecules). A cocrystal also refers to a compound in which the intermolecular interaction between the compound and the counter molecules (co-former molecules) is mediated by non-covalent, non-ionic chemical interactions such as hydrogen bonding or van der Waals forces.

[0028] Generally, salts are considered to be those in which proton transfer occurs between a compound and a counter molecule; however, it is known that in some cases, proton transfer may not be complete. This state is sometimes called a cocrystal because it is not a true salt. It is also known that proton transfer may change continuously depending on temperature. Therefore, as used herein, "a salt of a compound represented by formula (IX)" includes cocrystals and refers to a salt or cocrystal of a compound represented by formula (IX).

[0029] One aspect of the present specification is a pharmaceutically acceptable salt or co-crystal of a compound represented by formula (IX) with hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethylbenzenesulfonic acid, chlorobenzenesulfonic acid, methoxybenzenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malonic acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid, tartaric acid, benzoic acid, glutamic acid, aspartic acid, 2-naphthalenesulfonic acid, hexanoic acid, acetylsalicylic acid, or the like.

[0030] The study of salt and co-crystal formation provides a means to modify the physicochemical and resulting biological characteristics of a drug without altering its chemical structure. Salt and co-crystal formation can dramatically affect the properties of a drug. Hygroscopicity, stability, solubility, and processing characteristics are also important considerations in selecting an appropriate salt or co-crystal. The solubility of a salt or co-crystal can affect its suitability for use as a drug. If water solubility is low, the dissolution rate upon in vivo administration may be rate-limited by the absorption process, resulting in low bioavailability. Low water solubility can also make administration by injection difficult, limiting the selection of an appropriate administration route.

[0031] The complexes containing the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) of the present invention broadly include salts, cocrystals, and clathrates, or solvates thereof.

[0032] The compound of formula (IX) can form a solvate with water (i.e., a hydrate) or a common organic solvent. The salt of the compound of formula (IX) can form a solvate with water (i.e., a hydrate) or a common organic solvent.

[0033] The term "solvate" as used herein refers to a compound represented by, for example, formula (I), formula (II), formula (III), formula (III-1), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) or formula (X) in which any number of solvent molecules are regularly arranged. Examples of solvent molecules include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, pentane, pentane, pentane-1-isopropyl ether ... Examples of suitable solvents include ethanol, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, xylene, and t-butanol.Preferred examples include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, toluene, and tetrahydrofuran. More preferred are ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, toluene, trichloroacetic acid, and trifluoroacetic acid. As the solvate of the compound represented by formula (VI), a toluene solvate is preferred. Furthermore, when the compounds represented by formulas (I), (II), (III), (III-1), (IV), (V), (VI), (VII), (VIII), (IX), and (X) are left in the air, they may absorb moisture, and adsorbed water may adhere to them or they may form hydrates.

[0034] As used herein, "crystal" refers to a solid in which constituent atoms, ions, molecules, etc. are arranged in a three-dimensional order, and is distinguished from amorphous solids that do not have such an orderly internal structure. As used herein, crystals may be single crystals, twin crystals, polycrystals, etc. Furthermore, "crystals" may have "crystal polymorphs" that have the same composition but different arrangements within the crystal, and these are all referred to as "crystalline forms." "A compound represented by formula (IX) or a salt thereof" includes these crystal polymorphs. As used herein, crystals may be deuterium-converted products. As used herein, crystals refer to isotopes (e.g., ３ H.１４ C. ３５ S. １２５ The crystal form and / or crystallinity can be confirmed by spectroscopic methods such as X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, solid-state NMR, etc. The physical properties of the crystals can also be confirmed by a number of techniques such as differential scanning calorimetry, moisture adsorption / desorption measurements, and dissolution characteristics.

[0035] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (IX). As used herein, "anhydrous" is synonymous with "solvate-free," "nonsolvate," "anhydrate," and "nonhydrate." The theoretical content of water of crystallization in an anhydrous crystal of the compound represented by formula (IX) is 0% by weight. However, in analyzing the amount of water and / or solvent, values ​​higher than the theoretical content of water of crystallization may be obtained due to the influence of water and / or solvent attached to the crystal surface.

[0036] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (IX), which has characteristic peaks at diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2° in a powder X-ray diffraction pattern (CuKα radiation, λ=1.5418 Å).

[0037] One aspect of the present specification is an anhydrous crystal of the compound of formula (IX), characterized by the following crystallographic data when a single crystal diffraction experiment was carried out using CuKα radiation (λ=1.5418 Å) at 298 K (25° C.): Space group: Pbca a=14.67 ű0.05 Å b=11.83 ű0.05 Å c=27.10 ű0.05 Å α=90° β=90° γ=90°

[0038] One embodiment herein is an anhydrous crystalline form of the compound represented by formula (IX), which has a melting point of 261.3°C ± 2°C as measured by differential scanning calorimetry (DSC).

[0039] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (IX), which has a melting point of 265.6°C ± 2°C as determined by simultaneous differential thermal analysis-thermogravimetry (TG / DTA).

[0040] One aspect of the present specification is a Raman spectrum of 415.2 cm －１ ±2cm －１ , 502.7 cm －１ ±2cm －１ , 1431.4 cm －１ ±2cm －１ , 1714.8 cm －１ ±2cm －１ and 3065.4 cm －１ ±2cm －１ The anhydrous crystals of the compound represented by formula (IX) have characteristic peaks at

[0041] X-ray Powder Diffraction (XRPD) X-ray powder diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystalline form and crystallinity of solids. When X-rays are irradiated onto a crystal, they reflect off the crystal lattice planes and interfere with each other, producing ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, amorphous solids generally do not have an ordered repeating period in their structure, and therefore do not exhibit diffraction phenomena, producing a featureless, broad XRPD pattern (also called a halo pattern).

[0042] The crystalline forms of the compounds represented by Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), and Formula (X) can be distinguished by powder X-ray diffraction patterns and characteristic diffraction peaks. The crystalline forms of the compounds represented by Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), and Formula (X) can be distinguished from other crystalline forms by the presence of characteristic diffraction peaks. As used herein, a characteristic diffraction peak is a peak selected from the observed diffraction pattern. The characteristic diffraction peak is preferably selected from about 10, more preferably about 5, and even more preferably about 3 peaks in the diffraction pattern. When distinguishing between multiple crystals, a peak that is identified in the crystal and not in other crystals is a preferred characteristic peak for identifying the crystal, rather than peak intensity. As long as there are such characteristic peaks, even one or two peaks can characterize the crystal. The charts obtained by measurement are compared, and if these characteristic peaks match, it can be said that the powder X-ray diffraction spectra are substantially the same.

[0043] Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error within a range of ±0.2°, and therefore the value of the diffraction angle in powder X-ray diffraction should be understood to include values ​​within a range of about ±0.2°. Therefore, not only crystals in which the diffraction angles of peaks in powder X-ray diffraction perfectly match, but also crystals in which the diffraction angles of peaks match with an error of about ±0.2° are included in the present invention.

[0044] It is known that the intensities of the peaks displayed in the following tables and figures may generally vary depending on many factors, such as the effect of preferred orientation of the crystal relative to the X-ray beam, the influence of large particles, the purity of the material being analyzed, or the crystallinity of the sample. Peak positions may also shift based on variations in sample height. Furthermore, measurements using different wavelengths will result in different shifts according to the Bragg equation (nλ=2d sin θ), and compounds exhibiting different XRPD patterns obtained using such different wavelengths are also within the scope of the present invention.

[0045] (Single crystal structure analysis) This is one of the methods for identifying a crystal, and it is possible to obtain the crystallographic parameters of the crystal, as well as atomic coordinates (values ​​indicating the spatial positional relationship of each atom) and a three-dimensional structural model. See, for example, "X-Ray Structure Analysis Handbook" by Toshio Sakurai, published by Shokabo (1983), and "X-Ray Structure Determination: A Practical Guide" by Stout & Jensen, Macmillan Co., New York (1968). Single crystal structure analysis is useful for identifying the crystal structures of the complexes, salts, optical isomers, tautomers, and geometric isomers of the present invention.

[0046] (Raman spectroscopy) Raman spectra show the vibrational characteristics of molecules or complex systems. Its origin is the inelastic collision between molecules and photons, which are light particles that comprise light rays. The collision between a molecule and a photon results in an exchange of energy, which changes the energy and thus the wavelength of the photon. In other words, Raman spectra are spectral lines with extremely narrow wavelengths that are emitted when a photon is incident on a molecule of interest, so a laser or similar light source is used. The wavelength of each Raman line is expressed by the wavenumber shift from the incident light, which is the difference between the Raman line and the reciprocal of the wavelength of the incident light. Raman spectra measure the vibrational state of a molecule, which is determined by its molecular structure. Generally, Raman spectrum peaks (cm －１ ) is ±2cm －１ Since there may be an error within the range of ±2 cm －１ Therefore, it should be understood that the Raman spectrum includes not only crystals in which the Raman spectrum peaks completely coincide, but also crystals in which the Raman spectrum peaks are within ±2 cm. －１ Crystals that match within a certain degree of error are also included in the present invention.

[0047] (Differential Scanning Calorimetry (DSC)) DSC is one of the main methods of thermal analysis, and is a method for measuring the thermal properties of substances as an aggregate of atoms and molecules. DSC measures the change in heat quantity with temperature or time of a pharmaceutical active ingredient, and a differential scanning calorimetry curve is obtained by plotting the obtained data against temperature or time. From the differential scanning calorimetry curve, information can be obtained regarding the onset temperature when the pharmaceutical active ingredient melts, the maximum value of the endothermic peak curve associated with melting, and the enthalpy. It is known that the observed temperature in DSC can depend on the rate of temperature change, the sample preparation technique used, and the specific instrument. Therefore, the "melting point" in DSC refers to the onset temperature, which is less affected by the sample preparation technique. The error range for the onset temperature obtained from a differential scanning calorimetry curve is approximately ±2°C. When determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this may vary somewhat depending on the measurement conditions and instrument.

[0048] (Simultaneous Differential Thermal Analysis / Thermogravimetry (TG / DTA)) TG / DTA is one of the primary methods of thermal analysis, measuring the weight and thermal properties of substances as aggregates of atoms and molecules. TG / DTA measures the changes in weight and heat quantity of a pharmaceutical active ingredient with respect to temperature or time. By plotting the obtained data against temperature or time, TG (thermogravimetry) and DTA (differential thermal analysis) curves are obtained. TG / DTA curves can provide information on weight and heat quantity changes related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of a pharmaceutical active ingredient. It is known that the observed temperature and weight changes in TG / DTA can depend on the temperature change rate, the sample preparation technique used, and the specific instrument. Therefore, the "melting point" in TG / DTA refers to the onset temperature, which is less affected by the sample preparation technique. When determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this may vary somewhat depending on the measurement conditions and instrument.

[0049] The compound represented by formula (IX) produced by the production method of the present invention has coronavirus 3CL protease inhibitory activity and is therefore useful as a therapeutic and / or preventive agent for diseases associated with coronavirus 3CL protease. Diseases associated with coronavirus 3CL protease include viral infections, preferably coronavirus infections. In one embodiment, the coronavirus includes a coronavirus that infects humans. Examples of coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. In one embodiment, the coronavirus includes an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus, and even more preferably a sarbecovirus. In one embodiment, the alphacoronavirus includes HCoV-229E and HCoV-NL63. Particularly preferred is HCoV-229E. In one embodiment, the betacoronavirus includes HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, HCoV-OC43 or SARS-CoV-2 is used, and particularly preferably SARS-CoV-2. In one embodiment, the betacoronavirus includes betacoronavirus lineage A (β-coronavirus lineage A), betacoronavirus lineage B (β-coronavirus lineage B), and betacoronavirus lineage C (β-coronavirus lineage C). More preferred are beta coronavirus lineage A and beta coronavirus lineage B, with beta coronavirus lineage B being particularly preferred.Examples of betacoronavirus lineage A include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43. Examples of betacoronavirus lineage B include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2. Examples of betacoronavirus lineage C include MERS-CoV. In one embodiment, the coronavirus includes HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, particularly preferably SARS-CoV-2. It is generally known that viruses mutate during repeated proliferation and infection. The coronavirus includes not only mutant strains known in the art but also mutant strains that may emerge in the future, so long as the compound represented by formula (IX) produced by the production method of the present invention is capable of exhibiting coronavirus 3CL protease inhibitory activity. Known SARS-CoV-2 mutant strains include, for example, the mutant strains used in the Examples of this specification. Coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferred examples include infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred. Particularly preferred examples of coronavirus infections include novel coronavirus infection (COVID-19).

[0050] The production method according to the present invention will be described below. Step A: Production method of the compound represented by formula (III) The symbols in the formula are as defined above. In this step, a compound represented by formula (I) or a salt thereof and a compound represented by formula (II) or a salt thereof are reacted with T3P (registered trademark), ethylphosphonic anhydride, n-butylphosphonic anhydride, PyBOP (registered trademark), HATU, MsCl, WSCD, WSCD.HCl, and ClP(O)(OPh) in the presence or absence of a base. ２ This is a method for producing a compound represented by formula (III) or a salt thereof, characterized by reacting the compound represented by formula (I) or a salt thereof in the presence of a condensing agent selected from the group consisting of: The compound represented by formula (I) or a salt thereof and the compound represented by formula (II) or a salt thereof can be produced using commercially available reagents according to known methods, or commercially available products can be used. Relative to the compound represented by formula (I) or a salt thereof, the compound represented by formula (II) or a salt thereof can typically be used in an amount of 1.0 to 5.0 equivalents, for example, 1.0 to 3.0 equivalents. Relative to the compound represented by formula (I) or a salt thereof, the condensing agent can typically be used in an amount of 1.0 to 5.0 equivalents, for example, 1.0 to 3.0 equivalents. A preferred condensing agent is T3P (registered trademark). The solvent is not particularly limited as long as it efficiently progresses the above process. Examples of solvents include N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, etc., and these can be used alone or in combination. Examples of bases include triethylamine, diisopropylethylamine, DBU, etc. Alternatively, a base may not be used. The amount of base used relative to the compound represented by formula (I) or a salt thereof is usually 0.1 to 5.0 equivalents, for example, 1.0 to 2.0 equivalents. The reaction temperature is not particularly limited, but the reaction can be carried out usually at about 0°C to about 80°C, preferably room temperature to 60°C. The reaction time is not particularly limited, but is usually 0.1 to 12 hours, preferably 0.1 to 8 hours. Step B: Method for producing a compound represented by formula (V) The symbols in the formula are as defined above. This step is a method for producing a compound represented by formula (V) or a salt thereof, or a solvate thereof, which comprises reacting a compound represented by formula (III) or a salt thereof in the presence of N,N'-carbonyldiimidazole and a base. N,N'-carbonyldiimidazole can typically be used in an amount of 1.0 to 5.0 equivalents, for example, 1.0 to 3.0 equivalents, relative to the compound represented by formula (III) or a salt thereof. The solvent is not particularly limited as long as it allows the above step to proceed efficiently. Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,3-dimethylimidazolidinone, acetonitrile, ethyl acetate, etc., and these can be used alone or in combination. Examples of the base include DBU, potassium t-butoxide, and lithium diisopropylamide. DBU is preferred. The amount of base used is usually 1.0 to 5.0 equivalents, for example, 1.0 to 2.0 equivalents, relative to the compound represented by formula (III) or a salt thereof. The reaction temperature is not particularly limited, but the reaction can be carried out usually at about 0°C to about 80°C, preferably room temperature to 60°C. The reaction time is not particularly limited, but is usually 0.1 to 20 hours, preferably 0.1 to 5 hours. Step C: Method for producing a compound represented by formula (VII) The symbols in the formula are as defined above. This step is a method for producing a compound represented by formula (VII) or a salt thereof, which comprises reacting a compound represented by formula (V) or a salt thereof, or a solvate thereof with a chlorinating agent selected from the group consisting of phosphorus oxychloride, phenyl dichlorophosphate, and phenylphosphonic acid dichloride, in the presence or absence of one or more additives selected from the group consisting of water, sulfolane, n-butanol, DMF, and tetrabutylammonium chloride, and in the presence or absence of a solvent. The chlorinating agent can be used in an amount of typically 1.0 equivalent to a large excess, for example, 4.0 to 10.0 equivalents, relative to the compound represented by formula (V) or a salt thereof, or a solvate thereof. Preferred chlorinating agents include phosphorus oxychloride, phenyl dichlorophosphate, and the like. The solvent is not particularly limited as long as it efficiently progresses the above step. Examples of the solvent include sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, anisole, acetonitrile, and the like, which can be used alone or in combination. Alternatively, a solvent need not be used. The additive can be used in an amount of typically 0.1 to 20 equivalents, for example, 0.1 to 5 equivalents, relative to the compound represented by formula (V) or a salt thereof, or a solvate thereof. Water can be used as the additive. The amount of water used can be typically 0.1 to 10 equivalents, for example, 0.5 to 5.0 equivalents, relative to the compound represented by formula (V) or a salt thereof, or a solvate thereof. The reaction temperature is not particularly limited, but the reaction can be carried out at a temperature of typically about 0°C to about 200°C, preferably 100°C to 180°C. The reaction time is not particularly limited, but is typically 0.1 to 24 hours, preferably 0.1 to 12 hours.

[0051] The compound represented by formula (IX) produced by the production method of the present invention has coronavirus 3CL protease inhibitory activity and is therefore useful as a therapeutic and / or preventive agent for viral infections. Furthermore, the compound represented by formula (IX) produced by the production method of the present invention is useful as a pharmaceutical and preferably has one or more of the following excellent characteristics: a) weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.); b) good pharmacokinetics, such as high bioavailability and moderate clearance; c) high metabolic stability; d) no irreversible inhibitory effect on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein; e) no mutagenicity; f) low cardiovascular risk; g) high solubility; and h) high protein unbound rate (fu value). i) High coronavirus 3CL protease selectivity. j) High coronavirus growth inhibitory activity. For example, high coronavirus growth inhibitory activity is observed under the addition of human serum (HS) or human serum albumin (HSA). k) High growth inhibitory activity is also observed against 3CL protease inhibitor-resistant viruses. As a coronavirus growth inhibitor, for example, in the CPE inhibitory effect confirmation test (SARS-CoV-2) described below, ５０ is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less.

[0052] The pharmaceutical composition containing the compound of formula (IX) produced by the production method of the present invention can be administered orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, otic, and vaginal administration.

[0053] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0054] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0055] A pharmaceutical composition can be prepared by mixing an effective amount of the compound of formula (IX) produced by the production method of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount, dosage form, and / or various pharmaceutical additives of the compound of formula (IX) produced by the production method of the present invention, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, a pediatric pharmaceutical composition can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to patients aged 65 years or older.

[0056] The dosage of a pharmaceutical composition containing a compound represented by formula (IX) produced by the production method of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of disease, route of administration, etc., but in the case of oral administration, it is usually 0.01 to 100 mg / kg / day, preferably 0.05 to 50 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the route of administration, it is usually 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. This dosage may be administered once or in divided doses per day.

[0057] The compound represented by formula (IX) produced by the production method of the present invention may be used in combination with, for example, another therapeutic agent for novel coronavirus disease (COVID-19) (such therapeutic agents include approved agents and agents under development or to be developed in the future) (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration timing of the compound represented by formula (IX) produced by the production method of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound represented by formula (IX) produced by the production method of the present invention and the concomitant drug may be administered as two or more formulations containing the respective active ingredients, or as a single formulation containing those active ingredients.

[0058] The dosage of the concomitant drug can be appropriately selected based on the clinically used dose. Furthermore, the blending ratio of the compound represented by formula (IX) produced by the production method of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound represented by formula (IX) produced by the production method of the present invention.

[0059] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0060] The abbreviations used in this specification have the following meanings: Boc: tert-butoxycarbonyl CDI: N,N'-carbonyldiimidazole ClP(O)(OPh) ２ : Diphenyl chlorophosphate cps: Counts per second deg: ° DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMI: 1,3-dimethyl-2-imidazolidinone DMSO: Dimethyl sulfoxide DTT: Dithiothreitol EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDT: 1,2-ethanedithiol EDTA: Ethylenediaminetetraacetic acid Et ３ N: Triethylamine FBS: Fetal bovine serum H ２ O: Water HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate HCl: Hydrogen chloride HOBT: 1-hydroxybenzotriazole LDA: Lithium diisopropylamide MEM: Eagle's minimum essential medium MsCl: Methanesulfonyl chloride PhOPOCl ２ : Phenyl dichlorophosphate PhPOCl ２ : Phenylphosphonic acid dichloride POCl ３ : Phosphorus oxychloride PyBOP (registered trademark): (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate T3P (registered trademark): Propylphosphonic anhydride THF: Tetrahydrofuran n-Bu ４ NCl: tetrabutylammonium chloride n-BuOH: n-butanol t-BuOK: potassium tert-butoxide TFA: trifluoroacetic acid WSCD (also known as EDC): N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide WSCD.HCl: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride mM: mmol / L μM: μmol / L nM: nmol / L

[0061] (Method for identifying compounds) NMR analysis obtained in each example and reference example was carried out at 400 MHz. ６ , CDCl ３Measurement was performed using a NMR spectrometer. NMR data may not include all measured peaks. In the specification, "RT" or "retention time" refers to the retention time in LC / MS (liquid chromatography / mass spectrometry) or high-performance liquid chromatography (HPLC), and was measured under the following conditions. The "min" in "RT" refers to minutes. (Measurement Condition 1) Column: XBridge C18 (3.5 μm i.d. 4.6 x 150 mm) Column temperature: Constant temperature around 40°C UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography Gradient: 5% solvent [B] was maintained for 2 minutes, followed by a linear gradient of 5%-95% solvent [B] over 18 minutes, followed by 95% solvent [B] for 5 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL (Measurement condition 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×100 mm) (Waters) Column temperature: constant temperature of around 30° C. Flow rate: 0.4 mL / min UV detection wavelength: 247 nm Injection volume: 3 μL Mobile phase: [A] was an aqueous solution containing 0.1% formic acid, [B] was an acetonitrile solution containing 0.1% formic acid Gradient: a linear gradient of 15%-35% solvent [B] over 5 minutes, followed by a 20-minute hold at 35% solvent [B], followed by a 5-minute linear gradient of 35%-80% solvent [B], followed by a 3-minute hold at 80% solvent [B]. (Measurement Condition 3) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×100 mm) (Waters) Flow rate: 0.4 mL / min UV detection wavelength: 247 nm Mobile phase: [A] 0.1% formic acid aqueous solution, [B] 0.05% formic acid-containing acetonitrile solution Gradient: A linear gradient of 15%-35% solvent [B] was performed over 10 minutes, followed by maintaining 35% solvent [B] for 25 minutes, and then a linear gradient of 35%-80% solvent [B] over 5 minutes, followed by maintaining 80% solvent [B] for 3 minutes.(Measurement Condition 4) Column: Titan C18 (1.9 μm i.d. 2.1×50 mm) Column temperature: constant temperature of around 40° C. UV detection wavelength: 254 nm Flow rate: 0.6 mL / min Injection volume: 1 μL Mobile phase: [A] was an aqueous solution containing 0.1% formic acid, [B] was acetonitrile for liquid chromatography Gradient: a linear gradient of 5%-95% solvent [B] over 8 minutes, followed by maintaining 95% solvent [B] for 0.5 minutes. (Measurement Condition 5) Column: Titan C18 (1.9 μm i.d. 2.1×50 mm) Column temperature: constant temperature of around 40° C. UV detection wavelength: 254 nm Flow rate: 0.6 mL / min Injection volume: 1 μL Mobile phase: [A] was an aqueous solution containing 0.1% formic acid, [B] was acetonitrile for liquid chromatography Gradient: a linear gradient of 5%-95% solvent [B] over 3 minutes, followed by maintaining 95% solvent [B] for 0.5 minutes.

[0062] Powder X-ray diffraction experiment (XRPD) The solid forms (crystalline and amorphous) obtained in the examples were subjected to powder X-ray diffraction measurement according to the powder X-ray diffraction measurement method described in the general test methods of the Japanese Pharmacopoeia. The measurement conditions are shown below. Measurement condition 1: Powder X-ray diffractometer: Rigaku MinFlex600 Measurement method: Reflection method Wavelength used: CuKα ray Tube current: 15 mA Tube voltage: 40 kV Sample plate: Aluminum X-ray incident angle (θ): 4-40° Sampling width: 0.02° Measurement condition 2: Powder X-ray diffractometer: Rigaku SmartLab Measurement method: Reflection method Wavelength used: CuKα ray (λ=1.5418 Å) Tube current: 200 mA Tube voltage: 45 kV Sample plate: Aluminum X-ray incident angle: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (two-dimensional detection mode)

[0063] Measurement and Analysis Method for Single Crystal Structure Analysis Single crystal structure analysis was performed on the crystals obtained in the examples. The measurement conditions and analysis method are shown below. (Apparatus) Rigaku XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25°C Temperature controller: Rigaku sample spray cryogenic device Wavelength used: CuKα ray (λ = 1.5418 Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data was Lorentz and polarization corrected, and absorption corrected. (Crystal structure analysis) Phase determination was performed using the direct method program ShelXT (Sheldrick, G.M., 2015), and refinement was performed using full-matrix least-squares using ShelXL (Sheldrick, G.M., 2015). All non-hydrogen atom temperature factors were refined anisotropically. Hydrogen atoms were introduced by calculation using the default parameters of ShelXL unless otherwise specified and treated as riding atoms. Hydrogen atoms were also refined using isotropic parameters. PLATON (Spek, 1991) / ORTEP (Johnson, 1976) was used to draw the following structure diagram (30% PROBABILITY level).

[0064] Measurement of Raman Spectrum The measurement conditions for measuring the Raman spectrum of the crystals obtained in the examples and performing baseline correction are shown below. Measurement Condition 1 Measurement method: Microscopic laser Raman spectroscopy Laser wavelength: 671 nm Number of accumulations: 1 Exposure time: 1 second

[0065] Differential scanning calorimetry (DSC) DSC measurements were carried out on the crystals obtained in the examples. A sample was weighed into an aluminum pan, which was then simply sealed and measured. The measurement conditions are shown below. Note that measurements by differential scanning calorimetry (DSC) may have an error within a range of ±2°C. Apparatus: Discovery DSC / TA Instrument Measurement temperature range: -10°C to 270°C Heating rate: 10°C / min Atmosphere: N ２ 50mL / min

[0066] Simultaneous Differential Thermal Analysis - Thermogravimetry (TG / DTA) Simultaneous differential thermal analysis - thermogravimetry (TG / DTA) was carried out on the solid form (crystal) obtained in the examples. The samples obtained in the examples were weighed, placed in aluminum pans, and measured in an open system. The measurement conditions were as follows: Apparatus: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: room temperature - 350°C Heating rate: 10°C / min

[0067] Synthesis of anhydrous crystals of the compound of formula (IX)

[0068] Step 1: Synthesis of Compound 3 Compound 1 (25.8 kg, 200.7 mol), acetonitrile (155 L), pyridine (23.8 kg, 300.9 mol), and compound 2 (34.5 kg, 220.3 mol) were mixed and stirred at 25°C for 90 minutes. This reaction solution was added to 25% aqueous ammonia (129.7 kg, 1904.0 mol), and the mixture was stirred at 25°C for 270 minutes. The solid was collected by filtration, washed with 50% aqueous acetonitrile, and then dried to obtain compound 3 (30.57 kg, 178.2 mol, yield: 90.2%). HPLC (UV = 254 nm): RT = 7.0 min, HPLC measurement condition 1 １ H-NMR (DMSO-d6) δ: 6.17 (2H, s), 8.14-8.16 (2H, m), 8.38 (1H, d, J = 2.1Hz), 8.99 (1H, s).

[0069] Step 2: Synthesis of Compound 5 Compound 3 (30.6 kg, 178.3 mol), compound 4 (40.3 kg, 213.7 mol), N,N-dimethylacetamide (245 L), triethylamine (21.6 kg, 213.5 mol), and a solution of propylphosphonic anhydride in ethyl acetate (165.6 kg, 267.2 mol) were mixed and stirred at 50°C for 420 minutes. The reaction solution was cooled to 25°C, water (92 L) was added, and the mixture was stirred for 150 minutes. The solid was collected by filtration, washed with acetonitrile, and then dried to obtain compound 5 (56.05 kg, 163.8 mol, yield: 92.7%). HPLC (UV = 254 nm): RT = 15.1 min, HPLC measurement condition 1 １H-NMR (DMSO-d6) δ: 3.79 (2H, s), 7.31-7.35 (1H, m), 7.38 (1H, q, J = 8.7Hz), 7.56 (1H, dd, J = 7.3, 2.0 Hz), 8.23 ​​(1H, t, J = 2.2Hz), 8.33 (1H, d, J = 2.1Hz), 8.64 (1H, d, J = 2.1Hz), 10.6 (1H, s), 11.1 (1H, s).

[0070] Step 3: Synthesis of Compound 6 Compound 5 (56.1 kg, 164.0 mol), N,N'-carbonyldiimidazole (39.8 kg, 245.5 mol), tetrahydrofuran (561 L), and 1,8-diazabicyclo[5,4,0]-7-undecene (32.4 kg, 212.8 mol) were mixed and stirred at 25°C for 60 minutes. 7% hydrochloric acid (512.4 kg) was added to this reaction solution, and the mixture was separated into an organic layer and an aqueous layer. Toluene (56 L) and tetrahydrofuran (561 L) were added to the resulting aqueous layer for extraction. The combined organic layers were concentrated under reduced pressure to 56.2 kg, and toluene (729 L) and seed crystals of Compound 6 (0.54 kg, 1.3 mol) were added, followed by stirring at 25°C for 1 day. The slurry was cooled to 5°C, and the solid was collected by filtration and washed with a cooled mixture of tetrahydrofuran (67 L) and toluene (269 L). Drying gave Compound 6 (57.22 kg, 138.1 mol, yield: 85.2%). HPLC (UV = 254 nm): RT = 9.9 min, HPLC measurement condition 1 １ H-NMR (DMSO-d6) δ: 2.28 (1.5H, s), 7.12-7.18 (1.5H, m), 7.23-7.27 (1H, m), 7.31 (1H, br), 7.50 (1H, br), 7.69 (1H, d, J = 7.0 Hz), 8.01 (1H, t, J = 2.1 Hz), 8.50 (1H, br), 8.64 (1H, br), 11.1 (1H, s). NMR analysis of the resulting solid revealed that it contained 0.5 molecules of toluene, and that toluene was not removed under normal vacuum drying conditions. Compound 6 was confirmed to be a toluene solvate.

[0071] Step 4: Synthesis of Compound 7 Compound 6 (23.6 kg, 57.0 mol), phenyl dichlorophosphate (48.1 kg, 228.2 mol), and sulfolane (104.7 L) were mixed and stirred at 115°C for 540 minutes. The reaction solution was cooled to 25°C and added to a solution of potassium acetate (67.0 kg, 684.5 mol), water (203.0 L), and sulfolane (146.7 L) at 50°C. To the resulting slurry, sulfolane (20.6 L) and water (105.0 L) were added. The slurry was cooled to 25°C, and the solid was collected by filtration and washed with 76% aqueous 2-propanol. The collected solid was dissolved in N,N-dimethylacetamide (139.8 L), and 7% hydrochloric acid (21.6 kg) and 44% aqueous 2-propanol (189.0 kg) were added at 50°C. The slurry was cooled to 25°C, and the solid was collected by filtration, washed with a 65% aqueous solution of N,N-dimethylacetamide and 2-propanol, and then dried to obtain Compound 7 (16.9 kg, 43.6 mol, yield: 76.5%). HPLC (UV = 247 nm): RT = 12.6 min, HPLC measurement condition 2 １ H-NMR (DMSO-d6) δ: 7.35-7.39 (1H, m), 7.48 (1H, m) , 7.55 (1H, m), 8.07 (1H, t, J = 4.0Hz), 8.55 (1H, d, J = 4.0Hz), 8.71 (1H, d, J = 4.0Hz), 12.96 (1H, br).

[0072] Step 5: Synthesis of Compound 9 Compound 7 (16.5 kg, 42.7 mol), N,N-dimethylacetamide (115.5 L), N,N-diisopropylethylamine (8.3 kg, 64.0 mol), and compound 8 (6.1 kg, 51.2 mol) were mixed and stirred at 63°C for 3 hours. The reaction solution was cooled to 25°C, and acetone (82.5 L) was added, followed by dropwise addition of 5% hydrochloric acid (55.2 L) over 30 minutes. Water (49.5 L) was added to the resulting slurry, and the solid was collected by filtration and washed with 50% acetone-water. Ethyl acetate (181.5 L) was added to the resulting solid to dissolve it, and the mixture was concentrated to 104.0 kg. Ethyl acetate (82.5 L) was added to the concentrated solution, and the mixture was concentrated again to 82.5 kg. The resulting slurry was heated to 55°C to dissolve it, and then cooled to 35°C. The resulting slurry was stirred for 1 hour, and then heptane (247.5 L) was added. The mixture was cooled to 25°C, and the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane, and then dried to obtain Compound 9 (14.98 kg, 35.2 mol, yield: 82.4%). HPLC (UV = 247 nm): RT = 17.2 min, HPLC measurement condition 1 １ H-NMR (CDCl ３ ) δ: 5.13 (2H, s), 7.23-7.24 (2H, m), 7.42 (1H, d, J = 7.3Hz), 7.67 (1H, t, J = 2.1Hz), 8.45 (1H, d, J = 2.3Hz), 8.67 (1H, d, J = 2.3Hz).

[0073] Step 6: Synthesis of anhydrous crystals of the compound represented by formula (IX) Compound 9 (14.0 kg, 32.9 mol), N,N-dimethylacetamide (77 L), N,N-diisopropylethylamine (10.6 kg, 82.2 mol), and compound 10 (9.3 kg, 37.8 mol) were mixed and stirred at 50°C for 2 hours. The reaction solution was cooled to 25°C, and purified water (28 L) was added. A mixed solution of purified water (42 L), synthetic hydrochloric acid (1.4 kg, 13.2 mol), and 2-propanol (14 L) was added to the resulting slurry, and the solid was collected by filtration, washed with 50% 2-propanol water and 2-propanol, and then dried to obtain wet crystals of the compound represented by formula (IX). Acetone (112 L) was added to the resulting wet crystals, and the mixture was dissolved at 25°C. The resulting solution was treated with activated carbon, and the activated carbon was washed with acetone (28 L). Purified water (57 L) was then added to the treated solution. Purified water (84 L) was added to the resulting slurry, and the solid was collected by filtration, washed with 50% aqueous 2-propanol, and then dried to obtain anhydrous crystals of the compound represented by formula (IX) (15.7 kg, 30.0 mol, yield: 91.3%). HPLC (UV=247 nm): RT=26.8 min, HPLC measurement condition 3 １ H-NMR (CDCl ３ ) δ: 2.75 (4H, t, J = 12.0 Hz), 4.02 (4H, s), 4.74 (2H, s), 7.16-7.18 (2H, m), 7.32-7.35 (1H, m), 7.65 (1H, t, J = 2.1 Hz), 8.43 (1H, d, J = 2.3 Hz), 8.61 (1H, d, J=2.3 Hz).

[0074] (Crushing of anhydrous crystals of the compound represented by formula (IX)) The anhydrous crystals of the compound represented by formula (IX) were sieved through a 1000 μM mesh and then crushed under the following conditions: Apparatus: A-O jet mill (Seishin Enterprise Co., Ltd.) Feeding method: feeder Feeding rate: 20 g / hour Crushing pressure: 0.30 MPa Feeding pressure: 0.40 MPa

[0075] (Powder X-ray Diffraction Experiment of Anhydrous Crystals of the Compound Represented by Formula (IX)) A powder X-ray diffraction experiment was carried out on the pulverized anhydrous crystals of the compound represented by formula (IX) under the measurement condition 2 described above. The powder X-ray diffraction pattern is shown in FIG. 3, and a peak list of the powder X-ray diffraction pattern is shown in FIG. 4. In the table below listing the peaks of the powder X-ray diffraction pattern, Position indicates 2θ (°), and Intensity indicates intensity. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 6.5°±0.2°, 10.1°±0.2°, 13.0°±0.2°, 14.1°±0.2°, 15.3±0.2°, 15.6°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.7°±0.2°, 23.0°±0.2°, 23.8°±0.2°, 25.8°±0.2°, 28.8°±0.2°, and 30.6°±0.2°. The anhydrous crystals of the compound represented by formula (IX) showed characteristic peaks at diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2° in the powder X-ray diffraction pattern.

[0076] (Single Crystal Structure Analysis of Anhydrous Crystals of the Compound Represented by Formula (IX)) <Single Crystal Preparation Method> 400 μL of methanol was added to 1 mg of crystals of the compound represented by formula (IX) and dissolved by heating to 50° C. The solution was dispensed into 1.5 mL HPLC vials, the HPLC vials were capped, a syringe needle was pierced into the cap, and the solution was allowed to stand at room temperature. Single crystals were prepared by the solvent evaporation method. <Single Crystal Structure Analysis> Single crystal diffraction experiments and analysis were carried out by the method described above. Note that, since Cl1 and Cl7C, and H5CA and H6CA are in a disordered relationship, analysis was carried out at occupancy ratios of Cl1:Cl7C = 0.75:0.25 and H5CA:H6CA = 0.25:0.75.

[0077] The results of the single crystal structure analysis are shown below: R1 (I>2.00s(I)) was 0.0555, and the final difference Fourier analysis confirmed that there was no missing or misplaced electron density.

[0078] The crystallographic data are shown in Table 1. Here, V means the unit cell volume, and Z means the number of molecules in the unit cell.

[0079] Atomic fraction coordinates x, y, z (Å × 10 ４ ) and the equivalent isotropic temperature factor U(eq) (Equivalent Isotropic Displacement Parameters, Å ２ x10 ３ ) are shown in Table 2. Here, U(eq) is the orthogonalized U ｉｊ The numbers of the non-hydrogen atoms in Table 2 correspond to those in Figure 5.

[0080] Next, the atomic coordinates x, y, z of the hydrogen atom (Å×10 ４ ) and isotropic temperature factor U(eq) (Isotropic Displacement Parameters, Å ２ x10 ３ ) are shown in Table 3.

[0081] The structure in the asymmetric unit of the crystal structure is shown in Figure 5. The label numbers of the non-hydrogen atoms shown in Figure 5 correspond to the numbers of the non-hydrogen atoms in Table 2.

[0082] The crystal structure was identified as an anhydrous crystal of the compound represented by formula (IX) because only one molecule of the compound represented by formula (IX) was present in the asymmetric unit.

[0083] From the crystal structure, it was confirmed that the powder X-ray diffraction pattern (λ=1.5418 Å) calculated using Mercury (The Cambridge Crystallographic Data Centre, Ver. 4.0.0) generally coincided with the above powder X-ray diffraction pattern ( FIG. 3 ).

[0084] (Differential scanning calorimetry of the anhydrous crystals of the compound of formula (IX)) Approximately 2 mg of the anhydrous crystals of the compound of formula (IX) after pulverization was weighed into an aluminum pan and measured by the method described above. The results are shown in Figure 6. An endothermic peak was observed with an onset temperature of approximately 261.3°C.

[0085] (Simultaneous Differential Thermal and Thermogravimetric Measurement of Anhydrous Crystals of the Compound of Formula (IX)) The anhydrous crystals of the compound of formula (IX) after pulverization were measured by the method described above. The results are shown in Figure 7. An endothermic peak with an onset temperature of approximately 265.6°C was observed. No weight loss was observed.

[0086] (Raman Spectroscopic Measurement of Anhydrous Crystals of the Compound Represented by Formula (IX)) The anhydrous crystals of the compound represented by formula (IX) after pulverization were subjected to Raman spectroscopy under the measurement condition 1 described above. The results are shown in Figure 8. The main Raman peaks are shown below. The anhydrous crystal of the compound represented by formula (IX) has a Raman spectrum of 415.2 cm －１ ±2cm －１ , 502.7 cm －１ ±2cm －１ , 1431.4 cm －１ ±2cm －１ , 1714.8 cm －１ ±2cm －１ , and 3065.4 cm －１ ±2cm －１ showed a characteristic peak.

[0087] [Example 1A] Synthesis of anhydrous crystals of the compound represented by formula (IX) Step 1: Synthesis of Compound 3 Compound 1 (25.00 g, 194.5 mmol), acetonitrile (150.0 mL), pyridine (23.07 g, 291.7 mmol), and compound 2 (31.97 g, 204.2 mmol) were mixed and stirred at 25° C. for 80 minutes. This reaction solution was added to 28% aqueous ammonia (112.36 g, 1847.4 mmol), and the mixture was stirred at 25° C. for 5 hours. The mixture was cooled to 5° C. over 20 minutes, and the solid was collected by filtration, washed with 50% aqueous acetonitrile, and then dried to obtain compound 3 (32.7 g, 190.6 mmol, yield: 98.0%).

[0088] Step 2: Synthesis of Compound 5 Compound 3 (20.00 g, 116.6 mmol), compound 4 (24.18 g, 128.2 mmol), N,N-dimethylacetamide (160.0 mL), triethylamine (14.16 g, 139.9 mmol), and a 50% propylphosphonic anhydride ethyl acetate solution (104.59 g, 164.4 mmol) were mixed and stirred at 50°C for 24 hours. The reaction solution was cooled to 10°C over 1 hour, water (60.0 mL) was added, and the mixture was stirred for 1 hour. The solid was collected by filtration, washed with acetonitrile, and then dried to obtain compound 5 (36.60 g, 107.0 mmol, yield: 91.8%).

[0089] Step 3: Synthesis of Compound 6 Compound 5 (30.0 g, 87.7 mmol), N,N'-carbodiimidazole (21.3 g, 131.5 mmol), tetrahydrofuran (300.0 mL), and 1,8-diazabicyclo[5,4,0]-7-undecene (17.4 g, 114.0 mmol) were mixed and stirred at 25°C for 1 hour. To this reaction solution, tetrahydrofuran (255.0 mL), toluene (37.5 mL), and 11% hydrochloric acid (164.8 g, 526.1 mmol) were added and extracted. Water (150.0 mL) was added to the obtained organic layer and further extracted. Sulfolane (90.0 mL) was added to the obtained organic layer, and the mixture was concentrated under reduced pressure to 208.3 g. Toluene (210.0 mL) was added to the concentrated solution, and the mixture was further concentrated under reduced pressure to 206.9 g. Toluene (180 mL) was added to the concentrated solution, and the mixture was further concentrated under reduced pressure to 207.6 g. Toluene (3.0 mL) and seed crystal A of compound 6 (29.64 mg) were added, and the mixture was stirred at 20-30°C for 19 hours. Toluene (450.0 mL) was added, and the slurry was cooled to 5°C. The crystals were collected by filtration, washed with toluene, and then dried to obtain compound 6 (33.2 g, 80.2 mmol, yield: 91.4%). NMR measurement of the obtained solid showed that it contained the equivalent of 0.5 molecules of toluene, and toluene was not removed under vacuum drying within the normal operating range. It was confirmed that compound 6 was a toluene solvate. １H-NMR (DMSO-d6) δ: 2.30 (1.5H, s), 7.09-7.27 (2.5H, m), 7.35 (1H, br), 7.53 (1H, br), 7 .72 (1H, d, J=7.0Hz), 8.00 (1H, t, J=2.1Hz), 8.50 (1H, br), 8.65 (1H, br), 11.1 (1H, s).

[0090] Step 4: Synthesis of Compound 7 Compound 6 (55.00 kg, 132.8 mol), phenyl dichlorophosphate (112.0 kg, 530.9 mol), and sulfolane (308.2 kg) were mixed and stirred at 115°C for 9 hours. The reaction solution was cooled to 50°C, and sulfolane (123.3 kg) was added. The mixture was then added to a solution of potassium acetate (156.4 kg, 1593 mol), water (469 L), and sulfolane (369.8 kg) at 50°C. Water (244 L) was added to the resulting slurry. The slurry was cooled to 10°C, and the solid was collected by filtration and washed with 76% aqueous 2-propanol. The collected solid was dissolved in N,N-dimethylacetamide (459.5 kg), and 8% hydrochloric acid (51 kg) and 44% aqueous 2-propanol (436 kg) were added at 50°C. The resulting slurry was cooled to 5° C., and the solid was collected by filtration, washed with a 76% aqueous solution of 2-propanol and 2-propanol, and then dried to obtain Compound 7 (42.65 kg, 110.3 mol, yield: 83.1%).

[0091] Step 5: Synthesis of Compound 9 Compound 7 (42.05 kg, 108.8 mol), N,N-dimethylacetamide (276.8 kg), N,N-diisopropylethylamine (21.1 kg, 163 mol), and compound 8 (15.66 kg, 130.6 mol) were mixed and stirred at 60°C for 5 hours. The reaction solution was cooled to 25°C, and acetone (165.7 kg) was added. 5% hydrochloric acid (143 kg) was then added dropwise over approximately 30 minutes, followed by stirring at 25°C. Water (126 L) was added to the resulting slurry, and the solid was collected by filtration and washed with 44% acetone-water and 2-propanol. Ethyl acetate (151.7 kg) was added to the resulting solid, and the solid was dissolved at approximately 50°C. Heptane (57.5 kg) and seed crystals of compound 9 (21.0 g, synthesized in Example 1) were added, and the mixture was stirred at 45°C. Heptane (402.7 kg) was added and cooled to 0° C., and the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane, and then dried to obtain Compound 9 (41.69 kg, 97.95 mol, yield: 90.0%).

[0092] (Alternative Method) Synthesis Method Using Cyanomethyl p-Toluenesulfonate Compound 7 (4.00 g, 10.35 mmol), N,N-dimethylacetamide (28.0 mL), N,N-diisopropylethylamine (1.68 g, 12.9 mmol), and cyanomethyl p-toluenesulfonate (3.06 g, 14.5 mmol) were mixed and stirred at 60°C for 6 hours. The reaction solution was cooled to 25°C, and acetone (20.0 mL) was added. Then, 2 mol / L hydrochloric acid (9.30 mL, 18.6 mmol) and water (6.0 mL) were added dropwise over approximately 30 minutes, and the mixture was stirred at 25°C. Water (6.0 mL) was added to the resulting slurry, and the solid was collected by filtration and washed with 44% acetone in water and 2-propanol. Isopropyl acetate (24.0 mL) was added to the obtained solid and dissolved at about 50° C., and heptane (24.0 mL) was added and stirred at 35° C. Heptane (56.0 mL) was added, and the solid was collected by filtration, washed with a mixed solution of isopropyl acetate and heptane, and then dried to obtain Compound 9 (3.32 g, 7.80 mol, yield: 75.4%).

[0093] Step 6: Synthesis of anhydrous crystals of the compound represented by formula (IX) Compound 9 (20.00 g, 47.0 mmol), N,N-dimethylacetamide (100.0 mL), N,N-diisopropylethylamine (15.18 g, 117.5 mmol), and compound 10 (12.20 g, 49.3 mmol) were mixed and stirred at 60 °C for 4 hours. The reaction solution was cooled to 25 °C over 30 minutes, and purified water (40.0 mL) was added. A mixed solution of purified water (60.0 mL), synthetic hydrochloric acid (1.96 g, 18.8 mmol), and 2-propanol (20.0 mL) was added to the resulting slurry, and the solid was collected by filtration, washed with 50% 2-propanol water and 2-propanol, and then dried to obtain wet crystals of the compound represented by formula (IX). Acetone (160.0 mL) was added to the resulting wet crystals, and the mixture was dissolved at 25 °C. The obtained solution was treated with activated carbon, and the activated carbon was washed with acetone (40.0 mL). Purified water (200.0 mL) was then added to the treated solution, and the solid was collected by filtration, washed with 50% 2-propanol in water, and then dried to obtain anhydrous crystals of the compound represented by formula (IX) (22.90 g, 43.8 mmol, yield: 93.3%).

[0094] Synthesis of Compound 12

[0095] Step 1: Synthesis of Compound 12 Compound 5 (38.6 kg, 112.8 mol), N,N'-carbonyldiimidazole (27.4 kg, 169.0 mol), tetrahydrofuran (375 L), and DBU (22.3 kg, 146.5 mol) were mixed and stirred at 25°C for 60 minutes. 7% hydrochloric acid (352.5 kg) was added to this reaction solution, and the mixture was separated into an organic layer and an aqueous layer. Toluene (39 L) and tetrahydrofuran (386 L) were added to the resulting aqueous layer and extracted. The combined organic layers were concentrated under reduced pressure to 178.5 kg, toluene (579 L) was added, and the slurry was cooled to 5°C. The solid was collected by filtration and washed with a mixed solution of cooled tetrahydrofuran (46 L) and toluene (186 L). Drying afforded compound 12 (37.12 kg, 100.8 mol, yield: 89.4%). HPLC (UV=254nm): RT=9.9min, HPLC measurement conditions 1 １H-NMR (DMSO-d6) δ: 7.10 (1H, t, J = 9.2Hz), 7.90-7.92 (2H, m), 8.09 (2H, d, J = 7.3Hz), 8.37 (1H, s), 8.55 (1H, s), 9.90 (1H, s).

[0096] Synthesis of seed crystals of compound 6

[0097] Step 1: Synthesis of Seed Crystals of Compound 6 Compound 12 (1.0 kg, 2.72 mol), toluene (9.0 L), and acetonitrile (1.5 L) were mixed and stirred at 25° C. for 17 hours. The solid was collected by filtration and washed with toluene (5.0 L). By drying, seed crystals of Compound 6 (0.98 kg, 2.37 mol, yield: 87.1%) were obtained. HPLC (UV = 254 nm): RT = 9.9 min, HPLC measurement condition 1 [Example 3A] Synthesis of Seed Crystals A of Compound 6 Step 1: Synthesis of Seed Crystal A of Compound 6 Compound 12 (25.0 g, 2.67.9 mmol), sulfolane (50 mL), water (2.5 mL), and toluene (450.0 mL) were mixed and stirred at 25° C. for 2 hours. The solid was collected by filtration and washed with toluene (150.0 mL). The mixture was dried to obtain Seed Crystal A of Compound 6 (24.5 g, 59.2 mmol, yield: 87.1%). １ H-NMR (DMSO-d ６ ) δ: 2.30 (1.5H, s), 7.09-7.27 (2.5H, m), 7.35 (1H, br), 7.53 (1H, br), 7.72 (1H , d, J=7.0Hz), 8.00 (1H, t, J=2.1Hz), 8.47 (1H, br), 8.63 (1H, br), 11.2 (1H, s).

[0098] Synthesis of Compound 7 (Alternative Method) Compound 6 (4.49 g, 10.9 mmol), phosphorus oxychloride (7.50 g, 48.9 mmol), water (0.88 g, 48.89 mmol), and sulfolane (16 mL) were mixed and heated at 145°C for 40 minutes. The reaction solution was diluted with sulfolane (4 mL) and added to 19% aqueous potassium hydroxide solution (64 g). To the resulting solution, 1-butanol (20 mL) was added. After separating the aqueous layer, N,N-dimethylacetamide (40 mL) was added, followed by the addition of 16% hydrochloric acid (3.7 g) and water (20 mL) at 50°C. The slurry was cooled to 25°C, and the solid was collected by filtration, washed with 80% 2-propanol water and 2-propanol, and then dried to obtain compound 7 (3.70 g, yield: 88%). HPLC (UV = 247 nm): RT = 12.6 min, HPLC measurement condition 2

[0099] Synthesis of Compound 5 from Compound 3 using a condensing agent other than T3P (registered trademark) (In the above table, "V" is a unit representing the amount of solvent relative to the raw material, and when 1 mL of solvent is used per 1 g of raw material, it is expressed as 1V. When 10 mL of solvent is used per 1 g of raw material, it is expressed as 10V.) The above reaction was carried out under the conditions in Table 5 in the same manner as in Step 2 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 4). The "conversion rate" in Table 5 was calculated using the following formula: Conversion rate (%) = {peak area of ​​compound 5 in HPLC chart / (peak area of ​​compound 5 in HPLC chart + peak area of ​​compound 3 in HPLC chart)} x 100

[0100] (In the above reaction scheme, V has the same meaning as in Table 5.) MsCl and ClPO(OPh) as condensing agents ２A reaction using MsCl was carried out. An experiment using MsCl was carried out as follows. Compound 3 (50.21 mg, 0.29 mmol), 1,2-dimethoxyethane (200 μL), triethylamine (45 μL, 0.32 mmol), and methanesulfonyl chloride (25 μL, 0.32 mmol) were mixed, and then compound 4 (54.35 mg, 0.29 mmol) was added. Triethylamine (45 μL, 0.32 mmol) was added at 60°C, and the mixture was stirred for 2 hours. A sample was taken from the reaction solution while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). ClPO(OPh) ２ Experiments using the compound 3 were carried out as follows. Compound 3 (50.02 mg, 0.29 mmol), compound 4 (54.21 mg, 0.29 mmol), 1,2-dimethoxyethane (200 μL), triethylamine (81 μL, 0.58 mmol), and diphenyl chlorophosphate (90 μL, 0.44 mmol) were mixed and stirred at 60°C for 11 hours. The reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "conversion rate" in Table 6 was calculated using the following formula: Conversion rate (%) = {Peak area of ​​compound 5 in HPLC chart / (Peak area of ​​compound 5 in HPLC chart + Peak area of ​​compound 3 in HPLC chart)} x 100. As described above, WSCD·HCl, HATU, PyBOP (registered trademark), MsCl, and ClP(O)(OPh) were used. ２ It was confirmed that compound 5 was also produced when this compound was used as a condensation agent.

[0101] Synthesis of Compound 12 from Compound 5 using a base other than DBU (In the above table, V has the same meaning as in Table 5.) The above reaction was carried out under the conditions in Table 7 in the same manner as in Step 3 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 4). The "peak area ratio of compound 12" in Table 7 was calculated using the following formula: peak area ratio of compound 12 (%) = (peak area of ​​compound 5 in HPLC chart / sum of peak areas of all peaks in HPLC chart) x 100 As described above, it was confirmed that compound 12 was produced even when LDA and t-BuOK were used as bases.

[0102] PhPOCl ２ Synthesis of Compound 7 from Compound 6 using as a chlorinating agent The reaction was carried out under the conditions shown in Table 8 in the same manner as in Step 4 of Example 1. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "peak area ratio of compound 7" in Table 8 was calculated using the following formula: peak area ratio of compound 7 (%) = (peak area of ​​compound 7 in the HPLC chart / sum of peak areas of all peaks in the HPLC chart excluding the toluene peak) x 100. ２ It was confirmed that compound 7 was also produced when this compound was used as a chlorinating agent.

[0103] Synthesis of Compound 7 from Compound 12 using various additives and solvents (In the above table, V has the same meaning as in Table 5.) The above reaction was carried out under the conditions in Table 9 in the same manner as in Step 4 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "peak area ratio of compound 7" in Table 9 was calculated using the following formula: peak area ratio of compound 7 (%) = (peak area of ​​compound 7 in HPLC chart) / (sum of peak areas of all peaks in HPLC chart excluding the toluene peak) x 100. As described above, in the absence of a solvent, H ２ O, n-BuOH, and (DMF and H ２It was confirmed that compound 7 was also produced when HCl (C10) was used as an additive.

[0104] Synthesis of Compound 7 from Compound 6 using anisole as a solvent in the presence or absence of various additives (In the above table, V has the same meaning as in Table 5.) The above reaction was carried out under the conditions in Table 10 in the same manner as in Step 4 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "peak area ratio of compound 7" in Table 10 was calculated using the following formula: peak area ratio of compound 7 (%) = (peak area of ​​compound 7 in HPLC chart) / (sum of peak areas of all peaks in HPLC chart excluding the toluene peak) x 100. As described above, it was confirmed that compound 7 was produced even when anisole was used as a solvent in the absence of additives. Furthermore, when 97% sulfolane, H ２ O and n-Bu ４ It was confirmed that compound 7 was also produced when NCl was used as an additive.

[0105] A powder X-ray diffraction experiment was performed on Compound 6 obtained by the production method described in Example 1 under Measurement Condition 1 described above. The powder X-ray diffraction pattern is shown in FIG. 1, and a peak list for the powder X-ray diffraction pattern is shown in FIG. 2. In the table below listing the peaks for the powder X-ray diffraction pattern, height indicates intensity. In the powder X-ray diffraction pattern, characteristic peaks were observed at diffraction angles (2θ): 9.5±0.2°, 11.8±0.2°, 13.1±0.2°, 14.4±0.2°, 18.4±0.2°, 22.9±0.2°, 23.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.2±0.2°, and 29.2±0.2°. In the powder X-ray diffraction pattern, characteristic peaks were observed at diffraction angles (2θ): 9.5±0.2°, 11.8±0.2°, 18.4±0.2°, 22.9±0.2°, and 23.2±0.2°.

[0106] A powder X-ray diffraction experiment was performed on Compound 6 obtained by the production method described in Example 1A under the measurement condition 1 described above. The powder X-ray diffraction pattern is shown in FIG. 9, and a peak list of the powder X-ray diffraction pattern is shown in FIG. 10. In the table below showing the peak list of the powder X-ray diffraction pattern, height indicates intensity. In the powder X-ray diffraction pattern, characteristic peaks were observed at diffraction angles (2θ): 8.9±0.2°, 18.8±0.2°, 22.3±0.2°, 22.7±0.2°, 23.4±0.2°, 23.9±0.2, 25.1±0.2, 26.1±0.2, 26.4±0.2, 30.3±0.2, 31.3±0.2, and 36.8±0.2°.

[0107] (Reference example 1) Step 1: Synthesis of Compound 14 Compound 13 (5.50 g, 26.0 mmol), dichloromethane (110.0 mL), diethylamino(difluoro)sulfonium tetrafluoroborate (11.92 g, 52.1 mmol), and triethylamine trihydrofluoride (8.49 mL, 52.1 mmol) were mixed and stirred at 25°C for 21.5 hours. The reaction solution was filtered through Celite®, and the Celite® was washed with dichloromethane (11.0 mL). The resulting solution was added to 2 mol / L aqueous sodium hydroxide solution (110.0 mL) at 6°C or below. The mixture was filtered through Celite®, and the Celite® was washed with dichloromethane (11.0 mL). The organic layer was separated and concentrated. Methanol (16.5 mL) was added to the resulting concentrate, and the mixture was filtered through activated carbon (2.25 g). The activated carbon was washed with methanol (5.5 mL). Purified water (44.0 mL) was added to the resulting solution, and the solid was collected by filtration, washed with 20% aqueous methanol, and then dried to obtain Compound 14 (5.22 g, 22.4 mmol, 86.2%).

[0108] Step 2: Synthesis of Compound 10 Compound 14 (2.00 g, 8.57 mmol), dichloromethane (10.0 mL), and trifluoroacetic acid (4.89 g, 42.9 mmol) were mixed and stirred at 25° C. for 4 hours. Diisopropyl ether (20.0 mL) was added to the reaction solution, and then diisopropyl ether (70.0 mL) was added to the resulting slurry and stirred for 2 hours. The solid was collected by filtration, washed with diisopropyl ether, and dried to obtain Compound 10 (1.90 g, 7.69 mmol, 89.7%).

[0109] The following describes examples of biological tests of the compound represented by formula (IX) produced by the production method of the present invention. The compound represented by formula (IX) produced by the production method of the present invention has a coronavirus 3 CL protease inhibitory activity and may be any compound that inhibits coronavirus 3 CL protease. Specifically, in the evaluation method described below, IC ５０ is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. ５０ is preferably 10 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[0110] Test Example 1: Cytopathic effect (CPE) inhibitory effect confirmation test using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) <Procedure> - Dilution and dispensing of test sample: The test sample is diluted to an appropriate concentration with DMSO in advance, and a 2- to 5-fold serial dilution series is prepared, and then dispensed into a 384-well plate. - Dilution and dispensing of cells and SARS-CoV-2: HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5 x 10 ３ cells / well) and SARS-CoV-2 (200-600 TCID ５０ / well) was mixed with a medium (MEM, 2% FBS, penicillin-streptomycin), and the mixture was dispensed into the wells containing the test samples. ２Culture in an incubator for 3 days. Dispensing CellTiter-Glo® 2.0 and measuring luminescence signals After 3 days of culture, return the plate to room temperature, dispense CellTiter-Glo® 2.0 into each well, and mix using a plate mixer. After a certain period of time, measure the luminescence signal (Lum) using a plate reader. <Calculation of values ​​for each measurement item> 50% SARS-CoV-2-infected cell death inhibitory concentration (EC ５０ ) Calculation When x is the logarithm of the compound concentration and y is % efficacy, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is the EC ５０ Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100% cell control: the average of Lum of cell control wells virus control: the average of Lum of virus control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0111] Compounds of the invention were tested essentially as described above. ５０ The values ​​are shown below. (Results) Compound represented by formula (IX): 1.66 nM

[0112] Test Example 2: Inhibitory activity test against SARS-CoV-2 3CL protease <Materials> Commercially available recombinant SARS-CoV-2 3CL protease Commercially available substrate peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH ２ (SEQ ID NO: 1) Internal Standard Peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu ( １３ C ６ ,１５ N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu ( １３ C ６ , １５ N)-Gln can be synthesized with reference to the literature (Atherton, E.; Sheppard, RC, "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989, and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below. H-Lys-Thr-Ser-Ala-Val-Leu ( １３ C ６ , １５N)-Glu(resin)-OαOtBu (Lys side chain is protected with Boc, Thr side chain is protected with a tert-butyl group, Ser side chain is protected with a tert-butyl group, the C-terminal OH of Glu is protected with a tert-butyl group, and the carboxylic acid of the Glu side chain is condensed to the resin) is synthesized. The N-terminal Dabcyl group is modified by condensing 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin using EDC / HOBT. Final deprotection and cleavage from the resin are performed by treatment with TFA / EDT = 95:5. The product is then purified by reverse-phase HPLC. RapidFire Cartridge C4 Type A <Procedure> Assay buffer preparation: This test uses an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. Test sample dilution and dispensing: Test samples are diluted to an appropriate concentration with DMSO, and a 2- to 5-fold serial dilution series is prepared and dispensed into a 384-well plate. Enzyme and substrate addition: Enzyme reaction: 8 μM substrate and 6 nM or 0.6 nM enzyme solution are added to the prepared compound plate and incubated at room temperature for 3 to 5 hours. The enzyme reaction is then stopped by adding a reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10% or 25% acetonitrile). Measurement of reaction products The plate after the reaction is completed is measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a RapidFire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadruple). Solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid) are used as the mobile phase during measurement. The reaction products detected by the mass spectrometer are calculated using RapidFire Integrator or an equivalent analysis program to obtain the product area value. At the same time, the internal standard detected is also calculated and used as the internal standard area value.<Calculation of each measurement item value> Calculation of P / IS The area value obtained in the previous item is calculated using the following formula to calculate P / IS: P / IS = Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC ５０ ) Calculation When x is the logarithm of the compound concentration and y is % Inhibition, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is used to calculate the IC ５０ Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1-(Sample - Control(-)) / Control(+)-Control(-))} * 100 Control(-): the average of P / IS of enzyme inhibited condition wells Control(+): the average of P / IS of DMSO control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0113] The compound of formula (IX) prepared by the process of the present invention was tested essentially as described above. ５０ The values ​​are shown below. (Results) Compound represented by formula (IX): 0.00036 μM

[0114] The following formulation examples are merely illustrative and are not intended to limit the scope of the invention. The compound of formula (IX) prepared by the process of the present invention can be administered as a pharmaceutical composition by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules; parenterally, e.g., in the form of an injection solution or suspension; topically, e.g., in the form of a lotion, gel, ointment, or cream; or intranasally or as a suppository. Pharmaceutical compositions containing the compound of formula (IX) prepared by the process of the present invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0115] The compound represented by formula (IX) produced by the production method of the present invention has an inhibitory effect on coronavirus 3 CL protease and is considered to be useful as a therapeutic and / or preventive agent for diseases or conditions associated with coronavirus 3 CL protease. The novel synthetic intermediates or salts thereof of the present invention, and the production method of the present invention, are useful in the production of pharmaceuticals.

Claims

1. Formula (I): (In the formula, R １ is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, and Z is CH or N.) or a salt thereof with a compound represented by formula (II): (In the formula, R ２ are each independently halogen, haloC1-C4 alkyl or cyano, and n is an integer of 1 to 5.) or a salt thereof is reacted with T3P (registered trademark), ethylphosphonic anhydride, n-butylphosphonic anhydride, PyBOP (registered trademark), HATU, WSCD, WSCD.HCl, MsCl and ClP(O)(OPh) in the presence or absence of a base. ２ The compound of formula (III): (wherein the symbols are as defined above) or a salt thereof.

2. The process according to claim 1, wherein the condensing agent is T3P (registered trademark).

3. The method according to claim 1 or 2, which is carried out in the presence of triethylamine.

4. The compound represented by formula (III) is represented by formula (IV): The method according to claim 3, wherein the compound is represented by the formula:

5. Formula (III): (In the formula, R １ is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, Z is CH or N, R ２ are each independently halogen, haloC1-C4 alkyl or cyano, and n is an integer of 1 to 5.) or a salt thereof is reacted with N,N'-carbonyldiimidazole in the presence of a base, (wherein the symbols are as defined above) or a salt thereof, or a solvate thereof.

6. The process according to claim 5, wherein the base is DBU, LDA or potassium t-butoxide.

7. The process according to claim 5, wherein the base is DBU.

8. The compound represented by formula (V) is represented by formula (VI): The method according to any one of claims 5 to 7, wherein the compound is represented by the formula:

9. Formula (V): (In the formula, R １ is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, Z is CH or N, R ２ are each independently halogen, haloC1-C4 alkyl or cyano, and n is an integer of 1 to 5.) or a salt thereof, or a solvate thereof, is reacted with a chlorinating agent selected from the group consisting of phosphorus oxychloride, phenyl dichlorophosphate and phenylphosphonic acid dichloride in the presence or absence of one or more additives selected from the group consisting of water, sulfolane, n-butanol, DMF and tetrabutylammonium chloride, and in the presence or absence of a solvent, (wherein the symbols are as defined above) or a salt thereof.

10. The process according to claim 9, wherein the chlorinating agent is phosphorus oxychloride or phenyl dichlorophosphate.

11. The method according to claim 9 or 10, which is carried out in the presence of water.

12. The process according to claim 11, which is carried out in the presence of sulfolane.

13. The compound represented by formula (VII) is represented by formula (VIII): The method according to claim 12, wherein the compound is represented by the formula:

14. The method of claim 4, wherein the compound represented by formula (IV): or a salt thereof, comprising the step of obtaining a compound represented by formula (IX): A method for producing a compound represented by the formula:

15. The method of claim 8, wherein the compound of formula (VI): or a salt thereof, or a solvate thereof, A method for producing a compound represented by the formula:

16. The method of claim 13, comprising the steps of: or a salt thereof, comprising the step of obtaining a compound represented by formula (IX): A method for producing a compound represented by the formula:

17. The method of claim 4, comprising producing a compound represented by formula (IV): or a salt thereof, by the method according to claim 8, or a salt thereof, or a solvate thereof, by the method according to claim 13, or a salt thereof, comprising the steps of: A method for producing a compound represented by the formula:

18. Formula (IV): or a salt thereof.

19. Formula (VI): or a salt thereof, or a toluene solvate thereof.

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