WO2025018428A2 - ウラシル誘導体の製造方法 - Google Patents

ウラシル誘導体の製造方法 Download PDF

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WO2025018428A2
WO2025018428A2 PCT/JP2024/035562 JP2024035562W WO2025018428A2 WO 2025018428 A2 WO2025018428 A2 WO 2025018428A2 JP 2024035562 W JP2024035562 W JP 2024035562W WO 2025018428 A2 WO2025018428 A2 WO 2025018428A2
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formula
compound
compound represented
salt
acid
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WO2025018428A3 (ja
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陽一 平野
直登 佐原
勝也 山川
ティーン レー，フック
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Shionogi and Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/99—Enzyme inactivation by chemical treatment

Definitions

  • the present invention relates to a novel compound or a novel synthetic intermediate thereof, or a salt thereof, that exhibits coronavirus 3CL protease inhibitory activity, and a method for producing the same.
  • 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 the largest single-stranded positive-stranded RNA viruses known. Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Seven types of coronaviruses are known to infect humans: two types of Alphacoronavirus (HCoV-229E, HCoV-NL63) and five types of Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2).
  • HCoV-229E HCoV-NL63, HCoV-HKU1, and HCoV-OC43
  • SARS-CoV Severe Acute Respiratory Syndrome coronavirus
  • MERS Middle East Respiratory Syndrome coronavirus
  • SARS-CoV-2 Severe Acute Respiratory Syndrome coronavirus
  • SARS-CoV Middle East Respiratory Syndrome coronavirus
  • SARS-CoV-2 novel coronavirus
  • Non-Patent Document 1 The novel coronavirus disease (COVID-19), which broke out in December 2019, spread rapidly throughout the international community, and on March 11, 2020, the WHO declared it a pandemic.
  • Droplet infection, contact infection, and aerosol infection have been reported as the main routes of infection for SARS-CoV-2, and it has been confirmed that SARS-CoV-2 remains suspended in the air with aerosols for about three hours and maintains its infectiousness (Non-Patent Document 1).
  • the incubation period is about 2 to 14 days, and typical symptoms are cold-like, such as fever (87.9%), dry cough (67.7%), fatigue (38.1%), and phlegm (33.4%) (Non-Patent Document 2).
  • respiratory failure due to acute respiratory distress syndrome, acute lung injury, and interstitial pneumonia occurs.
  • Multiple organ failure such as renal failure and liver failure, has also been reported.
  • coronaviruses When coronaviruses infect cells, they synthesize two polyproteins. These two polyproteins contain a replication complex that creates the viral genome and two proteases. The proteases cleave the polyproteins synthesized by the virus and play an essential role in allowing each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the cleavage of the polyprotein (Non-Patent Document 3).
  • PF-00835231 Lufotrelvir (PF-07304814): PF-07321332: In December 2021, PAXLOVIDTM was approved for emergency use authorization in the United States, and on February 10, 2022, PAXLOVID® Pak was granted special approval in Japan.
  • Zocova registered trademark
  • 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).
  • Non-Patent Documents 4 to 7 and 12 to 15 Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 4 to 7 and 12 to 15, but none of these documents describes or suggests the compounds produced by the production method of the present invention.
  • Patent Documents 12 and 13 they do not describe or suggest the production method of the present invention.
  • Compounds having P2X3 and/or P2X2 /3 receptor inhibitory activity are disclosed in Patent Documents 3 to 9, but none of these documents describes or suggests 3CL protease inhibitory activity or antiviral effect.
  • a compound having an HIV-1 reverse transcriptase inhibitory activity is described in Non-Patent Document 10, but 3CL protease inhibitory activity and anti-coronavirus effect are neither described nor suggested.
  • the object of the present invention is to provide a novel compound having coronavirus 3CL protease inhibitory activity, or a novel synthetic intermediate thereof, or a salt thereof, and a method for producing the same.
  • the present invention relates to the following: (1) Formula (I): (wherein R 1 is halogen, C1-C4 alkyl, halo C1-C4 alkyl or cyano, and Z is CH or N), or a salt thereof, and a compound represented by formula (II): (wherein, each R2 is independently halogen, haloC1-C4 alkyl or cyano, and n is an integer of 1 to 5) or a salt thereof is reacted in the presence or absence of a base in the presence of a condensing agent selected from the group consisting of T3P (registered trademark), ethylphosphonic anhydride, n-butylphosphonic anhydride, PyBOP (registered trademark), HATU, WSCD, WSCD.HCl, MsCl and ClP(O)(OPh) 2 , (wherein the symbols are as defined above) or a salt thereof.
  • a condensing agent selected from the group consist
  • the compound represented by formula (III) is a compound represented by formula (IV): The method for producing a compound represented by the above item (3), (5) Formula (III): (wherein R 1 is halogen, C1-C4 alkyl, halo C1-C4 alkyl or cyano, Z is CH or N, each R 2 is independently halogen, halo C1-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.
  • the compound represented by formula (IX) produced by the production method according to the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and/or preventive agent for coronavirus infections. Furthermore, the compound represented by formula (IX) produced by the production method according to the present invention is useful as a pharmaceutical ingredient. Furthermore, a pharmaceutical composition containing the compound represented by formula (IX) produced by the production method according to the present invention is very useful as a therapeutic and/or preventive agent for novel coronavirus disease (COVID-19).
  • the production method according to the present invention is a method capable of producing the compound represented by formula (IX) in good yield.
  • 1 shows the powder X-ray diffraction pattern of compound 6.
  • the horizontal axis represents 2 ⁇ (deg) and the vertical axis represents intensity (cps).
  • the peak list of the powder X-ray diffraction pattern of Figure 1 is shown. In this peak list, the height indicates the intensity. The value in parentheses for each measured value indicates the standard deviation.
  • 1 shows a powder X-ray diffraction pattern of an anhydrous crystal of the compound represented by formula (IX), where the horizontal axis represents 2 ⁇ (°) and the vertical axis represents intensity.
  • the peak list of the powder X-ray diffraction pattern of Fig. 3 is shown below. In the table, Position indicates 2 ⁇ (°), and Intensity indicates intensity.
  • 1 shows the crystal structure (structure in the asymmetric unit) of an anhydrous crystal of the compound represented by formula (IX).
  • 1 shows the results of differential scanning calorimetry (DSC) of the anhydrous crystals of the compound represented by formula (IX), where 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 crystals of the compound represented by formula (IX).
  • the vertical axis shows the amount of heat ( ⁇ V) or the weight change (%), and the horizontal axis shows the temperature (°C).
  • Cel means degrees Celsius (°C).
  • 1 shows the Raman spectrum of anhydrous crystals of the compound of formula (IX), where the horizontal axis represents the Raman shift (cm ⁇ 1 ) and the vertical axis represents the peak intensity.
  • 1 shows the powder X-ray diffraction pattern of compound 6 obtained in step 3 of Example 1A.
  • the horizontal axis represents 2 ⁇ (deg), and the vertical axis represents intensity (cps).
  • the peak list of the powder X-ray diffraction pattern of Figure 9 is shown. In this peak list, the height indicates the intensity.
  • the value in parentheses for each measurement indicates the standard deviation.
  • Halogen includes fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are particularly preferred.
  • alkyl includes 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.
  • alkyl examples 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 includes straight or branched chain hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • 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 “halogens” are bonded to the above “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, 3,3,4,4,4-pentafluorobutyl, and the like.
  • Preferred embodiments of "halo C1-C4 alkyl" include trifluoromethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.
  • 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.
  • the compound represented by formula (V) includes the following tautomers.
  • the compound represented by formula (VI) includes the following tautomers.
  • One or more hydrogen, carbon and/or other atoms of 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.
  • isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H , 3H , 11C , 13C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F , 123I and 36Cl , respectively.
  • 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) also include compounds substituted with such isotopes.
  • the compounds substituted with the isotopes are also useful as pharmaceuticals.
  • 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 all radiolabeled compounds substituted with radioisotopes contained in the isotopes.
  • the present invention also includes a "radiolabeling method" for producing the "radiolabeled compound", and the "radiolabeled compound” is useful as a research and/or diagnostic tool in metabolism pharmacokinetic studies and binding assays.
  • 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.
  • 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 a suitable halogen-substituted precursor of the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base.
  • a suitable catalyst such as Pd/C
  • 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)".
  • 14 C-labeled compounds can be prepared by using a raw material having 14 C carbon.
  • 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 that has a chemically or metabolically decomposable group and is a compound that is pharmacologic 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 the living body, and compounds that are converted to a compound of formula (IX) by hydrolysis with gastric acid, etc. Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug may itself have activity.
  • the "compound represented by formula (IX)” may form a salt, a cocrystal, or a solvate thereof.
  • a compound represented by formula (IX) or a salt thereof also encompasses such various salts, cocrystals, and solvates thereof.
  • salt means that 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 are regularly arranged in the same crystal lattice, and may contain any number of counter molecules. It refers to a compound that is bonded via ionic bonds by proton transfer between the compound and the counter molecule in the crystal lattice.
  • Salts of the compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) include, for example, salts of the compounds represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, Examples of suitable salts include salts with amines such as amines, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc., and amino acids, or salts with inorganic acids (e.g.
  • 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 includes such various solvates, co-crystals and crystalline polymorphs.
  • a "solvate” may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) to the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X).
  • cocrystal means that 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 refers to an intermolecular interaction between a compound and a counter molecule (co-former molecule) that is mediated by a non-covalent and non-ionic chemical interaction such as a hydrogen bond or van der Waals force.
  • salts are considered to be a state in which proton transfer occurs between a compound and a counter molecule, but it is also 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 the temperature.
  • a salt of the compound represented by formula (IX) includes co-crystals and refers to a salt or co-crystal of the compound represented by formula (IX).
  • One embodiment of the present specification is a pharma- ceutically 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, hexanoi
  • 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 properties 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 poor, the dissolution rate during in vivo administration may be rate-limited by the absorption process, resulting in poor bioavailability. Poor water solubility can also limit the selection of an appropriate route of administration, as administration by injection may be difficult.
  • 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.
  • the "compound represented by formula (IX)” can form a solvate with water (i.e., a hydrate) or a common organic solvent.
  • the “salt of the compound represented by formula (IX)” can form a solvate with water (i.e., a hydrate) or a common organic solvent.
  • solvate 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.
  • 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,
  • 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.
  • a toluene solvate is preferred.
  • crystal as used herein means 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.
  • the crystal as used herein may be a single crystal, a twin crystal, a polycrystal, etc.
  • crystals can have “crystal polymorphs” that have the same composition but different arrangements within the crystal, and all of these are referred to as “crystal forms.”
  • the "compound represented by formula (IX) or a salt thereof” includes crystal polymorphs thereof.
  • the crystals used herein may be deuterium converted.
  • the crystals used herein may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.).
  • the crystal morphology and/or crystallinity can be confirmed by spectroscopic methods such as, for example, X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, solid-state NMR, etc.
  • the physical properties of the crystals can be confirmed by a number of techniques such as differential scanning calorimetry, moisture adsorption/desorption measurements, dissolution characteristics, etc.
  • anhydrous crystal of the compound represented by formula (IX) is synonymous with “nosolvate,””nonsolvate,””anhydrate,” and “nonhydrate.”
  • the theoretical content of water of crystallization in the anhydrous crystals of the compound represented by formula (IX) is 0% by weight. However, in the analysis of the water content and/or the solvent content, the value may be higher than the theoretical content of water of crystallization due to the influence of the water and/or the solvent attached to the crystal surface.
  • One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (IX) having a melting point of 261.3°C ⁇ 2°C in differential scanning calorimetry (DSC).
  • 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 measured by simultaneous thermogravimetry and differential thermal analysis (TG/DTA).
  • One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (IX) having characteristic peaks in a Raman spectrum at 415.2 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 502.7 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1431.4 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1714.8 cm ⁇ 1 ⁇ 2 cm ⁇ 1 and 3065.4 cm ⁇ 1 ⁇ 2 cm ⁇ 1 .
  • X-Ray Powder Diffraction X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD is one of the most sensitive analytical techniques for measuring the crystalline morphology and crystallinity of solids.
  • X-rays When X-rays are irradiated onto a crystal, they reflect off the crystal lattice planes and interfere with each other, resulting in orderly diffraction lines corresponding to the periodicity of the structure.
  • amorphous solids usually do not have an orderly repeating period in their structure, so they do not exhibit diffraction phenomena and show featureless broad XRPD patterns (also called halo patterns).
  • the crystalline forms of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) can be distinguished by powder X-ray diffraction patterns and characteristic diffraction peaks.
  • the crystalline forms of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) can be distinguished from other crystalline forms by the presence of characteristic diffraction peaks.
  • a characteristic diffraction peak is a peak selected from the observed diffraction pattern.
  • the characteristic diffraction peak is selected from about 10 peaks in the diffraction pattern, more preferably from about 5 peaks, and even more preferably from about 3 peaks.
  • a peak that is confirmed in the crystal and not confirmed in other crystals is a preferred characteristic peak for identifying the crystal, rather than the peak intensity. If there are such characteristic peaks, even one or two peaks can characterize the crystal. If the charts obtained by measurement are compared and these characteristic peaks match, it can be said that the powder X-ray diffraction spectra are substantially the same.
  • the diffraction angle (2 ⁇ ) in powder X-ray diffraction can have an error within the range of ⁇ 0.2°, so the value of the diffraction angle in powder X-ray diffraction should be understood to include values within the range of about ⁇ 0.2°. Therefore, the present invention includes not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction are perfectly consistent, but also crystals in which the diffraction angles of the peaks match with an error of about ⁇ 0.2°.
  • Single crystal structure analysis It 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 structure model. See, for example, "X-Ray Structure Analysis Handbook” by Toshio Sakurai, published by Shokabo Publishing (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 complex, salt, optical isomer, tautomer, and geometric isomer of the present invention.
  • Raman spectra show the vibrational characteristics of a molecule or complex system. It originates from inelastic collisions between molecules and photons, which are light particles that comprise a beam of light. Collisions between molecules and photons result in an exchange of energy, which changes the energy and therefore the wavelength of the photon. That is, Raman spectra are spectral lines with extremely narrow wavelengths that are emitted when photons are incident on a molecule of interest, so a laser or other light source is used. The wavelength of each Raman line is represented by a 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.
  • the Raman spectrum peak (cm -1 ) can have an error within the range of ⁇ 2 cm -1 , so the above Raman spectrum peak value should be understood to include a numerical value within the range of about ⁇ 2 cm -1 . Therefore, not only crystals whose Raman spectrum peaks in the Raman spectrum are completely identical, but also crystals whose Raman spectrum peaks are identical within an error of about ⁇ 2 cm -1 are included in the present invention.
  • DSC Differential Scanning Calorimetry
  • DSC is one of the main measurement methods in thermal analysis, and is a method for measuring the thermal properties of a substance as an aggregate of atoms and molecules.
  • DSC measures the change in heat quantity with respect to temperature or time of the medicament active ingredient, and the obtained data is plotted against temperature or time to obtain a differential scanning calorimetry curve. From the differential scanning calorimetry curve, information can be obtained regarding the onset temperature when the medicament active ingredient melts, the maximum value of the endothermic peak curve accompanying melting, and the enthalpy. It is known that for DSC, the observed temperature may depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used.
  • the "melting point" in DSC refers to the onset temperature that is not affected by the sample preparation technique.
  • the error range in the onset temperature obtained from the differential scanning calorimetry curve is approximately ⁇ 2°C. In identifying the identity of a crystal, not only the melting point but also the overall pattern is important, which may vary somewhat depending on the measurement conditions and the measurement instrument.
  • TG/DTA is one of the main measurement methods in thermal analysis, and is a method for measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules.
  • TG/DTA is a method for measuring the change in weight and heat quantity of a pharmaceutical active ingredient with respect to temperature or time. The obtained data is plotted against temperature or time to obtain TG (thermogravimetry) and DTA ( From the TG/DTA curve, information on the changes in weight and heat quantity related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the medicamentous active ingredient can be obtained.
  • the "melting point" in TG/DTA refers to the temperature at which the sample melts. This refers to the onset temperature that is not easily affected by the preparation technique. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and may vary slightly depending on the measurement conditions and measurement equipment.
  • the compound represented by formula (IX) produced by the production method according to the present invention has coronavirus 3 CL protease inhibitory activity, and is therefore useful as a therapeutic and/or preventive agent for diseases associated with coronavirus 3 CL protease.
  • Diseases in which coronavirus 3 CL protease is involved include viral infections, preferably coronavirus infections.
  • the coronavirus includes a coronavirus that infects humans, including HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2.
  • the coronavirus includes an alphacoronavirus and/or a betacoronavirus, more preferably a betacoronavirus, and even more preferably a sarbecovirus.
  • the alphacoronavirus includes HCoV-229E and HCoV-NL63, and is particularly preferably HCoV-229E.
  • the betacoronavirus includes HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, and more preferably SARS-CoV-2.
  • the beta coronavirus includes beta coronavirus lineage A, beta coronavirus lineage B, and beta coronavirus lineage C. More preferably, the beta coronavirus lineage A and beta coronavirus lineage B are included, and particularly preferably, the beta coronavirus lineage B is included.
  • the beta coronavirus A lineage include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43.
  • Examples of the beta coronavirus B lineage include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2.
  • Examples of the beta coronavirus C lineage include MERS-CoV.
  • the coronavirus includes HCoV-229E, HCoV-OC43, and/or SARS-CoV-2, with SARS-CoV-2 being particularly preferred. It is generally known that viruses mutate during repeated proliferation and infection.
  • the above coronaviruses include not only mutant strains known in the art, but also mutant strains that will appear in the future, so long as the compound represented by formula (IX) produced by the production method according to the present invention is a strain that can exhibit coronavirus 3CL protease inhibitory activity.
  • Known mutant strains of SARS-CoV-2 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.
  • infections caused by HCoV-229E, HCoV-OC43, and/or SARS-CoV-2 and more preferably infections caused by SARS-CoV-2.
  • a particularly preferred example of the coronavirus infection is the novel coronavirus disease (COVID-19).
  • Step A Preparation of the compound of formula (III)
  • This step is a method for producing a compound represented by formula (III) or a salt thereof, which comprises reacting a compound represented by formula (I) or a salt thereof with a compound represented by formula (II) 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), ethylphosphonic anhydride, n-butylphosphonic anhydride, PyBOP (registered trademark), HATU, MsCl, WSCD, WSCD.HCl and ClP(O)(OPh) 2 .
  • T3P registered trademark
  • ethylphosphonic anhydride ethylphosphonic anhydride
  • n-butylphosphonic anhydride PyBOP (registered trademark)
  • HATU MsCl
  • WSCD WSCD.HCl
  • the compound represented by formula (I) or a salt thereof, and the compound represented by formula (II) or a salt thereof can be produced from commercially available reagents according to known methods, or commercially available products can be used.
  • the compound represented by formula (II) or a salt thereof can be used in an amount of usually 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 be used in an amount of usually 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.
  • a preferred condensing agent is T3P®.
  • the solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, etc., and these can be used alone or in combination.
  • Examples of the base include triethylamine, diisopropylethylamine, DBU, etc. Alternatively, no base may be used.
  • the amount of the 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 usually be carried out at about 0°C to about 80°C, preferably room temperature to 60°C.
  • Step B Preparation of the compound of formula (V)
  • 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 be used in an amount of usually 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-mentioned step to proceed efficiently.
  • the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,3-dimethylimidazolidinone, acetonitrile, ethyl acetate, etc., which can be used alone or in combination.
  • the base include DBU, potassium t-butoxide, lithium diisopropylamide, etc.
  • DBU is used.
  • the amount of the base used relative to the compound represented by formula (III) or a salt thereof is usually 1.0 equivalent to 5.0 equivalents, for example, 1.0 equivalent to 2.0 equivalents.
  • reaction temperature is not particularly limited, but the reaction can usually be carried out 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.
  • 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.
  • a chlorinating agent selected from the group consisting of phosphorus oxychloride, phenyl dichlorophosphate, and phenylphosphonic acid dichloride
  • the chlorinating agent can be used in an amount of usually 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 allows the above-mentioned process to proceed efficiently. Examples of the solvent include sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, anisole, acetonitrile, etc., and these can be used alone or in combination. Alternatively, no solvent may be used.
  • the additive can be used in an amount of usually 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 an additive.
  • Water can be used in an amount of usually 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 usually be carried out at about 0°C to about 200°C, preferably 100°C to 180°C.
  • the reaction time is not particularly limited, but is usually 0.1 to 24 hours, preferably 0.1 to 12 hours.
  • the compound represented by formula (IX) produced by the production method according to the present invention has coronavirus 3CL protease inhibitory activity and is therefore useful as a therapeutic and/or preventive agent for viral infections.
  • the compound represented by formula (IX) produced by the production method of the present invention has pharmaceutical utility and preferably has one or more of the following excellent characteristics: a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits favorable pharmacokinetics, such as high bioavailability and moderate clearance. c) High metabolic stability.
  • coronavirus proliferation inhibitors include those having an EC 50 of 10 ⁇ M or less, preferably 1 ⁇ M or less, and more preferably 100 nM or less in the CPE suppression effect confirmation test (SARS-CoV-2) described below.
  • composition containing the compound represented by formula (IX) produced by the production method of the present invention can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, otic, and vaginal administration.
  • the drug 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, aromatic preparations, extracts, decoctions, tinctures, etc.), in accordance with the usual methods.
  • solid preparations for internal use e.g., tablets, powders, granules, capsules, pills, films, etc.
  • liquid preparations for internal use e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic preparations, extracts, decoctions, tinctures, etc.
  • 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.
  • any of the commonly used dosage forms such as injections, drops, topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, suppositories, etc.) can be suitably administered.
  • Injections may be emulsions such as O/W, W/O, O/W/O, and W/O/W types.
  • a pharmaceutical composition can be prepared by mixing an effective amount of the compound represented by formula (IX) produced by the production method according to the present invention with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, lubricants, etc., as necessary. Furthermore, the pharmaceutical composition can also be made into a pharmaceutical composition for children, elderly people, seriously ill patients, or surgical patients by appropriately changing the effective amount, dosage form, and/or various pharmaceutical additives of the compound represented by formula (IX) produced by the production method according to the present invention.
  • a pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (1 year to less than 7 years), children (7 years to less than 15 years), or patients aged 15 to 18 years.
  • a pharmaceutical composition for the elderly can be administered to patients aged 65 years or older.
  • the dosage of the pharmaceutical composition containing the compound represented by formula (IX) produced by the production method of the present invention is desirably set taking into consideration the age and weight of the patient, the type and severity of the disease, the route of administration, etc., but when administered orally, it is usually 0.01 to 100 mg/kg/day, preferably within the range of 0.05 to 50 mg/kg/day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 200 mg/kg/day, preferably within the range of 0.01 to 100 mg/kg/day. This can be administered once or in divided doses several times a day.
  • the compound represented by formula (IX) produced by the production method according to the present invention may be used in combination with, for example, another therapeutic drug for novel coronavirus disease (COVID-19) (including approved drugs and drugs 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.
  • a concomitant drug for the purpose of enhancing the effect of the compound or reducing the dosage of the compound.
  • the administration timing of the compound represented by formula (IX) produced by the production method according to the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times.
  • the compound represented by formula (IX) produced by the production method according to the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing those active ingredients.
  • the dosage of the concomitant drug can be appropriately selected based on the dosage used clinically.
  • the mixing 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 subject of administration, the administration route, the target disease, symptoms, combination, etc. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug may be used for 1 part by weight of the compound represented by formula (IX) produced by the production method of the present invention.
  • 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-undeceneDMA: N,N-dimethylacetamideDME: 1,2-dimethoxyethaneDMF: N,N-dimethylformamideDMI: 1,3-dimethyl-2-imidazolidinoneDMSO: dimethylsulfoxideDTT: dithiothreitolEDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideEDT: 1,2 -ethanedithiolEDTA: ethylenediaminetetraacetic acidEt3N: triethylamineFBS: fetal bovine serumH2O O:
  • X-ray powder diffraction experiments According to the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia, the solid forms (crystalline and amorphous) obtained in the examples were subjected to powder X-ray diffraction measurement under the following measurement conditions.
  • Measurement and analysis method for single crystal structure analysis The crystals obtained in the examples were subjected to single crystal structure analysis.
  • the measurement conditions and analysis method are shown below.
  • (Device) Rigaku XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25°C Temperature controller: Rigaku Corporation sample spraying low temperature device Wavelength used: CuK ⁇ radiation ( ⁇ 1.5418 ⁇ )
  • Data Processing Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
  • the data were Lorentzian, polarization and absorption corrected.
  • 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 Accumulation count: 1 Exposure time: 1 second
  • DSC Differential Scanning Calorimetry
  • the crystals obtained in the examples were subjected to DSC measurement.
  • the sample was weighed into an aluminum pan, sealed, and measured.
  • the measurement conditions are shown below. Note that the measurement by differential scanning calorimetry (DSC) may have an error within the range of ⁇ 2°C.
  • TG/DTA Simultaneous differential thermal and thermogravimetric measurement
  • the solid form (crystal) obtained in the examples was subjected to simultaneous differential thermal analysis and thermogravimetry (TG/DTA).
  • the samples obtained in the examples were weighed, placed in aluminum pans, and measured in an open system.
  • the measurement conditions are as follows. Equipment: Hitachi High-Technologies TG/DTA STA7200RV Measurement temperature range: Room temperature - 350°C Heating rate: 10° C./min
  • Step 1 Synthesis of Compound 3
  • Compound 1 25.8 kg, 200.7 mol
  • acetonitrile 155 L
  • pyridine 23.8 kg, 300.9 mol
  • compound 2 34.5 kg, 220.3 mol
  • This reaction solution was added to 25% aqueous ammonia (129.7 kg, 1904.0 mol) and stirred at 25° C. for 270 minutes.
  • the solid was filtered, washed with 50% aqueous acetonitrile, and then dried to obtain compound 3 (30.57 kg, 178.2 mol, yield: 90.2%).
  • 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 propylphosphonic anhydride ethyl acetate solution (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 stirred for 150 minutes.
  • the solid was filtered, washed with acetonitrile, and then dried to obtain compound 5 (56.05 kg, 163.8 mol, yield: 92.7%).
  • 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 organic layer and the aqueous layer were separated.
  • Toluene (56 L) and tetrahydrofuran (561 L) were added to the obtained aqueous layer for extraction.
  • 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., and sulfolane (20.6 L) and water (105.0 L) were added to the resulting slurry.
  • the slurry was cooled to 25° C., and the solid was collected by filtration and washed with 76% aqueous 2-propanol.
  • Step 5 Synthesis of Compound 9
  • N,N-dimethylacetamide 115.5 L
  • N,N-diisopropylethylamine 8.3 kg, 64.0 mol
  • compound 8 6.1 kg, 51.2 mol
  • the reaction liquid was cooled to 25 ° C
  • acetone 82.5 L
  • 5% hydrochloric acid 55.2 L
  • Water 49.5 L
  • Ethyl acetate (181.5 L) was added to the obtained solid to dissolve it, and it was concentrated to 104.0 kg.
  • 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 obtained slurry, and the solid was filtered, 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 obtained wet crystals and dissolved at 25° C.
  • the obtained solution was treated with activated carbon, the activated carbon was washed with acetone (28 L), and purified water (57 L) was added to the treated solution.
  • the anhydrous crystals of the compound represented by formula (IX) showed characteristic peaks in the powder X-ray diffraction pattern at diffraction angles (2 ⁇ ): 6.5° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, and 20.3° ⁇ 0.2°.
  • V means the unit cell volume
  • Z means the number of molecules in the unit cell.
  • 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.
  • 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 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 stirred for 1 hour.
  • the solid was filtered, washed with acetonitrile, and then dried to obtain compound 5 (36.60 g, 107.0 mmol, yield: 91.8%).
  • 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.
  • Tetrahydrofuran (255.0 mL), toluene (37.5 mL) and 11% hydrochloric acid (164.8 g, 526.1 mmol) were added to this reaction solution for extraction. Water (150.0 mL) was added to the obtained organic layer for further extraction.
  • 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.
  • sulfolane (123.3 kg) was added, and then added to a solution of potassium acetate (156.4 kg, 1593 mol), water (469 L) and sulfolane (369.8 kg) at 50° C., and water (244 L) was added to the resulting slurry.
  • the slurry was cooled to 10° C., and the solid was filtered and washed with 76% aqueous 2-propanol.
  • the filtered 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 2-propanol solution and 2-propanol, and then dried to obtain Compound 7 (42.65 kg, 110.3 mol, yield: 83.1%).
  • 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, acetone (165.7 kg) was added, and then 5% hydrochloric acid (143 kg) was added dropwise over about 30 minutes and stirred at 25°C.
  • Water (126 L) was added to the obtained slurry, and the solid was filtered and washed with 44% acetone water and 2-propanol.
  • reaction solution was cooled to 25° C., acetone (20.0 mL) was added, and then 2 mol/L hydrochloric acid (9.30 mL, 18.6 mmol) and water (6.0 mL) were added dropwise over about 30 minutes and stirred at 25° C.
  • Water (6.0 mL) was added to the obtained slurry, and the solid was collected by filtration and washed with 44% acetone water and 2-propanol.
  • Isopropyl acetate (24.0 mL) was added to the obtained solid, and the solid was dissolved at about 50° C., and heptane (24.0 mL) was added, followed by stirring at 35° C.
  • 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 obtained slurry, and the solid was filtered, 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 obtained undried crystals and dissolved at 25° C.
  • the obtained solution was treated with activated carbon, and the activated carbon was washed with acetone (40.0 mL).
  • 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
  • DBU 22.3 kg, 146.5 mol
  • 7% hydrochloric acid 352.5 kg was added to this reaction solution, and the organic layer and the aqueous layer were separated.
  • Toluene (39 L) and tetrahydrofuran (386 L) were added to the obtained aqueous layer and extracted.
  • 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).
  • the solid was dried to obtain seed crystals of compound 6 (0.98 kg, 2.37 mol, yield: 87.1%).
  • 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) ⁇ 100 As described above, it was confirmed that compound 5 was produced even when WSCD ⁇ HCl, HATU, PyBOP (registered trademark), MsCl, and ClP(O)(OPh) 2 were used as condensing agents.
  • 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) ⁇ 100 As described above, it was confirmed that compound 7 was produced even when anisole was used as a solvent in the absence of any additive, and also when 97% sulfolane, H 2 O, and n-Bu 4 NCl were used as additives in anisole solvent.
  • a powder X-ray diffraction experiment was carried out on compound 6 obtained by the production method described in Example 1 under the above-described measurement condition 1.
  • the powder X-ray diffraction pattern is shown in Figure 1, and a peak list of the powder X-ray diffraction pattern is shown in Figure 2.
  • the height indicates the intensity.
  • a powder X-ray diffraction experiment was carried out on compound 6 obtained by the production method described in Example 1A under the above-described measurement condition 1.
  • the powder X-ray diffraction pattern is shown in Figure 9, and a peak list of the powder X-ray diffraction pattern is shown in Figure 10.
  • the height indicates the intensity.
  • 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 (registered trademark), and the Celite (registered trademark) was washed with dichloromethane (11.0 mL).
  • 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%).
  • IC50 is preferably 50 ⁇ M or less, more preferably 1 ⁇ M or less, and even more preferably 100 nM or less.
  • EC50 is preferably 10 ⁇ M or less, more preferably 1 ⁇ M or less, and even more preferably 100 nM or less.
  • Test Example 1 Cytopathic effect (CPE) suppression test using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T/ACE2-TMPRSS2 cells) ⁇ Procedure> -Dilution and dispensing of test sample Test samples are preliminarily diluted with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared, and then dispensed into a 384-well plate.
  • CPE Cytopathic effect
  • Dilution and dispensing of cells and SARS-CoV-2 HEK293T/ACE2-TMPRSS2 cells (GCP-SL222, 5 x 103 cells/well) and SARS-CoV-2 ( 200-600TCID50 /well) were mixed in culture medium (MEM, 2% FBS, penicillin-streptomycin), dispensed into wells containing test samples, and then cultured in a CO2 incubator for 3 days. Dispensing of CellTiter-Glo® 2.0 and measurement of luminescence signal After the plate cultured for 3 days is returned to room temperature, CellTiter-Glo® 2.0 is dispensed into each well and mixed using a plate mixer.
  • the luminescence signal (Lum) is measured using a plate reader.
  • ⁇ Calculation of each measurement item value> Calculation of 50% SARS-CoV-2-infected cell death inhibitory concentration (EC 50 )
  • EC 50 50% SARS-CoV-2-infected cell death inhibitory concentration
  • 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, R.
  • Test samples are preliminarily diluted with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared, and then dispensed into a 384-well plate.
  • Addition of enzyme and substrate, enzyme reaction Add 8 ⁇ M substrate and 6 nM or 0.6 nM enzyme solution to the prepared compound plate and incubate at room temperature for 3 to 5 hours. After that, add reaction stop solution (0.067 ⁇ M Internal Standard, 0.1% formic acid, 10% or 25% acetonitrile) to stop the enzyme reaction.
  • the plate on which the reaction was completed is measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF), or a Rapid Fire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadrupole).
  • 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 a RapidFire Integrator or a program capable of equivalent analysis to obtain the product area value.
  • the internal standard detected at the same time is also calculated to obtain the internal standard area value.
  • ⁇ Calculation of each measurement item value> Calculate the area value obtained in the previous step using the following formula to calculate the P/IS.
  • P/IS Product area value/Internal Standard area value ⁇ 50%
  • IC 50 SARS-CoV-2 3CL protease inhibitory concentration
  • the formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
  • the compound of formula (IX) prepared by the process according to the present invention can be administered as a pharmaceutical composition by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions, topically, for example in the form of lotions, gels, ointments or creams, or in the form of intranasal or suppositories.
  • compositions containing the compound of formula (IX) prepared by the process according to the present invention in free form or in the form of a pharma-ceutically acceptable salt together with at least one pharma-ceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation or coating methods.
  • oral compositions can be tablets, granules or capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients, etc.
  • injectable compositions can be solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.
  • the compound represented by formula (IX) produced by the production method of the present invention has an inhibitory effect on coronavirus 3CL protease and is considered to be useful as a therapeutic and/or preventive agent for diseases or conditions in which coronavirus 3CL protease is involved.
  • the novel synthetic intermediates or salts thereof according to the present invention, and the production method according to the present invention are useful in the production of pharmaceuticals.

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