Method for producing cyclic organic compounds

Abstract

An object of the present invention is to provide a method for producing cyclic organic compounds using a CSTR (Continuous Stirred Tank Reactor), which can achieve excellent impurity suppression effects (improved quality), reduced reactor size, continuous production, etc. The inventors have attempted to conduct cyclization reactions using a CSTR, which has not traditionally been used in cyclization reactions of cyclic compounds, and have found that, compared to conventional cyclization methods, it is possible to achieve excellent impurity suppression effects (improved quality), reduced reactor size, continuous production, etc. Furthermore, by applying a simulation method that has traditionally been used primarily at the fine chemical plant level to the cyclization reaction of the present invention, the reaction rate of the cyclization reaction can be experimentally predicted, and the above-mentioned improvements can be efficiently achieved in the production of cyclic peptides and heterocyclic compounds by setting the flow rate (residence time), precursor and cyclic organic compound concentrations, and cyclization reaction temperature that affect these conditions in the cyclization reaction using a CSTR.

Description

[Technical field]

[0001] The present invention relates to a method for synthesizing a macrocyclic organic compound using a continuous tank reactor. [Background technology]

[0002] Macrocyclic compounds (cyclic compounds) refer to compounds including heterocyclic compounds (Non-Patent Document 1, Patent Document 1) and peptide compounds (Patent Document 2). Macrocyclic compounds are used in medicines and the like as natural and unnatural compounds with physiological activity, and the production of cyclic compounds for the supply of these medicines is an important mission in the pharmaceutical industry. And in order to produce these cyclic compounds, the cyclization process cannot be avoided. The cyclization reaction of a compound refers to a reaction in which one molecule reacts at two or more reaction points within the molecule to form a cyclic structure. There are various bond types, and cyclization reactions using various bonds such as amide bonds, ester bonds, ether bonds, thioether bonds, and disulfide bonds are known (Non-Patent Documents 2, 3, Patent Documents 3, 4).

[0003] It is known that in cyclization reactions, when the concentration is high, intramolecular reactions and intermolecular reactions compete with each other, resulting in the formation of dimers or higher polymerized compounds due to intermolecular reactions. In general polymer synthesis, the concentration can be maintained relatively high, but when the cyclization reaction is aimed at a single molecule, the reaction is carried out under dilute conditions to suppress the formation of polymers due to intermolecular reactions (Non-Patent Document 4, Patent Documents 1, 5, 6, 7). Therefore, the maximum production amount per batch is limited by the size of the reaction vessel. In addition, in order to simulate dilute conditions, a method of dripping the reaction substrate into a solution under reaction conditions in small fractions (reverse dripping) and a method of using a substrate supported on a solid phase in the reaction (on-resin cyclization) are known (Non-Patent Document 5, Patent Documents 8, 9). These methods can be used to obtain the desired cyclic compound while avoiding dilute conditions, but the production amount during production is also limited by the size of the reaction vessel and the properties of the reaction substrate.

[0004] A CSTR (Continuous Stirred Tank Reactor, Continuous Tank Reactor, or Mixed Flow Reactor) refers to a reactor in which a tank reactor is operated continuously. It is a reactor that is widely used for liquid-phase reactions, gas-phase reactions, and heterogeneous reactions along with batch reactors that operate tank reactors batchwise (Non-Patent Document 6). Ideally, in a tank reactor, the reaction fluid in the vessel is thoroughly mixed by stirring, the temperature and concentration are constant in the vessel, and the fluid is discharged from the vessel at the concentration and temperature in the reactor (mixed flow). In addition, a tubular reactor is a reaction device in which a single or multiple tubes are arranged in parallel, and a concentration distribution occurs in the axial direction of the tube (plug flow). Both CSTRs and tubular reactors are suitable for continuous production as flow reactors. CSTRs are common reactors in fine chemicals, and are known to be used in polymerization control of polymer compounds (Patent Document 10), enzyme reactions (Patent Document 11), and the like. In addition, by taking advantage of the continuous operability of CSTRs, combinations with other commonly known continuous operation techniques, such as continuous liquid-liquid separation and crystallization, are known (Non-Patent Document 7). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2008 / 105526 [Patent Document 2] WO2013 / 100132 [Patent Document 3] WO2014 / 151634 [Patent Document 4] WO2014 / 134922 [Patent Document 5] WO2013 / 167703 [Patent Document 6] WO2006 / 038088 [Patent Document 7] WO2010052559 [Patent Document 8] WO1995 / 09142 [Patent Document 9] WO2006 / 025859 [Patent Document 10] WO2007 / 011459 [Patent Document 11] WO2013 / 156600

[0006] [Non-Patent Document 1] Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors, A.Suda et al., Bioorganic & Medicinal Chemistry Letters 2012, 22, 1136-1141. [Non-Patent Document 2] Cyclodepipeptides: A rich source of biologically active compounds for drug research, J.Scherkenbeck et al., Molecules, 2014, 19 (8), 12368. [Non-Patent Document 3] Cyclic polymers by ring-closure strategies, P.Gerbaux and O.Coulembier et al., Angew.Chem.Int.Ed. 2016, 55, 13944. [Non-Patent Document 4] Macrocycles: lessons from the distnt pst, recent developments, and future directions. AKYudin, Chem. Sci., 2015, 6, 30. [Non-Patent Document 5] An improved method for the solution cyclization of peptides under pseudo-high dilution conditions', Norbert Sewald et al., Journal of Biotechnology 112 (2004) 73-77 [Non-Patent Document 6] 1. Chemical reaction engineering (revised edition), Kenji Hashimoto, Baifukan, 2. Chemical reaction engineering (third edition), Octave Levenspiel, Wiley [Non-Patent Document 7] Development of a Continuous Schotten-Baumann Route to an Acyl Sulfonamide., Timothy D. White et al., Org. Process Res. Dev., 2012, 16 (5), 939. Summary of the Invention [Problem to be solved by the invention]

[0007] Continuous reactors, which are used for mass production in the fine chemical field, have not been applied to the cyclization reaction of cyclic organic compounds (including heterocyclic compounds) in the pharmaceutical field, particularly cyclic peptide drugs. There are various reasons for this, including the fact that many commercially available cyclic peptide drugs are highly active and there has been little need for mass production. Known continuous reactors include continuous tank reactors (CSTRs) and tubular reactors. In tubular reactors, the concentrations of substrate and product at the inlet and outlet are different due to the reactor's principle. In the case of tubular reactors, in order to suppress intermolecular reactions when cyclizing heterocyclic compounds, peptide compounds, etc., it is necessary to pass a relatively dilute solution through the reactor, which requires a large amount of organic solvent. On the other hand, in the case of CSTRs, it is possible to uniformly control the concentration distribution of the cyclization precursor and cyclization product in the reaction vessel, and the present inventors have focused on the fact that by adjusting the residence time, etc., it is possible to reduce the amount of solvent used while maintaining a low concentration of the cyclization precursor in the reaction vessel. The present invention has been made in view of the above circumstances, and one of the objects of the present invention is to provide a method for producing a cyclic organic compound using a CSTR, which can achieve excellent impurity suppression effects (improved quality, for example, suppression of intermolecular cyclization reactions), reduction in reactor size, continuous production, etc., as compared with conventional cyclization methods. [Means for solving the problem]

[0008] In order to solve the above problems, the present inventors attempted to conduct a cyclization reaction using a CSTR (Continuous Stirred Tank Reactor), which has not been used in the cyclization reaction of cyclic compounds in the past. They found that, compared with conventional cyclization methods, this method can achieve excellent impurity suppression effects (improved quality), a reduction in the size of the reaction vessel, continuous production, and the like, and thus completed the present invention. Furthermore, the inventors have found that by applying a simulation method that has conventionally been mainly used at the fine chemical plant level to the cyclization reaction of the present invention, the reaction rate of the cyclization reaction can be experimentally predicted and the flow rate (residence time) in the cyclization reaction using a CSTR, the concentrations of the precursor and cyclic organic compound, and the cyclization reaction temperature that affect these conditions, etc., can be set, thereby efficiently achieving the above-mentioned improvement effects in the production of cyclic peptides and heterocyclic compounds.

[0009] The present invention is based on these findings, and specifically provides the following [1] to

[15] . [1] A method for producing a cyclic organic compound, comprising a cyclization reaction step of cyclizing a cyclization precursor of the cyclic organic compound in at least one continuous tank reactor (CSTR). [2] The method according to [1], wherein the cyclic organic compound is a peptide compound having a cyclic portion composed of natural amino acids and / or amino acid analogs. [3] The method according to [1] or [2], wherein the peptide compound having a cyclic portion comprises a cyclic portion consisting of 4 to 14 natural amino acid and / or amino acid analog residues, and the total number of natural amino acid and amino acid analog residues is 7 to 20. [4] The method according to [3], wherein the cyclic organic compound has the following characteristics (i) and (ii): (i) contains at least two N-substituted amino acids and at least one non-N-substituted amino acid; and (ii) The ClogP value is 6 or greater. [5] The method according to any one of [1] to [4], wherein the cyclization reaction is an intramolecular cyclization reaction via one or more bonds selected from the group consisting of the following (i) to (vii): (i) Amide bond (ii) Disulfide bonds (iii) Ether bond (iv) Thioether bond (v) Ester bond (vi) Thioester bond (vii) Carbon-carbon bonds [6] The method according to [1] or [2], wherein the cyclic organic compound is a compound represented by the following general formula (I): TIFF0007634933000001.tif43128 (wherein X represents CH or N; R1 represents a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-4 haloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, or a C1-6 alkylthio group; R2 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group, or R2 and R3 together form a ring; R3 represents a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or a C1-6 alkoxy group, or R2 and R3 together form a ring; R4 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group; R5, R6, R7 each independently represent a C1-6 alkylene group, a C2-6 alkenylene group, a C2-6 alkynylene group, a C3-10 cycloalkylene group, a C3-10 cycloalkenylene group, a C6-12 arylene group, -3-12 membered monocyclic heterocycle- which may have a substituent; L1, L2, L3 each independently represent a single bond, -CONR8-, -NR8CO-, -NR8-, -O-, -SO2NR8-, -NR8SO2-, -COO-, -NR8CONR8'-, -NR8COO-, or -OCONR8-; R8 and R8' each independently represent a hydrogen atom or a C1-6 alkyl group which may have a substituent. [7] The method according to any one of [1] to [6], wherein the cyclization reaction is carried out on an industrial scale using conditions obtained based on the results of a preliminary test of the cyclization reaction. [8] The method according to [7], wherein the condition is obtained by a process including the following steps (i) to (v): (i) in a preliminary test, acquiring data on the change in concentration over time at a plurality of temperatures for at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products; (ii) Using the concentration change data obtained in step (i) and the reaction rate equation for the cyclization reaction, a reaction rate constant k n A process of obtaining (iii) the temperature used in step (i), the reaction rate constant k determined in step (ii), n and the frequency factor A using the following formula (II): n and the activation energy E n A process of obtaining TIFF0007634933000002.tif14128(iv) The frequency factor A obtained in step (iii) n and the activation energy E n Using the above equation (II) and the above reaction rate equation, the reaction rate constant k at the temperature for cyclization in the CSTR is calculated. n A step of determining (v) The reaction rate constant k obtained in step (iv) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000003.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration. [9] The elementary reaction of the cyclization reaction is represented by the following formula (IV): The method according to [8], wherein the reaction rate constants k1, k2, and k3 are calculated using any one of the following formulas (V) to (IX): TIFF0007634933000005.tif81148 (wherein TM represents a cyclic organic compound, SM represents a cyclization precursor, ACT represents an activator, IM represents an intermediate, Dimer represents a dimer, and C represents a concentration (M).

[10] The elementary reaction of the cyclization reaction is represented by the following formula (X): The method according to [8], wherein the reaction rate constants k1 and k2 are calculated using any one of the following formulas (XI) to (XIII): TIFF0007634933000007.tif43131 (wherein r represents reaction rate, TM represents target product, SM represents cyclization precursor (= intermediate), ACT represents activator, Dimer represents dimer, and C represents concentration (M).

[11] The method according to any one of [7] to

[10] , wherein the condition is selected from the group consisting of a flow rate of a continuous tank reactor, a concentration of a cyclization precursor, and a concentration of a cyclic organic compound.

[12] A method for promoting intramolecular cyclization of a cyclization precursor of a cyclic organic compound, comprising the step of cyclizing the precursor in at least one continuous tank reactor (CSTR).

[13] A method for obtaining conditions for cyclizing a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor (CSTR) on an industrial scale, comprising the steps of: (i) in a preliminary test, acquiring data on the change in concentration over time at a plurality of temperatures for at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products; (ii) Using the concentration change data obtained in step (i) and the reaction rate equation for the cyclization reaction, a reaction rate constant k n A process of obtaining (iii) the temperature used in step (i), the reaction rate constant k determined in step (ii), n and the frequency factor A using the following formula (II): n and the activation energy E n A process of obtaining TIFF0007634933000008.tif14128(iv) The frequency factor A obtained in step (iii) n and the activation energy E n Using the above equation (II) and the above reaction rate equation, the reaction rate constant k at the temperature for cyclization in the CSTR is calculated. n A step of determining (v) The reaction rate constant k obtained in step (iv) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000009.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[14] To obtain conditions for cyclizing a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor (CSTR) on an industrial scale, a computer is provided that: (i) Using data on time-dependent changes in concentration at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products obtained in a preliminary test at multiple temperatures and a reaction rate equation for the cyclization reaction, a reaction rate constant k n A process of obtaining (ii) the temperature used in step (i), the reaction rate constant k determined in step (i), n and the frequency factor A using the following formula (II): n and the activation energy E n A process of obtaining TIFF0007634933000010.tif14128(iii) The frequency factor A obtained in step (ii) n and the activation energy E n Using the above equation (II) and the above reaction rate equation, the reaction rate constant k at the temperature for cyclization in the CSTR is calculated. n A step of determining (iv) The reaction rate constant k obtained in step (iii) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000011.tif15128 (in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration. A program for executing the above.

[15] A system for obtaining conditions for cyclizing a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor (CSTR) on an industrial scale, comprising the following means (i) to (iv): (i) Using data on time-dependent changes in concentration at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products obtained in a preliminary test at multiple temperatures and a reaction rate equation for the cyclization reaction, a reaction rate constant k n The means to seek (ii) the temperature used in step (i), the reaction rate constant k determined in step (i), n and the frequency factor A using the following formula (II): n and the activation energy E n The means to seek TIFF0007634933000012.tif14128(iii) The frequency factor A obtained in step (ii) n and the activation energy E n Using the above equation (II) and the above reaction rate equation, the reaction rate constant k at the temperature for cyclization in the CSTR is calculated. n and (iv) The reaction rate constant k obtained in step (iii) n A means for acquiring the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000013.tif15128 (in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[0010] Furthermore, the following inventions are provided: [2-1] A method for suppressing an intermolecular reaction of a cyclization precursor of a cyclic organic compound, comprising a step of cyclizing the cyclization precursor in at least one continuous tank reactor. [2-2] Use of a continuous-tank reactor for intramolecularly cyclizing a cyclization precursor of a cyclic organic compound in at least one continuous-tank reactor. [2-3] The method according to [7], wherein the condition is obtained by a process including the following steps (i) to (iii): (i) in a preliminary test, acquiring data on the change in concentration over time at one temperature for at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products; (ii) Using the concentration change data obtained in step (i) and the reaction rate equation for the cyclization reaction, a reaction rate constant k n A process of obtaining (iii) The reaction rate constant k determined in step (ii) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000014.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration. [2-4] A method for obtaining conditions for cyclizing a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor (CSTR) on an industrial scale, the method comprising the steps of: (i) in a preliminary test, acquiring data on the change in concentration over time at one temperature for at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products; (ii) Using the concentration change data obtained in step (i) and the reaction rate equation for the cyclization reaction, a reaction rate constant k n A process of obtaining (iii) The reaction rate constant k determined in step (ii) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000015.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration. [2-5] To obtain conditions for industrial-scale cyclization of a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor (CSTR), a computer is programmed to: (i) Using data on the change in concentration over time at one temperature for at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products obtained in a preliminary test, and a reaction rate equation for the cyclization reaction, a reaction rate constant k n A process of obtaining (ii) The reaction rate constant k determined in step (i) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000016.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration. A program for executing the above. [2-6] A system for obtaining conditions for cyclizing a cyclization precursor of a cyclic organic compound on an industrial scale in at least one continuous tank reactor, the system comprising the following means (i) and (ii): (i) Using data on the change in concentration over time at one temperature for at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products obtained in a preliminary test, and a reaction rate equation for the cyclization reaction, a reaction rate constant k n The means to seek (ii) The reaction rate constant k obtained in the method (i) n A means for acquiring the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000017.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration. Effect of the Invention

[0011] In the present invention, a method for producing a cyclic organic compound is provided that, by performing the cyclization reaction using a CSTR, is able to achieve superior impurity suppression effects, reduction in the size of the reaction vessel, continuous production, and the like, compared to conventional cyclization methods. Furthermore, in the present invention, a production method is provided that can more efficiently achieve the above-mentioned improved effects by applying a simulation method to setting the conditions for the cyclization reaction. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a diagram showing an assumed facility for synthesizing 2 kg of a target product using a CSTR (conditions for Run 4 in Example 1). [Diagram 2] FIG. 1 shows a diagram illustrating a hypothetical facility for synthesizing 2 kg of the target product by pseudo high-dilution (conditions for Run 3 in Example 1). [Diagram 3] FIG. 1 shows a 1H NMR chart of a cyclized precursor preparation of cyclosporine A (Example 2). [Figure 4] FIG. 1 is a diagram showing the equipment for producing cyclosporine A by CSTR in Example 3. [Diagram 5] FIG. 1 shows a 1H NMR chart of a Desmopressin preparation (Example 4). [Figure 6] FIG. 1 shows a 1H NMR chart of a cyclized precursor sample of Desmopressin (Example 4). [Figure 7] FIG. 1 shows a 1H NMR chart of a cyclosporine A derivative sample (Example 5). [Figure 8] FIG. 1 shows a 1H NMR chart of a cyclized precursor sample of a cyclosporin A derivative (Example 5). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] <Definition of Substituents, etc.> As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, does not contain heteroatoms or unsaturated carbon-carbon bonds in the backbone, and has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. The carbon chain length n ranges from 1 to 20, and is preferably a C2-C10 alkyl. Examples of alkyl include "C1 to C6 alkyl", and specific examples thereof include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, t-butyl group, sec-butyl group, 1-methylpropyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, isopentyl, neopentyl, and the like.

[0014] As used herein, "alkenyl" refers to a monovalent group having at least one double bond (two adjacent SP2 carbon atoms). Depending on the configuration of the double bond and the substituents (if any), the geometry of the double bond can be in an Entgegen (E) or Zusammen (Z), cis or trans configuration. Alkenyls include linear or branched chains, including linear chains containing internal olefins. C2-C10 alkenyls are preferred, and C2-C6 alkenyls are more preferred. Specific examples of such alkenyl include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, and hexenyl.

[0015] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). It includes straight-chain or branched-chain alkynyl, including internal alkylene. It is preferably C2-C10 alkynyl, more preferably C2-C6 alkynyl. Specific examples of alkynyl include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0016] In the present specification, "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including a monocyclic ring, a bicyclic ring, and a spirocyclic ring. Preferred is C3-C10 cycloalkyl. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicyclo[2.2.1]heptyl.

[0017] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring, preferably C6-C10 aryl. Specific examples of aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl).

[0018] In the present specification, "heteroaryl" refers to a monovalent aromatic ring group containing preferably 1 to 5 heteroatoms in the atoms constituting the ring, which may be partially saturated. The ring may be a single ring or two condensed rings (for example, a bicyclic heteroaryl condensed with benzene or a single ring heteroaryl). The number of atoms constituting the ring is preferably 5 to 10 (5-membered to 10-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridyl.

[0019] In the present specification, the term "aryl alkyl (aralkyl)" refers to a group containing both aryl and alkyl, for example, a group in which at least one hydrogen atom of the alkyl is substituted with aryl, preferably, "C5-C10 aryl C1-C6 alkyl", for example, benzyl.

[0020] In the present specification, "arylene" means a divalent group derived by further removing one arbitrary hydrogen atom from the aryl. The arylene may be a single ring or a condensed ring. The number of atoms constituting the ring is not particularly limited, but is preferably 6 to 10 (C6-10 arylene). Specific examples of the arylene include phenylene and naphthylene.

[0021] In the present specification, "heteroarylene" means a divalent group derived by removing one arbitrary hydrogen atom from the heteroaryl. The heteroarylene may be a single ring or a condensed ring. The number of atoms constituting the ring is not particularly limited, but is preferably 5 to 10 (5-membered to 10-membered heteroarylene). Specific examples of heteroarylene include pyrrolediyl, imidazolediyl, pyrazolediyl, pyridinediyl, pyridazinediyl, pyrimidinediyl, pyrazinediyl, triazolediyl, triazinediyl, isoxazolediyl, oxazolediyl, oxadiazolediyl, isothiazolediyl, thiazolidinyl, thiadiazolediyl, furandiyl, and thiophenediyl.

[0022] In the present invention, the “amino acids” constituting the peptide may be “natural amino acids” or “amino acid analogs.” “Amino acids,” “natural amino acids,” and “amino acid analogs” may be referred to as “amino acid residues,” “natural amino acid residues,” and “amino acid analog residues,” respectively.

[0023] "Natural amino acids" are α-aminocarboxylic acids (α-amino acids) and refer to the 20 types of amino acids contained in proteins, specifically Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro.

[0024] The "amino acid analogue" includes, but is not limited to, β-amino acids, γ-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, hydroxycarboxylic acids, and non-natural amino acids (amino acids whose side chains are different from natural ones; for example, non-natural α-amino acids, β-amino acids, and γ-amino acids). In the case of α-amino acids, they may be D-amino acids or α,α-dialkyl amino acids. In the case of β-amino acids and γ-amino acids, any steric configuration is allowed, as in the case of α-amino acids. The side chain (main chain methylene) of the amino acid analogue is not particularly limited, and may have, in addition to hydrogen atoms, for example, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and cycloalkyl. Each of them may have one or more substituents, and the substituents can be selected from any functional group including, for example, halogen atoms, N atoms, O atoms, S atoms, B atoms, Si atoms, and P atoms. For example, in the present specification, "C1-C6 alkyl which may have halogen as a substituent" means "C1-C6 alkyl" substituted with one or more halogen atoms, and specific examples thereof include trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoroethyl, tetrafluoroethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloromethyl, dichloromethyl, chloromethyl, pentachloroethyl, tetrachloroethyl, trichloroethyl, dichloroethyl, chloroethyl, etc. In addition, for example, "C5-C10 aryl C1-C6 alkyl which may have a substituent" means a group in which at least one hydrogen atom of the aryl and / or alkyl of "C5-C10 aryl C1-C6 alkyl" is substituted with a substituent. Furthermore, these "cases in which two or more substituents are present" also include, for example, a functional group containing an S atom, which further includes a functional group such as amino or halogen. For example, a side chain having a polyethylene glycol structure is an example of a side chain of an amino acid analog.

[0025] The main chain amino group of the amino acid analogue may be unsubstituted (NH2 group) or substituted (i.e., NHR group: R represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl, which may have a substituent, and the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring, as in proline. The substituent is the same as the side chain substituent, and examples thereof include halogen, oxy, and hydroxy.). Furthermore, the definitions of these substituents, "alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and cycloalkyl", are defined mutatis mutandis as those of the functional group described above. For example, in this specification, "alkoxy" refers to a group in which the hydrogen atom of a hydroxyl group is substituted with the alkyl group, and a preferred example thereof is "C1-C6 alkoxy".

[0026] Halogen-derived substituents include fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), and the like.

[0027] Substituents derived from O atoms include hydroxyl (-OH), oxy (-OR), carbonyl (-C=OR), carboxyl (-COH), oxycarbonyl (-C=O-OR), carbonyloxy (-OC=OR), thiocarbonyl (-C=O-SR), carbonylthio group (-SC=OR), aminocarbonyl (-C=O-NHR), carbonylamino (-NH-C=OR), oxycarbonylamino (-NH-C=O-OR), sulfonylamino (-NH-SO2-R), aminosulfonyl (-SO2-NHR), sulfamoylamino (-NH-SO2-NHR), thiocarboxyl (-C(=O)-SH), and carboxylcarbonyl (-C(=O)-COH).

[0028] Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, and the like.

[0029] Examples of carbonyl (-C=OR) include formyl (-C=OH), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0030] Examples of oxycarbonyl (-C=O-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0031] Examples of carbonyloxy (-OC=OR) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, and the like.

[0032] Examples of thiocarbonyl (-C=O-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, aralkylthiocarbonyl, and the like.

[0033] Examples of carbonylthio (-SC=OR) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio, and the like.

[0034] Examples of aminocarbonyl (-C=O-NHR) include alkylaminocarbonyl, cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition, compounds in which the H atom bonded to the N atom in -C=O-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0035] Examples of carbonylamino (-NH-C=OR) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C=OR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0036] Examples of oxycarbonylamino (-NH-C=O-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxycarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C=O-OR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0037] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-SO2-R is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0038] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, etc. In addition to these, compounds in which the H atom bonded to the N atom in -SO2-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0039] Examples of sulfamoylamino (-NH-SO2-NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, aralkylsulfamoylamino, etc. Furthermore, the two H atoms bonded to the N atom in -NH-SO2-NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

[0040] Substituents derived from S atoms include thiol (-SH), thio (-SR), sulfinyl (-S=OR), sulfonyl (-S(O)2-R), and sulfo (-SO3H).

[0041] Examples of thio (-SR) are selected from among alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0042] Examples of sulfinyl (-S=OR) include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, and the like.

[0043] Examples of sulfonyl (-S(O)2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0044] Substituents derived from the N atom include azido (-N3, also known as an "azido group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R), tertiary amino (-NR(R')), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R"), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R"), and aminocarbonylamino (-NR-CO-NR'R").

[0045] Examples of secondary amino (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, aralkylamino, and the like.

[0046] Examples of tertiary amino (-NR(R')) include amino groups having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl(aralkyl)amino, and these two substituents may form a ring.

[0047] Examples of substituted amidino (-C(=NR)-NR'R") include groups in which the three substituents R, R', and R" on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.

[0048] Examples of substituted guanidino (-NR-C(=NR''')-NR'R") include groups in which R, R', R", and R''' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these form a ring.

[0049] Examples of aminocarbonylamino (-NR-CO-NR'R") include those in which R, R', and R" are each independently selected from a hydrogen atom, an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, and an aralkyl, or these groups form a ring.

[0050] Substituents derived from the B atom include boryl (-BR(R')) and dioxyboryl (-B(OR)(OR')). These two substituents R and R' are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or may form a ring.

[0051] In the present invention, at least one atom constituting an "amino acid" may be an atom (isotope) with the same atomic number (number of protons) but different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in an "amino acid" include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, and a chlorine atom, each of which is 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31P, 32 P, 35 S, 18 F, 36 Cl etc. are included.

[0052] Examples of amino acid analogs that can be used in the present invention include, but are not limited to, the following. Many of these amino acid analogs can be purchased commercially with or without the side chains protected and the amine moiety protected or unprotected. Those that cannot be purchased commercially can be synthesized by known methods. TIFF0007634933000018.tif186168TIFF0007634933000019.tif76169

[0053] As amino acid analogs, the following N-Me amino acids can be used: N-methylalanine, N-methylglycine, N-methylphenylalanine, N-methyltyrosine, N-methyl-3-chlorophenylalanine, N-methyl-4-chlorophenylalanine, N-methyl-4-methoxyphenylalanine, N-methyl-4-thiazolealanine, N-methylhistidine, N-methylserine, and N-methylaspartic acid. TIFF0007634933000020.tif57168TIFF0007634933000021.tif37169

[0054] As amino acid analogs, the following N-alkylamino acids can also be used. TIFF0007634933000022.tif33170TIFF0007634933000023.tif29169

[0055] As amino acid analogs, the following D-amino acids can also be used: TIFF0007634933000024.tif40151

[0056] As amino acid analogs, the following α,α-dialkylamino acids can also be used. TIFF0007634933000025.tif35145

[0057] The following amino acids can also be used as amino acid analogs: TIFF0007634933000026.tif25146

[0058] In one non-limiting aspect, the present invention provides a method for producing a cyclic organic compound, the method comprising a cyclization step of cyclizing a cyclization precursor of the cyclic organic compound in at least one continuous tank reactor. In one non-limiting aspect, the present invention provides a method for promoting intramolecular cyclization of a cyclization precursor of a cyclic organic compound, the method comprising the step of cyclizing the cyclization precursor in at least one or more continuous tank reactors. In one non-limiting embodiment, the present invention provides a method for suppressing an intermolecular reaction of a cyclization precursor of a cyclic organic compound, the method comprising the step of cyclizing the cyclization precursor in at least one or more continuous tank reactors. In one non-limiting embodiment, the present invention provides the use of a continuous-tank reactor for intramolecular cyclization of a cyclization precursor of a cyclic organic compound in at least one continuous-tank reactor.

[0059] The term "cyclic organic compound" in the present invention means an organic compound having a cyclic portion. The "cyclic organic compound" in the present invention is not particularly limited as long as it has such characteristics, and examples thereof include medium molecular weight compounds (e.g., molecular weight of about 500 to 6000) and low molecular weight compounds (e.g., molecular weight of about 500 to 500) including natural products, sugar chains, peptides, and nucleic acid drugs, and preferably peptide compounds having a cyclic portion. For example, by measuring the molecular weight of the compound produced by the method of the present invention using techniques known to those skilled in the art, such as MS or SDS-PAGE, it is possible to evaluate whether the desired cyclic organic compound has been produced.

[0060] The term "cyclization precursor" as used herein means a non-cyclic organic compound (precursor) before undergoing a cyclization step, as opposed to the cyclic organic compound of the present invention produced through a cyclization step. Although not limited thereto, it is preferred that the chemical structure of the cyclization precursor has the same chemical structure as the cyclic organic compound, except for the structural portion involved in the cyclization reaction. The structural portion involved in the cyclization reaction includes a structure such as a reaction promoter for the cyclization reaction, which can be removed after the bonding reaction. For example, when the cyclization precursor is a low molecular weight organic compound, the cyclization precursor can be produced by using an organic synthesis method known to those skilled in the art. On the other hand, when the cyclization precursor is a peptide compound, in addition to the above organic synthesis methods, it is also possible to obtain the peptide by synthesis using a cell-free translation system or by expressing a gene encoding the peptide compound in an appropriate host cell.

[0061] In a non-limiting embodiment, the cyclization reaction in the present invention is an intramolecular cyclization reaction via one or more bonds selected from the group consisting of the following (i) to (vii): (i) Amide bond (ii) Disulfide bonds (iii) Ether bond (iv) Thioether bond (v) Ester bond (vi) Thioester bond (vii) Carbon-carbon bonds For example, the intramolecular cyclization in the above embodiment can be formed by bonding two amino acids together via a disulfide bond, an amide bond, a peptide bond, an alkyl bond, an alkenyl bond, an ester bond, a thioester bond, an ether bond, a thioether bond, a phosphonate ether bond, an azo bond, a C=NC bond, an amide bond, a lactam bridge, a carbamoyl bond, a urea bond, a thiourea bond, an amine bond, a thioamide bond, a sulfinyl bond, a sulfonyl bond, or the like, but the type of bond used in the intramolecular cyclization reaction is not limited to these. In the above-mentioned embodiment, the intramolecular cyclization is preferably carried out via a covalent bond such as an amide bond, a carbon-carbon bond forming reaction, an S-S bond, a thioether bond, a triazole bond, or a benzoxazole bond, but is not limited thereto (WO2013 / 100132, WO2012 / 026566, WO2012 / 033154, WO2012 / 074130, WO2015 / 030014, WO2018 / 052002, Comb Chem High Throughput Screen. 2010;13:75-87, Nature Chem. Bio. 2009, 5, 502, Nat Chem Biol. 2009, 5, 888-90, Bioconjugate Chem., 2007, 18, 469-476, ChemBioChem, 2009, 10, 787-798, Chemical Communications (Cambridge, United Kingdom) (2011), 47(36), 9946-9958).

[0062] Compounds obtained by further chemically modifying the above compounds are also included in the cyclic organic compounds and peptide compounds having a cyclic portion of the present invention. The peptide compound of the present invention may have a linear portion. The number of amide bonds or ester bonds (number and length of natural amino acids or amino acid analogs) is not particularly limited, but when the linear portion is present, the total number of amino acids in the cyclic portion and the linear portion is preferably 30 or less. In order to obtain high metabolic stability, the total number of amino acids is preferably 6 or more, or more preferably 9 or more. In addition to the above, the number of natural amino acids and amino acid analogs constituting the cyclic portion is more preferably 4 to 14, 4 to 13, 5 to 13, 5 to 12, 6 to 12, or 7 to 12, and further preferably 7 to 11 or 8 to 11 residues. In particular, 9 to 11 residues (10 or 11 residues) are preferred. The number of amino acids and amino acid analogs in the linear portion is preferably 0 to 8, 0 to 7, 0 to 6, 0 to 5, or 0 to 4, and more preferably 0 to 3. The total number of natural amino acids and amino acid analogues is preferably 6 to 30, 6 to 25, 6 to 20, 7 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 8 to 14, or 9 to 13 residues. In the present application, unless otherwise specified, amino acids include natural amino acids and amino acid analogues. In addition, the membrane permeability and metabolic stability in this specification mean that the peptide compound has a membrane permeability and metabolic stability to such an extent that it can be used as a pharmaceutical, at least when it is an oral agent, or when it targets an intracellular protein, a nucleic acid, an intracellular region of a membrane protein, or a transmembrane domain of a membrane protein.

[0063] The cyclic portion of the peptide compound of the present invention having a cyclic portion is not particularly limited as long as it forms a ring. For example, the cyclic portion is preferably a cyclic portion including a cyclization site formed by a functional group that can achieve both membrane permeability and metabolic stability. In cyclization reactions in which the reactive sites are structurally close, such as the construction of a five-membered ring from an indole or the construction of an oxirane ring from an epoxide, there is little possibility that intramolecular and intermolecular cyclization reactions will compete with each other (the intramolecular cyclization reaction mainly proceeds), and therefore it is expected that the advantage of the present invention when such cyclization reactions are used in the present invention will not be very large.

[0064] As used herein, the "number of amino acids" refers to the number of amino acid residues (amino acid units) that constitute a peptide, and means the number of amino acid units that are generated when the amide bonds, ester bonds, and cyclized bonds that link the amino acids are cleaved.

[0065] The term "tank reactor" in this invention refers to a reactor equipped with an agitator, in which the reaction fluid in the vessel is thoroughly mixed, and the concentration and temperature can be considered uniform at each point in the vessel. When a vessel reactor is operated batchwise, it is called a "batch reactor" and when it is operated continuously, it is called a "continuous tank reactor" (CSTR) (see Chemical Engineering Handbook, 6th Revised Edition, Maruzen Co., Ltd., 3·5 Fundamentals of Reactor Design). In order to maximize productivity, product characteristics, and general process efficiency, a single continuous tank reactor, multiple continuous tank reactors in parallel, and a series continuous tank reactor consisting of multiple continuous tank reactors connected in series are also used. The reaction raw materials fed into a CSTR are immediately mixed and the reaction proceeds, and the raw materials are discharged from the vessel at the same concentration and temperature as those in the vessel. As a non-limiting embodiment, the continuous tank reactor used in the present invention can be used not only for homogeneous liquid phase reactions but also for heterogeneous reactions such as liquid-liquid reactions, gas-liquid reactions, and gas-liquid-solid catalytic reactions. In addition, those skilled in the art can appropriately select an optimal reactor size depending on the type of the desired cyclization reaction and the production scale.

[0066] As a non-limiting embodiment, in the method for producing a cyclic organic compound using a CSTR of the present invention, the reaction liquid may be continuously reacted in a separate flow reactor or batch reactor until a steady state is reached in the reactor, or the CSTR may be carried out in a reaction vessel in which a steady state has been created in advance by a batch reactor high dilution condition method or back drip method. This makes it possible to minimize the possibility of the reaction raw materials being discharged outside the vessel without reacting, and to effectively utilize all of the substrate.

[0067] In a non-limiting embodiment, the present invention provides a method for producing a cyclic organic compound using a CSTR, in which the cyclic organic compound is a peptide compound having a cyclic portion constituted by natural amino acids and / or amino acid analogs. Although not limited thereto, it is preferable that the total number of natural amino acid and amino acid analog residues is 4 to 14, and the total number of natural amino acid and amino acid analog residues is 7 to 20. Furthermore, it is preferable that the total number of natural amino acid and amino acid analog residues is 5 to 12, 6 to 12, 7 to 12, 8 to 12, or 9 to 12, and it is preferable that the total number of natural amino acid and amino acid analog residues is 8 to 14, 9 to 13, 10 to 13, or 11 to 13. Although not particularly limited, the total number of amino acids contained in the peptide compound is preferably 25 or less, 20 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, and more preferably 13 or less (e.g., 12, 11, 10, or 9).

[0068] In a non-limiting embodiment, the cyclic organic compound of the present invention has the following characteristics (i) and (ii): (i) contains at least two N-substituted amino acids and at least one non-N-substituted amino acid; and (ii) The ClogP value is 6 or greater. In the above-mentioned embodiment, the cyclic organic compound of the present invention preferably contains at least two N-substituted amino acids (preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, particularly preferably 5, 6 or 7), and preferably contains at least one, two, three, or four non-N-substituted amino acids. Furthermore, the ClogP value is preferably 7 or more, 8 or more, or 9 or more. Examples of "N-substitution" include, but are not limited to, substitution of a hydrogen atom bonded to an N atom with a methyl group, an ethyl group, a propyl group, a butyl group, or a hexyl group. Examples of N-substituted amino acids include, preferably, amino acids in which the amino group contained in a natural amino acid is N-methylated. When a peptide contains a chemically modified amino acid analog, taking into consideration the shape of the molecule (main chain structure) when all chemical modifications are completed, compounds having a ClogP (a partition coefficient calculated by a computer, which can be calculated using, for example, Daylight Version 4.9 from Daylight Chemical Information Systems, Inc.) of 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more are preferred, and compounds having a ClogP of 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, or 15 or less are preferred.

[0069] The compound targeted by the cyclization reaction using the CSTR in the present invention is not particularly limited, but preferably has a molecular weight of 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, 550 or more, 600 or more, 650 or more, 700 or more, 750 or more, 800 or more, 850 or more, 900 or more, or 950 or more, and more preferably has a molecular weight of 1000 or more, 1100 or more, 1200 or more, 1300 or more, 1400 or more, 1500 or more, 1600 or more, 1700 or more, or 1800 or more. The upper limit of the molecular weight is not particularly limited, but preferably has a molecular weight of 6000 or less, a molecular weight of 5000 or less, a molecular weight of 4000 or less, a molecular weight of 3000 or less, a molecular weight of 2500 or less, or a molecular weight of 2000 or less.

[0070] With regard to metabolic stability, for example, when the stability in liver microsomes is measured according to the above-mentioned method, if the hepatic intrinsic clearance (CLh int (μL / min / mg protein)) value is 150 or less, preferably 100 or less, 90 or less, 80 or less, 70 or less, or 60 or less, and particularly preferably 50 or less, 40 or less, or 30 or less, it can be considered that the metabolic stability is sufficient for use as an oral pharmaceutical. For drugs metabolized by CYP3A4, the intrinsic hepatic clearance is preferably 78 or less to avoid small intestinal metabolism in humans (Non-Patent Document: M. Kato et al. The intestinal first-pass metabolism of substances of CYP3A4 and P-glycoprotein-quantitative analysis based on information from the literature. Drug Metab. Pharmacokinet. 2003, 18(6), 365-372.), and more preferably 35 or less (assuming FaFg=1 and 0% protein binding) to show a bioavailability of about 30% or more in humans.

[0071] Furthermore, the cyclic organic compound in the present invention may be a poorly water-soluble compound. For example, the term "poorly water-soluble compound" refers to a compound having a solubility in ion-exchanged water at 20° C. of preferably 10 mg / mL or less, 1 mg / mL or less, more preferably 0.1 mg / mL or less, 0.01 mg / mL or less, or 0.001 mg / mL or less.

[0072] In a non-limiting embodiment, the cyclization precursor of the present invention can have a reaction promoter for the cyclization reaction. In the present invention, the "reaction promoter" is a group that is introduced near the functional group to be bonded in order to selectively cause a reaction at a desired position, and activates the functional group for the bonding reaction. For example, in order to react a carbonyl group with an amino group, a reaction promoter can be introduced to either or both of the carbonyl group and the amino group. Examples of such reaction promoters include SH. Such reaction promoters can be removed during or after the bonding reaction.

[0073] In a non-limiting embodiment, the cyclic organic compound of the present invention is a compound represented by the following general formula (I): TIFF0007634933000027.tif59128 (wherein X represents CH or N; R1 represents a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-4 haloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, or a C1-6 alkylthio group; R2 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group, or R2 and R3 together form a ring; R3 represents a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or a C1-6 alkoxy group, or R2 and R3 together form a ring; R4 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group; R5, R6, and R7 each independently represent a C1-6 alkylene group, a C2-6 alkenylene group, a C2-6 alkynylene group, a C3-10 cycloalkylene group, a C3-10 cycloalkenylene group, a C6-12 arylene group, or -3-12-membered monocyclic heterocycle-, which may have a substituent; L1, L2, and L3 each independently represent a single bond, -CONR8-, -NR8CO-, -NR8-, -O-, -SO2NR8-, -NR8SO2-, -COO-, -NR8CONR8'-, -NR8COO-, or -OCONR8-; R8 and R8' each independently represent a hydrogen atom or a C1-6 alkyl group which may have a substituent.

[0074] The terms used only for compounds represented by general formula (I) above are defined in this paragraph as follows. The term "C1-6 alkyl group" refers to a linear or branched saturated monovalent C1-6 hydrocarbon group, and examples thereof include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, tert-butyl, 1-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, isopentyl, and neopentyl.

[0075] The term "C1-3 alkyl group" refers to a linear or branched saturated monovalent C1-3 hydrocarbon group, and examples thereof include methyl, ethyl, propyl, and isopropyl groups.

[0076] The term "C1-4 alkyl group" refers to a straight-chain or branched, saturated monovalent C1-4 hydrocarbon group, and examples include methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, and tert-butyl groups.

[0077] The term "C1-4 haloalkyl group" refers to a "C1-4 alkyl group" substituted with one or more halogen atoms. It is preferably a C1-2 alkyl group substituted with one or more fluorine or chlorine atoms, and examples thereof include a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, a pentafluoroethyl group, a tetrafluoroethyl group, a trifluoroethyl group, a difluoroethyl group, a fluoroethyl group, a trichloromethyl group, a dichloromethyl group, a chloromethyl group, a pentachloroethyl group, a tetrachloroethyl group, a trichloroethyl group, a dichloroethyl group, and a chloroethyl group.

[0078] The term "C2-6 alkenyl group" means a C2-6 hydrocarbon group having at least one double bond, and examples thereof include ethenyl (vinyl) group, 1-propenyl group, 2-propenyl (allyl) group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl (homoallyl) group, pentenyl group, and hexenyl group.

[0079] The term "C2-6 alkynyl group" means a C2-6 hydrocarbon group having at least one triple bond, and examples thereof include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, and hexynyl group.

[0080] The term "C1-6 alkoxy group" means an -O-C1-6 alkyl group, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, an isobutoxy group, a tert-butoxy group, a pentoxy group, a 3-methylbutoxy group, a 2-methylbutoxy group, a 1-methylbutoxy group, a 1-ethylpropoxy group, a hexyloxy group, a 4-methylpentoxy group, a 3-methylpentoxy group, a 2-methylpentoxy group, a 1-methylpentoxy group, a 3-ethylbutoxy group, and a 2-ethylbutoxy group.

[0081] The term "C1-4 alkoxy group" means an -O-C1-4 alkyl group, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, an isobutoxy group, and a tert-butoxy group.

[0082] The term "C1-3 alkoxy C1-3 alkoxy group" means an -O-C1-3 alkyl-O-C1-3 alkyl group, and examples thereof include a methoxymethoxy group, a methoxyethoxy group, and an ethoxyethoxy group.

[0083] The term "C1-6 alkylthio group" means an -S-C1-6 alkyl group, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a sec-butylthio group, an isobutylthio group, a tert-butylthio group, a pentylthio group, a 3-methylbutylthio group, a 2-methylbutylthio group, a 1-methylbutylthio group, a 1-ethylpropylthio group, a hexylthio group, a 4-methylpentylthio group, a 3-methylpentylthio group, a 2-methylpentylthio group, a 1-methylpentylthio group, a 3-ethylbutylthio group, and a 2-ethylbutylthio group.

[0084] "Halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine or chlorine.

[0085] The term "C3-10 cycloalkyl group" means a saturated C3-10 carbocyclic group, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.

[0086] The term "C3-10 cycloalkenyl group" means a C3-10 carbocyclic group having at least one double bond, and examples thereof include a cyclopentenyl group, a cyclohexenyl group, and a cycloheptenyl group.

[0087] The term "C6-12 aryl group" refers to a monocyclic or bicyclic aromatic carbon ring having 6 to 12 ring carbon atoms, such as a phenyl group, a naphthyl group, an indanyl group, an indenyl group, an isoindenyl group, etc. A phenyl group is preferred.

[0088] The term "3- to 12-membered monocyclic heterocycle" refers to a monocyclic aromatic or non-aromatic heterocycle having 3 to 12 atoms constituting the ring, and containing one or more (for example, 1 to 4) heteroatoms selected from N, O, or S in the atoms constituting the ring. The bonding position of the heteroatom is not particularly limited, and may be bonded at any desired position. Specific examples include pyrrolidine, oxazolidine, isoxazolidine, oxazoline, isoxazoline, thiazolidine, isothiazolidine, thiazoline, isothiazoline, imidazolidine, imidazoline, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan, imidazole, pyrazole, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dioxane, tetrahydrothiopyran, pyran, thiopyran, pyridine, pyrazine, pyrimidine, pyridazine, and the like.

[0089] The term "3-12-membered monocyclic alicyclic monospiro ring" refers to a group in which a monocyclic alicyclic hydrocarbon having 3 to 12 atoms constituting the ring is combined with one carbon atom on a C1-6 alkylene group to form a ring. The position of the spiro carbon on the C1-6 alkylene group is not particularly limited, and may be shared at any desired position. Specific examples include cyclopropanone, cyclobutanone, cyclopentanone, cyclohexanone, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc.

[0090] The term "3-12-membered monocyclic heterocyclic monospiro ring" refers to a monocyclic ring in which the number of atoms constituting the ring is 3 to 12, and the non-aromatic heterocycle containing one or more (for example, 1 to 4) heteroatoms selected from N, O, or S in the atoms constituting the ring is combined with one carbon atom on the C1-6 alkylene group to form a ring. The bonding position of the heteroatom is not particularly limited, and it may be bonded at a desired position. Furthermore, the position of the spiro carbon on the C1-6 alkylene group is not particularly limited, and it may be shared at a desired position. Specific examples include oxetane, tetrahydrofuran, tetrahydropyran, thietane, tetrahydrothiophene, tetrahydrothiopyran, azetidine, pyrrolidine, piperidine, oxetanone, tetrahydrofuranone, tetrahydropyranone, azetidinone, pyrrolidinone, piperidinone, dioxolane, dioxane, dithiolane, dithiane, and the like.

[0091] The term "C1-6 alkylene group" refers to a divalent group derived by further removing one arbitrary hydrogen atom from the above-defined "C1-6 alkyl group."

[0092] The term "C2-6 alkenylene group" means a divalent group derived by further removing one arbitrary hydrogen atom from the above-defined "C2-6 alkenyl group".

[0093] The term "C2-6 alkynylene group" means a divalent group derived by further removing one optional hydrogen atom from the above-defined "C2-6 alkynyl group".

[0094] The term "C3-10 cycloalkylene group" means a divalent group derived by further removing one optional hydrogen atom from the above-defined "C3-10 cycloalkyl group".

[0095] The term "C3-10 cycloalkenylene group" means a divalent group derived by further removing one optional hydrogen atom from the above-defined "C3-10 cycloalkenyl group".

[0096] The term "C6-12 arylene group" means a divalent group derived by further removing any one hydrogen atom from the above-defined "C6-12 aryl group".

[0097] The term "-3 to 12-membered monocyclic heterocycle-" means a divalent group derived by removing any two hydrogen atoms from the above-defined "3 to 12-membered monocyclic heterocycle."

[0098] When simply described as "ring", this refers to a concept that encompasses all of the above-mentioned "C3-10 cycloalkyl group", "C3-10 cycloalkenyl group", "C6-12 aryl group", and "5-12 membered monocyclic heterocycle".

[0099] In the formula, when R5, R6 and R7 are "optionally substituted C1-6 alkylene groups", the substituents are preferably groups selected from Group A below. Group A: C1-6 alkyl groups which may have a substituent (the substituent is a hydroxyl group or a dimethylamino group), halogen atoms, hydroxyl groups, cyano groups, -NR9R10 (R9 and R10 each independently represent a hydrogen atom, a C1-3 alkyl group, -C(=O)CH3, -C(=O)CF3, -C(=O)CH(NH2)CH(CH3)2 or a group represented by -C(=O)CH(NH2)(4-OH)Ph. ], a group represented by -C(=O)NR11R12 [R11 and R12 each independently represent a hydrogen atom, a C1-6 alkyl group which may have a substituent (the substituent is at least one selected from the group consisting of a hydroxyl group, a C1-6 alkoxy group, a C1-3 alkoxy C1-3 alkoxy group, a morpholinyl group, a piperidinyl group and a 4-methylpiperidinyl group), or a 3- to 12-membered monocyclic heterocycle in which R11 and R12 together form a ring], a group represented by -C(=O)OR13 [R13 represents a hydrogen atom or a C1-3 alkyl group. a 3- to 12-membered monocyclic alicyclic monospiro ring optionally having a substituent (the substituent may be a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 acyl group, a carboxyl group, a carbamoyl group, a C1-6 alkoxycarbonyl group, a C1-6 alkoxycarbonyloxy group, a mono-C1-6 alkylaminocarbonyl group, a mono-C1-6 alkyl It represents at least one selected from the group consisting of an aminocarbonyloxy group, a di-C1-6 alkylaminocarbonyl group, a di-C1-6 alkylaminocarbonyloxy group, an amino group, a mono-C1-6 alkylamino group, a di-C1-6 alkylamino group, a mono-C1-6 acylamino group, a C1-6 alkylsulfonylamino group, a C1-6 alkoxycarbonylamino group, an N'-mono-C1-6 alkylureido group, an N',N'-di-C1-6 alkylureido group, and the like.), or a 3-12-membered monocyclic heterocyclic monospiro ring optionally having a substituent (the substituents are a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an oxo group, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 acyl group, a carboxyl group, a carbamoyl group, a C1-6 alkoxycarbonyl group, a C1-6 alkoxycarbonyloxy group, a mono-C1-6 alkylaminocarbonyl group, a mono-C1-6 alkyl It represents at least one selected from the group consisting of an aminocarbonyloxy group, a di-C1-6 alkylaminocarbonyl group, a di-C1-6 alkylaminocarbonyloxy group, an amino group, a mono-C1-6 alkylamino group, a di-C1-6 alkylamino group, a mono-C1-6 acylamino group, a C1-6 alkylsulfonylamino group, a C1-6 alkoxycarbonylamino group, an N'-mono-C1-6 alkylureido group, an N',N'-di-C1-6 alkylureido group, and the like.

[0100] The number of the substituents may be two or more, and when two or more are present, they may be the same or different. The number of the substituents is preferably one or two.

[0101] In the formula, when R8 and R8' are "optionally substituted C1-6 alkyl groups", preferred examples of the substituent include groups selected from Group B below. Group B: a hydroxyl group, a morpholinyl group, a piperidinyl group, a 4-methylpiperidinyl group, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C6-12 aryl group, or a C1-6 alkoxy group.

[0102] The number of the substituents may be two or more, and when two or more are present, they may be the same or different. The number of the substituents is preferably one or two.

[0103] <Simulation> In one non-limiting embodiment, the cyclization reaction of the present invention can be carried out on an industrial scale using conditions obtained based on the results of preliminary testing of the cyclization reaction. In this embodiment, "simulation" refers to a test carried out before carrying out an industrial-scale reaction, i.e., a method for producing a cyclic organic compound, which includes a step of cyclizing a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor, for the purpose of obtaining optimal reaction conditions on an industrial scale. The simulation of the present invention includes a step of carrying out a preliminary test, and a step of calculating conditions for carrying out a cyclization reaction on an industrial scale based on the results of the preliminary test. The "simulation" in the present invention is not particularly limited as long as it is a test carried out for such a purpose, but also includes, for example, obtaining conditions that can be obtained based on already known literature values, etc. In this embodiment, "industrial scale" preferably refers to factory-level scale or plant scale, but is not particularly limited thereto, and includes a prototype scale (bench scale) carried out in a stage prior to the production of cyclic organic compounds at a plant scale, and a laboratory scale.

[0104] Thus, in one non-limiting aspect, the present invention also provides a method for obtaining conditions for industrial-scale cyclization of a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor.The present invention also provides, in one non-limiting aspect, a method for obtaining conditions for industrial-scale production of a cyclic organic compound in at least one continuous tank reactor. In the preliminary test of the present invention, data on the change in concentration over time at one or more temperatures is obtained for at least one selected from the group consisting of a cyclization precursor, a cyclic organic compound, one or more intermediates, and one or more by-products. The preliminary test of the present invention can be performed by the method described in the Examples as well as by a method well known to those skilled in the art.

[0105] In one non-limiting embodiment, the optimal conditions for cyclization on an industrial scale using a CSTR can be obtained by a method comprising the following steps (i) to (v). (i) in a preliminary test, acquiring data on the change in concentration over time at a plurality of temperatures for at least one selected from the group consisting of the cyclization precursor, the cyclic organic compound, one or more intermediates, and one or more by-products; (ii) Using the data of the concentration change obtained in step (i) and the reaction rate equation for the cyclization reaction (Equations (V) to (IX) or Equations (XI) to (XIII) in this specification), the reaction rate constant k at each temperature at which the preliminary test was performed is calculated. n A process of obtaining (iii) the temperature used in step (i), the reaction rate constant k determined in step (ii), n and the frequency factor A using the following formula (II): n and the activation energy E n A process of obtaining TIFF0007634933000028.tif14128(in the formula, k n : reaction rate constant, A n :frequency factor, E n : activation energy, R: gas constant, T: temperature. (iv) The frequency factor A obtained in step (iii) n and the activation energy E n Using the above equation (II) and the above reaction rate equation, the reaction rate constant k at the temperature for cyclization in the CSTR is calculated. n A step of determining (v) The reaction rate constant k obtained in step (iv) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000029.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[0106] In the above embodiment, the "plurality of temperatures" in step (i) is preferably, but not limited to, 2 or more, 3 or more, 4 or more, or 5 or more temperatures. In the above embodiment, the reaction rate constant (k) at the temperature for cyclization in the CSTR can be obtained by substituting the frequency factor value (A) and activation energy value (E) obtained in step (iii) into the above Arrhenius equation (III). By substituting the reaction rate constant (k) at the temperature for cyclization in the CSTR into the reaction rate equation for the cyclization reaction and setting the initial concentration conditions, it is possible to obtain the change in concentration of each component over time at the temperature for cyclization in the CSTR. In the present invention, the temperature for cyclization in the CSTR can be set arbitrarily, making it possible to optimize the temperature for cyclization on an industrial scale. Although not limited thereto, the optimal condition of "the temperature for cyclization in a CSTR" in the present invention is preferably the temperature condition of the cyclization reaction in a CSTR at which the target product concentration (cyclic organic compound concentration) is maximized. By carrying out the above steps (i) to (v), it is possible to simulate the progress of the cyclization reaction (changes in concentration of each component over time) at any temperature, which makes it possible to predict, for example, the reaction conversion rate (proportion of the cyclization precursor consumed by the reaction) and selectivity (proportion of the target product in the total products) in the reaction. Based on the results of such simulations, it is possible to determine the optimal conditions for the reaction on an industrial scale (for example, the supply concentration (initial concentration) of the cyclization precursor, the residence time in the reaction vessel, the reaction temperature, etc.). In a non-limiting embodiment, the temperature for cyclization in the CSTR in step (iv) can be appropriately selected by a person skilled in the art from the multiple temperatures at which data on concentration changes were obtained in step (i) or temperatures around the relevant temperature (±5° C., ±10° C.) without carrying out the above-mentioned step of optimizing the temperature on an industrial scale.

[0107] In one non-limiting embodiment, the optimal conditions for cyclization on an industrial scale using a CSTR can be obtained by a method comprising the following steps (i) to (iii): (i) in a preliminary test, acquiring data on the change in concentration over time at one temperature for at least one selected from the group consisting of a cyclization precursor, a cyclic organic compound, one or more intermediates, and one or more by-products; (ii) Using the concentration change data obtained in step (i) and the reaction rate equation for the cyclization reaction (the following formulas (V) to (IX) or formulas (XI) to (XIII)), a reaction rate constant k n A step of determining (iii) The reaction rate constant k obtained in step (ii) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000030.tif15128 (in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[0108] In the present invention, the term "intermediate" refers to a substance produced in the process of a chemical reaction from a reactant to a product. When the chemical reaction is a multi-step reaction, the intermediate refers to a substance produced in each elementary reaction.

[0109] In the present invention, the term "by-product" refers to a product resulting from a chemical reaction other than the main product (target product). Examples of the by-product in the present invention include, but are not limited to, a polymer (straight-chain product) of a cyclization precursor of a cyclic organic compound, a cyclization product of the polymer, and the like. Examples of the polymer include, but are not limited to, a dimer, a trimer, and the like.

[0110] In the present invention, "concentration change" refers to the change in concentration of the substance to be measured over time. In the present invention, it is necessary to obtain data on the concentration change of the cyclization precursor. In addition, it is preferable to obtain data on the concentration change of at least one selected from the group consisting of the cyclic organic compound, one or more intermediates, and one or more by-products. In particular, in the present invention, it is preferable to obtain data on the concentration change of the cyclization precursor and the cyclic organic compound, and it is particularly preferable to obtain data on the concentration change of the cyclization precursor, the cyclic organic compound, and the by-product. The data on the concentration change can be obtained by a method known to those skilled in the art, such as the method described in the Examples.

[0111] In a non-limiting embodiment, the elementary reaction of the cyclization reaction of the present invention can be represented by the following formula (IV). TIFF0007634933000031.tif30167Here, in the above (IV), when the reaction from the cyclization precursor (SM) and the activator (ACT) to give the intermediate (IM) is faster than the reaction from the intermediate (IM) to give the target product (TM) and a dimer (Dimer), as a non-limiting embodiment, the elementary reaction of the cyclization reaction of the present invention can also be represented by the following formula (X). TIFF0007634933000032.tif37163

[0112] When the elementary reaction of the cyclization reaction is represented by the above formula (IV), the reaction rate constants k1, k2, and k3 can be determined using any one of the following formulas (V) to (IX) or a combination of these. TIFF0007634933000033.tif74135 (wherein r represents reaction rate, TM represents cyclic organic compound, SM represents cyclization precursor, ACT represents activator, IM represents intermediate, Dimer represents dimer, and C represents concentration (M). The above k1, k2, and k3 correspond to the reaction rate constants in the following reaction in the above formula (IV). k1: Cyclization precursor (SM) + activator (ACT) → intermediate (IM) k2: intermediate (IM) → target product (TM) k3: Intermediate (IM) → Dimer

[0113] On the other hand, when the elementary reaction of the cyclization reaction is represented by the above formula (X), the reaction rate constants k1 and k2 can be determined using any one of the following formulas (XI) to (XIII) or a combination of these. TIFF0007634933000034.tif43131 (wherein r represents reaction rate, TM represents target product, SM represents cyclization precursor (= intermediate), ACT represents activator, Dimer represents dimer, and C represents concentration (M). The above k1 and k2 correspond to the reaction rate constants in the following reaction in the above formula (X). k1: Cyclization precursor (SM) (= intermediate (IM)) (+ activator (ACT)) → target product (TM) k2: Cyclization precursor (SM) (= intermediate (IM)) (+ activator (ACT)) → dimer The applicability of the simplified reaction formula such as the formula (X) above can be appropriately determined by a person skilled in the art depending on the accuracy of the required experimental data. In general, the applicability can be appropriately determined by a person skilled in the art depending on whether the concentration time change results of the cyclic organic compound obtained in advance can be reproduced using the formulas (XI) to (XIII) below. The residual sum of squares can be used as a criterion for this determination.

[0114] Furthermore, in the above formulas (IV) and (X), when the concentration of the activator (ACT) is high relative to the concentration of the cyclization precursor (SM), the activator concentration (C ACT ) may be omitted in some cases. The applicability of the above omission can be appropriately determined by a person skilled in the art depending on the accuracy of the required experimental data. In general, the concentration-time change result of the cyclic organic compound obtained in advance is used as the activator concentration (C ACT A person skilled in the art can appropriately judge whether the result can be reproduced using an equation in which the second digit is omitted. The residual sum of squares can be used as a criterion for this judgment.

[0115] Alternatively, in the present invention, the rate constant can be calculated, for example, as follows: When the logarithm of the Arrhenius equation (II) is taken, it can be expressed as the following equation (XIV). TIFF0007634933000035.tif14128 An Arrhenius plot is prepared by plotting the logarithm (lnk) of the reaction rate constant (k) in the reaction rate equations calculated from the concentration-time change result of the cyclic organic compound obtained by cyclizing the cyclization precursor and the reaction rate equations (V) to (IX) and (XI) to (XIII) on the vertical axis and the reciprocal of the temperature at that time (1 / T) on the horizontal axis, and then using a regression analysis method known to those skilled in the art, the frequency factor value (A) and the activation energy value (E) can be obtained (intercept: lnA, slope: -E / R). These calculations can be performed by a person skilled in the art using, for example, Microsoft Excel. On the other hand, in addition to the above-mentioned methods, the frequency factor value (A) and the activation energy value (E) can also be directly calculated using software. For example, gPROMS from PSE or Aspen Batch modeler from Aspen Technology can be used.

[0116] The frequency factor value (A) and activation energy value (E) obtained by the above-mentioned method are substituted into the above Arrhenius equation (II) to obtain the reaction rate constant (k) at any temperature. The reaction rate constant (k) for cyclization in a CSTR at any temperature is substituted into the reaction rate equations (V) to (IX) and (XI) to (XIII) to set the initial concentration conditions, and the concentration-time change of each component at any temperature can be obtained. By obtaining the concentration-time change, it is possible to optimize the temperature used on an industrial scale. Although not limited thereto, the optimal condition of the "temperature for cyclization in a CSTR" of the present invention is preferably the temperature condition of the cyclization reaction that maximizes the target product concentration.

[0117] In the present invention, 1) The reaction rate constant k obtained by the above method n or 2) The reaction rate constant k was calculated using the concentration change data obtained at one temperature and the reaction rate equations (V)-(IX), (XI)-(XIII) for the cyclization reaction. n , Using the following formula (XV), which is the mass balance equation for the CSTR, the optimal cyclization reaction condition values ​​on an industrial scale can be calculated. TIFF0007634933000036.tif15128(in the formula, r n : reaction rate ((V)~(IX), (XI)~(XIII)), τ: residence time (space time), C0: supply concentration, C: concentration.

[0118] For example, by setting the residence time, feed concentration, and temperature, the outlet concentration of each component can be calculated using equation (XV) and equations (V)-(IX) and (XI)-(XIII). The mass balance of reactant A when a simple reaction occurs in a CSTR can be expressed by the following equation, assuming a steady state, with the accumulation term set to zero (see Chapter 12 Reaction Engineering, 12.5 Continuously Stirred Tank Reactors (page 316) in Chemical Engineering (Revised 3rd Edition) - Explanations and Exercises - (Edited by the Society of Chemical Engineers, Yutaka Tada)). TIFF0007634933000037.tif10128 (where v O is the amount of inflow liquid into the reaction system per unit time, C A,O is the concentration of A in the influent (initial concentration), v is the amount of effluent from the reaction system per unit time, C A is the concentration of A in the effluent (outlet concentration), r A is the reaction rate of A (the change in the concentration of A per unit time), V is the reactor volume, and v O C A,O is the inflow of A per unit time, vC A is the outflow rate of A per unit time, (-r A )V is the reaction amount of A per unit time, and the zero on the right side represents the accumulation term.

[0119] If the reaction system is liquid, and the volume change due to the reaction can be ignored, the flow rate v = v O Therefore, τ = V (reactor volume) / v OBy rearranging equation (XVI) as (flow rate per unit time), we obtain the following equation, which is called the design equation for CSTR. TIFF0007634933000038.tif14128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration, X A : Represents the reaction conversion rate.) τ = V (reactor volume) / v O (Flow rate per unit time) indicates how many times the reactor volume is the processing volume per unit time, or the time required to process raw materials equivalent to the reactor volume, which is called spatial time. The reciprocal of spatial time is called space velocity (SV). In a non-limiting embodiment, the optimal cyclization reaction condition value on an industrial scale in the present invention is one or more reaction condition values ​​selected from the group consisting of a flow rate of a continuous tank reactor, a concentration of a cyclization precursor, and a concentration of a cyclic organic compound, but is not limited thereto.

[0120] In a non-limiting aspect, the present invention relates to a program for causing a computer to execute the following steps in order to obtain conditions for cyclizing a cyclization precursor of a cyclic organic compound in at least one continuous tank reactor (CSTR) on an industrial scale, and a recording medium having the program recorded thereon. (i) Using data on the change in concentration over time at multiple temperatures for at least one selected from the group consisting of a cyclization precursor, a cyclic organic compound, one or more intermediates, and one or more by-products obtained in the preliminary test, and a reaction rate equation for the cyclization reaction (Equations (V) to (IX) or (XI) to (XIII) in this specification), a reaction rate constant k at each temperature at which the preliminary test was performed is calculated. n The procedure for obtaining (ii) The temperature in step (i), the reaction rate constant k determined in step (i) n and the frequency factor A using the following formula (II): n and the activation energy E n The procedure for obtaining TIFF0007634933000039.tif14128(in the formula, kn : reaction rate constant, A n :frequency factor, E n : activation energy, R: gas constant, T: temperature. (iii) The frequency factor A obtained in step (ii) n and the activation energy E n Using the above formula (II) and the above reaction rate equation, the reaction rate constant k at the temperature for cyclization in the CSTR is n and (iv) The reaction rate constant k obtained in step (iii) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000040.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[0121] In a non-limiting embodiment, the program of the present invention is a program for causing a computer to execute the following steps (i) and (ii): (i) Using data on the change in concentration over time at one temperature for at least one selected from the group consisting of a cyclization precursor, a cyclic organic compound, one or more intermediates, and one or more by-products obtained in a preliminary test, and a reaction rate equation for the cyclization reaction (Equations (V) to (IX) or (XI) to (XIII) in this specification), a reaction rate constant k n and (ii) The reaction rate constant k obtained in step (i) n A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000041.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[0122] In a non-limiting embodiment, the program of the present invention is a program for executing the above-mentioned procedure using a computer equipped with a data input means, a data storage means, a data processing means, and a data output means. The program of the present invention can be prepared by a method known to those skilled in the art based on the elementary reaction formulas (IV) and (X) of the cyclization reaction, the calculation formulas (V) to (IX) and (XI) to (XIII) of the reaction rate constants, the Arrhenius formula (II), the material balance formula (III) of the CSTR, and the like described in this specification.

[0123] Furthermore, in a non-limiting aspect, the present invention provides a system for obtaining conditions for cyclizing a cyclization precursor of a cyclic organic compound on an industrial scale in at least one continuous tank reactor (CSTR), the system comprising the following means (i) to (iv): (i) Using data on the change in concentration over time at multiple temperatures for at least one selected from the group consisting of a cyclization precursor, a cyclic organic compound, one or more intermediates, and one or more by-products obtained in the preliminary test, and a reaction rate equation for the cyclization reaction (Equations (V) to (IX) or (XI) to (XIII) in this specification), a reaction rate constant k at each temperature at which the preliminary test was performed is calculated. n The means to seek (ii) The temperature in the means (i), the reaction rate constant k determined in the step (i) n and the frequency factor A using the following formula (II): n and the activation energy E n The means to seek TIFF0007634933000042.tif14128(in the formula, k n : reaction rate constant, A n :frequency factor, E n : activation energy, R: gas constant, T: temperature. (iii) The frequency factor A obtained in step (ii) n and the activation energy E n Using the above formula (II) and the above reaction rate equation, the reaction rate constant k at the temperature for cyclization in the CSTR is nand (iv) The reaction rate constant k obtained by means of (iii) n A means for acquiring the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000043.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[0124] In a non-limiting embodiment, the present invention provides a system for obtaining conditions for cyclizing a cyclization precursor of a cyclic organic compound on an industrial scale in at least one continuous tank reactor (CSTR), the system comprising the following means (i) and (ii): (i) Using data on the change in concentration over time at one temperature for at least one selected from the group consisting of a cyclization precursor, a cyclic organic compound, one or more intermediates, and one or more by-products obtained in a preliminary test, and a reaction rate equation for the cyclization reaction (Equations (V) to (IX) or (XI) to (XIII) in this specification), a reaction rate constant k n and (ii) The reaction rate constant k obtained by means (i) n A means for acquiring the conditions using the reaction rate equation and the following CSTR material balance equation (III): TIFF0007634933000044.tif15128(in the formula, r n : reaction rate, τ: residence time (space time), C0: supply concentration, C: concentration.

[0125] <Pharmaceutical Composition> The present invention provides peptide compounds produced by the methods of the present invention, and pharmaceutical compositions containing the compounds. The pharmaceutical composition of the present invention can be formulated by a known method by incorporating a pharma- ceutical acceptable carrier in addition to the peptide compound produced by the method of the present invention. For formulation, commonly used excipients, binders, lubricants, colorants, flavorings, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used, and the composition is formulated by a conventional method by mixing ingredients generally used as raw materials for pharmaceutical preparations. For example, to produce an oral preparation, the compound of the present invention or a pharmacologically acceptable salt thereof and an excipient are added, and further, if necessary, a binder, a disintegrant, a lubricant, a colorant, a flavoring agent, etc. are added, and then the compound is made into powders, fine granules, granules, tablets, coated tablets, capsules, etc. by a conventional method.

[0126] Examples of these components include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate, and purified water.

[0127] Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide.

[0128] Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer, and meglumine.

[0129] Disintegrants include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium.

[0130] Lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils, and the like.

[0131] Coloring agents are those permitted to be added to pharmaceuticals, and flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, cinnamon powder, etc.

[0132] Of course, these tablets and granules may be coated with sugar or other suitable coatings as necessary. When producing liquid preparations such as syrups and injection preparations, the compound of the present invention or a pharmacologically acceptable salt thereof is formulated in a conventional manner by adding a pH adjuster, a solubilizer, an isotonicity agent, and, if necessary, a solubilizing agent and a stabilizer.

[0133] For example, it can be used parenterally in the form of a sterile solution or suspension injection in water or other pharma- ceutically acceptable liquid. For example, it can be formulated by appropriately combining with a pharmacologically acceptable carrier or vehicle, specifically, sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., and mixing in a unit dose form required for generally accepted pharmaceutical practice. Specific examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetal diethyl amino acetate, polyvinyl pyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch, inorganic salts, etc. The amount of active ingredient in these formulations is such that an appropriate dose within the indicated range can be obtained. Sterile compositions for injection can be formulated according to standard pharmaceutical practice using vehicles such as distilled water for injection.

[0134] Examples of aqueous solutions for injection include isotonic solutions containing physiological saline, glucose or other auxiliary drugs, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may be used in combination with an appropriate solubilizing agent, such as alcohol, specifically ethanol, polyalcohols, such as propylene glycol and polyethylene glycol, and nonionic surfactants, such as Polysorbate 80 (registered trademark) and HCO-50.

[0135] The oily liquid may be sesame oil or soybean oil, and may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizing agent. Buffers such as phosphate buffer, sodium acetate buffer, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants may also be used. The prepared injection solution is usually filled into a suitable ampule.

[0136] The administration is preferably oral administration, but the administration method is not limited to oral administration. Specific examples of parenteral administration include injections, nasal administration, pulmonary administration, and transdermal administration. Examples of injections include intravenous injections, intramuscular injections, intraperitoneal injections, and subcutaneous injections, which can be administered systemically or locally.

[0137] In addition, the administration method can be appropriately selected depending on the age and symptoms of the patient. The dosage of the pharmaceutical composition containing the peptide compound produced by the method of the present invention can be selected, for example, from the range of 0.0001 mg to 1000 mg per kg of body weight per administration. Alternatively, the dosage can be selected, for example, from the range of 0.001 to 100000 mg / body per patient, but is not necessarily limited to these values. The dosage and administration method vary depending on the weight, age, symptoms, etc. of the patient, but can be appropriately selected by those skilled in the art.

[0138] All prior art documents cited in this specification are hereby incorporated by reference. EXAMPLES

[0139] The present invention is further illustrated by the following non-limiting examples. Example 1: 4-Amino-18,20-dimethyl-7-thia-3,5,11,15-tetraaza-tricyclo[15.3.1.1 2,6 Synthesis of ]docosa-1(20),2(22),3,5,17(21),18-hexaene-10,16-dione TIFF0007634933000045.tif65166

[0140] protocol: -Reaction rate parameter simulation To calculate the reaction rate parameters, data on the change in concentration of each compound depending on the temperature and reaction time were collected. The cyclization precursor 2 mesylate monohydrate (7 mM) (Solution A) prepared in a 1:1 solution of N,N-dimethylacetamide (DMA) and acetonitrile was reacted with a solution containing O-(benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU) and diisopropylethylamine (DIPEA) at concentrations of 10 mM and 32 mM (Solution B) prepared in a 1:1 solution of DMA and acetonitrile at 0°C, 24°C, and -9°C. The reaction was quenched with a methylamine solution. The reaction was performed using a plug flow reactor, and the reaction time was adjusted by adjusting the flow rates of solutions A and B, and the data in Table 1 was obtained. The compound concentration was calculated by converting the initial concentration of the cyclization precursor (3.5 mM in the reaction mixture in the above experiment) into HPLC Area %, assuming that the molar absorption coefficients of the cyclization precursor and the target compound are the same.

[0141] [Table 1]

[0142] From the data obtained, the mechanism of this cyclization reaction was considered as follows. The reaction from the cyclization precursor and HBTU to give the activated intermediate was relatively fast, and the reaction from the activated intermediate to give the target product and a dimer was assumed to be the rate-determining step (James C. Collins and Keith James, Med. Chem. Commun., 2012(3), 12, 1489-1495). The concentration of the activator was omitted because it did not have a significant effect on the reaction rate. However, some of the activated intermediate remained, and was detected as by-product 1 when the reaction was stopped with methylamine. By-product 1 was added to the raw material and used as the raw material concentration to calculate each parameter for subsequent experiments. TIFF0007634933000047.tif36166By-product 1: N-methylamide, LCMS: ESI (m / z): calcd: 417.21, found: 417[M+H]+ . TIFF0007634933000048.tif104128

[0143] Using the experimentally obtained concentration change over time data and temperature data (Table 1), the reaction rate constants k1 and k2 for each elementary reaction at each temperature (0°C, 24°C, -9°C) were calculated. The following equations were used to calculate the reaction rate constants k1 and k2. TIFF0007634933000049.tif18128SM: Cyclization precursor, TM: Target, Dimer: Dimer (linear), c-Dimer: Dimer (cyclic) C: concentration (M), kn: reaction rate constant

[0144] The frequency factor (A) and activation energy (E) of each elementary reaction were calculated by Arrhenius plot using the reaction rate constants k1 and k2 at each temperature and the temperature. Microsoft Excel was used for the calculation. As a result, the data shown in Table 2 was obtained. [Table 2]

[0145] The obtained frequency factor (A) and activation energy (E) of each elementary reaction were substituted into the Arrhenius equation below, and the reaction rate constants k1 and k2 were calculated using the reaction rate equation when the temperature for the cyclization reaction in the CSTR was set to 0°C (Table 3). TIFF0007634933000051.tif23128 [Table 3]

[0146] Next, the reaction conversion rate, selectivity, and residence time when the cyclization precursor concentration was 0.05 mol / l and the reaction temperature was 0°C were calculated using the reaction rate constants k1 and k2 in Table 3 and the following material balance equation and reaction rate equation (Table 4). TIFF0007634933000053.tif36128

[0147] [Table 4] In Cases 1 to 3 in Table 4, the residence time was calculated to obtain results with high reaction conversion and selectivity. In this example, Case 2 (Run 4) and Case 3 (Run 5) were carried out. *Calculation formula Reaction conversion rate: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Selectivity: target concentration / (target concentration + dimer (linear + cyclic) concentration) TIFF0007634933000055.tif27128

[0148] Run 1: Batch high-dilution Following the patent literature (patent number: JP5235859) and non-patent literature (A.Suda et al., Bioorganic & Medicinal Chemistry Letters 22 (2012) 1136-1141), the cyclization precursor 2 mesylate monohydrate (39.9 mg, content 86%, 0.056 mmol) was dissolved in N,N-dimethylformamide (DMF) (16.3 mL) and tetrahydrofuran (16.3 mL), and N-hydroxybenzotriazole (HOBt) monohydrate (50.2 mg, 5.9 equiv.), DIPEA (0.23 mL, 23.6 equiv.), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (125.7 mg, 11.7 equiv.) were added to this mixture in sequence. The resulting mixture was reacted at room temperature for 13 hours. The concentration of the target compound in the reaction solution was quantified, and the yield was calculated to be equivalent to 18.5 mg (86% yield). (From A. Suda et al., Bioorganic & Medicinal Chemistry Letters 22 (2012) 1136-1141, the two-step isolated yield was 21%)

[0149] Run 2: Batch high-dilution Following Run 1, the cyclization precursor (40.5 mg, content 86%, 0.057 mmol) was dissolved in DMF (16.3 mL) and acetonitrile (16.3 mL), and HBTU (30.5 mg, 1.4 equiv.) and DIPEA (0.046 mL, 4.6 equiv.) were added to this mixture in sequence. The resulting mixture was reacted at room temperature for 1 hour. The solution concentration of the target product in the reaction solution was quantified, and the yield was calculated to be equivalent to 18.4 mg (84% yield).

[0150] ·Run 3: Batch pseudo high-dilution A solution of the cyclization precursor compound (1.0036 g, content 86%, 1.41 mmol) and DIPEA (1.14 mL, 4.6 equiv.) in DMA (10 mL) was added dropwise to a solution of HBTU (0.7441 g, 1.4 equiv.) and acetonitrile (15 mL) over 300 minutes at 0° C. The solution concentration of the target product was quantified after about 60 minutes, and the yield was calculated to be equivalent to 485.2 mg (89% yield).

[0151] Run 4: CSTR The cyclization precursor (2.3004 g, content 86%, 3.22 mmol) and DIPEA (2.6 mL, 4.6 eqiv.) were dissolved in DMA (31.9 mL). The substrate concentration was 0.09 mmol / mL. Meanwhile, HBTU (1.7042 g, 1.4 equiv.) was dissolved in acetonitrile (34.5 mL). The reagent concentration was 0.13 mmol / mL. These solutions were added to 16.5 mL of DMA / acetonitrile (1 / 1) solution at 0°C at an input rate of 0.05 mL / min, and the reaction solution was simultaneously extracted at an output rate of 0.1 mL / min. The reaction solution was collected at 165 min (θ*), 330 min (2θ), 495 min (3θ), and 660 min (4θ) after the start of the run, and quenched with dimethylamine solution for sampling. The output solutions were all added together, and the concentration was quantified to calculate the yield, which was equivalent to 987.2 mg (87% yield). *θ=elapsed time / average residence time

[0152] Run 5: CSTR The cyclization precursor (2.3001 g, content 86%, 3.22 mmol) and DIPEA (2.6 mL, 4.6 eqiv.) were dissolved in DMA (31.9 mL). The substrate concentration was 0.09 mmol / mL. Meanwhile, HBTU (1.7083 g, 1.4 equiv.) was dissolved in acetonitrile (34.5 mL). The reagent concentration was 0.13 mmol / mL. These solutions were added to 33 mL of DMA / acetonitrile (1 / 1) solution at 0°C at an input rate of 0.05 mL / min, and the reaction solution was simultaneously extracted at an output rate of 0.1 mL / min. The reaction solution was collected at 165 min (0.5θ), 330 min (θ), and 495 min (1.5θ) after the start of the run, quenched with dimethylamine solution, and sampled.

[0153] Analysis conditions: HPLC, LCMS conditions: Column: Ascentis C18, 4.6 mm ID × 50 mmL, 2.7 μm, Supelco Mobile phase: A) Water:TFA = 2000:1, B) Acetonitrile:TFA = 2000:1 Column temperature: 30 °C Flow rate: 1.0 mL / min Gradient (B%): 0~3.5 min (5→23), 3.5~8.0 min (23→61), 8.0~9.5 min (61→100), 9.5~9.6 min (100), 9.6~9.7 min (100→5), 9.7~12.0 min (5). MS detection mode: ESI (LC / MS): m / z

[0154] Objective: LCMS: ESI(m / z):386[M+H] + , Flow time: 3.9 minutes 1 HNMR (DMSO-d6): Consistent with the patent literature.

[0155] Cyclization prosome: Content: 86% ( 1 HMNMR: DMSO-d6, internal standard: 1,3,5-Torotron キシベンゼンのデータより) LCMS: ESI(m / z): calcd; 404.18, found; 404 [M+H] + , Flow time: 3.6 minutes 1 H-NMR (DMSO-D6) δ: 8.14 (1H, t, J = 5.7 Hz), 7.91 (1H, s), 7.76-7.66 (1H, m), 7.73 (2H, br s), 7.34 (1H, s), 6.99 (1H, s), 3.41 (2H, t, J = 6.8 Hz), 3.16-3.12 (2H, m), 2.83-2.77 (2H, m), 2.60 (2H, t, J = 6.8 Hz), 2.57 (3H, s), 2.40 (6H, s), 2.38 (3H, s), 1.73-1.67 (2H, m). TIFF0007634933000056.tif93128

[0156] ダイマー(Cyclized body) LCMS: ESI (m / z): calcd: 771.32, found: 771[M+H] + , Flow time: 4.7 points TIFF0007634933000057.tif62128

[0157] ダイマー(straight lock body) LCMS: ESI (m / z): calcd: 789.33, found:789[M+H] + , Flow time: 4.6 minutes TIFF0007634933000058.tif101128

[0158] result:

Table 5

[0159] [Table 6]

[0160] [Table 7]

[0161] [Table 8] In Run 3, it was confirmed that the simulation and experimental results were in close agreement.

[0162] [Table 9] In Runs 4 and 5, it was confirmed that the simulation and experimental results were in close agreement.

[0163] Calculation formula Reaction Conversion Rate Simulation: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Experimental results: (Initial Area% of cyclized precursor - Area% of cyclized precursor) / Initial Area% of cyclized precursor Selectivity Simulation: target concentration / (target concentration + dimer (linear + cyclic) concentration) Experimental results: Target Area% / (Target Area% + Dimer (straight chain + cyclic) Area%)

[0164] In Runs 4 and 5, the Area% of the dimer due to side reactions was lower than in the high-dilution of Runs 1-2, and the Area% of the target cyclized product was improved. In other words, high selectivity was obtained by using a CSTR, and selectivity equivalent to or higher than that of the batch pseudo high-dilution of Run 3 was achieved (Table 5). Furthermore, the use of a CSTR allows production in smaller facilities than batch reactions. Figures 1 and 2 compare the size of the equipment for a CSTR reaction, assuming a product of about 2 kg, and a pseudo high-dilution batch reaction using back-drop of the raw materials. In both cases, it takes one operating day to obtain 2 kg of the target product, but the size of the equipment, particularly the reaction vessel, can be reduced by about 20 times. Furthermore, the use of a CSTR makes it possible to carry out operations continuously, which is expected to improve the efficiency of operations, including subsequent processing.

[0165] Example 2: Synthesis of Cyclosporin A TIFF0007634933000064.tif50170

[0166] protocol: Synthesis of cyclization precursors Following the method described in non-patent literature (Bernard Riss, Arnaud Grandeury, Thorsten Gut, Manuela Seeger-Weibel, Christian Zuercher, Jinjing Li, and Fabrice Gallou. Org. Process Res. Dev. 2014, 18, 1763-1770.), 165.2 g of the ring-opened product 1 was synthesized from 198.3 g of cyclosporine A. TIFF0007634933000065.tif112170 The aforementioned ring-opening product 1 (10.0 g) was dissolved in methanol (300 mL), and the resulting solution was reacted with a methanol solution of sodium methoxide (28% w / w, 5.7 g). After stirring at room temperature for 14 hours, 1M aqueous sodium hydroxide solution (37 mL) was added and reacted at room temperature for another 4 hours. Next, the mixture was neutralized with 1M potassium hydrogen sulfate solution under ice cooling, and the pH of the reaction solution was added to about 7. The precipitated solid was filtered, and the filtrate was extracted twice with ethyl acetate (200 mL). The organic layer was further washed with water and concentrated with an evaporator to obtain the cyclization precursor 2 (8.1 g) as a white powder.

[0167] -Reaction rate parameter simulation To calculate the reaction rate parameters, the concentration change data of each compound with respect to temperature and reaction time were collected at 5°C, 21°C, and -9°C. The concentration data at 5°C and 21°C were collected using a plug flow reactor. That is, a DMF solution (solution A) of the cyclization precursor (3 mM) and DIPEA (16 mM) was reacted with a DMF solution (solution B) of 8 mM O-(7-azabenzotriazol-1-ly)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) at 5°C and 21°C. The reaction was quenched with a methylamine solution. The reaction time was adjusted by the flow rate of solutions A and B. Meanwhile, the data at -9°C was collected using a batch reactor. Specifically, the cyclization precursor (35.0 mg, content 74%, 0.02 mmol) was dissolved in DMF (14.3 mL), DIPEA (20 mL, 5.4 equiv.) and HATU (22.3 mg, 2.8 equiv.) were added, and the reaction solution was sampled over time. The cyclization precursor was detected as a methylamide. The compound concentrations shown in Table 10 were calculated from HPLC data based on the HPLC assay values ​​of the cyclized precursor and cyclosporine A. The cyclized precursor was detected as a cyclized precursor methylamide, and the absorption coefficients of these were assumed to be equal. The absorption coefficients of cyclosporine A and the dimer (cyclized product) were also assumed to be equal.

[0168] [Table 10]

[0169] From the data obtained, the mechanism of this cyclization reaction was considered as follows: The activating agent was omitted because it had no effect on the reaction rate. TIFF0007634933000067.tif26159

[0170] Using the experimentally obtained concentration change over time data and temperature data (Table 10), the reaction rate constants k1, k2, and k3 for each elementary reaction at each temperature (-9°C, 5°C, and 21°C) were calculated. The following formula was used to calculate the reaction rate constants k1, k2, and k3. TIFF0007634933000068.tif57162TM: Cyclosporine A, SM: Cyclization precursor, SM-HATU: Active intermediate, Dimer: Dimer C: concentration (M), k: reaction rate constant

[0171] The frequency factor (A) and activation energy (E) of each elementary reaction were calculated by Arrhenius plot using the reaction rate constants k1, k2, and k3 at each temperature and the temperature. Microsoft Excel was used for the calculation. As a result, the data shown in Table 11 was obtained. [Table 11]

[0172] The obtained frequency factor (A) and activation energy (E) of each elementary reaction were substituted into the Arrhenius equation below, and the reaction rate constants k1, k2, and k3 were calculated using the reaction rate equation when the temperature for the cyclization reaction in the CSTR was set to 25°C (Table 12). TIFF0007634933000070.tif26128 [Table 12]

[0173] Next, the reaction conversion rate, selectivity, and residence time when the cyclization precursor concentration was 0.04 mol / l and the reaction temperature was 25°C were calculated using the reaction rate constants k1, k2, and k3 in Table 12 and the following material balance equation and reaction rate equation (Table 13). TIFF0007634933000072.tif74162

[0174] [Table 13] In Cases 1 and 2 in Table 13, the residence time was calculated to obtain results with high reaction conversion and selectivity. In this example, Case 2 (Run 3) was carried out.

[0175] *Calculation formula Reaction conversion rate: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Selectivity: Cyclosporine A concentration / (Cyclosporine A + dimer (cyclized form) concentration) TIFF0007634933000074.tif26159

[0176] Run 1: Batch high-dilution HATU (18.9 mg, 2.7 equiv.) was added to a solution of the precursor compound (30.0 mg, content 74%, 0.02 mmol) and DIPEA (17 μL, 5.4 equiv.) in DMF (12.3 mL) and the mixture was allowed to react for 1 hour. The concentration of cyclosporine A in the reaction solution was quantified, and the yield was calculated to be 15.8 mg (72% yield).

[0177] ·Run 2: Batch pseudo high-dilution A solution of the precursor compound (500.5 mg, content 74%, 0.30 mmol) and DIPEA (0.3 mL, 5.7 equiv.) in DMF (4.7 mL) was added dropwise to a solution of HATU (311.9 mg, 2.7 equiv.) and DMF (10 mL) over 180 minutes. The concentration of cyclosporine A in the reaction solution after about 60 minutes was quantified, and the yield was calculated to be 348.3 mg (95% yield).

[0178] Run 3: CSTR The cyclization precursor (1.9009 g, content 74%, 1.15 mmol) and DIPEA (1.1 mL, 5.5 eqiv.) were dissolved in DMF (27.4 mL,). The substrate concentration was 0.04 mmol / mL. Meanwhile, HATU (1.1904 g, 2.7 equiv.) was dissolved in DMF (28.5 mL,). The reagent concentration was 0.11 mmol / mL. These solutions were added to 12.8 mL of DMF solvent at 25 °C with an input rate of 0.04 mL / min, and the reaction solution was simultaneously extracted at an output rate of 0.08 mL / min. After the start of the operation, the reaction solution was collected at 160 min (1θ), 320 min (2θ), 480 min (3θ), and 640 min (4θ), and quenched with dimethylamine solution and sampled. After 640 minutes, the output solution and the solution in the reaction vessel were all added together, and the concentration was quantified to calculate the yield, which was equivalent to 1.14 g (98% yield). In Run 3, improvement in the purity of the target product was observed after the working time 2θ compared to the pseudo high-dilution method in Run 2. Under the conditions of Run 3, production of 2 kg per day can be achieved in a 7 L reaction vessel (same as in Example 1, FIG. 1).

[0179] Analysis conditions: Column: BIOshell C18, 2.1 mm ID × 150 mmL, 2.6 μm Column temperature: 60℃ Flow rate: 0.5 mL / min Gradient (B%): 0~40.0 min (30→100), 40.0~40.6 min (100), 40.6~40.7 min (100→30), 40.7~45.0 min (30).

[0180] Cyclization precursor: LCMS(m / z) [M+H] + : calcd 1220.8598 found: 1220.8674, flow time: 11.3 min. The reaction was tracked by detecting the methylamide form after quenching. Flow time: 11.7 min.

[0181] Assay: 74% based on qNMR and HPLC assays a. Standard qNMR: Measurement conditions: DMSO-d6, 100 o C, Pulse angle 90 o , Digital resolution 0.15Hz, Relaxation time: 60 seconds, No spin, Accumulation count 64 times 1HNMR peak assignment (see Figure 3): (Me of two Ala, total 6H), (iPrCH of NH-Val, 1H) Identified by COSY and TOCSY. Internal standard: sodium 3-(trimethylsilyl)-1-propane-1,1,2,2,3,3-d6-sulfonate Content: 81.2%

[0182] b. The raw material used in this example was used as a standard in HPLC assay, and the result was 91.7%. TIFF0007634933000075.tif113153

[0183] Cyclosporine A: LCMS: m / z[M+H] + : calcd 1202.8492, found: 1202.8589, spill time: 21.5 minutes 1 HNMR (CDCl3): The following coincided with the literature information: Kessler et al., Helvetica Chimica Acta, 1985, 68, 661. TIFF0007634933000076.tif119159

[0184] Dimer (cyclization): m / z[M+2H] 2+ : calcd: 1203.3509, found: 1203.3517, flow time: 29.1 minutes TIFF0007634933000077.tif155170

[0185] β-elimination impurity: LCMS: m / z[M+H] +: calc. 1202.8492, found: 1202.8587, Outflow time: 12.6 minutes TIFF0007634933000078.tif124159

[0186] β-elimination impurity (cyclized product): LCMS (m / z) [M+H] + : calcd. 1184.8386, found:1184.8448, flow time:22.0 minutes TIFF0007634933000079.tif123164

[0187] result: [Table 14] *Calculations were based on 100% for cyclized precursor, cyclosporine A, dimer (cyclized product), and β-elimination impurity (cyclized product). The same applies to Runs 2 and 3.

[0188] [Table 15]

[0189] [Table 16]

[0190] [Table 17] In Run 2, it was confirmed that the simulation and experimental results were in close agreement.

[0191] [Table 18] In Run 3, it was confirmed that the simulation and experimental results were in close agreement.

[0192] *Calculation formula Reaction Conversion Rate Simulation: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Experimental results: (Initial Area% of cyclized precursor - Area% of cyclized precursor) / Initial Area% of cyclized precursor Selectivity Simulation: Cyclosporine A concentration / (Cyclosporine A + dimer (cyclized form) concentration) Experimental results: Cyclosporine A Area% / (Cyclosporine A Area% + Dimer (cyclized form) Area%)

[0193] In Run 3 (Table 16), the Area% of the dimer due to side reactions was lower than in the high-dilution in Run 1 (Table 14), and the Area% of the target cyclized product was improved. In other words, high selectivity was obtained by using a CSTR, and selectivity equivalent to or higher than that of the batch pseudo high-dilution in Run 2 (Table 15) was achieved.

[0194] Example 3: Production of Cyclosporin A TIFF0007634933000085.tif50170 Scaling up was carried out with reference to the data obtained in Example 2. As described herein, a pseudo steady state was prepared in advance by batch pseudo high-dilution, and the reaction was carried out using a CSTR.

[0195] Batch pseudo high-dilution When the precursor compound (20.6354 g, content 59%, 10 mmol) was dissolved in DMF (155 mL), insoluble matter was observed, so it was filtered off, and after confirming that the solid did not contain the precursor compound, DIPEA (10 mL, 5.7 equiv.) was added to the filtrate to prepare the cyclization precursor solution. The cyclization precursor solution was added dropwise over 195 minutes to a solution of HATU (10.2745 g, 2.7 equiv.) and DMF (330 mL) previously prepared in a 1 L reaction kettle, and the obtained solution was stored at room temperature for 1 day.

[0196] ·CSTR The cyclization precursor (61.902 g, content 59%, 30 mmol) was mixed with DMF (713 mL), and after removing the insoluble matter, DIPEA (30 mL, 5.7 equiv.) was added to prepare the reaction substrate solution. The substrate concentration was 0.04 mmol / mL. Meanwhile, HATU (36.145 g) was dissolved in DMF (866 mL) to prepare the reaction reagent solution. The reagent concentration was 0.11 mmol / mL. The reaction substrate solution and reaction reagent solution were added to the preparation solution prepared by batch pseudo high-dilution at an input rate of 1.5 mL / min, respectively, and the reaction solution was output at 3.0 mL / min at the same time. Ethyl acetate was mixed into the output line at 6.0 mL / min in a T-tube, followed by water at 3.0 mL / min in a T-mixer. The mixed solution was checked for interfacial separation in a cylinder, and the upper layer (organic phase) and lower layer (aqueous phase) were output at 5.5-6.5 mL / min, respectively. The output flow rate was adjusted so that the liquid separation interface was constant. The upper layer (organic phase) was temporarily stored in a surge tank, and when the volume reached about 400 mL, it was concentrated in an evaporator. The external temperature during concentration was 40°C, and concentration was continued while adding organic layer with a cycle time of 15 to 20 minutes. The entire input to the kettle was added over 550 minutes. The post-treatment (separation and concentration of the reaction solution as described above) was carried out in parallel with the reaction, and an additional work of 160 minutes was required at the end. Finally, 439.86 g of concentrated residue was obtained. The assay result indicated that the obtained cyclosporine was equivalent to 44.2 g (92% yield). Cyclization precursor: The content was determined to be 59% by qNMR and HPLC assay.

[0197] result: [Table 19] * Calculations were based on 100% for cyclized precursor, cyclosporine A, dimer (cyclized product), and β-elimination impurity (cyclized product).

[0198] Comparison of simulation and experimental results [Table 20] The results of the batch pseudo high-dilution were almost the same as those in Example 2.

[0199] [Table 21] It was confirmed that the results of the simulation and the experiment were almost identical in the CSTR. The homology was also higher than in Example 2.

[0200] *Calculation formula Reaction Conversion Rate Simulation: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Experimental results: (Initial Area% of cyclized precursor - Area% of cyclized precursor) / Initial Area% of cyclized precursor Selectivity Simulation: Cyclosporine A concentration / (Cyclosporine A + dimer (cyclized form) concentration) Experimental results: Cyclosporine A Area% / (Cyclosporine A Area% + Dimer (cyclized form) Area%)

[0201] In this study, by continuously carrying out the reaction and work-up in a 1 L vessel, it was possible to produce 44.2 g of cyclosporine A in 710 minutes (550 minutes for the reaction and 160 minutes for the remaining work-up).

[0202] [Example 4] Synthesis of Desmopressin TIFF0007634933000089.tif71170 Protocol: -Reaction rate parameter simulation To calculate the reaction rate parameters, data on the change in concentration of each compound depending on the temperature and reaction time was collected. A cyclization precursor (8.92 mM) (Solution A) prepared in a solution of N,N-dimethylformamide (DMF) and acetic acid at a ratio of 4:1 was reacted with a 32 mM solution of iodine (Solution B) prepared in a solution of DMF and acetic acid at a ratio of 4:1 at 0°C, 23°C, and 40°C. The reaction was quenched with a 1% sodium dithionite solution. The reaction was carried out using a plug flow reactor, and the reaction time was adjusted by adjusting the flow rate of solutions A and B, to obtain the data in Table 22. The compound concentration was calculated by converting the initial concentration of the cyclization precursor (4.46 mM as the reaction mixture in the above experiment) into HPLC area %, assuming that the molar absorption coefficients of the cyclization precursor and the target compound are the same. The concentration was calculated assuming that the absorbance of the dimer was twice that of the cyclization precursor.

[0203] [Table 22]

[0204] From the obtained data, the cyclization reaction mechanism was considered as follows. Since the reaction from the cyclization precursor to the iodide intermediate is considered to be fast, the reaction from the iodide intermediate to the target product and dimer (multiple compounds) is considered to be rate-determining. Although the concentration of the iodide intermediate could not be measured, it is considered possible that the iodide intermediate returns to the cyclization precursor by quenching before analysis, and considering the above-mentioned reaction rate difference, it is considered that there is no problem even if the iodine intermediate concentration and the cyclization precursor concentration obtained by analysis are equal. Therefore, each parameter was calculated using the elementary reaction shown in the following formula. In addition, iodine was used in excess of the cyclization precursor, and since no significant effect was observed on the reaction rate, it was omitted in the reaction rate simulation. TIFF0007634933000091.tif34138

[0205] Using the experimentally obtained concentration change over time data and temperature data (Table 22), the frequency factor (A) and activation energy (E) of each elementary reaction were calculated using the following formula. TIFF0007634933000092.tif31170SM: cyclization precursor, TM: target product, Dimer: sum of linear and cyclic dimers C: concentration (M), kn: reaction rate constant, An: frequency factor, En: activation energy, T: temperature, R: gas constant In addition, the calculation was performed using Aspen custom modeler from Aspen Technology, Inc. As a result, the data shown in Table 23 was obtained.

[0206] [Table 23]

[0207] From the frequency factor (A) and activation energy (E) of each elementary reaction obtained, the reaction rate constants k1 and k2 were calculated when the temperature for the cyclization reaction in the CSTR was set to 25°C (Table 24).

[0208] [Table 24]

[0209] Next, the reaction conversion rate, selectivity, and residence time when the cyclization precursor concentration was 0.04 mol / l and the reaction temperature was 25°C were calculated using the reaction rate constants k1 and k2 in Table 24 and the following material balance equation and reaction rate equation (Table 25). TIFF0007634933000095.tif32170

[0210] [Table 25] In Cases 1 to 3 in Table 4, the residence time that would give results with high reaction conversion and selectivity was calculated. In this example, Case 2 (Run 3) was carried out.

[0211] *Calculation formula Reaction conversion rate: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Selectivity: target concentration / (target concentration + dimer (linear + cyclic) concentration) TIFF0007634933000097.tif32170

[0212] Run 1: Batch high-dilution Following the method described in the non-patent literature (Dominic Ormerod, Bart Noten, Matthieu Dorbec, Lars Andersson, Anita Buekenhoudt, and Ludwig Goetelen. Org. Process Res. Dev. 2015, 19, 841-848.), the cyclization precursor (200.8 mg, content 86.2%, 0.143 mmol) was dissolved in N,N-dimethylformamide (DMF) (4.4 mL) and acetic acid (1.6 mL), and a DMF solution (solution volume 2.5 mL) of iodine (4.4 equiv.) was added to this mixture at room temperature. The resulting mixture was reacted at room temperature for 5 minutes. After the reaction solution was quenched with an aqueous sodium dithionite solution, the solution concentration of the target product was quantified, and the yield was calculated to be equivalent to 121.6 mg (80% yield).

[0213] ·Run 2: Batch pseudo high-dilution To a solution of iodine (0.3212 g, 3.5 equiv.), DMF (10 mL), and acetic acid (2.5 mL), a solution of the cyclization precursor compound (502.0 mg, content 86.2%, 0.357 mmol), DMF (6 mL), and acetic acid (1.5 mL) was added dropwise over 60 minutes at 22° C. The solution concentration of the target product was quantified approximately 30 minutes after the dropwise addition, and the yield was calculated to be equivalent to 284.4 mg (75% yield).

[0214] Run 3: CSTR The cyclization precursor (1.2040 g, content 86.2%, 0.855 mmol) was dissolved in DMF (19.2 mL) and acetic acid (4.8 mL). The substrate concentration was 0.04 mmol / mL. Meanwhile, iodine (0.8497 g, 3.348 mmol) was dissolved in DMF (20.0 mL) and acetic acid (5.0 mL). The reagent concentration was 0.13 mmol / mL. These solutions were added to a DMF (9.6 mL) / acetic acid (2.4 mL) solution at 23°C at an input rate of 0.1 mL / min, and the reaction solution was simultaneously withdrawn at an output rate of 0.2 mL / min. The reaction solution was collected 60 min (θ*), 120 min (2θ), 180 min (3θ), and 240 min (4θ) after the start of the run, and quenched with 0.05% sodium dithionite solution for sampling. The output solutions when 97.3% of the prepared raw materials were input were all added together, and the concentration was quantified to calculate the yield, which was equivalent to 831.9 mg (93% yield). *θ = elapsed time / average residence time

[0215] Analysis conditions: HPLC, LCMS conditions: Column: Biochell C18, 2.1 mm ID ×150 mm, 2.6 μm. Mobile phase: A) Water:TFA = 2000:1, B) Acetonitrile:TFA = 2000:1 Column temperature: 60 °C Flow rate: 0.5 mL / min Gradient (B%): 0~20 min (5→45), 20.1~23.0 min (100), 23.1~ min (5). MS detection mode: ESI (LC / MS): m / z

[0216] Objective (Desmopressin): LCMS: ESI (m / z):1069 [M+H] + , Flow time: 8.8 minutes Standard qNMR (trifluoroacetate): Measurement conditions: DMSO-d6, 75℃, pulse angle 90°, digital resolution 0.29 Hz, relaxation time: 30 seconds, no spin, accumulation number 64 times Gln CH protons (total 1H, δ: 3.985-4.021 ppm) are used for quantification. Internal standard: 3,5-bis(trifluoromethyl)benzoic acid Content:77.4% TIFF0007634933000098.tif72170

[0217] Cyclization precursor: LCMS:ESI (m / z):1213 [M+H] + ,Flow time: 7.6 minutes Standard qNMR (trifluoroacetate): Measurement conditions: DMSO-d6, 23℃, pulse angle 90°, digital resolution 0.29 Hz, relaxation time: 60 seconds, no spin, 8 accumulations The CH protons of the α carbon (total 3H, δ: 4.516-4.722 ppm) are used for quantification. Internal standard: 3,5-dinitrobenzoic acid methyl ester Content: 86.2% TIFF0007634933000099.tif59170

[0218] Dimer (cyclized product-1) LCMS: ESI (m / z):1070 [M+2H] 2+ , Flow time: 10.5 min TIFF0007634933000100.tif96170

[0219] Dimer (cyclized product-2) LCMS: ESI (m / z):1070 [M+2H] 2+ , Flow time: 12.2 minutes TIFF0007634933000101.tif98170

[0220] Byproduct: LCMS: ESI (m / z): 1195 [M+H]+ , Flow time: 11.6 minutes TIFF0007634933000102.tif83170

[0221] result: [Table 26]

[0222] [Table 27]

[0223] [Table 28] A slight difference was observed between the simulation and experimental results in Run 2. This is thought to be because, due to the extremely fast nature of the reaction rate, when the cyclization precursor was added dropwise on the scale of Run 2, the reaction proceeded before it could be uniformly diffused, and it was thought that the results would match the simulation results if the experimental scale was increased.

[0224] [Table 29] In Run 3, it was confirmed that the simulation and experimental results were in close agreement.

[0225] *Calculation formula Reaction Conversion Rate Simulation: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Experimental results: (Initial Area% of cyclized precursor - Area% of cyclized precursor) / Initial Area% of cyclized precursor Selectivity Simulation: target concentration / (target concentration + dimer (linear + cyclic) concentration) Experimental results: Target Area% + Byproduct Area% / (Target Area% + Byproduct Area% + Dimer (straight chain + cyclic) Area%) (Byproduct is the target further iodized, so it was calculated together with the target.)

[0226] [Example 5] Synthesis of Cyclosporin A Derivatives TIFF0007634933000107.tif70170

[0227] protocol: Synthesis of cyclization precursor 5 Cyclization precursor 5 was synthesized from the above-mentioned compound 2 (cyclization precursor 2 in Example 2) via three steps. TIFF0007634933000108.tif114170

[0228] Preparation of compound 3 The above compound 2 (7.1 g) was dissolved in N,N-dimethylformamide (71 mL), and N,N-diisopropylethylamine (3 mL) and chloroacetyl chloride (1.85 mL) were added under ice cooling. After stirring at room temperature for 2 hours, 5% potassium hydrogen sulfate solution (100 mL) and ethyl acetate (100 mL) were added to the reaction solution and separated. The organic layer was concentrated using an evaporator and further purified by silica gel chromatography (ethyl acetate / heptane / methanol) to obtain compound 3 (5.0 g) as a yellow oily liquid. LCMS: ESI (m / z): 1297 [M+H] +

[0229] Preparation of compound 4 Compound 3 (5.0 g) obtained in the previous step was dissolved in N,N-dimethylformamide (50 mL), and S-trityl-L-cysteine ​​methyl ester hydrochloride (4.0 g), HOAt (1.6 g), and EDC hydrochloride (2.6 g) were added. After stirring at room temperature for 2 hours, saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL) were added to the reaction solution and the liquids were separated. The organic layer was concentrated using an evaporator and further purified by silica gel chromatography (ethyl acetate / heptane / methanol) to obtain compound 4 (4.7 g) as a yellow oily liquid. LCMS: ESI (m / z): 1656 [M+H] +

[0230] Preparation of cyclization precursor 5 Compound 4 (4.7 g) obtained in the previous step was dissolved in dichloromethane (47 mL), and triisopropylsilane (3 mL) and trifluoroacetic acid (5.5 mL) were added under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was concentrated with an evaporator, and the residue was purified by silica gel chromatography (ethyl acetate / heptane / methanol / trifluoroacetic acid). It was further purified by reverse phase chromatography (water / acetonitrile / trifluoroacetic acid) to obtain the cyclization precursor 5 (2.1 g) as a white powder.

[0231] -Reaction rate parameter simulation To calculate the reaction rate parameters, data on the change in concentration of each compound depending on the temperature and reaction time was collected. N,N-diisopropylethylamine (DIPEA) (9.9-10.9 eq.) was added to the cyclization precursor (4.63 mM) prepared in N,N-dimethylformamide (DMF) solution, and the reaction was carried out at 3°C, 24°C, and 46°C. The reaction was quenched with a 0.5% TFA solution in acetonitrile-water (1:1). The reaction was tracked over time by HPLC, and the data in Table 30 were obtained. The concentration of each compound was calculated by converting the cyclization precursor concentration of 4.63 mM into HPLC Area%. In addition, the concentration was calculated assuming that the extinction coefficient of the dimer was twice that of the cyclization precursor, and that of the trimer was three times that of the cyclization precursor.

[0232] [Table 30]

[0233] From the data obtained, the mechanism of this cyclization reaction was considered as follows. The reaction of the cyclization precursor and DIPEA to the intermediate was sufficiently fast, so the rate of production of the target product and dimers and trimers (multiple compounds) from the intermediate is considered to be rate-limiting. Although the intermediate concentration could not be measured, it was considered highly likely that the intermediate would return to the cyclization precursor by quenching before analysis, and considering the difference in reaction rate, it was considered that there was no problem in calculating each parameter assuming that the raw material concentration and intermediate concentration obtained in the analysis were equal. In addition, DIPEA was omitted because an excess amount was used compared to the cyclization precursor and its effect on the reaction rate was small. TIFF0007634933000110.tif27170

[0234] Using the experimentally obtained concentration change over time data and temperature data (Table 30), the frequency factor (A) and activation energy (E) of each elementary reaction were calculated using the following formula. TIFF0007634933000111.tif31170SM: Cyclization precursor, IM: Intermediate, TM: Target, Dimer: Sum of dimer and trimer C: concentration (M), kn: reaction rate constant, An: frequency factor, En: activation energy, T: temperature, R: gas constant The calculations were performed using Aspen custom modeler from Aspen Technology, Inc. As a result, the data shown in Table 31 was obtained.

[0235] [Table 31]

[0236] From the frequency factor (A) and activation energy (E) of each elementary reaction obtained, the reaction rate constants k2 and k3 were calculated when the temperature for the cyclization reaction in the CSTR was set to 25°C (Table 32).

[0237] [Table 32]

[0238] Next, the reaction conversion rate, selectivity, and residence time when the cyclization precursor concentration was 0.027 mol / l and the reaction temperature was 25°C were calculated using the reaction rate constants k2 and k3 in Table 32 and the following mass balance equation and reaction rate equation (Table 33). TIFF0007634933000114.tif34170

[0239] [Table 33]

[0240] In Cases 1 to 3 in Table 33, the residence time was calculated to obtain results with high reaction conversion rate and selectivity. In this example, Case 3 was carried out.

[0241] *Calculation formula Reaction conversion rate: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Selectivity: target concentration / (target concentration + dimer (dimer + trimer) concentration)

[0242] Run 1: Batch high-dilution The cyclization precursor (49.7 mg, content 77.3%, 0.0272 mmol) was dissolved in DMF (8.8 mL), and DIPEA (0.28 mmol, 10 equiv.) was added to the mixture at room temperature. The resulting mixture was reacted at room temperature for 1 hour. A portion of the reaction solution was quenched with a solution of 0.5% trifluoroacetic acid in acetonitrile-water (1:1), and the solution concentration of the target product was quantified, and the yield was calculated to be equivalent to 30.8 mg (82% yield).

[0243] ·Run 2: Batch pseudo high-dilution To a solution of DIPEA (1.72 mmol, 10 equiv.) in DMF (7.5 mL), a solution of the cyclization precursor compound (300.9 mg, content 77.3%, 0.164 mmol) in DMF (4.6 mL) was added dropwise over 3 hours at 22° C. The solution concentration of the target product was quantified approximately 1 hour after the addition, and the yield was calculated to be equivalent to 187.3 mg (83% yield).

[0244] Run 3: CSTR The cyclization precursor (1.3671 g, content 77.3%, 0.747 mmol) was dissolved in DMF (27.3 mL). The substrate concentration was 0.027 mmol / mL. Meanwhile, DIPEA (7.73 mmol, 10 equiv.) was dissolved in DMF (27.3 mL). The reagent concentration was 0.283 mmol / mL. These solutions were added to DMF (13.2 mL) at 23 °C with an input rate of 0.04 mL / min, and the reaction solution was simultaneously withdrawn at an output rate of 0.08 mL / min. The reaction solution was collected at 165 min (θ*), 330 min (2θ), 495 min (3θ), and 660 min (4θ) after the start of the run, and quenched with a solution of 0.5% trifluoroacetic acid in acetonitrile-water (1:1) for sampling. The yield was calculated by adding up all the output solutions and quantifying the concentration, which was equivalent to 793.9 mg (82% yield). The yield of the raw material solution was calculated based on the input amount (94.5% of the total amount). *θ = elapsed time / average residence time

[0245] Analysis conditions: HPLC, LCMS conditions: Column: Kinetex Biphenyl, 2.1 mm ID ×150 mm, 2.6 μm. Mobile phase: A) Water:TFA = 2000:1, B) Acetonitrile:TFA = 2000:1 Column temperature: 60 °C Flow rate: 0.5 mL / min Gradient (B%): 0~30 min (10→100), 30.0~30.6 min (100), 30.7~ min (10) MS detection mode: ESI (LC / MS): m / z

[0246] Objective (Cyclosporin A derivative): LCMS: ESI (m / z): 1378 [M+H] + , Flow time: 17.5 min Yields were quantified by HPLC assay using the following standards: Standard qNMR: Measurement conditions: DMSO-d6, 147℃, pulse angle 90°, digital resolution 0.25 Hz, relaxation time: 60 seconds, no spin, 32 accumulations Use CH protons (total 1H) of MeVal β carbon for quantification Internal standard: Maleic acid Content: 94.4% TIFF0007634933000116.tif72170

[0247] Cyclization precursor: LCMS: ESI (m / z): 1414 [M+H] + , Flow time: 13.9 minutes Content: 77.3% based on qNMR and HPLC assays. a. Standard qNMR: Measurement conditions: DMSO-d6, 90℃, pulse angle 90°, digital resolution 0.25 Hz, relaxation time: 60 seconds, no spin, 32 accumulations Use CH protons (total 1H) of MeVal β carbon for quantification Internal standard: 3,5-bis(trifluoromethyl)benzoic acid Content: 91.8% b. The raw material used in this example was assayed by HPLC and the result was 84.2%. TIFF0007634933000117.tif77170

[0248] Dimer LCMS: ESI (m / z): 1378 [M+2H] 2+ , Flow time: 21.8 minutes TIFF0007634933000118.tif145170

[0249] Trimmer LCMS: ESI (m / z): 1378 [M+3H] 3+ , Flow time: 24.1 minutes TIFF0007634933000119.tif156170

[0250] result: [Table 34]

[0251] [Table 35]

[0252] [Table 36] A slight difference was observed between the simulation and experimental results in Run 2. This is thought to be because, due to the extremely fast nature of the reaction rate, when the cyclization precursor was added dropwise on the scale of Run 2, the reaction proceeded before it could be uniformly diffused, and it was thought that the results would match the simulation results if the experimental scale was increased.

[0253] [Table 37] In Run 3, it was confirmed that the simulation and experimental results were in close agreement.

[0254] Calculation formula Reaction Conversion Rate Simulation: (initial concentration of cyclization precursor - concentration of cyclization precursor) / initial concentration of cyclization precursor Experimental results: (Initial Area% of cyclized precursor - Area% of cyclized precursor) / Initial Area% of cyclized precursor Selectivity Simulation: target concentration / (target concentration + dimer + trimer concentration) Experimental results: (target area%) / (target area% + dimer + trimer area%) [Industrial Applicability]

[0255] The present invention provides a new method for producing a cyclic organic compound, which includes carrying out a cyclization reaction using a CSTR. The invention provided by the present invention is useful for continuously producing a cyclic organic compound in a smaller reaction vessel with fewer impurities.

Claims

1. A method for producing a peptide compound having a cyclic portion, the peptide compound being composed of natural amino acids and / or amino acid analogs, the method comprising a cyclization reaction step of cyclizing a cyclization precursor of the peptide compound, the total number of which is 6 to 30 residues of natural amino acids and amino acid analogs, in at least one continuous tank reactor (CSTR); A method for producing a peptide compound, the peptide compound being characterized in that it (i) comprises at least two N-substituted amino acids and at least one non-N-substituted amino acid, and (ii) has a ClogP value of 6 or more, except for the method comprising the steps of: (a) simultaneously adding a substrate feed and a solvent for diluting the substrate feed to form a reaction mixture in a reactor, and causing the substrate to form a reaction product in the reaction mixture; (b) discharging the reaction mixture including the reaction product and the solvent from an outlet of the reactor; (c) directing the entire reaction mixture discharged in step (b) to a filtration membrane, the filtration membrane being provided so as to be permeable to the solvent and impermeable to the reaction product; (d) recycling the solvent that has permeated the filtration membrane for diluting the substrate feed in step (a); and (e) directing the retentate from the filtration membrane including the reaction product to a reservoir other than the reactor.

2. 2. The method of claim 1, wherein the peptide compound comprises a cyclic portion consisting of 4 to 14 naturally occurring amino acid and / or amino acid analog residues, and the total number of naturally occurring amino acid and amino acid analog residues is 7 to 20.

3. The method according to claim 1 or 2, wherein the cyclization reaction is an intramolecular cyclization reaction via one or more bonds selected from the group consisting of the following (i) to (vii): (i) Amide bond (ii) Disulfide bonds (iii) Ether bond (iv) Thioether bond (v) Ester bond (vi) Thioester bond (vii) Carbon-carbon bond

4. 4. The method of any one of claims 1 to 3, wherein the cyclization reaction is carried out on an industrial scale using conditions obtained based on the results of a preliminary test of the cyclization reaction.

5. The method of claim 4, wherein the condition is obtained by a process comprising the following steps (i) to (v): (i) acquiring data on the change in concentration over time at a plurality of temperatures for at least one selected from the group consisting of the cyclization precursor, the peptide compound, one or more intermediates, and one or more by-products in a preliminary test; (ii) Using the concentration change data obtained in step (i) and the reaction rate equation for the cyclization reaction, a reaction rate constant k ｎ A process of obtaining (iii) the temperature used in step (i), the reaction rate constant k determined in step (ii) ｎ and the frequency factor A using the following formula (II): ｎ and the activation energy E ｎ A process of obtaining [0010] (iv) The frequency factor A obtained in step (iii) ｎ and the activation energy E ｎ , the reaction rate constant k at the temperature for cyclization in the CSTR using the above equation (II) and the above reaction rate equation. ｎ A step of determining (v) The reaction rate constant k ｎ A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): [0025] (In the formula, r n : reaction rate, τ: residence time (space time), C 0 : supply concentration, C: concentration.

6. The elementary reaction of the cyclization reaction is represented by the following formula (IV): [0030] Reaction rate constant k １ , k ２ , k ３ The method according to claim 5, wherein is determined using any of the following formulas (V) to (IX): [0045] (In the formula, TM: peptide compound having a cyclic portion, SM: cyclization precursor, ACT: activator, IM: intermediate, Dimer: dimer, and C: concentration (M).

7. The elementary reaction of the cyclization reaction is represented by the following formula (X): [0050] Reaction rate constant k １ , k ２ The method according to claim 5, wherein is determined using any one of the following formulas (XI) to (XIII): [006] (In the formula, r represents reaction rate, TM represents target substance, SM represents cyclization precursor (= intermediate), ACT represents activator, Dimer represents dimer, and C represents concentration (M).

8. The method according to any one of claims 4 to 7, wherein the condition is selected from the group consisting of a flow rate of a continuous tank reactor, a concentration of a cyclization precursor, and a concentration of a peptide compound.

9. The method includes a step of cyclizing a cyclization precursor of a peptide compound having a cyclic portion in at least one continuous tank reactor (CSTR), the peptide compound is composed of natural amino acids and / or amino acid analogs, (i) contains at least two N-substituted amino acids and at least one non-N-substituted amino acid, and (ii) has a ClogP value of 6 or more; A method for promoting intramolecular cyclization of a cyclization precursor of a peptide compound, the cyclization precursor being one having a total of 6 to 30 residues of natural amino acids and amino acid analogs, except for a method comprising the steps of: (a) simultaneously adding a substrate feed and a solvent for diluting the substrate feed to form a reaction mixture in a reactor, and causing the substrate to form a reaction product in the reaction mixture; (b) discharging the reaction mixture including the reaction product and the solvent from an outlet of the reactor; (c) directing the entire reaction mixture discharged in (b) to a filtration membrane, the filtration membrane being provided so as to be permeable to the solvent and impermeable to the reaction product; (d) recycling the solvent that has permeated the filtration membrane for diluting the substrate feed in (a); and (e) directing the retentate from the filtration membrane including the reaction product to a reservoir other than the reactor.

10. A method for cyclizing a cyclization precursor of a peptide compound having a cyclic portion on an industrial scale in at least one continuous tank reactor (CSTR), comprising the steps of: the peptide compound is composed of natural amino acids and / or amino acid analogs, (i) contains at least two N-substituted amino acids and at least one non-N-substituted amino acid, and (ii) has a ClogP value of 6 or more; A method for obtaining conditions for a method in which the total number of natural amino acids and amino acid analogs in the cyclized precursor of the peptide compound is 6 to 30 residues, except for a method comprising the steps of: (a) simultaneously adding a substrate feed and a solvent for diluting the substrate feed to form a reaction mixture in a reactor, and allowing the substrate to form a reaction product in the reaction mixture; (b) discharging the reaction mixture including the reaction product and the solvent from an outlet of the reactor; (c) directing the entire reaction mixture discharged in step (b) to a filtration membrane, the filtration membrane being provided so as to be permeable to the solvent and impermeable to the reaction product; (d) recycling the solvent that has permeated the filtration membrane for diluting the substrate feed in step (a); and (e) directing the retentate from the filtration membrane including the reaction product to a reservoir other than the reactor. (i) acquiring data on the change in concentration over time at a plurality of temperatures for at least one selected from the group consisting of the cyclized precursor, the peptide compound having a cyclic portion, one or more intermediates, and one or more by-products in a preliminary test; (ii) Using the concentration change data obtained in step (i) and the reaction rate equation for the cyclization reaction, a reaction rate constant k ｎ A process of obtaining (iii) the temperature used in step (i), the reaction rate constant k determined in step (ii) ｎ and the frequency factor A using the following formula (II): ｎ and the activation energy E ｎ A process of obtaining [0070] (iv) The frequency factor A obtained in step (iii) ｎ and the activation energy E ｎ , the reaction rate constant k at the temperature for cyclization in the CSTR using the above equation (II) and the above reaction rate equation. ｎ A step of determining (v) The reaction rate constant k ｎ A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): [0080] (In the formula, r n : reaction rate, τ: residence time (space time), C 0 : supply concentration, C: concentration.

11. 1. A method for cyclizing a cyclization precursor of a peptide compound having a cyclic portion on an industrial scale in at least one continuous tank reactor (CSTR), comprising: the peptide compound is composed of natural amino acids and / or amino acid analogs, (i) contains at least two N-substituted amino acids and at least one non-N-substituted amino acid, and (ii) has a ClogP value of 6 or more; a step of: (a): simultaneously adding a substrate feed and a solvent for diluting the substrate feed to form a reaction mixture in a reactor, and causing the substrate to form a reaction product in the reaction mixture; (b): discharging the reaction mixture including the reaction product and the solvent from an outlet of the reactor; (c): directing the entire reaction mixture discharged in step (b) to a filtration membrane, the filtration membrane being provided so as to be permeable to the solvent and impermeable to the reaction product; (d): recycling the solvent that has permeated the filtration membrane for diluting the substrate feed in step (a); and (e): directing the retentate from the filtration membrane including the reaction product to a reservoir other than the reactor, the step of: (i) calculating a reaction rate constant k using data on the change in concentration over time at a plurality of temperatures for at least one selected from the group consisting of the cyclization precursor, the peptide compound having a cyclic portion, one or more intermediates, and one or more by-products obtained in a preliminary test, and a reaction rate equation for the cyclization reaction; ｎ A process of obtaining (ii) the temperature used in step (i), the reaction rate constant k determined in step (i), ｎ and the frequency factor A using the following formula (II): ｎ and the activation energy E ｎ A process of obtaining [0097] (iii) The frequency factor A obtained in step (ii) ｎ and the activation energy E ｎ , the reaction rate constant k at the temperature for cyclization in the CSTR using the above equation (II) and the above reaction rate equation. ｎ A step of determining (iv) The reaction rate constant k obtained in step (iii) ｎ A step of obtaining the conditions using the reaction rate equation and the following CSTR material balance equation (III): [0010] (In the formula, r n : reaction rate, τ: residence time (space time), C 0 : supply concentration, C: concentration. A program for executing the above.

12. 1. A method for cyclizing a cyclization precursor of a peptide compound having a cyclic portion on an industrial scale in at least one continuous tank reactor (CSTR), comprising: the peptide compound is composed of natural amino acids and / or amino acid analogs, (i) contains at least two N-substituted amino acids and at least one non-N-substituted amino acid, and (ii) has a ClogP value of 6 or more; A system for obtaining conditions for a method in which the cyclization precursor of the peptide compound is one in which the total number of natural amino acids and amino acid analogs is 6 to 30 residues (excluding a method comprising the steps of: (a): simultaneously adding a substrate feed and a solvent for diluting the substrate feed to form a reaction mixture in a reactor, and causing the substrate to form a reaction product in the reaction mixture; (b): discharging the reaction mixture containing the reaction product and the solvent from an outlet of the reactor; (c): directing the entire reaction mixture discharged in step (b) to a filtration membrane, the filtration membrane being provided so as to be permeable to the solvent and impermeable to the reaction product; (d): recycling the solvent that has permeated the filtration membrane for diluting the substrate feed in step (a); and (e): directing the retentate from the filtration membrane containing the reaction product to a reservoir other than the reactor), the system comprising the following means (i) to (iv): (i) calculating a reaction rate constant k using data on the change in concentration over time at multiple temperatures for at least one selected from the group consisting of the cyclization precursor, the peptide compound, one or more intermediates, and one or more by-products obtained in a preliminary test, and a reaction rate equation for the cyclization reaction; ｎ The means to seek (ii) the temperature used in step (i), the reaction rate constant k determined in step (i), ｎ and the frequency factor A using the following formula (II): ｎ and the activation energy E ｎ The means to seek ##EQU00011## (iii) The frequency factor A obtained in step (ii) ｎ and the activation energy E ｎ , the reaction rate constant k at the temperature for cyclization in the CSTR using the above equation (II) and the above reaction rate equation. ｎ and (iv) The reaction rate constant k obtained in step (iii) ｎ A means for acquiring the conditions using the reaction rate equation and the following CSTR material balance equation (III): ##EQU00012## (In the formula, r n : reaction rate, τ: residence time (space time), C 0 : supply concentration, C: concentration.

Images