Method for producing cyclic peptide derivative and method for producing cyclic peptide compound

Abstract

To provide a method for efficiently producing a cyclic peptide derivative that can be used to produce a cyclic peptide compound.SOLUTION: In a production method of a cyclic peptide derivative represented by the specified formula (1), a product obtained by oxidation reaction of a compound represented by the specified formula (2) is subjected to condensation reaction with a compound having both of a carboxy group and an amino group, or a salt or ester of the compound.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for producing a cyclic peptide derivative and a method for producing a cyclic peptide compound.

Background Art

[0002] The cyclic peptide compound represented by the following general formula (A)

[0003]

Chemical formula

[0004] is known to exhibit specific proliferative activity against astrocytes, which are a type of cell constituting the mammalian brain (see Patent Document 1).

[0005] This cyclic peptide compound can be isolated by pulverizing the whole including the fruiting body of Isaria japonica, which is a fungus of Cordyceps militaris using the silkworm (Bombyx mori) pupa as a host, and the infected host, and using this as an extraction material, and repeating hot water extraction, reverse phase flash column chromatography, and reverse phase HPLC for purification.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] However, since the cyclic peptide compound described in Patent Document 1 is an extract from a natural product, it is not always possible to stably supply the cyclic peptide compound, and there are problems from the viewpoint of productivity.

[0008] The present invention has been made in view of the above, and an object thereof is to provide a method for efficiently producing a cyclic peptide derivative that can be used for producing a cyclic peptide compound. [Means for Solving the Problems]

[0009] As a result of intensive studies to achieve the above object, the present inventors have found that the above object can be achieved by employing an oxidation reaction and a condensation reaction using a specific compound, and have completed the present invention.

[0010] That is, the present invention includes, for example, the subject matters described in the following items. Item 1 The following general formula (1)

[0011] [Chemical Formula]

[0012] (In formula (1), R1 represents a hydrogen atom or a hydrocarbon group, R2 represents a hydrogen atom or a hydrocarbon group, R3 represents a hydrogen atom or a hydrocarbon group, R4 represents a hydrogen atom or a hydrocarbon group, R5 is -O-R 51 (R 51 represents a hydrogen atom or a protecting group), R 61 is -O-R6 (R6 represents a hydrogen atom, a hydrocarbon group or a protecting group), R7 represents a hydrogen atom, a hydrocarbon group or a protecting group, R8 represents a hydrogen atom, a hydrocarbon group or a protecting group, R9 represents a hydrogen atom, a hydrocarbon group or a protecting group, R 10 represents a hydrogen atom, a hydrocarbon group or a protecting group, R 11 represents a hydrogen atom, a hydrocarbon group or a protecting group, R 12 represents a hydrogen atom or a protecting group, R 14 is -(CH2) n -COOR 13 (R 13 represents a hydrogen atom or a protecting group, and n is a number of 1 or more), and provided that at least one of R 51 , R6, R 12 , and R 13 is other than a hydrogen atom, and m is 1) A method for producing a cyclic peptide derivative represented by the following general formula (2)

[0013]

Chemical formula

[0014] (In formula (2), R1, R2, R3, R4, R5, R 61 , R7, R8, R9, R 10 and m are respectively synonymous with R1, R2, R3, R4, R5, R 61 , R7, R8, R9, R 10 and m in the above formula (1)) A production method comprising a step of subjecting a product obtained by an oxidation reaction of a compound represented by to a condensation reaction with a compound having both a carboxy group and an amino group, or a salt or ester of the compound. Item 2 The production method according to item 1, wherein the compound having both a carboxy group and an amino group is an amino acid. Item 3 The production method according to item 2, wherein the amino acid is glutamic acid or aspartic acid. Item 4 The production method according to any one of items 1 to 3, wherein the oxidation reaction includes Dess-Martin oxidation and Pinnick oxidation. Item 5 The production method according to any one of items 1 to 4, wherein a phosphorus-based condensing agent is used in the condensation reaction. Item 6 In the formula (1), R2 is an alkynyl group. The production method according to any one of items 1 to 5. Item 7 In formula (1), R 14 is -(CH2)2-COOR 13 (R 13 is synonymous with R in the formula (1) 13 ). The production method according to any one of items 1 to 6. Item 8 A method for producing a cyclic peptide compound, comprising a step of obtaining a cyclic peptide compound by subjecting the cyclic peptide derivative obtained by the production method according to any one of items 1 to 7 to a hydrogenation reduction reaction. Item 9 The cyclic peptide compound is represented by the following general formula (10)

[0015]

Chemical formula

[0016] (In formula (10), R1, R2, R3, R4, R 61 , R7, R8, R9, R 10 and R 11 are respectively synonymous with R1, R2, R3, R4, R 61 , R7, R8, R9, R 10 and R 11 in the formula (1)) The production method according to item 8, which is a compound represented by.

Advantages of the Invention

[0017] According to the present invention, a cyclic peptide derivative can be obtained in a high yield, and a cyclic peptide compound can be obtained from the cyclic peptide derivative in a high yield by a simple method.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Embodiments for Carrying Out the Invention

[0019] Hereinafter, embodiments of the present invention will be described in detail. In this specification, the expressions "containing" and "comprising" include the concepts of "containing", "comprising", "consisting essentially of", and "consisting only of".

[0020] 1. Method for producing cyclic peptide derivative In the method for producing the cyclic peptide derivative of the present invention, a cyclic peptide derivative represented by the following general formula (1) is produced.

[0021]

Chem.

[0022] Here, in formula (1), R1 represents a hydrogen atom or a hydrocarbon group, R2 represents a hydrogen atom or a hydrocarbon group, R3 represents a hydrogen atom or a hydrocarbon group, R4 represents a hydrogen atom or a hydrocarbon group, R5 is -O-R 51 (R 51 represents a hydrogen atom or a protecting group), R 61 is -O-R6 (R6 represents a hydrogen atom, a hydrocarbon group or a protecting group), R7 represents a hydrogen atom, a hydrocarbon group or a protecting group, R8 represents a hydrogen atom, a hydrocarbon group or a protecting group, R9 represents a hydrogen atom, a hydrocarbon group or a protecting group, R 10 represents a hydrogen atom, a hydrocarbon group or a protecting group, R 11 represents a hydrogen atom, a hydrocarbon group or a protecting group, R 12 represents a hydrogen atom or a protecting group, R 14 is -(CH2) n -COOR 13 (R 13 represents a hydrogen atom or a protecting group, and n is a number of 1 or more), However, at least one of R 51 , R6, R 12 , and R 13 is other than a hydrogen atom, m is 1.

[0023] In particular, the production method of the present invention includes a step of subjecting a product obtained by an oxidation reaction of a compound represented by the following general formula (2) to a condensation reaction with a compound having both a carboxy group and an amino group, or a salt or ester of the compound (hereinafter, this step is abbreviated as "Step A" in this specification).

[0024]

Chemical formula

[0025] Here, in formula (2), R1, R2, R3, R4, R5, R 61 , R7, R8, R9, R 10 and m are respectively synonymous with R1, R2, R3, R4, R5, R 61 , R7, R8, R9, R 10 and m in the above formula (1). In particular, R1, R2, R3, R4, R5, R 61 , R7, R8, R9, R 10 and m in formula (2) are respectively the same as R1, R2, R3, R4, R5, R 61 , R7, R8, R9, R 10 and m in the above formula (1).

[0026] In the present invention, the hydrocarbon group may be any of an alkyl group, an alkenyl group, and an alkynyl group. The number of carbon atoms of the hydrocarbon group is not particularly limited, and is, for example, 1 to 10, preferably 1 to 5, more preferably 1 to 4, and particularly preferably 1 to 3. Specifically, examples of the hydrocarbon group include a methyl group, an ethyl group, a vinyl group, an ethynyl group, a propyl group, an isopropyl group, a propenyl group, and the like. The hydrocarbon group may be linear or branched.

[0027] In the present invention, the protecting group is other than the above hydrocarbon group, and examples thereof include an aromatic group; a heterocyclic group; an oxygen-containing functional group having an alkoxyalkyl group, a carbonyl group, an ester, etc.; a group having a silicon atom such as a silyl group.

[0028] When the protecting group is an aromatic group, examples thereof include a phenyl group, a benzyl group, an oxybenzyl group (-O-CH2-Ph), a 2-nitrobenzenesulfonyl group (nosyl group), and the like. When the protecting group is an oxygen-containing functional group, a tert-butoxycarbonyl group (Boc group) can be mentioned. When the protecting group is a group having a silicon atom, a tert-butyldimethylsilyl group (-Si(t-Bu)(CH3)2), a tert-diphenylsilyl group (-Si(t-Bu)Ph2), and the like can be mentioned.

[0029] In formulas (1) and (2), when R1 is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, even more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0030] In formulas (1) and (2), when R1 is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms or an alkynyl group having 2 to 5 carbon atoms, more preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms or an alkynyl group having 2 to 3 carbon atoms, and particularly preferably an ethynyl group (-C≡C). Particularly in formula (2), when R2 is an ethynyl group, the steric hindrance is smaller than that of an ethyl group or the like, so that the condensation reaction described below proceeds more easily.

[0031] In formulas (1) and (2), when R3 is a hydrocarbon group, it is preferably an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, even more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0032] In formulas (1) and (2), when R4 is a hydrocarbon group, it is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, even more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0033] In Formulas (1) and (2), R5 is -O-R 51 (R 51 represents a hydrogen atom or a protecting group), and R 51 is preferably a protecting group, more preferably an aromatic group, and particularly preferably an oxybenzyl group (-O-CH2-Ph).

[0034] In Formulas (1) and (2), R 61 is -O-R6 (where R6 represents a hydrogen atom, a hydrocarbon group or a protecting group), and R6 is preferably a hydrocarbon group or a protecting group. When R6 is a hydrocarbon group, it is preferably an allyl group. When R6 is a protecting group, examples include a tert-butyldimethylsilyl group (-Si(t-Bu)(CH3)2), a tert-diphenylsilyl group (-Si(t-Bu)Ph2), a benzyl group, a methoxymethyl group (MOM), etc. R6 is preferably a tert-butyldimethylsilyl group.

[0035] In Formulas (1) and (2), R7 is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0036] In Formulas (1) and (2), R8 is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0037] In Formulas (1) and (2), R9 is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a methyl group.

[0038] In formulas (1) and (2), R 10 is preferably the protecting group, and particularly preferably a 2-nitrobenzenesulfonyl group (nosyl group).

[0039] In formula (1), R 11 is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, still more preferably a hydrogen atom, a methyl group or an ethyl group, and particularly preferably a hydrogen atom.

[0040] In formula (1), R 12 is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0041] In formula (1), R 14 is -(CH2) n -COOR 13 (n is 1 to 4), and more preferably -(CH2)2-COOR 13 . R 13 is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0042] In formulas (1) and (2), the bonding position of R5 is not particularly limited, and for example, it can be the bonding position represented by the following formula (1').

[0043]

Chemical formula

[0044] Here, in formula (1'), R1 to R5, R7 to R 12 and R 14 are synonymous with R1 to R5, R7 to R 12 and R 14 in the above formula (1), and R 61 is synonymous with R 61 in the above formula (1).

[0045] In Process A, it includes the oxidation reaction of the compound represented by formula (2). Specifically, the oxidation reaction is a reaction for oxidizing alcohol to carboxylic acid. Thereby, the hydroxyl group indicated by the arrow in the compound represented by formula (2) changes to a carboxyl group.

[0046] In Process A, the type of the oxidation reaction is not particularly limited. For example, the oxidation reactions of known alcohol compounds can be widely adopted. The oxidation reaction may be, for example, a two-step reaction in which alcohol is oxidized to aldehyde and then this aldehyde is oxidized to carboxylic acid. When the oxidation reaction is carried out in two steps in this way, it is easy to prevent the oxidation reaction of unintended functional groups from occurring.

[0047] In Process A, it is preferable that the oxidation reaction includes Dess-Martin oxidation and Pinnick oxidation. Thereby, racemization is easily suppressed, and oxidation easily occurs under mild reaction conditions. For example, by Dess-Martin oxidation, the hydroxyl group is oxidized to aldehyde, and then by Pinnick oxidation, the aldehyde is oxidized to carboxylic acid.

[0048] In Process A, when carrying out the oxidation reaction, it is preferable to use 1 to 5 moles of the oxidizing agent per mole of the compound represented by formula (2). The type of the oxidizing agent is not particularly limited, and known oxidizing agents used in the oxidation reaction can be widely used.

[0049] In Dess-Martin oxidation, it is preferable to use 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (DMP) as the oxidizing agent. In the case of Dess-Martin oxidation, it is preferable to use 1 to 5 moles of the oxidizing agent per mole of the compound represented by formula (2), and more preferably 1 to 3 moles.

[0050] In Pinnick oxidation, it is preferable to use sodium chlorite (NaClO₂) as an oxidizing agent. In the case of Pinnick oxidation, it is preferable to use 1 to 5 moles, more preferably 2 to 5 moles of the oxidizing agent per mole of the compound represented by the formula (2).

[0051] Other oxidizing agents can also be used in the oxidation reaction. For example, oxidizing agents combining nitroxyl radical species such as 2,2,6,6-tetramethylpiperidine 1-oxyl and iodosobenzene diacetate can be exemplified.

[0052] In step A, a solvent can also be used in the oxidation reaction as needed. As the solvent in the oxidation reaction, for example, chlorine-containing compounds such as dichloromethane and dichloroethane, acetonitrile, and tert-butanol can be used.

[0053] In step A, the reaction temperature of the oxidation reaction is not particularly limited, and for example, it can be carried out at -20 to 60 °C, preferably at 0 to 30 °C.

[0054] In step A, after the oxidation reaction, the product (carboxylic acid compound) obtained in the oxidation reaction is subjected to a condensation reaction with a compound having both a carboxy group and an amino group, or a salt or ester of the compound. Hereinafter, a compound having both a carboxy group and an amino group, or a salt or ester of the compound is abbreviated as "compound C".

[0055] Among compound C, the compound having both a carboxy group and an amino group is not particularly limited, and for example, amino acids can be mentioned, and glutamic acid or aspartic acid is preferably used.

[0056] In particular, in Step A, it is preferable to carry out a condensation reaction between the product (carboxylic acid compound) obtained in the oxidation reaction and a glutamic acid ester or an aspartic acid ester. By using a glutamic acid ester in the condensation reaction, the resulting cyclic peptide derivative, that is, the cyclic peptide derivative represented by the general formula (1), has R in the formula (1) 14 being -(CH2)2-COOR 13 When an aspartic acid ester is used in the condensation reaction, the resulting cyclic peptide derivative, that is, the cyclic peptide derivative represented by the general formula (1), has R in the formula (1) 14 being -(CH2)-COOR 13 In either case, R 13 is preferably a protecting group, more preferably an aromatic group, and particularly preferably a benzyl group.

[0057] In the condensation reaction of Step A, the amount of Compound C used per mole of the carboxylic acid compound obtained in the oxidation reaction is preferably 1 to 5 moles, more preferably 2 to 5 moles, and even more preferably 3 to 4 moles.

[0058] For example, in Step A, when a condensation reaction is carried out between the product (carboxylic acid compound) obtained in the oxidation reaction and a glutamic acid ester, the resulting cyclic peptide derivative represented by the formula (1) is represented by the following general formula (1A).

[0059]

Chemical formula

[0060] Here, in the formula (1A), R1 to R5, R 61 , R7 to R 13 and m have the same meanings as R1 to R5 and, R 61 , R7 to R 13 and m in the formula (1).

[0061] In Project A, the method of the condensation reaction is not particularly limited. For example, the conditions of known condensation reactions can be widely adopted. From the viewpoint of being easy to suppress racemization and promoting oxidation under mild reaction conditions, a condensing agent can also be used in the condensation reaction.

[0062] The type of the condensing agent is not particularly limited. For example, known condensing agents can be widely used. In particular, in the condensation reaction of Project A, it is preferable to use a phosphorus-based condensing agent as the condensing agent. Examples of such condensing agents include, for example, 3-(Diethoxyphosphoryloxy)-3H-benzo[d][1,2,3]triazin-4-one (DEPBT), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride, 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium Chloride, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-[Bis(dimethylamino)methylene]-1H-benzotriazolium 3-Oxide Hexafluorophosphate, N-[1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate and the like. The phosphorus-based condensing agent is preferably a phosphoric acid azide compound, and particularly preferably DEPBT.

[0063] When using a condensing agent, its usage amount is not particularly limited. For example, per mole of the carboxylic acid compound obtained in the oxidation reaction, the usage amount of the condensing agent is preferably 1 to 3 moles, and more preferably 1.2 to 2.5 moles.

[0064] In the condensation reaction of Project A, a solvent can be used as needed. This solvent is not particularly limited, and examples include aliphatic hydrocarbons such as hexane and heptane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; alcohols such as methanol, ethanol, isopropyl alcohol, and t-butanol; amide solvents such as N,N-dimethylacrylamide; and the like.

[0065] The condensation reaction may be carried out in the presence of a base catalyst such as diisopropylethylamine and dimethylaminopyridine.

[0066] In Project A, the reaction temperature of the condensation reaction is not particularly limited, and for example, it can be carried out at -20 to 60°C, preferably at 0 to 30°C.

[0067] In Project A, by performing an oxidation reaction and then a subsequent condensation reaction, a cyclic peptide derivative represented by formula (1) can be produced in a high yield. Conventionally, there has been no known method for stereoselectively reacting a cyclic peptide derivative in which a β-hydroxydopa unit, a macrocyclic lactam structure containing a structure derived from a non-natural amino acid such as a β-hydroxyisoleucine unit, and an amino acid derivative such as a glutamate derivative are condensed and linked. In contrast, in the present invention, by adopting Project A using the compound represented by formula (2), the cyclic peptide derivative represented by formula (1) is enabled. Therefore, the cyclic peptide derivative represented by formula (1) has a structure containing a β-hydroxydopa unit and a β-hydroxyisoleucine unit.

[0068] Generally, in biosynthesis, it is known that cyclic peptide derivatives are produced by first binding all the peptides and then cyclizing them. In contrast, in the method for producing a cyclic peptide derivative of the present invention, compound C (for example, glutamic acid ester) is bound to a compound having a cyclic structure. That is, in the method for producing a cyclic peptide derivative of the present invention, since compound C is finally bound, depending on the type of compound C, there is an advantage that cyclic peptide derivatives to which various amino acids and the like are bound can be obtained. Further, as in the present invention, a route of constructing a ring structure in advance and then introducing a side chain (compound C) can simplify the steps involved in the removal of protecting groups and has an advantage of being able to provide the target product in a high yield.

[0069] 2. Method for producing cyclic peptide compound The method for producing a cyclic peptide compound of the present invention includes a step of obtaining a cyclic peptide compound by subjecting the cyclic peptide derivative obtained by the method for producing the cyclic peptide derivative to a hydrogenation reduction reaction. That is, the method for producing a cyclic peptide compound of the present invention includes a step of performing a hydrogenation reduction reaction after the condensation reaction in step A in the method for producing a cyclic peptide derivative.

[0070] In the method for producing a cyclic peptide compound, the method of the hydrogenation reduction reaction is not particularly limited, and for example, known hydrogenation reduction reaction conditions can be widely adopted. For example, in the presence of a catalyst, a hydrogenation reduction reaction can be carried out by using hydrogen. As the catalyst, for example, a known catalyst used in a hydrogenation reduction reaction can be used, and specifically, palladium carbon can be mentioned. A solvent can also be used in the hydrogenation reduction reaction as needed. Examples of this solvent include lower alcohols such as methanol and ethanol.

[0071] When the cyclic peptide derivative represented by the formula (1) obtained in the condensation reaction of Project A has a protecting group such as a tert-butoxycarbonyl group (Boc group), a tert-butyldimethylsilyl group (TBS group), or a 2-nitrobenzenesulfonyl group (nosyl group), the protecting group can be deprotected in advance and then a hydrogenation reduction reaction can be carried out. The method of deprotection is not particularly limited, and for example, known deprotection methods can be widely adopted. For example, the deprotection of the TBS group and the deprotection of the nosyl group can be carried out in this order.

[0072] When the cyclic peptide derivative represented by the formula (1) has an alkynyl group (for example, R2 in the formula (1)), the alkynyl group can be changed to an alkyl group by the hydrogenation reduction reaction. For example, when an ethynyl group is present in the cyclic peptide derivative represented by the formula (1), it can be changed to an ethyl group by the hydrogenation reduction reaction.

[0073] In one aspect of the method for producing the cyclic peptide compound of the present invention, for example, the cyclic peptide derivative represented by the formula (1) obtained in the condensation reaction of Project A is deprotected, and then a hydrogenation reduction reaction is carried out. As a result, for example, a compound represented by the following formula (10) is generated, and as a specific example, a compound represented by the following formula (A) can be generated.

[0074]

Chemical formula

[0075] In the formula (10), R1, R2, R3, R4, R 61 , R7, R8, R9, R 10 and R 11 are respectively synonymous with R1, R2, R3, R4, R 61 , R7, R8, R9, R 10 and R 11 in the formula (1). In this case, R 61 is preferably a hydroxyl group.

[0076] In the formula (A), R1, R3 and R4 have the same meanings as R1, R3 and R4 in the formula (1). Specifically, in the compound represented by the formula (A), R5 in the formula (1) is a hydroxyl group (where m is 1), R 12 is a hydrogen atom, and R 14 is -(CH2)2-COOH. In the formula (A), R2 is an ethyl group, R 61 is OH, R7, R8, R9 and R 11 are hydrogen atoms, and R 10 is a methyl group, but it is not limited thereto.

[0077] In the hydrogenation reduction reaction, when the cyclic peptide derivative represented by the formula (1) has an alkynyl group, it changes to an alkyl group. For example, the ester moiety derived from compound C changes to a carboxylic acid. Also, when R5 has a protecting group (for example, when it is a group containing an ether structure such as an oxybenzyl group), R5 can change to a hydroxyl group by the hydrogenation reduction reaction (see the formula (A) above).

[0078] The cyclic peptide compound obtained by the hydrogenation reduction reaction is not particularly limited as long as it can be produced by hydrogenating the compound represented by the formula (1). Preferably, R5 in the formula (1) is a hydroxyl group, R 12 is a hydrogen atom, and R 14 in COOR 13 where R 13 is a hydrogen atom. In this case, it is also preferable that R2 is an ethyl group. For the cyclic peptide compound, it is more preferable that R 14 is -(CH2)2-COOH or -CH2-COOH. Most preferably, the cyclic peptide compound obtained by the hydrogenation reduction reaction is a compound in which R1, R3 and R4 are all methyl groups in the compound represented by the general formula (A).

[0079] In the method for producing the cyclic peptide compound of the present invention, since the cyclic peptide compound can be obtained by subjecting the cyclic peptide derivative obtained by the above-described method for producing the cyclic peptide derivative to a hydrogenation reduction reaction, the cyclic peptide compound can be obtained in a high yield. Moreover, depending on the type of Compound C used in the method for producing the cyclic peptide derivative, cyclic peptide compounds to which various amino acids and the like are bonded can be obtained.

[0080] 3. Preparation method of raw materials used in the present invention Hereinafter, in the method for producing the cyclic peptide derivative of the present invention, an example of the method for producing the compound represented by formula (2) used in step A will be described. The method for producing the compound represented by formula (2) is not particularly limited, and for example, known production methods can be widely adopted.

[0081] In the method for producing the compound represented by formula (2), when R 6 is a protecting group, for example, it can include a step of obtaining a compound represented by the following formula (22a) by an intramolecular cyclization reaction of a cyclization precursor represented by the following formula (21a) (hereinafter referred to as a cyclization step).

[0082]

Chemical formula

[0083] In formula (21a), R1 to R5 and m are synonymous with R1 to R5 and m in formula (1) above. In formula (21a), MOM represents a methoxymethyl group (hereinafter the same). TBS represents a tert-butyldimethylsilyl group.

[0084]

Chemical formula

[0085] In formula (22a), R1 to R5 and m are synonymous with R1 to R5 and m in formula (1) above.

[0086] In the cyclization step, an intramolecular cyclization reaction of the cyclization precursor represented by formula (21a) forms an amide bond between the β-hydroxyisoleucine unit and the β-hydroxydopa unit, thereby forming a compound represented by formula (22a).

[0087] Regarding the intramolecular cyclization reaction, in a conventionally known method (for example, the method described in P. Li, C. D. Evans, M. M. Joullie, Org. Lett., 2005, 7, 5325), the yield remains at 10 - 20%, and it was known that a large amount of the dimer of the cyclization precursor was by-produced. Also, in another method (for example, P. Li, C. D. Evans, Y. Wu, B. Cao, E. Hamel, M. M. Joullie, J. Am. Chem. Soc., 2008, 130, 2351), although the yield was improved to 30 - 40%, it still did not exceed 40%.

[0088] In this regard, in the present invention, in the cyclization step, by dropping a dilute substrate solution into a solvent containing a binder, the concentration of the substrate (that is, the compound represented by formula (21a)) is diluted, the progress of the intermolecular reaction is suppressed, and the progress of the intramolecular cyclization reaction is promoted, so that the intramolecular cyclization reaction can be carried out at a higher yield than before. By carrying out such an intramolecular cyclization reaction, the intermolecular reaction can be suppressed, and it is presumed that the yield of the target cyclized compound (that is, the compound represented by formula (22a)) will increase.

[0089] In the cyclization step, the type of the binder is not particularly limited, and binders used in the intramolecular cyclization reaction can be widely used. Examples of the binder include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).

[0090] The solvent used for dissolving the binder and the substrate in the cyclization step is not particularly limited, and it is preferably a polar solvent such as chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; alcohols such as methanol, ethanol, isopropyl alcohol and t-butanol; amide solvents such as N,N-dimethylacrylamide; etc. The solvents may be used alone or in combination of two or more.

[0091] As the concentration of the binder, for example, based on the solvent used, it can be in the range of 1 mM to 15 mM. Also, the concentration of the substrate can be in the range of 0.1 mM to 1.5 mM based on the solvent used.

[0092] The temperature in the intramolecular cyclization reaction is not particularly limited, and for example, it can be carried out at -20 to 60 °C, preferably at 0 to 30 °C. The reaction time can be appropriately set according to the reaction temperature etc. For example, after the substrate is added dropwise over 6 to 24 hours, the reaction can be continued for 6 to 24 hours, but it is not limited thereto. In particular, by reacting over time at low temperature, the intramolecular cyclization reaction is promoted, and the yield of the cyclized compound (the compound represented by formula (22a)) can be improved by about 1.5 to 2.5 times compared to the conventional cyclization reaction.

[0093] After obtaining the compound represented by formula (22a) by the intramolecular cyclization reaction, the compound represented by formula (2) can be obtained by deprotecting MOM. The method for deprotecting MOM is not particularly limited, and for example, it can be carried out under the same conditions as the known method for deprotecting MOM. Before deprotecting MOM, for example, the protecting group in the compound represented by formula (22a) can be replaced with another protecting group (for example, the Boc group substituted on the N atom is replaced with a nosyl group). Furthermore, before deprotecting MOM, the N atom to which a protecting group such as a nosyl group is bonded can also be methylated. Methylation can widely adopt known methods, and methylation with methyl p-nitrobenzenesulfonate is exemplified.

[0094] The production method for obtaining the compound represented by formula (21a) used in the cyclization step is not particularly limited. For example, the compound represented by formula (21a) can be obtained by known reactions. As an example, the compound represented by formula (21a) can be obtained through a step of reacting the compound represented by the following formula (7a) with the compound represented by the following formula (8a).

[0095]

Chemical formula

[0096] In formula (7a), R5 and m have the same meanings as R5 and m in formula (1) above. The compound represented by formula (7a) is a β-hydroxydopa unit.

[0097]

Chemical formula

[0098] In formula (8a), R1 and R2 have the same meanings as R1 and R2 in formula (1) above. The compound represented by formula (8a) is an aziridine compound.

[0099] For the reaction between the compound represented by formula (7a) and the compound represented by formula (8a), for example, conditions similar to known ring-opening reactions can be adopted. In this ring-opening reaction, for example, it can be carried out in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).

[0100] In formula (8a), when R2 is an ethynyl group, the nucleophilic reaction rate is extremely fast, whereby the nucleophilic addition reaction between the β-hydroxydopa unit and aziridine proceeds rapidly, and the yield of the reaction product also increases. Therefore, the production method of the present invention also has an advantage in that aziridine that has not reacted with the amino acid can be used.

[0101] After the reaction of the compound represented by formula (7a) and the compound represented by formula (8a), through the reaction of introducing a protecting group (MOM), the compound represented by the following formula (13a) is synthesized. The reaction conditions for introducing the protecting group are not particularly limited and can be the same as known methods.

[0102]

Chemical formula

[0103] In formula (13a), R1, R2, R5 and m have the same meanings as R1, R2, R5 and m in the above formula (1).

[0104] Thereafter, by undergoing a deprotection reaction and an esterification reaction of the compound represented by formula (13a), the compound represented by the following formula (18a) can be obtained. The deprotection reaction and esterification reaction conditions are not particularly limited and can be the same as known methods.

[0105]

Chemical formula

[0106] In formula (18a), R1, R2, R5 and m have the same meanings as R1, R2, R5 and m in the above formula (1).

[0107] After deprotecting the Troc group (2,2,2-trichloroethoxycarbonyl group) of the obtained compound represented by formula (18a), for example, performing a condensation reaction with a valine compound having a 9-fluorenylmethyloxycarbonyl group and further performing deprotection, the compound represented by formula (21a) (cyclization precursor) is produced. In this condensation reaction, an appropriate condensing agent can be used.

[0108] In addition, when R2 is an ethynyl group, reduction can be carried out as necessary. This reduction can be carried out in the step of performing a hydrogen reduction reaction after the condensation reaction in Step A as described above, or can be carried out at any time as long as it is after the nucleophilic addition reaction with the aziridine. In this regard, when R2 is an ethynyl group, since the ethynyl group is not particularly bulky compared to an alkyl group and is less likely to inhibit the reaction, the ethynyl group can be maintained without reduction until the hydrogen reduction reaction.

[0109] In addition, the method for producing the compound represented by the formula (7a) is not particularly limited. For example, it can be produced by a reaction using the compound represented by the following formula (1a) and the compound represented by the following formula (2a) as starting materials.

[0110] [Chemical formula]

[0111] [Chemical formula]

[0112] In the formula (2a), R5 and m have the same meanings as R5 in the formula (1).

[0113] On the other hand, the compound represented by the formula (8a) can be obtained, for example, by a known production method, or can also be obtained from a commercially available product. [Examples]

[0114] Hereinafter, the present invention will be described more specifically by way of examples, but the present invention is not limited to the embodiments of these examples.

[0115] (Production Example 1; Synthesis of β-hydroxydopamine unit) According to the scheme shown in Figure 1, the β-hydroxydopa unit (the compound represented by formula (7a)) was synthesized. The inventors have previously found that when aryl bromide 2 is added to Garner aldehyde 1 (the numbers after the compound names correspond to the numbers attached to the structural formulas in the figure; the same applies hereinafter), the S-alcohol is obtained with a selectivity of 82:18. Using this S-alcohol, the configuration of the secondary hydroxy group was inverted and led to the R-alcohol 4, thereby selectively synthesizing the desired catechol form (β-hydroxydopa unit) 5. This will be described in detail below.

[0116] Specifically, first, halogen-lithium exchange was carried out on 2 equivalents of aryl bromide 2 with n-BuLi, and then it was added to Garner aldehyde 1 in THF under the condition of -78 °C to obtain the S-alcohol in a yield of 86% and a diastereoselectivity of 4:1. By Swern oxidation of the S-alcohol, ketone 3 was obtained in a yield of 86%. Since ketone 3 could be synthesized, subsequent stereoselective reduction was carried out. When reacted with 2 equivalents of K-Selectride in THF, the reaction proceeded rapidly under the condition of -15 °C, giving the R-alcohol 4 as the main product with a stereoselectivity of 5.6:1.

[0117] Subsequently, the hydroxyl group of the alcohol 4 obtained by reducing the ketone was protected with a TBS group and led to compound 5. The stereoselectivity of alcohol 4 was determined by the integration ratio of the Si-Me spectral peaks of 1H-NMR at this stage. Subsequently, aldehyde 6 was obtained by hydrolyzing the dioxane moiety. Without purifying aldehyde 6, it was possible to lead to the target catechol form 7 (β-hydroxydopa unit 7) by Dakin oxidation. When the physical properties of the obtained β-hydroxydopa unit 7 were confirmed by specific rotation measurement method and high-resolution mass spectrometry, "[α]" 1 =-40.8 (c 1.20, CHCl3); HRMS (ESI) calcd for C D 20 H 13 H 18 N2Na1O3S1, m / z 566.2914 [M + Na] +, it was "found 566.2914".

[0118] In Figs. 2(a) and (b), respectively, the 1 1H-NMR (300 MHz, CDCl3) and 13 13C-NMR (100 MHz, CDCl3) results are shown. From these NMR results, it was confirmed that the target compound was successfully synthesized.

[0119] (Production Example 2; Synthesis of β-Hydroxyisoleucine Unit) Since β-Hydroxydopa Unit 7 could be synthesized in Production Example 1, subsequent linkage of amino acid fragments was carried out to attempt the synthesis of β-Hydroxyisoleucine Unit. This reaction was carried out in three steps: the first step shown in Fig. 3, the second step shown in Fig. 4, and the third step shown in Fig. 5.

[0120] According to the scheme shown in Fig. 3, as the first step, in the presence of TBD (1,5,7-Triazabicyclo[4.4.0]dec-5-ene), the coupling of Catechol Body 7 and known Aziridine 8 was carried out at room temperature in toluene. The reaction proceeded regioselectively to obtain Ether 9. By reacting 1.5 equivalents of TBAF (Tetrabutylammonium Fluoride) with Ether 9 at 0 °C, only the primary TBS group was selectively deprotected, and Alcohol 10 was obtained in an 82% yield in two steps. Subsequently, an attempt was made to change the protecting group as a preliminary step for the linkage with valine. First, the nosyl group was deprotected from Alcohol 10, and the resulting Amine 11 was protected with Troc (2,2,2-Trichloroethoxycarbonyl). Subsequently, the primary alcohol of Troc Body 12 was protected with MOM (Methoxymethyl).

[0121] As shown in Fig. 4, as the second step, the Acetonide 13 obtained in the first step was selectively deprotected using CeCl3 to obtain Alcohol 14 in a 63% yield. At this time, Diol 15 in which the secondary TBS group was also deprotected simultaneously was obtained in a 13% yield. The obtained Diol 15 was protected with TBS, and by deprotecting only the primary TBS group, it was led to Alcohol 14.

[0122] Next, as shown in FIG. 5, as the third step, alcohol 14 was derived into carboxylic acid 17 by known Dess-Martin oxidation and Pinnick oxidation. Thereafter, by reacting diazomethane in diethyl ether, it was converted into methyl ester 18 in a yield of 91%. When the physical properties of the obtained methyl ester 18 were confirmed by specific rotation measurement method and high-resolution mass spectrometry, "[α] D 20 = -38.9 (c 0.20, CHCl3); HRMS (ESI) calcd for C 39 H 55 Cl3N2Na1O 11 S1, m / z 883.2509 [M+Na] + , found 883.2520".

[0123] FIGS. 6(a) and (b) respectively show the 1 1H-NMR (400 MHz, CDCl3) and 13 13C-NMR (100 MHz, CDCl3) results of methyl ester 18. From these NMR results, it was confirmed that the target compound was successfully synthesized.

[0124] (Production Example 3; Synthesis of Cyclization Precursor) According to the scheme shown in FIG. 7, the Tro group was deprotected from methyl ester 18 with Zn and condensed with Fmoc-Val (N-(9-fluorenylmethoxycarbonyl)-L-valine) without purification. 3-(Diethoxyphosphoryloxy)-3H-benzo[d][1,2,3]triazin-4-one (DEPBT) was used as the condensing agent. The obtained condensate 20 was simultaneously deprotected with LiOH for the methyl ester and the Fmoc group to synthesize a cyclization precursor 21 (a compound represented by formula (21a)).

[0125] When the physical properties of the obtained cyclization precursor 21 were confirmed by specific rotation measurement method and high-resolution mass spectrometry, "[α] D 20=-31.4 (c 0.10, CHCl3) FTIR (neat) cm -1 ; HRMS (ESI) calcd for C 40 H 61 N3Na1O 10 S1, m / z 794.4024 [M+Na] + , found 794.4030」.

[0126] Figures 8(a) and (b) respectively show the 1 1H-NMR (400 MHz, MeOD) and 13 13C-NMR (100 MHz, MeOD) results of the cyclization precursor 21. From these NMR results, it was confirmed that the target compound was successfully synthesized.

[0127] (Example 1) Synthesis of macrolactam structure According to the scheme shown in Figure 9, the cyclization reaction of the cyclization precursor 21 obtained in Production Example 3 was carried out.

[0128] The condensing agent was prepared to a concentration of 10 mM in CH2Cl2, and the cyclization precursor 21 was prepared to a concentration of 1 mM in CH2Cl2 as the substrate. A dilute substrate solution was dropped into the solvent containing the binder to carry out the intramolecular cyclization reaction of the cyclization precursor 21. By diluting the concentration of the substrate in this way, the progress of the intermolecular reaction was suppressed, and the progress of the intramolecular cyclization reaction was promoted. The cyclization reaction was carried out with the reagents used at room temperature for 22 hours. By slowly reacting at low temperature, the intramolecular cyclization reaction was promoted, and it was confirmed that the yield of the cyclized product 22 (the compound represented by formula (22a)) reached 59%.

[0129] When the physical properties of the obtained cyclized product 22 were confirmed by the specific rotation measurement method and the high-resolution mass spectrometry method, "[α] D 20 =-48.7 (c 0.10, CHCl3); HRMS (ESI) calcd for C 40 H 59 N3Na1O9S1, m / z 776.3918 [M+Na] +, it was "found 776.3914".

[0130] In FIGS. 10(a) and (b), respectively, for the cyclized product 22 1 1H-NMR (400 MHz, CDCl3) and 13 13C-NMR (100 MHz, CDCl3) results are shown. From these NMR results, it was confirmed that the target compound had been synthesized.

[0131] Linkage with glutamic acid Next, according to the scheme shown in FIG. 11, using the obtained cyclized product 22, attempts were made for N-methylation and ligation with glutamic acid.

[0132] First, for the obtained cyclized product 22, in the presence of TMSOTf (trimethylsilyl trifluoromethanesulfonate) and 2,2'-bipyridyl, the reaction was carried out in CH2Cl2 at room temperature to deprotect the Boc group. The resulting amine was nosyl-protected to obtain the nosyl product 23 in a 78% yield. The nosyl product 23 was reacted with methyl p-nitrobenzenesulfonate in toluene to quantitatively synthesize the N-methyl product 24.

[0133] Subsequently, in order to carry out the ligation with glutamic acid, the MOM group was deprotected in advance with catecholborane bromide to obtain alcohol 25 (the compound represented by formula (2)) in a 98% yield. Alcohol 25 was induced to carboxylic acid 26 by known Dess-Martin oxidation and Pinnick oxidation. The obtained carboxylic acid 26 was condensed with dibenzyl glutamate without purification to synthesize the condensate 27 in a 66% yield in three steps. Thus, the synthesis of the protected form of the cyclic peptide derivative, which is the compound represented by formula (1), could be achieved in a high yield.

[0134] In FIG. 12, the 1 1H-NMR (400 MHz, CDCl3) results of the obtained condensate 27 are shown. From this NMR result, it was confirmed that the target compound had been synthesized.

[0135] (Example 2; Synthesis of Cyclic Peptide Derivative by Deprotection) According to the scheme shown in Fig. 13, using the obtained condensate 27, the synthesis of the cyclic peptide derivative by deprotection was carried out.

[0136] By reacting TBAF (tetrabutylammonium fluoride) with condensate 27, the TBS group was deprotected to obtain alcohol 28 in a 96% yield. Subsequently, by reacting PhSH and Cs2CO3 with alcohol 28, the nosyl group was deprotected to obtain precursor 29 of the cyclic peptide derivative. For precursor 29, the alkyne was reduced using a Pd / C catalyst under a hydrogen atmosphere to synthesize cyclic peptide derivative (A) (the cyclic peptide derivative represented by formula (A)) in a 57% yield.

[0137] When the physical properties of the obtained cyclic peptide derivative (A) were confirmed by specific rotation measurement method and high-resolution mass spectrometry, it was found that "[α] D 25 =-42.5(c 0.10,H2O) natural product, [α] D 28 =-44.3(c 0.20,H2O); HRMS(FAB) calcd for C 26 H 37 N4O 10 , m / z 565.2515 [M-H] - , found 565.2512". The 1 1H-NMR (400 MHz, CDCl3) and 13 13C-NMR (300 MHz, D2O) results of cyclic peptide derivative (A) are shown below. " 11H NMR (300 MHz, D2O) δ7.16 (dd, J = 8.5, 2.0 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1 H), 6.94 (d, J = 2.0 Hz, 1 H), 4.74-4.84 (m, 2 H), 4.17 (m, 1 H), 4.08 (d, J = 10.5 Hz, 1 H), 3.90 (d, J = 9.6 Hz, 1 H), 2.71 (s, 3 H), 2.26 (brt, J = 7.7 Hz, 2 H), 2.16-2.02 (m, 2 H), 1.92-1.80 (m, 2 H), 1.72 (s, 3 H), 1.66 (m, 1 H), 1.08 (t, J = 7.2 Hz, 3 H), 0.82 (d, J = 6.6 Hz, 3 H), 0.70 (d, J = 6.6 Hz, 3 H); 13 13C NMR (150 MHz, D2O) δ182.1, 180.1, 173.0, 172.5, 168.3, 153.0, 144.9, 132.7, 125.8, 124.7, 121.1, 88.2, 75.3, 71.1, 62.2, 61.7, 57.4, 41.4, 34.6, 34.5, 31.1, 30.3, 23.4, 20.6, 20.2, 10.1 It was confirmed that the obtained cyclic peptide derivative (A) has the same NMR spectrum as the cyclic peptide derivative derived from natural products.

Claims

1. The following general formula (1): 【Chemical Formula 1】 (In formula (1), R １ represents a hydrogen atom or a hydrocarbon group, R ２ represents a hydrogen atom or a hydrocarbon group, R ３ represents a hydrogen atom or a hydrocarbon group, R ４ represents a hydrogen atom or a hydrocarbon group, R ５ is -O-R ５１ (R ５１ represents a hydrogen atom or a protecting group), R ６１ is -O-R ６ (R ６ represents a hydrogen atom, a hydrocarbon group or a protecting group), R ７ represents a hydrogen atom, a hydrocarbon group or a protecting group, R ８ represents a hydrogen atom, a hydrocarbon group or a protecting group, R ９ represents a hydrogen atom, a hydrocarbon group or a protecting group, R １０ represents a hydrogen atom, a hydrocarbon group or a protecting group, R １１ represents a hydrogen atom, a hydrocarbon group or a protecting group, R １２ represents a hydrogen atom or a protecting group, R １４ is -(CH ２ ) ｎ -COOR １３ (R １３ represents a hydrogen atom or a protecting group, and n is a number of 1 or more), Provided that at least one of R ５１ , R ６ , R １２ and R １３ is other than a hydrogen atom, and m is 1) A method for producing a cyclic peptide derivative represented by The following general formula (2) 【Chemical Formula 2】 (In formula (2), R １ , R ２ , R ３ , R ４ , R ５ , R ６１ , R ７ , R ８ , R ９ , R １０ and m are respectively the same as R １ , R ２ , R ３ , R ４ , R ５ , R ６１ , R ７ , R ８ , R ９ , R １０ and m in the following formula (1)) A step of subjecting a product obtained by an oxidation reaction of a compound represented by the formula to a condensation reaction with a compound having both a carboxy group and an amino group, or a salt or ester of the compound, wherein the compound represented by the formula (2) is the following formula (21a) 【Chemical Formula 3】 (In formula (21a), R １ , R ２ , R ３ , R ４ , R ５ and m are the same as R １ , R ２ , R ３ , R ４ , R ５ and m in the following formula (1), MOM represents a methoxymethyl group, TBS represents a tert-butyldimethylsilyl group, and Boc represents a tert-butoxycarbonyl group) By an intramolecular cyclization reaction of a cyclization precursor represented by the formula, the following formula (22a) 【Chemical Formula 4】 (In formula (22a), R １ , R ２ , R ３ , R ４ , R ５ and m are the same as R １ , R ２ , R ３ , R ４ , R ５ and are synonymous with m, MOM represents a methoxymethyl group, TBS represents a tert-butyldimethylsilyl group, and Boc represents a tert-butoxycarbonyl group) including a step of obtaining by a method comprising a cyclization step of producing a compound represented by In the cyclization step, the compound represented by the formula (21a) is dropped into a binder having a concentration of 1 mM to 15 mM, the production method.

2. The method according to claim 1, wherein the compound having both the carboxy group and the amino group is an amino acid.

3. The method according to claim 2, wherein the amino acid is glutamic acid or aspartic acid.

4. The production method according to any one of claims 1 to 3, wherein the oxidation reaction includes Dess-Martin oxidation and Pinnick oxidation.

5. The production method according to any one of claims 1 to 4, wherein a phosphorus-based condensing agent is used in the condensation reaction.

6. In the formula (1), R ２ is an alkynyl group, the production method according to any one of claims 1 to 5.

7. In the formula (1), R １４ is -(CH ２ ) ２ -COOR １３ (R １３ is synonymous with R １３ of the formula (1)), the production method according to any one of claims 1 to 6.

8. A method for producing a cyclic peptide compound, comprising a step of obtaining a cyclic peptide compound by subjecting the cyclic peptide derivative obtained by the production method according to any one of claims 1 to 7 to a hydrogenation reduction reaction.

9. The cyclic peptide compound is represented by the following general formula (10). 【Chemical 5】 (In formula (10), R １ , R ２ , R ３ , R ４ , R ６１ , R ７ , R ８ , R ９ , R １０ , and R １１ are each synonymous with R １ , R ２ , R ３ , R ４ , R ６１ , R ７ , R ８ , R ９ , R １０ , and R １１ in formula (1)).) The production method according to claim 8, which is a compound represented by .

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