Method for deprotecting peptide compound or amide compound and method for removing resin in solid-phase reaction as well as method for producing peptide compound

Abstract

To provide a method for removing a protecting group that can be removed under acidic conditions while suppressing side reactions such as the cleavage or transfer of an amide bond contained in a peptide compound, to provide a method for removing resin in solid-phase reaction, and to provide a method for obtaining a deprotected and / or deresined peptide compound in high yield and high purity with a simple operation.SOLUTION: A method for producing a peptide compound from which a protecting group has been deprotected includes a step of deprotecting the protecting group that can be deprotected by a silylating agent from a starting peptide compound by contacting the starting peptide compound / starting amide compound with the silylating agent. The method can produce a peptide compound / amide compound from which a desired protecting group has been deprotected and / or which has been deresined from a resin for solid-phase synthesis without causing damage to the main chain.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for deprotecting a peptide compound or an amide compound, a method for removing a resin from a resin in a solid-phase reaction, and a method for producing a peptide compound. [Background technology]

[0002] Peptides are molecules consisting of a large number of linked amino acids. In addition to research into the synthesis of peptides produced by living organisms, research into artificially designing peptide structures to produce peptides with desired functions is being actively conducted (Non-Patent Document 1).

[0003] Peptides can be produced by linking multiple amino acids together by repeating steps (i) to (iii) of (i) reacting an activated ester, which has a protecting group at its N-terminus and has the carboxyl group of an amino acid with no C-terminus protection activated with a condensing agent or the like, with a peptide with no N-terminus protection to obtain a peptide with a new amino acid extension, and (iii) removing the protecting group at the N-terminus of the extended peptide (Non-Patent Document 2).

[0004] The production of peptides is roughly divided into solid-phase and liquid-phase methods. In the solid-phase method, a coupling reaction is carried out in which the amino group of an amino acid or its derivative (protected amino acid) or a peptide or its derivative, which is supported at the C-terminus of the amino acid or peptide, is used as a nucleophilic point, and the carbonyl group of an N-terminus-protected peptide or amino acid is used as an electrophilic point, on a solid-phase synthesis resin such as CTC resin, Wang resin, or SASRIN resin, which contains a chlorotrityl group or a benzyl group. In the liquid-phase method, a coupling reaction is carried out in which the carbonyl group of an N-terminus-protected amino acid or peptide is used as an electrophilic point, and the amino group of an amino acid or peptide is used as a nucleophilic point. In cases where the side chains of an amino acid or peptide are subjected to undesired functional group conversion by these coupling reactions, it is necessary to introduce protective groups to these side chains. Protective groups that can be removed under acidic conditions, such as Boc, t-Bu, or trityl groups, are commonly used as protective groups for protecting the C-terminus of an amino acid or peptide, the N-terminus of an amino acid or peptide, and the side chains of an amino acid or peptide. In addition, in a de-resination reaction in which a peptide bound to a solid-phase synthesis resin is cleaved from the solid-phase synthesis resin, solid-phase synthesis resins that can be removed under acidic conditions, such as CTC resin, Wang resin, and SASRIN resin, are widely used (Non-Patent Document 4).

[0005] Further, protecting groups that are deprotected under acidic conditions include 3,5-dimethoxyphenylisopropoxycarbonyl (Ddz) group, benzyloxycarbonyl (Cbz) group, benzyl (Bn) group, and cyclohexyl (cHx) group (Non-Patent Documents 4 and 5). Under the reaction conditions of these deprotection reactions or resin removal reactions, side reactions such as cleavage of amide bonds in peptides and unintended functional group conversion of amino acid side chains may occur, and peptides with unintended sequences may be by-produced. Therefore, it is required to obtain the desired peptide without causing damage reactions to the main chain, such as cleavage reactions of amide bonds and transfer reactions of the main chain of peptides.

[0006] The above-mentioned protecting groups that can be removed under acidic conditions are often removed by treatment with hydrochloric acid, sulfuric acid, methanesulfonic acid, or TFA (Non-Patent Documents 2, 3, 4). Furthermore, TFA is usually used for the resin removal reaction in solid-phase synthesis (Non-Patent Document 6). However, it has been reported that amide bonds may be cleaved even under the acidic conditions of TFA, which is a milder acid among these (Non-Patent Document 7).

[0007] In addition, it has been described that the problem of cleavage of amide bonds was attempted to be solved by performing the Boc-removal reaction under diluted TFA conditions and under mild conditions, but neither of these conditions improved the situation (Non-Patent Document 8, Patent Document 1). In addition, a method has been reported in which the protecting group of a protected amino acid is removed by using TFE, which is less acidic (Non-Patent Document 5, Patent Document 1). In these documents, the reaction conversion rate is low, so the reaction needs to be performed under harsher reaction conditions, such as adding more acid to proceed with the reaction or increasing the reaction temperature. However, when reaction conditions in which acid is added or the reaction temperature is increased are applied to peptides, there is a concern that the peptide backbone may be damaged. In fact, a de-Boc reaction was attempted by treating Boc-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl with hydrogen chloride in TFE, but the backbone was cleaved before the completion of the Boc-removal reaction.

[0008] It has also been reported that cleavage of amide bonds can be suppressed by performing the reaction under low-temperature conditions and stopping the reaction before side reactions occur (Non-Patent Document 9). However, this method requires strict control of the reaction time, and it is easily predicted that such control will be difficult in mass production, where it is difficult to stop the reaction in a short time.

[0009] In a deprotection method under acidic conditions, attempts have been made to add a cation scavenger to suppress side reactions of the coexisting t-Bu cation with the side chain during deprotection of the Boc group or t-Bu group (Non-Patent Document 10).

[0010] In this case, in order to capture the t-Bu cation derived from the t-Bu group, a method of deprotection under acidic conditions by adding a sulfur-containing additive such as dimethyl sulfide or thioanisole has been attempted. However, it has been reported that a side reaction of cleaving the amide bond occurs during this process, resulting in a decrease in yield and purity (Non-Patent Document 7).

[0011] In addition, a method of reacting thioanisole with TfOH in a TFA solution, or thioanisole with trimethylsilyl bromide or trimethylsilyl triflate in a TFA solution has also been reported (Non-Patent Document 12).

[0012] However, many of the sulfur-containing additives, such as dimethyl sulfide and thioanisole, have a foul odor, which is a concern for production workers. Another problem is that the additives require a removal process using column chromatography, which is not suitable for mass production.

[0013] It has also been reported that even when water is used as a cation scavenger, cleavage of peptide chains increases (Non-Patent Document 11).

[0014] As a deprotection method using a silicon-containing additive as a cation scavenger instead of a sulfur-containing additive, triisopropylsilane (iPr 3 SiH) as a cation scavenger, e.g., TFA:iPr 3 SiH:H 2 O = 95:2.5:2.5 ratio (Non-Patent Document 13), or TFA:iPr 3 SiH:H 2A method has been reported in which an N-Boc-protected compound containing an amide bond is treated with O:PhOH=1000:50:67:50 (Non-Patent Document 14) to remove the Boc group. However, these methods only describe conditions that are difficult to implement in mass production, such as a short treatment time of several minutes to suppress cleavage of the amide bond. In fact, when a de-Boc reaction was attempted for Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MePhe-MeAla-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl under the conditions of Non-Patent Documents 13 and 14, cleavage of the amide bond between both MePhe and MeAla was observed before the removal of the Boc group was completed. In addition, the cleavage rate increased with time.

[0015] As described above, deprotection under acidic conditions and deresination in solid-phase synthesis may not only result in the desired deprotection or deresination, but may also result in damage to the main chain, such as cleavage of the amide bond in the main chain of the peptide chain and transfer of the side chain functional group of the amino acid to the main chain. It is known that the generation of by-products due to such damage to the main chain reduces the yield and purity of the target product, which is a problem in synthesizing peptides efficiently.

[0016] On the other hand, it has been reported that the structural features of a peptide are related to the stability and susceptibility to damage of the amide bond. For example, it is known that the acid lability of an amide bond increases due to distortion of the amide bond (Non-Patent Documents 15 and 16).

[0017] In addition to the distortion of the bond, in the case of amide bonds in peptides, the type of amino acid side chain, the substitution pattern of the nitrogen atom, and the number of amino acid residues in the peptide and the amino acid sequence affect the intramolecular hydrogen bond pattern and the stable conformation of the peptide. Depending on these conformational changes, the basicity of the carbonyl oxygen may increase, making it more susceptible to protonation (Non-Patent Documents 18 and 19). In some cases, it is known that oxazolone is formed, damaging the amide bond (Non-Patent Document 17).

[0018] It has also been reported that peptides containing N-Me amino acids, in which the nitrogen atom of the amino acid is methylated, may undergo cleavage of the amide bond under acidic conditions (Non-Patent Documents 11, 17, 20). Furthermore, in the case of a peptide in which the C-terminus is an N-Me amino acid, it is known that exposure to TFA acidic conditions may result in cleavage of the amide bond between the first and second residues of the peptide, resulting in the by-product of a peptide lacking the C-terminal residue (Non-Patent Document 21). In other words, it is known that the amide bond containing the N-Me group of the N-Me amino acid is easily cleaved.

[0019] In addition, peptides with a sequence of two or more consecutive N-Me amino acid residues are often unstable to acids, and it is known that amide bonds are cleaved during the resin removal reaction in solid-phase synthesis (Non-Patent Document 11). That is, it is known that amide bonds containing the N-Me group of the N-Me amino acid and / or amide bonds containing the carbonyl group of the N-Me amino acid are easily cleaved.

[0020] In addition, peptides containing Asp or Gln are also unstable to acid depending on the sequence (Non-Patent Documents 22 and 23). For example, it is known that when a peptide sequence containing Asp is treated with an acid such as hydrogen fluoride or methanesulfonic acid, a nucleophilic attack of the nitrogen atom of the main chain amide on the carbonyl group of the side chain proceeds, resulting in the by-product of aspartimide (Non-Patent Document 23). In other words, it is known that even in N-unsubstituted amino acids, the amide bond at a site containing an amino acid with a specific side chain is easily cleaved.

[0021] When this aspartimide intermediate is hydrolyzed, a rearrangement product with a changed amide structure and a main chain cleavage product are produced as by-products, resulting in a decrease in the yield and purity of the target product. The formation of aspartimides is prominent when peptides containing sequences such as Asp(OBn)-Gly, Asp(OBn)-Ser, Asp(OBn)-Thr, Asp(OBn)-Asn, and Asp(OBn)-Gln are deprotected under acidic conditions. For example, it is known that when Boc-Phe-Asp(OBn)-Asn-Ala-OBn is deprotected using methanesulfonic acid, most of the peptide is converted to an aspartimide form, which does not have the desired amino acid sequence, that is, a main chain damage reaction occurs (Non-Patent Document 24).

[0022] It is also known that when a peptide derivative containing Asp-Pro in its sequence is subjected to acidic conditions such as trifluoroacetic acid, hydrofluoric acid, formic acid, or acetic acid, the Asp side chain reacts with the nitrogen atom of Pro, similar to the above-mentioned side reaction, and the amide bond is cleaved (Non-Patent Documents 25 and 26).

[0023] Several methods have been reported to avoid side reactions during the deprotection reaction, which occur due to the amino acid sequence-dependent instability of amide bonds to acids.

[0024] For example, as a method for suppressing the formation of aspartimide in the deprotection or deresination reaction of an aspartic acid amide derivative, a known example is to protect the protecting group of the carboxyl group in the aspartic acid side chain with a cyclohexyl group so that nucleophilic attack on the nitrogen atom of the main chain amide does not proceed under the deprotection conditions of the desired protecting group, and it has been reported that the formation of aspartimide is significantly suppressed compared to when a benzyl protecting group is used as the side chain protecting group (Non-Patent Document 27). However, the subsequent removal of the cyclohexyl group requires highly corrosive strong acidic conditions such as hydrofluoric acid, and it is easily inferred that the reaction and post-treatment are not simple.

[0025] Also, a method of treating with 1M trimethylsilyl bromide / TFA in the presence of thioanisole is known (Non-Patent Document 28). However, this condition requires the use of a solvent amount of TFA, and as mentioned above, the use of thioanisole, which is unsuitable for mass production, is problematic. Furthermore, it has been reported that the by-product aspartimide increases significantly when trimethylsilyl triflate is used instead of trimethylsilyl bromide, suggesting that trimethylsilyl bromide is superior to trimethylsilyl triflate.

[0026] Methods are known in which peptide de-Boc and ester de-t-Bu are carried out in the presence of a tertiary amine and trimethylsilyl triflate or TBDMSOTf. For example, there are known examples in which N-Boc deprotection is carried out in the presence of other functional groups under the conditions of TMSOTf / 2,6-lutidine using 2,6-lutidine as a tertiary amine, thereby selectively deprotecting Boc (Non-Patent Documents 29, 30, 31). There are also known examples in which the de-resin reaction and de-Boc reaction from a solid-phase synthesis resin, which may occur simultaneously under acidic conditions using TFA, are carried out under the conditions of trimethylsilyl triflate / 2,6-lutidine, thereby selectively de-Boc-removing (Non-Patent Documents 32, 33). In these cases, the method is also applied to compounds having amide bonds, but is not intended to avoid damage to the amide bonds.

[0027] In addition, under the condition of trimethylsilyl triflate / 2,6-lutidine, deprotection of t-Bu esters has been selectively carried out in the presence of TBS groups, TIPS groups, and thioacetals (Non-Patent Document 34). Using this method, de-t-Bu conversion of t-Bu esters in peptides has also been reported. For example, there are known cases where deprotection of t-Bu esters has been carried out under the condition of TMSOTf / 2,6-lutidine (Non-Patent Documents 35 and 36). However, even in this case, the purpose is not to avoid cleavage of amide bonds.

[0028] In addition, it is known that when trimethylsilyl triflate / 2,6-lutidine is used in the N-Boc removal reaction in the total synthesis of natural peptide compounds, which gives a complex mixture when treated with protonic acid, the reaction suppresses by-products and gives the target product preferentially (Non-Patent Document 37). However, the side reactions described therein are not described in detail, and the versatility of the reaction conditions and the possibility of avoiding damage to amide bonds have not been examined at all. Furthermore, a large excess of reagents (20 equivalents or more) is required, which leaves problems in terms of the generality of applicable substrates and production costs. In this case, trimethylsilyl triflate / 2,6-lutidine is simply applied to a compound having an amide bond, and there is no mention of whether the side reaction is due to cleavage of the amide bond.

[0029] Thus, in the solid-phase method, in the reaction of cleaving a peptide from a resin carrying the peptide (resin removal reaction) to obtain an extended peptide, and in both the solid-phase method and the liquid-phase method, in the reaction of removing a protecting group that can be removed under acidic conditions among the protecting groups of the N-terminus, C-terminus, and side chain of an amino acid, a treatment under acidic conditions using a Brönsted acid, typically trifluoroacetic acid, is generally used. There are also known cases where the deprotection reaction is carried out in the presence of a Lewis acid. However, although it is known that when a peptide containing a non-natural amino acid, typically N-Me amino acid, is treated by a conventional method to carry out a resin removal reaction or a deprotection reaction, the peptide's main chain cleavage or transition (main chain damage) proceeds in association with the intended reaction, and a large amount of reagent is required, no solution to these problems is known (Non-Patent Documents 20, 22, 37).

[0030] In particular, research into non-natural artificial peptides often encounters unexpected side reactions when using conventional synthesis methods, so it is extremely important to develop methods for industrially and efficiently synthesizing non-natural artificial peptides and their derivatives. However, the production of these peptides containing non-natural amino acids has only been achieved by adapting conventional methods for producing peptides made from natural amino acids, and no efficient synthesis method was known that focuses on and solves the problems inherent in the production of peptides containing non-natural amino acids, particularly the unique problem of damage to the main chain during deprotection or deresination reactions. [Prior art documents] [Patent documents]

[0031] [Patent Document 1] International Publication No. 2014 / 033466 [Non-patent literature]

[0032] [Non-Patent Document 1] Future Med. Chem., 2009, 1,1289-1310. [Non-Patent Document 2] Amino Acids, Peptides and Proteins in Organic Chemistry: Building Blocks, Catalysis and CouplingChemistry, Volume 3, 2011 [Non-Patent Document 3] Amino Acids, 2018, 50, 39-68. [Non-Patent Document 4] Chem. Rev., 2009, 109,2455-2504. [Non-Patent Document 5] Russ. J. Bioorg. Chem. 2016,42, 143-152. [Non-Patent Document 6] J. Comb. Chem. 2002, 4, 1-16. [Non-Patent Document 7] J. Am. Chem. Soc. 1999, 121,6786-6791. [Non-licensed document 8] Org. Lett. 2012, 14, 612-615.

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[0033] The present inventors have found that when the same conditions as those of the treatment with an acid, typically TFA, which is commonly used in the deprotection step of removing the protecting group of an amino acid or peptide, or in the deresin step of cutting out a peptide from a resin in a solid-phase reaction, are applied to a peptide compound containing a non-natural amino acid, the main chain of the peptide compound is significantly damaged, such as by cleavage or transfer of the amide bond, and the peptide compound of the desired sequence cannot be efficiently obtained, making it difficult to produce the peptide compound. Specifically, the inventors have found that the amide bond of the portion containing an amino acid in which the nitrogen atom is N-substituted (e.g., N-alkylated) or the amide bond of the portion containing aspartic acid in a peptide compound is a bond whose main chain is easily damaged under acidic conditions. In addition to these problems, the present inventors have also found many more amino acid sequences that cause main chain damage under conventional acidic conditions. The present invention aims to provide a method for a reaction to remove a protecting group that can be removed under acidic conditions while suppressing side reactions such as cleavage or rearrangement of an amide bond contained in a peptide compound, and a reaction to remove a resin in a solid-phase reaction, and to provide a method for obtaining a deprotected and / or deresined peptide compound in high yield and high purity by a simple operation. [Means for solving the problem]

[0034] The present inventors have actively studied reactions for removing protective groups removable under acidic conditions, or de-resination reactions in solid-phase reactions, while suppressing side reactions such as cleavage or transfer of amide bonds in peptide compounds mainly containing N-substituted (e.g., N-alkylated) amino acids. After examining methods for reacting a silyl compound in the presence of an electrophilic species scavenger, they found that the protective group and / or resin can be removed by treating a peptide compound having an acid-labile amide bond with a silyl compound or acid in combination with an electrophilic species scavenger, and that the desired deprotected and / or de-resined product can be obtained in high yield and high purity without the concomitant damage to the main chain, which has been a concern. The present inventors have also found that, as a reagent for such deprotection and / or deresination, a suitable silyl compound or acid can be used in combination with a compound exemplified by imidate (formula 2), amide (formula 3), ketene acetal (formula 4), ketene alkoxyhemiaminal (formula 4), enol ether (formula 4), enol ester (formula 4), imine (formula 5), ​​amine (formula 6), diamine (formula 7), dialkylcarbodiimide (formula 8), urea (formula 9), or urethane (formula 10) as an electrophilic species capture agent. By using the present invention, the target peptide compound can be obtained more efficiently, in higher yield, and in higher purity than conventional methods, without the concomitant cleavage of the amide bond.

[0035] The present invention includes, in one non-limiting specific embodiment, the following. [1] A method for producing a peptide compound from which a protecting group has been deprotected, the method comprising the step of contacting a starting peptide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby deprotecting a protecting group that can be deprotected by the silylating agent from the starting peptide compound, the method comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting peptide compound comprises at least one deprotectable protecting group, and The starting peptide compound comprises at least one N-substituted amino acid residue. [2] A method for producing a peptide compound from which a solid-phase synthesis resin has been removed, comprising the step of contacting a starting peptide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby removing a solid-phase synthesis resin that can be removed by the silylating agent from the starting peptide compound, the method comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; the starting peptide compound is linked to the removable solid phase synthesis resin; and The starting peptide compound comprises at least one N-substituted amino acid residue. [3] The starting peptide compound is represented by the following general formula (I): [ka] [In the formula, R 1 is hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue; R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 4 Or R 2 and R 4’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 Form a 3- to 7-membered heterocyclic ring optionally substituted by alkoxy, where R 2 and R 4 When taken together, form a heterocycle, R 4’ is hydrogen, and R 2 and R 4’ When taken together, form a heterocycle, R 4 is hydrogen, R 4 and R 4’ is R 2 and R 4 or R 2 and R 4’except when taken together to form a heterocycle, (a)R 4’ is hydrogen and R 4 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 2 , N-PG 3 -Indol-3-ylmethyl, 4-(PG 2 O) Benzyl, PG 2 -O-methyl, 1-(PG 2 O) Ethyl, 2-(PG 2 O) Ethyl, PG 2 -OCO(CH 2 )-, P.G. 2 -OCO(CH 2 ) 2 -, P.G. 3 Nn-Butyl, -CON(R 14A )(R 14B ), -CH 2 -CON(R 14A )(R 14B ), and -(CH 2 ) 2 CON(R 14A )(R 14B ) or (b)R 4 and R 4’ is independently an optionally substituted C 1 -C 6 is alkyl, or (c)R 4 and R 4’ form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 5 is a single bond or -C(R 5A )(R 5B)-and R 5A and R 5B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 6 is hydrogen, and C 1 -C 6 alkyl; or R 6 and R 7 Or R 6 and R 7’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 Form a 3- to 7-membered heterocyclic ring optionally substituted by alkoxy, where R 6 and R 7 When taken together, form a heterocycle, R 7’ is hydrogen, and R 6 and R 7’ When taken together, form a heterocycle, R 7 is hydrogen, R 7 and R 7’ is R 6 and R 7 or R 6 and R 7’ except when taken together to form a heterocycle, (a)R 7’ is hydrogen and R 7 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 4 , N-PG 5 -Indol-3-ylmethyl, 4-(PG 4 O) Benzyl, PG 4 -O-methyl, 1-(PG 4 O) Ethyl, 2-(PG 4 O) Ethyl, PG 4 -OCO(CH 2 )-, P.G. 4 -OCO(CH 2 ) 2 -, P.G. 5 Nn-Butyl, -CON(R 15A )(R 15B ), -CH 2 -CON(R 15A )(R 15B ), and -(CH 2 ) 2 CON(R 15A )(R 15B ) or (b)R 7 and R 7’ is independently an optionally substituted C 1 -C 6 is alkyl, or (c)R 7 and R 7’ form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 8 is a single bond or -C(R 8A )(R 8B )-and R 8A and R 8B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4is selected from the group consisting of alkyl, R 9 is hydroxy, -O-PG 6 , a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES; RES is a resin for solid phase synthesis. R 14A and R 14B are independently hydrogen, C 1 -C 4 alkyl or R 14A and R 14B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R 15A and R 15B are independently hydrogen, C 1 -C 4 alkyl or R 15A and R 15B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 1 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 2 and P.G. 4 are independently hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl; PG 3 and P.G. 5 is independently selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; PG 6is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, and 2-(trimethylsilyl)ethyl. The method according to [1] or [2], comprising at least one structure in which at least two amino acid residues represented by the formula: [4] The starting peptide compound has the following general formula (II) at its C-terminus: [ka] [In the formula, R 1’ is a group represented by formula (III), [ka] * indicates a connection point R 1 is hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue; R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 10 Or R 2 and R 10’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 Form a 3- to 7-membered heterocyclic ring optionally substituted by alkoxy, where R 2 and R 10 When taken together, form a heterocycle, R 10’ is hydrogen, and R 2 and R 10’ When taken together, form a heterocycle, R 10 is hydrogen, R 10 and R 10’ is R 2 and R 10 or R 2 and R 10’ except when taken together to form a heterocycle, (a)R10’ is hydrogen and R 10 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 8 , N-PG 9 -Indol-3-ylmethyl, 4-(PG 8 O) Benzyl, PG 8 -O-methyl, 1-(PG 8 O) Ethyl, 2-(PG 8 O) Ethyl, PG 8 -OCO(CH 2 )-, P.G. 8 -OCO(CH 2 ) 2 -, P.G. 9 Nn-Butyl, -CON(R 16A )(R 16B ), -CH 2 -CON(R 16A )(R 16B ), and -(CH 2 ) 2 CON(R 16A )(R 16B ) or (b)R 10 and R 10’ is, independently, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 3 -C 6 Cycloalkyl C 1 -C 4 is alkyl, or (c)R 10 and R 10’ form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 11 is a single bond or -C(R 11A )(R 11B )-and R 11A and R 11B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 12 and R 12’ are independently hydrogen, PG 10 -O-methyl, -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES, RES is a resin for solid phase synthesis. n is 0, 1, or 2; R 6 is hydrogen, and C 1 -C 6 is selected from the group consisting of alkyl, R 13 is C 1 -C 4 Alkyl, or -(CH 2 ) m CON(R 17A )(R 17B ) and m is 0, 1, or 2; R 16A and R 16B are independently hydrogen or C 1 -C 4 alkyl or R 16A and R 16Btogether with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R 17A and R 17B are independently hydrogen, C 1 -C 4 alkyl or R 17A and R 17B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 1 is independently selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 8 is hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl; PG 9 is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and (2-(trimethylsilyl)ethyl). The method according to any one of [1] to [3], wherein the structure comprises at least two linked amino acid residues represented by the following formula: [5] A method for producing an amide compound from which a protecting group has been deprotected, comprising a step of contacting a starting amide compound with a silylating agent in a solvent, thereby deprotecting a protecting group that can be deprotected by a silylating agent from the starting amide compound, the method comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting amide compound has the following general formula (II): [ka] [In the formula, R 1’ is a hydrogen atom or PG 7 and R 12 and R 12’ are independently hydrogen, PG 10 -O-methyl, -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES, RES is a resin for solid phase synthesis. n is 0, 1, or 2; R 6 is hydrogen, and C 1 -C 6 is selected from the group consisting of alkyl, R 13 is C 1 -C 4 Alkyl, or -(CH 2 ) m CON(R 17A )(R 17B ) and m is 0, 1, or 2; R 17A and R 17B are independently hydrogen, C 1 -C 4 alkyl or R 17A and R 17Btogether with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and (2-(trimethylsilyl)ethyl). and The starting amide compound comprises at least one of the deprotectable protecting groups. [6] A method for producing an amide compound from a resin for solid phase synthesis, comprising a step of contacting a starting amide compound with a silylating agent in a solvent to remove the starting amide compound from the resin for solid phase synthesis, comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting amide compound has the following general formula (II): [ka] [In the formula, R 1’ is a hydrogen atom or PG 7 and R 12 and R 12’ are independently hydrogen, PG 10 -O-methyl, -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES, RES is a resin for solid phase synthesis, where R 12 and R 12’ At least one of the groups is -(CH 2 ) n COO-RES, or -(CH 2 ) n CONH-RES, RES is a resin for solid phase synthesis. n is 0, 1, or 2; R 6 is hydrogen, and C 1 -C 6 is selected from the group consisting of alkyl, R 13 is C 1 -C 4 Alkyl, or -(CH 2 ) m CON(R 17A )(R 17B ) and m is 0, 1, or 2; R 17A and R 17B are independently hydrogen, C 1 -C 4 alkyl or R 17A and R 17B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl. The method is represented by [7] The method according to any one of [1] and [3] to [5], wherein the deprotectable protecting group is selected from the group consisting of t-Bu, triphenylmethyl, 2-(trimethylsilyl)-ethyl, Boc, Teoc, Cbz, methoxycarbonyl, tetrahydropyranyl, 1-ethoxyethyl, methoxytrityl, and cumyl. [8] The silyl compound is represented by the following formula 1: [ka] [In the formula, R AX , R AY , and R AZ is independently 1 -C 4 alkyl or phenyl, and X is -OTf, -OClO 3 , Cl, Br, and I. The method according to any one of [1] to [7], [9] Silyl compounds are TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, TMSOClO 3 The method according to claim 8, wherein the TMSI is selected from the group consisting of:

[10] The acid is HX (wherein X is -OTf, -OClO 3 The method according to any one of [1] to [7], wherein the compound is represented by the formula (I), wherein the compound is selected from the group consisting of Cl, Br, and I.

[11] The electrophilic species scavenger is represented by the following formulas (2) to (10): [ka] [In formula 2, R B is a substituted silyl group, and R C is a substituted silyl group, or R B and R C form a 5- to 7-membered ring together with the nitrogen and carbon atoms to which they are attached, R DC may be substituted with one or more fluorine atoms 1 -C 4 alkyl or optionally substituted methylene, where R D When is an optionally substituted methylene, formula 2 dimerizes to the following formula: [ka] forming a compound represented by In formula 3, R G is one or more C 1 -C 4 is an alkyl-substituted silyl group, R H is hydrogen, or C 1 -C 4 is alkyl, R I is hydrogen or C which may be substituted with one or more fluorine atoms 1 -C 4 is alkyl, In formula 4, (a-1)R J is a substituted silyl group, R K is C 1 -C 4 Alkoxy and R M and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (a-2)R J is a substituted silyl group, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L form a 5- to 8-membered ring containing an oxygen atom together with the carbon atom to which they are attached, or (b-1)R J is a substituted silyl group, R K is C 1 -C 4 alkyl, and R M and R L are independently hydrogen or C1 -C 4 Is it an alkyl group? (b-2)R J is a substituted silyl group, R M is hydrogen, or C 1 -C 4 alkyl, and R K and R L form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (c-1)R J and R M form a 5- to 7-membered ring containing an oxygen atom together with the carbon atom to which they are attached, and R K is hydrogen, or C 1 -C 4 alkyl, and R L is C 1 -C 4 Is it an alkyl group? (c-2)R J and R M form a 5- to 7-membered ring containing an oxygen atom together with the carbon atom to which they are attached, and R K and R L form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (d-1)R J is C 1 -C 4 alkyl, and R M , R K , and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (d-2)R J is C 1 -C 4 is alkyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L form 5-8 rings together with the carbon atoms to which they are attached, or (e-1)R J is C 1 -C 3 alkylcarbonyl, and RM , R K , and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (e-2)R J is C 1 -C 3 alkylcarbonyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (f-1)R J is a substituted silyl group or C 1 -C 4 is alkyl, R K is optionally substituted di-C 1 -C 4 alkylamino, and R M and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (f-2) or R J is a substituted silyl group or C 1 -C 4 is alkyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L form a 5- to 8-membered ring containing a nitrogen atom together with the carbon atom to which they are attached, and the 5- to 8-membered ring is 1 -C 4 may be substituted by alkyl, In formula 5, R N , R N’ , and R O are independently hydrogen or C 1 -C 4 is alkyl, In formula 6, R P is a substituted silyl group, R Qis a substituted silyl group, or C 1 -C 4 alkyl, and R R is hydrogen, a substituted silyl group, or C 1 -C 4 is alkyl, or R Q and R R form together with the nitrogen atom to which they are attached a 5- to 8-membered heterocycle which may contain one or more additional heteroatoms; In formula 7, X is a single bond or a carbon atom; where X is a single bond, R S does not exist, and R UA and R R together with the carbon and nitrogen atoms to which they are attached form an optionally substituted 6-membered aromatic heterocycle, and R UB and R T together with the carbon and nitrogen atoms to which they are attached form an optionally substituted 6-membered aromatic heterocycle; When X is a carbon atom, R UA and R UB is independently 1 -C 4 alkyl, and R R and R S and R T together with the carbon atoms to which they are attached form the following structure: [ka] Forming In formula 8, R V is C 1 -C 4 Alkyl or C 3 -C 6 is cycloalkyl, In formula 9, R W and R X is independently 1 -C 4 an alkyl or substituted silyl group; In formula 10, R Y and R Z is independently 1 -C 4 is an alkyl, or substituted silyl group. The method according to any one of [1] to

[10] , selected from the group consisting of:

[12] The method according to

[11] , wherein the electrophilic species scavenger is selected from the group consisting of N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilylacetamide, N-methyl-N-trimethylsilyltrifluoroacetamide, dimethylketene methyltrimethylsilyl acetal, isopropenyloxytrimethylsilane, 2,2,4,4-tetramethylpentanone imine, 1,1,1,3,3,3-hexamethyldisilazane (HMDS), N-trimethylsilylmorpholine, N-trimethylsilyldiethylamine, and N-tert-butyltrimethylsilylamine.

[13] The method according to any one of [1] to [9] and

[11] to

[12] , wherein 1 to 5 equivalents of a silyl compound and 1 to 10 equivalents of an electrophilic species scavenger are mixed relative to 1 equivalent of a protecting group to be removed or 1 equivalent of a resin to be removed.

[14] The method according to any one of [1] to

[12] , wherein 0.1 to 0.5 equivalents of a silyl compound or an acid are mixed with respect to 1 equivalent of a protecting group to be removed or 1 equivalent of a resin to be removed, the electrophilic species scavenger is selected from the group consisting of N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilylacetamide, N-methyl-N-trimethylsilyltrifluoroacetamide, dimethylketene methyltrimethylsilyl acetal, and isopropenyloxytrimethylsilane; The silyl compounds are TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, and TMSOClO. 3 is selected from the group consisting of The acid is HX (wherein X is -OTf, -OClO3 , Cl, Br, and I).

[15] The method according to any one of [1] to

[14] , wherein the starting peptide compound contains 1 to 30 amino acid residues and is linear or cyclic.

[16] The method according to any one of [1] to [4] and [6] to

[15] , wherein the resin for solid phase synthesis is a CTC resin, a Wang resin, or a SASRIN resin.

[17] The method according to any one of [1] to

[16] , comprising mixing a starting peptide compound with a solvent, followed by mixing with an electrophilic species scavenger, and then mixing with a silyl compound or an acid.

[18] The method according to any one of [1] to

[17] , wherein the solvent is selected from ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, toluene, and acetonitrile.

[19] An amide compound represented by the following general formula (A) or a salt thereof: [ka] During the ceremony, R 1’ is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; R 17A and R 17B are both methyl or R 17A and R 17B together with the nitrogen atom to which they are attached form piperidine or morpholine, R 18 is hydrogen or PG 10 where PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4alkyl, and 2-(trimethylsilyl)ethyl.

[20] The amide compound or a salt thereof according to

[19] , selected from the group consisting of: (3-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-3) tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-4) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl, (3-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl (3-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl (3-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-11) tert-Butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl (3-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-15) tert-Butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl, (3-17) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoic acid, (3-18) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate allyl, (3-19) tert-butyl 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate, (3-20) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate benzyl (2-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-3) tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-4) benzyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl (2-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-11) tert-Butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl (2-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate allyl, (2-15) tert-Butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl, (2-17) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoic acid, (2-18) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate allyl, (2-19) tert-butyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate, (2-20) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate benzyl, (4-1) 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (4-2) Allyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-3) tert-butyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-4) benzyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-5) 3-(methylamino)-4-morpholino-4-oxobutanoic acid, (4-6) Allyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-7) tert-butyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-8) benzyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-9) 4-(dimethylamino)-3-(methylamino)-4-oxobutanoic acid, (4-10) Allyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, (4-11) tert-butyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, (4-12) benzyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, (1-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-3) tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-4) benzyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl (1-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-11) tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl (1-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate allyl, (1-15) tert-butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl, (1-17) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-18) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate allyl, (1-19) tert-Butyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, and (1-20) Benzyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate.

[21] A method for producing a peptide compound in which a protecting group has been deprotected, the method comprising the step of contacting a starting peptide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby deprotecting a protecting group that can be deprotected by the silylating agent from the starting peptide compound, the method comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting peptide compound has the following general formula (I): [ka] [In the formula, R 1 is hydrogen, PG1 , a natural amino acid residue, or an amino acid analog residue; R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 4 Or R 2 and R 4’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 forming a 3- to 7-membered heterocycle which may be substituted by alkoxy; R 4 and R 4’ is R 2 Except when taken together with (a)R 4’ is hydrogen and R 4 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 2 , N-PG 3 -Indol-3-ylmethyl, 4-(PG 2 O) Benzyl, PG 2 -O-methyl, 1-(PG 2 O) Ethyl, 2-(PG 2 O) Ethyl, PG 2 -OCO(CH 2 )-, P.G. 2 -OCO(CH 2 ) 2 -, P.G. 3 Nn-Butyl, -CON(R 14A )(R 14B ), -CH 2 -CON(R 14A )(R 14B), and -(CH 2 ) 2 CON(R 14A )(R 14B ) or (b)R 4 and R 4’ is independently an optionally substituted C 1 -C 6 is alkyl, or (c)R 4 and R 4’ form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 5 is a single bond or -C(R 5A )(R 5B )-and R 5A and R 5B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 6 is hydrogen, and C 1 -C 6 alkyl; or R 6 and R 7 Or R 6 and R 7’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 forming a 3- to 7-membered heterocycle which may be substituted by alkoxy; R 7 and R 7’ is R 6 Except when taken together with (a)R 7’ is hydrogen and R 7 is hydrogen, optionally substituted C 1 -C6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 4 , N-PG 5 -Indol-3-ylmethyl, 4-(PG 4 O) Benzyl, PG 4 -O-methyl, 1-(PG 4 O) Ethyl, 2-(PG 4 O) Ethyl, PG 4 -OCO(CH 2 )-, P.G. 4 -OCO(CH 2 ) 2 -, P.G. 5 Nn-Butyl, -CON(R 15A )(R 15B ), -CH 2 -CON(R 15A )(R 15B ), and -(CH 2 ) 2 CON(R 15A )(R 15B ) or (b)R 7 and R 7’ is, independently, optionally substituted C 1 -C 6 is alkyl, or (c)R 7 and R 7’ form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 8 is a single bond or -C(R 8A )(R 8B )-and R 8A and R 8B are independently hydrogen, C 1 -C 6Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 9 is hydroxy, -O-PG 6 , a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES; RES is a resin for solid phase synthesis. R 14A and R 14B are independently hydrogen, C 1 -C 4 alkyl or R 14A and R 14B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R 15A and R 15B are independently hydrogen, C 1 -C 4 alkyl or R 15A and R 15B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 1 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 2 and P.G. 4 are independently hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl; PG3 and P.G. 5 is independently selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; PG 6 is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, and 2-(trimethylsilyl)ethyl. The structure includes two amino acid residues linked together, the starting peptide compound optionally contains additional naturally occurring amino acid residues and / or amino acid analog residues; and The starting peptide compound comprises at least one deprotectable protecting group.

[22] A method for producing a peptide compound from a resin for solid phase synthesis, comprising the step of contacting a starting peptide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby removing the starting peptide compound from the resin for solid phase synthesis, The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting peptide compound has the following general formula (I): [ka] [In the formula, R 1 is hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue; R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 4 Or R 2 and R 4’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 forming a 3- to 7-membered heterocycle which may be substituted by alkoxy; R4 and R 4’ is R 2 Except when taken together with (a)R 4’ is hydrogen and R 4 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 2 , N-PG 3 -Indol-3-ylmethyl, 4-(PG 2 O) Benzyl, PG 2 -O-methyl, 1-(PG 2 O) Ethyl, 2-(PG 2 O) Ethyl, PG 2 -OCO(CH 2 )-, P.G. 2 -OCO(CH 2 ) 2 -, P.G. 3 Nn-Butyl, -CON(R 14A )(R 14B ), -CH 2 -CON(R 14A )(R 14B ), and -(CH 2 ) 2 CON(R 14A )(R 14B ) or (b)R 4 and R 4’ is independently an optionally substituted C 1 -C 6 is alkyl, or (c)R 4 and R 4’ form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 5is a single bond or -C(R 5A )(R 5B )-and R 5A and R 5B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 6 is hydrogen, and C 1 -C 6 alkyl; or R 6 and R 7 Or R 6 and R 7’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 forming a 3- to 7-membered heterocycle which may be substituted by alkoxy; R 7 and R 7’ is R 6 Except when taken together with (a)R 7’ is hydrogen and R 7 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 4 , N-PG 5 -Indol-3-ylmethyl, 4-(PG 4 O) Benzyl, PG 4 -O-methyl, 1-(PG4 O) Ethyl, 2-(PG 4 O) Ethyl, PG 4 -OCO(CH 2 )-, P.G. 4 -OCO(CH 2 ) 2 -, P.G. 5 Nn-Butyl, -CON(R 15A )(R 15B ), -CH 2 -CON(R 15A )(R 15B ), and -(CH 2 ) 2 CON(R 15A )(R 15B ) or (b)R 7 and R 7’ is independently an optionally substituted C 1 -C 6 is alkyl, or (c)R 7 and R 7’ form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 8 is a single bond or -C(R 8A )(R 8B )-and R 8A and R 8B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 9 is hydroxy, -O-PG 6 , a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES; RES is a resin for solid phase synthesis. R 14A and R 14B are independently hydrogen, C1 -C 4 alkyl or R 14A and R 14B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R 15A and R 15B are independently hydrogen, C 1 -C 4 alkyl or R 15A and R 15B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 1 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 2 and P.G. 4 are independently hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl; PG 3 and P.G. 5 is independently selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; PG 6 is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, and 2-(trimethylsilyl)ethyl. The structure includes two amino acid residues linked together, the starting peptide compound optionally contains additional naturally occurring amino acid residues and / or amino acid analog residues; and The method, wherein the starting peptide compound comprises at least one amino acid residue attached to a resin for solid phase synthesis.

[23] A method for producing a peptide compound or amide compound from which a protecting group has been deprotected, the method comprising the step of contacting a starting peptide compound or a starting amide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby deprotecting a protecting group that can be deprotected by the silylating agent from the starting peptide compound or the starting amide compound, The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting peptide compound or the starting amide compound has a structure represented by the following general formula (II): [ka] [In the formula, R 1’ is a hydrogen atom, PG 7 or a group represented by formula (III), [ka] * indicates a connection point R 1 is hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue; R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 10 Or R 2 and R 10’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 forming a 3- to 7-membered heterocycle which may be substituted by alkoxy; R 10 and R 10’ is R 2 Except when taken together with (a)R 10’ is hydrogen and R 10 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 8 , N-PG 9 -Indol-3-ylmethyl, 4-(PG 8 O) Benzyl, PG 8 -O-methyl, 1-(PG 8 O) Ethyl, 2-(PG 8 O) Ethyl, PG 8 -OCO(CH 2 )-, P.G. 8 -OCO(CH 2 ) 2 -, P.G. 9 Nn-Butyl, -CON(R 16A )(R 16B ), -CH 2 -CON(R 16A )(R 16B ), and -(CH 2 ) 2 CON(R 16A )(R 16B ) or (b)R 10 and R 10’ is, independently, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 3 -C 6 Cycloalkyl C 1 -C 4 is alkyl, or (c)R 10 and R 10’form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 11 is a single bond or -C(R 11A )(R 11B )-and R 11A and R 11B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 12 and R 12’ are independently hydrogen, PG 10 -O-methyl, -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES, RES is a resin for solid phase synthesis. n is 0, 1, or 2; R 6 is hydrogen, and C 1 -C 6 is selected from the group consisting of alkyl, R 13 is C 1 -C 4 Alkyl, or -(CH 2 ) m CON(R 17A )(R 17B ) and m is 0, 1, or 2; R 16A and R 16B are independently hydrogen or C 1 -C 4 alkyl or R 16A and R 16Btogether with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R 17A and R 17B are independently hydrogen, C 1 -C 4 alkyl or R 17A and R 17B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 1 and P.G. 7 is independently selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 8 is hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl; PG 9 is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and (2-(trimethylsilyl)ethyl). or a structure in which two amino acid residues are linked together, the starting peptide compound optionally contains additional naturally occurring amino acid residues and / or amino acid analog residues; and The starting peptide compound or starting amide compound comprises at least one deprotectable protecting group.

[24] A method for producing a peptide compound or amide compound from a resin for solid phase synthesis, comprising the step of contacting a starting peptide compound or a starting amide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby removing the starting peptide compound or the starting amide compound from the resin for solid phase synthesis, The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting peptide compound or the starting amide compound has a structure represented by the following general formula (II): [ka] [In the formula, R 1’ is a hydrogen atom, PG 7 or a group represented by formula (III), [ka] * indicates a connection point R 1 is hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue; R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 10 Or R 2 and R 10’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 forming a 3- to 7-membered heterocycle which may be substituted by alkoxy; R 10 and R 10’ is R 2Except when taken together with (a)R 10’ is hydrogen and R 10 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 8 , N-PG 9 -Indol-3-ylmethyl, 4-(PG 8 O) Benzyl, PG 8 -O-methyl, 1-(PG 8 O) Ethyl, 2-(PG 8 O) Ethyl, PG 8 -OCO(CH 2 )-, P.G. 8 -OCO(CH 2 ) 2 -, P.G. 9 Nn-Butyl, -CON(R 16A )(R 16B ), -CH 2 -CON(R 16A )(R 16B ), and -(CH 2 ) 2 CON(R 16A )(R 16B ) or (b)R 10 and R 10’ is independently an optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 3 -C 6 Cycloalkyl C 1 -C 4 is alkyl, or (c)R 10 and R 10’form, together with the carbon atom to which they are attached, a 3- to 7-membered alicyclic ring; R 11 is a single bond or -C(R 11A )(R 11B )-and R 11A and R 11B are independently hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 is selected from the group consisting of alkyl, R 12 and R 12’ are independently hydrogen, PG 10 -O-methyl, -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES, RES is a resin for solid phase synthesis, where R 12 and R 12’ At least one of the groups is -(CH 2 ) n COO-RES, or -(CH 2 ) n CONH-RES, RES is a resin for solid phase synthesis. n is 0, 1, or 2; R 6 is hydrogen, and C 1 -C 6 is selected from the group consisting of alkyl, R 13 is C 1 -C 4 Alkyl, or -(CH 2 ) m CON(R 17A )(R 17B) and m is 0, 1, or 2; R 16A and R 16B are independently hydrogen or C 1 -C 4 alkyl or R 16A and R 16B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R 17A and R 17B are independently hydrogen, C 1 -C 4 alkyl or R 17A and R 17B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; PG 1 and P.G. 7 is independently selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; PG 8 is hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl; PG 9 is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C4 alkyl, and 2-(trimethylsilyl)ethyl. or a structure in which two amino acid residues are linked together, The starting peptide compound optionally comprises additional natural amino acid residues and / or amino acid analog residues.

[25] A deprotecting agent for use in deprotecting a protecting group, comprising a silyl compound or an acid, and an electrophilic species scavenger.

[26] A resin removal agent for use in cleaving a peptide compound from a resin in a solid-phase reaction, comprising a silyl compound or an acid, and an electrophilic species capture agent. Effect of the Invention

[0036] The advantages of the present invention are that, compared with known methods, a large amount of Bronsted acid, which is likely to damage amide bonds, is not used, the equivalent amount of the reagent can be reduced, the reagent used is easy to remove, and the reaction in the next step is not affected. For example, 2,6-lutidine is difficult to remove by distillation due to its high boiling point (144°C). In addition, since 2,6-lutidine is a basic compound, it can be removed with an acid, but when the target compound is a peptide compound, the product is a compound having a basic amino group, so the method of removing excess 2,6-lutidine under acidic conditions is inefficient. In addition, during the condensation reaction (reaction to extend the amide bond) following the deprotection reaction, if 2,6-lutidine used in the previous step remains, the condensing agent will react with the remaining 2,6-lutidine, or the condensation reaction cannot be performed under the desired conditions due to the presence of a base during the condensation reaction. On the other hand, for example, when the silylamines of the present invention are used, by treating with water after the reaction, the silylamines are hydrolyzed and converted into highly water-soluble compounds that are easily removed. Therefore, the reagents derived from the silylamines can be easily removed by washing with an aqueous solution, and the peptide elongation in the next step is not affected, which is superior to the case where the conventional 2,6-lutidine is used.

[0037] Furthermore, among the compounds used as electrophilic species scavengers exemplified by imidates (Formula 2), amides (Formula 3), ketene acetals (Formula 4), ketene alkoxyhemiaminals (Formula 4), enol ethers (Formula 4), enol esters (Formula 4), imines (Formula 5), ​​amines (Formula 6), diamines (Formula 7), dialkylcarbodiimides (Formula 8), ureas (Formula 9), and urethanes (Formula 10), imidates (Formula 2), amides (Formula 3), ketene acetals (Formula 4), ketene alkoxyhemiaminals (Formula 4), enol ethers (Formula 4), enol esters (Formula 4), and imines (Formula 5) can be converted to low-boiling compounds that are easily removed by mild hydrolysis treatment after the reaction, and therefore, removal of excess reagents used in the reaction is remarkably easier than with 2,6-lutidine. In addition, not only the amide compound (formula 3) but also the imidates are converted into compounds that are easily removed by mild hydrolysis after the reaction, so there is no effect on the next step. In addition, the amines used as electrophilic species traps are not limited to the well-known tertiary amines, and secondary amines can also be used, which allows the deprotection to be performed while suppressing damage to the amide bond.

[0038] In one aspect, the present invention can perform N-Boc removal of a peptide compound while suppressing damage to the main chain of the peptide compound. In another aspect, the present invention can perform t-Bu removal of t-Bu esters at the C-terminus of the main chain and side chain of a peptide compound, debenzylation of benzyl esters, and detritylation of trityl esters while suppressing damage to the main chain of the peptide compound. Furthermore, in another aspect, the resin removal reaction of a peptide compound from a resin bound to the C-terminus of the main chain or side chain of the peptide compound can be performed while suppressing damage to the main chain of the peptide compound. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] The abbreviations used in the present invention are listed below. AcOEt: ethyl acetate Alloc: Allyloxycarbonyl Allyl: Allyl BEP: 2-bromo-1-ethylpyridinium tetrafluoroborate Bn: Benzyl Boc: tert-butoxycarbonyl BSA: N,O-bis(trimethylsilyl)acetamide BSTFA: N,O-bis(trimethylsilyl)trifluoroacetamide Bu: butyl Cbz: benzyloxycarbonyl cHx: cyclohexyl Cl-CTC resin: 2-Chlorotrityl chloride polymer resin CPME: Cyclopentyl methyl ether CTC: 2-chlorotrityl chloride DBU: 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine DdZ: 3,5-dimethoxyphenylisopropoxycarbonyl DIC: N,N'-diisopropylcarbodiimide DIPEA: N,N-diisopropylethylamine DMA: N,N-Dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide eq.: equivalent EtOH: Ethanol Et: Ethyl Fmoc: 9-fluorenylmethyloxycarbonyl HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HMDS: Hexamethyldisilazane HOAt: 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol HOBt: 1,2,3-benzotriazol-1-ol HPLC: High-performance liquid chromatography i-PrOAc: isopropyl acetate i-Pr: Isopropyl LCMS: Liquid Chromatography Mass Spectrometry MeCN: Acetonitrile Me: Methyl MS: Mass spectrometry MsOH: methanesulfonic acid MSTFA: N-methyl-N-trimethylsilyl trifluoroacetamide MTBE: Methyl tert-butyl ether ND:not determined NMI: 1-methylimidazole NMP: N-methylpyrrolidone oxyma: ethyl cyano(hydroxyimino)acetate Pd / C: Palladium on carbon Ph: Phenyl pip: piperidinyl prep.:preparation T3P: Propylphosphonic anhydride TBDPS: tert-butyldiphenylsilyl TBS: tert-butyldimethylsilyl t-Bu: tert-butyl TEA: Triethylamine Teoc: 2-(trimethylsilyl)ethoxycarbonyl TES: Triethylsilyl TFA: Trifluoroacetic acid TFE: 2,2,2-trifluoroethanol TfOH: Trifluoromethanesulfonic acid Tf: Trifluoromethanesulfonyl THF: tetrahydrofuran 2-MeTHF: 2-methyltetrahydrofuran TIPS: Triisopropylsilyl TMSOTf: Trimethylsilyl trifluoromethanesulfonate TMS: Trimethylsilyl Tr: Trityl TTMS: Tris(trimethylsilyl)silyl vol.:volume Gly: glycine Ala: Alanine Ser: Serine Thr: Threonine Val: Valin Leu: Leucine Ile: Isoleucine Phe: Phenylalanine Tyr: Tyrosine Trp: Tryptophan His: Histidine Glu: glutamic acid Asp: Aspartic acid Gln: glutamine Asn: Asparagine Cys: Cysteine Met: methionine Lys: Lysine Arg: arginine Pro: Proline MeGly: N-Me glycine MeAla: N-Me alanine MeSer: N-Me serine MeThr: N-Me Threonine MeVal:N-Me Valin MeLeu:N-Me Leucine MeIle:N-Me isoleucine MePhe: N-Me phenylalanine MeTyr: N-Me tyrosine MeTrp: N-Me tryptophan MeHis: N-Me histidine MeGlu: N-Me glutamic acid MeAsp: N-Me aspartic acid MeGln: N-Me glutamine MeAsn: N-Me asparagine MeCys: N-Me cysteine MeMet: N-Me methionine MeLys: N-Me Lysine MeArg: N-Me arginine

[0040] (Definition of Functional Groups) In this specification, "alkyl" refers to a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, and has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. The alkyl includes linear and branched ones. The alkyl includes those having 1 to 20 carbon atoms (C 1 -C 20 , hereinafter referred to as “C p -C q " means that the number of carbon atoms is p to q.) alkyl, C 1 -C 6 Alkyl, C 1 -C 4 Specific examples of the alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, and sec-butyl.

[0041] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. Cycloalkyl may also be partially unsaturated. Cycloalkyl is preferably C 3 -C 6 Included are cycloalkyls, which include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0042] As used herein, "cycloalkylalkyl" refers to a group in which any hydrogen atom in the above-defined "alkyl" is replaced with the above-defined "cycloalkyl". As the cycloalkylalkyl, C3-6 Cycloalkyl C 1-6 Alkyl, C 3-6 Cycloalkyl C 1-4 Specific examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0043] In the present specification, "alkoxy" refers to an oxy group to which the above-defined "alkyl" is bonded, and preferably C 1-4 Alkoxy, C 1-3 Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, and tert-butoxy.

[0044] In the present specification, the term "alicyclic ring" refers to a monovalent non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond in the ring, or may be a polycyclic group having two or more rings. The carbon atoms constituting the ring may be oxidized to form a carbonyl. The number of atoms constituting the alicyclic ring is preferably 3 to 7 (3- to 7-membered alicyclic ring). Specific examples of the alicyclic ring include a cycloalkyl ring, a cycloalkenyl ring, and a cycloalkynyl ring.

[0045] In the present specification, the term "heterocycle" refers to a non-aromatic monovalent or divalent heterocycle containing preferably 1 to 5 heteroatoms in the atoms constituting the ring. The heterocycle may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl, and may be a monocycle, a condensed ring, or a spiro ring. The number of atoms constituting the ring is preferably 3 to 12 (3- to 12-membered heterocycle), more preferably 4 to 7 (4- to 7-membered heterocycle), and even more preferably 5 to 6 (5- to 6-membered heterocycle). Specific examples of the heterocycle include azetidine, piperazine, pyrrolidine, piperidine, morpholine, homomorpholine, (R)-hexahydropyrrolo[1,2-a]pyrazine, (S)-hexahydropyrrolo[1,2-a]pyrazine, 3-oxopiperazine, 2-oxopyrrolidine, azetidine, 2-oxoimidazolidine, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyridine, thiomorpholine, pyrazolidine, imidazoline, oxazolidine, isoxazolidine, thiazolidine, imidazolidine, isothiazolidine, thiadiazolidine, oxazolidone, benzodioxane, benzoxazoline, dioxolane, dioxane, and tetrahydrothiopyran.

[0046] In the present specification, the term "aromatic heterocycle" refers to an aromatic monovalent or divalent heterocycle containing preferably 1 to 5 heteroatoms in the atoms constituting the ring. The aromatic heterocycle may be partially saturated, and may be a monocycle, a condensed ring (for example, a bicyclic aromatic heterocycle in which a monocyclic aromatic heterocycle is condensed with a benzene ring or a monocyclic aromatic heterocycle), or a spirocycle. The number of atoms constituting the ring is preferably 4 to 10 (4- to 10-membered aromatic heterocycle). Specific examples of aromatic heterocycles include furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzofuran, benzothiophene, benzothiadiazole, benzothiazole, benzoxazole, benzoxadiazole, benzimidazole, indole, isoindole, indazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, indolizine, and imidazopyridine.

[0047] As used herein, "aryl" refers to a monovalent aromatic hydrocarbon ring, preferably C 6-10Specific examples of the aryl include phenyl and naphthyl (for example, 1-naphthyl and 2-naphthyl).

[0048] In the present specification, "heteroaryl" refers to an aromatic monovalent heterocyclic group containing preferably 1 to 5 heteroatoms in the atoms constituting the ring. The heteroaryl may be partially saturated and may be a monocyclic ring or a condensed ring (for example, a bicyclic heteroaryl condensed with a benzene ring or a monocyclic heteroaryl ring). The number of atoms constituting the ring is preferably 5 to 10 (5- to 10-membered heteroaryl).

[0049] 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, azaindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridyl.

[0050] In the present specification, "heterocyclyl" refers to a non-aromatic monovalent heterocyclic group containing preferably 1 to 5 heteroatoms in the atoms constituting the ring. The heterocyclyl may have a double or triple bond in the ring, a carbon atom may be oxidized to form a carbonyl, and may be a single ring or a condensed ring. The number of atoms constituting the ring is preferably 3 to 10 (3- to 10-membered heterocyclyl).

[0051] Specific examples of heterocyclyl include oxetanyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, azetidinyl, oxazolidone, benzodioxanyl, benzoxazolyl, dioxolanyl, and dioxanyl.

[0052] As used herein, the term "arylalkyl" refers to a group in which any hydrogen atom in the above-defined "alkyl" is replaced with the above-defined "aryl". The arylalkyl is preferably C 6-10 Aryl C 1-4 Alkyl, C 6-10 Aryl C 1-3 Specific examples include benzyl, phenylmethyl, phenethyl (phenylethyl), naphthylmethyl, and the like.

[0053] In the present specification, the term "heteroarylalkyl" refers to a group in which any hydrogen atom in the above-defined "alkyl" is replaced with the above-defined "heteroaryl". As the heteroarylalkyl, a 5- to 10-membered heteroaryl C 1-3 Specific examples include pyrrolylmethyl, imidazolylmethyl, thienylmethyl, pyridylmethyl, pyrimidylmethyl, quinolylmethyl, and pyridylethyl.

[0054] In the present specification, the term "substituted silyl" refers to a silyl group substituted with one to three substituents. The substituents may be the same or different. Examples of the substituents include C 1 -C 6 Alkyl, aryl, triC 1 -C 6Alkylsilyl is preferred, specifically, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tris(trimethylsilyl)silyl, etc.

[0055] In the present specification, when the modifier "optionally substituted" is used, examples of the substituent include alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, substituted silyl, halogen atom, nitro, amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, formyl, and the like.

[0056] As used herein, the term "deprotection" refers to removing a protecting group to restore the original functional group before protection.

[0057] As used herein, the term "resin removal" refers to the cleavage of a peptide compound from a peptide compound bound to a resin for solid-phase synthesis. The resin for solid-phase synthesis is preferably bound to the C-terminal amino acid residue of the starting peptide compound.

[0058] One aspect of the present invention is to provide a method for producing a peptide drug containing an amino acid analog useful for the peptide drug. Another aspect of the present invention is to provide a method for producing a peptide containing a high-quality amino acid analog for supplying an active pharmaceutical ingredient for the drug. Yet another aspect of the present invention is to provide a novel amide compound useful for producing a peptide compound.

[0059] (Deprotection / resin removal method) In one aspect, the present invention relates to a method for producing a peptide compound in which a protecting group has been deprotected, the method comprising the step of contacting a starting peptide compound containing natural amino acid residues and / or amino acid analog residues with a silylating agent in a solvent, thereby deprotecting a protecting group that can be deprotected by the silylating agent from the starting peptide compound.

[0060] In one aspect, the present invention relates to a method for producing a peptide compound from a resin for solid phase synthesis, comprising the step of contacting a starting peptide compound containing natural amino acid residues and / or amino acid analog residues with a silylating agent in a solvent, thereby removing the starting peptide compound from the resin for solid phase synthesis.

[0061] As used herein, the term "starting peptide compound" refers to a starting "peptide compound" to be subjected to the deprotection reaction and / or the resin removal reaction of the present invention. The starting peptide compound preferably contains at least one N-substituted amino acid residue.

[0062] The "peptide compound" of the present invention includes linear or cyclic peptide compounds containing natural amino acid residues and / or amino acid analog residues. Note that a cyclic peptide compound is synonymous with a "peptide compound having a cyclic portion."

[0063] The "linear peptide compound" in the present invention is not particularly limited as long as it is a peptide compound formed by forming an amide bond or an ester bond between natural amino acids or amino acid analogs and does not have a cyclic portion. The total number of natural amino acids or amino acid analogs constituting the linear peptide compound can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30, and the preferred range of the number of amino acids constituting the linear peptide compound is 1 to 30, 6 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 8 to 14, or 9 to 13.

[0064] The term "peptide compound having a cyclic portion" as used herein is a peptide compound formed by the formation of an amide bond or an ester bond between natural amino acids or amino acid analogs, and is not particularly limited as long as it is a compound having a cyclic portion. The cyclic portion is preferably formed via a covalent bond such as an amide bond, a carbon-carbon bond forming reaction, an S-S bond, a thioether bond, or a triazole bond (WO2013 / 100132, WO2012 / 026566, WO2012 / 033154, WO2012 / 074130, WO2015 / 030014, Comb Chem High Throughput Screen. 2010;13:75-87,Nature Chem. Bio. 2009, 5, 502, Nat Chem Biol. 2009, 5, 888-90, BioconjugateChem., 2007, 18, 469-476, ChemBioChem, 2009, 10, 787-798, ChemicalCommunications (Cambridge, United Kingdom) (2011), 47(36), 9946-9958). Compounds obtained by further chemically modifying the compound are also included in the peptide compound of the present invention. The peptide compound of the present invention having a cyclic portion may further 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 a linear portion is present, the total number of residues 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 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 preferably 5 to 12, more preferably 6 to 12, or 7 to 12, even more preferably 7 to 11, or 8 to 11, and particularly preferably 9 to 11 (10 or 11). 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 analogs is preferably 1 to 30, 6 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 8 to 14, or 9 to 13.

[0065] The type of natural amino acid residue or amino acid analog residue forming the cyclic portion of the peptide compound having a cyclic portion of the present invention is not particularly limited, but the cyclization portion is preferably composed of a natural amino acid residue or amino acid analog residue having a functional group with excellent metabolic stability. The cyclization method of the peptide compound having a cyclic portion of the present invention is not particularly limited as long as it is capable of forming such a cyclic portion. Examples include an amide bond formed from a carboxylic acid and an amine, and carbon-carbon bond reactions catalyzed by transition metals such as the Suzuki reaction, the Heck reaction, and the Sonogashira reaction. Therefore, the peptide compound of the present invention contains at least one pair of functional groups capable of these bond reactions before cyclization. In particular, from the viewpoint of metabolic stability, it is preferable that the peptide compound contains a functional group that forms an amide bond by a bond reaction.

[0066] The formation of the cyclic portion is preferably a bond containing a heteroatom that may be easily oxidized, and does not contain a bond that hinders metabolic stability. Examples of the bond formed by cyclization include an amide bond formed by the bond between an active ester and an amine, and a bond formed by a Heck reaction product between a carbon-carbon double bond and an aryl halide.

[0067] The "peptide compound" in the present invention may be a linear or cyclic peptide that contains at least one N-substituted amino acid (preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30, and particularly preferably 5, 6, or 7), and at least one non-N-substituted amino acid, in addition to the total number of natural amino acids and amino acid analogs described above, or alone. The number of N-substituted amino acids is preferably in the range of 1 to 30, 6 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 8 to 14, or 9 to 13.

[0068] In one aspect, the starting peptide compound contains 1 to 30 amino acid residues and is linear or cyclic. The amino acids contained in the starting peptide compound may be "natural amino acids" or "amino acid analogs". In this specification, "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. The starting peptide compound may be formed of secondary amides, tertiary amides, or a mixture of secondary amides and tertiary amides.

[0069] "Natural amino acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro.

[0070] 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 stereoconfiguration is allowed, as in the case of α-amino acids. Examples of N-substituted amino acids include those in which the amino group of an amino acid is substituted with any substituent, and examples of the substituent include, but are not limited to, an alkyl group, an aryl group, and an aralkyl group. Examples of N-substituted amino acids include N-alkyl amino acids, N-aryl amino acids, and N-methyl amino acids. The amino acid side chain is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and a cycloalkyl group, and one or two non-adjacent methylene groups in these groups may be replaced with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO 2Each of them may be substituted with one or more substituents, which are freely selected from any functional group including, for example, a halogen atom, an N atom, an O atom, an S atom, a B atom, an Si atom, or a P atom (i.e., an optionally substituted alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a cycloalkyl group, etc.).

[0071] The "natural amino acids" and "amino acid analogs" constituting the peptide compound include all of their corresponding isotopes. Isotopes of "natural amino acids" and "amino acid analogs" are those in which at least one atom has been replaced with an atom that has the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the "natural amino acids" and "amino acid analogs" constituting the peptide compound of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each of which is 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 35 S, 18 F, 36 Cl etc. are included.

[0072] In this specification, examples of the substituent containing a halogen atom include alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and the like, each of which has a halogen as a substituent. More specific examples of the substituent include fluoroalkyl, difluoroalkyl, trifluoroalkyl, and the like.

[0073] Substituents containing O atoms include hydroxy (-OH), oxy (-OR), carbonyl (-C=OR), carboxy (-CO 2H), oxycarbonyl (-C=O-OR), carbonyloxy (-OC=OR), thiocarbonyl (-C=O-SR), carbonylthio (-SC=OR), aminocarbonyl (-C=O-NHR), carbonylamino (-NH-C=OR), oxycarbonylamino (-NH-C=O-OR), sulfonylamino (-NH-SO 2 -R), aminosulfonyl (-SO 2 -NHR), sulfamoylamino (-NH-SO 2 -NHR), thiocarboxyl (-C(=O)-SH), carboxylcarbonyl (-C(=O)-CO 2 H).

[0074] Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, and the like. Alkoxy includes C 1 -C 4 Alkoxy, C 1 -C 2 Alkoxy is preferred, and among these, methoxy or ethoxy is more preferred.

[0075] Examples of carbonyl (-C=OR) include formyl (-C=OH), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0076] Examples of oxycarbonyl (-C=O-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0077] Examples of carbonyloxy (-OC=OR) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, and the like.

[0078] Examples of thiocarbonyl (-C=O-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, aralkylthiocarbonyl, and the like.

[0079] Examples of carbonylthio (-SC=OR) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio, and the like.

[0080] Examples of aminocarbonyl (-C=O-NHR) include alkylaminocarbonyl (e.g., C 1 -C 6 Or C 1 -C 4 Examples thereof include alkylaminocarbonyl, particularly ethylaminocarbonyl, methylaminocarbonyl, etc.), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, examples thereof include compounds in which the H atom bonded to the N atom in -C=O-NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0081] 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.

[0082] 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.

[0083] Sulfonylamino (-NH-SO 2 Examples of -R include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, and the like. In addition, -NH-SO 2 Examples of the compound include compounds in which the H atom bonded to the N atom in -R is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0084] Aminosulfonyl (-SO 2 Examples of -NHR include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, and the like.2 Examples of the compound include compounds in which the H atom bonded to the N atom in -NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0085] Sulfamoylamino (-NH-SO 2 Examples of -NHR include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, aralkylsulfamoylamino, and the like. 2 The two H atoms bonded to the N atom in -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.

[0086] Substituents containing S atoms include thiol (-SH), thio (-SR), sulfinyl (-S=OR), and sulfonyl (-SO 2 -R), sulfo (-SO 3 H).

[0087] Examples of thio (-SR) are selected from among alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0088] Sulfonyl (-SO 2 Examples of -R include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0089] As a substituent containing a nitrogen atom, azide (-N 3 , also known as "azido group"), cyano (-CN), primary amino (-NH 2), secondary amino (-NH-R; also called monosubstituted amino), tertiary amino (-NR(R'); also called disubstituted amino), amidino (-C(=NH)-NH 2 ), substituted amidino (-C(=NR)-NR'R"), guanidino (-NH-C(=NH)-NH 2 ), substituted guanidino (-NR-C(=NR''')-NR'R"), aminocarbonylamino (-NR-CO-NR'R"), pyridyl, piperidino, morpholino, azetidinyl and the like groups.

[0090] Examples of secondary amino (-NH-R; monosubstituted amino) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, aralkylamino, and the like.

[0091] Examples of tertiary amino (-NR(R'); disubstituted amino) include, for example, alkyl(aralkyl)amino and other amino groups having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., and these two substituents may form a ring. Specifically, dialkylamino, particularly C 1 -C 6 Dialkylamino, C 1 -C 4 Examples of the amino group include dialkylamino, dimethylamino, and diethylamino. p -C q "Dialkylamino group" means an amino group having C p -C q A group substituted with two alkyl groups, both C p -C q The alkyl groups can be the same or different.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] In one aspect, the starting peptide compound to be deprotected and / or deresinated contains at least one N-substituted amino acid residue. The number of N-substituted amino acid residues contained in the starting peptide compound is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30, and the preferred range of the number of N-substituted amino acid residues is 6 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 8 to 14, or 9 to 13. Two or more N-substituted amino acid residues may be linked in the starting peptide compound.

[0096] In one aspect, it is preferred that at least half of the amino acids constituting the peptide compound of the present invention (for example, when the number of amino acids constituting the peptide compound is 2n (n is an integer), at least n, and when the number is 2n+1, at least n+1) are N-substituted amino acids.

[0097] As used herein, "N-substitution" in N-substituted amino acids includes, but is 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, a hexyl group, etc. Preferred examples of N-substituted amino acids include amino acids in which the amino group contained in a natural amino acid is N-methylated, N-ethylated, N-propylated, N-butylated, or N-pentylated, and these are referred to as N-methyl amino acid, N-ethyl amino acid, N-propyl amino acid, N-butyl amino acid, or N-pentyl amino acid.

[0098] When the starting peptide compound contains at least one N-substituted amino acid residue (for example, when the starting peptide compound contains a partial structure in which the N-substituted amino acid residue is linked to an adjacent amino acid residue, more specifically, one or more partial structures containing at least two amino acid residues represented by general formula (I) and / or general formula (II)), the main chain is easily damaged, such as cleavage of the amide bond or rearrangement of the peptide main chain, by using the method of the present invention, the desired protecting group can be efficiently deprotected in high yield and high purity without damaging the main chain, and the peptide compound can be efficiently cleaved from the resin in a solid-phase reaction in high yield and high purity.

[0099] In some embodiments, the starting peptide compound of the invention may not contain any N-substituted amino acid residues or substructures in which an N-substituted amino acid residue is linked to an adjacent amino acid residue.

[0100] In one aspect, the starting peptide compound to be deprotected and / or de-resined contains at least one partial structure in which at least two amino acid residues are linked, the partial structure being represented by the following general formula (I): [ka]

[0101] In formula (I), R 1 is hydrogen, PG 1, a naturally occurring amino acid residue, or an amino acid analog residue. When the structure represented by formula (I) is present at the N-terminus of the starting peptide compound, R 1 is hydrogen, or PG 1 On the other hand, when the structure represented by formula (I) is present at any position other than the N-terminus of the starting peptide compound, R 1 is preferably a natural amino acid residue or an amino acid analog residue.

[0102] In formula (I), R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 4 Or R 2 and R 4’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 It forms a 3- to 7-membered heterocycle which may be substituted by alkoxy. In some situations, R 2 But, C 1 -C 6 When it is an alkyl group, the C 1 -C 6 Alkyl is preferably methyl, ethyl, propyl, butyl, pentyl. In some situations, R 2 and R 4 Or R 2 and R 4’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 When a 3- to 7-membered heterocyclic ring which may be substituted by alkoxy is formed, the 3- to 7-membered heterocyclic ring formed is preferably an azetidine ring, a pyrrolidine ring, or a piperidine ring. 2 and R 4 When taken together, form a heterocycle, R 4’ is hydrogen and R 2 and R 4’ When taken together, form a heterocycle, R 4 is hydrogen.

[0103] In formula (I), R 4 and R 4’ is R 2 and R 4 or R 2 and R 4’ except when taken together to form a heterocycle, (a)R 4’ is hydrogen and R 4 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 2 , N-PG 3 -Indol-3-ylmethyl, 4-(PG 2 O) Benzyl, PG 2 -O-methyl (i.e., -CH 2 -O-PG 2 ), 1-(PG 2 O) Ethyl, 2-(PG 2 O) Ethyl, PG 2 -OCO(CH 2 )-, P.G. 2 -OCO(CH 2 ) 2 -, P.G. 3 Nn-Butyl, -CON(R 14A )(R 14B ), -CH 2 -CON(R 14A )(R 14B ), and -(CH 2 ) 2 CON(R 14A )(R 14B ) or (b)R 4 and R 4’ is, independently, optionally substituted C 1 -C6 is alkyl, or (c)R 4 and R 4’ together with the carbon atom to which they are attached form a 3- to 7-membered alicyclic ring.

[0104] R 4 and R 4’ The combinations of are a hydrogen atom and a hydrogen atom, a methyl and a hydrogen atom, an ethyl and a hydrogen atom, an isopropyl and a hydrogen atom, an isobutyl and a hydrogen atom, a cyclopropyl and a hydrogen atom, a cyclopropylmethyl and a hydrogen atom, a cyclopentyl and a hydrogen atom, a cyclohexyl and a hydrogen atom, an optionally substituted phenyl and a hydrogen atom, an optionally substituted phenylmethyl and a hydrogen atom, an optionally substituted phenylethyl and a hydrogen atom, a 2-(methylthio)ethyl and a hydrogen atom, -CH 2 SPG 2 and hydrogen atom, N-PG 3 -Indol-3-ylmethyl and hydrogen atom, 4-(PG 2 O) Benzyl and hydrogen atom, PG 2 -O-methyl and hydrogen atom, 1-(PG 2 O) Ethyl and hydrogen atom, 2-(PG 2 O) Ethyl and hydrogen atom, PG 2 -OCO(CH 2 )- and hydrogen atom, PG 2 -OCO(CH 2 ) 2 - and hydrogen atoms, PG 3 Nn-Butyl and hydrogen atom, -CON(R 14A )(R 14B ) and a hydrogen atom, -CH 2 -CON(R 14A )(R 14B ) and a hydrogen atom, -(CH 2 ) 2 CON(R 14A )(R 14B ) and a hydrogen atom, methyl and methyl, and methyl and ethyl are preferred. 4 and R 4’However, when they form a 3- to 7-membered alicyclic ring together with the carbon atom to which they are bonded, the alicyclic ring is preferably a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.

[0105] In formula (I), R 5 is a single bond or -C(R 5A )(R 5B )-and R 5A and R 5B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 alkyl.

[0106] R 5 is a single bond or R 5A and R 5B is a hydrogen atom and a hydrogen atom, a methyl and a hydrogen atom, an ethyl and a hydrogen atom, an isopropyl and a hydrogen atom, an isobutyl and a hydrogen atom, a cyclopropyl and a hydrogen atom, a cyclopropylmethyl and a hydrogen atom, an optionally substituted phenyl and a hydrogen atom, an optionally substituted phenylmethyl and a hydrogen atom, an optionally substituted phenylethyl and a hydrogen atom, a methyl and a methyl, or a methyl and an ethyl. 5A )(R 5B )- is preferred.

[0107] In formula (I), R 6 is hydrogen, and C 1 -C 6 alkyl; or R 6 and R 7 Or R 6 and R 7’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4It forms a 3- to 7-membered heterocycle which may be substituted by alkoxy.

[0108] In some situations, R 6 But, C 1 -C 6 When it is an alkyl group, the C 1 -C 6 Alkyl is preferably methyl, ethyl, propyl, butyl, pentyl.

[0109] In some situations, R 6 and R 7 Or R 6 and R 7’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 When a 3- to 7-membered heterocyclic ring which may be substituted by alkoxy is formed, the 3- to 7-membered heterocyclic ring formed is preferably an azetidine ring, a pyrrolidine ring, or a piperidine ring. 6 and R 7 When taken together, form a heterocycle, R 7’ is hydrogen and R 6 and R 7’ When taken together, form a heterocycle, R 7 is hydrogen.

[0110] In formula (I), R 2 and R 6 Preferably, both or either one of R 2 and R 6 Either or both are C 1 -C 6 It is more preferably an alkyl group.

[0111] In formula (I), R 7 and R 7’ is R 6 and R 7 or R 6 and R 7’ except when taken together to form a heterocycle, (a)R 7’ is hydrogen and R 7is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 4 , N-PG 5 -Indol-3-ylmethyl, 4-(PG 4 O) Benzyl, PG 4 -O-methyl (i.e., -CH 2 -O-PG 4 ), 1-(PG 4 O) Ethyl, 2-(PG 4 O) Ethyl, PG 4 -OCO(CH 2 )-, P.G. 4 -OCO(CH 2 ) 2 -, P.G. 5 Nn-Butyl, -CON(R 15A )(R 15B ), -CH 2 -CON(R 15A )(R 15B ), and -(CH 2 ) 2 CON(R 15A )(R 15B ) or (b)R 7 and R 7’ is independently an optionally substituted C 1 -C 6 is alkyl, or (c)R 7 and R 7’ together with the carbon atom to which they are attached form a 3- to 7-membered alicyclic ring. R 7 and R 7’The combinations of are a hydrogen atom and a hydrogen atom, a methyl and a hydrogen atom, an ethyl and a hydrogen atom, an isopropyl and a hydrogen atom, an isobutyl and a hydrogen atom, a cyclopropyl and a hydrogen atom, a cyclopropylmethyl and a hydrogen atom, a cyclopentyl and a hydrogen atom, a cyclohexyl and a hydrogen atom, an optionally substituted phenyl and a hydrogen atom, an optionally substituted phenylmethyl and a hydrogen atom, an optionally substituted phenylethyl and a hydrogen atom, a 2-(methylthio)ethyl and a hydrogen atom, -CH 2 SPG 4 and hydrogen atom, N-PG 5 -Indol-3-ylmethyl and hydrogen atom, 4-(PG 4 O) Benzyl and hydrogen atom, PG 4 -O-methyl and hydrogen atom, 1-(PG 4 O) Ethyl and hydrogen atom, 2-(PG 4 O) Ethyl and hydrogen atom, PG 4 -OCO(CH 2 )- and hydrogen atom, PG 4 -OCO(CH 2 ) 2 - and hydrogen atoms, PG 5 Nn-Butyl and hydrogen atom, -CON(R 15A )(R 15B ) and a hydrogen atom, -CH 2 -CON(R 15A )(R 15B ) and a hydrogen atom, -(CH 2 ) 2 CON(R 15A )(R 15B ) and a hydrogen atom, methyl and methyl, and methyl and ethyl are preferred. 7 and R 7’ However, when they form a 3- to 7-membered alicyclic ring together with the carbon atom to which they are bonded, the alicyclic ring is preferably a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.

[0112] In formula (I), R 8 is a single bond or -C(R 8A )(R 8B )-and R 8A and R 8B are independently hydrogen, C1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 alkyl.

[0113] R 8 is a single bond or R 8A and R 8B is a hydrogen atom and a hydrogen atom, a methyl and a hydrogen atom, an ethyl and a hydrogen atom, an isopropyl and a hydrogen atom, an isobutyl and a hydrogen atom, a cyclopropyl and a hydrogen atom, a cyclopropylmethyl and a hydrogen atom, an optionally substituted phenyl and a hydrogen atom, an optionally substituted phenylmethyl and a hydrogen atom, an optionally substituted phenylethyl and a hydrogen atom, a methyl and a methyl, or a methyl and an ethyl. 8A )(R 8B )- is preferred.

[0114] In formula (I), R 9 is hydroxy, -O-PG 6 , a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES, where RES is a resin for solid phase synthesis. When the structure represented by formula (I) is present at the C-terminus of the starting peptide compound, R 9 is hydroxy, -O-PG 6 On the other hand, when the structure represented by formula (I) is present at any position other than the C-terminus of the starting peptide compound, R 9 is preferably a natural amino acid residue or an amino acid analog residue.

[0115] In formula (I), R 14A and R 14B are independently hydrogen, C 1 -C 4 alkyl or R 14A and R 14BR together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms. 14A and / or R 14B C 1 -C 4 When it is an alkyl group, the C 1 -C 4 As the alkyl, methyl, ethyl, and propyl are preferred. 14A and R 14B When these are combined with the nitrogen atom to which they are bonded to form a 4- to 8-membered ring which may contain one or more additional heteroatoms, the 4- to 8-membered ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0116] In formula (I), R 15A and R 15B are independently hydrogen, C 1 -C 4 alkyl or R 15A and R 15B R together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms. 15A and / or R 15B C 1 -C 4 When it is an alkyl group, the C 1 -C 4 As the alkyl, methyl, ethyl, and propyl are preferred. 15A and R 15B When these are combined with the nitrogen atom to which they are bonded to form a 4- to 8-membered ring which may contain one or more additional heteroatoms, the 4- to 8-membered ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0117] In formula (I), PG 1 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl. PG 1 As such, Fmoc, Boc and Cbz are preferred.

[0118] In formula (I), PG 2 and P.G. 4 are independently hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl. PG 2 , P.G. 4 methyl, allyl, t-Bu, trityl, methoxytrityl, cumyl, THP, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 Alkyl is preferred.

[0119] In formula (I), PG 3 and P.G. 5 is independently selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl. PG 3 , P.G. 5 As the alkyl group, Fmoc, Boc, Cbz, t-Bu and trityl are preferred.

[0120] In formula (I), PG 6 is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, and 2-(trimethylsilyl)ethyl. PG 6 As the aryl group, t-Bu, trityl, cumyl, benzyl, methyl and allyl are preferable.

[0121] Many of the structures in which at least two amino acid residues are linked, as represented by general formula (I), are susceptible to cleavage or damage when known deprotection or deresination conditions are used. By using the reaction conditions of the present invention, only the desired protecting group or solid-phase synthesis resin can be selectively and efficiently deprotected and / or deresinated without such cleavage or damage.

[0122] In one aspect, the structure of at least two amino acid residues linked together represented by general formula (I) includes one N-substituted amino acid and one N-non-substituted amino acid linked together, and two N-substituted amino acids linked together. Specific examples of such amino acid residues include R 5 and R 8 is a single bond, and two amino acid residues represented by the following general formula (I') are linked together. [ka] Each group in formula (I') can be the same as each group in formula (I) above.

[0123] In one aspect, in formula (I'), R 1 is hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue.

[0124] In one aspect, in formula (I'), R 2 and R 6 Preferably, both or either one of R 2 and R 6 Either or both are C 1 -C 6 It is more preferably an alkyl group.

[0125] In one aspect, in formula (I'), R 2 , and R 6 is independently 1 -C 6It can be alkyl, of which methyl, ethyl, propyl, butyl, pentyl are preferred.

[0126] In one aspect, in formula (I'), R 2 and R 4 Or R 2 and R 4’、 R 6 and R 7 Or R 6 and R 7’ each independently, together with the nitrogen and carbon atoms to which they are attached, represents a hydroxyl or 1 -C 4 R may form a 3- to 7-membered heterocycle which may be substituted by alkoxy. 2 and R 4 When taken together, form a heterocycle, R 4’ is hydrogen and R 2 and R 4’ When taken together, form a heterocycle, R 4 is hydrogen. R 6 and R 7 When taken together, form a heterocycle, R 7’ is hydrogen and R 6 and R 7’ When taken together, form a heterocycle, R 7 is hydrogen.

[0127] In one aspect, in formula (I'), R 9 is hydroxy, -O-PG 6 , a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES, where RES is a resin for solid phase synthesis.

[0128] In one aspect, in formula (I'), R 4 and R 4’ , or R 7 and R 7’ Both are C 1 -C 6 alkyl or R 4 and R 4’ , or R 7 and R 7’may form a 3- to 7-membered alicyclic ring together with the carbon atom to which they are attached.

[0129] In one aspect, in formula (I'), R 4’ is hydrogen and R 4 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 2 , N-PG 3 -Indol-3-ylmethyl, 4-(PG 2 O) Benzyl, PG 2 -O-methyl, 1-(PG 2 O) Ethyl, 2-(PG 2 O) Ethyl, PG 2 -OCO(CH 2 )-, P.G. 2 -OCO(CH 2 ) 2 -, P.G. 3 Nn-Butyl, -CON(R 14A )(R 14B ), -CH 2 -CON(R 14A )(R 14B ), and -(CH 2 ) 2 CON(R 14A )(R 14B ) may be selected from the group consisting of

[0130] In one aspect, in formula (I'), R 7’ is hydrogen and R 7 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 4 , N-PG 5 -Indol-3-ylmethyl, 4-(PG 4 O) Benzyl, PG 4 -O-methyl, 1-(PG 4 O) Ethyl, 2-(PG 4 O) Ethyl, PG 4 -OCO(CH 2 )-, P.G. 4 -OCO(CH 2 ) 2 -, P.G. 5 Nn-Butyl, -CON(R 15A )(R 15B ), -CH 2 -CON(R 15A )(R 15B ), and -(CH 2 ) 2 CON(R 15A )(R 15B ) may be selected from the group consisting of

[0131] As the structure represented by the general formula (I'), R 1 But hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue; R 2 , and R 6 is methyl or ethyl, and / or R 2 and R 4 Or R 2 and R 4’、 R 6 and R 7 Or R 6 and R 7’ each independently, together with the nitrogen and carbon atoms to which they are attached, represents a hydroxyl or 1 -C 4R forms a 4- to 6-membered heterocycle which may be substituted by alkoxy. 2 and R 4 When taken together, form a heterocycle, R 4’ is hydrogen, and R 2 and R 4’ When taken together, form a heterocycle, R 4 is hydrogen. Also, R 6 and R 7 When taken together, form a heterocycle, R 7’ is hydrogen, and R 6 and R 7’ When taken together, form a heterocycle, R 7 is hydrogen. Also, R 9 -O-PG 6 , a natural amino acid residue, an amino acid analog residue, or -O-RES, where RES can be a CTC resin, Wang resin, or SASRIN resin for solid phase synthesis. R 4 and R 4’ , or R 7 and R 7’ can each independently be methyl or ethyl, and R 4 and R 4’ , or R 7 and R 7’ may be taken together with the nitrogen and carbon atoms to which they are attached to form a 5- or 6-membered alicyclic ring. R 4’ and R 7’ If is hydrogen, then R 4 and R 7are each independently hydrogen or alkyl selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, and sec-butyl, or can be optionally substituted phenylmethyl, optionally substituted phenylethyl, benzyloxymethyl, 1-benzyloxyethyl, 2-benzyloxyethyl, tert-butoxycarbonylmethyl, methoxycarbonylmethyl, tert-butoxycarbonylethyl, methoxycarbonylethyl, tert-butoxycarbamoylbutyl, N,N-dimethylaminocarbonyl, piperidylcarbonyl, pyrrolidylcarbonyl, N,N-dimethylaminocarbonylmethyl, piperidylcarbonylmethyl, pyrrolidylcarbonylmethyl, N,N-dimethylaminocarbonylethyl, piperidylcarbonylethyl, or pyrrolidylcarbonylethyl.

[0132] In one aspect, the starting peptide compound may contain, in addition to one or more structures represented by general formula (I), one or more additional naturally occurring amino acid residues and / or amino acid analog residues.

[0133] In one aspect, the starting peptide compound contains at least one protecting group that can be removed by the method of the present invention. Such a protecting group may be contained in the structure represented by general formula (I) or in an amino acid residue other than the structure represented by general formula (I).

[0134] In one aspect, the starting peptide compound contains at least one resin for solid-phase synthesis that can be deresined by the method of the present invention. Such a resin may be contained in the structure represented by general formula (I) or may be contained in an amino acid residue other than the structure represented by general formula (I).

[0135] In one aspect, the resin for solid phase synthesis is bound to a carboxyl group contained in the C-terminal amino acid residue of the starting peptide compound.

[0136] In one aspect, the starting peptide compound to be deprotected and / or deprotected contains a structure in which at least two amino acid residues represented by the following general formula (II) are linked at its C-terminus. [ka]

[0137] R 1’ is a group represented by formula (III). [ka] In the formula, * denotes a point of attachment.

[0138] In formula (III), R 1 is hydrogen, PG 1 , a naturally occurring amino acid residue, or an amino acid analog residue.

[0139] In formula (III), R 2 is hydrogen, and C 1 -C 6 alkyl; or R 2 and R 10 Or R 2 and R 10’ together with the nitrogen and carbon atoms to which they are attached form hydroxy or C 1 -C 4 R forms a 3- to 7-membered heterocycle which may be substituted by alkoxy. 2 and R 10 When taken together, form a heterocycle, R 10’ is hydrogen and R 2 and R 10’ When taken together, form a heterocycle, R 10 is hydrogen. In some situations, R 2 But, C 1 -C 6 When it is an alkyl group, the C 1 -C 6 Alkyl is preferably methyl, ethyl, propyl, butyl, pentyl. In some situations, R 2 and R 10 Or R 2 and R 10’ together with the nitrogen and carbon atoms to which they are attached, form hydroxy or C 1 -C 4 When a 3- to 7-membered heterocycle which may be substituted by alkoxy is formed, the formed 3- to 7-membered heterocycle is preferably an azetidine ring, a pyrrolidine ring, or a piperidine ring.

[0140] In formula (III), R 10 and R 10’ is R 2 and R 10 or R 2 and R 10’ Except when taken together with the group form a heterocycle, (a)R 10’ is hydrogen and R 10 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 8 , N-PG 9 -Indol-3-ylmethyl, 4-(PG 8 O) Benzyl, PG 8 -O-methyl (i.e., -CH 2 -O-PG 8 ), 1-(PG 8 O) Ethyl, 2-(PG 8 O) Ethyl, PG 8 -OCO(CH 2 )-, P.G. 8 -OCO(CH 2 ) 2 -, P.G. 9 Nn-Butyl, -CON(R 16A )(R 16B ), -CH2 -CON(R 16A )(R 16B ), and -(CH 2 ) 2 CON(R 16A )(R 16B ) or (b)R 10 and R 10’ is independently an optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 3 -C 6 Cycloalkyl C 1 -C 4 is alkyl, or (c)R 10 and R 10’ together with the carbon atom to which they are attached form a 3- to 7-membered alicyclic ring.

[0141] R 10 and R 10’ The combinations of are a hydrogen atom and a hydrogen atom, a methyl and a hydrogen atom, an ethyl and a hydrogen atom, an isopropyl and a hydrogen atom, an isobutyl and a hydrogen atom, a cyclopropyl and a hydrogen atom, a cyclopropylmethyl and a hydrogen atom, an optionally substituted phenyl and a hydrogen atom, an optionally substituted phenylmethyl and a hydrogen atom, an optionally substituted phenylethyl and a hydrogen atom, a 2-(methylthio)ethyl and a hydrogen atom, -CH 2 SPG 8 and hydrogen atom, N-PG 9 -Indol-3-ylmethyl and hydrogen atom, 4-(PG 8 O) Benzyl and hydrogen atom, PG 8 -O-methyl and hydrogen atom, 1-(PG 8 O) Ethyl and hydrogen atom, 2-(PG 8 O) Ethyl and hydrogen atom, PG 8 -OCO(CH 2 )- and hydrogen atom, PG 8 -OCO(CH 2 ) 2 - and hydrogen atoms, PG 9 Nn-Butyl and hydrogen atom, -CON(R16A )(R 16B ) and a hydrogen atom, -CH 2 -CON(R 16A )(R 16B ) and a hydrogen atom, -(CH 2 ) 2 CON(R 16A )(R 16B ) and a hydrogen atom, methyl and methyl, and methyl and ethyl are preferred. 10 and R 10’ However, when they form a 3- to 7-membered alicyclic ring together with the carbon atom to which they are bonded, the alicyclic ring is preferably a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.

[0142] In formula (III), R 11 is a single bond or -C(R 11A )(R 11B )-and R 11A and R 11B are independently hydrogen, C 1 -C 6 Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylC 1 -C 4 Alkyl and optionally substituted heteroaryl C 1 -C 4 alkyl.

[0143] R 11 is a single bond or R 11A and R 11B is a hydrogen atom and a hydrogen atom, a methyl and a hydrogen atom, an ethyl and a hydrogen atom, an isopropyl and a hydrogen atom, an isobutyl and a hydrogen atom, a cyclopropyl and a hydrogen atom, a cyclopropylmethyl and a hydrogen atom, an optionally substituted phenyl and a hydrogen atom, an optionally substituted phenylmethyl and a hydrogen atom, an optionally substituted phenylethyl and a hydrogen atom, a methyl and a methyl, or a methyl and an ethyl. 11A )(R 11B )- is preferred.

[0144] In formula (II), R 12 and R 12’ are independently hydrogen, PG 10 -O-methyl (i.e., -CH 2 -O-PG 10 ), -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES, where RES is a resin for solid phase synthesis, and n is 0, 1, or 2.

[0145] In one aspect, when used in the resin removal method of the present invention, R 12 and R 12’ Either one of the following is -(CH 2 ) n COO-RES, and -(CH 2 ) n It is preferably selected from CONH-RES.

[0146] In formula (II), R 6 is hydrogen, and C 1 -C 6 In one aspect, R 6 But, C 1 -C 6 When it is an alkyl group, the C 1 -C 6 Alkyl is preferably methyl, ethyl, propyl, butyl, pentyl.

[0147] In formula (II) and formula (III), R 2 and R 6 Preferably, both or either one of R 2 and R 6 Either or both are C 1 -C 6 It is more preferably an alkyl group.

[0148] In formula (II), R 13 is C1 -C 4 Alkyl, or -(CH 2 ) m CON(R 17A )(R 17B ), where m is 0, 1, or 2; R 17A and R 17B are independently hydrogen, C 1 -C 4 alkyl or R 17A and R 17B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms.

[0149] In some situations, R 13 But, C 1 -C 4 When it is an alkyl group, the C 1 -C 4 Alkyl is preferably methyl or ethyl.

[0150] In some situations, R 17A and R 17B When they are combined with the nitrogen atom to which they are attached to form a 4- to 8-membered ring which may contain one or more additional heteroatoms, the ring formed is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0151] In formula (II), R 16A and R 16B are independently hydrogen or C 1 -C 4 alkyl or R 16A and R 16B together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms.

[0152] R 16A and R 16B C 1 -C 4 When it is an alkyl group, the C 1 -C4 As the alkyl, methyl, ethyl and propyl are preferred.

[0153] R 16A and R 16B When these are combined with the nitrogen atom to which they are bonded to form a 4- to 8-membered ring which may contain one or more additional heteroatoms, the 4- to 8-membered ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0154] PG 1 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl. PG 1 As such, Fmoc, Boc and Cbz are preferred.

[0155] In formula (II), PG 8 is hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl. PG 8 methyl, allyl, t-Bu, trityl, methoxytrityl, cumyl, THP, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 Alkyl is preferred.

[0156] In formula (II), PG 9 is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl. PG 9As the alkyl group, Fmoc, Boc, Cbz, t-Bu and trityl are preferred.

[0157] In formula (II), PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 PG is selected from the group consisting of alkyl, 2-(trimethylsilyl)ethyl, and 2-(trimethylsilyl)ethyl. 10 As the aryl group, t-Bu, trityl, cumyl, benzyl, methyl and allyl are preferable.

[0158] In one aspect, PG may be included in the general formulas (I) to (III). 1 ~PG 10 can each independently be a protecting group that can be removed by the deprotection method of the present invention, such protecting groups including t-Bu, triphenylmethyl, 2-(trimethylsilyl)-ethyl, Boc, Teoc, Cbz, methoxycarbonyl, tetrahydropyranyl, 1-ethoxyethyl, and the like.

[0159] In some cases, PG 1 ~PG 10 can each independently be a protecting group that is not removed by the deprotection method of the present invention. Such protecting groups include Fmoc, Alloc, and the like.

[0160] In some cases, PG 1 ~PG 10 may each independently be a group that does not act as a protecting group, for example, a group that is not removable, or a group that can be transformed. Examples of such protecting groups include those described in "Greene's, "Protective Groups in Organic Synthesis" (5th Edition, John Wiley & Sons 2014).

[0161] Many of the structures in which at least two amino acid residues are linked, as represented by general formula (II), are susceptible to cleavage or rearrangement when known deprotection or resin removal conditions are used. Such cleavage or rearrangement is sometimes called damage. By using the reaction conditions of the present invention, only the desired protecting group or solid-phase synthesis resin can be selectively and efficiently deprotected without such damage.

[0162] In one aspect, the structure of two amino acid residues linked together represented by general formula (II) includes one N-substituted amino acid and one N-non-substituted amino acid linked together, and two N-substituted amino acids linked together. Specific examples of such structures include those represented by general formula (II) R 1’ is represented by the general formula (III), and R 11 -C(R 11A )(R 11B )- or the structure (formula IV) in which R 11 is a single bond (Formula V). [ka] Each group in formula (IV) and formula (V) can be the same as each group in formula (II) and formula (III) above, respectively.

[0163] In one aspect, in formula (IV) and formula (V), R 1 is hydrogen, PG 1 , a naturally occurring amino acid residue, or an amino acid analog residue.

[0164] In one aspect, in formula (IV) and formula (V), R 1 is hydrogen, PG 1 , a natural amino acid residue or an amino acid analog residue; R 2 , and R 10 is preferably methyl, ethyl, propyl, butyl, or pentyl.

[0165] In one aspect, in formula (IV) and formula (V), R1 is hydrogen, PG 1 , a natural amino acid residue or an amino acid analog residue; R 2 and R 10 Or R 2 and R 10’ each independently, together with the nitrogen and carbon atoms to which they are attached, represents a hydroxyl or 1 -C 4 It is preferable that R forms a 3- to 7-membered heterocycle which may be substituted by alkoxy. 2 and R 10 When taken together, form a heterocycle, R 10’ is hydrogen and R 2 and R 10’ When R is taken together with R to R to form a 3- to 7-membered heterocycle, 10 is hydrogen.

[0166] In one aspect, in formula (IV) and formula (V), R 10’ is hydrogen and R 10 is hydrogen, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl C 1 -C 4 Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH 2 SPG 8 , N-PG 9 -Indol-3-ylmethyl, 4-(PG 8 O) Benzyl, PG 8 -O-methyl, 1-(PG 8 O) Ethyl, 2-(PG 8 O) Ethyl, PG 8 -OCO(CH 2 )-, P.G. 8 -OCO(CH 2 ) 2 -, P.G. 9 Nn-Butyl, -CON(R 16A )(R 16B), -CH 2 -CON(R 16A )(R 16B ), and -(CH 2 ) 2 CON(R 16A )(R 16B ) may be selected from the group consisting of

[0167] In one aspect, in formula (IV) and formula (V), preferably, R 6 is C 1 -C 6 It can be alkyl, of which methyl, ethyl, propyl, butyl, pentyl are preferred.

[0168] In one aspect, in formula (IV) and formula (V), R 13 is C 1 -C 4 It can be alkyl, of which methyl, ethyl, propyl, or butyl is preferred, and methyl or ethyl is more preferred.

[0169] In one aspect, in formula (IV) and formula (V), R 13 is -(CH 2 ) m CON(R 17A )(R 17B ), where m is 0, 1, or 2. In this case, R 17A and / or R 17B is independently 1 -C 4 alkyl, 1 -C 4 The alkyl group is preferably methyl or ethyl. 17A and R 17B can form a 4- to 8-membered ring, together with the nitrogen atom to which they are bonded, which may contain one or more additional heteroatoms, and the 4- to 8-membered ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0170] In one aspect, in formula (IV) and formula (V), R12 , and R 12’ are independently hydrogen, PG 10 -O-methyl, -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES. 12 , and R 12’ But, P.G. 10 -O-methyl, -(CH 2 ) n COO-PG 10 , -(CH 2 ) n COO-RES, or -(CH 2 ) n If CONH-RES, n is 0, 1, or 2, and PG 10 is preferably t-Bu, trityl, cumyl, benzyl, methyl, or allyl. RES is a resin for solid phase synthesis, preferably CTC resin or Wang resin.

[0171] In one aspect, when used in the resin removal method of the present invention, R 12 and R 12’ Either one of the following is -(CH 2 ) n COO-RES, and -(CH 2 ) n It is preferably selected from CONH-RES.

[0172] In one aspect, in formula (IV) and formula (V), more preferably, R 1 But hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue; R 2 is methyl, ethyl, and / or R 2 and R 10 together with the nitrogen and carbon atoms to which they are attached, form hydroxy or C 1 -C 4It forms a 4- to 6-membered heterocycle which may be substituted by alkoxy. Also, R 10 and R 10’ are each independently selected from methyl or ethyl, or R 10 and R 10’ may be joined together to form a 5- or 6-membered alicyclic ring. Alternatively, R 10’ is hydrogen and R 10 is hydrogen or an alkyl selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl, or can be optionally substituted phenylmethyl, optionally substituted phenylethyl, benzyloxymethyl, 1-benzyloxyethyl, 2-benzyloxyethyl, tert-butoxycarbonylmethyl, methoxycarbonylmethyl, tert-butoxycarbonylethyl, methoxycarbonylethyl, tert-butoxycarbamoylbutyl, N,N-dimethylaminocarbonyl, piperidylcarbonyl, pyrrolidylcarbonyl, N,N-dimethylaminocarbonylmethyl, piperidylcarbonylmethyl, pyrrolidylcarbonylmethyl, N,N-dimethylaminocarbonylethyl, piperidylcarbonylethyl, or pyrrolidylcarbonylethyl. R 6 can be methyl or ethyl; R 13 is methyl or -(CH 2 ) m CON(R 17A )(R 17B ) can be R 13 Ga-(CH 2 ) m CON(R 17A )(R 17B ), then R 17A and R 17B together with the nitrogen atom to which they are attached form a piperidine ring. R 12 , and R 12’ are independently hydrogen, PG 10 -O-methyl, -(CH 2 ) n COO-PG10 , -(CH 2 ) n COO-RES, and -(CH 2 ) n CONH-RES is selected from the group consisting of:

[0173] In one aspect, the starting peptide compound may contain one or more additional natural amino acid residues and / or amino acid analog residues in addition to the structure represented by general formula (II). The starting peptide compound contains one or more structures represented by general formula (I), contains a structure represented by general formula (II) at the C-terminus, and may further contain one or more additional natural amino acid residues and / or amino acid analog residues. The peptide compound may be formed with secondary amides, tertiary amides, or a mixture of secondary and tertiary amides.

[0174] In one aspect, the starting peptide compound contains at least one protecting group that can be removed by the method of the present invention. Such a protecting group may be contained in the structure represented by general formula (II) or in an amino acid residue other than the structure represented by general formula (II).

[0175] In one aspect, the starting peptide compound comprises at least one resin for solid-phase synthesis that can be deresined by the method of the present invention. When the starting peptide compound comprises a structure represented by general formula (II), such a resin is included in the structure represented by general formula (II).

[0176] In one aspect, the present invention relates to a method for producing an amide compound from which a protecting group has been deprotected, the method comprising the step of contacting a starting amide compound with a silylating agent in a solvent, thereby deprotecting a protecting group that can be deprotected by a silylating agent from the starting amide compound.

[0177] In one aspect, the present invention relates to a method for producing an amide compound from a resin for solid phase synthesis, comprising the step of contacting a starting amide compound with a silylating agent in a solvent to thereby remove the starting amide compound from the resin for solid phase synthesis.

[0178] In one aspect, the starting amide compound to be deprotected / removed from the resin is represented by the general formula (II). [ka]

[0179] In formula (II), R 1’ is a hydrogen atom or PG 7 and the other groups are as defined above. 6 is C 1 -C 6 It is preferably alkyl. PG 7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl, with Fmoc, Boc, and Cbz being preferred.

[0180] The starting amide compound represented by general formula (II), particularly the N-substituted compound, is susceptible to damage such as rearrangement when known deprotection or deresination conditions are used. By using the reaction conditions of the present invention, only the desired protecting group or solid phase synthesis resin can be selectively and efficiently deprotected and / or deresinated without such damage.

[0181] In the present specification, the term "silylation agent" is not particularly limited as long as it can be used in the deprotection or deresination reaction of the present invention, and refers to an agent that can act as a deprotection agent or deprotection reagent, and / or a deresination agent or deresination reagent. In the present specification, the term "silylation agent" may be referred to as a deprotection agent or deprotection reagent, and / or a deresination agent or deresination reagent. The silylation agent can be generated, for example, by mixing the silyl compound and the electrophilic species trapping agent in a solvent, or by mixing an acid and an electrophilic species trapping agent having a silyl group. The silyl compound and the electrophilic species trapping agent, or the acid and the electrophilic species trapping agent having a silyl group may be mixed in advance, in a solvent, or in the presence or absence of the starting peptide compound.

[0182] In this specification, the term "silyl compound" includes, for example, a silyl compound having a leaving group (X) represented by the following formula 1. [ka] [In the formula, R AX , R AY , and R AZ is independently 1 -C 4 alkyl or phenyl, and X is -OTf, -OClO 3 , Cl, Br, and I.] R AX , R AY , and R AZ may be preferably selected independently from methyl, ethyl, i-propyl, t-butyl, and phenyl. More specifically, such silyl compounds include TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, and TMSOClO. 3 , and TMSI.

[0183] In the present specification, the "acid" that can be used to generate the silylating agent is not particularly limited as long as it can generate the silyl compound, and examples thereof include an acid represented by HX (wherein X has the same meaning as X in formula (1)).

[0184] In the present specification, the term "electrophilic species scavenger" refers to a compound that can form an adduct or salt with a proton, or a compound that reacts with a cationic species and is not easily silylated. Examples of such electrophilic species scavenger include imidates (formula 2), amides (formula 3), ketene acetals (formula 4), ketene alkoxyhemiaminals (formula 4), enol ethers (formula 4), enol esters (formula 4), imines (formula 5), ​​amines (formula 6), diamines (formula 7), dialkylcarbodiimides (formula 8), ureas (formula 9), and urethanes (formula 10). Some of these have a substituted silyl group, and in this case, specific examples of the substituted silyl group include TMS (trimethylsilyl), TES (triethylsilyl), TBS (trimethylbutylsilyl), TIPS (triisopropylsilyl), and TBDPS (t-butyl-dimethylsilyl).

[0185] The imidate is represented by formula 2. [ka] [In the formula, R B is a substituted silyl group, and R C is a substituted silyl group, or R B and R C form a 5- to 7-membered ring together with the nitrogen and carbon atoms to which they are attached, R D C may be substituted with one or more fluorine atoms 1 -C 4 alkyl or optionally substituted methylene, where R D When is an optionally substituted methylene, formula 2 dimerizes to the following formula: [ka] forming a compound represented by the formula:

[0186] Preferable examples of the imidate include N-silylimidates represented by formula 2-1 and bisoxazolines represented by the following formula 2-2. [ka] [In the formula, R BX , R BY , and R BZ is independently 1 -C 4 alkyl or phenyl; R C and R D is the same as above, R E and R F is independently 1 -C 4 is alkyl] Also, R BX , R BY , and R BZ may be preferably selected independently from methyl, ethyl, i-propyl, t-butyl, and phenyl.

[0187] Preferred examples of the N-silylimidates include N,O-bis(trimethylsilyl)acetamides represented by formula 2-1-1, and preferred examples of the bisoxazolines include 4-substituted bisoxazolines represented by formula 2-2-1. [ka]

[0188] More preferred examples of the N-silylimidates include N,O-bis(trimethylsilyl)acetamide represented by formula 2-1-1-1 and N,O-bis(trimethylsilyl)trifluoroacetamide represented by formula 2-1-1-2. More preferred examples of the bisoxazolines include N,O-bis(trimethylsilyl)trifluoroacetamide 2,2'-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] represented by formula 2-2-1-1. [ka]

[0189] The amide is represented by formula 3: [ka] [In the formula, R G is one or more C 1 -C 4 is an alkyl-substituted silyl group, R H is hydrogen, C 1 -C 4 is alkyl, R I is hydrogen, C which may be substituted with one or more fluorine atoms 1 -C 4 is alkyl.

[0190] A preferred example of the amide is the N-silyl amide represented by formula 3-1. [ka] [In the formula, R GX , R GY and R GZ is independently 1 -C 4 alkyl or phenyl; R H and R I is the same as above] Also, R GX , R GY and R GZ may be preferably selected independently from methyl, ethyl, i-propyl, t-butyl, and phenyl.

[0191] Preferred examples of the N-silylamide include N-trimethylsilylacetamides represented by formula 3-1-1. [ka] [In the formula, R H and R I is the same as above]

[0192] More preferred examples of the N-trimethylsilylacetamides include N-methyl-N-trimethylsilylacetamide represented by formula 3-1-1-1 and N-methyl-N-trimethylsilyltrifluoroacetamide represented by formula 3-1-1-2. [ka]

[0193] The ketene acetal, ketene alkoxyhemiaminal, enol ether, and enol ester are all represented by formula 4. [ka] [In the formula, (a-1)R J is a substituted silyl group, R K is C 1 -C 4 Alkoxy and R M and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (a-2)R J is a substituted silyl group, R M is hydrogen or C 1 -C 4alkyl, and R K and R L form a 5- to 8-membered ring containing an oxygen atom together with the carbon atom to which they are attached, or (b-1)R J is a substituted silyl group, R K is C 1 -C 4 alkyl, and R M and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (b-2)R J is a substituted silyl group, R M is hydrogen, or C 1 -C 4 alkyl, and R K and R L form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (c-1)R J and R M form a 5- to 7-membered ring containing an oxygen atom together with the carbon atom to which they are attached, and R K is hydrogen, or C 1 -C 4 alkyl, and R L is C 1 -C 4 Is it an alkyl group? (c-2)R J and R M form a 5- to 7-membered ring containing an oxygen atom together with the carbon atom to which they are attached, and R K and R L form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (d-1)R J is C 1 -C 4 alkyl, and R M , R K , and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (d-2)R J is C 1 -C4 is alkyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L form 5-8 rings together with the carbon atoms to which they are attached, or (e-1)R J is C 1 -C 3 alkylcarbonyl, and R M , R K , and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (e-2)R J is C 1 -C 3 alkylcarbonyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (f-1)R J is a substituted silyl group or C 1 -C 4 is alkyl, R K is optionally substituted di-C 1 -C 4 alkylamino, and R M and R L are independently hydrogen or C 1 -C 4 Is it an alkyl group? (f-2) or R J is a substituted silyl group or C 1 -C 4 is alkyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L form a 5- to 8-membered ring containing a nitrogen atom together with the carbon atom to which they are attached, and the 5- to 8-membered ring is 1 -C 4may be substituted by alkyl. Here, the preferred C 1 -C 4 Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl. 1 -C 3 Alkylcarbonyl includes acetyl and propionyl.

[0194] A preferred example of the ketene acetal is a silyl ketene acetal represented by formula 4-1. [ka] [In the formula, R JX1 , R JY1 and R JZ1 is independently 1 -C 4 alkyl or phenyl; R KX1 is C 1 -C 4 is alkyl, R L , and R M is the same as above] Here, the preferred C 1 -C 4 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl. Also, R JX1 , R JY1 and R JZ1 may be preferably selected independently from methyl, ethyl, i-propyl, t-butyl, and phenyl.

[0195] A preferred example of the ketene silyl acetal is ketene trimethylsilyl acetal represented by formula 4-1-1. [ka] [In the formula, R KX1 , RL , and R M is the same as above] Also, the preferred R KX1 , R L , and R M Examples of aryl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0196] A preferred example of the ketene trimethylsilyl acetal is dimethylketene methyltrimethylsilyl acetal represented by formula 4-1-1-1. [ka]

[0197] A preferred example of the enol ether is the silyl enol ether represented by formula 4-2. [ka] [In the formula, R JX2 , R JY2 and R JZ2 is independently 1 -C 4 alkyl or phenyl; R KX2 is hydrogen, or C 1 -C 4 is alkyl, R L , and R M is the same as above] Also, R KX1 , R L , and R M C 1 -C 4 Preferred examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl. Also, R JX2 , R JY2 and R JZ2is preferably independently selected from the group consisting of methyl, ethyl, i-propyl, t-butyl, and phenyl.

[0198] A preferred example of the silyl enol ether is trimethylsilyl enol ether represented by formula 4-2-1. [ka] [In the formula, R KX2 , R L , and R M is the same as above]

[0199] A preferred example of the trimethylsilyl enol ether is isopropenyloxytrimethylsilane represented by the formula 4-2-1-1. [ka]

[0200] In another embodiment, the enol ether preferably includes a cyclic enol ether represented by formula 4-3. [ka] [In the formula, R KX3 , and R L1 are independently hydrogen or C 1 -C 4 is alkyl]

[0201] A preferred example of the cyclic enol ether is a dihydropyran represented by formula 4-3-1. [ka]

[0202] In another embodiment, the enol ether preferably includes an on-chain enol ether, and the on-chain enol ether preferably includes ethyl vinyl ether represented by formula 4-4. [ka]

[0203] The imine is represented by formula 5. [ka] [In the formula, R N , R N’ , and R O are independently hydrogen or C 1 -C 4 is alkyl. R N , R N’ , and R O C 1 -C 4 Preferred examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0204] A preferred imine is a ketimine represented by formula 5-1. [ka] [In the formula, R N is the same as above] Preferred R N , R N’ Examples of aryl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0205] A preferred example of the ketimine is 2,2,4,4-tetramethylpentanoneimine represented by formula 5-1-1. [ka]

[0206] The amine is represented by formula 6: [ka] [In the formula, R P is a substituted silyl group, R Q is a substituted silyl group, or C 1 -C 4 alkyl, and R R is hydrogen, a substituted silyl group, or C 1 -C 4 is alkyl, or R Q and R R form a 5- to 8-membered heterocycle containing an oxygen atom together with the nitrogen atom to which they are attached.

[0207] Preferred amines include disilylamines represented by formula 6-1. [ka] [In the formula, R PX1 , R PY1 , R PZ1 , R QX1 , R QY1 and R QZ1 is independently 1 -C 4 alkyl or phenyl] Also, R PX1 , R PY1 , R PZ1 , R QX1 , R QY1 and R QZ1 is preferably independently selected from the group consisting of methyl, ethyl, i-propyl, t-butyl, and phenyl.

[0208] A preferred example of the disilylamine is 1,1,1,3,3,3-hexamethyldisilazane (HMDS) represented by formula 6-1-1. [ka]

[0209] In another embodiment, the amine preferably includes an N-dialkyl-N-silylamine represented by formula 6-2. [ka] [In the formula, R PX2 , R PY2 and R PZ2 is independently 1 -C 4 alkyl or phenyl; R Q and R R is the same as above] Also, R PX2 , R PY2 and R PZ2 C 1 -C 4 Preferred examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl. Also, R PX2 , R PY2 and R PZ2 are preferably independently selected from the group consisting of methyl, ethyl, i-propyl, t-butyl, and phenyl.

[0210] A preferred example of the N-dialkyl-N-silylamine is N-dialkyl-N-trimethylsilylamine represented by formula 6-2-1. [ka] [In the formula, R Q and R R is the same as above]

[0211] Preferred examples of the N-dialkyl-N-trimethylsilylamine include N-trimethylsilylmorpholine represented by formula 6-2-1-1 and N-trimethylsilyldiethylamine represented by formula 6-2-1-2. [ka]

[0212] In another embodiment, preferred amines include N-alkyl-N-disilylamines represented by formula 6-3. [ka] [In the formula, R QX3 , R QY3 , R QZ3 , R RX1 , R RY1 and R RZ1 is independently 1 -C 4 alkyl or phenyl; R R is C 1 -C 4 is alkyl] Specifically, for example, R QX3 , R QY3 , R QZ3 , R RX1 , R RY1 and R RZ1 may be independently selected from methyl, ethyl, i-propyl, t-butyl, and phenyl. Also, R R Preferred C 1 -C 4 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0213] A preferred example of the N-alkyl-N-disilylamine is N-alkyl-N-bistrimethylsilylamine represented by formula 6-3-1. [ka] [In the formula, R R is C 1 -C 4 is alkyl] R R Preferred C 1 -C 4 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0214] In another embodiment, the amine preferably includes an N-alkyl-N-silylamine represented by formula 6-4. [ka] [In the formula, R PX2 , R PY2 , and R PZ2 is independently 1 -C 4 alkyl or phenyl; R Q is C 1 -C 4 is alkyl] R PX2 , R PY2 , and R PZ2 is preferably independently selected from the group consisting of methyl, ethyl, i-propyl, t-butyl, and phenyl. Also, R Q C 1 -C 4 Preferred examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0215] A preferred example of the N-alkyl-N-silylamine is N-alkyl-N-trimethylsilylamine represented by formula 6-4-1. [ka] [In the formula, R Q is C1 -C 4 is alkyl] R Q C 1 -C 4 Preferred examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0216] A preferred example of the N-alkyl-N-trimethylsilylamine is N-tert-butyltrimethylsilylamine represented by formula 6-4-1-1. [ka]

[0217] The diamine is represented by formula 7: [ka] [In the formula, X is a single bond or a carbon atom; where X is a single bond, R S does not exist, and R UA and R R together with the carbon and nitrogen atoms to which they are attached form an optionally substituted 6-membered aromatic heterocycle, and R UB and R T together with the carbon and nitrogen atoms to which they are attached form an optionally substituted 6-membered aromatic heterocycle; When X is a carbon atom, R UA and R UB is independently 1 -C 4 alkyl, and R R and R S and R T together with the carbon atoms to which they are attached form the following structure: [ka] ]

[0218] When X in formula 7 is a carbon atom, the diamine is preferably a tetraalkylnaphthalenediamine represented by formula 7-1. [ka] [In the formula, R UA and R UB is independently 1 -C 4 is alkyl.

[0219] A preferred example of the tetraalkylnaphthalenediamine is N,N,N',N'-tetramethyl-1,8-naphthalenediamine represented by formula 7-1-1. [ka]

[0220] In another embodiment, when X in formula 7 is a single bond, the diamine is preferably 2,2'-bipyridine represented by formula 7-2-1. [ka]

[0221] The dialkylcarbodiimide is represented by formula 8. [ka] [In the formula, R V is C 1 -C 4 Alkyl or C 3 -C 6 It is cycloalkyl. R V C 1 -C 4 Preferred examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, t-butyl, and cyclohexyl.

[0222] A preferred dialkylcarbodiimide is diisopropylcarbodiimide represented by formula 8-1. [ka]

[0223] The urea is represented by formula 9. [ka] [In the formula, R W and R X is independently 1 -C 4 alkyl, or substituted silyl groups.

[0224] A preferred example of the urea is N,N'-bis(trimethylsilyl)urea represented by formula 9-1. [ka]

[0225] The urethane is represented by formula 10: [ka] [In the formula, R Y and R Z is independently 1 -C 4 is an alkyl, or substituted silyl group.

[0226] A preferred example of the urethane is N,O-bis(trimethylsilyl)urea represented by formula 10-1. [ka]

[0227] In one aspect, the peptide compound, the solvent, the electrophilic species scavenger, and the silyl compound or acid can be mixed in any order to generate the silylating agent, preferably by mixing the peptide compound with the solvent, followed by the electrophilic species scavenger, and then the silyl compound or acid.

[0228] In one aspect, the solvent may be an aprotic solvent, and examples of such solvents include esters, ethers, alkylnitriles, halogenated hydrocarbons, and hydrocarbons. Among these, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, toluene, or acetonitrile is preferred, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, or 1,2-dichloroethane is more preferred, and ethyl acetate or 2-methyltetrahydrofuran is particularly preferred.

[0229] In one aspect, in the present invention, a stoichiometric amount or more of a silyl compound and an electrophilic species scavenger can be used to generate a silylating agent to deprotect and / or remove a protecting group and / or a resin from a peptide compound. In this case, for example, 1 to 5 equivalents, preferably 2 to 4 equivalents of a silyl compound and 1 to 10 equivalents, preferably 1 to 8 equivalents of an electrophilic species scavenger can be used per equivalent of a protecting group to be removed contained in a peptide or per equivalent of a resin to be removed.

[0230] In one aspect, a catalytic amount, for example, 0.1 to 0.5 equivalents, preferably 0.3 to 0.4 equivalents of a silyl compound per equivalent of the protecting group to be removed or per equivalent of the resin to be removed, can be combined with an electrophilic species scavenger to generate a silylating agent. In this case, the silylating agent is TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, or TMSOClO 3is preferably used, and the electrophilic species scavenger is preferably N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilylacetamide, N-methyl-N-trimethylsilyltrifluoroacetamide, dimethylketenemethyltrimethylsilylacetal, or isopropenyloxytrimethylsilane. In this case, 1 to 10 equivalents, preferably 1 to 8 equivalents of the electrophilic species scavenger can be used per equivalent of the protecting group to be removed or per equivalent of the resin to be removed.

[0231] In one aspect, a catalytic amount, for example, 0.1 to 0.5 equivalents, preferably 0.3 to 0.4 equivalents, of an acid relative to 1 equivalent of the protecting group to be removed or 1 equivalent of the resin to be removed, can be combined with an electrophilic species scavenger to generate a silylation agent. In this case, the acid is TfOH, HOClO 3 , HCl, HBr, HI are preferably used, and TfOH is more preferably used. As the electrophilic species capture agent, N-silylimidat (formula 2-1), N-silylamide (formula 3-1), ketene silyl acetal (formula 4-1), silyl enol ether (formula 4-2) are preferably used, and N,O-bis(trimethylsilyl)acetamide (formula 2-1-1-1), N,O-bis(trimethylsilyl)trifluoroacetamide (formula 2-1-1-2), N-methyl-N-trimethylsilylacetamide (formula 3-1-1-1), N-methyl-N-trimethylsilyltrifluoroacetamide (formula 3-1-1-2), dimethylketene methyl trimethylsilyl acetal (formula 4-1-1-1), or isopropenyloxytrimethylsilane (formula 4-2-1-1) are more preferably used. Among these, N,O-bis(trimethylsilyl)trifluoroacetamide and N-methyl-N-trimethylsilyltrifluoroacetamide are particularly preferred. In this case, 1 to 10 equivalents, preferably 1 to 8 equivalents of the electrophilic species scavenger can be used per equivalent of the protecting group to be removed or per equivalent of the resin to be removed.

[0232] In one aspect, the "protective group that can be deprotected by a silylating agent" is not particularly limited as long as it is a protective group that can be deprotected by the silylating agent. Specific examples of such protective groups include carboxyl protective groups such as t-Bu, benzyl, triphenylmethyl, cumyl, and 2-(trimethylsilyl)-ethyl, amino protective groups such as Boc, Teoc, Cbz, methoxycarbonyl, and cumyl, hydroxy protective groups such as tetrahydropyranyl and 1-ethoxyethyl, and SH protective groups such as triphenylmethyl and methoxytrityl.

[0233] The chemical synthesis method of the starting peptide compound in this specification includes, for example, liquid phase synthesis, solid phase synthesis using Fmoc synthesis or Boc synthesis, and combinations thereof. In Fmoc synthesis, the main chain amino group is protected by an Fmoc group, the side chain functional group is protected as necessary by a protecting group that is not cleaved by a base such as piperidine, and the main chain carboxylic acid is not protected, and the basic unit is an amino acid. The basic unit is not particularly limited as long as it has an Fmoc-protected amino group and a carboxylic acid group. For example, a dipeptide may be used as the basic unit. The basic unit to be placed at the N-terminus may be other than an Fmoc amino acid. For example, it may be a Boc amino acid or a carboxylic acid analog without an amino group. The main chain carboxylic acid group is supported on the solid phase by a chemical reaction with a functional group of the solid phase support. The Fmoc group is then deprotected with a base such as piperidine or DBU, and the newly generated amino group is condensed with the protected amino acid having a carboxylic acid of the basic unit to be added subsequently to generate an amide bond. In the condensation reaction, various combinations such as a combination of DIC and HOBt, a combination of DIC and HOAt, and a combination of HATU and DIPEA are possible. The desired peptide sequence can be generated by repeating the Fmoc group removal and the subsequent amide bond formation reaction. After the desired sequence is obtained, the resin is removed from the solid phase and the protective group of the side chain functional group introduced as necessary is deprotected. The deprotection method and the deprotection method of the present invention can be provided for the resin removal from the solid phase and the deprotection of the protective group of the side chain functional group. A step such as cyclization can be performed between or at the end of the resin removal step from the solid phase or the deprotection step. For example, a side chain carboxylic acid can be condensed with an amino group of the N-terminal main chain, or a side chain amino group can be condensed with a carboxylic acid of the C-terminal main chain. In this case, reaction orthogonality is required between the carboxylic acid on the C-terminal side and the side chain carboxylic acid to be cyclized, or between the main chain amino group or hydroxy group on the N-terminal side and the side chain amino group to be cyclized, and the protecting group is selected in consideration of the orthogonality of the protecting group. The reaction product thus obtained can be purified using a reverse phase column, a molecular sieve column, etc. Details of these are described in, for example, the Solid Phase Synthesis Handbook published by Merck Ltd. on May 1, 2002.

[0234] In the present specification, the term "resin for solid-phase synthesis" is not particularly limited as long as it can be used in the synthesis of peptide compounds by the solid-phase method and can be removed by the silylating agent of the present invention. Specific examples of such resins for solid-phase synthesis include CTC resin, Wang resin, SASRIN resin, trityl chloride resin (Trt resin), 4-methyltrityl chloride resin (Mtt resin), 4-methoxytrityl chloride resin (Mmt), and other resins that can be removed under acidic conditions. The resin can be appropriately selected according to the functional group of the amino acid used. For example, when a carboxylic acid (main chain carboxylic acid or side chain carboxylic acid represented by Asp or Glu) or a hydroxy group on an aromatic ring (phenol group represented by Tyr) is used as the functional group of the amino acid, it is preferable to use trityl chloride resin (Trt resin) or 2-chlorotrityl chloride resin (CTC resin). When an aliphatic hydroxy group (an aliphatic alcohol group represented by Ser or Thr) is used as the functional group on the amino acid side, it is preferable to use trityl chloride resin (Trt resin), 2-chlorotrityl chloride resin (CTC resin) or 4-methyltrityl chloride resin (Mtt resin) as the resin.

[0235] The type of polymer constituting the resin is not particularly limited. In the case of a resin made of polystyrene, either 100-200 mesh or 200-400 mesh may be used. The cross-linking rate is also not particularly limited, but 1% DVB (divinylbenzene) cross-linking is preferable. The type of polymer constituting the resin includes Tentagel and Chemmatrix.

[0236] In one aspect, the deprotection reaction and / or the resin removal reaction of the present invention can be carried out at a reaction temperature of -50 to 100°C, preferably -20 to 50°C, and more preferably 0 to 30°C.

[0237] In one aspect, the deprotection reaction and / or resin removal reaction of the present invention can be carried out for a reaction time of 10 minutes to one week, preferably 10 minutes to 6 hours, more preferably 1 to 3 hours.

[0238] In one aspect, the deprotection reaction and / or the resin removal reaction of the present invention can be terminated by adding alcohol or water to the reaction solution, and the target product can be obtained by precipitating, or the organic layer can be washed with water or saline and then concentrated under reduced pressure to obtain the target product. The alcohol is not particularly limited, but one that is water-soluble and has a low boiling point is preferred, and methanol is particularly preferred. The water used to terminate the reaction is not particularly limited, but alkaline water is preferred, and sodium bicarbonate or dipotassium hydrogen phosphate is particularly preferred. When washing the organic layer, the concentration of the saline is not particularly limited, but saturated saline or 5% saline is preferred.

[0239] In one aspect, when a starting peptide compound contains both a protecting group that can be deprotected by the method of the present invention and a solid-phase synthesis resin that can be deresined by the method of the present invention, the deprotection reaction and the deresining reaction can be carried out simultaneously. That is, the present invention also relates to a method for producing a peptide compound, which comprises a step of contacting a starting peptide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, in which the protecting group that can be deprotected by the silylating agent is deprotected from the starting peptide compound, and the solid-phase synthesis resin that can be deresined by the silylating agent is deresined from the starting peptide compound.

[0240] In one aspect, the present invention provides a compound of formula (A): [ka] or a salt thereof.

[0241] In formula (A), R 1 R′ is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl. 1’is preferably hydrogen, Fmoc, Boc, or Cbz.

[0242] In formula (A), R 17A and R 17B are both methyl or R 17A and R 17B together with the nitrogen atom to which they are attached to form piperidine or morpholine

[0243] In formula (A), R 18 is hydrogen or PG 10 PG 10 is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 Alkyl, optionally substituted heteroaryl C 1 -C 4 R is selected from the group consisting of alkyl, 2-(trimethylsilyl)ethyl, and 2-(trimethylsilyl)ethyl. 18 is preferably a hydrogen atom, t-Bu, benzyl, or allyl.

[0244] R in formula (A) 1’ and R 18 Preferred combinations of Fmoc and a hydrogen atom, Fmoc and an allyl, Fmoc and t-Bu, Fmoc and benzyl, Boc and a hydrogen atom, Boc and an allyl, Boc and t-Bu, Boc and benzyl, Cbz and a hydrogen atom, Cbz and an allyl, Cbz and t-Bu, Cbz and benzyl, Alloc and a hydrogen atom, Alloc and an allyl, Alloc and t-Bu, Alloc and benzyl, Teoc and a hydrogen atom, Teoc and an allyl, Teoc and t-Bu, Teoc and benzyl, a hydrogen atom and a hydrogen atom, a hydrogen atom and an allyl, a hydrogen atom and t-Bu, a hydrogen atom and benzyl, and the like.

[0245] Specific examples of the amide compound represented by formula (A) include the following compounds: (1-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-3) tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-4) benzyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl (1-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-11) tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl (1-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate allyl, (1-15) tert-butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl, (1-17) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-18) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate allyl, (1-19) tert-Butyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-20) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl, (2-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-3) tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-4) benzyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl (2-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-11) tert-Butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl (2-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate allyl, (2-15) tert-Butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl, (2-17) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoic acid, (2-18) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate allyl, (2-19) tert-butyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate, (2-20) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate benzyl, (3-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-3) tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-4) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl, (3-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl (3-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl (3-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-11) tert-Butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl (3-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-15) tert-Butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl, (3-17) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoic acid, (3-18) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate allyl, (3-19) tert-butyl 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate, (3-20) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate benzyl (4-1) 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (4-2) Allyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-3) tert-butyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-4) benzyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-5) 3-(methylamino)-4-morpholino-4-oxobutanoic acid, (4-6) Allyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-7) tert-butyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-8) benzyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-9) 4-(dimethylamino)-3-(methylamino)-4-oxobutanoic acid, (4-10) Allyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, (4-11) tert-Butyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, or (4-12) Benzyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate.

[0246] The amide compound represented by formula (A) of the present invention can be synthesized, for example, according to the following scheme. [ka]

[0247] The amidation step in the above scheme can be carried out by, for example, the method described in Handbook of Solid Phase Synthesis (published by Merck Ltd., published on May 1, 2002) or the method of Albert et al. (Synthesis, 1987, 7, 635-637) with any amine ((R 17A )(R 17B This can be achieved by condensing the aryl group (NH) with a carboxyl group using a dehydrating condensing agent such as a carbodiimide compound.

[0248] The deprotection step in the above scheme can be carried out, for example, using the method described in "Greene's, "Protective Groups in Organic Synthesis" (5th Edition, John Wiley & Sons 2014)" or the deprotection method described herein.

[0249] The compounds according to the present invention may be in the form of a free form or a salt thereof, and both are included in the present invention. Examples of such "salts" include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, etc.

[0250] Examples of inorganic acid salts include hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates. Examples of organic acid salts include acetates, succinates, fumarates, maleates, tartrates, citrates, lactates, stearates, benzoates, methanesulfonates, benzenesulfonates, and p-toluenesulfonates.

[0251] Examples of inorganic base salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, and ammonium salts. Examples of organic base salts include diethylamine salts, diethanolamine salts, meglumine salts, and N,N-dibenzylethylenediamine salts.

[0252] Examples of the acidic amino acid salts include aspartic acid salts and glutamic acid salts, and examples of the basic amino acid salts include arginine salts, lysine salts and ornithine salts.

[0253] The compound of the present invention may absorb water, for example, when left in the air, to become a hydrate, and such hydrates are also included in the present invention.

[0254] Furthermore, the compounds of the present invention may absorb certain other solvents to form solvates, and such solvates are also included in the present invention.

[0255] In this specification, the structural formula of the compound of the present invention may conveniently represent a certain isomer, but all isomers and isomer mixtures arising from the structure of the compound, such as geometric isomers, optical isomers, tautomers, etc., are included in the present invention and are not limited to the description of the convenient formula. For example, when the compound has an asymmetric carbon atom in the molecule and has optically active and racemic isomers, both are included in the present invention.

[0256] All prior art documents cited in this specification are hereby incorporated by reference. EXAMPLES

[0257] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0258] Solvents used in the practice of the present invention, such as methylene chloride, ethyl acetate, 2-MeTHF, dichloroethane, or DMF, were obtained from commercial suppliers without purification, and in reactions in which water was not added as a solvent, dehydrated, ultradehydrated, or anhydrous solvents were obtained from commercial suppliers without purification.

[0259] Reagents used in carrying out the present invention, such as silyl compounds exemplified by TMSOTf, and electrophilic species scavengers exemplified by BSA and BSTFA, were obtained from commercial suppliers without purification unless otherwise specified.

[0260] The starting peptide compounds and starting amide compounds used in carrying out the present invention were obtained from commercial suppliers without purification unless otherwise specified, and were prepared according to known methods as necessary.

[0261] The following examples were analyzed by HPLC methods 1-4 or one or more of methods A, B, C, D, E, F, G, and H.

[0262] Analysis: HPLC (reaction conversion rate, purity) HPLC method 1 Instrument: Waters ACQUITY UPLC H-Class Column: Ascentis Express C18 (2.7 μm, 4.6mm x 50 mm), Supelco Eluent: A) 0.05% TFA / water, B) 0.05% TFA / CH 3 CN Gradient (B): 5% (0 min.) ⇒ 100% (6 min.) ⇒5% (7 min.) ⇒ 5% (9 min.) Flow rate: 1.0 mL / min. Detection: 210nm Injection vol.: 5 μL Sample prep.: 5 μL / 1.00 mL

[0263] HPLC method 2 Instrument: Waters LCT Premier Column: Ascentis Express C18 (2.7 μm, 4.6mm x 50 mm), Supelco Column temp.: 35 deg. Eluent: A) 0.05% TFA / water, B) 0.05% TFA / CH 3 CN Gradient (B): 50% (0 min.) ⇒ 100% (6 to 11min.) ⇒ 50% (11 min.) ⇒50% (13 min.) Flow rate: 1.0 mL / min. Detection: 210 nm Injection vol.: 5 μL Sample prep.: 5 μL / 1.00 mL

[0264] HPLC method 3 Instrument: Waters ACQUITY UPLC H-Class Column: Ascentis Express C18, (2.7 μm, 2.1mm x 50 mm), Supelco Column temp.: 35 deg. Eluent: A) 0.05% TFA / water, B) 0.05% TFA / CH 3 CN Gradient (A): 95%(0 min) → 0%(4.0 min) →0%(4.5 min) → 95%(4.6 min) → 95%(6 min) Flow rate: 0.25 mL / min Detection: PDA 210 nm (200 - 400 nm PDAtotal) Injection vol.: 0.3 μL Sample prep.: 50 μL / 10 mL

[0265] HPLC method 4 Instrument: Waters ACQUITY UPLC H-Class Column: CAPCELL CORE ADME, (2.7 μm, 3.0 mmx 150 mm) Column temp.: 30 deg. Solvents: A) 0.05% TFA / water, B) 0.05% TFA / CH 3 CN Gradient (A): 70%(0 min) → 30%(20.0 min) →0%(20.1 min) → 0%(22.0 min) → 70%(22.1 min) → 70%(24 min) Flow rate: 0.3 mL / min Detection: PDA 254 nm (200 - 400 nm PDAtotal) Injection vol.: 0.3 μL Sample prep.: amorphous 10.0 mg in CH 3 CN10 ml; this solution 0.3 mL / 0.7 mL CH 3 CN

[0266] A. Boc-removal reaction experiment Example 1 De-Boc reaction of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 3a) (6 mer: TfOH-BSTFA method) [ka] 77.7 mg of the raw material was weighed out and dissolved in 5 v / w ethyl acetate in a reaction vessel, and the reaction vessel was cooled on ice. After 10 minutes under a nitrogen atmosphere, 0.055 ml (2.4 eq) of BSTFA and 3.0 μl (0.4 eq) of TfOH were added in that order, and the reaction solution was stirred. Three hours after the addition of the reagents, the reaction was analyzed by LCMS, and the disappearance of the raw material was confirmed. The reaction was quenched with saturated sodium bicarbonate water. The organic layer was washed with saturated sodium bicarbonate water and 5% saline. The resulting organic layer was concentrated under reduced pressure to quantitatively obtain 77.3 mg of the deprotected product. No cleavage of the amide bond was observed.

[0267] [Table 1]

[0268] [Table 2]

[0269] Example 2 De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-HMDS method) [ka] 0.0810 g of the raw material was weighed out and dissolved in 10 v / w ethyl acetate in a reaction vessel, and the reaction vessel was cooled on ice. After 10 minutes under a nitrogen atmosphere, 0.079 ml (7.2 eq) of HMDS and 34 μl (3.6 eq) of TMSOTf were added in that order, and the reaction solution was stirred. Four hours after the addition of the reagents, the reaction was analyzed by LCMS, and the disappearance of the raw material was confirmed. No cleavage of the amide bond was confirmed. After confirming the completion of the raw material reaction, the reaction solution was stirred for another hour and the reaction was analyzed by LCMS. No cleavage of the amide bond was confirmed. The reaction vessel was poured into 1 ml of saturated saline to stop the reaction. Then, 5 ml of ethyl acetate was added to separate the two layers. The organic layer was washed with a mixture of 1 ml of saturated sodium bicarbonate water and 1 ml of saturated saline. The obtained organic layer was concentrated to obtain 68.0 mg of the deprotected product as a transparent film in a yield of 90%.

[0270] [Table 3]

[0271] [Table 4]

[0272] [Table 5]

[0273] Example 3 De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-HMDS method) [ka] The reaction was carried out according to Example 2. 19 hours after the start of the reaction, the reaction was analyzed by LCMS, but no decomposition of the product was confirmed.

[0274] [Table 6]

[0275] [Table 7]

[0276] Example 4 De-Boc reaction of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-MeIle-Ala-MePhe-MeVal-Asp(OBn)-pip (compound 2a) (11 mer: TfOH-BSTFA method) [ka] The reaction was carried out according to Example 1.

[0277] [Table 8]

[0278] [Table 9]

[0279] [Table 10]

[0280] Example 5 De-Boc reaction of Boc-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 4a) (5mer: TfOH-BSTFA method) [ka] The reaction was carried out according to Example 1.

[0281] [Table 11]

[0282] [Table 12]

[0283] Example 6 De-Bocation of Boc-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 8a) and elongation reaction to Boc-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (3mer: TfOH-BSTFA method) [ka] 73.3 mg of the starting material was weighed out and dissolved in 5 v / w isopropyl acetate. After cooling the reaction vessel with ice, 0.085 ml of BSTFA and 0.0047 ml of TfOH were added and stirred for 2 hours. After confirming by LC that deprotection was completed without cleavage of the main chain, 5 v / w water and 186.9 mg of dipotassium hydrogen phosphate were added. Next, 40.1 mg of Boc-Leu-OH·monohydrate and 63.1 mg of DMT-MM were added and stirred under ice cooling. 17 hours after the addition of the reagents, the completion of the reaction was confirmed by LC. The reaction was stopped by adding 5 v / w of 1 N aqueous sodium hydroxide solution. The organic layer was separated by liquid separation, washed once with 1 N aqueous sodium hydroxide solution, twice with 5% aqueous potassium hydrogen sulfate solution, and once with 5% aqueous sodium chloride solution, and then concentrated under reduced pressure. 82.0 mg (93% yield) of crude product was obtained as an oily liquid.

[0284] [Table 13]

[0285] [Table 14]

[0286] [Table 15]

[0287] Example 6a De-Teocylation of Teoc-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 80b) and elongation reaction to Boc-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (7a) (3mer: TfOH-BSTFA method) [ka] After removing the Teoc group by the same procedure as in Example 6, compound 7a can be obtained by reacting with Boc-Leu-OH without causing cleavage of the main chain.

[0288] Example 7 De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(OBn)-pip (compound 5a) (5mer: TfOH-BSTFA method) [ka] According to the experimental method described in Example 6, the deprotection reaction and the elongation reaction were carried out in one pot.

[0289] [Table 16]

[0290] [Table 17]

[0291] [Table 18]

[0292] [Table 19]

[0293] Example 8 De-Bocylation and elongation reaction of Boc-Ala-MePhe-MeVal-Asp(OBn)-pip (compound 6a) (4mer: TfOH-BSTFA method) [ka] According to the experimental method described in Example 6, the deprotection reaction and the elongation reaction were carried out in one pot.

[0294] [Table 20]

[0295] [Table 21]

[0296] [Table 22]

[0297] Example 9 De-Boc reaction of Boc-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 7a) (4 mer: TfOH-BSTFA method) [ka] According to the experimental method described in Example 6, the deprotection reaction and the elongation reaction were carried out in one pot.

[0298] [Table 23]

[0299] [Table 24] [Table 25]

[0300] Example 10 De-Boc reaction of Boc-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 7a) under known conditions (4mer: HCl method) (Russ. J. Bioorg.Chem., 2016, 42, 143.) [ka] 18.7 mg of the raw material was weighed into a reaction vessel and dissolved in 10 v / w trifluoroethanol. Then, 8.5 μl (1.2 eq) of 4N HCl (ethyl acetate solution) was added and the reaction solution was stirred. Two hours after the addition of the reagents, the reaction was analyzed by LCMS (HPLC method 1) and the conversion rate (= target product / (target product + starting product)) was confirmed to be 81%. At this point, 0.861% of H-Thr(OBn)-MeGly-OAllyl (compound 7c) and 1.275% of H-Leu-MeLeu-Thr(OBn)-OH (compound 7d) were detected as compounds in which the amide bond had been cleaved.

[0301] [Table 26]

[0302] Example 11 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) and elongation reaction to Boc-Ala-MePhe-MeVal-Asp(OBn)-pip (3mer: TMSOTf-BSTFA method) [ka] According to the experimental method described in Example 6, the deprotection reaction and the elongation reaction were carried out in one pot.

[0303] [Table 27]

[0304] [Table 28]

[0305] [Table 29]

[0306] Example 12 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (3 mer: TMSOTf-MSTFA method) [ka] According to the experimental method described in Example 6, the deprotection reaction and the elongation reaction were carried out in one pot.

[0307] [Table 30]

[0308] [Table 31]

[0309] [Table 32]

[0310] Example 13 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (3 mer: TMSOTf-BSA method TMSOTf 2.4 eq, BSA 2.4 eq) [ka] According to the experimental method described in Example 6, the deprotection reaction and the elongation reaction were carried out in one pot.

[0311] [Table 33]

[0312] [Table 34]

[0313] [Table 35]

[0314] Example 14 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (3 mer: TMSOTf-HMDS method) [ka] 107.4 mg of the raw material was weighed out and dissolved in 5 v / w ethyl acetate in a reaction vessel, and the reaction vessel was cooled on ice. After 10 minutes under a nitrogen atmosphere, 0.085 ml (2.4 eq) of HMDS (1,1,1,3,3,3-hexamethyldisilazane) and 35 μl (1.2 eq) of TMSOTf were added in sequence, and the reaction solution was stirred. Two hours after the addition of the reagents, the reaction was analyzed by LCMS, and the conversion rate was 55.8%, so 20 μl (0.69 eq) of TMOSTf was added. One hour after the addition of the reagents, the disappearance of the raw material was confirmed by LCMS. No cleavage of the amide bond was confirmed. To a reaction vessel, 373.4 mg (13.3 eq) of dipotassium hydrogen phosphate was added, followed by addition of 0.89 ml of water and stirring for 20 minutes. Then, 3 ml of ethyl acetate was added to the reaction vessel, and the two layers were separated. The organic layer was washed with a mixture of 1 ml of saturated sodium bicarbonate water and 1 ml of saturated saline. The obtained organic layer was concentrated. The oily liquid obtained was then dissolved in 1 ml of ethyl acetate, and 251.0 mg of dipotassium hydrogen phosphate was added. After adding 0.89 ml of water, the reaction vessel was cooled on ice. 36.8 mg of Boc-Ala-OH and 79.5 mg of DMT-MM were added, and the mixture was stirred overnight while in an ice bath. After 15.5 hours, the disappearance of the raw materials was confirmed by LCMS, and then separation treatment was performed. The obtained organic layer was washed twice with 5% potassium carbonate, once with water, twice with 5% potassium hydrogen sulfate, and once with saturated saline, and concentrated. 0.1075 g (yield 90%) of the crude product was obtained as a white solid.

[0315] [Table 36]

[0316] [Table 37]

[0317] [Table 38]

[0318] B. Screening for electrophile scavengers Example 15 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: N-(trimethylsilyl)diethylamine) [ka] 99.5 mg of the raw material was weighed out and dissolved in 5 v / w ethyl acetate in a reaction vessel, and the reaction vessel was cooled on ice. Under a nitrogen atmosphere, 0.070 ml (2.4 eq) of N-((trimethylsilyl)diethylamine) and 0.032 ml (1.2 eq) of TMSOTf were added in that order, and the reaction solution was stirred. 1.5 hours after the addition of the reagents, the reaction was analyzed by LCMS, and the conversion rate was 30%, so 0.029 ml (1.1 eq) of TMOSTf was added. 4 hours after the start of the reaction, the reaction was analyzed by LCMS, and the disappearance of the raw material was confirmed. At that time, no cleavage of the amide bond was confirmed. The reaction solution was stirred overnight, and the reaction was analyzed again by LCMS 20 hours after the start of the reaction. No cleavage of the amide bond was confirmed at this time either. 21 hours after the start of the reaction, 0.2032 g of dipotassium hydrogen phosphate and 0.50 mL of water were added to the reaction solution and stirred for 30 minutes. The reaction solution was diluted with 4 mL of ethyl acetate, and the two layers were separated to obtain the organic layer. The obtained organic layer was washed twice with a mixed solvent of 0.5 mL of saturated saline and 0.5 mL of saturated sodium bicarbonate. It was then washed with 0.5 mL of saturated saline, and the organic layer was concentrated. This residue was dissolved in 4 mL of isopropyl acetate, and washed twice with a mixed solvent of 1 mL of 0.5 M sodium hydroxide aqueous solution and 0.5 mL of saturated saline. It was then washed with 0.5 mL of 10% saline, and the organic layer was concentrated under reduced pressure to obtain 81.7 mg of the deprotected product in a yield of 97%.

[0319] [Table 39]

[0320] [Table 40]

[0321] (Example 16) Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: N-(trimethylsilyl)morpholine) [ka] The experiment was carried out according to the method described in Example 15.

[0322] [Table 41]

[0323] [Table 42]

[0324] (Example 17) Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: N-tert-butyltrimethylsilylamine) [ka] The experiment was carried out according to the method described in Example 15.

[0325] [Table 43]

[0326] [Table 44]

[0327] (Example 18) Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: 2,2,4,4-tetramethylpentanoneimine) [ka] The experiment was carried out according to the method described in Example 15.

[0328] [Table 45]

[0329] [Table 46]

[0330] (Example 19) Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: isopropenyloxytrimethylsilane) [ka] The experiment was carried out according to the method described in Example 15.

[0331] [Table 47]

[0332] [Table 48]

[0333] (Example 20) Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: Dimethylketene methyltrimethylsilyl acetal) [ka] The experiment was carried out according to the method described in Example 15.

[0334] [Table 49]

[0335] [Table 50]

[0336] Example 21 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: 3,4-dihydro-2H-pyran) [ka] The experiment was carried out according to the method described in Example 15.

[0337] [Table 51]

[0338] [Table 52]

[0339] Example 22 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: N,N,N',N'-tetramethyl-1,8-naphthalenediamine) [ka] The experiment was carried out according to the method described in Example 15.

[0340] [Table 53]

[0341] [Table 54] (The LCA% of the product does not include the residual base after post-treatment.)

[0342] (Example 23) Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: 2,2'-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline]) [ka] The experiment was carried out according to the method described in Example 15.

[0343] [Table 55]

[0344] [Table 56] (The LCA% of the product does not include the residual base after post-treatment.)

[0345] Example 24 Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (Base: diisopropylcarbodiimide) [ka] The experiment was carried out according to the method described in Example 15.

[0346] [Table 57]

[0347] [Table 58] (The LCA% of the product does not include the residual base after post-treatment.)

[0348] C. Screening of electrophile traps (experiments with 11-mer peptides) (Example 25) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-BSTFA method) [ka] The experiment was carried out in accordance with Example 2.

[0349] [Table 59]

[0350] [Table 60]

[0351] (Example 26) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-BSA method) [ka] The experiment was carried out in accordance with Example 2.

[0352] [Table 61]

[0353] [Table 62]

[0354] Example 27 De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-silylamine method) [ka] The experiment was carried out in accordance with Example 2.

[0355] [Table 63]

[0356] [Table 64]

[0357] (Example 28) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-silylamine method) [ka] The experiment was carried out in accordance with Example 2.

[0358] [Table 65]

[0359] [Table 66]

[0360] (Example 29) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-imine method) [ka] The experiment was carried out in accordance with Example 2.

[0361] [Table 67]

[0362] [Table 68]

[0363] (Example 30) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-MSTFA method) [ka] The experiment was carried out in accordance with Example 2.

[0364] [Table 69]

[0365] [Table 70]

[0366] (Example 31) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-silylamine method) [ka] The experiment was carried out in accordance with Example 2.

[0367] [Table 71]

[0368] [Table 72]

[0369] Example 32 De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-ketene silyl acetal method) [ka] The experiment was carried out in accordance with Example 2.

[0370] [Table 73]

[0371] [Table 74]

[0372] (Example 33) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-proton sponge method) [ka] The experiment was carried out in accordance with Example 2.

[0373] [Table 75] (The base remains even after post-treatment.)

[0374] [Table 76] (The LCA% of the product does not include the residual base after post-treatment.)

[0375] (Example 34) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-lutidine method) [ka] 18.8 mg of the raw material was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. 0.005 ml (3.6 eq) of 2,6-lutidine and 0.0078 ml (3.6 eq) of TMSOTf were then added and the reaction mixture was stirred. 4 hours after the addition of the reagents, the reaction was analyzed by LCMS (HPLC method 1) and the conversion rate (= target product / (target product + starting product)) was confirmed to be 14%. The reaction was then analyzed by LCMS 19 hours after the addition of the reagents, and the conversion rate remained at 14%. No cleavage of the amide bond was observed.

[0376] [Table 77]

[0377] [Table 78]

[0378] [Table 79]

[0379] Example 35 De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-lutidine method) [ka] 89.3 mg of the raw material was weighed into a reaction vessel and dissolved in 1 ml of ethyl acetate. Then, 0.016 ml (2.4 eq) of 2,6-lutidine and 0.012 ml (1.2 eq) of TMSOTf were added and the reaction solution was stirred. 1.25 hours after the addition of the reagents, the reaction was analyzed by LCMS (HPLC method 1) and the conversion rate (= target product / (target product + starting material)) was 0%, so 0.032 ml (4.8 eq) of 2,6-lutidine and 0.024 ml (2.4 eq) of TMSOTf were added. The reaction was analyzed by LCMS 1.25 hours and 14 hours after the addition of the reagents, but the conversion rate remained at 0%. No cleavage of the amide bond was observed.

[0380] [Table 80]

[0381] [Table 81]

[0382] [Table 82]

[0383] (Example 36) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-2,6-di-tert-butylpyridine method) [ka] 14.9 mg of the raw material was weighed into a reaction vessel and dissolved in 0.2 ml of ethyl acetate. 0.011 ml (5.4 eq) of 2,6-di-t-butylpyridine and 0.0062 ml (3.6 eq) of TMSOTf were then added and the reaction mixture was stirred. 4 hours after the addition of the reagents, the reaction was analyzed by LCMS (HPLC method 1) and the conversion rate (= target product / (target product + starting material)) was 59%. The reaction was analyzed again by LCMS 22 hours after the start of the reaction, and the conversion rate remained at 59%. No cleavage of the amide bond was observed.

[0384] [Table 83]

[0385] [Table 84]

[0386] [Table 85]

[0387] (Example 37) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-tert-amine method) [ka] 17.7 mg of the raw material was weighed out and dissolved in 0.20 ml of ethyl acetate in a reaction vessel. Then, 0.0057 ml (3.6 eq) of triethylamine and 0.0074 ml (3.6 eq) of TMSOTf were added and the reaction solution was stirred. The reaction was analyzed by LCMS (HPLC method 1) 1 hour and 4 hours after the addition of the reagent, and the conversion rate (= target product / (target product + starting material)) was only 0.7% in both cases. No cleavage of the amide bond was confirmed.

[0388] [Table 86]

[0389] [Table 87]

[0390] [Table 88]

[0391] (Example 38) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-tert-amine method) [ka] 19.1 mg of the raw material was weighed out in a reaction vessel and dissolved in 0.20 ml of ethyl acetate. Then, 0.0074 ml (3.6 eq) of diisopropylethylamine and 0.0077 ml (3.6 eq) of TMSOTf were added and the reaction solution was stirred. The reaction was analyzed by LCMS (HPLC method 1) 2 hours and 4 hours after the addition of the reagent, and the conversion rate (= target product / (target product + starting product)) was within 0.8% in both cases. No cleavage of the amide bond was confirmed.

[0392] [Table 89]

[0393] [Table 90]

[0394] [Table 91]

[0395] (Example 39) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TMSOTf-tert-amine method) [ka] 92.9 mg of the raw material was weighed out and dissolved in 1 ml of ethyl acetate in a reaction vessel, and the reaction vessel was cooled on ice. Next, 0.015 ml (2.4 eq) of diisopropylethylamine and 0.013 ml (1.2 eq) of TMSOTf were added under a nitrogen atmosphere, and the reaction solution was stirred. The reaction was analyzed 2 hours after the addition of the reagents, but the conversion rate (= target product / (target product + starting material)) was 0%, so 0.030 ml (4.8 eq) of diisopropylethylamine and 0.026 ml (2.4 eq) of TMSOTf were added 3 hours after the addition of the reagents. The reaction was analyzed again 3 hours after the addition of the reagents, but the conversion rate was 0%. No cleavage of the amide bond was confirmed.

[0396] [Table 92]

[0397] [Table 93]

[0398] [Table 94]

[0399] (Example 40) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: carried out in the absence of an organic base, using only TMSOTf) [ka] 18.3 mg of the raw material was weighed out and dissolved in 0.2 ml of ethyl acetate in a reaction vessel, and the reaction vessel was cooled on ice. Then, 0.0077 ml (3.6 eq) of TMSOTf was added under a nitrogen atmosphere, and the reaction solution was stirred. The reaction was analyzed 1.5 hours after the addition of the reagent, and the formation of multiple amide bond cleavage products was confirmed at a conversion rate (= target product / (target product + starting material)) of 68%.

[0400] [Table 95]

[0401] [Table 96]

[0402] [Table 97] Compound 1g: structure unknown

[0403] (Example 41) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: carried out with TMSOTf and triisopropylsilane in the absence of an organic base.) [ka] 20.5 mg of the raw material was weighed out and dissolved in 0.2 ml of ethyl acetate in a reaction vessel, and then the reaction vessel was cooled on ice. Next, 0.0097 ml (3.6 eq) of triisopropylsilane and 0.0085 ml (3.6 eq) of TMSOTf were added under a nitrogen atmosphere, and the reaction solution was stirred. The reaction was analyzed 1 hour after the addition of the reagents, and the formation of multiple amide bond cleavage products was confirmed at a conversion rate (= target product / (target product + starting product)) of 43%.

[0404] [Table 98]

[0405] [Table 99]

[0406] [Table 100] Compound 1g: structure unknown

[0407] (Example 42) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TFA method) [ka] 35.3 mg of the raw material was weighed out and dissolved in 10 v / w methylene chloride, and the reaction vessel was cooled on ice. Then, 0.004 ml (2.3 eq) of trifluoroacetic acid was added under a nitrogen atmosphere, and the reaction solution was stirred. The reaction was analyzed 10 minutes after the addition of the reagent, and the conversion rate (= target product / (target product + starting material)) was 0%, so 0.004 ml (2.3 eq) of trifluoroacetic acid was added. The reaction was analyzed again 10 minutes after the addition of the reagent, and the conversion rate was 0%, so 0.0094 ml (5.4 eq) of trifluoroacetic acid was added. 10 minutes after the addition of the reagent, the temperature was raised to room temperature, and the stirring of the reaction solution was continued. After raising the temperature to room temperature, the reaction was analyzed at 4 hours, and the formation of the amide bond cleavage product 1e was confirmed at a conversion rate of 2%.

[0408] [Table 101]

[0409] [Table 102]

[0410] [Table 103] Compound 1g: structure unknown

[0411] (Example 43) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TFA-TIPS-H 2 O-PhOH method) Reference: J. Am. Chem. Soc., 2015, 137, 13488 [ka] 15.9 mg of the raw material was weighed into a reaction vessel, 0.0125 ml of water and 0.0125 ml of triisopropylsilane were added, and the mixture was cooled to -10 °C. 0.48 ml of trifluoroacetic acid was then added, and the reaction mixture was stirred. The reaction was analyzed 2 hours after the addition of the reagents, and the formation of amide bond cleavage products 1d and 1e was confirmed when the conversion rate (= target product / (target product + starting material)) was 89%. The reaction was reanalyzed 14.5 hours after the addition of the reagents, and the consumption of the raw material and the increase in the formation of amide bond cleavage products 1d and 1e were confirmed.

[0412] [Table 104]

[0413] [Table 105]

[0414] [Table 106]

[0415] [Table 107]

[0416] (Example 44) De-Boc reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl (compound 1a) (11 mer: TFA-TIPS-H 2 O-PhOH method) Reference: J. Am. Chem. Soc., 2012, 134, 13244 [ka] 10.3 mg of phenol was weighed out into a reaction vessel, 0.034 ml of water and 0.025 ml of triisopropylsilane were added, and the mixture was cooled to -10 °C. 0.50 ml of trifluoroacetic acid was then added, and 6 minutes later, 13.4 mg of the raw material was added and the reaction mixture was stirred. The reaction was analyzed 2 hours after the addition of the raw material, and the production of amide bond cleavage products 1d and 1e was confirmed when the conversion rate (= target product / (target product + starting material)) was 82%. In addition, the reaction was reanalyzed 7 hours after the addition of the raw material, and the consumption of the raw material and the increase in the production of amide bond cleavage products 1d and 1e were confirmed.

[0417] [Table 108]

[0418] [Table 109]

[0419] [Table 110]

[0420] [Table 111]

[0421] As shown in Examples 2, 3, and 26 to 44, it was found that imidates, amides, ketene acetals, enol ethers, imines, amines, diamines, and dialkylcarbodiimides are excellent as electrophilic species scavengers, suppress damage to the main chain, and efficiently carry out the Boc deprotection reaction of peptides with long main chains, such as 11-mers.

[0422] D. Comparison of the TFA method and the TMSOTf-HMDS method for the tBu removal reaction (Table 112) [ka] (Example 45) De-t-Bu reaction of compound 13a (TFA method) 29.8 mg of substrate 13a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (10 eq.) was added to this solution at room temperature. Four hours after the addition of the reagent, additional TFA (10 eq.) was added. After another 1.5 hours from the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 52%, with a 22% decrease in purity and 10% by-product due to amide bond cleavage.

[0423] (Example 46) De-t-Bu reaction of compound 13a (TMSOTf-HMDS method) 30.0 mg of substrate 13a was weighed out and dissolved in 10 v / w ethyl acetate in a reaction vessel. HMDS (3.0 eq.) and TMSOTf (2.0 eq.) were added to this solution at 0°C in that order. Two hours after the addition of the reagents, the temperature was raised to room temperature. 2.5 hours after the temperature was raised, HMDS (3 eq.) and TMSOTf (2 eq.) were added. Thirty minutes after the addition of the reagents, the reaction was analyzed by LCMS, and it was confirmed that the conversion rate was 99% or more. At this time, no amide bond cleavage was confirmed.

[0424] [ka] (Example 47) De-t-Bu reaction of compound 14a (TFA method) 29.7 mg of substrate 14a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (20 eq.) was added to this solution at room temperature. 7 hours after the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 92%, with a 46% decrease in purity and 24% by-products due to amide bond cleavage.

[0425] (Example 48) De-t-Bu reaction of compound 14a (TMSOTf-HMDS method) 30.0 mg of substrate 14a was weighed out in a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (3.0 eq.) and TMSOTf (2.0 eq) were added to this solution in sequence at 0°C. Six hours after the addition of the reagents, the reaction was analyzed by LCMS to confirm the disappearance of the raw materials. At this time, no amide bond cleavage was confirmed. After confirming the completion of the reaction, 44.5 mg (8.0 eq) of potassium hydrogen phosphate and 0.30 mL of water were added to the reaction solution and stirred for 30 minutes under ice cooling. 1 mL of ethyl acetate was added to this reaction solution and washed with 0.30 mL of Brine. The organic layer was filtered through Celite, concentrated and dried under reduced pressure to obtain 26.8 mg of 2b with a purity of 99%.

[0426] [ka] (Example 49) De-t-Bu reaction of compound 15a (TFA method) 29.9 mg of substrate 15a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (20 eq.) was added to this solution at room temperature. 5.5 hours after the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 50%, and 28% of by-products due to amide bond cleavage were observed.

[0427] (Example 50) De-t-Bu reaction of compound 15a (TMSOTf-HMDS method) 30.0 mg of substrate 15a was weighed out and dissolved in 10 v / w ethyl acetate in a reaction vessel. HMDS (3.6 eq) and TMSOTf (2.4 eq) were added to this solution at room temperature in that order. Five hours after the addition of the reagents, HMDS (1.8 eq.) and TMSOTf (1.2 eq.) were added. One hour after the addition of the reagents, the reaction was analyzed by LCMS to confirm the disappearance of the raw material. At this time, no amide bond cleavage was confirmed.

[0428] [ka] (Example 51) De-t-Bu reaction of compound 16a (TFA method) 30.2 mg of substrate 16a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (20 eq.) was added to this solution at room temperature. 4.5 hours after the addition of the reagent, TFA (10 eq.) was added. After another hour from the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 65%, with 7.0% of by-products due to amide bond cleavage observed.

[0429] (Example 52) De-t-Bu reaction of compound 16a (TMSOTf-HMDS method) 29.9 mg of substrate 16a was weighed out and dissolved in 10 v / w ethyl acetate in a reaction vessel. HMDS (3.6 eq) and TMSOTf (2.4 eq) were added to this solution at room temperature in that order. Four hours after the addition of the reagents, the reaction was analyzed by LCMS to confirm the disappearance of the raw materials. At this time, no amide bond cleavage was confirmed.

[0430] [ka] (Example 53) De-t-Bu reaction of compound 17a (TFA method) 50.0 mg of substrate 17a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (5 eq.) was added to this solution at 0 °C. 2 hours after the addition of the reagent, TFA (5 eq.) was added. After a further 15.5 hours, the temperature was raised to room temperature. 3 hours after the temperature was raised, TFA (10 eq.) was added. After a further 1.5 hours, TFA (20 eq.) was added. After a further 1.5 hours from the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 54%, with 26% by-products due to amide bond cleavage being observed.

[0431] (Example 54) De-t-Bu reaction of compound 17a (TMSOTf-HMDS method) 30.0 mg of substrate 17a was weighed out in a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (5.4 eq.) and TMSOTf (3.6 eq.) were added to this solution at 0°C in that order. 4 hours after the addition of the reagents, the temperature was raised to room temperature. 3 hours after the temperature increase, the reaction was analyzed by LCMS to confirm the disappearance of the raw material. At this time, no amide bond cleavage was confirmed.

[0432] [ka] (Example 55) De-t-Bu reaction of compound 18a (TFA method) 29.9 mg of substrate 18a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (20 eq.) was added to this solution at 0 °C. 4.5 hours after the addition of the reagent, TFA (10 eq.) was added and the temperature was raised to room temperature. After another 2 hours from the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 82%, with 34% by-products due to amide bond cleavage.

[0433] (Example 56) De-t-Bu reaction of compound 18a (TMSOTf-HMDS method) 29.8 mg of substrate 18a was weighed out and dissolved in 10 v / w ethyl acetate in a reaction vessel. HMDS (7.2 eq.) and TMSOTf (4.8 eq.) were added to this solution at 0°C in that order. 3 hours after the addition of the reagents, the temperature was raised to room temperature. 3.5 hours after the temperature was raised, the reaction was analyzed by LCMS, and the disappearance of the raw material was confirmed. At this time, no amide bond cleavage was confirmed.

[0434] [ka] (Example 57) De-t-Bu reaction of compound 19a (TFA method) 50.0 mg of substrate 19a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (5 eq.) was added to this solution at 0 °C. 2 hours after the addition of the reagent, TFA (5 eq.) was added. After a further 15.5 hours, the temperature was raised to room temperature. 3 hours after the temperature was raised, TFA (10 eq.) was added. After a further 1.5 hours, TFA (20 eq.) was added. After a further 1.5 hours from the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 82%, with 14% by-products due to amide bond cleavage observed.

[0435] (Example 58) De-t-Bu reaction of compound 19a (TMSOTf-HMDS method) 30.0 mg of substrate 19a was weighed out and dissolved in 10 v / w ethyl acetate in a reaction vessel. HMDS (3.6 eq.) and TMSOTf (2.4 eq.) were added to this solution in sequence at 0°C. 3.5 hours after the addition of the reagents, the temperature was raised to room temperature, and HMDS (3.6 eq.) and TMSOTf (2.4 eq.) were added. One hour after the addition of the reagents, the reaction was analyzed by LCMS, and the disappearance of the raw material was confirmed. At this time, no amide bond cleavage was confirmed. As shown in Examples 45 to 58, it was found that the TMSOTf-HMDS method, which combines a silylating agent and an electrophilic species scavenger, efficiently proceeds with the deprotection reaction without damaging the main chain in the tBu removal reaction, as compared with the conventional TFA method.

[0436] [Table 112] JPEG2025004110000234.jpg130149

[0437] (Product Identification) [Table 113]

[0438] [Table 114] JPEG2025004110000237.jpg43149

[0439] The structures of compounds 13c to 19h are shown below. [ka] [ka] [ka] [ka]

[0440] (Example 59) De-t-Bu reaction of Fmoc-MeAsp(OtBu)-pip (compound 12a) (1mer: TFA method) [ka] 48.0 mg of the raw material was weighed into a reaction vessel and dissolved in 9 v / w dichloromethane. Then, 1 v / w trifluoroacetic acid was added and the reaction solution was stirred. 19 hours after the addition of the reagent, the reaction was analyzed by LCMS (HPLC method 4) and the conversion rate (= target product / (target product + starting product)) was confirmed to be 77%. At this point, the rearrangement product 12c and hydrolysis product 12d were observed as compounds with damaged amide bonds. An impurity of unknown structure was also produced.

[0441] [Table 115] Raw material purity analysis (HPLC method 1)

[0442] [Table 116]

[0443] [Table 117]

[0444] (Example 60) De-t-Bu reaction of Fmoc-MeAsp(OtBu)-pip (compound 12a) (1mer: TMSOTf-HMDS method) [ka] The experiment was carried out in accordance with Example 2.

[0445] [Table 118]

[0446] [Table 119]

[0447] [Table 120]

[0448] E. Comparison of the TFA method and the TMSOTf-HMDS method for the t-Bu removal reaction (Table 121) [ka] (Example 61) De-t-Bu reaction of compound 20a (TFA method) 27.1 mg of substrate 20a was weighed out and dissolved in 10 v / w dichloromethane in a reaction vessel. TFA (10 eq.) was added to this solution at room temperature. 8 hours after the addition of the reagent, the reaction was analyzed by LCMS, and the reaction conversion was 76%, with an 11% decrease in purity and 8.1% of a by-product due to cleavage of the amide bond. The reaction was also carried out in the same manner for substrate 21a. (Table 121)

[0449] (Example 62) De-t-Bu reaction of compound 20a (TMSOTf-HMDS method) 27.6 mg of substrate 20a was weighed out and dissolved in 10 v / w ethyl acetate in a reaction vessel. HMDS (2.4 eq) and TMSOTf (2.4 eq) were added to this solution at room temperature in that order. Two hours after the addition of the reagents, the reaction was analyzed by LCMS to confirm the disappearance of the raw materials. At this time, no amide bond cleavage was confirmed. A similar reaction was carried out with substrate 21a. (Table 121)

[0450] [Table 121]

[0451] (Product Identification)

[0452] [Table 122] [ka]

[0453] F. Comparative experiment of TFA method and TMSOTf-HMDS method for resin removal reaction (Table 123) [ka] (Example 65) De-resination reaction of resin 22a (TFA method) 30.2 mg of resin 22a was weighed out and placed in a reaction vessel, and 10 v / w dichloromethane was added to swell the resin. After removing the dichloromethane from the reaction solution, 10 v / w% TFA (5% dichloromethane solution) was added at room temperature, and the mixture was shaken at 25°C. One hour after the start of shaking, the reaction was analyzed by LCMS, and 7.8% of by-products due to amide bond cleavage were found to have been produced. The same reaction was carried out for resins 23a to 24a. (Table 123)

[0454] (Example 66) De-resination reaction of resin 22a (TMSOTf-HMDS method) 23.0 mg of substrate 22a was weighed out in a reaction vessel, and 10 v / w of 1,2-dichloroethane was added to swell the resin. After removing 1,2-dichloroethane from the reaction solution, a solution of HMDS (3.6 eq.) and TMSOTf (2.4 eq.) dissolved in 10 v / w of 1,2-dichloroethane was added to the reaction vessel. After shaking for 4 hours at 25°C, the reaction was analyzed by LCMS, and no amide bond cleavage was confirmed. The same reaction was carried out for resins 23a to 24a. (Table 123)

[0455] [Table 123]

[0456] (Product Identification) HPLC method A Instrument: Waters ACQUITY UPLC H-Class Column: Ascentis Express C18 (2.7 μm, 4.6mm x 50 mm), Supelco Eluent: A) 0.05% TFA / water, B) 0.05%TFA / CH3CN Gradient (B): 5% (0 min.) ⇒ 100% (4 min.) ⇒100% (4.5 min.) ⇒ 5% (4.6 min.) ⇒ 5% (6 min.) Flow rate: 1.0 mL / min. Detection: 210 nm Injection vol.: 5 μL Sample prep.: 25 μL / 0.975 mL MeCN

[0457] HPLC method B Instrument: Waters ACQUITY UPLC H-Class Column: Ascentis Express C18 (2.7 μm, 4.6mm x 50 mm), Supelco Eluent: A) 0.05% TFA / water, B) 0.05%TFA / CH3CN Gradient (B): 5% (0 min.) ⇒ 100% (4 min.) ⇒100% (4.5 min.) ⇒ 5% (4.6 min.) ⇒ 5% (6 min.) Flow rate: 1.0 mL / min. Detection: 210 nm Injection vol.: 5 μL Sample prep.: 5 μL / 1.00 mL (MeCN 0.950 ml +0.1 M phosphate buffer (pH 8.0) 0.050 ml)

[0458] HPLC method C Instrument: Waters ACQUITY UPLC H-Class Column: Ascentis Express C18 (2.7 μm, 4.6mm x 50 mm), Supelco Eluent: A) 0.05% TFA / water, B) 0.05%TFA / CH3CN Gradient (B): 5% (0 min.) ⇒ 100% (4 min.) ⇒100% (4.5 min.) ⇒ 5% (4.6 min.) ⇒ 5% (6 min.) Flow rate: 1.0 mL / min. Detection: 210 nm Injection vol.: 5 μL Sample prep.: 5 μL / 1.00 mL MeCN

[0459] HPLC method D Instrument: Shimadzu LCMS-2020 Column: Ascentis Express C18 (2.7 μm, 2.1mm x 50 mm), Supelco Eluent: A) 0.1% FA / water, B) 0.1% FA / CH 3 CN Gradient (B): 5% (0 min.) ⇒ 100% (4.5 min.)⇒ 100% (5 min.) Flow rate: 1.0 mL / min. Detection: 210 nm - 400 nm Injection vol.: 1 μL

[0460] HPLC method E Instrument: SHIMADZU LCMS-2020 Column: Ascentis Express C18 2.1 mm x 50mm,Supelco Eluent: A) 0.1% FA / water, B) 0.1% FA / CH3 CN Gradient (B): 5% (0 min.) ⇒ 100% (1.5 min.)⇒ 100% (2 min.) Flow rate: 1.0 mL / min. Detection: PDA 210 nm - 400 nm Injection vol.: 1 μL

[0461] HPLC method F Instrument: Waters Acquity UPLC / SQD2 Column: Ascentis Express C18 (2.7 μm, 2.1mm x 50 mm), Supelco Eluent: A) 0.1% FA / water, B) 0.1% FA / CH 3 CN Gradient (B): 5% (0 min.) ⇒ 100% (1 min.) ⇒100% (1.4 min.) Flow rate: 1.0 mL / min. Detection: 210nm - 400 nm Injection vol.: 1 μL

[0462] HPLC method G Instrument: Waters Acquity UPLC / SQD2 Column: Ascentis Express C18 (2.7 μm, 2.1mm x 50 mm), Supelco Eluent: A) 0.1% FA / water, B) 0.1% FA / CH 3 CN Gradient (B): 5% (0 min.) ⇒ 100% (1 min.) ⇒100% (1.4 min.) Flow rate: 1.0 mL / min. Detection: 210 nm - 400 nm Injection volume: 1 μL

[0463] HPLC method H Instrument: Waters Acquity UPLC / SQD Column: Ascentis Express C18 (2.7 μm, 2.1mm x 50 mm), Supelco Eluent: A) 0.1% FA / water, B) 0.1% FA / CH3CN Gradient (B): 5% (0 min.) ⇒ 100% (4.5 min.) ⇒ 100% (5.0 min.) Flow rate: 1.0 mL / min. Detection: 210 nm - 400 nm Injection volume: 2 μL

[0464] [Table 124] [ka]

[0465] G. Comparative experiment of TFA method and TMSOTf-HMDS method for resin removal reaction (Table 125) [ka] (Example 71) CTC-removal and t-Bu-removal reaction of resin 25a (TFA method) 20.0 mg of resin 25a was weighed out in a reaction vessel, and 10 v / w dichloromethane was added to swell the resin. After removing dichloromethane from the reaction solution, 10 v / w% TFA (10% dichloromethane solution) was added at room temperature, and the mixture was shaken at 25°C. One hour after the start of shaking, the reaction was analyzed by LCMS, and the reaction conversion rate was 17%, with 3.8% of by-products due to amide bond cleavage. The reaction was also carried out in the same manner with resin 26a. (Table 125)

[0466] (Example 72) CTC-removal and tBu-removal reaction of resin 25a (TMSOTf-HMDS method) 23.0 mg of substrate 25a was weighed out into a reaction vessel, and 10 v / w of 1,2-dichloroethane was added to swell the resin. After removing the 1,2-dichloroethane from the reaction solution, a solution of HMDS (10.7 eq.) and TMSOTf (7.1 eq.) dissolved in 10 v / w of 1,2-dichloroethane was added to the reaction vessel. After shaking for 4 hours at 25°C, the reaction was analyzed by LCMS, and the disappearance of t-Bu ester was confirmed. The reaction was carried out similarly for resin 26a. (Table 125)

[0467] [Table 125]

[0468] (Product Identification) [Table 126] [ka]

[0469] H. Synthesis of raw materials for Boc removal reaction, t-Bu removal reaction, and resin removal reaction (Example 75) Synthesis of 3-mer starting material for Boc removal reaction (Boc-Asp(OBn)-pip) [ka] The procedure was similar to that of Example 88.

[0470] [Table 127]

[0471] [Table 128]

[0472] (Example 76) Synthesis of 2-mer (Boc-MeVal-Asp(OBn)-pip) [ka] 5.714 g of the raw material was weighed into a reaction vessel, and 29 ml of MeCN was added. After adding 2.3 ml of methanesulfonic acid, the reaction vessel was heated by setting the oil bath to 45°C. After 70 minutes, the reaction vessel was returned to room temperature, and then immersed in an ice bath. 14 ml of diisopropylethylamine was added to the reaction solution, followed by 4.046 g of Boc-MeVal-OH and 5.284 g of DMT-MM. One hour after adding the reagents, the reaction solution was concentrated. Ethyl acetate and 5% potassium carbonate aqueous solution were added to the concentrated solution to stop the reaction. After separating the organic layer by liquid separation, the organic layer was washed twice with 5% potassium carbonate aqueous solution, once with water, three times with 5% potassium hydrogen sulfate aqueous solution, once with 10% sodium chloride aqueous solution, and once with saturated saline. The organic layer was concentrated under reduced pressure to obtain 7.055 g of a pale yellow solid (yield 96%).

[0473] [Table 129]

[0474] [Table 130]

[0475] (Example 77) Synthesis of 3-mer (Boc-MePhe-MeVal-Asp(OBn)-pip) [ka] 7.055 g of the raw material was weighed into a reaction vessel, and 35 ml of MeCN was added. After adding 2.2 ml of methanesulfonic acid, the reaction vessel was heated by setting the oil bath to 45°C. After 70 minutes, the reaction vessel was returned to room temperature, and the reaction solution was concentrated. After concentration, 35 ml of ethyl acetate was added, the reaction vessel was immersed in an ice bath, and 9.466 g of sodium hydrogen carbonate was added. Next, 35 ml of water was added, followed by 4.61 g of Boc-MePhe-OH and 7.73 g of DMT-MM. After 6 hours, the reaction was tracked by LCMS, and it was confirmed that the raw material consumption rate was 99%. One hour after the analysis, ethyl acetate and water were added and separation treatment was performed to obtain an organic layer. The organic layer was washed three times with 5% potassium carbonate aqueous solution, once with water, three times with 5% potassium hydrogen sulfate aqueous solution, and once with saturated saline. The organic layer was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography, and 6.9757 g (75% yield) of the target product was obtained as a white solid.

[0476] [Table 131]

[0477] [Table 132]

[0478] (Example 78) Synthesis of Boc-MeGly-OAllyl [ka] 9.286 g of the raw material was weighed into a reaction vessel, and 46 ml of DMF was added. After cooling the reaction vessel on ice, 10.20 g of potassium carbonate and 4.15 ml of allyl bromide were added. After 15 minutes, the reaction vessel was returned to room temperature and stirred overnight. MTBE was added to the reaction vessel, and the reaction was stopped with water. After separation, the organic layer was washed once with saturated saline. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 10.083 g (yield 90%) of the target product 31 as a transparent oily liquid.

[0479] [Table 133]

[0480] (Example 79) Synthesis of Boc-Thr(OBn)-MeGly-OAllyl [ka] Deprotection and condensation reaction were carried out according to Example 76.

[0481] [Table 134]

[0482] [Table 135]

[0483] (Example 80) Synthesis of Boc-MeLeu-Thr(OBn)-MeGly-OAllyl [ka] Deprotection and condensation reactions were carried out in the same manner as described above.

[0484] (Example 80a) Synthesis of Teoc-MeLeu-OPfp by esterification of Teoc-MeLeu-OH with pentafluorophenol (Pfp-OH) [ka] 926 mg of the raw material and 736 mg of pentafluorophenol (Pfp-OH) were weighed into a reaction vessel, and 7.8 mL of isopropyl acetate was added. 767 mg of EDCI hydrochloride was added and stirred at room temperature for 2 hours. The organic layer was washed twice with 8 mL of 0.5 N hydrochloric acid and twice with 8 mL of 5% potassium carbonate aqueous solution, and 2 g of sodium sulfate was added to the organic layer. The solid was removed by filtration, and the organic layer was concentrated under reduced pressure to obtain the target product as a transparent oily liquid. The obtained compound was used in the next reaction without purification.

[0485] [Table 136]

[0486] (Example 80b) Synthesis of Teoc-MeLeu-Thr(OBn)-MeGly-OAllyl [ka] After removing the protecting group at the end of compound 33, a pentafluorophenyl ester (compound 80a) is reacted to form an amide bond, and compound 80b can be synthesized by a condensation reaction using the method of Meneses et al. (J. Org. Chem., 2010, 75, 564-569).

[0487] [Table 137]

[0488] [Table 138]

[0489] (Example 81) Synthesis of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OAllyl [ka] The reaction was carried out according to Example 88.

[0490] [Table 139]

[0491] [Table 140]

[0492] (Example 82) Synthesis of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OH [ka] 1.1180 g of the raw material was weighed into a reaction vessel, and 2.2 ml each of THF, methanol, and water were added. Next, 102.8 mg of lithium hydroxide monohydrate was added, and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction by LC, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the concentrate, and then 0.5 N hydrochloric acid was added to stop the reaction. The organic layer was separated by liquid separation, and then washed twice with 0.5 N hydrochloric acid and twice with 5% sodium chloride aqueous solution. The solvent was distilled off by vacuum concentration, and 918.8 mg of a white solid was obtained (yield 86%).

[0493] [Table 141]

[0494] [Table 142]

[0495] (Example 83) Synthesis of Fmoc-Asp(OtBu)-pip [ka] The reaction was carried out according to Example 88.

[0496] [Table 143]

[0497] [Table 144]

[0498] (Example 84) Synthesis of FmocAsp(OH)pip [ka] 45.4 g of the raw material was weighed into a reaction vessel, and 454 ml of trifluoroethanol was added. Then, 24 ml of trimethylsilane chloride was added and stirred at room temperature. Two and a half hours after the start of the reaction, 910 ml of water was added in two portions to precipitate crystals. The crystals were filtered and dried to obtain 25.8 g of the target product 36 (yield 61%).

[0499] [Table 145]

[0500] [Table 146]

[0501] (Example 85) Loading of Fmoc-Asp(OH)-pip onto CTC resin [ka] The loading step was carried out in the same manner as described in Example 112. The product was analyzed after 5-mer extension and the de-resin step.

[0502] [Table 147]

[0503] (Example 86) Solid phase synthesis (2mer extension) [ka] The reactions were carried out on columns for solid phase synthesis. 1) Deprotection step: DMF (104 mL) was added to the resin Fmoc-MeAla-OCTC (37, theoretical amino acid loading amount 9.49 mmol), and a 20% DMF solution of piperidine (104 mL) was added at 30° C., followed by shaking for 15 minutes at 30° C. After discharging the solution, a 20% DMF solution of piperidine (104 mL) was added again, followed by shaking for 15 minutes at 30° C. After discharging the solution, the resin was washed with DMF (130 ml) for 2 minutes 7 times. 2) Elongation step: 6.62 g of Fmoc-MeVal-OH and 2.93 g of Oxyma were dissolved in 52 ml of DMF in a reaction vessel separate from the solid-phase column, and then 5.87 ml of DIC was added and the mixture was shaken at 30° C. for 30 minutes. This solution was added to the solid-phase synthesis column and shaken at 30° C. for 2 hours. After discharging the solution, the resin was washed with DMF (130 ml) for 2 minutes x 6 times.

[0504] (Example 87) Solid-phase synthesis (sequential elongation from 2-mer to 5-mer and de-resination) [ka] The deprotection and elongation steps were repeated according to the method described in Example 86 to obtain Boc-MeIle-Ala-MePhe-MeVal-Asp(OCTC)-pip. 147 ml of a mixed solvent of diisopropylethylamine, trifluoroethanol, and methylene chloride (diisopropylethylamine 2%, solvent volume ratio 1:1) was added to the obtained resin and shaken at 30°C for 2.5 hours. The drained de-resined peptide solution was collected. After draining the de-resined solution, the resin was washed twice with 25 ml of a mixed solvent of trifluoroethanol and methylene chloride (volume ratio 1:1), and these solutions were concentrated. The concentrate was dissolved in 130 ml of ethyl acetate, washed twice with an aqueous potassium carbonate solution, twice with potassium hydrogen sulfate, and once with an aqueous sodium chloride solution, and then the organic layer was concentrated under reduced pressure. After drying, 4.9821 g (69% yield) of a white solid was obtained.

[0505] [Table 148]

[0506] [Table 149]

[0507] (Example 88) Synthesis of Fmoc-MeAsp(OtBu)-pip [ka] 49.6 g of EDCI hydrochloride was weighed out into a reaction vessel, and 400 ml of DMF was added. After cooling the reaction vessel to 0°C, 100.050 g of Fmoc-MeAsp(OtBu)-OH was added. Next, a solution of 40.1 g of Oxyma in 100 ml of DMF was added using a dropping funnel, followed by 34.9 ml of piperidine. The reaction was analyzed by LCMS 4 hours and 30 minutes after the end of the dropping of piperidine, and the disappearance of the raw material was confirmed. After diluting the reaction solution with ethyl acetate, 500 ml of 0.5 N hydrochloric acid was added to stop the reaction. After separating the organic layer, the organic layer was washed twice with water, twice with a 5% aqueous sodium carbonate solution, and twice with a 5% aqueous sodium chloride solution. The obtained organic layer was concentrated under reduced pressure. The obtained crude product was recrystallized from ethyl acetate and heptane, and 86.230 g of the target product was obtained (yield 75%).

[0508] [Table 150]

[0509] (Example 89) Synthesis of an intermediate (Cbz-Asp(OtBu)-pip(41)) of an 11-residue peptide (tBu form, Cbz-MeAla-MePhe-Leu-MeLeu-Val-MeGly-MeIle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(22)) [ka] 17.5 g of Cbz-Asp(OtBu)-OH was weighed into a reaction vessel, and 175 mL of ethyl acetate was added. After cooling the reaction solution to 0 °C, piperidine (3 eq.), diisopropylethylamine (6 eq.), and a 1.7 M solution of T3P in ethyl acetate (3 eq.) were added. The reaction solution was warmed to room temperature and stirred at room temperature for 10 minutes, after which 175 mL of 5% aqueous potassium carbonate was added. After removing the aqueous layer, the organic layer was washed twice with 175 mL of 5% aqueous potassium hydrogen sulfate. The resulting organic layer was concentrated and further dried under reduced pressure to obtain 20 g of Cbz-Asp(OtBu)-pip (41) in a 100% yield.

[0510] (Example 90) Synthesis of H-Asp(OtBu)-pip (42) [ka] 9.5 g of Cbz-Asp(OtBu)-pip (41) was weighed into each of two reaction vessels, and 50 mL of CPME was added to each vessel. After adding 10% Pd / C (20 w / w%) to both vessels, the reaction was carried out at 30 °C under a hydrogen atmosphere of 3 bar. After 3 hours from the start of the reaction, the two reaction solutions were mixed, filtered, and washed with 100 mL of CPME. The resulting mixture was concentrated and further dried under reduced pressure to obtain 12.3 g of H-Asp(OtBu)-pip (42) in a yield of 99%. The 11-mer (22) was synthesized from H-Asp(OtBu)-pip (42) via the 19 steps described below. The synthesized intermediates are shown below. [ka]

[0511] (Example 91) Peptide chain elongation (elongation method A) 8.6 g of 42 was weighed into a reaction vessel, and 108 mL of CPME was added. Cbz-MeVal-OH (1.1 eq.), diisopropylethylamine (3 eq.), and then a solution of BEP (1.5 eq.) dissolved in 21.5 mL of MeCN were added. After stirring at room temperature for 3 minutes, 15 mL of 10% aqueous sodium hydrogen sulfate solution was added. After removing the aqueous layer, 15 mL of 5% aqueous potassium carbonate solution and trimethylamine hydrochloride (3 eq.) were added to the organic layer at room temperature. The mixture was heated to 40 °C and stirred at 40 °C for 90 minutes. After cooling to room temperature and removing the aqueous layer, the obtained organic layer was washed with 15 mL of 5% aqueous potassium carbonate solution. The obtained organic layer was concentrated and further dried under reduced pressure to quantitatively obtain 17 g of 43.

[0512] (Example 92) Removal of N-terminal Cbz (deprotection method A) 9.5 g of 43 was weighed into two reaction vessels, and 50 mL of CPME was added to each vessel. 10% Pd / C (20 w / w%) was added to both vessels, and the reaction was carried out at 35 °C under a hydrogen atmosphere of 3 bar. Two hours after the start of the reaction, the two reaction solutions were mixed, filtered, and washed with 100 mL of CPME. The resulting mixture was concentrated and further dried under reduced pressure to give 14 g of 44 in 100% yield.

[0513] (Example 93) Peptide chain elongation (elongation method B) 14 g of 44 was weighed into a reaction vessel, and 126 mL of CPME and 14 mL of acetonitrile were added. Cbz-MePhe-OH (1.1 eq.), diisopropylethylamine (8 eq.), and a 1.7 M solution of T3P in ethyl acetate (3 eq.) were added in sequence at room temperature. After stirring at room temperature for 1 hour, 140 mL of a 5% aqueous potassium hydrogen sulfate solution was added. After removing the aqueous layer, 140 mL of a 5% aqueous potassium carbonate solution and trimethylamine hydrochloride (3 eq.) were added at room temperature. After stirring at room temperature for 30 minutes, the aqueous layer was removed. The resulting organic layer was washed with 140 mL of a 5% aqueous potassium carbonate solution. The resulting organic layer was concentrated and further dried under reduced pressure to obtain 24.1 g of 45 in a yield of 96%.

[0514] (Example 94) Removal of N-terminal Cbz (deprotection method B) 9.2 g of 15a was weighed into each of two reaction vessels, and 46 mL of CPME was added to each vessel. 10% Pd / C (20 w / w%) was added to both vessels, and the reaction was carried out under a hydrogen atmosphere of 5 bar at 35 °C. After 6 hours from the start of the reaction, the reaction was cooled to room temperature and stored overnight under air at room temperature. The reaction was further carried out under a hydrogen atmosphere of 5 bar at 45 °C for 4 hours. The two reaction solutions were mixed, filtered, and washed with 92 mL of CPME. The resulting mixture was concentrated and further dried under reduced pressure to obtain 15.9 g of 51 in a yield of 98%. Peptides of 2-mer to 11-mer were synthesized by the same method. The differences from the reaction conditions described above, except for the reaction time and the mass of the raw materials used, are listed in the "Reaction method" column.

[0515] [Table 151]

[0516] Among the synthesized intermediates, 13a, 14a, 15a, 16a, 17a, 18a, and 19a were used in the tBu removal experiment. The compounds used in the tBu removal reaction were analyzed by LCMS as shown in Table 152.

[0517] [Table 152]

[0518] I. Synthesis of C-terminal tBu-protected dipeptides [ka] (Example 110) Synthesis of Fmoc-MeAla-MeAla-OtBu (20a) 99.7 mg of H-MeAla-OtBu hydrochloride and 710 mg of dipotassium hydrogen phosphate were weighed into a reaction vessel, and 2-MeTHF and water were added in a 10 v / w ratio to H-MeAla-OtBu hydrochloride. Fmoc-MeAla-OH (167 mg) and DMT-MM (211 mg) were added successively at 0 °C, and the temperature was raised to room temperature. After stirring at room temperature for 16 hours, the reaction was analyzed by LCMS, and the disappearance of Fmoc-MeAla-OH was confirmed. The reaction solution was transferred to a separatory funnel using 4 mL of water and 6 mL of 2-MeTHF, and the aqueous layer was removed. The obtained organic layer was washed with saturated saline (3 mL), 15% aqueous sodium hydrogen sulfate solution (3 mL), and 5% aqueous sodium carbonate solution (3 mL), and the solvent was removed by concentration under reduced pressure. The resulting crude product was purified by silica gel column chromatography under the following conditions, and the fraction containing the target compound was concentrated and dried under reduced pressure to obtain 227.6 mg of 20a in a yield of 96% and a purity of 99.5%.

[0519] (Example 111) Synthesis of Fmoc-MePhe-MeAla-OtBu (21a) H-MeAla-OtBu hydrochloride (99.8 mg) and Fmoc-MePhe-OH (205 mg) were weighed into a reaction vessel, and 8 v / w isopropyl acetate, 2 v / w acetonitrile, and diisopropylethylamine (4 eq.) were added to the reaction vessel. 1.7 M ethyl acetate solution of T3P (2.5 eq.) was added at room temperature. After stirring for 4 hours at room temperature, 1.7 M ethyl acetate solution of T3P (0.5 eq.) and diisopropylethylamine (0.8 eq.) were added. 30 minutes after the addition of the reagents, the reaction was analyzed by LCMS, and the reaction conversion rate was 98.5%. NMI (2 eq.) was added at room temperature, and the mixture was stirred at 50 °C for 5 minutes. The reaction solution was transferred to a separatory funnel using 6 mL of ethyl acetate, and the aqueous layer was removed. The obtained organic layer was washed with 5% aqueous sodium carbonate solution (3 mL), 5% aqueous potassium hydrogen sulfate solution (3 mL), and 5% aqueous sodium carbonate solution (3 mL). The organic layer was dehydrated with sodium sulfate for 30 minutes, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by silica gel column chromatography under the following conditions, and the fraction containing the target product was concentrated and dried under reduced pressure to obtain 227.6 mg of 21a in a yield of 96% and a purity of 99.5%.

[0520] [Table 153]

[0521] J. Synthesis of CTC resin-supported dipeptides [ka] (Example 112) Loading of Fmoc-MeAla-OH onto CTC resin 4.47 g of Cl-CTC resin was weighed into a reaction column, and dichloromethane (36 mL) was added and shaken at 30 °C for 60 min. After draining the dichloromethane, a solution of Fmoc-MeAla-OH (1.24 g) and diisopropylethylamine (1.4 mL) dissolved in dichloromethane (36 mL) was added at room temperature. After shaking at 30 °C for 3 h, the reaction was analyzed by LCMS, and the reaction conversion was 96.0%. After draining the reaction solution, a solution of methanol (3.6 mL) and diisopropylethylamine (1.8 mL) dissolved in DMF (30 mL) was added at room temperature. After shaking at 30 °C for 1.5 h, the reaction solution was drained. The resin was washed with 36 mL of DMF four times and further dried under reduced pressure to obtain 4.80 g of 55. 56 was also synthesized by the same method. The product was analyzed in the next step.

[0522] [Table 154] [ka]

[0523] (Example 114) Synthesis of Fmoc-MeAla-MeAla-OCTC (22a), Fmoc-MeVal-MeAla-OCTC (23a), Fmoc-Pro-MeAla-OCTC (24a) Dipeptides 22a-24a were simultaneously synthesized using a peptide solid-phase synthesizer Prelude X. 676 mg, 687 mg, and 705 mg of resin Fmoc-MeAla-OCTC (55) were weighed into three reaction vessels. DMF (8 mL) was added to the resin, and the resin was allowed to swell at room temperature for 1 hour. After discharging the DMF, a 20% DMF solution of piperidine (8 mL) was added and the mixture was shaken at room temperature for 15 minutes. After discharging the solution, a 20% DMF solution of piperidine (8 mL) was added again and the mixture was shaken at room temperature for 15 minutes. The following cocktails 1-3 were added to RV1-3, respectively, and then a 12.5% ​​DMF solution of DIC (4 eq.) was added. The mixture was shaken at room temperature for 3 hours while blowing in nitrogen. After discharging the solution, the resin was washed with DMF (8 v / w) for 2 min x 5 times and with MTBE (8 v / w) for 2 min x 4 times, each time by shaking at room temperature. The resins obtained were dried under reduced pressure to obtain 30a, 31a, and 32a, respectively. The compounds obtained were identified by the resin removal reactions of Examples 65, 67, and 69. Approximately 20 mg of the three resins obtained were weighed into three reaction vessels, and a 20% DMF solution of piperidine (100 mL) was added to each vessel, followed by stirring at room temperature for 2 hours. The loading rate of each dipeptide was calculated by quantifying dibenzofulvene from the absorbance of the solution (Table 155).

[0524] (Example 115) Synthesis of Fmoc-MeAla-MeAsp(OtBu)-OCTC (25a) and Fmoc-MeLeu-MeAsp(OtBu)-OCTC (26a) Dipeptides 25a-26a were simultaneously synthesized using a peptide solid-phase synthesizer Prelude X. 340 mg of resin Fmoc-MeAsp(OtBu)-OCTC(10) was weighed into two reaction vessels. DMF (8 mL) was added to the resin, and the resin was allowed to swell at room temperature for 30 minutes. After discharging the DMF, a 20% DMF solution of piperidine (8 v / w) was added and the mixture was shaken at room temperature for 5 minutes. After discharging the solution, a 20% DMF solution of piperidine (8 v / w) was added again and the mixture was shaken at room temperature for 20 minutes. After discharging the solution, the following cocktails 1 and 2 were added to the corresponding reaction vessels, followed by the addition of a 12.5% ​​DMF solution of DIC (4 eq.) and shaking at room temperature for 3 hours while blowing in nitrogen. After discharging the solution, the resin was washed with DMF (8 v / w) for 2 min × 4 times and with MTBE (8 v / w) for 2 min × 4 times, each time by shaking at room temperature. The resin obtained was dried under reduced pressure to obtain 994 mg of 25a and 1.00 g of 26a, respectively. The obtained compounds were identified by the resin removal reactions of Examples 71 and 73. Approximately 20 mg of the two resins obtained were weighed out and placed in two reaction vessels, and a 20% DMF solution of piperidine (100 mL) was added to each, followed by stirring at room temperature for 2 hours. The loading rate of each dipeptide was calculated by quantifying dibenzofulvene from the absorbance of the solution (Table 155).

[0525] [Table 155]

[0526] (Example 116) Synthesis of Fmoc-MeAsp(OAllyl)-mor [ka] Fmoc-MeAsp(OAllyl)-OH (56, 87.9 g) was added to a reaction vessel and dissolved in DMF (430 ml). Then, HOBt (31.9 g) and EDCI hydrochloride (49.4 g) were added at ambient temperature, and the reaction solution was cooled to 0°C. Morpholine (20.4 ml) was gradually added to the reaction solution, and the mixture was stirred at 0°C for 45 minutes. Water (180 ml) was added to the reaction solution at 0°C, and the mixture was stirred at ambient temperature for 1 hour, and water (180 ml) was further added and the mixture was stirred at ambient temperature for 1.75 hours. The resulting solid was filtered using a Kiriyama funnel, and the obtained solid was washed twice with water (450 ml). The solid after washing was dried under reduced pressure, and the target product was obtained as a colorless solid in 86.8 g (yield 85%).

[0527] (Example 117) Synthesis of Fmoc-MeAsp(OAllyl)-NMe2 [ka] Under a nitrogen stream, EDCI hydrochloride (27.4 g) and DMF (217 ml) were added to a reaction vessel, followed by the addition of HOBt (17.7 g) and a dichloromethane-DMF solution (90 ml-90 ml) of Fmoc-MeAsp(OAllyl)-OH (56, 48.8 g) at 0° C. After stirring the reaction solution at 0° C. for 30 minutes, dimethylamine-THF solution (2N, 65.6 ml) was added dropwise to the reaction solution over 2 minutes, and the reaction solution was stirred at 0° C. for 30 minutes. The reaction solution was diluted with ethyl acetate (488 ml), and the organic layer was washed with 1 N hydrochloric acid (391 ml x 2), water (488 ml), 5% aqueous sodium bicarbonate solution (488 ml x 2), and 18% aqueous sodium chloride solution (488 ml), and then the organic layer was dried over sodium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure to obtain 51.2 g (yield 98%) of the desired product as a colorless oily substance.

[0528] (Example 118) Synthesis of Fmoc-MeAsp(OH)-mor [ka] Fmoc-MeAsp(OAllyl)-mor (57, 22.8 g) and dichloromethane (50 ml) were added to a reaction vessel under a nitrogen stream, followed by the addition of tetrakistriphenylphosphinepalladium (0.55 g) at ambient temperature. Phenylsilane (3.61 g) was added dropwise, and the mixture was stirred at ambient temperature for 30 minutes. The reaction solution was diluted with MTBE (228 ml) and extracted with 5% aqueous sodium bicarbonate solution (228 ml). The aqueous layer was acidified to about pH 3 with 85% aqueous phosphoric acid solution (12 ml), and the aqueous layer was extracted with MTBE (228 ml). This organic layer was washed with 18% aqueous sodium chloride solution (228 ml twice), and then dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 20.3 g (yield 97%) of the target product as colorless amorphous crystals.

[0529] (Example 119) Synthesis of Fmoc-MeAsp(OH)-NMe2 [ka] Under a nitrogen stream, Fmoc-MeAsp(OAllyl)-NMe2 (58, 32.0 g) and tetrakistriphenylphosphine palladium (0.847 g) were added to a reaction vessel, followed by dichloromethane (73.3 ml). Phenylsilane (5.55 g) was added dropwise to the reaction solution, which was then stirred at ambient temperature for 30 minutes. The reaction solution was diluted with MTBE (320 ml) and extracted with 5% aqueous sodium bicarbonate solution (308 ml). The aqueous layer was acidified to approximately pH 2 with 85% aqueous phosphoric acid solution (30.1 ml), and the aqueous layer was extracted with MTBE (320 ml). This organic layer was washed with 18% aqueous sodium chloride solution (320 ml twice), and then dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 25.1 g (yield 86%) of the target product as light brown amorphous crystals.

[0530] [Table 156]

[0531] (Example 120) Synthesis of Fmoc-MeAsp(OtBu)-mor (61) [ka] Under a nitrogen stream, Fmoc-MeAsp(OtBu)-OH (39, 3.0 g) and Oxyma (1.1 g) were added to a reaction vessel, followed by the addition of dimethylformamide (15 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g) and morpholine (0.74 mL) were added to the reaction solution while maintaining the temperature of the reaction solution below 10°C, and the mixture was stirred for 3 hours. AcOEt (15 mL) and 0.5N hydrochloric acid (15 mL) were added to the reaction solution. The organic layer was washed with water (15 mL) and further washed with 5% aqueous sodium carbonate solution (15 mL). After washing the organic layer with 5% aqueous sodium chloride solution (15 mL), the organic layer was concentrated under reduced pressure to obtain 3.50 g (100%) of the target product as yellow amorphous crystals. The compound obtained was used in the next reaction without purification.

[0532] (Example 121) Synthesis of Fmoc-MeAsp(OtBu)-NMe2 (62) [ka] Under a nitrogen stream, Fmoc-MeAsp(OtBu)-OH (39, 3.0 g) and Oxyma (1.1 g) were added to a reaction vessel, followed by dimethylformamide (15 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g), dimethylamine hydrochloride (0.69 g), and N,N-diisopropylethylamine (1.5 ml) were added to the reaction solution while maintaining the temperature of the reaction solution below 10°C, and the mixture was stirred for 3 hours. Ethyl acetate (15 mL) and then 0.5 N hydrochloric acid (15 mL) were added to the reaction solution. The organic layer was washed with water (15 mL) and then with 5% aqueous sodium carbonate solution (15 mL). The organic layer was washed with 5% aqueous sodium chloride solution (15 mL), and then concentrated under reduced pressure to obtain 3.17 g (95%) of the target product as a colorless oily substance. The compound obtained was used in the next reaction without purification.

[0533] (Example 122) Synthesis of Fmoc-MeAsp(OH)-mor (59) [ka] Under a nitrogen stream, Fmoc-MeAsp(OtBu)-mor (61, 1.8 g) and 2-methyltetrahydrofuran (9.2 mL) were added to a reaction vessel, followed by the addition of HMDS (0.86 mL). The reaction vessel was cooled to 0°C, TMSOTf (0.81 mL) was added, and the mixture was stirred at 25°C for 1 hour. The reaction vessel was cooled to 0°C, and 5% potassium dihydrogen phosphate aqueous solution (9.2 mL) was added to the reaction solution to separate the organic layer. 5% sodium carbonate aqueous solution (9.2 mL) was added to separate the aqueous layer. MTBE (9.2 mL) and 2N hydrochloric acid (5.0 mL) were added to the aqueous layer to separate the organic layer. The organic layer was washed with 5% potassium dihydrogen phosphate aqueous solution (9.2 mL), and then washed with 10% sodium chloride aqueous solution (9.2 mL). The organic layer was concentrated under reduced pressure to obtain 1.31 g (97%) of the target product as yellow amorphous crystals.

[0534] (Example 123) Synthesis of Fmoc-MeAsp(OH)-NMe2(60) [ka] Under a nitrogen stream, Fmoc-MeAsp(OtBu)-NMe2 (62, 1.6 g) and 2-methyltetrahydrofuran (7.9 mL) were added to a reaction vessel, followed by the addition of HMDS (0.80 mL). The reaction vessel was cooled to 0°C, TMSOTf (0.75 mL) was added, and the mixture was stirred at 25°C for 1 hour. 5% potassium dihydrogen phosphate aqueous solution (7.9 mL) was added to the reaction solution to separate the organic layer. 5% sodium carbonate aqueous solution (7.9 mL) was added to separate the aqueous layer. MTBE (7.9 mL) and 2N hydrochloric acid (5.0 mL) were added to the aqueous layer to separate the organic layer. The organic layer was washed with 5% potassium dihydrogen phosphate aqueous solution (7.9 mL), followed by washing with 10% sodium chloride aqueous solution (7.9 mL). The organic layer was concentrated under reduced pressure to obtain 1.31 g (95%) of the target product as a colorless oily substance.

[0535] [Table 157] [Industrial Applicability]

[0536] The present invention provides a method for producing a peptide compound by a novel deprotection method and / or resin removal method using a silylating agent. The present invention can provide an industrially applicable and efficient peptide synthesis method.

Claims

1. A method for producing a peptide compound in which a protecting group has been deprotected, the method comprising the step of contacting a starting peptide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby deprotecting a protecting group that can be deprotected by the silylating agent from the starting peptide compound, the method comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting peptide compound comprises at least one deprotectable protecting group, and The method, wherein the starting peptide compound comprises at least one N-substituted amino acid residue.

2. A method for producing a peptide compound from which a solid-phase synthesis resin has been removed, the method comprising the step of contacting a starting peptide compound containing a natural amino acid residue and / or an amino acid analog residue with a silylating agent in a solvent, thereby removing a solid-phase synthesis resin that can be removed by the silylating agent from the starting peptide compound, the method comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; the starting peptide compound is linked to the removable solid phase synthesis resin; and The method, wherein the starting peptide compound comprises at least one N-substituted amino acid residue.

3. The starting peptide compound has the following general formula (I): 【Chemistry 1】 [In the formula, R １ is hydrogen, PG １ , a natural amino acid residue, or an amino acid analog residue; R ２ is hydrogen, and C １ -C ６ alkyl; or R ２ and R ４ Or R ２ and R ４’ together with the nitrogen and carbon atoms to which they are attached, represent hydroxy or C １ -C ４ Forms a 3- to 7-membered heterocyclic ring optionally substituted by alkoxy, where R ２ and R ４ When taken together, form a heterocycle, R ４’ is hydrogen, R ２ and R ４’ When taken together, form a heterocycle, R ４ is hydrogen, R ４ and R ４’ is R ２ and R ４ Or R ２ and R ４’ except when taken together to form a heterocycle, (a) R ４’ is hydrogen and R ４ is hydrogen, optionally substituted C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkyl C １ -C ４ Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH ２ SPG ２ , N-PG ３ -indol-3-ylmethyl, 4-(PG ２ O) Benzyl, P.G. ２ -O-methyl, 1-(PG ２ O) Ethyl, 2-(PG ２ O) Ethyl, PG ２ -OCO(CH ２ ) -, P.G. ２ -OCO(CH ２ ) ２ -, P.G. ３ N-n-butyl, -CON(R １４Ａ ) (R １４Ｂ ), -CH ２ -CON(R １４Ａ ) (R １４Ｂ ), and -(CH ２ ) ２ CON (R １４Ａ ) (R １４Ｂ or (b) R ４ and R ４’ is independently an optionally substituted C １ -C ６ is alkyl, or (c) R ４ and R ４’ form together with the carbon atom to which they are attached a 3- to 7-membered alicyclic ring; R ５ is a single bond or -C(R ５Ａ ) (R ５Ｂ ) - and R ５Ａ and R ５Ｂ are independently hydrogen, C １ -C ６ Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl C １ -C ４ Alkyl and optionally substituted heteroaryl C １ -C ４ is selected from the group consisting of alkyl, R ６ is hydrogen, and C １ -C ６ alkyl; or R ６ and R ７ Or R ６ and R ７’ together with the nitrogen and carbon atoms to which they are attached, represent hydroxy or C １ -C ４ Forms a 3- to 7-membered heterocyclic ring optionally substituted by alkoxy, where R ６ and R ７ When taken together, form a heterocycle, R ７’ is hydrogen, R ６ and R ７’ When taken together, form a heterocycle, R ７ is hydrogen, R ７ and R ７’ is R ６ and R ７ Or R ６ and R ７’ except when taken together to form a heterocycle, (a) R ７’ is hydrogen and R ７ is hydrogen, optionally substituted C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkyl C １ -C ４ Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH ２ SPG ４ , N-PG ５ -indol-3-ylmethyl, 4-(PG ４ O) Benzyl, P.G. ４ -O-methyl, 1-(PG ４ O) Ethyl, 2-(PG ４ O) Ethyl, PG ４ -OCO(CH ２ ) -, P.G. ４ -OCO(CH ２ ) ２ -, P.G. ５ N-n-butyl, -CON(R １５Ａ ) (R １５Ｂ ), -CH ２ -CON(R １５Ａ ) (R １５Ｂ ), and -(CH ２ ) ２ CON (R １５Ａ ) (R １５Ｂ or (b) R ７ and R ７’ is independently an optionally substituted C １ -C ６ is alkyl, or (c) R ７ and R ７’ form together with the carbon atom to which they are attached a 3- to 7-membered alicyclic ring; R ８ is a single bond or -C(R ８Ａ ) (R ８Ｂ ) - and R ８Ａ and R ８Ｂ are independently hydrogen, C １ -C ６ Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl C １ -C ４ Alkyl and optionally substituted heteroaryl C １ -C ４ is selected from the group consisting of alkyl, R ９ is hydroxy, -O-PG ６ , a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES; RES is a resin for solid phase synthesis; R １４Ａ and R １４Ｂ are independently hydrogen, C １ -C ４ alkyl or R １４Ａ and R １４Ｂ together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R １５Ａ and R １５Ｂ are independently hydrogen, C １ -C ４ alkyl or R １５Ａ and R １５Ｂ together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; P.G. １ is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; P.G. ２ and P.G. ４ are independently hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl C １ -C ４ alkyl, and 2-(trimethylsilyl)ethyl; P.G. ３ and P.G. ５ is independently selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; P.G. ６ is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, and 2-(trimethylsilyl)ethyl. The method according to claim 1 or 2, comprising at least one structure in which at least two amino acid residues represented by the formula:

4. The starting peptide compound has at its C-terminus the following general formula (II): 【Chemistry 2】 [In the formula, R １’ is a group represented by formula (III), 【Chemistry 3】 * indicates a bonding point. R １ is hydrogen, PG １ , a natural amino acid residue, or an amino acid analog residue; R ２ is hydrogen, and C １ -C ６ alkyl; or R ２ and R １０ Or R ２ and R １０’ together with the nitrogen and carbon atoms to which they are attached, represent hydroxy or C １ -C ４ Forms a 3- to 7-membered heterocyclic ring optionally substituted by alkoxy, where R ２ and R １０ When taken together, form a heterocycle, R １０’ is hydrogen, R ２ and R １０’ When taken together, form a heterocycle, R １０ is hydrogen, R １０ and R １０’ is R ２ and R １０ Or R ２ and R １０’ except when taken together to form a heterocycle, (a) R １０’ is hydrogen and R １０ is hydrogen, optionally substituted C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkyl C １ -C ４ Alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH ２ SPG ８ , N-PG ９ -indol-3-ylmethyl, 4-(PG ８ O) Benzyl, P.G. ８ -O-methyl, 1-(PG ８ O) Ethyl, 2-(PG ８ O) Ethyl, PG ８ -OCO(CH ２ ) -, P.G. ８ -OCO(CH ２ ) ２ -, P.G. ９ N-n-butyl, -CON(R １６Ａ ) (R １６Ｂ ), -CH ２ -CON(R １６Ａ ) (R １６Ｂ ), and -(CH ２ ) ２ CON (R １６Ａ ) (R １６Ｂ or (b) R １０ and R １０’ is independently an optionally substituted C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C ３ -C ６ Cycloalkyl C １ -C ４ is alkyl, or (c) R １０ and R １０’ form together with the carbon atom to which they are attached a 3- to 7-membered alicyclic ring; R １１ is a single bond or -C(R １１Ａ ) (R １１Ｂ ) - and R １１Ａ and R １１Ｂ are independently hydrogen, C １ -C ６ Alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl C １ -C ４ Alkyl and optionally substituted heteroaryl C １ -C ４ is selected from the group consisting of alkyl, R １２ and R １２’ are independently hydrogen, PG １０ -O-methyl, -(CH ２ ) ｎ COO-PG １０ , -(CH ２ ) ｎ COO-RES, and -(CH ２ ) ｎ CONH-RES; RES is a resin for solid phase synthesis; n is 0, 1, or 2; R ６ is hydrogen, and C １ -C ６ is selected from the group consisting of alkyl, R １３ is C １ -C ４ Alkyl, or -(CH ２ ) ｍ CON (R １７Ａ ) (R １７Ｂ ) and m is 0, 1, or 2; R １６Ａ and R １６Ｂ are independently hydrogen or C １ -C ４ alkyl or R １６Ａ and R １６Ｂ together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; R １７Ａ and R １７Ｂ are independently hydrogen, C １ -C ４ alkyl or R １７Ａ and R １７Ｂ together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; P.G. １ is independently selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; P.G. ８ is hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl C １ -C ４ alkyl, and 2-(trimethylsilyl)ethyl; P.G. ９ is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; P.G. １０ is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl C １ -C ４ alkyl, and (2-(trimethylsilyl)ethyl). The method according to any one of claims 1 to 3, comprising a structure in which at least two amino acid residues represented by the following formula (1) are linked together.

5. A method for producing an amide compound from which a protecting group has been deprotected, comprising the step of deprotecting a protecting group that can be deprotected by a silylating agent from the starting amide compound by contacting the starting amide compound with a silylating agent in a solvent, the method comprising the steps of: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting amide compound has the following general formula (II): 【Chemistry 4】 [In the formula, R １’ is a hydrogen atom, or PG ７ and R １２ and R １２’ are independently hydrogen, PG １０ -O-methyl, -(CH ２ ) ｎ COO-PG １０ , -(CH ２ ) ｎ COO-RES, and -(CH ２ ) ｎ CONH-RES; RES is a resin for solid phase synthesis; n is 0, 1, or 2; R ６ is hydrogen, and C １ -C ６ is selected from the group consisting of alkyl, R １３ is C １ -C ４ Alkyl, or -(CH ２ ) ｍ CON (R １７Ａ ) (R １７Ｂ ) and m is 0, 1, or 2; R １７Ａ and R １７Ｂ are independently hydrogen, C １ -C ４ alkyl or R １７Ａ and R １７Ｂ together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; P.G. ７ is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; P.G. １０ is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl C １ -C ４ alkyl, and (2-(trimethylsilyl)ethyl). and The starting amide compound comprises at least one of the deprotectable protecting groups.

6. A method for producing an amide compound from a resin for solid phase synthesis, comprising the step of contacting a starting amide compound with a silylating agent in a solvent, thereby removing the starting amide compound from the resin for solid phase synthesis, comprising: The silylating agent is generated by combining a silyl compound or an acid with an electrophilic species scavenger; The starting amide compound has the following general formula (II): 【Chemistry 5】 [In the formula, R １’ is a hydrogen atom, or PG ７ and R １２ and R １２’ are independently hydrogen, PG １０ -O-methyl, -(CH ２ ) ｎ COO-PG １０ , -(CH ２ ) ｎ COO-RES, and -(CH ２ ) ｎ CONH-RES; RES is a resin for solid phase synthesis, where R １２ and R １２’ At least one of the groups is -(CH ２ ) ｎ COO-RES, or -(CH ２ ) ｎ CONH-RES, RES is a resin for solid phase synthesis; n is 0, 1, or 2; R ６ is hydrogen, and C １ -C ６ is selected from the group consisting of alkyl, R １３ is C １ -C ４ Alkyl, or -(CH ２ ) ｍ CON (R １７Ａ ) (R １７Ｂ ) and m is 0, 1, or 2; R １７Ａ and R １７Ｂ are independently hydrogen, C １ -C ４ alkyl or R １７Ａ and R １７Ｂ together with the nitrogen atom to which they are attached form a 4- to 8-membered ring which may contain one or more additional heteroatoms; P.G. ７ is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; P.G. １０ is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl C １ -C ４ alkyl, and 2-(trimethylsilyl)ethyl. The method is represented by

7. 6. The method of any one of claims 1 and 3 to 5, wherein the deprotectable protecting group is selected from the group consisting of t-Bu, triphenylmethyl, 2-(trimethylsilyl)-ethyl, Boc, Teoc, Cbz, methoxycarbonyl, tetrahydropyranyl, 1-ethoxyethyl, methoxytrityl, and cumyl.

8. The silyl compound is represented by the following formula 1: 【Chemistry 6】 [In the formula, R ＡＸ , R ＡＹ , and R ＡＺ is independently １ -C ４ alkyl or phenyl, and X is -OTf, -OClO ３ , Cl, Br, and I. The method according to any one of claims 1 to 7, wherein

9. Silyl compounds include TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, TMSOClO ３ 9. The method of claim 8, wherein the .alpha.-methyltransferase is selected from the group consisting of:

10. The acid is HX (wherein X is -OTf, -OCIO ３ 8. The method according to claim 1, wherein the aryl group is selected from the group consisting of Cl, Br, and I.

11. The electrophilic species scavenger is represented by the following formulas (2) to (10): 【Chemistry 7】 [In formula 2, R Ｂ is a substituted silyl group, and R Ｃ is a substituted silyl group, or R Ｂ and R Ｃ form a 5- to 7-membered ring together with the nitrogen and carbon atoms to which they are attached, R Ｄ C may be substituted with one or more fluorine atoms １ -C ４ alkyl or optionally substituted methylene, where R Ｄ When is an optionally substituted methylene, formula 2 dimerizes to the following formula: 【Chemistry 8】 forming a compound represented by In formula 3, R Ｇ is one or more C １ -C ４ is an alkyl-substituted silyl group, R Ｈ is hydrogen, or C １ -C ４ is alkyl, R Ｉ is hydrogen or C optionally substituted with one or more fluorine atoms １ -C ４ is alkyl, In formula 4, (a-1) R Ｊ is a substituted silyl group, R Ｋ is C １ -C ４ Alkoxy, and R Ｍ and R Ｌ are independently hydrogen or C １ -C ４ Is it an alkyl group? (a-2) R Ｊ is a substituted silyl group, R Ｍ is hydrogen or C １ -C ４ alkyl, and R Ｋ and R Ｌ together with the carbon atom to which they are attached form a 5- to 8-membered ring containing an oxygen atom, or (b-1) R Ｊ is a substituted silyl group, R Ｋ is C １ -C ４ alkyl, and R Ｍ and R Ｌ are independently hydrogen or C １ -C ４ Is it an alkyl group? (b-2) R Ｊ is a substituted silyl group, R Ｍ is hydrogen, or C １ -C ４ alkyl, and R Ｋ and R Ｌ form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (c-1) R Ｊ and R Ｍ form a 5- to 7-membered ring containing an oxygen atom together with the carbon atom to which they are attached, and R Ｋ is hydrogen, or C １ -C ４ alkyl, and R Ｌ is C １ -C ４ Is it an alkyl group? (c-2) R Ｊ and R Ｍ form a 5- to 7-membered ring containing an oxygen atom together with the carbon atom to which they are attached, and R Ｋ and R Ｌ form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (d-1) R Ｊ is C １ -C ４ alkyl, and R Ｍ , R Ｋ , and R Ｌ are independently hydrogen or C １ -C ４ Is it an alkyl group? (d-2) R Ｊ is C １ -C ４ alkyl, R Ｍ is hydrogen or C １ -C ４ alkyl, and R Ｋ and R Ｌ form a 5-8 ring together with the carbon atom to which they are attached, or (e-1) R Ｊ is C １ -C ３ alkylcarbonyl, and R Ｍ , R Ｋ , and R Ｌ are independently hydrogen or C １ -C ４ Is it an alkyl group? (e-2) R Ｊ is C １ -C ３ alkylcarbonyl, R Ｍ is hydrogen or C １ -C ４ alkyl, and R Ｋ and R Ｌ form a 5- to 8-membered ring together with the carbon atom to which they are attached, or (f-1) R Ｊ is a substituted silyl group or C １ -C ４ alkyl, R Ｋ is optionally substituted di-C １ -C ４ alkylamino, and R Ｍ and R Ｌ are independently hydrogen or C １ -C ４ Is it an alkyl group? (f-2) or R Ｊ is a substituted silyl group or C １ -C ４ alkyl, R Ｍ is hydrogen or C １ -C ４ alkyl, and R Ｋ and R Ｌ together with the carbon atom to which they are attached form a 5- to 8-membered ring containing a nitrogen atom, and the 5- to 8-membered ring is １ -C ４ may be substituted by alkyl, In formula 5, R Ｎ , R Ｎ’ , and R Ｏ are independently hydrogen or C １ -C ４ is alkyl, In formula 6, R Ｐ is a substituted silyl group, R Ｑ is a substituted silyl group, or C １ -C ４ alkyl, and R Ｒ is hydrogen, a substituted silyl group, or C １ -C ４ is alkyl, or R Ｑ and R Ｒ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycle which may contain one or more additional heteroatoms; In formula 7, X is a single bond or a carbon atom; where X is a single bond, R Ｓ does not exist, and R ＵＡ and R Ｒ form an optionally substituted 6-membered aromatic heterocycle together with the carbon atom and nitrogen atom to which they are attached, and R ＵＢ and R Ｔ together with the carbon atom and nitrogen atom to which they are attached form an optionally substituted 6-membered aromatic heterocycle; When X is a carbon atom, R ＵＡ and R ＵＢ is independently １ -C ４ alkyl, and R Ｒ and R Ｓ and R Ｔ together with the carbon atoms to which they are attached form the following structure: 【Chemistry 9】 Forming In formula 8, R Ｖ is C １ -C ４ Alkyl or C ３ -C ６ is cycloalkyl, In formula 9, R Ｗ and R Ｘ is independently １ -C ４ an alkyl or substituted silyl group; In formula 10, R Ｙ and R Ｚ is independently １ -C ４ is an alkyl, or a substituted silyl group. The method according to any one of claims 1 to 10, wherein the compound is selected from the group consisting of:

12. 12. The method of claim 11, wherein the electrophilic species scavenger is selected from the group consisting of N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilylacetamide, N-methyl-N-trimethylsilyltrifluoroacetamide, dimethylketene methyltrimethylsilyl acetal, isopropenyloxytrimethylsilane, 2,2,4,4-tetramethylpentanoneimine, 1,1,1,3,3,3-hexamethyldisilazane (HMDS), N-trimethylsilylmorpholine, N-trimethylsilyldiethylamine, and N-tert-butyltrimethylsilylamine.

13. The method according to any one of claims 1 to 9 and 11 to 12, wherein 1 to 5 equivalents of a silyl compound and 1 to 10 equivalents of an electrophilic species scavenger are mixed per equivalent of a protecting group to be removed or per equivalent of a resin to be removed.

14. The method according to any one of claims 1 to 12, wherein 0.1 to 0.5 equivalents of a silyl compound or an acid are mixed with respect to 1 equivalent of a protecting group to be removed or 1 equivalent of a resin to be removed, the electrophilic species scavenger is selected from the group consisting of N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilylacetamide, N-methyl-N-trimethylsilyltrifluoroacetamide, dimethylketene methyltrimethylsilyl acetal, and isopropenyloxytrimethylsilane; The silyl compounds are TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, and TMSOClO. ３ is selected from the group consisting of The acid is HX (wherein X is -OTf, -OCIO ３ , Cl, Br, and I).

15. The method of any one of claims 1 to 14, wherein the starting peptide compound comprises 1 to 30 amino acid residues and is linear or cyclic.

16. The method according to any one of claims 1 to 4 and 6 to 15, wherein the resin for solid phase synthesis is a CTC resin, a Wang resin, or a SASRIN resin.

17. 17. The method of any one of claims 1 to 16, comprising mixing the starting peptide compound with a solvent, followed by mixing with an electrophilic species scavenger, and then mixing with a silyl compound or an acid.

18. An amide compound represented by the following general formula (A) or a salt thereof: 【Chemistry 10】 During the ceremony, R １’ is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; R １７Ａ and R １７Ｂ are both methyl, or R １７Ａ and R １７Ｂ together with the nitrogen atom to which they are attached form piperidine or morpholine, R １８ is hydrogen or PG １０ where PG １０ is t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl C １ -C ４ alkyl, and 2-(trimethylsilyl)ethyl.

19. 19. The amide compound of claim 18, or a salt thereof, selected from the group consisting of: (3-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-3) tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-4) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl, (3-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl (3-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl (3-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-11) tert-Butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl (3-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoic acid, (3-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate allyl, (3-15) tert-Butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate, (3-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutanoate benzyl, (3-17) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoic acid, (3-18) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate allyl, (3-19) tert-butyl 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate, (3-20) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutanoate benzyl (2-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-3) tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-4) benzyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl (2-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid allyl ester, (2-11) tert-Butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl (2-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoic acid, (2-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate allyl, (2-15) tert-Butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate, (2-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutanoate benzyl, (2-17) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoic acid, (2-18) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate allyl, (2-19) tert-butyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate, (2-20) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutanoate benzyl, (4-1) 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (4-2) Allyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-3) tert-butyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-4) benzyl 3-(methylamino)-4-oxo-4-(piperidin-1-yl)butanoate, (4-5) 3-(methylamino)-4-morpholino-4-oxobutanoic acid, (4-6) Allyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-7) tert-butyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-8) benzyl 3-(methylamino)-4-morpholino-4-oxobutanoate, (4-9) 4-(dimethylamino)-3-(methylamino)-4-oxobutanoic acid, (4-10) Allyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, (4-11) tert-butyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, (4-12) benzyl 4-(dimethylamino)-3-(methylamino)-4-oxobutanoate, (1-1) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-2) 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-3) tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-4) benzyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-5) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-6) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-7) tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl (1-9) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-10) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid allyl ester, (1-11) tert-Butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl (1-13) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-14) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate allyl, (1-15) tert-Butyl 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, (1-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate benzyl, (1-17) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoic acid, (1-18) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate allyl, (1-19) tert-Butyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate, and (1-20) Benzyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate.

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