Deprotection method for peptide compound or amide compound and resin removal method in solid phase reaction, and method for producing peptide compound

Abstract

The present invention relates to a deprotection method for a peptide compound or an amide compound and a resin removal method in a solid phase reaction and a method for producing a peptide compound. The inventors of the present invention have found that a desired peptide compound / amide compound in which the protecting group has been removed and / or the resin for solid-phase synthesis has been removed can be produced without main chain disruption by bringing the starting peptide compound / starting amide compound into contact with a silylating agent.

Description

[0001] This application is a divisional application of PCT international application filed on November 29, 2019, PCT international application number PCT / JP2019 / 046805, Chinese national application number 201980075795.3, entitled "A method for deprotection of peptide compounds or amide compounds and a method for resin removal in solid-phase reaction and a method for producing peptide compounds". [Technical Field]

[0002] This invention relates to methods for deprotecting peptide or amide compounds and methods for removing such compounds from resins in solid-phase reactions, as well as methods for producing peptide compounds. [Background Technology]

[0003] Peptides are molecules in which many amino acids are linked together. Extensive research has been conducted not only on the synthesis of peptides produced by organisms, but also on peptides with artificially designed structures and desired functions (Non-Patent Literature 1).

[0004] Peptides can be produced by linking multiple amino acids by repeating the following steps: (i) activating the carboxyl group of an N-terminal protected, C-terminal unprotected amino acid with a condensing agent or the like to provide an active ester, (ii) reacting the active ester with the N-terminal unprotected peptide to provide a peptide elongated by the amino acid, and (iii) removing the N-terminal protecting group (NPL2) from the elongated peptide.

[0005] Peptide production methods are broadly classified into solid-phase and liquid-phase methods. Solid-phase methods involve binding the C-terminus of an amino acid or its derivative (protected amino acid) or its peptide or derivative to a solid-phase synthetic resin such as CTC resin, Wang resin, or SASRIN resin containing chlorotriphenylmethyl, benzyl, etc., and then coupling the amino group of the resulting amino acid or peptide, acting as a nucleophile, to the carbonyl group of the N-terminus protected peptide or amino acid, acting as an electrophile. Liquid-phase methods involve coupling the carbonyl group of the N-terminus protected amino acid or peptide, acting as an electrophile, to the amino group of the amino acid or peptide, acting as a nucleophile. When such coupling reactions could lead to undesirable transformations of functional groups in the side chains of amino acids or peptides, protecting groups must be introduced into these side chains beforehand. Protecting groups that can be removed under acidic conditions, such as Boc, t-Bu, or triphenylmethyl, are commonly used to protect the C-terminus, N-terminus, and side chains of amino acids or peptides. In resin removal reactions used to dissociate peptides from solid-phase synthesis resins bound to peptides, solid-phase synthesis resins that can be removed under acidic conditions, such as CTC resin, Wang resin, and SASRIN resin (NPL 4), are commonly used.

[0006] Protecting groups that can be removed under acidic conditions also include 3,5-dimethoxyphenylisopropoxycarbonyl (Ddz), benzyloxycarbonyl (Cbz), benzyl (Bn), and cyclohexyl (cHx) groups (NPL 4 and NPL 5). Under the conditions of their deprotection reactions or resin removal reactions, side reactions may occur, such as the breaking of amide bonds in the peptide and unintended transformations of functional groups in the amino acid side chains, leading to byproduct peptides with unexpected sequences. Therefore, reactions that provide the target peptide without disrupting the peptide backbone are needed, such as amide bond breaking and rearrangement reactions of the peptide backbone.

[0007] The protecting groups mentioned above, which can be removed under acidic conditions, are typically removed by treatment with hydrochloric acid, sulfuric acid, methanesulfonic acid, or TFA (NPL 2, NPL 3, and NPL 4). TFA is commonly used for resin removal reactions in solid-phase synthesis (NPL 6). However, it has been described that even under acidic conditions, using TFA (the mildest of these acids) can cause amide bonds to break (NPL 7).

[0008] Attempts to address the amide bond cleavage problem have been described by reacting under diluted TFE conditions and by Boc deprotection under mild conditions; however, the problem was not resolved in either case (NPL 8, PTL 1). Methods for removing protecting groups from protected amino acids using less acidic TFE have also been reported (NPL 5, PTL 1). In these studies, reaction conversions were low, and therefore it was necessary to add more acid or proceed under more stringent reaction conditions, such as increased reaction temperature, to advance the reaction. However, when reaction conditions, including the addition of acid or increased reaction temperature, are applied to peptides, there is a problem that the peptide backbone may be disrupted. Indeed, when Boc-Leu-MeLeu-Thr(OBn)-MeGly-O allyl groups were reacted with hydrogen chloride in TFE for Boc deprotection, backbone cleavage was observed before the Boc deprotection reaction was complete.

[0009] It was also reported that amide bond cleavage could be successfully suppressed (NPL 9) by conducting the reaction at low temperatures and stopping the reaction before side reactions occur. However, this technique requires strict control of the reaction time, and it is easy to assume that such control would be challenging in mass production, where it would be difficult to stop the reaction within a short time.

[0010] As a deprotection method under acidic conditions, attempts have been made to suppress side reactions between the side chains and the t-Bu cations generated simultaneously during the removal of Boc or t-Bu groups by adding cation scavengers (NPL 10).

[0011] In this case, sulfur-containing additives such as dimethyl sulfide and thioanisole are used for deprotection under acidic conditions to remove t-Bu cations derived from the t-Bu group. However, this has been reported to cause amide bond cleavage as a side reaction, resulting in reduced yield and purity (NPL 7).

[0012] Methods that allow thioanisole and TfOH to function in TFA solutions or that allow thioanisole and trimethylsilyl bromide or trimethylsilyl trifluoromethanesulfonate to function in TFA solutions have also been reported (NPL 12).

[0013] However, many sulfur-containing additives, such as dimethyl sulfide and anisole, have unpleasant odors, and therefore their impact on manufacturing workers is a problem. Furthermore, the need for column chromatography to remove such additives is problematic, as it is unsuitable for large-scale production.

[0014] It has also been reported that peptide chain breakage increases even when water is used as a cationic scavenger (NPL 11).

[0015] Deprotection methods using silicon-containing additives instead of sulfur-containing additives as cation scavengers have been reported. In these methods, N-Boc-protected compounds containing amide bonds are treated with cation scavengers such as triisopropylsilane (iPr3SiH), for example, at a TFA:iPr3SiH:H2O ratio of 95:2.5:2.5 (NPL 13) or a TFA:iPr3SiH:H2O:PhOH ratio of 1000:50:67:50 (NPL 14). However, these methods only describe conditions difficult to implement on a large scale, such as short treatment times of a few minutes to suppress amide bond breaking. In fact, when Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MePhe-MeAla-Leu-MeLeu-Thr(OBn)-MeGly-O allyl groups undergo a Boc deprotection reaction under NPL 13 and NPL 14 conditions, amide bond cleavage between MePhe and MeAla is observed before the complete removal of the Boc group. The cleavage rate also increases over time.

[0016] As mentioned above, when deprotection and resin removal reactions are carried out in solid-phase synthesis under acidic conditions, they not only involve the desired deprotection or resin removal reactions, but also disrupt the peptide backbone, such as the breaking of amide bonds constituting the peptide backbone and the rearrangement of functional groups in amino acid side chains into the backbone. It is known that the generation of byproducts due to such backbone disruption reduces the yield and purity of the target product and becomes a problem for the efficient synthesis of peptides.

[0017] Meanwhile, it has also been reported that the structural features of peptides are related to the stability or destructibility of amide bonds.

[0018] For example, it is known that the twisting of the amide bond increases the acid instability of the amide bond (NPL 15 and NPL 16).

[0019] In addition to bond twisting, in the case of peptide amide bonds, the type of amino acid side chain, the substitution pattern of the nitrogen atom, 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 such conformational changes, the carbonyl oxygen may become more basic and more readily protonated (NPL 18 and NPL 19). It is known that in some cases, the amide bond... The formation of azole is disrupted (NPL 17).

[0020] It has also been reported that peptides containing N-Me amino acids (which are amino acids with methylated nitrogen atoms) can undergo stepwise amide bond cleavage under acidic conditions (NPL 11, NPL 17, and NPL 20). Furthermore, it is known that when peptides with N-Me amino acids at the C-terminus undergo TFA acidic conditions, the amide bond between the first and second residues of the peptide may break, resulting in a byproduct peptide lacking the C-terminal residue (NPL 21). Therefore, it is known that amide bonds containing N-Me groups in N-Me amino acids are prone to cleavage.

[0021] Furthermore, it is known that peptides with sequences of two or more consecutive N-Me amino acid residues are generally unstable in acid and undergo amide bond cleavage (NPL11) during resin removal reactions in solid-phase synthesis. Therefore, it is known that amide bonds containing N-Me groups in N-Me amino acids and / or amide bonds containing carbonyl groups in N-Me amino acids are prone to cleavage.

[0022] Peptides containing Asp or Gln are also acid-instable in a sequence-dependent manner (NPL 22 and NPL 23). For example, it is known that when a peptide sequence containing Asp is treated with acids such as hydrogen fluoride and methanesulfonic acid, the carbonyl group of its side chain is nucleophilically attacked by the nitrogen atom of the main chain amide, resulting in aspartimide as a byproduct (NPL 23). Therefore, it is known that even if the amino acid is N-unsubstituted, the amide bond is readily broken at sites containing amino acids with specific side chains.

[0023] When this asparagine intermediate undergoes hydrolysis, rearrangement byproducts with altered amide structures and backbone breakage byproducts are generated, thereby reducing the yield and purity of the target product. Asparagine formation is significant when peptides containing sequences such as Asp(OBn)-Gly, Asp(OBn)-Ser, Asp(OBn)-Thr, Asp(OBn)-Asn, or Asp(OBn)-Gln are deprotected under acidic conditions. For example, it is known that when Boc-Phe-Asp(OBn)-Asn-Ala-OBn is deprotected by methanesulfonic acid, it is largely converted to asparagine and lacks the desired amino acid sequence, i.e., a backbone-breaking reaction occurs (NPL 24).

[0024] It is also known that when peptide derivatives containing Asp-Pro in their sequence are subjected to acidic conditions such as trifluoroacetic acid, hydrofluoric acid, formic acid, and acetic acid, the side chain of Asp reacts with the nitrogen atom of Pro, as in the aforementioned side reactions, and thus the amide bond is broken (NPL 25 and NPL 26).

[0025] Several methods have been reported for avoiding side reactions in deprotection reactions caused by the amino acid sequence-dependent instability of amide bonds in acids.

[0026] For example, a method for suppressing asparagine formation during the deprotection and resin removal reactions of asparagine derivatives is known, wherein the carboxyl group of the aspartic acid side chain is protected with a cyclohexyl group, so that the nitrogen atom of the main-chain amide will not undergo nucleophilic attack under the deprotection conditions used to protect the group of interest. This method has been reported to significantly suppress asparagine formation compared to the use of a benzyl protecting group as the side chain protecting group (NPL 27). However, the subsequent removal of the cyclohexyl group requires highly corrosive, highly acidic conditions such as hydrofluoric acid, and it is readily assumed that both the reaction and the post-treatment are not convenient to perform.

[0027] A method for treatment with 1M trimethylsilyl bromide / TFA in the presence of thioanisole is also known (NPL 28). However, this condition is unfavorable because it requires the use of a solvent amount of TFA and the use of thioanisole, which, as mentioned above, is unsuitable for large-scale production. Furthermore, it has been described that when trimethylsilyl trifluoromethanesulfonate is used instead of trimethylsilyl bromide, the byproduct asparagine increases significantly, thus indicating that trimethylsilyl bromide is superior to trimethylsilyl trifluoromethanesulfonate.

[0028] A known method involves the Boc removal of peptides and the t-Bu removal of esters in the presence of a tertiary amine and trimethylsilyl trifluoromethanesulfonate or TBDMSOTf. One known example is the use of 2,6-dimethylpyridine as the tertiary amine and N-Boc removal under TMSOTf / 2,6-dimethylpyridine conditions in the presence of other functional groups, thereby selectively removing the Boc group (NPL 29, NPL 30, and NPL 31). In another known example, reactions for Boc removal and removal from resins used in solid-phase synthesis (which can occur simultaneously under acidic conditions using TFA) are carried out under trimethylsilyl trifluoromethanesulfonate / 2,6-dimethylpyridine conditions to selectively achieve Boc removal (NPL 32 and 33). These methods have also been applied to compounds containing amide bonds, but without intending to avoid breaking the amide bonds.

[0029] Selective deprotection of t-Bu esters in the presence of TBS and TIPS groups and thioacetal has been carried out under trimethylsilyl trifluoromethanesulfonate / 2,6-dimethylpyridine conditions (NPL 34). The removal of t-Bu from peptide t-Bu esters using this technique has also been reported. For example, deprotection reactions of t-Bu esters under TMSOTf / 2,6-dimethylpyridine conditions are known (NPL 35 and NPL 36). However, this approach does not necessarily prevent amide bond cleavage.

[0030] It is known that when trimethylsilyl trifluoromethanesulfonate / 2,6-dimethylpyridine is used in the N-Boc removal reaction in the total synthesis of natural peptide compounds (which provides a complex mixture after treatment with a protic acid), these reactions preferentially produce the target product while suppressing the formation of byproducts (NPL 37). However, the side reactions mentioned therein are not described in detail, and the reaction conditions are not examined for general applicability or the possibility of avoiding amide bond breakage. Furthermore, large excess amounts of reagent (above 20 equivalents) are required, thus posing a problem from the perspective of applicability to substrates and the versatility of manufacturing costs. In this case, trimethylsilyl trifluoromethanesulfonate / 2,6-dimethylpyridine is only applied to compounds with amide bonds, and it is not mentioned whether side reactions are caused by amide bond cleavage.

[0031] As mentioned above, treatment with Brønsted acids, represented by trifluoroacetic acid, under acidic conditions is commonly used for reactions that cleave peptides from resins loaded with peptides (resin deprotection reactions) to provide elongated peptides in solid-phase methods, and for removing removable protecting groups from N-terminal, C-terminal, and amino acid side-chain protecting groups in both solid-phase and liquid-phase methods. There are also known examples where deprotection reactions are carried out in the presence of Lewis acids. However, despite the known fact that conventional methods for treating peptides containing non-natural amino acids, represented by N-Me amino acids, for resin deprotection or deprotection reactions result in the intended reaction, accompanied by backbone breakage or rearrangement (backbone disruption), and require large amounts of reagents, solutions to these problems are not yet clear (NPL 20, NPL 22, and NPL37).

[0032] In particular, because the study of non-natural artificial peptides often encounters unexpected side reactions when using conventional synthetic methods, it is extremely important to develop techniques for the industrially efficient synthesis of non-natural artificial peptides and their derivatives. However, in the production of such peptides containing non-natural amino acids, only conventional methods for preparing peptides composed of natural amino acids have been used. There are no known efficient synthetic methods that address and resolve the problems in the production of peptides containing non-natural amino acids, especially the specific problems of main chain damage caused by deprotection or resin removal reactions.

[0033] [List of Citations]

[0034] Patent Documents

[0035] [PTL 1]WO 2014 / 033466

[0036] [Non-patent literature]

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[0038] [NPL 2] Amino Acids, Peptides and Proteins in Organic Chemistry: Building Blocks, Catalysis and Coupling Chemistry, VoluMe 3, 2011

[0039] [NPL 3] Amino Acids, 2018, 50, 39-68.

[0040] [NPL 4]Chem.Rev.,2009,109,2455-2504。

[0041] [NPL 5]Russ.J.Bioorg.Chem.2016,42,143-152。

[0042] [NPL 6]J.Comb.Chem.2002,4,1-16。

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[0046] [NPL 10]J.Chem.Soc.D,1970,0,406b-407。

[0047] [NPL 11]J.Peptide RES.2005,65,153-166。

[0048] [NPL 12]J.Chem.Soc.Chem.Commun.1987,274-275。

[0049] [NPL 13]J.Am.Chem.Soc.2015,137,13488-134918。

[0050] [NPL 14]J.Am.Chem.Soc.2012,134,13244-13247。

[0051] [NPL 15]J.Am.Chem.Soc.,2016,138,969-974。

[0052] [NPL 16]Tetrahedron Lett.,1998,39,865-868。

[0053] [NPL 17]J.Mass.Spectrom.,1998,33,505-524。

[0054] [NPL 18]J.Am.Chem.Soc.,1994,116,11512-11521。

[0055] [NPL 19] J. Am. Soc. Mass Spectrom, 1995, 6, 91-101.

[0056] [NPL 20] Int. J. Peptide Protein RES. 1996, 47, 182-189.

[0057] [NPL 21] Int. J. Peptide Protein RES. 1988, 31, 186-191.

[0058] [NPL 22] Molecular Biomethods Handbook, pp. 515-547.

[0059] [NPL 23] J. Mol. Model, 2013, 19, 3627-3636.

[0060] [NPL 24] Chem. Pharm. Bull., 1981, 29, 2825-2831.

[0061] [NPL 25] Side reactions in Peptide Synthesis, 2015, 1-31, Academic Press.

[0062] [NPL 26] Biochem. Biophys. RES. Commun. 1970, 40, 1173-1178.

[0063] [NPL 27] Tetrahedron Lett., 1979, 20, 4033-4036.

[0064] [NPL 28] Tetrahedron, 1988, 44, 805-819.

[0065] [NPL 29] Tetrahedron Lett., 1988, 29, 1181-1184.

[0066] [NPL 30] J. Org. Chem. 1997, 62, 3880-3889.

[0067] [NPL 31] Org. Lett. 2018, 20, 4637-4640.

[0068] [NPL 32] Eur. J. Org. Chem., 2012, 6204-6211.

[0069] [NPL 33] Tetrahedron Lett., 1998, 39, 7439-7442.

[0070] [NPL 34] J. Org. Chem. 1990, 55, 2786-2797.

[0071] [NPL 35] Bioorg. Med. Chem. Lett. 2008, 18, 3902-3905.

[0072] [NPL 36] Tetrahedron 2004, 60, 8509-8527.

[0073] [NPL 37] J. Org. Chem., 2016, 81, 532-544. [Summary of the Invention]

[0074] [Technical Issues]

[0075] The inventors subjected peptide compounds containing non-natural amino acids to the same conditions as in treatment with acids represented by TFAs, which are commonly used to remove protecting groups from amino acids or peptides or to cleave peptides from resins in solid-phase reactions, as is typically done in conventional peptide synthesis. As a result, the inventors found that the peptide compounds exhibited significant disruptions in the backbone, such as amide bond breaking or rearrangement, and were not efficiently obtained with the expected sequences, making the production of these peptide compounds difficult. Specifically, the inventors found that under acidic conditions, the backbone is readily disrupted at the amide bonds of moieties containing N-substituted (e.g., N-alkylated) amino acids (for peptide compounds containing such amino acids) or at the amide bonds of moieties containing aspartic acid. In addition to these problems, the inventors also discovered numerous amino acid sequences that cause backbone disruption under conventional acidic conditions. One object of the present invention is to provide techniques for removing removable protecting groups under acidic conditions and for removing resins in solid-phase reactions, while suppressing side reactions such as the breaking or rearrangement of amide bonds contained in peptide compounds, and to provide a method for obtaining deprotected and / or resin-deprotected peptide compounds in high yield and purity in a simple operation.

[0076] [Solution to the problem]

[0077] While suppressing side reactions such as the breaking or rearrangement of amide bonds in peptide compounds containing N-substituted (e.g., N-alkylated) amino acids, the inventors have primarily investigated reactions for the removal of protecting groups that can be removed under acidic conditions or for the removal of resins in solid-phase reactions. The inventors investigated techniques for reacting peptide compounds with silyl compounds in the presence of electrophilic species scavengers and discovered that treatment of peptide compounds containing acid-labile amide bonds with silyl compounds or acids in combination with electrophilic species scavengers can remove protecting groups and / or resins without involving damage to the main chain of concern, thereby obtaining deprotected and / or resin-removed target products in high yield and purity. Regarding reagents used for such deprotection and / or resin removal, the inventors have also discovered that compounds such as imide (Formula 2), amide (Formula 3), enone acetal (Formula 4), enone alkoxy hemiacetal (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 carbamate (Formula 10) can be combined with suitable silyl compounds or acids as electrophilic species scavengers. Compared to conventional techniques, the present invention can provide target peptide compounds more efficiently and in higher yields without involving amide bond cleavage.

[0078] In a non-limiting embodiment, the present invention includes the following.

[0079] [1] A method for producing a peptide compound in which a protecting group removable by a silylating agent has been removed, the method comprising the steps 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 protecting group from the starting peptide compound.

[0080] The silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger.

[0081] The starting peptide compound contains at least one protecting group that can be removed by a silylating agent, and

[0082] The starting peptide compound contains at least one N-substituted amino acid residue.

[0083] [2] A method for producing a peptide compound in which a solid-phase synthesis resin removable by a silylating agent has been removed, the method comprising the steps 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 solid-phase synthesis resin from the starting peptide compound.

[0084] The silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger.

[0085] The starting peptide compound is linked to the removable solid-phase synthesis resin, and

[0086] The starting peptide compound contains at least one N-substituted amino acid residue.

[0087] [3] According to the method of [1] or [2], the starting peptide compound comprises at least one structure in which at least two amino acid residues are linked together, wherein the structure is represented by the following general formula (I):

[0088]

[0089] in

[0090] R1 is hydrogen, PG1, a natural amino acid residue, or an amino acid analog residue.

[0091] R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R4 or R2 and R 4′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles optionally substituted with hydroxyl or C1-C4 alkoxy groups, wherein when R2 and R4 form the heterocycle together, R... 4′ It is hydrogen, and when R2 and R 4′ When the heterocycle is formed together, R4 is hydrogen;

[0092] However, this does not include the following cases: when R2 and R4 or R2 and R... 4′ When the heterocycle is formed together,

[0093] (a)R 4′ It is hydrogen, and R4 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG2, N-PG3-indol-3-ylmethyl, 4-(PG2O)benzyl, PG2-O-methyl, 1-(PG2O)ethyl, 2-(PG2O)ethyl, PG2-OCO(CH2)-, PG2-OCO(CH2)2-, PG3N-n-butyl, -CON(R 14A (R) 14B ), -CH2-CON(R 14A (R) 14B ) and -(CH2)2CON(R 14A (R) 14B ),

[0094] (b) R4 and R 4′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0095] (c) R4 and R 4′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0096] R5 is a single bond or -C(R) 5A (R) 5B )-;

[0097] R 5A and R 5B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0098] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R6 and R7 or R6 and R 7′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles optionally substituted with hydroxyl or C1-C4 alkoxy groups, wherein when R6 and R7 form the heterocycle together, R... 7′ It is hydrogen, and when R6 and R 7′ When the heterocycle is formed together, R7 is hydrogen;

[0099] However, this does not include the following cases: when R6 and R7 or R6 and R... 7′ When the heterocycle is formed together,

[0100] (a)R 7′ It is hydrogen, and R7 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG4, N-PG5-indol-3-ylmethyl, 4-(PG4O)benzyl, PG4-O-methyl, 1-(PG4O)ethyl, 2-(PG4O)ethyl, PG 4- OCO(CH2)-, PG4-OCO(CH2)2-, PG5N-n-butyl, -CON(R) 15A (R) 15B ), -CH2-CON(R 15A (R) 15B ) and -(CH2)2CON(R 15A (R) 15B ),or

[0101] (b) R7 and R 7′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0102] (c)R7 and R 7′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0103] R8 is a single bond or -C(R 8A (R) 8B )-;

[0104] R 8A and R 8B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0105] R9 is a hydroxyl group, -O-PG6, a native amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES;

[0106] RES is a resin used in solid-phase synthesis;

[0107] R 14A and R 14B It is independently hydrogen or C1-C4 alkyl, or R 14A and R 14B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0108] R 15A and R 15B It is independently hydrogen or C1-C4 alkyl, or R 15A and R 15B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0109] PG1 is selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;

[0110] PG2 and PG4 are independently selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumenyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl;

[0111] PG3 and PG5 are independently selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl; and

[0112] PG6 is selected from the group consisting of the following: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl and 2-(trimethylsilyl)ethyl.

[0113] [4] The method according to any one of [1] to [3], wherein the starting peptide compound comprises a structure in which at least two amino acid residues at the C-terminus are linked to each other, wherein the structure is represented by the following general formula (II):

[0114]

[0115] in

[0116] R 1′ It is a group represented by the following general formula (III):

[0117]

[0118] * indicates a connection point;

[0119] R1 is hydrogen, PG1, a natural amino acid residue, or an amino acid analog residue.

[0120] R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R 10 Or R2 and R 10′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles optionally substituted with hydroxyl or C1-C4 alkoxy groups, wherein when R2 and R... 10 When the heterocycle is formed together, R 10′ It is hydrogen, and when R2 and R 10′ When the heterocycle is formed together, R 10 It is hydrogen;

[0121] However, this does not include the following case: when R2 and R... 10 Or R2 and R 10′ When the heterocycle is formed together,

[0122] (a)R 10′ It is hydrogen, and R 10 Choose from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG8, N-PG9-indol-3-ylmethyl, 4-(PG8O)benzyl, PG8-O-methyl, 1-(PG8O)ethyl, 2-(PG8O)ethyl, PG8-OCO(CH2)-, PG8-OCO(CH2)2-, PG9N-n-butyl, -CON(R 16A (R) 16B), -CH2-CON(R 16A (R) 16B )and

[0123] -(CH2)2CON(R 16A (R) 16B ),or

[0124] (b)R 10 and R 10′ Independently, it may be an optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C4 alkyl, or

[0125] (c)R 10 and R 10′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0126] R 11 Is it a single bond or -C(R)? 11A (R) 11B )-;

[0127] R 11A and R 11B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0128] R 12 and R 12′ Choose independently the group consisting of the following items: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES;

[0129] RES is a resin used in solid-phase synthesis;

[0130] n is 0, 1, or 2;

[0131] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups;

[0132] R 13 It is a C1-C4 alkyl group or -(CH2) m CON(R 17A (R) ]7B );

[0133] m is 0, 1, or 2;

[0134] R 16A and R16B It is independently hydrogen or C1-C4 alkyl, or R 16A and R 16B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0135] R 17A and R 17B It is independently hydrogen or C1-C4 alkyl, or R 17A and R 17B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0136] PG1 is independently selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc and trifluoroacetyl;

[0137] PG8 is selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumene, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl.

[0138] PG9 is selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl; and

[0139] PG 10 Choose from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0140] [5] A method for producing an amide compound in which a protecting group removable by a silylating agent has been removed, the method comprising the steps of: contacting a starting amide compound with a silylating agent in a solvent, thereby removing the protecting group from the starting amide compound.

[0141] The silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger.

[0142] The initiating amide compound is represented by the following general formula (II):

[0143]

[0144] in

[0145] R 1′ It is a hydrogen atom or PG7;

[0146] R 12 and R 12 Choose independently the following groups: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES;

[0147] RES is a resin used in solid-phase synthesis;

[0148] n is 0, 1, or 2;

[0149] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups;

[0150] R 13 It is a C1-C4 alkyl group or -(CH2) m CON(R 17A (R) 17B );

[0151] m is 0, 1, or 2;

[0152] R 17A and R 17B It is independently hydrogen or C1-C4 alkyl, or R 17A and R 17B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0153] PG7 is selected from the group consisting of: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; and

[0154] PG 10 Choose from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0155] The starting amide compound contains at least one protecting group that can be removed by a silylating agent.

[0156] [6] A method for producing an amide compound in which the solid-phase synthesis resin has been removed, the method comprising the steps of: contacting a starting amide compound with the silylating agent in a solvent, thereby removing the starting amide compound from the solid-phase synthesis resin.

[0157] The silylating agent is prepared by mixing a silyl compound or acid with an electrophilic species scavenger, and

[0158] The initiating amide compound is represented by the following general formula (II):

[0159]

[0160] in

[0161] R 1′ It is a hydrogen atom or PG7;

[0162] R 12 and R 12′ Choose independently the group consisting of the following items: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES;

[0163] RES is a resin used in solid-phase synthesis, wherein R 12 and R 12′ At least one of them is -(CH2). n COO-RES or -(CH2) n CONH-RES;

[0164] RES is a resin used in solid-phase synthesis;

[0165] n is 0, 1, or 2;

[0166] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups;

[0167] R 13 It is a C1-C4 alkyl group or -(CH2) m CON(R 17A (R) 17B );

[0168] m is 0, 1, or 2;

[0169] R 17A and R 17B It is independently hydrogen or C1-C4 alkyl, or R 17A and R17B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0170] PG7 is selected from the group consisting of: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl; and

[0171] PG 10 Choose from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0172] [7] The method according to any one of [1] and [3] to [5], wherein the removable protecting group is selected from the group consisting of: t-Bu, triphenylmethyl, 2-(trimethylsilyl)-ethyl, Boc, Teoc, Cbz, methoxycarbonyl, tetrahydropyranyl, 1-ethoxyethyl, methoxytriphenylmethyl and cumeneyl.

[0173] [8] The method according to any one of [1] to [7], wherein the silyl compound is represented by the following formula 1:

[0174]

[0175] Where R AX R AY and R AZ It is independently a C1-C4 alkyl or phenyl, and X is selected from the group consisting of: -OTf, -OClO3, Cl, Br and I.

[0176] [9] According to the method of [8], the silyl compound is selected from the group consisting of: TMSOTf, TESOTf, TB SOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, TMSOClO3 and TMSI.

[0177]

[10] The method according to any one of [1] to [7], wherein the acid is represented by HX, wherein X is selected from the group consisting of: -OTf, -OClO3, Cl, Br and I.

[0178]

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

[10] , wherein the electrophilic species scavenger is selected from the group consisting of the following formulas (2) to (10):

[0179]

[0180] In Equation 2,

[0181] RB is a substituted silyl group, and R C It is a substituted silyl group, or

[0182] RB and R c Together with the nitrogen and carbon atoms they are attached to, they form 5- to 7-membered rings; and

[0183] R D It is a C1-C4 alkyl group optionally substituted with one or more fluorine atoms, or an optionally substituted methylene group, wherein when R D When the methylene group is optionally substituted, formula 2 dimerizes to form a compound represented by the following formula:

[0184]

[0185] In Equation 3,

[0186] R G It is a silyl group substituted with one or more C1-C4 alkyl groups;

[0187] R H It is hydrogen or C1-C4 alkyl; and

[0188] R I It is a hydrogen or a C1-C4 alkyl group optionally substituted with one or more fluorine atoms;

[0189] In Equation 4,

[0190] (a-1)R J It is a substituted silyl group, R K It is a C1-C4 alkoxy group, and R M and R L It is independently hydrogen or C1-C4 alkyl;

[0191] (a-2)R J It is a substituted silyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings containing oxygen atoms;

[0192] (b-1)R J It is a substituted silyl group, R K It is a C1-C4 alkyl group, and R M and R L It is independently hydrogen or C1-C4 alkyl;

[0193] (b-2)R J It is a substituted silyl group, RM It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings; or

[0194] (c-1)R J and R M Together with the carbon atoms they are attached to, they form 5- to 7-membered rings containing oxygen atoms, R K It is hydrogen or C1-C4 alkyl, and R L It is a C1-C4 alkyl group;

[0195] (c-2)R J and R M Together with the carbon atoms they are attached to, they form 5- to 7-membered rings containing oxygen atoms, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings;

[0196] (d-1)R J It is a C1-C4 alkyl group, and R M R K and R L It is independently hydrogen or C1-C4 alkyl;

[0197] (d-2)R J It is a C1-C4 alkyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings;

[0198] (e-1)R J It is a C1-C3 alkyl carbonyl group, and R M R K and R L It is either hydrogen or C1-C4 alkyl:

[0199] (e-2)R J It is a C1-C3 alkyl carbonyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings;

[0200] (f-1)R J It is a substituted silyl or C1-C4 alkyl group, R K It is an optionally substituted di-C1-C4 alkylamino group, and R M and R L It is independently hydrogen or C1-C4 alkyl; or

[0201] (f-2)R J It is a substituted silyl or C1-C4 alkyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms to which they are attached, they form 5 to 8-membered rings containing nitrogen atoms, wherein the 5 to 8-membered rings are optionally substituted with C1-C4 alkyl groups;

[0202] In Equation 5,

[0203] R N R N′ and R O It is independently hydrogen or C1-C4 alkyl;

[0204] In Equation 6,

[0205] RP is a substituted silyl group; and

[0206] R Q It is a substituted silyl or C1-C4 alkyl group, and R R It is hydrogen, substituted silyl or C1-C4 alkyl, or

[0207] R Q and R R Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered heterocycles that optionally contain one or more additional heteroatoms;

[0208] In Equation 7,

[0209] X is a single bond or a carbon atom.

[0210] Where X is a single bond, R S It does not exist, R UA and R R Together with the carbon and nitrogen atoms to which they are attached, they form optionally substituted 6-membered aromatic heterocycles, and R UB and R T Together with the carbon and nitrogen atoms they are attached to, they form optionally substituted 6-membered aromatic heterocycles, and

[0211] When X is a carbon atom, R UA and R UB Independently, it is a C1-C4 alkyl group, and R R R s and R T Together with the carbon atoms they are attached to, they form the following structure:

[0212]

[0213] In Equation 8,

[0214] R V It is a C1-C4 alkyl or a C3-C6 cycloalkyl;

[0215] In Equation 9,

[0216] R W and R X Independently, it is a C1-C4 alkyl or a substituted silyl group; and

[0217] In Equation 10,

[0218] R Y and R Z It is independently a C1-C4 alkyl or a substituted silyl group.

[0219]

[12] According to the method of

[11] , 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.

[0220]

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

[11] to

[12] , wherein for each equivalent of the protective base to be removed or for each equivalent of the resin to be removed, 1 to 5 equivalents of the silyl compound and 1 to 10 equivalents of the electrophilic species scavenger are mixed.

[0221]

[14] According to any one of [1] to

[12] , wherein for each equivalent of the protecting group to be removed or for each equivalent of the resin to be removed, 0.1 to 0.5 equivalents of the silane compound or acid are mixed.

[0222] The electrophilic species scavenger mentioned above 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.

[0223] The silyl compound mentioned herein is selected from the group consisting of: TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, and TMSOClO3, and

[0224] The acid is represented by HX, where X is selected from the group consisting of: -OTf, -OClO3, Cl, Br and I.

[0225]

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

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

[0226]

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

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

[0227]

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

[16] , wherein the method comprises mixing the starting peptide compound with the solvent, then mixing with the electrophilic species scavenger, and subsequently mixing with the silyl compound or acid.

[0228]

[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.

[0229]

[19] An amide compound or a salt thereof represented by the following general formula (A):

[0230]

[0231] in

[0232] R 1′ Choose from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;

[0233] R 17A and R 17B They are all methyl, or R 17A and R 17B Together with the nitrogen atoms they are attached to, they form piperidine or morpholine; and

[0234] R 18 Is it hydrogen or PG? 10 PG 10Choose from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0235]

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

[19] , wherein the amide compound is selected from the group consisting of:

[0236] (3-1)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0237] (3-2)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-(dimethylamino)_4-oxobutyric acid allyl ester,

[0238] (3-3)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-(dimethylamino)_4-oxobutyrate tert-butyl ester,

[0239] (3-4)3-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid benzyl group,

[0240] (3-5)3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0241] (3-6)3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid allyl ester,

[0242] (3-7)3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate tert-butyl ester,

[0243] (3-8)3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate benzyl ester,

[0244] (3-9)3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0245] (3-10)3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid allyl ester,

[0246] (3-11)3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate tert-butyl ester,

[0247] (3-12)3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate benzyl ester,

[0248] (3-13)3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0249] (3-14)3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid allyl ester,

[0250] (3-15)3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate tert-butyl ester,

[0251] (3-16)3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate benzyl ester,

[0252] (3-17)4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyric acid,

[0253] (3-18)4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyric acid allyl ester,

[0254] (3-19) tert-butyl 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyrate,

[0255] (3-20)4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyrate benzyl ester,

[0256] (2-1)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-morpholino_4-oxobutyric acid,

[0257] (2-2)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0258] (2-3)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0259] (2_4)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-morpholino_4-oxobutyrate benzyl ester,

[0260] (2-5)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid,

[0261] (2-6)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0262] (2-7)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0263] (2-8)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0264] (2-9)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid,

[0265] (2-10)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0266] (2-11)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0267] (2-12)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0268] (2-13)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid,

[0269] (2-14)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0270] (2-15)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0271] (2-16)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0272] (2-17)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyric acid,

[0273] (2-18)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0274] (2-19)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0275] (2-20)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0276] (4-1)3-(methylamino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0277] (4-2)3-(methylamino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester

[0278] (4-3)3-(methylamino)-4-oxo-4-(piperidin-1-yl)tert-butyl butyrate,

[0279] (4-4)3-(methylamino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0280] (4-5)3-(methylamino)-4-morpholino-4-oxobutyric acid,

[0281] (4-6)3-(methylamino)-4-morpholino-4-oxobutyric acid allyl ester,

[0282] (4-7)3-(methylamino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0283] (4-8)3-(methylamino)-4-morpholino-4-oxobutyrate benzyl ester,

[0284] (4-9)4-(dimethylamino)-3-(methylamino)-4-oxobutyric acid,

[0285] (4-10)4-(dimethylamino)-3-(methylamino)-4-oxobutyric acid allyl ester,

[0286] (4-11) tert-butyl 4-(dimethylamino)-3-(methylamino)-4-oxobutyrate,

[0287] (4-12) 4-(dimethylamino)-3-(methylamino)-4-oxobutyrate benzyl ester,

[0288] (1-1)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-oxo_4-(piperidin-1-yl)butyric acid,

[0289] (1-2)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0290] (1-3)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)tert-butyl butyrate,

[0291] (1_4)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-oxo-4-(piperidin-1-yl)]benzyl ester,

[0292] (1-5)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0293] (1-6)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0294] (1-7)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyrate tert-butyl ester,

[0295] (1-8)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0296] (1-9)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0297] (1-10)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0298] (1-11)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyrate tert-butyl ester,

[0299] (1-12)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0300] (1-13)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0301] (1-14)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0302] (1-15)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyrate tert-butyl ester,

[0303] (1-16)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0304] (1-17)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0305] (1-18)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0306] (1-19) tert-butyl 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butyrate, and

[0307] (1-20)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate.

[0308]

[21] A method for producing a peptide compound in which a protecting group removable by a silylating agent has been removed, the method comprising the steps 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 protecting group from the starting peptide compound.

[0309] The silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger.

[0310] The starting peptide compound comprises a structure in which two amino acid residues are linked together, and the structure is represented by the following general formula (I):

[0311]

[0312] in

[0313] R1 is hydrogen, PG1, a natural amino acid residue, or an amino acid analog residue.

[0314] R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R4 or R2 and R 4′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups;

[0315] However, this does not include the following case: when R4 and R 4′ When each forms the heterocycle together with R2,

[0316] (a)R 4′It is hydrogen, and R4 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG2, N-PG3-indol-3-ylmethyl, 4-(PG2O)benzyl, PG2-O-methyl, 1-(PG2O)ethyl, 2-(PG2O)ethyl, PG2-OCO(CH2)-, PG2-OCO(CH2)2-, PG3N-n-butyl, -CON(R 14A (R) 14B ), -CH2-CON(R 14A (R) 14B ) and -(CH2)2CON(R 14A (R) 14B ),

[0317] (b) R4 and R 4′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0318] (c) R4 and R 4′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0319] R5 is a single bond or -C(R) 5A (R) 5B )-;

[0320] R 5A and R 5B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0321] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R6 and R7 or R6 and R 7′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups;

[0322] However, the following situation is excluded: when R7 and R 7′ When each forms the heterocycle together with R6,

[0323] (a)R 7′It is hydrogen, and R7 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG4, N-PG5-indol-3-ylmethyl, 4-(PG4O)benzyl, PG4-O-methyl, 1-(PG4O)ethyl, 2-(PG4O)ethyl, PG4-OCO(CH2)-, PG4-OCO(CH2)2-, PG5N-n-butyl, -CON(R 15A (R) 15B ), -CH2-CON(R 15A (R) 15B ) and -(CH2)2CON(R 15A (R) 15B ),

[0324] (b) R7 and R 7′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0325] (c)R7 and R 7′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0326] R8 is a single bond or -C(R 8A (R) 8B )-;

[0327] R 8A and R 8B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0328] R9 is a hydroxyl group, -O-PG6, a native amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES;

[0329] RES is a resin used in solid-phase synthesis;

[0330] R 14A and R 14B It is independently hydrogen or C1-C4 alkyl, or R 14A and R 14B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0331] R 15A and R 15B It is independently hydrogen or C1-C4 alkyl, or R 15A and R 15BTogether with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0332] PG1 is selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;

[0333] PG2 and PG4 are independently selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumenyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl;

[0334] PG3 and PG5 are independently selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl; and

[0335] PG6 is selected from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, and 2-(trimethylsilyl)ethyl.

[0336] The starting peptide compound optionally contains additional natural amino acid residues and / or amino acid analog residues, and

[0337] The starting peptide compound contains at least one protecting group that can be removed by a silylating agent.

[0338]

[22] A method for producing a peptide compound in which a solid-phase synthesis resin has been removed, the method comprising the steps 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 solid-phase synthesis resin.

[0339] The silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger.

[0340] The starting peptide compound comprises a structure in which two amino acid residues are linked together, and the structure is represented by the following general formula (I):

[0341]

[0342] in

[0343] R1 is hydrogen, PG1, a natural amino acid residue, or an amino acid analog residue.

[0344] R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R4 or R2 and R 4′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups;

[0345] However, this does not include the following case: when R4 and R 4′ When each forms the heterocycle together with R2,

[0346] (a)R 4′ It is hydrogen, and R4 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG2, N-PG3-indol-3-ylmethyl, 4-(PG2O)benzyl, PG2-O-methyl, 1-(PG2O)ethyl, 2-(PG2O)ethyl, PG2-OCO(CH2)-, PG2-OCO(CH2)2-, PG3N-n-butyl, -CON(R 14A (R) 14B ), -CH2-CON(R 14A (R) 14B ) and -(CH2)2CON(R 14A (R) 14B ),

[0347] (b) R4 and R 4′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0348] (c) R4 and R 4′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0349] R5 is a single bond or -C(R) 5A (R) 5B )-;

[0350] R SA and R 5B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0351] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R6 and R7 or R6 and R 7′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups;

[0352] However, the following situation is excluded: when R7 and R 7′ When each forms the heterocycle together with R6,

[0353] (a)R 7′ It is hydrogen, and R7 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG4, N-PG5-indol-3-ylmethyl, 4-(PG4O)benzyl, PG4-O-methyl, 1-(PG4O)ethyl, 2-(PG4O)ethyl, PG4-OCO(CH2)-, PG4-OCO(CH2)2-, PG5N-n-butyl, -CON(R 15A (R) 15B ), -CH2-CON(R 15A (R) 15B ) and -(CH2)2CON(R 15A (R) 15B ),

[0354] (b) R7 and R 7′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0355] (c)R7 and R 7′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0356] R8 is a single bond or -C(R 8A (R) 8B )-;

[0357] R 8A and R 8B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0358] R9 is a hydroxyl group, -O-PG6, a native amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES;

[0359] RES is a resin used in solid-phase synthesis;

[0360] R 14A and R 14B It is independently hydrogen or C1-C4 alkyl, or R 14A and R 14B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0361] R 15A and R 15B It is independently hydrogen or C1-C4 alkyl, or R 15A and R 15B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0362] PG1 is selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;

[0363] PG2 and PG4 are independently selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumenyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl;

[0364] PG3 and PG5 are independently selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl; and

[0365] PG6 is selected from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, and 2-(trimethylsilyl)ethyl.

[0366] The starting peptide compound optionally contains additional natural amino acid residues and / or amino acid analog residues, and

[0367] The starting peptide compound contains at least one amino acid residue that is bound to the solid-phase synthesis resin.

[0368]

[23] A method for producing a peptide or amide compound in which a protecting group removable by a silylating agent has been removed, the method comprising the steps of: contacting a starting peptide or amide compound comprising natural amino acid residues and / or amino acid analog residues with a silylating agent in a solvent, thereby removing the protecting group from the starting peptide or amide compound.

[0369] The silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger.

[0370] The initiating peptide or amide compound comprises an amino acid residue at the C-terminus or a structure in which two amino acid residues are linked together, wherein the amino acid residues or structure are represented by general formula (II):

[0371]

[0372] in

[0373] R 1′ It is a hydrogen atom, PG7, or a group represented by the following formula (III):

[0374]

[0375] * indicates a connection point;

[0376] R1 is hydrogen, PG1, a natural amino acid residue, or an amino acid analog residue.

[0377] R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R 10 Or R2 and R 10′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups;

[0378] However, the following situation is excluded: when R 10 and R 10′ When each forms the heterocycle together with R2,

[0379] (a)R 10′ It is hydrogen, and R 10 Choose from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG8, N-PG9-indol-3-ylmethyl, 4-(PG8O)benzyl, PG8-O-methyl, 1-(PG8O)ethyl, 2-(PG8O)ethyl, PG8-OCO(CH2)-, PG8-OCO(CH2)2-, PG9N-n-butyl, -CON(R 16A (R1) 6B ), -CH2-CON(R 16A (R) 16B ) and -(CH2)2CON(R 16A (R) 16B ),

[0380] (b)R 10 and R 10′ Independently, it may be an optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C4 alkyl, or

[0381] (c)R 10 and R 10′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0382] R 11 Is it a single bond or -C(R1)? 1A (R1) 1B )-;

[0383] R 11A and R 11B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0384] R 12 and R 12 Choose independently the following groups: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES;

[0385] RES is a resin used in solid-phase synthesis;

[0386] n is 0, 1, or 2;

[0387] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups;

[0388] R 13 It is a C1-C4 alkyl group or -(CH2) m CON(R 17A (R) 17B );

[0389] m is 0, 1, or 2;

[0390] R 16A and R 16B It is independently hydrogen or C1-C4 alkyl, or R 16A and R 16B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0391] R 17A and R 17B It is independently hydrogen or C1-C4 alkyl, or R 17A and R 17B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0392] PG1 and PG7 are independently selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;

[0393] PG8 is selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumene, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl.

[0394] PG9 is selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl; and

[0395] PG 10 Choose from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0396] The starting peptide compound optionally contains additional natural amino acid residues and / or amino acid analog residues, and

[0397] The starting peptide or amide compound contains at least one protecting group that can be removed by a silylating agent.

[0398]

[24] A method for producing a peptide or amide compound in which a solid-phase synthesis resin has been removed, the method comprising the steps of: contacting a starting peptide or amide compound containing natural amino acid residues and / or amino acid analog residues with a silylating agent in a solvent, thereby removing the starting peptide or amide compound from the solid-phase synthesis resin.

[0399] The silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger.

[0400] The initiating peptide or amide compound comprises an amino acid residue at the C-terminus or a structure in which two amino acid residues are linked together, wherein the amino acid residues or structure are represented by the following general formula (II):

[0401]

[0402] in

[0403] R 1′ It is a hydrogen atom, PG7, or a group represented by formula (III):

[0404]

[0405] * indicates a connection point;

[0406] R1 is hydrogen, PG1, a natural amino acid residue, or an amino acid analog residue.

[0407] R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R 10 Or R2 and R 10′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups;

[0408] However, the following situation is excluded: when R 10 and R 10′ When each forms the heterocycle together with R2,

[0409] (a)R 10′ It is hydrogen, and R 10 Choose from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG8, N-PG9-indol-3-ylmethyl, 4-(PG8O)benzyl, PG8-O-methyl, 1-(PG8O)ethyl, 2-(PG8O)ethyl, PG8-OCO(CH2)-, PG8-OCO(CH2)2-, PG9N-n-butyl, -CON(R 16A (R) 16B ), -CH2-CON(R 16A (R) 16B ) and -(CH2)2CON(R 16A (R) 16B ),

[0410] (b)R 10 and R 10′ Independently, it may be an optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C4 alkyl, or

[0411] (c)R 10 and R 10′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings;

[0412] R 11 Is it a single bond or -C(R)? 11A (R) 11B )-;

[0413] R 11A and R 11BIndependently selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl;

[0414] R 12 and R 12 Choose independently the following groups: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES;

[0415] RES is a resin used in solid-phase synthesis, wherein R 12 and R 12 At least one of them is -(CH2). n COO-RES or -(CH2) n CONH-RES;

[0416] RES is a resin used in solid-phase synthesis;

[0417] n is 0, 1, or 2;

[0418] R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups;

[0419] R 13 It is a C1-C4 alkyl group or -(CH2) m CON(R 17A (R) 17B );

[0420] m is 0, 1, or 2;

[0421] R 16A and R 16B It is independently hydrogen or C1-C4 alkyl, or R 16A and R 16B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0422] R 17A and R 17B It is independently hydrogen or C1-C4 alkyl, or R 17A and R 17B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms;

[0423] PG1 and PG7 are independently selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;

[0424] PG8 is selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumene, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl.

[0425] PG9 is selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl; and

[0426] PG 10 Choose from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0427] The starting peptide compound optionally contains additional natural amino acid residues and / or amino acid analog residues.

[0428]

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

[0429]

[26] A resin remover for removing peptide compounds from resins in solid-phase reactions, comprising a silyl compound or an acid and an electrophilic species scavenger.

[0430] [Invention Effects]

[0431] This invention is advantageous over known methods because it avoids the use of large amounts of Brønsted acids, which readily break amide bonds, reducing the reagent stoichiometry. The reagents used can be easily removed, and the reactions in subsequent steps remain unaffected. For example, 2,6-dimethylpyridine has a high boiling point (144°C) and therefore evaporates very little. Although 2,6-dimethylpyridine is a basic compound and can therefore be removed by acid, removing excess 2,6-dimethylpyridine under acidic conditions is inefficient when the target compound is a peptide, because the product is a compound with a basic amino group. The problem is that when the 2,6-dimethylpyridine used in the previous step remains in the condensation reaction (the reaction that elongates the amide bond) after the deprotection reaction, the condensing agent still reacts with the residual 2,6-dimethylpyridine, or the condensation reaction cannot proceed under the desired conditions due to the presence of a base during the condensation reaction. Conversely, for example, the silylamine of the present invention is more convenient to use than conventionally used 2,6-dimethylpyridine because the silylamine is hydrolyzed by water treatment after the reaction and converted into a highly water-soluble compound that can be easily removed, so that reagents derived from such silylamine can be easily removed by washing with aqueous solution without affecting peptide elongation in subsequent steps.

[0432] Among compounds used as electrophilic species scavengers, such as imine esters (Formula 2), amides (Formula 3), enone acetals (Formula 4), enone alkoxy hemiacetals (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), or carbamates (Formula 10), imine esters (Formula 2), amides (Formula 3), enone acetals (Formula 4), enone alkoxy hemiacetals (Formula 4), enol ethers (Formula 4), enol esters (Formula 4), or imines (Formula 5) can be converted into easily removable low-boiling-point compounds by mild hydrolysis after the reaction. Therefore, the excess reagent used in the reaction can be removed significantly more easily than excess 2,6-dimethylpyridine. Not only amide compounds (Formula 3) but also imine esters are converted into easily removable compounds by mild hydrolysis after the reaction, and therefore do not affect subsequent steps. The characteristic is that, in addition to the traditionally well-known tertiary amines, the amines used as electrophilic species scavengers can also be secondary amines, and such amines can achieve deprotection while inhibiting the destruction of amide bonds.

[0433] In one aspect of the invention, the N-Boc group of the peptide compound can be removed while suppressing damage to the main chain of the peptide compound. In another aspect of the invention, at the C-terminus of the peptide compound's main chain and in the side chain, the t-Bu group of the t-Bu ester can be removed, the benzyl group of the benzyl ester can be removed, and the triphenylmethyl group of the triphenylmethyl ester can be removed, while suppressing damage to the main chain of the peptide compound. In yet another aspect of the invention, the peptide compound can be removed from a resin bound to the C-terminus or side chain of the peptide compound's main chain while suppressing damage to the main chain of the peptide compound. [Detailed Implementation]

[0434] The following are the abbreviations used in this invention:

[0435] AcOEt: Ethyl acetate

[0436] Alloc: allyloxycarbonyl

[0437] Allyl: allyl

[0438] BEP: 2-bromo-1-ethylpyridinium tetrafluoroborate

[0439] Bn: Benzyl

[0440] Boc: tert-butoxycarbonyl

[0441] BSA: N,O-bis(trimethylsilyl)acetamide

[0442] BSTFA: N,O-bis(trimethylsilyl)trifluoroacetamide

[0443] Bu: Butyl

[0444] Cbz: Benzyloxycarbonyl

[0445] cHx: Cyclohexyl

[0446] Cl-CTC resin: 2-Chlorotriphenylmethyl chloride polymer resin

[0447] CPME: Cyclopentylmethyl ether

[0448] CTC: 2-Chlorotriphenylmethyl chloride

[0449] DBU: 2,3,4,6,7,8,9,10-octahydropyrimidino[1,2-a]aza

[0450] DdZ: 3,5-Dimethoxyphenylisopropoxycarbonyl

[0451] DIC: N,N′-Diisopropylcarbodiimide

[0452] DIPEA: N,N-Diisopropylethylamine

[0453] DMA: N,N-dimethylacetamide

[0454] DME: 1,2-Dimethoxyethane

[0455] DMF: N,N-dimethylformamide

[0456] DMSO: Dimethyl sulfoxide

[0457] DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0458] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

[0459] eq.: equivalent

[0460] EtOH: Ethanol

[0461] Et: Ethyl

[0462] Fmoc: 9-fluorenylmethoxycarbonyl

[0463] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0464] HMDS: Hexamethyldisilazane

[0465] HOAt: 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol

[0466] HOBt: 1,2,3-benzotriazol-1-ol

[0467] HPLC: High Performance Liquid Chromatography

[0468] i-PrOAc: Isopropyl acetate

[0469] i-Pr: Isopropyl

[0470] LCMS: Liquid Chromatography-Mass Spectrometry

[0471] MeCN: Acetonitrile

[0472] Me: Methyl

[0473] MS: Mass Spectrometry

[0474] MsOH: Methanesulfonic acid

[0475] MSTFA: N-Methyl-N-trimethylsilyltrifluoroacetamide

[0476] MTBE: Methyl tert-butyl ether

[0477] ND: Not measured

[0478] NMI: 1-Methylimidazole

[0479] NMP: N-methylpyrrolidone

[0480] oxyma: Ethyl cyano(hydroxyimino)

[0481] Pd / C: Palladium supported on carbon

[0482] Ph: Phenyl

[0483] pip: piperidinyl

[0484] prep.: preparative

[0485] T3P: Propylphosphonic anhydride

[0486] TBDPS: tert-butyldiphenylsilyl

[0487] TBS: tert-butyldimethylsilyl

[0488] t-Bu: tert-butyl

[0489] TEA: Triethylamine

[0490] Teoc: 2-(trimethylsilyl)ethoxycarbonyl

[0491] TES: Triethylsilyl

[0492] TFA: Trifluoroacetic acid

[0493] TFE: 2,2,2-trifluoroethanol

[0494] TfOH: Trifluoromethanesulfonic acid

[0495] Tf: Trifluoromethanesulfonyl group

[0496] THF: Tetrahydrofuran

[0497] 2-MeTHF: 2-Methyltetrahydrofuran

[0498] TIPS: Triisopropylsilyl

[0499] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0500] TMS: Trimethylsilyl

[0501] Tr: Triphenylmethyl

[0502] TTMS: Tris(trimethylsilyl)silyl

[0503] vol.: volume

[0504] Glycine

[0505] Ala: Alanine

[0506] Serine

[0507] Threonine

[0508] Valine

[0509] Leu: Leucine

[0510] Ile: Isoleucine

[0511] Phe: Phenylalanine

[0512] Tyr: Tyrosine

[0513] Trp: Tryptophan

[0514] His: Histidine

[0515] Glu: Glutamic acid

[0516] Aspartic acid (ASP)

[0517] Gln: glutamine

[0518] Asn: Asparagine

[0519] Cys: Cysteine

[0520] Met: Methionine

[0521] Lysine

[0522] Arginine

[0523] Pro: Proline

[0524] MeGly: N-Meglycine

[0525] MeAla: N-Me alanine

[0526] MeSer: N-Me serine

[0527] MeThr: N-Methreonine

[0528] MeVal: N-Mevaline

[0529] MeLeu: N-Meleucine

[0530] MeIle: N-Me isoleucine

[0531] MePhe: N-Me phenylalanine

[0532] MeTyr: N-Me tyrosine

[0533] Me%p: N-Me tryptophan

[0534] MeHis: N-Me histidine

[0535] MeGlu: N-Me glutamic acid

[0536] MeAsp: N-Me aspartic acid

[0537] MeGln: N-Me glutamine

[0538] MeAsn: N-Me asparagine

[0539] MeCys: N-Me cysteine

[0540] MeMet: N-Memethionine

[0541] MeLys: N-Me lysine

[0542] MeArg: N-Me arginine (definition of functional group)

[0543] As used herein, the term "alkyl" refers to a monovalent group derived by removing any hydrogen atom from an aliphatic hydrocarbon, and covers a subgroup of hydrocarbon groups or groups containing hydrogen and carbon atoms but without heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in their skeleton. "Alkyl" includes straight-chain or branched alkyl groups. Alkyl groups are those having 1 to 20 carbon atoms (C1-C2). 20 In the following text, "C" p -C q "" refers to an alkyl group having p to q carbon atoms, examples of which include C1-C6 alkyl and C1-C4 alkyl groups. Specific examples of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, and sec-butyl.

[0544] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic groups. Cycloalkyl groups may be partially unsaturated. Preferred examples of cycloalkyl groups include C3-C6 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0545] As used herein, the term "cycloalkylalkyl" refers to a group in which any hydrogen atom in the "alkyl" defined above is replaced by a "cycloalkyl" defined above. Preferred examples of cycloalkylalkyl groups include C 3-6 cycloalkyl-C 1-6 Alkyl and C 3-6 cycloalkyl-C1-4 Alkyl groups. Specific examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0546] As used herein, the term "alkoxy" refers to an oxygen group that incorporates an "alkyl" group as defined above. Preferred examples include C 1-4 Alkoxy and C 1-3 Alkoxy groups. Specific examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0547] As used herein, the term "alicyclic ring" refers to a monovalent non-aromatic hydrocarbon ring. The alicyclic ring may have unsaturated bonds in the ring and may be a polycyclic ring having two or more rings. The carbon atoms constituting the ring may be oxidized to form a carbonyl group. The number of atoms forming the alicyclic ring is preferably 3 to 7 (3 to 7-membered alicyclic ring). Specific examples of alicyclic rings include cycloalkyl rings, cycloalkenyl rings, and cycloalkynyl rings.

[0548] As used herein, the term "heterocycle" refers to a non-aromatic monovalent or divalent heterocycle that preferably comprises 1 to 5 heteroatoms in the cyclic atom. The heterocycle may have double and / or triple bonds in the ring, may have carbon atoms oxidized to form a carbonyl group in the ring, and may be a monocyclic, fused, or spirocyclic ring. The number of cyclic atoms is preferably 3 to 12 (3 to 12-membered heterocycle), more preferably 4 to 7 (4 to 7-membered heterocycle), and still more preferably 5 to 6 (5 to 6-membered heterocycle).

[0549] Specific examples of the heterocycles include azacyclic butane, piperazine, pyrrolidine, piperidine, morpholine, homomorpholine, (R)-hexahydropyrrolo[1,2-a]pyrazine, (S)-hexahydropyrrolo[1,2-a]pyrazine, 3-oxopiperazine, 2-oxopyrrolidine, azacyclic butane, 2-oxoimidazoline, oxacyclic butane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, tetrahydropyridine, thiomorpholine, pyrazolidine, imidazoline, and others. azole, isopropanone Alzolidine, Thiazolidine, Imidazolidine, Isothiazolidine, Thiadiazolidine azole ketones, benzo[a]pyridine Alkane, benzo[ azoline, dioxolane, dioxolane Alkane and tetrahydrothiaran.

[0550] As used herein, the term "aromatic heterocycle" refers to an aromatic monovalent or divalent heterocycle, preferably comprising 1 to 5 heteroatoms in the cyclic atom group. The aromatic heterocycle may be partially saturated and may be a monocyclic, fused (e.g., a bicyclic aromatic heterocycle fused with a benzene ring or a monocyclic aromatic heterocycle), or spirocyclic. The number of cyclic atoms is preferably 4 to 10 (4 to 10-membered aromatic bicyclic aromatic heterocycles).

[0551] Specific examples of aromatic heterocycles include furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, and isothiazole. azole, isotonic azole, Diazole, thiadiazole, triazole, tetraazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, benzofuran, benzothiophene, benzothiadiazole, benzothiazolium, benzo[] azole, benzo[ Diazole, benzimidazole, indole, isoindole, indazole, quinoline, isoquinoline, zoline, quinazoline, quinoxaline, indolezine, and imidazopyridine.

[0552] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring, with preferred examples including C6-C. 10 Aryl. Specific examples of aryl groups include phenyl and naphthyl (e.g., 1-naphthyl or 2-naphthyl).

[0553] As used herein, the term "heteroaryl" refers to a monovalent aromatic heterocyclic group preferably comprising 1 to 5 heteroatoms in the cyclic atom. The heteroaryl group may be partially saturated and may be monocyclic or fused (e.g., a bicyclic heteroaryl group in which the heteroaryl group is fused to a benzene ring or a monocyclic heteroaryl ring). The number of cyclic atoms is preferably 5 to 10 (5 to 10-membered heteroaryl groups).

[0554] Specific examples of heteroaryl groups include furanyl, thiophene, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, and isothiazolyl. azole group, iso azole group, Diazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzothiadiazolyl, benzothiazolyl, benzo[] azole, benzo[ Diazolyl, benzimidazolyl, indoleyl, isoindoleyl, azaindoleyl, indazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, benzo[m]dioxacyclopentenyl, indoleazinyl, and imidazopyridyl.

[0555] As used herein, the term "heterocyclic group" refers to a non-aromatic monovalent heterocyclic group that preferably contains 1 to 5 heteroatoms in the cyclic atom. The heterocyclic group may have double or triple bonds in the ring, may have a carbon atom that is oxidized to form a carbonyl group, and may be a monocyclic or fused ring. The number of cyclic atoms is preferably 3 to 10 (3 to 10-membered heterocyclic group).

[0556] Specific examples of heterocyclic groups include oxobutyranyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazine, pyrazolyl, imidazolinyl, and imidazolinyl. azolealkyl, isopropyl Alzolyl, thiazolyl, isothiazolyl, thiadiazolyl, azacyclobutyl azole ketones, benzo[a]pyridine Alkyl, benzo azole group, dioxolane group and dioxolane group alkyl.

[0557] As used herein, the term "arylalkyl" refers to a group in which any hydrogen atom in the "alkyl" as defined above is replaced by an "aryl" as defined above. Preferred examples of arylalkyl groups include C 6-10 Aryl-C 1-4 Alkyl and C 6-10 Aryl-C 1-3 Alkyl groups. Specific examples include benzyl, phenylmethyl, phenethyl (phenylethyl), and naphthylmethyl.

[0558] As used herein, the term "heteroarylalkyl" refers to a group in which any one of the hydrogen atoms in the "alkyl" defined above is replaced by a "heteroaryl" defined above. Preferred examples of heteroarylalkyl groups include 5- to 10-membered heteroaryl-C 1-3 Alkyl groups. Specific examples include pyrrolithic methyl, imidazolyl methyl, thienyl methyl, pyridyl methyl, pyrimidinyl methyl, quinolinyl methyl, and pyridyl ethyl.

[0559] As used herein, the term "substituted silyl" refers to a silyl group substituted with one to three substituents. The substituents may be the same or different. Such substituents are preferably C1-C6 alkyl, aryl, and tri-C1-C6 alkylsilyl. Specific examples include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and tris(trimethylsilyl)silyl.

[0560] When the modifier "optionally substituted" is provided herein, examples of such substituents include alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, substituted silyl, halogen atom, nitro, amino, hexylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, and formyl.

[0561] As used herein, the term "deprotection / removal of protecting groups" refers to the process of converting a protected functional group back to its original functional group by removing the protecting group.

[0562] As used herein, the term "resin removal" refers to the dissociation of a peptide compound from a solid-phase synthesis resin bound to it. The solid-phase synthesis resin is preferably bound to the C-terminal amino acid residue of the starting peptide compound.

[0563] In one embodiment, the present invention provides a method for producing a peptide drug comprising an amino acid analog that can be used in peptide pharmaceuticals. In other embodiments, the present invention provides a method for producing peptides comprising high-quality amino acid analogs for supplying pharmaceutical pharmaceutical substances. In yet another embodiment, the present invention provides novel amide compounds that can be used in the production of peptide compounds.

[0564] (Deprotection / Resin Removal Method)

[0565] In some aspects, the present invention relates to a method for producing a peptide compound, wherein a protecting group removable by a silylating agent has been removed, the method comprising the steps 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 protecting group from the starting peptide compound.

[0566] In some aspects, the present invention relates to a method for producing peptide compounds, wherein a resin for solid-phase synthesis has been removed, the method comprising the steps 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.

[0567] As used herein, the term "starting peptide compound" refers to a "peptide compound" that is a starting material to undergo the deprotection reaction and / or resin removal reaction of the present invention. The starting peptide compound preferably contains at least one N-substituted amino acid residue.

[0568] In this invention, "peptide compound" includes linear or cyclic peptide compounds comprising natural amino acid residues and / or amino acid analog residues. Cyclic peptide compounds are synonymous with "peptide compounds having a cyclic moiety".

[0569] As used in this invention, there is no particular limitation on the term "linear peptide compound," as long as they are peptide compounds formed by natural amino acids or amino acid analogs that form amide or ester bonds and do not have a cyclic moiety. Such linear peptide compounds can be formed from a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15, 20, 25, or 30 natural amino acids or amino acid analogs. The number of amino acids constituting the linear peptide compound 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.

[0570] As used in this invention, there is no particular limitation on "peptide compounds having a cyclic moiety", as long as they are peptide compounds formed from natural amino acids or amino acid analogs that form amide or ester bonds and have a cyclic moiety. Such cyclic moieties are preferably formed by covalent bonds such as amide bonds, carbon-carbon bonds, SS bonds, thioether bonds and triazole bonds (WO2013 / 100132, WO2012 / 026566, WO2012 / 033154, WO2012 / 074130, WO2015 / 030014, CombChem High Ihroughput Screen. 2010; 13: 75-87, Nature Chem. Bio. 2009, 5, 502, Nat ChemBiol. 2009, 5, 888-90, Bioconjugate Chem. 2007, 18, 469-476, ChemBioChem, 2009, 10, 787-798, Chemical Communications (Cambridge, United Kingdom) (2011), 47(36), 9946-9958). Compounds obtained by further chemical modification of such compounds are also included in the peptide compounds of the present invention. The peptide compounds of the present invention having a cyclic moiety may also have a linear moiety. There is no particular limitation on the number of amide or ester bonds (the number or length of natural amino acids or amino acid analogs), but when the peptide compound has a linear moiety, the combined cyclic and linear moiety preferably have 30 or fewer residues. For high metabolic stability, the total number of amino acids is more preferably 9 or more. In addition to the above, the cyclic moiety is preferably formed of 5 to 12, 6 to 12, or 7 to 12, still more preferably 7 to 11 or 8 to 11, and particularly preferably 9 to 11 (10 or 11) natural amino acids and amino acid analogs. The linear moiety preferably has 0 to 8, 0 to 7, 0 to 6, 0 to 5, or 0 to 4, and more preferably 0 to 3 amino acids and amino acid analogs. 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.

[0571] While there are no particular limitations on the types of native amino acid residues and amino acid analog residues that form the cyclic moiety of the peptide compounds of the present invention, the cyclic moiety is preferably formed from native amino acid residues and amino acid analog residues with functional groups having high metabolic stability. There are no particular limitations on the method of cyclizing the peptide compounds of the present invention having cyclic moieties, as long as the method can form such a cyclic moiety. Examples of cyclization methods include amide bond formation from carboxylic acids and amines; and carbon-carbon bond formation reactions using transition metals as catalysts, such as the Suzuki reaction, the Heck reaction, and the Sonogashira reaction. Therefore, the peptide compounds of the present invention contain at least one set of functional groups that allow such bond formation reactions prior to cyclization. In particular, for the purpose of metabolic stability, they preferably contain functional groups that form amide bonds through bond formation reactions.

[0572] Preferably, for example, the formed cyclic moiety does not include bonds containing heteroatoms that may be easily oxidized and that hinder metabolic stability. Examples of bonds generated by cyclization include amide bonds formed from reactive esters and amines, as well as bonds generated from Heck reaction products derived from carbon-carbon double bonds and aryl halides.

[0573] Under the condition of the total number of natural amino acids and amino acid analogs described above, or independently of this condition, the "peptide compound" of the present invention can be a linear or cyclic peptide comprising 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, particularly preferably 5, 6 or 7 N-substituted amino acids) and at least one N-unsubstituted amino acid. 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.

[0574] In some respects, the starting peptide compound contains 1 to 30 amino acid residues and is either linear or cyclic. The amino acid contained in the starting peptide compound can be a "natural amino acid" or an "amino acid analog." "Amino acid," "natural amino acid," and "amino acid analog" may be referred to herein as "amino acid residue," "natural amino acid residue," and "amino acid analog residue," respectively. The starting peptide compound can be formed from secondary amides, tertiary amides, or a mixture of secondary and tertiary amides.

[0575] The term "natural amino acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, or Pro.

[0576] There are no particular limitations on "amino acid analogs," and they include 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 differ from those of natural amino acids: e.g., non-natural α-amino acids, β-amino acids, and γ-amino acids). α-amino acids can be D-amino acids or α,α-dialkyl amino acids. In a similar manner to α-amino acids, β-amino acids and γ-amino acids are also allowed to have arbitrary configurations. Examples of N-substituted amino acids include amino acids whose amino groups are substituted with arbitrary substituents. Examples of such substituents include, but are not particularly limited to, alkyl, aryl, and aralkyl groups. N-substituted amino acids include N-alkyl amino acids, N-aryl amino acids, and N-methyl amino acids. There are no particular limitations on the choice of amino acid side chains, but they can be freely selected from, for example, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and cycloalkyl groups, except for the hydrogen atom. In such groups, one or more non-adjacent methylene groups are optionally substituted with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO2-). Each group may have one, two, or more substituents. For example, the substituents are freely selected from any functional group, including halogen atoms, N atoms, O atoms, S atoms, B atoms, Si atoms, or P atoms (i.e., optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and cycloalkyl groups).

[0577] As used herein, the “natural amino acids” and “amino acid analogs” constituting the peptide compounds include all isotopes corresponding to each amino acid. An isotope of a “natural amino acid” or “amino acid analog” refers to one having at least one atom replaced by an atom of the same number (number of protons) but a different mass number (total number of protons and neutrons). Examples of isotopes contained in the “natural amino acids” or “amino acid analogs” constituting the peptide compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising… 2 H and 3 H; 1 3C and 14 C; 15 N; 17 O and 18 O; 32 P; 35 S; 18 F; and 36 Cl.

[0578] As used herein, examples of substituents containing a halogen atom include halogen-substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl groups. More specific examples include fluoroalkyl, difluoroalkyl, and trifluoroalkyl groups.

[0579] Substituents containing an O atom include groups such as hydroxyl (-OH), oxy (-OR), carbonyl (-C==OR), carboxyl (-CO2H), 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-SO2-R), aminosulfonyl (-SO2-NHR), aminosulfonylamino (-NH-SO2-NHR), thiocarboxyl (-C(=O)-SH), and carboxylcarbonyl (-C(=O)-CO2H).

[0580] Examples of oxy groups (-OR) include alkoxy, cycloalkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and arylalkoxy. Alkoxy groups are preferably C1-C4 alkoxy and C1-C2 alkoxy groups, and particularly preferably methoxy or ethoxy groups.

[0581] Examples of carbonyl groups (-C=OR) include formyl (-C==OH), alkyl carbonyl, cycloalkyl carbonyl, alkenyl carbonyl, alkynyl carbonyl, aryl carbonyl, heteroaryl carbonyl, and aralkyl carbonyl.

[0582] Examples of oxycarbonyl groups (-C==O-OR) include alkoxycarbonyl, cycloalkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and arylalkoxycarbonyl.

[0583] Examples of carbonyloxy groups (-OC == OR) include alkyl carbonyloxy, cycloalkyl carbonyloxy, alkenyl carbonyloxy, alkynyl carbonyloxy, aryl carbonyloxy, heteroaryl carbonyloxy, and aralkyl carbonyloxy.

[0584] Examples of thiocarbonyl groups (-C==O-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenethiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and arylalkylthiocarbonyl.

[0585] Examples of carbonyl thio groups (-SC=OR) include alkyl carbonyl thio, cycloalkyl carbonyl thio, alkenyl carbonyl thio, alkynyl carbonyl thio, aryl carbonyl thio, heteroaryl carbonyl thio, and aralkyl carbonyl thio.

[0586] Examples of aminocarbonyl groups (-C=O-NHR) include alkylaminocarbonyl groups (examples of which include C1-C6 or C1-C4 alkylaminocarbonyl groups, particularly ethylaminocarbonyl and methylaminocarbonyl), cycloalkylaminocarbonyl groups, alkenylaminocarbonyl groups, alkynylaminocarbonyl groups, arylaminocarbonyl groups, heteroarylaminocarbonyl groups, and aralkylaminocarbonyl groups. Further examples include compounds in which the H atom bonded to the N atom in -C=O-NHR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0587] Examples of carbonylamino (-NH-C=OR) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. Further examples include compounds in which the H atom bonded to the N atom in -NH-C=OR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0588] Examples of oxycarbonylamino (-NH-C==O-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenoxycarbonylamino, alkynoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and arylalkoxycarbonylamino. Further examples include compounds in which the H atom bonded to the N atom in -NH-C==O-OR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or arylalkyl group.

[0589] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. Further examples include compounds in which the H atom bonded to the N atom in -NH-SO2-R is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0590] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. Further examples include compounds in which the H atom bonded to the N atom in -SO2-NHR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0591] Examples of aminosulfonylamino (-NH-SO2-NHR) include alkylaminosulfonylamino, cycloalkylaminosulfonylamino, alkenylaminosulfonylamino, alkynylaminosulfonylamino, arylaminosulfonylamino, heteroarylaminosulfonylamino, and aralkylaminosulfonylamino. In -NH-SO2-NHR, the two H atoms bonded to the N atom can be further substituted independently with substituents selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents can form a ring.

[0592] Substituents containing an S atom include groups such as thiohydroxy (-SH), thio (-SR), sulfinyl (-S=OR), sulfonyl (-SO2-R), and sulfonyl (-SO3H).

[0593] Examples of thio groups (-SR) include alkylthio, cycloalkylthio, olefin thio, alkynylthio, aryl thio, heteroaryl thio, and arylalkylthio.

[0594] Examples of sulfonyl groups (-SO2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

[0595] Substituents containing an N atom include azido (-N3, also known as "azido group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R; also known as monosubstituted amino), tertiary amino (-NR(R′); also known as disubstituted amino), amido (-C(=NH)-NH2), substituted amido (-C(=NR)-NR′R″), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR″′)-NR′R″), aminocarbonylamino (-NR-CO-NR′R″), pyridyl, piperidinyl, morpholinyl, and aziridine.

[0596] Examples of secondary amino groups (-NH-R; monosubstituted amino groups) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0597] Examples of tertiary amino groups (-NR(R′); disubstituted amino groups) include amino groups having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, such as alkyl (aralkyl)amino groups, wherein any two such substituents can form a ring. Specific examples include dialkylamino groups, particularly C1-C6 dialkylamino groups, C1-C4 dialkylamino groups, dimethylamino groups, and diethylamino groups. As used herein, the term "C" is used in conjunction with the terminology used in the study of amino groups. p -C q Dialkylamino" refers to a compound formed by two C atoms. p -Cq Alkyl-substituted amino groups, wherein the two Cs p -C q Alkyl groups can be the same or different.

[0598] Examples of substituted amidoyl groups (-C(=NR)-NR′R″) include those 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 groups, such as alkyl(aralkyl)(aryl)amidinyl.

[0599] Examples of substituted guanidino groups (-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 groups, or groups in which these substituents form a ring.

[0600] Examples of aminocarbonylamino (-NR-CO-NR′R″) include groups in which R, R′ and R″ are each independently selected from hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and aralkyl groups, or groups in which these substituents form a ring.

[0601] In some aspects, the starting peptide compound to be deprotected and / or resin-removed contains at least one N-substituted amino acid residue. Examples of the number of N-substituted amino acid residues contained in the starting peptide compound include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30. The number of N-substituted amino acid residues is preferably in the range of 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 together in the starting peptide compound.

[0602] In some aspects, when the peptide compound of the present invention is composed of 2n amino acids, more than half of the amino acids constituting the peptide compound (e.g., more than n amino acids (where n is an integer), or more than n+1 amino acids when the peptide compound is composed of 2n+1 amino acids) are preferably N-substituted amino acids.

[0603] As used herein, the term "N-substituted" in N-substituted amino acids means, but is not limited to, replacing the hydrogen atom attached to the N atom with a methyl, ethyl, propyl, butyl, or hexyl group. Preferred N-substituted amino acids include those in which the amino group in the native amino acid is N-methylated, N-ethylated, N-propylated, N-butylated, or N-pentylated. Such amino acids are referred to as N-methyl amino acids, N-ethyl amino acids, N-propyl amino acids, N-butyl amino acids, and N-pentyl amino acids.

[0604] When the starting peptide compound contains at least one N-substituted amino acid residue (e.g., when the starting peptide compound contains one or more partial structures in which the N-substituted amino acid residue is linked to an adjacent amino acid residue, more specifically, one or more partial structures each containing at least two amino acid residues, represented by general formula (I) and / or (II)), conventional deprotection / resin removal methods readily cause backbone disruption, such as amide bond breakage or peptide backbone rearrangement. Even in the case of such starting peptide compounds, the method of the present invention can efficiently remove the protecting group of interest in high yield and purity without involving backbone disruption, and can efficiently dissociate the peptide compound from the resin in a solid-phase reactive manner with high yield and purity.

[0605] In some embodiments, the starting peptide compound of the present invention may not contain N-substituted amino acid residues or may not contain a portion of the structure in which N-substituted amino acid residues are linked to adjacent amino acid residues.

[0606] In some respects, the starting peptide compound to be deprotected and / or resin-removed comprises at least one partial structure in which at least two amino acid residues are linked together, wherein the structure is expressed by the following general formula (I).

[0607]

[0608] In formula (I), R1 is hydrogen, PG1, a natural amino acid residue or an amino acid analog residue.

[0609] When the structure represented by formula (I) is located at the N-terminus of the starting peptide compound, R1 is preferably hydrogen or PG1. On the other hand, when the structure represented by formula (I) is located at a position different from the N-terminus of the starting peptide compound, R1 is preferably a native amino acid residue or an amino acid analog residue.

[0610] In formula (I), R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R4 or R2 and R 4′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups.

[0611] In some respects, when R2 is a C1-C6 alkyl group, the C1-C6 alkyl group is preferably methyl, ethyl, propyl, butyl, or pentyl.

[0612] In some respects, when R2 and R4 or R2 and R 4′ When R2 and R4 form a 3- to 7-membered heterocycle, optionally substituted with a hydroxyl or C1-C4 alkoxy group, together with the nitrogen and carbon atoms to which they are attached, the formed 3- to 7-membered heterocycle is preferably an azo-butane ring, a pyrrolidine ring, or a piperidine ring. When R2 and R4 form a heterocycle together, R...4′ It is hydrogen, and when R2 and R 4′ When the heterocycle is formed together, R4 is hydrogen.

[0613] In equation (I), but excluding the following cases: when R2 and R4 or R2 and R 4′ When they form a heterocyclic ring together,

[0614] (a)R 4′ It is hydrogen, and R4 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG2, N-PG3-indol-3-ylmethyl, 4-(PG2O)benzyl, PG2-O-methyl (i.e., -CH2-O-PG2), 1-(PG2O)ethyl, 2-(PG2O)ethyl, PG2-OCO(CH2)-, PG2-OCO(CH2)2-, PG3N-n-butyl, -CON(R 14A (R) 14B ), -CH2-CON(R 14A (R) 14B ) and -(CH2)2CON(R 14A (R) 14B ),

[0615] (b) R4 and R 4′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0616] (c) R4 and R 4′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings.

[0617] R4 and R 4′ Preferred combinations include hydrogen atoms and hydrogen atoms, methyl and hydrogen atoms, ethyl and hydrogen atoms, isopropyl and hydrogen atoms, isobutyl and hydrogen atoms, cyclopropyl and hydrogen atoms, cyclopropylmethyl and hydrogen atoms, cyclopentyl and hydrogen atoms, cyclohexyl and hydrogen atoms, optionally substituted phenyl and hydrogen atoms, optionally substituted phenylmethyl and hydrogen atoms, optionally substituted phenylethyl and hydrogen atoms, 2-(methylthio)ethyl and hydrogen atoms, -CH2SPG2 and hydrogen atoms, N-PG3-indol-3-ylmethyl and hydrogen atoms, 4-(PG2O)benzyl and hydrogen atoms, PG2-O-methyl and hydrogen atoms, 1-(PG2O)ethyl and hydrogen atoms, 2-(PG2O)ethyl and hydrogen atoms, PG2-OCO(CH2)- and hydrogen atoms, PG2-OCO(CH2)2- and hydrogen atoms, PG3N-n-butyl and hydrogen atoms, -CON(R 14A (R) 14B) and hydrogen atoms, -CH2-CON(R 14A (R) 14B ) and hydrogen atoms, -(CH2)2CON(R 14A (R) 14B ) and hydrogen atoms, methyl and methyl groups, and methyl and ethyl groups. When R4 and R 4′ When the carbon atoms to which they are attached form a 3- to 7-membered alicyclic ring, the alicyclic ring is preferably a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring.

[0618] In equation (I), R5 is a single bond or -C(R 5A (R) 5B )-;and

[0619] R SA and R 5B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl.

[0620] R5 is preferably a single bond or -C(R) 5A (R) 5B )-, where R SA and R 5B The combinations are hydrogen atoms and hydrogen atoms, methyl and hydrogen atoms, ethyl and hydrogen atoms, isopropyl and hydrogen atoms, isobutyl and hydrogen atoms, cyclopropyl and hydrogen atoms, cyclopropylmethyl and hydrogen atoms, optionally substituted phenyl and hydrogen atoms, optionally substituted phenylmethyl and hydrogen atoms, optionally substituted phenylethyl and hydrogen atoms, methyl and methyl, or methyl and ethyl.

[0621] In formula (I), R6 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R6 and R7 or R6 and R 7′ Together with the nitrogen and carbon atoms to which they are attached, they form 3 to 7-membered heterocycles that are optionally substituted with hydroxyl or C1-C4 alkoxy groups.

[0622] In some respects, when R6 is a C1-C6 alkyl group, the C1-C6 alkyl group is preferably methyl, ethyl, propyl, butyl, or pentyl.

[0623] In some respects, when R6 and R7 or R6 and R 7′ When R6 and R7 together form a 3- to 7-membered heterocycle optionally substituted with a hydroxyl group or a C1-C4 alkoxy group, the formed 3- to 7-membered heterocycle is preferably an azo-butane ring, a pyrrolidine ring, or a piperidine ring. When R6 and R7 together form the heterocycle, R... 7′ It is hydrogen, and when R6 and R 7′ When the heterocycle is formed together, R7 is hydrogen.

[0624] In formula (I), preferably, one or both of R2 and R6 are different from hydrogen, and more preferably, one or both of R2 and R6 are C1-C6 alkyl groups.

[0625] In equation (I), but excluding the following cases: when R6 and R7 or R6 and R 7′ When they form a heterocyclic ring together,

[0626] (a)R 7′ It is hydrogen, and R7 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG4, N-PG5-indol-3-ylmethyl, 4-(PG4O)benzyl, PG4-O-methyl (i.e., -CH2-O-PG4), 1-(PG4O)ethyl, 2-(PG4O)ethyl, PG4-OCO(CH2)-, PG4-OCO(CH2)2-, PG5N-n-butyl, -CON(R 15A (R) 15B ), -CH2-CON(R 15A (R) 15B ) and -(CH2)2CON(R 15A (R) 15B ),

[0627] (b) R7 and R 7′ Independently, it is an optional substituted C1-C6 alkyl group, or

[0628] (c)R7 and R 7′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings.

[0629] R7 and R 7′ Preferred combinations include hydrogen atoms and hydrogen atoms, methyl and hydrogen atoms, ethyl and hydrogen atoms, isopropyl and hydrogen atoms, isobutyl and hydrogen atoms, cyclopropyl and hydrogen atoms, cyclopropylmethyl and hydrogen atoms, cyclopentyl and hydrogen atoms, cyclohexyl and hydrogen atoms, optionally substituted phenyl and hydrogen atoms, optionally substituted phenylmethyl and hydrogen atoms, optionally substituted phenylethyl and hydrogen atoms, 2-(methylthio)ethyl and hydrogen atoms, -CH2SPG4 and hydrogen atoms, N-PG5-indol-3-ylmethyl and hydrogen atoms, 4-(PG4O)benzyl and hydrogen atoms, PG4-O-methyl and hydrogen atoms, 1-(PG4O)ethyl and hydrogen atoms, 2-(PG4O)ethyl and hydrogen atoms, PG4-OCO(CH2)- and hydrogen atoms, PG4-OCO(CH2)2- and hydrogen atoms, PG5N-n-butyl and hydrogen atoms, -CON(R 15A (R)15B ) and hydrogen atoms, -CH2-CON(R 15A (R) 15B ) and hydrogen atoms, -(CH2)2CON(R 15A (R) 15B ) and hydrogen atoms, methyl and methyl groups, and methyl and ethyl groups. When R7 and R 7′ When the carbon atoms to which they are attached form a 3- to 7-membered alicyclic ring, the alicyclic ring is preferably a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring.

[0630] In equation (I), R8 is a single bond or -C(R 8A (R) 8B )-;and

[0631] R 8A and R 8B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl.

[0632] R8 is preferably a single bond or -C(R) 8A (R) 8B )-, where R 8A and R 8B The combinations are hydrogen atom and hydrogen atom, methyl and hydrogen atom, ethyl and hydrogen atom, isopropyl and hydrogen atom, isobutyl and hydrogen atom, cyclopropyl and hydrogen atom, cyclopropylmethyl and hydrogen atom, optionally substituted phenyl and hydrogen atom, optionally substituted phenylmethyl and hydrogen atom, optionally substituted phenylethyl and hydrogen atom, methyl and methyl or methyl and ethyl.

[0633] In formula (I), R9 is a hydroxyl group, -O-PG6, a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES, where RES is a resin for solid-phase synthesis.

[0634] When the structure represented by formula (I) is located at the C-terminus of the starting peptide compound, R9 is preferably a hydroxyl group, -O-PG6, -O-RE, or -NH-RES. On the other hand, when the structure represented by formula (I) is located at a position different from the C-terminus of the starting peptide compound, R9 is preferably a natural amino acid residue or an amino acid analog residue.

[0635] In equation (I), R 14A and R 14B It is independently hydrogen or C1-C4 alkyl, or R 14A and R 14B Together with the nitrogen atoms they are attached to, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms. When R14A and / or R 14B When it is a C1-C4 alkyl group, the C1-C4 alkyl group is preferably methyl, ethyl, or propyl. When R... 14A and R 14B When the nitrogen atoms to which they are attached form a 4- to 8-membered ring that optionally contains one or more additional heteroatoms, the 4- to 8-membered ring is preferably an aza-butane ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0636] In equation (I), R 15A and R 15B It is independently hydrogen or C1-C4 alkyl, or R 15A and R 15B Together with the nitrogen atoms they are attached to, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms. When R 15A and / or R 15B When it is a C1-C4 alkyl group, the C1-C4 alkyl group is preferably methyl, ethyl, or propyl. When R... 15A and R 15B When the nitrogen atoms to which they are attached form a 4- to 8-membered ring that optionally contains one or more additional heteroatoms, the 4- to 8-membered ring is preferably an aza-butane ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0637] In formula (I), PG1 is selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc and trifluoroacetyl.

[0638] PG1 is preferably Fmoc, Boc or Cbz.

[0639] In formula (I), PG2 and PG4 are independently selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumene, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0640] PG2 and PG4 are preferably methyl, allyl, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumene, THP, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl or optionally substituted heteroaryl-C1-C4 alkyl.

[0641] In formula (I), PG3 and PG5 are independently selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl.

[0642] PG3 and PG5 are preferably Fmoc, Boc, Cbz, t-Bu or triphenylmethyl.

[0643] In formula (I), PG6 is selected from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl and 2-(trimethylsilyl)ethyl.

[0644] PG6 is preferably t-Bu, triphenylmethyl, cumene, benzyl, methyl or allyl.

[0645] Structures represented by general formula (I) in which at least two amino acid residues are linked together include many such structures that are easily broken or destroyed when using known deprotection or resin removal conditions. By using the reaction conditions of the present invention, the protecting group of interest or the resin used in solid-phase synthesis can be selectively and effectively removed without such breakage or destruction.

[0646] In some respects, structures represented by general formula (I) in which at least two amino acid residues are linked to each other include those structures in which one N-substituted amino acid is linked to an N-unsubstituted amino acid, and those structures in which two N-substituted amino acids are linked to each other. Specific examples of such amino acid residues include structures represented by general formula (I′) in which two amino acid residues are linked to each other, where R5 and R8 in general formula (I) are single bonds.

[0647]

[0648] Each group in formula (I′) can be the same as that in formula (I) above.

[0649] In some respects, in formula (I'), R1 is preferably hydrogen, PG1, a natural amino acid residue or an amino acid analog residue.

[0650] In some respects, in formula (I'), preferably, one or both of R2 and R6 are different from hydrogen, and more preferably, one or both of R2 and R6 are C1-C6 alkyl groups.

[0651] In some respects, in formula (I'), R2 and R6 can be independently C1-C6 alkyl groups, preferably methyl, ethyl, propyl, butyl or pentyl.

[0652] In some respects, in equation (I'), R2 and R4 or R2 and R 4′ Or R6 and R7 or R6 and R 7′ Each can independently form a 3- to 7-membered heterocycle with the nitrogen and carbon atoms to which they are attached, optionally substituted with hydroxyl or C1-C4 alkoxy groups. When R2 and R4 form the heterocycle together, R... 4′It is hydrogen, and when R2 and R 4′ When R4 forms the heterocycle together, it is hydrogen. When R6 and R7 form the heterocycle together, R... 7′ It is hydrogen, and when R6 and R 7′ When the heterocycle is formed together, R7 is hydrogen.

[0653] In some respects, in formula (I'), R9 is a hydroxyl group, -O-PG6, a natural amino acid residue, an amino acid analog residue, -O-RES, or -NH-RES, where RES is a resin for solid-phase synthesis.

[0654] In some respects, in equation (I'), R4 and R 4′ Or R7 and R 7′ They can each be C1-C6 alkyl groups, or R4 and R 4′ Or R7 and R 7′ They can form 3 to 7-membered alicyclic rings together with the carbon atoms they are attached to.

[0655] In some respects, in equation (I'), R 4′ It can be hydrogen, and R4 can be selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG2, N-PG3-indol-3-ylmethyl, 4-(PG2O)benzyl, PG2-O-methyl, 1-(PG2O)ethyl, 2-(PG2O)ethyl, PG2-OCO(CH2)-, PG2-OCO(CH2)2-, PG3N-n-butyl, -CON(R 14A (R) 14B ), -CH2-CON(R 14A (R) 14B ) and -(CH2)2CON(R 14A (R) 14B ).

[0656] In some respects, in equation (I'), R 7′ It can be hydrogen, and R7 can be selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG4, N-PG5-indol-3-ylmethyl, 4-(PG4O)benzyl, PG4-O-methyl, 1-(PG4O)ethyl, 2-(PG4O)ethyl, PG4-OCO(CH2)-, PG4-OCO(CH2)2-, PG5N-n-butyl, -CON(R15A (R) 15B ), -CH2-CON(R 15A (R) 15B ) and -(CH2)2CON(R 15A (R) 15B ).

[0657] More preferably, in the structure represented by the general formula (I′), R1 is hydrogen, PG1, a natural amino acid residue or an amino acid analog residue;

[0658] R2 and R6 are methyl or ethyl; and / or

[0659] R2 and R4 or R2 and R 4′ Or R6 and R7 or R6 and R 7′ Each of them independently forms a 4- to 6-membered heterocycle with the nitrogen and carbon atoms to which they are attached, optionally substituted with hydroxyl or C1-C4 alkoxy groups. When R2 and R4 form the heterocycle together, R 4′ It is hydrogen, and when R2 and R 4′ When R4 forms the heterocycle together, it is hydrogen. When R6 and R7 form the heterocycle together, R... 7′ It is hydrogen, and when R6 and R 7′ When the heterocycle is formed together, R7 is hydrogen.

[0660] R9 can be -O-PG6, a natural amino acid residue, an amino acid analog residue, or -O-RES, where RES is a solid-phase synthesized CTC, Wang, or SASRIN resin.

[0661] R4 and R 4′ Or R7 and R 7′ They can each be methyl or ethyl independently, and R4 and R 4′ Or R7 and R 7′ They can form 5- or 6-membered alicyclic rings together with the nitrogen and carbon atoms they are attached to.

[0662] When R 4′ and R 7′ R4 and R7 can be hydrogen independently, or alkyl groups selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, and sec-butyl, or optionally substituted phenylmethyl, optionally substituted phenylethyl, benzyloxymethyl, 1-benzyloxyethyl, 2-benzyloxyethyl, tert-butoxycarbonylmethyl, methoxycarbonylmethyl, tert-butoxycarbonylethyl, methoxycarbonylethyl, tert-butoxycarbamoylbutyl, N,N-dimethylaminocarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, N,N-dimethylaminocarbonylmethyl, piperidinylcarbonylmethyl, pyrrolidinylcarbonylmethyl, N,N-dimethylaminocarbonylethyl, piperidinylcarbonylethyl, or pyrrolidinylcarbonylethyl.

[0663] In some respects, in addition to one or more structures represented by general formula (I), the starting peptide compound may also contain one or more additional natural amino acid residues and / or amino acid analog residues.

[0664] In some respects, 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 a structure represented by general formula (I) or may be contained in an amino acid residue that is different from the structure represented by general formula (I).

[0665] In some aspects, the starting peptide compound comprises at least one solid-phase synthesis resin that can be removed by the method of the present invention. Such a resin may be contained in a structure represented by general formula (I), or may be contained in amino acid residues that are different from the structure represented by general formula (I).

[0666] In some respects, solid-phase synthesis uses resins to bind to carboxyl groups contained in the C-terminal amino acid residues of the starting peptide compound.

[0667] In some respects, the starting peptide compound to be deprotected and / or resin-removed comprises a structure in which at least two amino acid residues at the C-terminus are linked to each other, wherein the structure is represented by the following general formula (II).

[0668]

[0669] R 1′ It is a group represented by formula (III):

[0670]

[0671] The asterisk (*) indicates a connection point.

[0672] In formula (III), R1 is hydrogen, PG1, a natural amino acid residue or an amino acid analog residue.

[0673] In formula (III), R2 is selected from the group consisting of hydrogen and C1-C6 alkyl groups, or R2 and R 10 Or R2 and R 10′ Together with the nitrogen and carbon atoms to which they are attached, they form 3- to 7-membered heterocycles optionally substituted with hydroxyl or C1-C4 alkoxy groups. When R2 and R 10 When the heterocycle is formed together, R 10′ It is hydrogen, or when R2 and R 10′ When the heterocycle is formed together, R 10 It is hydrogen.

[0674] In some respects, when R2 is a C1-C6 alkyl group, the C1-C6 alkyl group is preferably methyl, ethyl, propyl, butyl, or pentyl.

[0675] In some respects, when R2 and R 10 Or R2 and R 10 When a 3- to 7-membered heterocycle is formed together with the nitrogen and carbon atoms to which they are attached, optionally substituted with hydroxyl or C1-C4 alkoxy groups, the 3- to 7-membered heterocycle formed is preferably an azo-butane ring, a pyrrolidine ring, or a piperidine ring.

[0676] In equation (III), but excluding the following case: when R2 and R 10 Or R2 and R 10′ When the heterocycle is formed together,

[0677] (a)R 10′ It is hydrogen, and R 10 Choose from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG8, N-PG9-indol-3-ylmethyl, 4-(PG8O)benzyl, PG8-O-methyl (i.e., -CH2-O-PG8), 1-(PG8O)ethyl, 2-(PG8O)ethyl, PG8-OCO(CH2)-, PG8-OCO(CH2)2-, PG9N-n-butyl, -CON(R 16A (R) 16B ), -CH2-CON(R 16A (R) 16B ) and -(CH2)2CON(R 16A (R) 16B ),

[0678] (b)R 10 and R 10′ Independently, it may be an optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C4 alkyl, or

[0679] (c)R 10 and R 10′ Together with the carbon atoms they are attached to, they form 3 to 7-membered alicyclic rings.

[0680] R 10 and R 10′Preferred combinations include hydrogen atoms and hydrogen atoms, methyl and hydrogen atoms, ethyl and hydrogen atoms, isopropyl and hydrogen atoms, isobutyl and hydrogen atoms, cyclopropyl and hydrogen atoms, cyclopropylmethyl and hydrogen atoms, optionally substituted phenyl and hydrogen atoms, optionally substituted phenylmethyl and hydrogen atoms, optionally substituted phenylethyl and hydrogen atoms, 2-(methylthio)ethyl and hydrogen atoms, -CH2SPG8 and hydrogen atoms, N-PG9-indol-3-ylmethyl and hydrogen atoms, 4-(PG8O)benzyl and hydrogen atoms, PG8-O-methyl and hydrogen atoms, 1-(PG8O)ethyl and hydrogen atoms, 2-(PG8O)ethyl and hydrogen atoms, PG8-OCO(CH2)- and hydrogen atoms, PG8-OCO(CH2)2- and hydrogen atoms, PG9N-n-butyl and hydrogen atoms, -CON(R 16A (R) 16B ) and hydrogen atoms, -CH2-CON(R 16A (R) 16B ) and hydrogen atoms, -(CH2)2CON(R 16A (R) 16B ) and hydrogen atoms, methyl and methyl groups, or methyl and ethyl groups. When R 10 and R 10′ When the carbon atoms to which they are attached form a 3- to 7-membered alicyclic ring, the alicyclic ring is preferably a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring.

[0681] In equation (III), R 11 Is it a single bond or -C(R)? 11A (R) 11B )-;and

[0682] R 11A and R 11B Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C4 alkyl and optionally substituted heteroaryl-C1-C4 alkyl.

[0683] R 11 The preferred option is a single bond or -C(R) 11A (R) 11B )-, where R 11A and R 11B The combinations are hydrogen atoms and hydrogen atoms, methyl and hydrogen atoms, ethyl and hydrogen atoms, isopropyl and hydrogen atoms, isobutyl and hydrogen atoms, cyclopropyl and hydrogen atoms, cyclopropylmethyl and hydrogen atoms, optionally substituted phenyl and hydrogen atoms, optionally substituted phenylmethyl and hydrogen atoms, optionally substituted phenylethyl and hydrogen atoms, methyl and methyl, or methyl and ethyl.

[0684] In equation (II), R 12 and R 12Choose independently the following groups: hydrogen, PG 10 -O-methyl (i.e., -CH2-O-PG) 10 ), -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES. RES is a resin for solid-phase synthesis, and n is 0, 1, or 2.

[0685] In some aspects, when used in the resin removal method of the present invention, R 12 and R 12 Any of the preferred choices in ′ is selected from -(CH2). n COO-RES and -(CH2) n CONH-RES.

[0686] In formula (II), R6 is selected from the group consisting of hydrogen and C1-C6 alkyl. In some aspects, when R6 is a C1-C6 alkyl, the C1-C6 alkyl is preferably methyl, ethyl, propyl, butyl, or pentyl.

[0687] In formulas (II) and (III), preferably, one or both of R2 and R6 are different from hydrogen, and more preferably, one or both of R2 and R6 are C1-C6 alkyl groups.

[0688] In equation (II), R 13 It is a C1-C4 alkyl group or -(CH2) m CON(R 17A (R) 17B ), where m is 0, 1, or 2, and R 17A and R 17B It is independently hydrogen or C1-C4 alkyl, or R 17A and R 17B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms.

[0689] In some respects, when R 13 When it is a C1-C4 alkyl group, the C1-C4 alkyl group is preferably methyl or ethyl.

[0690] In some respects, when R 17A and R 17B When a 4- to 8-membered ring is formed together with the nitrogen atoms to which they are attached, optionally containing one or more additional heteroatoms, the formed ring is preferably an aza-butane ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0691] In equation (II), R16A and R 16B It is independently hydrogen or C1-C4 alkyl, or R 16A and R 16B Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered rings that optionally contain one or more additional heteroatoms.

[0692] When R 16A and R 16B When it is a C1-C4 alkyl group, the C1-C4 alkyl group is preferably methyl, ethyl or propyl.

[0693] When R 16A and R 16B When the nitrogen atoms to which they are attached form a 4- to 8-membered ring that optionally contains one or more additional heteroatoms, the 4- to 8-membered ring is preferably an aza-butane ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0694] PG1 is selected from the group consisting of the following: Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl.

[0695] PG1 is preferably Fmoc, Boc or Cbz.

[0696] In formula (II), PG8 is selected from the group consisting of: hydrogen, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumene, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.

[0697] PG8 is preferably methyl, allyl, t-Bu, triphenylmethyl, methoxytriphenylmethyl, cumene, THP, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl or optionally substituted heteroaryl-C1-C4 alkyl.

[0698] In formula (II), PG9 is selected from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, triphenylmethyl, cumene, and benzyl. PG9 is preferably Fmoc, Boc, Cbz, t-Bu, or triphenylmethyl.

[0699] In equation (II), PG 10 Choose from the group consisting of: t-Bu, triphenylmethyl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl. PG 10The preferred compounds are t-Bu, triphenylmethyl, cumene, benzyl, methyl, or allyl.

[0700] In some respects, PG1 to PG can be included in general formulas (I) to (III). 10 Each of these protecting groups can be removed independently by the deprotection method of the present invention. Such protecting groups include t-Bu, triphenylmethyl, 2-(trimethylsilyl)-ethyl, Boc, Teoc, Cbz, methoxycarbonyl, tetrahydropyranyl, and 1-ethoxyethyl.

[0701] In some respects, PG1 to PG 10 Each of these protecting groups can be removed independently using the deprotection method of this invention. Such protecting groups include Fmoc and Alloc.

[0702] In some respects, PG1 to PG 10 These can be groups that do not act as protecting groups independently; for example, groups that cannot be removed or can be structurally transformed. Examples of such protecting groups include those described in Greene's "Protective Groups in Organic Synthesis" (5th edition, John Wiley & Sons 2014).

[0703] Structures represented by general formula (II) in which at least two amino acid residues are linked together include many such structures that are prone to breakage or rearrangement when using known deprotection or resin removal conditions. Such breakage and rearrangement can be referred to as destruction. Using the reaction conditions of the present invention, it is possible to selectively and effectively remove only the protecting group of interest or the resin used in solid-phase synthesis without such destruction.

[0704] In some respects, structures represented by general formula (II) in which two amino acid residues are linked to each other include those structures in which one N-substituted amino acid is linked to an N-unsubstituted amino acid, and those structures in which two N-substituted amino acids are linked to each other. Specific examples of such structures include those in which R of general formula (II) 1′ Represented by general formula (III) and R in formula (III) 11 It is -C(R) 11A (R) 11B R of (Formula IV) or (Formula III) 11 It has a single bond (V) structure.

[0705]

[0706] The groups in formulas (IV) and (V) can be the same as those in formulas (II) and (III) above.

[0707] In some respects, in formulas (IV) and (V), R1 is hydrogen, PG1, a natural amino acid residue, or an amino acid analog residue.

[0708] In some respects, in formulas (IV) and (V), R1 is hydrogen, PG1, a native amino acid residue, or an amino acid analog residue, and R2 and R 10 The preferred compounds are methyl, ethyl, propyl, butyl, or pentyl.

[0709] In some respects, in formulas (IV) and (V), R1 is hydrogen, PG1, a native amino acid residue, or an amino acid analog residue, and R2 and R 10 Or R2 and R 10′ Preferably, each of them independently forms a 3- to 7-membered heterocycle with the nitrogen and carbon atoms to which they are attached, optionally substituted with hydroxyl or C1-C4 alkoxy groups. When R2 and R 10 When the heterocycle is formed together, R 10′ It is hydrogen, and when R2 and R 10′ When the 3 to 7-membered heterocycles are formed together, R 10 It is hydrogen.

[0710] In some respects, in equations (IV) and (V), R 10′ It can be hydrogen, and R 10 The following groups can be selected: hydrogen, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, -CH2SPG8, N-PG9-indol-3-ylmethyl, 4-(PG8O)benzyl, PG8-O-methyl, 1-(PG8O)ethyl, 2-(PG8O)ethyl, PG8-OCO(CH2)-, PG8-OCO(CH2)2-, PG9N-n-butyl, -CON(R 16A (R) 16B ), -CH2-CON(R 16A (R) 16B ) and -(CH2)2CON(R 16A (R) 16B ).

[0711] In some respects, in formulas (IV) and (V), R6 may preferably be a C1-C6 alkyl group, preferably methyl, ethyl, propyl, butyl or pentyl.

[0712] In some respects, in equations (IV) and (V), R ]3 It can be a C1-C4 alkyl group, preferably methyl, ethyl, propyl or butyl, and more preferably methyl or ethyl.

[0713] In some respects, in equations (IV) and (V), R 13 It could be -(CH2) m CON(R 17A (R) 17B ), and m is 0, 1, or 2. In this case, R 17A and / or R 17B It can be a C1-C4 alkyl group independently, and the C1-C4 alkyl group is preferably methyl or ethyl. R 17A and R 17B They can form 4- to 8-membered rings together with the nitrogen atoms to which they are attached, optionally containing one or more additional heteroatoms, and the 4- to 8-membered rings are preferably aza-butane rings, pyrrolidine rings, piperidine rings, piperazine rings or morpholine rings.

[0714] In some respects, in equations (IV) and (V), R 12 and R 12 Choose independently the following groups: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES. When R 12 and R 12 'Is PG 10 -O-methyl, -(CH2) n COO-PG 10 -(CH2) n COO-RES or -(CH2) n CONH-RES, n is 0, 1 or 2, and PG 10 Preferred resins are t-Bu, triphenylmethyl, cumene, benzyl, methyl, or allyl. RES is a resin for solid-phase synthesis, and is preferably a CTC resin or a Wang resin.

[0715] In some aspects, when used in the resin removal method of the present invention, R 12 and R 12′ Any of the preferred choices is selected from -(CH2). n COO-RES and -(CH2) n CONH-RES.

[0716] In some respects, more preferably in formulas (IV) and (V), R1 is hydrogen, PG1, a natural amino acid residue or an amino acid analog residue.

[0717] R2 is methyl and ethyl; and / or

[0718] R2 and R 10 Together with the nitrogen and carbon atoms to which they are attached, they form 4 to 6-membered heterocycles that may be optionally substituted with hydroxyl or C1-C4 alkoxy groups.

[0719] R 10 and R 10′ Each can be independently selected from methyl or ethyl, or R 10 and R 10′ They can form 5- or 6-membered alicyclic rings together. Alternative site, R 10′ It can be hydrogen, and R 10 It can be hydrogen, or an alkyl group selected from methyl, ethyl, isopropyl, isobutyl and sec-butyl, or optionally substituted phenylmethyl, optionally substituted phenylethyl, benzyloxymethyl, 1-benzyloxyethyl, 2-benzyloxyethyl, tert-butoxycarbonylmethyl, methoxycarbonylmethyl, tert-butoxycarbonylethyl, methoxycarbonylethyl, tert-butoxycarbamoylbutyl, N,N-dimethylaminocarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, N,N-dimethylaminocarbonylmethyl, piperidinylcarbonylmethyl, pyrrolidinylcarbonylmethyl, N,N-dimethylaminocarbonylethyl, piperidinylcarbonylethyl or pyrrolidinylcarbonylethyl.

[0720] R6 can be methyl or ethyl, and

[0721] R 13 It can be methyl or -(CH2). m CON(R 17A (R) 17B When R 13 It is -(CH2) m CON(R 17A (R) 17B When R 17A and R 17B Together with the nitrogen atoms they are attached to, they form a piperidine ring.

[0722] R 12 and R 12 Choose independently the following groups: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 ,-(CH2) n COO-RES and -(CH2) n CONH-RES.

[0723] In some respects, in addition to the structure represented by general formula (II), the starting peptide compound may also contain one or more additional native amino acid residues and / or amino acid analog residues. The starting peptide compound may contain one or more structures represented by general formula (I), may contain a structure represented by general formula (II) at the C-terminus, and may optionally further contain one or more additional native amino acid residues and / or amino acid analog residues. The peptide compound may be formed from secondary amides, tertiary amides, or a mixture of secondary and tertiary amides.

[0724] In some respects, 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 a structure represented by general formula (II), or may be contained in an amino acid residue that is different from the structure represented by general formula (II).

[0725] In some aspects, the starting peptide compound comprises at least one solid-phase synthesis resin that is removable 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).

[0726] In some aspects, the present invention relates to a method for producing an amide compound in which a protecting group removable by a silylating agent has been removed, the method comprising the steps of contacting a starting amide compound with a silylating agent in a solvent, thereby removing the protecting group from the starting amide compound.

[0727] In some aspects, the present invention relates to a method for producing an amide compound in which the solid-phase synthesis resin has been removed, the method comprising the steps of contacting a starting amide compound with the silylating agent in a solvent, thereby removing the starting amide compound from the solid-phase synthesis resin.

[0728] In some respects, the starting amide compound to be deprotected / reinforced is represented by general formula (II).

[0729]

[0730] In equation (II), R 1′ It is a hydrogen atom or PG7, and the other groups are the same as defined above. R6 is preferably a C1-C6 alkyl group. PG7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc and trifluoroacetyl, and is preferably Fmoc, Boc or Cbz.

[0731] When using known deprotection or resin removal conditions, the starting amide compounds represented by general formula (II), especially N-substituted compounds, are prone to destruction, such as rearrangement. Using the reaction conditions of the present invention, the protecting group of interest or the resin used in solid-phase synthesis can be selectively and effectively removed without such destruction.

[0732] In this document, there is no particular limitation on the term "silylating agent," as long as it can be used in the deprotection or resin removal reaction of the present invention, and the term refers to a reagent that can act as a deprotecting agent or deprotecting reagent and / or a resin removing agent or resin removing reagent. In this document, "silylating agent" may be referred to as a deprotecting agent or deprotecting reagent and / or a resin removing agent or resin removing reagent. Silyylating agents can be prepared, for example, by mixing a silyl compound with an electrophilic species scavenger or mixing an acid with an electrophilic species scavenger having a silyl group in a solvent. The mixing of the silyl compound with the electrophilic species scavenger or the mixing of the acid with the electrophilic species scavenger having a silyl group can be carried out in advance, in a solvent, or in the presence or absence of a starting peptide compound.

[0733] As used herein, examples of "silyl compounds" include silyl compounds having a leaving group (X) represented by Formula 1:

[0734]

[0735] Where R AX R AY and R AZ It is independently a C1-C4 alkyl or phenyl, and X is selected from the group consisting of: -OTf, -OClO3, Cl, Br and I.

[0736] Preferably, R AX R AY and R AZ It can be independently selected from methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0737] More specific examples of such silyl compounds include TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, TMSOClO3, and TMSI.

[0738] There are no particular limitations on the “acid” that can be used in this document to prepare silylating agents, as long as it can produce silyl compounds, and examples of such acids include acids represented by HX (where X is the same as defined for X in formula (1)).

[0739] As used herein, the term "electrophilic species scavenger" refers to a compound that can form adducts or salts with protons or is reactive with cationic species and is not readily silylated. Such electrophilic species scavengers include imine esters (Formula 2), amides (Formula 3), enone acetals (Formula 4), enone alkoxy hemiacetals (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), or carbamates (Formula 10). They may have substituted silyl groups, specific examples of which include TMS (trimethylsilyl), TES (triethylsilyl), TBS (tributylsilyl), TIPS (triisopropylsilyl), and TBDPS (tert-butyl-dimethylsilyl).

[0740] Imino esters are represented by formula 2:

[0741]

[0742] in

[0743] RB is a substituted silyl group, and R C It is a substituted silyl group, or

[0744] RB and R C Together with the nitrogen and carbon atoms they are attached to, they form 5- to 7-membered rings; and

[0745] R D It is a C1-C4 alkyl group optionally substituted with one or more fluorine atoms, or an optionally substituted methylene group, wherein when R D When the methylene group is optionally substituted, formula 2 dimerizes to form a compound represented by the following formula:

[0746]

[0747] Preferred imino esters include N-methylsilylimino esters represented by Formula 2-1 and bis-imino esters represented by Formula 2-2. Azoline:

[0748]

[0749] in

[0750] RB X RB Y and RB Z Independently, it is a C1-C4 alkyl or phenyl group, R C and R D As defined above; and

[0751] RE and RF are independently C1-C4 alkyl groups.

[0752] Preferably, RB X RB Y and RB Z It can be independently selected from methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0753] Preferred N-silyl imine esters include N,O-bis(trimethylsilyl)acetamide represented by formula 2-1-1. Azoline includes 4-substituted dizoline represented by formula 2-2-1 Azoline.

[0754]

[0755] More preferred N-silyl imine esters 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 bis... Azoline includes N,O-bis(trimethylsilyl)trifluoroacetamide 2,2′-isopropylidene bis[(4S)-4-tert-butyl-2- (azolino)

[0756]

[0757] Amides are represented by formula 3:

[0758]

[0759] in

[0760] R G It is a silyl group substituted with one or more C1-C4 alkyl groups;

[0761] R H It is hydrogen or C1-C4 alkyl; and

[0762] R I It is a hydrogen or a C1-C4 alkyl group optionally substituted with one or more fluorine atoms.

[0763] Preferred amides include N-methylsilylamides represented by Formula 3-1:

[0764]

[0765] in

[0766] R GX R GY and R GZ It is independently a C1-C4 alkyl or phenyl; and

[0767] R H and R I As defined above.

[0768] Preferably, R GX R GY and R GZ It can be independently selected from methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0769] Preferred N-methylsilylamides include N-trimethylsilylacetamide represented by formula 3-1-1:

[0770]

[0771] Where R H and R I As defined above.

[0772] More preferably, N-trimethylsilylacetamide includes N-methyl-N-trimethylsilylacetamide represented by formula 3-1-1-1 and N-methyl-N-trimethylsilyltrifluoroacetamide represented by formula 3-1-1-2.

[0773]

[0774] Enone acetals, enone alkoxy hemiacetals, enol ethers, and enol esters are each represented by formula 4:

[0775]

[0776] in

[0777] (a-1)R J It is a substituted silyl group, R K It is a C1-C4 alkoxy group, and R M and R L It is independently hydrogen or C1-C4 alkyl;

[0778] (a-2)R J It is a substituted silyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings containing oxygen atoms;

[0779] (b-1)R J It is a substituted silyl group, R K It is a C1-C4 alkyl group, and R M and R L It is independently hydrogen or C1-C4 alkyl;

[0780] (b-2)R JIt is a substituted silyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings;

[0781] (c-1)R J and R M Together with the carbon atoms they are attached to, they form 5- to 7-membered rings containing oxygen atoms, R K It is hydrogen or C1-C4 alkyl, and R L It is a C1-C4 alkyl group;

[0782] (c-2)R J and R M Together with the carbon atoms they are attached to, they form 5- to 7-membered rings containing oxygen atoms, and R K RI and the carbon atoms they are attached to form 5 to 8-membered rings;

[0783] (d-1)R J It is a C1-C4 alkyl group, and R M R K and R L It is independently hydrogen or C1-C4 alkyl;

[0784] (d-2)R J It is a C1-C4 alkyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings;

[0785] (e-1)R J It is a C1-C3 alkyl carbonyl group, and R M R K and R L It is independently hydrogen or C1-C4 alkyl;

[0786] (e-2)R J It is a C1-C3 alkyl carbonyl group, R M It is hydrogen or C1-C4 alkyl, and R K and R L Together with the carbon atoms they are attached to, they form 5 to 8-membered rings;

[0787] (f-1)R J It is a substituted silyl or C1-C4 alkyl group, R K It is an optionally substituted di-C1-C4 alkylamino group, and R M and R I It is independently hydrogen or C1-C4 alkyl; or

[0788] (f-2)R J It is a substituted silyl or C1-C4 alkyl group, R M It is hydrogen or C1-C4 alkyl, and RK and R L Together with the carbon atoms to which they are attached, they form 5 to 8-membered rings containing nitrogen atoms, and these 5 to 8-membered rings are optionally substituted with C1-C4 alkyl groups.

[0789] Preferred examples of C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Preferred examples of C1-C3 alkyl carbonyl groups include acetyl and propionyl.

[0790] Preferred enone acetals include silyl enone acetals represented by Formula 4-1:

[0791]

[0792] in

[0793] R JX1 R JY1 and R JZ1 It is independently a C1-C4 alkyl or phenyl group;

[0794] R KX1 It is a C1-C4 alkyl group; and

[0795] R L and R M As defined above.

[0796] Preferred examples of C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0797] Preferably, R JX1 R JY1 and R JZ1 It can be independently selected from methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0798] Preferred enone silyl acetals include enone trimethyl silyl acetals represented by formula 4-1-1:

[0799]

[0800] Where R KX1 R L and R M As defined above.

[0801] Preferred R KX1 R L and R M Including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0802] Preferred ketene trimethylsilyl acetals include dimethyl ketene methyltrimethylsilyl acetal represented by formula 4-1-1-1.

[0803]

[0804] Preferred enol ethers include silyl enol ethers represented by formula 4-2:

[0805]

[0806] in

[0807] R JX2 R JY2 and R JZ2 It is independently a C1-C4 alkyl or phenyl group;

[0808] R KX2 It is hydrogen or C1-C4 alkyl; and

[0809] R L and R M As defined above.

[0810] R KX1 R L and R M Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0811] Preferably, R JJX2 R JJY2 and R JZ2 Choose independently from the group consisting of: methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0812] Preferred silyl enol ethers include trimethylsilyl enol ether represented by formula 4-2-1:

[0813]

[0814] in

[0815] R KX2 R L and R M As defined above.

[0816] Preferred trimethylsilyl enol ethers include isopropenyloxytrimethylsilane represented by formula 4-2-1-1.

[0817]

[0818] In other embodiments, preferred enol ethers include cyclic enol ethers represented by formula 4-3:

[0819]

[0820] in

[0821] R KX3 and R L1 It is either hydrogen or C1-C4 alkyl.

[0822] Preferred cyclic enol ethers include dihydropyrans represented by formula 4-3-1.

[0823]

[0824] In other embodiments, preferred enol ethers include straight-chain enol ethers, and preferred straight-chain enol ethers include ethyl vinyl ethers represented by formula 4-4.

[0825]

[0826] Imine is represented by formula 5:

[0827]

[0828] in

[0829] R N R N′ and R o It is either hydrogen or C1-C4 alkyl.

[0830] R N R N′ and R o Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0831] Preferred imines include ketoimines represented by Formula 5-1:

[0832]

[0833] Where R N As defined above.

[0834] Preferred R N and R N′ Including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0835] Preferred ketoimines include 2,2,4,4-tetramethylpentanoneimine represented by formula 5-1-1.

[0836]

[0837] Amines are represented by formula 6:

[0838]

[0839] in

[0840] RP is a substituted silyl group; and

[0841] R Q It is a substituted silyl or C1-C4 alkyl group, and R R It is hydrogen, substituted silyl or C1-C4 alkyl, or

[0842] R Q and R R Together with the nitrogen atoms they are attached to, they form 5 to 8-membered heterocycles containing oxygen atoms.

[0843] Preferred amines include dimethylsilylamines represented by Formula 6-1:

[0844]

[0845] in

[0846] R PX1 R PY1 R PZ1 R QX1 R QY1 and R QZ1 It is independently a C1-C4 alkyl or phenyl group.

[0847] Preferably, R PX1 R PY1 R PZ1 R QX1 R QY1 and R QZ1 Choose independently from the group consisting of: methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0848] Preferred dimethylsilylamines include 1,1,1,3,3,3-hexamethyldisilazane (HMS) represented by formula 6-1-1.

[0849]

[0850] In other embodiments, preferred amines include N-dialkyl-N-methylsilylamines represented by formula 6-2:

[0851]

[0852] in

[0853] RP X2 RP Y2 and RPZ2 It is independently a C1-C4 alkyl or phenyl; and

[0854] R Q and R R As defined above.

[0855] RP X2 RP Y2 and RP Z2 Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0856] Preferably, R PX2 R PY2 and R PZ2 Choose independently from the group consisting of: methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0857] Preferred N-dialkyl-N-methylsilylamines include N-dialkyl-N-trimethylsilylamine represented by formula 6-2-1:

[0858]

[0859] in

[0860] R Q and R R As defined above.

[0861] Preferred N-dialkyl-N-trimethylsilylamines include N-trimethylsilylmorpholine represented by formula 6-2-1-1 and N-trimethylsilyldiethylamine represented by formula 6-2-1-2.

[0862]

[0863] In other embodiments, preferred amines include N-alkyl-N-dimethylsilylamines represented by formula 6-3:

[0864]

[0865] in

[0866] R QX3 R QY3 R QZ3 R RX1 R RY1 and R RZ1 It is independently a C1-C4 alkyl or phenyl; and

[0867] R R It is a C1-C4 alkyl group.

[0868] Specifically, for example, R QX3 RQY3 R QZ3 R RX1 R RY1 and R RZ1 It can be independently selected from methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0869] R R Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0870] Preferred N-alkyl-N-dimethylsilylamines include N-alkyl-N-bistrimethylsilylamine represented by formula 6-3-1:

[0871]

[0872] in

[0873] R R It is a C1-C4 alkyl group.

[0874] R R Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0875] In other embodiments, preferred amines include N-alkyl-N-methylsilylamines represented by formula 6_4:

[0876]

[0877] in

[0878] RP X2 RP Y2 and RP Z2 It is independently a C1-C4 alkyl or phenyl; and

[0879] R Q It is a C1-C4 alkyl group.

[0880] Preferably, RP X2 RP Y2 and RP Z2 Choose independently from the group consisting of: methyl, ethyl, isopropyl, tert-butyl, and phenyl.

[0881] R Q Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0882] Preferred N-alkyl-N-methylsilylamines include N-alkyl-N-trimethylsilylamine represented by formula 6_4-1:

[0883]

[0884] Where R Q It is a C1-C4 alkyl group.

[0885] R Q Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0886] Preferred N-alkyl-N-trimethylsilylamines include N-tert-butyltrimethylsilylamine represented by formula 6-4-1-1.

[0887]

[0888] Diamine is represented by formula 7:

[0889]

[0890] in

[0891] X is a single bond or a carbon atom.

[0892] Where X is a single bond, R s It does not exist, R UA and R R Together with the carbon and nitrogen atoms to which they are attached, they form optionally substituted 6-membered aromatic heterocycles, and R UB and R T Together with the carbon and nitrogen atoms they are attached to, they form optionally substituted 6-membered aromatic heterocycles, and

[0893] When X is a carbon atom, R UA and R UB Independently, it is a C1-C4 alkyl group, and R R R s and R T Together with the carbon atoms they are attached to, they form the following structure:

[0894]

[0895] When X in Formula 7 is a carbon atom, the preferred diamine includes tetraalkylnaphthalene diamine represented by Formula 7-1:

[0896]

[0897] Where R UA and R UB It is independently a C1-C4 alkyl group.

[0898] Preferred tetraalkylnaphthyldiamines include N,N,N′,N′-tetramethyl-1,8-naphthyldiamine represented by formula 7-1-1.

[0899]

[0900] In other embodiments, when X in Formula 7 is a single bond, the preferred diamine comprises 2,2′-bipyridine represented by Formula 7-1-1.

[0901]

[0902] Dialkylcarbodiimide is represented by formula 8:

[0903]

[0904] Where R V It is a C1-C4 alkyl or a C3-C6 cycloalkyl.

[0905] R V Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and cyclohexyl.

[0906] Preferred dialkylcarbodiimides include diisopropylcarbodiimide represented by formula 8-1.

[0907]

[0908] Urea is represented by Formula 9:

[0909]

[0910] Where R w and R X It is independently a C1-C4 alkyl or a substituted silyl group.

[0911] Preferred ureas include N,N′-bis(trimethylsilyl)urea represented by Formula 9-1.

[0912]

[0913] Ethyl carbamate is represented by formula 10:

[0914]

[0915] Where R Y RZ is independently a C1-C4 alkyl or substituted silyl group.

[0916] Preferred urethanes include N,O-bis(trimethylsilyl)urea represented by formula 10-1.

[0917]

[0918] In some respects, silylating agents can be prepared by mixing a peptide compound, a solvent, an electrophilic species scavenger, and a silyl compound or acid in any order. Preferably, the peptide compound is mixed with a solvent, then with an electrophilic species scavenger, and subsequently with a silyl compound or acid.

[0919] In some aspects, the solvent used can be an aprotic solvent, examples of which include esters, ethers, alkyl nitriles, 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 are preferred, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, or 1,2-dichloroethane are more preferred, and ethyl acetate or 2-methyltetrahydrofuran is particularly preferred.

[0920] In some aspects, to produce the silylating agent of the present invention, a stoichiometric amount or greater of a silyl compound and an electrophilic species scavenger can be used to remove the protecting group and / or remove the resin from the peptide compound. In this case, for example, for one equivalent of the protecting group to be removed or one equivalent of the resin to be removed contained in the peptide, 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.

[0921] In some aspects, for each equivalent of protecting group to be removed or for each equivalent of resin to be removed, the silylating agent can be prepared by combining an electrophilic species scavenger with a catalytic amount, for example, 0.1 to 0.5 equivalents, preferably 0.3 to 0.4 equivalents, of a silyl compound. In this case, TMSOTf, TESOTf, TBSOTf, TIPSOTf, TBDPSOTf, TTMSOTf, TMSCl, TMSBr, or TMSOClO3 are preferably used as such silylating agents, and N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilylacetamide, N-methyl-N-trimethylsilyltrifluoroacetamide, dimethylketene methyltrimethylsilyl acetal, or isopropenyloxytrimethylsilane are preferably used as such electrophilic species scavengers. In this case, for each equivalent of the protective base to be removed or each equivalent of the resin to be removed, 1 to 10 equivalents, preferably 1 to 8 equivalents, of electrophilic species remover can be used.

[0922] In some respects, for each equivalent of protecting group to be removed or for each equivalent of resin to be removed, the silylating agent can be prepared by combining an electrophilic species scavenger with a catalytic amount, for example, 0.1 to 0.5 equivalents, preferably 0.3 to 0.4 equivalents, of an acid. In this case, TfOH, HOClO3, HCl, HBr, or HI are preferred, and TfOH is more preferably used as such an acid. N-silyl imine ester (Formula 2-1), N-silyl amide (Formula 3-1), enone silyl acetal (Formula 4-1), and 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-trimethylsilyl acetamide (Formula 3-1-1-1), N-methyl-N-trimethylsilyl trifluoroacetamide (Formula 3-1-1-2), dimethyl ketene methyltrimethylsilyl acetal (Formula 4-1-1-1), and isopropenyloxytrimethylsilane (Formula 4-2-1-1) are more preferably used as such electrophilic species scavengers. Among them, N,O-bis(trimethylsilyl)trifluoroacetamide and N-methyl-N-trimethylsilyl trifluoroacetamide are particularly preferred. In this case, for each equivalent of the protective base to be removed or each equivalent of the resin to be removed, 1 to 10 equivalents, preferably 1 to 8 equivalents, of electrophilic species remover can be used.

[0923] In some respects, there are no particular limitations on "protecting groups that can be removed by silylating agents," as long as the protecting group can be removed by silylating agents. Specific examples of such protecting groups include protecting groups for carboxyl groups, such as t-Bu, benzyl, triphenylmethyl, cumenyl, and 2-(trimethylsilyl)-ethyl; protecting groups for amino groups, such as Boc, Teoc, Cbz, methoxycarbonyl, and cumenyl; protecting groups for hydroxyl groups, such as tetrahydropyranyl and 1-ethoxyethyl; and protecting groups for SH groups, such as triphenylmethyl and methoxytriphenylmethyl.

[0924] The chemical synthesis methods used for starting peptide compounds described in this article include, for example, liquid-phase synthesis, solid-phase synthesis using Fmoc synthesis, Boc synthesis, and combinations thereof. In Fmoc synthesis, an amino acid is used as the basic unit, wherein the main chain amino group is protected by an Fmoc group, the side chain functional groups are protected, if necessary, by a protecting group that is not cleaved by a base such as piperidine, and the main chain carboxylic acid group is not protected. There are no particular restrictions on this basic unit, and it can be any other combination, as long as it has an Fmoc-protected amino and carboxylic acid group. For example, a dipeptide can be used as the basic unit. The basic unit located at the N-terminus can be a basic unit that is not an Fmoc amino acid. For example, it can be a Boc amino acid, or a carboxylic acid analog without an amino group. The main chain carboxylic acid group is fixed to the solid phase by a chemical reaction with the functional groups on the solid phase support. Next, the Fmoc group is deprotected by a base such as piperidine or DBU, and the newly generated amino group and the subsequently added basic unit (i.e., the protected amino acid with the carboxylic acid) undergo a condensation reaction to form an amide bond. In the condensation reaction, combinations such as DIC and HOBt, DIC and HOAt, and HATU and DIPEA are possible. Repeated deprotection of the Fmoc group and subsequent amide bond formation reaction enable the production of the desired peptide sequence. After obtaining the desired sequence, resin removal from the solid phase is performed, and protecting groups introduced into the side chain functional groups are deprotected if necessary. The deprotection and resin removal method of the present invention can provide for removal from the solid-phase resin and removal of protecting groups from the side chain functional groups. Steps such as cyclization can also be performed during or at the end of the solid-phase resin removal or deprotection steps. For example, the side-chain carboxylic acid can be condensed with the N-terminal amino group of the main chain, while the side-chain amino group can be condensed with the C-terminal carboxylic acid of the main chain. In this case, reaction orthogonality is required between the C-terminal carboxylic acid and the side-chain carboxylic acid to be cyclized, or between the N-terminal amino or hydroxyl group of the main chain and the side-chain amino group to be cyclized, and the protecting group is selected with consideration of the orthogonality of the protecting group. The reaction product thus obtained can be purified by reverse-phase column, molecular sieve column, etc. Detailed descriptions can be found, for example, in the “Solid-Phase Synthesis Handbook” published by Merck KK on May 1, 2002.

[0925] In this document, there is no particular limitation on the term "resin for solid-phase synthesis," as long as it can be used for the synthesis of peptide compounds by solid-phase methods and can be removed by the silylating agent of the present invention. Specific examples of such resins for solid-phase synthesis include those that can be removed under acidic conditions, such as CTC resin, Wang resin, SASRIN resin, triphenylmethyl chloride resin (Trt resin), 4-methyltriphenylmethyl chloride resin (Mtt resin), and 4-methoxytriphenylmethyl chloride resin (Mmt). The resin can be appropriately selected according to the functional group on the amino acid to be used. For example, when a carboxylic acid (main-chain carboxylic acid or side-chain carboxylic acid represented by Asp or Glu) or a hydroxyl group on an aromatic ring (phenolic group represented by Tyr) is used as the functional group on the amino acid, triphenylmethyl chloride resin (Trt resin) or 2-chlorotriphenylmethyl chloride resin (CTC resin) is preferably used. When aliphatic hydroxyl groups (represented by aliphatic alcohol groups such as Ser or Thr) are used as functional groups on amino acids, triphenylmethyl chloride resin (Trt resin), 2-chlorotriphenylmethyl chloride resin (CTC resin) or 4-methyltriphenylmethyl chloride resin (Mtt resin) are preferably used as the resin.

[0926] Furthermore, there are no particular restrictions on the type of polymer constituting the resin. For resins composed of polystyrene, 100 to 200 mesh or 200 to 400 mesh can be used. There are no particular restrictions on the crosslinking percentage, but those crosslinked with 1% divinylbenzene (DVB) are preferred. Types of polymers forming the resin include Tentagel or Chemmatrix.

[0927] In some aspects, the deprotection reaction and / or 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 most preferably 0 to 30°C.

[0928] In some aspects, 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, and most preferably 1 to 3 hours.

[0929] In some aspects, in the deprotection reaction and / or resin removal reaction of the present invention, the target product can be obtained by adding alcohol or water to the reaction solution to quench the reaction, precipitating the target product, or washing the organic layer with water or brine, and then concentrating the organic layer under reduced pressure. There are no particular limitations on the alcohol, but water-soluble and low-boiling-point alcohols are preferred, and methanol is particularly preferred. There are no particular limitations on the water used for quenching the reaction, but alkaline water is preferred, and aqueous solutions of sodium bicarbonate or dipotassium hydrogen phosphate are particularly preferred. When washing the organic layer, there are no particular limitations on the concentration of the brine, but brine or 5% brine is preferred.

[0930] In some aspects, when the starting peptide compound contains both a protecting group removable by the method of the present invention and a solid-phase synthesis resin removable by the method of the present invention, the deprotection and resin removal reactions can be carried out simultaneously. Specifically, the present invention also relates to a method for producing a peptide compound in which a protecting group removable by a silylating agent has been removed from a starting peptide compound containing natural amino acid residues and / or amino acid analog residues, and a solid-phase synthesis resin removable by a silylating agent has been removed from the starting peptide compound, the method comprising the step of contacting the starting peptide compound with a silylating agent in a solvent.

[0931] In some aspects, the present invention relates to amide compounds or salts thereof represented by the following formula (A):

[0932]

[0933] In equation (A), R 1′ Choose from the group consisting of: hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl. R 1′ The preferred materials are hydrogen, Fmoc, Boc, or Cbz.

[0934] In equation (A), R 17A and R 17B They are all methyl, or R 17A and R 17B Together with the nitrogen atoms they are attached to, they form piperidine or morpholine.

[0935] In equation (A), R 18 Is it hydrogen or PG? 10 PG 10 Choose from the group consisting of: t-Bu, triphenylmethyl, cumene, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl. 18 The preferred atoms are hydrogen atoms, t-Bu, benzyl, or allyl.

[0936] R in equation (A) 1′ and R 18Preferred compositions include Fmoc and hydrogen atom, Fmoc and allyl, Fmoc and t-Bu, Fmoc and benzyl, Boc and hydrogen atom, Boc and allyl, Boc and t-Bu, Boc and benzyl, Cbz and hydrogen atom, Cbz and allyl, Cbz and t-Bu, Cbz and benzyl, Alloc and hydrogen atom, Alloc and allyl, Alloc and t-Bu, Alloc and benzyl, Teoc and hydrogen atom, Teoc and allyl, Teoc and t-Bu, Teoc and benzyl, hydrogen atom and hydrogen atom, hydrogen atom and allyl, hydrogen atom and t-Bu, and hydrogen atom and benzyl.

[0937] Specific examples of amide compounds represented by formula (A) include the following compounds:

[0938] (1-1)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-oxo_4-(piperidin-1-yl)butyric acid,

[0939] (1-2)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0940] (1-3)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)tert-butyl butyrate,

[0941] (1_4)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-oxo_4-(piperidin-1-yl)benzyl butyrate,

[0942] (1-5)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0943] (1-6)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0944] (1-7)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyrate tert-butyl ester,

[0945] (1-8)3-((tert-butoxycarbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0946] (1-9)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0947] (1-10)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0948] (1-11)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)tert-butyl butyrate,

[0949] (1-12)3-(((benzyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0950] (1-13)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0951] (1-14)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0952] (1-15)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)butyrate tert-butyl ester,

[0953] (1-16)3-(((allyloxy)carbonyl)(methyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0954] (1-17)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0955] (1-18)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[0956] (1-19) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)tert-butyl butyrate,

[0957] (1-20)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[0958] (2-1)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-morpholino_4-oxobutyric acid,

[0959] (2-2)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0960] (2-3)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0961] (2_4)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)_4-morpholino_4-oxobutyrate benzyl ester,

[0962] (2-5)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid,

[0963] (2-6)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0964] (2-7)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0965] (2-8)3-((tert-butoxycarbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0966] (2-9)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid,

[0967] (2-10)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0968] (2-11)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0969] (2-12)3-(((benzyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0970] (2-13)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid,

[0971] (2-14)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0972] (2-15)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0973] (2-16)3-(((allyloxy)carbonyl)(methyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0974] (2-17) 3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyric acid,

[0975] (2-18)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyric acid allyl ester,

[0976] (2-19)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[0977] (2-20)3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-morpholino-4-oxobutyrate benzyl ester,

[0978] (3-1)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0979] (3-2)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid allyl ester,

[0980] (3-3)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate tert-butyl ester,

[0981] (3-4)3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate benzyl ester,

[0982] (3-5)3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0983] (3-6)3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid allyl ester,

[0984] (3-7) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate tert-butyl ester,

[0985] (3-8) 3-((tert-butoxycarbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate benzyl ester,

[0986] (3-9)3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0987] (3-10)3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid allyl ester,

[0988] (3-11)3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate tert-butyl ester,

[0989] (3-12) 3-(((benzyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate benzyl ester,

[0990] (3-13)3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid,

[0991] (3-14)3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyric acid allyl ester,

[0992] (3-15)3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate tert-butyl ester,

[0993] (3-16) 3-(((allyloxy)carbonyl)(methyl)amino)-4-(dimethylamino)-4-oxobutyrate benzyl ester,

[0994] (3-17) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyric acid,

[0995] (3-18)4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyric acid allyl ester,

[0996] (3-19) 4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyrate tert-butyl ester,

[0997] (3-20)4-(dimethylamino)-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)-4-oxobutyrate benzyl ester,

[0998] (4-1)3-(methylamino)-4-oxo-4-(piperidin-1-yl)butyric acid,

[0999] (4-2)3-(methylamino)-4-oxo-4-(piperidin-1-yl)butyric acid allyl ester,

[1000] (4-3)3-(methylamino)-4-oxo-4-(piperidin-1-yl)tert-butyl butyrate,

[1001] (4-4)3-(methylamino)-4-oxo-4-(piperidin-1-yl)benzyl butyrate,

[1002] (4-5)3-(methylamino)-4-morpholino-4-oxobutyric acid,

[1003] (4-6)3-(methylamino)-4-morpholino-4-oxobutyric acid allyl ester,

[1004] (4-7)3-(methylamino)-4-morpholino-4-oxobutyrate tert-butyl ester,

[1005] (4-8)3-(methylamino)-4-morpholino-4-oxobutyrate benzyl ester,

[1006] (4-9)4-(dimethylamino)-3-(methylamino)-4-oxobutyric acid,

[1007] (4-10)4-(dimethylamino)-3-(methylamino)-4-oxobutyric acid allyl ester,

[1008] (4-11) tert-butyl 4-(dimethylamino)-3-(methylamino)-4-oxobutyrate, or

[1009] (4-12)4-(dimethylamino)-3-(methylamino)-4-oxobutyrate benzyl ester.

[1010] For example, the amide compounds of the present invention represented by formula (A) can be synthesized according to the following scheme.

[1011]

[1012] For example, according to the Handbook of Solid-Phase Synthesis (publisher: Merck KK, publication date: May 1, 2002) or the method of Albert et al. (Synthesis, 1987, 7, 635-637), a dehydrating condensing agent such as a carbodiimide compound can be used to synthesize an arbitrary amine ((R 17A (R) 17B The amidation step in the above scheme is achieved by condensing NH with a carboxyl group.

[1013] For example, the deprotection step in the above scheme can be achieved using the method described in Greene's "Protective Groups in Organic Synthesis" (5th edition, John Wiley & Sons 2014) or the deprotection method described herein.

[1014] The compounds of the present invention may be in their free form or salts thereof, both of which are included in the present invention. Examples of such "salts" include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, and acidic or basic amino acid salts.

[1015] Examples of inorganic acid salts include hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates. Examples of organic acid salts include acetates, succinates, fumarates, maleates, tartrates, citrates, lactates, stearates, benzoates, methanesulfonates, benzenesulfonates, and p-toluenesulfonates.

[1016] Examples of inorganic alkali salts include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, and ammonium salts. Examples of organic alkali salts include diethylamine salts, diethanolamine salts, meglumine salts, and N,N-dibenzylethylenediamine salts.

[1017] Examples of acidic amino acid salts include aspartate and glutamate. Examples of basic amino acid salts include arginine, lysine, and ornithine.

[1018] For example, when left in the air, the compounds of the present invention can absorb water to form hydrates. Such hydrates are also included in the present invention.

[1019] Furthermore, the compounds of the present invention can absorb certain other solvents to form solvates. Such solvates are also included in the present invention.

[1020] In this document, although the structural formulas of the compounds of the present invention may represent certain isomers for convenience, the present invention includes all isomers and mixtures of isomers possible in terms of compound structure, such as geometric isomers, optical isomers, and tautomers, and these compounds are not limited to the structural formulas described for convenience. For example, compounds having asymmetric carbon atoms in the molecule and existing as optically active isomers and racemic derivatives are both included in the present invention.

[1021] All prior art references cited in this document are incorporated herein by reference.

[1022] [Example]

[1023] The present invention will be further illustrated with reference to the following embodiments, but the present invention is not limited thereto.

[1024] The solvents used in the practice of this invention, such as dichloromethane, ethyl acetate, 2-MeTHF, dichloroethane, or DMF, are those obtained from commercial suppliers and used without purification. In the absence of added water as a solvent, the solvents used in the reaction, such as dehydrating solvents, ultra-dehydrating solvents, or anhydrous solvents, are those obtained from commercial suppliers and used without purification.

[1025] Unless otherwise stated, the silyl compounds such as TMSOTf used in the practice of this invention, or the reagents such as electrophilic species scavengers such as BSA and BSTFA used in the practice of this invention, are those obtained from commercial suppliers and used without purification.

[1026] Unless otherwise stated, the starting peptides or amide compounds used in the practice of this invention are those obtained from commercial suppliers and used without purification. If desired, such compounds are produced and used by known methods.

[1027] In the following examples, analysis was performed using any one or more of HPLC methods 1 to 4, or methods A, B, C, D, E, F, G, or H.

[1028] Analysis: HPLC (reaction conversion, purity)

[1029] HPLC Method 1

[1030] Instrument: Waters ACQUITY UPLC H-Class

[1031] Column: Ascentis Express C18 (2.7μm, 4.6mm x 50mm), Supelco

[1032] Eluents: A) 0.05% TFA / water, B) 0.05% TFA / CH3CN

[1033] Gradient (B):

[1034] Flow rate: 1.0 mL / min.

[1035] Detection: 210nm

[1036] Injection volume: 5μL

[1037] Sample preparation: 5 μL / 1.00 mL

[1038] HPLC Method 2

[1039] Instrument: Waters LCT Premier

[1040] Column: Ascentis Express C18 (2.7μm, 4.6mm x 50mm), Supelco

[1041] Column temperature: 35°C.

[1042] Eluents: A) 0.05% TFA / water, B) 0.05% TFA / CH3CN

[1043] Gradient (B):

[1044] Flow rate: 1.0 mL / min.

[1045] Detection: 210nm

[1046] Injection volume: 5μL

[1047] Sample preparation: 5 μL / 1.00 mL

[1048] HPLC Method 3

[1049] Instrument: Waters ACQUITY UPLC H-Class

[1050] Column: Ascentis Express C18, (2.7μm, 2.1mm x 50mm), Supelc0

[1051] Column temperature: 35°C.

[1052] Eluents: A) 0.05% TFA / water, B) 0.05% TFA / CH3CN

[1053] Gradient (A): 95% (0 min) → 0% (4.0 min) → 0% (4.5 min) → 95% (4.6 min) → 95% (6 min)

[1054] Flow rate: 0.25 mL / min

[1055] Testing: PDA 210nm (Total 200-400nm PDAs)

[1056] Injection volume: 0.3 μL

[1057] Sample preparation: 50 μL / 10 mL

[1058] HPLC Method 4

[1059] Instrument: Waters ACQUITY UPLC H-Class

[1060] Column: CAPCELL CORE ADME (2.7μm, 3.0mm x 150mm)

[1061] Column temperature: 30°C.

[1062] Solvents: A) 0.05% TFA / water, B) 0.05% TFA / CH3CN

[1063] Gradient (A): 70% (0 min) → 30% (20.0 min) → 0% (20.1 min) → 0% (22.0 min) → 70% (22.1 min) → 70% (24 min)

[1064] Flow rate: 0.3 mL / min

[1065] Testing: PDA 254nm (Total of 200-400nm PDAs)

[1066] Injection volume: 0.3 μL

[1067] Sample preparation: 10.0 mg of non-crystalline solution in 10 mL of CH3CN; this solution is prepared in 0.3 mL / 0.7 mL CH3CN solutions.

[1068] A. Boc removal reaction experiment

[1069] (Example 1)

[1070] Boc removal reaction of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 3a) (6-mer:TfOH-BSTFA method)

[1071]

[1072] 77.7 mg of the starting material was weighed into a reaction vessel and dissolved in ethyl acetate at 5 v / w. The reaction vessel was then cooled with ice. After 10 minutes, 0.055 mL (2.4 eq) of BSTFA and 3.0 μL (0.4 eq) of TfOH were added sequentially under a nitrogen atmosphere, and the reaction solution was stirred. Three hours after the addition of the reagents, the reaction was analyzed by LC-MS to confirm the disappearance of the starting material.

[1073] The reaction was quenched with a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and 5% brine. The resulting organic layer was concentrated under reduced pressure to quantitatively yield 77.3 mg of the deprotected product.

[1074] It was confirmed that no amide bonds were broken.

[1075] [Table 1]

[1076] Weight (mg) Yield (%) Raw material (compound 3a) 77.7 - Product (compound 3b) 77.3 Quantitative

[1077] [Table 2]

[1078] Analysis (HPLC Method 1)

[1079] MW m / z rt Purity LC A% Raw material (compound 3a) 906.55 807.55([M-Boc+H]+) 5.976 93.83 Product (compound 3b) 806.49 807.49([M+H]+) 3.968 94.36

[1080] (Example 2)

[1081] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-HMDS method)

[1082]

[1083] 0.0810 g of the starting material was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. The reaction vessel was then cooled with ice. After 10 minutes, 0.079 mL (7.2 eq) of HMDS and 34 μL (3.6 eq) of TMSOTf were added sequentially under a nitrogen atmosphere, and the reaction solution was stirred. Four hours after the addition of the reagents, the reaction was analyzed by LCMS to confirm the disappearance of the starting material. No amide bond cleavage was confirmed.

[1084] After confirming that the starting material had disappeared, the reaction solution was stirred for another hour and the reaction was analyzed by LCMS. At this point, it was confirmed that no amide bonds had broken.

[1085] 1 ml of brine was added to the reaction vessel to quench the reaction. Then 5 ml of ethyl acetate was added and the two layers were separated. The organic layer was washed with a mixture of 1 ml of saturated sodium bicarbonate aqueous solution and 1 ml of brine. The obtained organic layer was concentrated to give 68.0 mg of the deprotected product, as a transparent film, in 90% yield.

[1086] [Table 3]

[1087] Weight (mg) Yield (%) Raw material (compound 1a) 81.0 - Product (compound 1b) 68.0 90

[1088] [Table 4]

[1089] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1090] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.78 4.635 98.003

[1091] [Table 5]

[1092] Analysis (HPLC Method 2: Mass Spectrometry)

[1093] MW m / z rt Raw material (compound 1a) 1560.96 1561.4097([M+H]+) 5.883 Product (compound 1b) 1460.90 1461.5303([M+H]+) 4.817

[1094] (Example 3)

[1095] Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) Boc removal reaction (11-mer: TMSOTf-HMDS method)

[1096]

[1097] The reaction was carried out according to Example 2. The reaction was analyzed by LCMS 19 hours after the start of the reaction. However, no decomposition of the product was confirmed.

[1098] [Table 6]

[1099] Weight (mg) Yield (%) Raw material (compound 1a) 21.7 - Product (compound 1b) Not separated Not separated

[1100] [Table 7]

[1101] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1102] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1241.89 6.476 98.408 Product (compound 1b) 1460.90 731.76 4.562 97.256

[1103] (Example 4)

[1104] Boc removal reaction of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-MeIle-Ala-MePhe-MeVal-Asp(OBn)-pip (compound 2a) (11-mer:TfOH-BSTFA method)

[1105]

[1106] The reaction was carried out according to Example 1.

[1107] [Table 9]

[1108] Weight (mg) Yield (%) Raw material (compound 2a) 48.1 - Product (compound 2b) Not separated Not separated

[1109] [Table 10]

[1110] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1111] MW m / z rt Purity LC A% Raw material (compound 2a) 1610.97 ND 6.492 84.00 Product (compound 2b) 1510.92 ND 4.776 81.54

[1112] [Table 11]

[1113] Analysis (HPLC Method 2: Mass Spectrometry)

[1114] MW m / z rt Raw material (compound 2a) 1610.97 1611.43([M+H]+) 5.96 Product (compound 2b). 1510.92 1511.53([M+H]+) 2.84

[1115] (Example 5)

[1116] Boc removal reaction of Boc-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 4a) (5-mer:TfOH-BSTFA method)

[1117]

[1118] The reaction was carried out according to Example 1.

[1119] [Table 12]

[1120] Weight (mg) Yield (%) Raw material (compound 4a) 98.5 - Product (compound 4b) 78.7 91

[1121] [Table 13]

[1122] Analysis (HPLC Method 1)

[1123] MW m / z rt Purity LC A% Raw material (compound 4a) 821.49 844.4([M+Na]+) 6.033 90.51 Product (compound 4b) 721.44 722.46([M+H]+) 3.879 93.30

[1124] (Example 6)

[1125] The reaction for the removal and elongation of Boc from Boc-MeLeu-Thr(OBn)-MeGly-O allyl (compound 8a) to form Boc-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (3mer: TfOH-BSTFA method)

[1126]

[1127] 73.3 mg of the starting material was weighed into a reaction vessel 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 the reaction solution was stirred for two hours. After confirming by LC that deprotection was complete without main chain cleavage, 5 v / w water and 186.9 mg of dipotassium hydrogen phosphate were added. Then, 40.1 mg of Boc-Leu-OH monohydrate and 63.1 mg of DMT-MM were added, and the reaction solution was stirred while ice-cooled. The reaction was confirmed by LC 17 hours after the addition of the reagents. The reaction was quenched by adding 1 N sodium hydroxide aqueous solution. The organic layer was separated by liquid separation, followed by washing once with 1 N sodium hydroxide aqueous solution, twice with 5% potassium hydrogen sulfate aqueous solution, and washing with ethanol with 5% sodium chloride aqueous solution, and then concentrated under reduced pressure. 82.0 mg (93% yield) of crude product was obtained as an oily liquid.

[1128] [Table 14]

[1129] Weight (mg) Yield (%) Raw material (compound 8a) 73.3 - Product (compound 7a) 82.0 93

[1130] [Table 15]

[1131] Analysis of deprotection reactions (HPLC method 1)

[1132] MW m / z rt Purity LC A% Raw material (compound 8a) 547.33 448.30([M-Boc+H]+) 5.513 96.17 Boc-removal products 447.27 ND 2.938 95.95

[1133] [Table 16]

[1134] Analysis of the elongation reaction (HPLC method 1)

[1135] MW m / z rt Purity LC A% Product (compound 8b) 660.85 561.28([M-Boc+H]+) 5.657 95.36

[1136] (Example 6a)

[1137] The reaction of TeoC removal and elongation of Teoc-MeLeu-Thr(OBn)-MeGly-O allyl (compound 80b) to form Boc-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (7a) (3-mer: TfOH-BSTFA method)

[1138]

[1139] Compound 7a can be obtained without main chain breakage by removing the Teoc group and then reacting it with Boc-Leu-OH in the same manner as in Example 6.

[1140] (Example 7)

[1141] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(OBn)-pip (compound 5a) (5-mer:TfOH-BSTFA method)

[1142]

[1143] The deprotection and elongation reactions were carried out in a one-pot operation according to the experimental method described in Example 6.

[1144] [Table 17]

[1145] Weight (mg) Yield (%) Raw material (compound 5a) 105.3 - Product (compound 2a) 153.6 78％

[1146] [Table 18]

[1147] Analysis of deprotection reactions (HPLC method 1)

[1148] MW m / z rt Purity LC A% Raw material (compound 5a) 862.52 573.33 5.978 95.01 Deprotected product (compound 5b) 762.47 763.47([M+H]+) 3.779 94.05

[1149] [Table 19]

[1150] Analysis of the product after elongation (HPLC method 1: determination of impurities in raw materials and target product)

[1151] MW m / z rt Purity LC A% Product (compound 2a) 1610.97 ND 6.699 85.93

[1152] [Table 20]

[1153] Analysis of the product after elongation (HPLC method 2: mass spectrometry)

[1154] MW m / z rt Product (compound 2a) 1610.97 1611.43([M+H]+) 5.96

[1155] (Example 8)

[1156] Boc removal and elongation reaction of Boc-Ala-MePhe-MeVal-Asp(OBn)-pip (compound 6a) (4-mer:TfOH-BSTFA method)

[1157]

[1158] The deprotection and elongation reactions were carried out in a one-pot operation according to the experimental method described in Example 6.

[1159] [Table 21]

[1160] Weight (mg) Yield (%) Raw material (compound 6a) 277 - Product (compound 5a) 308.9 95％

[1161] [Table 22]

[1162] Analysis of deprotected products (HPLC method 1)

[1163] MW m / z rt Purity LC A% Raw material (compound 6a) 735.42 758.4([M+Na]+) 5.357 98.921 Deprotected product (compound 6b) 635.37 636.40([M+H]+) 3.383 97.893

[1164] [Table 23]

[1165] Analysis after the elongation reaction (HPLC method 1)

[1166] MW m / z rt Purity LC A% Product (compound 5a) 862.52 573.33 5.978 96.938

[1167] (Example 9)

[1168] Boc removal reaction of Boc-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 7a) (4-mer:TfOH-BSTFA method)

[1169]

[1170] The deprotection and elongation reactions were carried out in a one-pot operation according to the experimental method described in Example 6.

[1171] [Table 24]

[1172] Weight (mg) Yield (%) Raw material (compound 7a) 82.0 - Product (compound 4a) 98.5 97

[1173] [Table 25]

[1174] Analysis (HPLC Method 1)

[1175] MW m / z rt Purity LC A% Raw material (compound 7a) 660.41 561.28([M-100+H]+) 5.657 95.36 Intermediate (compound 7b) 560.36 561.40([M+H]+) 3.545 94.04

[1176] [Table 26]

[1177] Analysis (HPLC Method 1)

[1178] MW m / z rt Purity LC A% Product (compound 4a) 821.49 844.4([M+Na]+) 6.034 90.36

[1179] (Example 10)

[1180] Boc removal reaction of Boc-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 7a) under known conditions (4-mer:HCl method) (Russ. J. Bioorg. Chem., 2016, 42, 143).

[1181]

[1182] 18.7 mg of the starting 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 (= target product / (target product + starting material)) was confirmed to be 81%. At this time, 0.861% of H-Thr(OBn)-MeGly-O allyl (compound 7c) and 1.275% of H-Leu-MeLeu-Thr(OBn)-OH (compound 7d) were detected, which are compounds in which the amide bond is broken.

[1183] [Table 27]

[1184] Analysis (HPLC Method 1)

[1185]

[1186] (Example 11)

[1187] The reaction for deprotection and elongation of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) to form Boc-Ala-MePhe-MeVal-Asp(OBn)-pip (3-mer: TMSOTf-B STFA method)

[1188]

[1189] The deprotection and elongation reactions were carried out in a one-pot operation according to the experimental method described in Example 6.

[1190] [Table 28]

[1191] Weight (mg) Yield (%) Raw material (compound 9a) 253.2 - Product (compound 6a) 319.4 Quantitative

[1192] [Table 29]

[1193] Analysis of deprotection reactions (HPLC method 1)

[1194] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5647 99.206 Deprotection products 564.33 565.31([M+H]+) 3.338 98.885

[1195] [Table 30]

[1196] Analysis of the elongation reaction (HPLC method 1)

[1197] MW m / z rt Purity LC A% Product (compound 6a) 735.92 758.4([M+Na]+) 5.377 99.538

[1198] (Example 12)

[1199] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (3-mer: TMSOTf-MSTFA method)

[1200]

[1201] The deprotection and elongation reactions were carried out in a one-pot operation according to the experimental method described in Example 6.

[1202] [Table 31]

[1203] Weight (mg) Yield (%) Raw material (compound 9a) 200.6 - Product (compound 6a) 220.6 95

[1204] [Table 32]

[1205] Analysis of deprotection reactions (HPLC method 1)

[1206] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 6875([M+Na]+) 5647 99206 Deprotected product (compound 9b) 564.33 565.31([M+H]+) 3.338 97.921

[1207] [Table 33]

[1208] Analysis of the elongation reaction (HPLC method 1)

[1209] MW m / z rt Purity LC A% Product (compound 6a) 735.92 758.4([M+Na]+) 5.308 99.279

[1210] (Example 13)

[1211] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (3-mer: TMSOTf-BSA method, TMSOTf 2.4eq, BSA 2.4eq)

[1212]

[1213] The deprotection and elongation reactions were carried out in a one-pot operation according to the experimental method described in Example 6.

[1214] [Table 34]

[1215] Weight (mg) Yield (%) Raw material (compound 9a) 204.6 - Product (compound 6a) 219.0 97

[1216] [Table 35]

[1217] Analysis of deprotection reactions (HPLC method 1)

[1218] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Deprotected product (compound 9b) 564.33 565.31([M+H]+) 3.338 98.970

[1219] [Table 36]

[1220] Analysis of the elongation reaction (HPLC method 1)

[1221] MW m / z rt Purity LC A% Product (compound 6a) 735.92 758.5([M+Na]+) 5.301 99.573

[1222] (Example 14)

[1223] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (3-mer: TMSOTf-HMDS method)

[1224]

[1225] 107.4 mg of the starting material was weighed into a reaction vessel and dissolved in ethyl acetate at 5 v / w. The reaction vessel was then cooled with ice. After 10 minutes, 0.085 mL (2.4 eq) of HMS (1,1,1,3,3,3-hexamethyldisilazane) and 35 μL (1.2 eq) of TMSOTf were added sequentially under a nitrogen atmosphere, and the reaction solution was stirred. Two hours after the addition of the reagents, the conversion rate was analyzed by LCMS and found to be 55.8%. Therefore, 20 μL (0.69 eq) of TMSOTf was further added. One hour after the addition of the reagents, the starting material was confirmed to have disappeared by LCMS. No amide bond cleavage was confirmed.

[1226] Add 373.4 mg (13.3 eq) of dipotassium hydrogen phosphate to the reaction vessel, then add 0.89 ml of water and stir the reaction solution for 20 minutes.

[1227] Then, 3 ml of ethyl acetate was added to the reaction vessel, and the two layers were separated. The organic layer was treated with a mixture of 1 ml of saturated sodium bicarbonate aqueous solution and 1 ml of brine. The resulting organic layer was then concentrated.

[1228] The resulting oily liquid 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 with ice. 36.8 mg of [the solution was then added].

[1229] mg of Boc-Ala-OH and 79.5 mg of DMT-MM were added, and the reaction solution was stirred overnight in an ice bath. After 15.5 hours, the disappearance of the starting material was confirmed by LCMS, followed by liquid separation. The resulting organic layer was washed twice with 5% potassium carbonate, once with water, twice with 5% potassium bisulfate, and once with brine, and then concentrated. 0.1075 g (90% yield) of crude product was obtained as a white solid.

[1230] [Table 37]

[1231] Weight (mg) Yield (%) Raw material (compound 9a) 107.4 - Product (compound 6a) 107.5 90

[1232] [Table 38]

[1233] Analysis of deprotection reactions (HPLC method 1)

[1234] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Intermediate (compound 9b) 564.33 565.31([M+H]+) 3.360 98.783

[1235] [Table 39]

[1236] Analysis of the elongation reaction (HPLC method 1)

[1237] MW m / z rt Purity LC A% Product (compound 9a) 735.42 758.4([M+Na]+) 5.268 98.031

[1238] B. Screening of electrophilic species scavengers

[1239] (Example 15)

[1240] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a)

[1241] (Base: N-(trimethylsilyl)diethylamine)

[1242]

[1243] 99.5 mg of the starting material was weighed into a reaction vessel and dissolved in ethyl acetate at 5 v / w. The reaction vessel was then cooled with 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 sequentially, and the reaction solution was stirred. 1.5 hours after the addition of the reagents, LCMS analysis showed a conversion of 30%. Therefore, 0.029 mL (1.1 eq) of TMSOTf was further added. Four hours after the start of the reaction, LCMS analysis confirmed the disappearance of the starting material. At this point, no amide bond breakage was confirmed. The reaction solution was stirred overnight, and 20 hours after the start of the reaction, LCMS analysis was performed again. Again, at this time, no amide bond breakage was confirmed.

[1244] Twenty-one 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 the mixture was stirred for 30 min. The reaction solution was diluted with 4 mL of ethyl acetate, and the two layers were separated to provide the organic layer. The resulting organic layer was washed twice with a mixed solvent of 0.5 mL of brine and 0.5 mL of saturated sodium bicarbonate aqueous solution. The organic layer was then washed with 0.5 mL of brine and concentrated. The 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 brine. The organic layer was then washed with 0.5 mL of 10% brine and concentrated under reduced pressure to give 81.7 mg of the deprotected product in 97% yield.

[1245] [Table 40]

[1246] Weight (mg) Yield (%) Raw material (compound 9a) 99.5 - Product (compound 9b) 81.7 97

[1247] [Table 41]

[1248] Analysis (HPLC Method 1)

[1249] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 6875([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.27([M+H]+) 3.364 95.547

[1250] (Example 16)

[1251] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a)

[1252] (Base: N-(trimethylsilyl)morpholine)

[1253]

[1254] The experiment was conducted according to the method described in Example 15.

[1255] [Table 42]

[1256] Weight (mg) Yield (%) Raw material (compound 9a) 98.4 - Product (compound 9b) 117.8 Quantitative

[1257] [Table 43]

[1258] Analysis (HPLC Method 1)

[1259] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.30([M+H]+) 3.350 98.652

[1260] (Example 17)

[1261] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a)

[1262] (Base: N-tert-butyltrimethylsilylamine)

[1263]

[1264] The experiment was conducted according to the method described in Example 15.

[1265] [Table 44]

[1266] Weight (mg) Yield (%) Raw material (compound 9a) 100.9 - Product (compound 9b) 128.6 Quantitative

[1267] [Table 45]

[1268] Analysis (HPLC Method 1)

[1269] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.28([M+H]+) 3.354 98.631

[1270] (Example 18)

[1271] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (base: 2,2,4,4-tetramethylpentanoneimine)

[1272]

[1273] The experiment was conducted according to the method described in Example 15.

[1274] [Table 46]

[1275] Weight (mg) Yield (%) Raw material (compound 9a) 88.0 - Product (compound 9b) 102.5 Quantitative

[1276] [Table 47]

[1277] Analysis (HPLC Method 1)

[1278] MW m / z rt <![CDATA[ | Purity LC A% <![CDATA[Starting material (Compound 9a) | > 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 56528([M+H]+) 3.338 98.433

[1279] (Example 19)

[1280] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (base: isopropenyloxytrimethylsilane)

[1281]

[1282] The experiment was conducted according to the method described in Example 15.

[1283] [Table 48]

[1284] Weight (mg) Yield (%) Raw material (compound 9a) 44.3 - Product (compound 9b) 44.2 Quantitative

[1285] [Table 49]

[1286] Analysis (HPLC Method 1)

[1287] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.27([M+H]+) 3.340 97.587

[1288] (Example 20)

[1289] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (base: dimethyl ketene methyltrimethylsilyl acetal)

[1290]

[1291] The experiment was conducted according to the method described in Example 15.

[1292] [Table 50]

[1293] Weight (mg) Yield (%) Raw material (compound 9a) 44.9 - Product (compound 9b) 44.7 Quantitative

[1294] [Table 51]

[1295] Analysis (HPLC Method 1)

[1296] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.27([M+H]+) 3.348 98.352

[1297] (Example 21)

[1298] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a) (base: 3,4-dihydro-2H-pyran)

[1299]

[1300] The experiment was conducted according to the method described in Example 15.

[1301] [Table 52]

[1302] Weight (mg) Yield (%) Raw material (compound 9a) 53.7 - Product (compound 9b) 69.2 Quantitative

[1303] [Table 53]

[1304] Analysis (HPLC Method 1)

[1305] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.27([M+H]+) 3.325 98.503

[1306] (Example 22)

[1307] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a)

[1308] (Base: N,N,N′,N′-tetramethyl-1,8-naphthyldiamine)

[1309]

[1310] The experiment was conducted according to the method described in Example 15.

[1311] [Table 54]

[1312] Weight (mg) Yield (%) Raw material (compound 9a) 50.6 - Product (compound 9b) 57.6 Quantitative

[1313] [Table 55]

[1314] Analysis (HPLC Method 1)

[1315] MW m / z rt Purity LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.28([M+H]+) 3.353 98.409

[1316] (The LCA% of the above products was obtained by excluding the base remaining after post-treatment.)

[1317] (Example 23)

[1318] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a)

[1319] (Base: 2,2′-isopropylidene bis[(4S)-4-tert-butyl-2-) [zoline]

[1320]

[1321] The experiment was conducted according to the method described in Example 15.

[1322] [Table 56]

[1323] Weight (mg) Yield (%) Raw material (compound 9a) 45.7 - Product (compound 9b) 128.5 Quantitative

[1324] [Table 57]

[1325] Analysis (HPLC Method 1)

[1326] MW m / z rt LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.28([M+H]+) 3.353 90.099

[1327] (The LCA% of the above products was obtained by excluding the base remaining after post-treatment.)

[1328] (Example 24)

[1329] Deprotection of Boc-MePhe-MeVal-Asp(OBn)-pip (compound 9a)

[1330] (Base: diisopropylcarbodiimide)

[1331]

[1332] The experiment was conducted according to the method described in Example 15.

[1333] [Table 58]

[1334] Weight (mg) Yield (%) Raw material (compound 9a) 36.8 - Product (compound 9b) 31.2 85

[1335] [Table 59]

[1336] Analysis (HPLC Method 1)

[1337] MW m / z rt LC A% Raw material (compound 9a) 664.38 687.5([M+Na]+) 5.647 99.206 Product (compound 9b) 564.33 565.28([M+H]+) 3.347 89.920

[1338] (The LCA% of the above products was obtained by excluding the base remaining after post-treatment.)

[1339] C. Screening of electrophilic species scavengers (experiments in 11-mer peptide)

[1340] (Example 25)

[1341] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-BSTFA method)

[1342]

[1343] The experiment was conducted according to Example 2.

[1344] [Table 60]

[1345] Weight (mg) Yield (%) Raw material (compound 1a) 19.7 - Product (compound 1b) 14.8 80

[1346] [Table 61]

[1347] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1348] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.67 4.638 96.275

[1349] (Example 26)

[1350] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-BSA method)

[1351]

[1352] The experiment was conducted according to Example 2.

[1353] [Table 62]

[1354] Weight (mg) Yield (%) Raw material (compound 1a) 18.0 - Product (compound 1b) 11.8 70

[1355] [Table 63]

[1356] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1357] MW m / z rt Purity LC A% Raw material (compound 1 a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.67 4.633 94.636

[1358] (Example 27)

[1359] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-silylamine method)

[1360]

[1361] The experiment was conducted according to Example 2.

[1362] [Table 64]

[1363] Weight (mg) Yield (%) Raw material (compound 1a) 19.3 - Product (compound 1b) 16.1 89

[1364] [Table 65]

[1365] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1366] MW m / z rt Purity LCA% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.68 4.627 96.267

[1367] (Example 28)

[1368] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-silylamine method)

[1369]

[1370] The experiment was conducted according to Example 2.

[1371] [Table 66]

[1372] Weight (mg) Yield (%) Raw material (compound 1a) 20.2 - Product (compound 1b) 15.3 81

[1373] [Table 67]

[1374] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1375] MW m / z rt Purity LC A% Raw material (compound 1 a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.65 4.626 97.574

[1376] (Example 29)

[1377] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-imine method)

[1378]

[1379] The experiment was conducted according to Example 2.

[1380] [Table 68]

[1381] Weight (mg) Yield (%) Raw material (compound 1a) 18.7 - Product (compound 1b) 15.7 90

[1382] [Table 69]

[1383] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1384] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.70 4.631 97.089

[1385] (Example 30)

[1386] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-MSTFA method)

[1387]

[1388] The experiment was conducted according to Example 2.

[1389] [Table 70]

[1390] Weight (mg) Yield (%) Raw material (compound 1a) 21.7 - Product (compound 1b) 15.7 77

[1391] [Table 71]

[1392] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1393] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.61 4.616 96.490

[1394] (Example 31)

[1395] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-silylamine method)

[1396]

[1397] The experiment was conducted according to Example 2.

[1398] [Table 72]

[1399] Weight (mg) Yield (%) Raw material (compound 1a) 17.5 - Product (compound 1b) 13.5 81

[1400] [Table 73]

[1401] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1402] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.71 4.629 97.390

[1403] (Example 32)

[1404] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-enone silyl acetal method)

[1405]

[1406] The experiment was conducted according to Example 2.

[1407] [Table 74]

[1408] Weight (mg) Yield (%) Raw material (compound 1a) 23.6 - Product (compound 1b) 19.8 90

[1409] [Table 75]

[1410] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1411] MW m / z rt Purity LC A% Raw material (compound 1 a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.63 4.620 97.488

[1412] (Example 33)

[1413] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-proton sponge method)

[1414]

[1415] The experiment was conducted according to Example 2.

[1416] [Table 76]

[1417] Weight (mg) Yield (%) Raw material (compound 1a) 17.5 - Product (compound 1b) 16.2 97

[1418] (The alkali is even retained after post-processing.)

[1419] [Table 77]

[1420] Analysis (HPLC Method 1: Determination of impurities in raw materials and target products)

[1421] MW m / z rt Purity LCA% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680 Product (compound 1b) 1460.90 731.68 4.628 96.025

[1422] (The LCA% of the above products was obtained by excluding the base remaining after post-treatment.)

[1423] (Example 34)

[1424] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-dimethylpyridine method)

[1425]

[1426] 18.8 mg of the starting material was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. Then, 0.005 mL (3.6 eq) of 2,6-dimethylpyridine and 0.0078 mL (3.6 eq) of TMSOTf were added, and the reaction solution was stirred. Four hours after the addition of the reagents, the reaction was analyzed by LCMS (HPLC method 1), and the conversion (target product / (target product + starting material)) was confirmed to be 14%. Next, 19 hours after the addition of the reagents, the reaction was analyzed by LCMS, and the conversion was still 14%, confirming no amide bond cleavage.

[1427] [Table 78]

[1428] Weight (mg) Yield (%) Raw material (compound 1a) 18.8 - Product (compound 1b) Not separated Not separated

[1429] [Table 79]

[1430] Analysis (HPLC Method 1: Determination of raw material purity)

[1431] MW m / z rt Purity LC A% Raw material (compound 1 a) 1560.96 1242.05 6.519 96.680

[1432] [Table 80]

[1433] Analysis (HPLC Method 1: Determination of Conversion)

[1434] MW m / z rt LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 75.059 Product (compound 1b) 1460.90 731.67 4.620 11.831

[1435] (Example 35)

[1436] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-dimethylpyridine method)

[1437]

[1438] 89.3 mg of the starting 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-dimethylpyridine 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 found to be 0%. Therefore, 0.032 mL (4.8 eq) of 2,6-dimethylpyridine and 0.024 mL (2.4 eq) of TMSOTf were further added. LCMS analysis was performed 1.25 hours and 14 hours after the further addition of reagents, and the conversion rate remained 0%, confirming that no amide bond cleavage occurred.

[1439] [Table 81]

[1440] Weight (mg) Yield (%) Raw material (compound 1a) 89.3 - Product (compound 1b) Not separated Not separated

[1441] [Table 82]

[1442] Analysis (HPLC Method 1: Determination of raw material purity)

[1443] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.545 89.564

[1444] [Table 83]

[1445] Analysis (HPLC Method 1: Determination of Conversion)

[1446] MW m / z rt LC A% Raw material (compound 1 a) 1560.96 1242.05 6.571 89.649 Product (compound 1b) 1460.90 ND ND 0

[1447] (Example 36)

[1448] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-2,6-di-tert-butylpyridine method)

[1449]

[1450] 14.9 mg of the starting material was weighed into a reaction vessel and dissolved in 0.2 mL of ethyl acetate. Then, 0.011 mL (5.4 eq) of 2,6-di-tert-butylpyridine and 0.0062 mL (3.6 eq) of TMSOTf were added, and the reaction solution was stirred. Four 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 found to be 59%. Twenty-two hours after the start of the reaction, the reaction was analyzed again by LCMS, and the conversion rate remained at 59%, confirming that no amide bond cleavage occurred.

[1451] [Table 84]

[1452] Weight (mg) Yield (%) Raw material (compound 1a) 14.9 - Product (compound 1b) Not separated Not separated

[1453] [Table 85]

[1454] Analysis (HPLC Method 1: Determination of raw material purity)

[1455] MW m / z rt Purity LC A% Raw material (compound 1 a) 1560.96 1242.05 6.545 96.680

[1456] [Table 86]

[1457] Analysis (HPLC Method 1: Determination of Conversion)

[1458]

[1459] (Example 37)

[1460] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-tertiary amine method)

[1461]

[1462] 17.7 mg of the starting material was weighed into a reaction vessel and dissolved in 0.20 mL of ethyl acetate. 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) at one and four hours after the addition of the reagents, and the conversion rate (target product / (target product + starting material)) was only 0.7% at each time point. This confirmed that no amide bond cleavage occurred.

[1463] [Table 87]

[1464]

[1465] [Table 88]

[1466] Analysis (HPLC Method 1: Determination of raw material purity)

[1467] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680

[1468] [Table 89]

[1469] Analysis (HPLC Method 1: Determination of Conversion)

[1470]

[1471] (Example 38)

[1472] Boc removal reaction of Boc-Melle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-tertiary amine method)

[1473]

[1474] 19.1 mg of the starting material was weighed into 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 2) at two and four hours after the addition of the reagents, and the conversion rate (target product / (target product + starting material)) was found to be less than 0.8% at each time point. This confirmed the absence of amide bond cleavage.

[1475] [Table 90]

[1476] Weight (mg) Yield (%) Raw material (compound 1a) 19.1 - Product (compound 1b) Not separated Not separated

[1477] [Table 91]

[1478] Analysis (HPLC Method 1: Determination of raw material purity)

[1479] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680

[1480] [Table 92]

[1481] Analysis (HPLC Method 1: Determination of Conversion)

[1482]

[1483] (Example 39)

[1484] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TMSOTf-tertiary amine method)

[1485]

[1486] 92.9 mg of the starting material was weighed into a reaction vessel and dissolved in 1 ml of ethyl acetate. The reaction vessel was then cooled with ice. Under a nitrogen atmosphere, 0.015 ml (2.4 eq) of diisopropylethylamine and 0.013 ml (1.2 eq) of TMSOTf were added, and the reaction solution was stirred. Two hours after the addition of the reagents, the reaction was analyzed, and the conversion rate (target product / (target product + starting material)) was found to be 0%. Therefore, three hours after the addition of the reagents, 0.030 ml (4.8 eq) of diisopropylethylamine and 0.026 ml (2.4 eq) of TMSOTf were further added. Three hours after the further addition of reagents, the reaction was analyzed again, and the conversion rate was found to be 0%. This confirmed that no amide bond cleavage occurred.

[1487] [Table 93]

[1488] Weight (mg) Yield (%) Raw material (compound 1a) 92.9 - Product (compound 1b) Not separated Not separated

[1489] [Table 94]

[1490] Analysis (HPLC Method 1: Determination of raw material purity)

[1491] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1241.93 6.538 89.465

[1492] [Table 95]

[1493] Analysis (HPLC Method 1: Determination of Conversion)

[1494] MW m / z rt LC A% Raw material (compound 1a) 1560.96 1242.05 6.568 89.432 Product (compound 1b) 1460.90 ND ND 0

[1495] (Example 40)

[1496] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: carried out using only TMSOTf in the absence of organic bases.)

[1497]

[1498] 18.3 mg of the starting material was weighed into a reaction vessel and dissolved in 0.2 mL of ethyl acetate. The reaction vessel was then cooled with ice. 0.0077 mL (3.6 eq) of TMSOTf was then added under a nitrogen atmosphere, and the reaction solution was stirred. The reaction was analyzed 1.5 hours after the addition of the reagents, confirming that products with multiple amide bond cleavage were generated at a conversion rate of 68% (= target product / (target product + starting material)).

[1499] [Table 96]

[1500] Weight (mg) Yield (%) Raw material (compound 1a) 18.3 - Product (compound 1b) Not separated Not separated

[1501] [Table 97]

[1502] Analysis (HPLC Method 1: Determination of raw material purity)

[1503] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680

[1504] [Table 98]

[1505] Analysis (HPLC Method 1: Determination of conversion rate and by-product formation rate)

[1506] MW m / z rt LC A% Raw material (compound 1 a) 1560.96 1241.77 6.575 15.543 Product (compound 1b) 1460.90 731.72 4.630 32.712 Fracture product (compound 1c) 377.23 378.22([M+H]+) 2.269 0.986 Fracture products (compound 1d) 757.47 758.40([M+H]+) 2.758 9.731 Fracture products (compound 1e) 721.44 722.43([M+H]+) 3.893 15·859 Fracture products (compound 1f) 1101.68 1102.56([M+H]+) 4.220 4.701 Fracture products (compound 1 g) Unknown 573.27 4.788 4.808 Ethyl acetate 1.840 15.660

[1507] The structure of compound 1g is unknown.

[1508] (Example 41)

[1509] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: carried out using TMSOTf and triisopropylsilane in the absence of organic base.)

[1510]

[1511] 20.5 mg of the starting material was weighed into a reaction vessel and dissolved in 0.2 mL of ethyl acetate. The reaction vessel was then cooled with ice. Under a nitrogen atmosphere, 0.0097 mL (3.6 eq) of triisopropylsilane and 0.0085 mL (3.6 eq) of TMSOTf were added, and the reaction solution was stirred. The reaction was analyzed one hour after the addition of the reagents, confirming that products with multiple amide bond cleavage were produced at a conversion rate of 43% (= target product / (target product + starting material)).

[1512] [Table 99]

[1513] receive Weight (mg) Yield (%) Raw material (compound 1a) 20.5 - Product (compound 1b) Not separated Not separated

[1514] [Table 100]

[1515] Analysis (HPLC Method 1: Determination of raw material purity)

[1516] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.538 96.680

[1517] [Table 101]

[1518] Analysis (HPLC Method 1: Determination of conversion rate and by-product formation rate)

[1519]

[1520] The structure of compound 1g is unknown.

[1521] (Example 42)

[1522] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TFA method)

[1523]

[1524] 35.3 mg of the starting material was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. The reaction vessel was then cooled with ice. 0.004 mL (2.3 eq) of trifluoroacetic acid was added under a nitrogen atmosphere, and the reaction solution was stirred. Analysis of the reaction 10 minutes after the addition of the reagent revealed a conversion rate (target product / (target product + starting material)) of 0%. Therefore, another 0.004 mL (2.3 eq) of trifluoroacetic acid was added. Analysis of the reaction again 10 minutes after the further addition of the reagent revealed a conversion rate of 0%. Therefore, another 0.0094 mL (5.4 eq) of trifluoroacetic acid was added. Ten minutes after the further addition of the reagent, the reaction solution was warmed to room temperature and stirred continuously. Four hours after warming to room temperature, analysis of the reaction confirmed that product 1e, resulting from the amide bond cleavage, was produced with a conversion rate of 2%.

[1525] [Table 102]

[1526] Weight (mg) Yield (%) Raw material (compound 1a) 35.3 - Product (compound 1b) Not separated Not separated

[1527] [Table 103]

[1528] Analysis (HPLC Method 1: Determination of raw material purity)

[1529] MW m / z rt Purity LC A% Raw material (compound 1 a) 1560.96 1242.05 6.519 96.680

[1530] [Table 104]

[1531] Analysis (HPLC Method 1: Determination of conversion rate and by-product formation rate)

[1532] MW m / z rt LC A% Raw material (compound 1a) 1560.96 1242.05 6.568 93.488 Product (compound 1b) 1460.90 731.67 4.637 2.048 Fracture products (compound 1e) 721.44 722.47([M+H]+) 3.900 0.880 Impurities (1g of compound) Unknown 573.29 4.789 1.020 dichloromethane 2.375 1.059

[1533] The structure of compound 1g is unknown.

[1534] (Example 43)

[1535] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TFA-TIPS-H2O-PhOH method)

[1536] Reference: J. Am. Chem. Soc., 2015, 137, 13488

[1537]

[1538] 15.9 mg of the starting material was weighed into a reaction vessel, and 0.0125 mL of water and 0.0125 mL of triisopropylsilane were added. The reaction vessel was then cooled to -10 °C. 0.48 mL of trifluoroacetic acid was added, and the reaction solution was stirred. The reaction was analyzed two hours after the addition of the reagents, confirming that products 1d and 1e, resulting from amide bond cleavage, were produced with a conversion rate of 89% (target product / (target product + starting material)). The reaction was analyzed again 14.5 hours after the addition of the reagents, confirming that the starting material was consumed and that products 1d and 1e, resulting from amide bond cleavage, were produced in increasing quantities.

[1539] [Table 105]

[1540] Weight (mg) Yield (%) Raw material (compound 1a) 15.9 - Product (compound 1b) Not separated Not separated

[1541] [Table 106]

[1542] Analysis (HPLC Method 1: Determination of raw material purity)

[1543] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.519 96.680

[1544] [Table 107]

[1545] Analysis (HPLC Method 1: Conversion and byproduct formation were determined two hours after the reaction)

[1546] MW m / z rt LC A% Raw material (compound 1a) 1560.96 1241.57 6.527 9.531 Product (compound 1b) 1460.90 731.67 4.629 77.361 Fracture products (compound 1d) 757.47 758.41([M+H]+) 2.761 5.716 Impurities (compound 1e) 721.44 722.47([M+H]+) 3.902 7.392

[1547] [Table 108]

[1548] Analysis (HPLC Method 1: Formation rate of target product and byproducts at 14.5 hours after reaction)

[1549] MW m / z rt LC A% Raw material (compound 1 a) 1560.96 ND ND 0 Product (compound 1b) 1460.90 731.67 4.631 29.383 Fracture products (compound 1d) 757.47 758.39([M+H]+) 2.757 37.117 Fracture products (compound 1e) 721.44 722.41([M+H]+) 3.892 32.950

[1550] (Example 44)

[1551] Boc removal reaction of Boc-MeIle-Ala-MePhe-MeVal-Asp(pip)-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl (compound 1a) (11-mer: TFA-TIPS-H2O-PhOH method)

[1552] Reference: J. Am. Chem. Soc., 2012, 134, 13244

[1553]

[1554] 10.3 mg of phenol was weighed into a reaction vessel, along with 0.034 mL of water and 0.025 mL of triisopropylsilane. The reaction vessel was then cooled to -10 °C. Next, 0.50 mL of trifluoroacetic acid was added. Six minutes after the addition, 13.4 mg of the starting material was added, and the reaction solution was stirred. Two hours after the addition of the starting material, the reaction was analyzed, confirming that products 1d and 1e, resulting from amide bond cleavage, were produced with a conversion rate of 82% (target product / (target product + starting material)). Seven hours after the addition of the starting material, the reaction was analyzed again, confirming that the starting material was consumed and that products 1d and 1e, resulting from amide bond cleavage, were produced in increasing quantities.

[1555] [Table 109]

[1556] Weight (mg) Yield (%) Raw material (compound 1a) 10.3 - Product (compound 1b) Not separated Not separated

[1557] [Table 110]

[1558] Analysis (HPLC Method 1: Determination of raw material purity)

[1559] MW m / z rt Purity LC A% Raw material (compound 1a) 1560.96 1242.05 6.538 96.680

[1560] [Table 111]

[1561] Analysis (HPLC Method 1: Conversion and byproduct formation were determined two hours after the reaction)

[1562] MW m / z rt LC A% Raw material (compound 1 a) 1560.96 1242.05 6.523 6.500 Product (compound 1b) 1460.90 731.67 4.628 30.640 Fracture products (compound 1d) 757.47 758.38([M+H]+) 2.769 1.583 Fracture products (compound 1e) 721.44 722.37([M+H]+) 3.884 2.659 phenol 2.172 58.619

[1563] [Table 112]

[1564] Analysis (HPLC Method 1: Formation rate of target product and byproducts at five hours after reaction)

[1565] MW m / z rt LC A% Raw material (compound 1a) 1560.96 ND ND 0 Product (compound 1b) 1460.90 731.67 4.633 25.258 Fracture products (compound 1d) 757.47 758.40([M+H]+) 2.769 8.506 Fracture products (compound 1e) 721.44 722.39([M+H]+) 3.884 8.035 phenol 2.172 58.200

[1566] As shown in Examples 2, 3 and 26 to 44, imine esters, amides, enone acetals, enol ethers, imines, amines, diamines and dialkylcarbodiimides were found to be excellent electrophilic species scavengers, inhibiting backbone destruction and allowing efficient Boc removal reactions of titanium with long backbones, such as 11-mer.

[1567] D. Comparative experiments between the TFA method and TMSOTf-HMDS in the tBu removal reaction (Table 113)

[1568]

[1569] (Example 45)

[1570] t-Bu removal reaction of compound 13a (TFA method)

[1571] 29.8 mg of substrate 13a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. 10 eq. of TFA was added to the solution at room temperature. Four hours after the addition of the reagent, another 10 eq. of TFA was added. 1.5 hours after the further addition of the reagent, the reaction was analyzed by LCMS, revealing a conversion of 52%. The purity decreased by 22%, and 10% of byproducts due to amide bond cleavage were observed.

[1572] (Example 46)

[1573] t-Bu removal reaction of compound 13a (TMSOTf-HMDS method)

[1574] 30.0 mg of substrate 13a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (3.0 eq.) and TMSOTf (2.0 eq.) were added sequentially to the solution at 0 °C. Two hours after the addition of reagents, the reaction solution was warmed to room temperature. 2.5 hours after warming, HMDS (3 eq.) and TMSOTf (2 eq.) were added. Thirty minutes after the further addition of reagents, the reaction was analyzed by LCMS, confirming a conversion of over 99%. At this point, no amide bond cleavage was confirmed.

[1575]

[1576] (Example 47)

[1577] t-Bu removal reaction of compound 14a (TFA method)

[1578] 29.7 mg of substrate 14a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. TFA (20 eq.) was added to the solution at room temperature. Seven hours after the addition of the reagent, the reaction was analyzed by LCMS, revealing a conversion rate of 92%. Purity decreased by 46%, and 24% of byproducts due to amide bond cleavage were observed.

[1579] (Example 48)

[1580] t-Bu removal reaction of compound 14a (TMSOTf-HMDS method)

[1581] 30.0 mg of substrate 14a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (3.0 eq.) and TMSOTf (2.0 eq.) were added sequentially to the solution at 0 °C. Six hours after the addition of reagents, the reaction was analyzed by LC-MS to confirm the disappearance of the starting material. At this point, 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 the mixture was stirred for 30 minutes under ice-cooling. 1 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 0.30 mL of brine. The organic layer was filtered through diatomaceous earth, concentrated, and dried under reduced pressure to give 26.8 mg of 2b with a purity of 99%.

[1582]

[1583] (Example 49)

[1584] t-Bu removal reaction of compound 15a (TFA method)

[1585] 29.9 mg of substrate 15a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. TFA (20 eq.) was added to the solution at room temperature. The reaction was analyzed by LC-MS 5.5 hours after the addition of the reagent, and the conversion rate was found to be 50%. 28% of byproducts due to amide bond cleavage were observed.

[1586] (Example 50)

[1587] t-Bu removal reaction of compound 15a (TMSOTf-HMDS method)

[1588] 30.0 mg of substrate 15a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMS (3.6 eq.) and TMSOTf (2.4 eq.) were added sequentially to the solution at room temperature. Five hours after the addition of reagents, HMS (1.8 eq.) and TMSOTf (1.2 eq.) were added. One hour after the further addition of reagents, the reaction was analyzed by LC-MS to confirm the disappearance of the starting material. At this point, no amide bond cleavage was confirmed.

[1589]

[1590] (Example 51)

[1591] t-Bu removal reaction of compound 16a (TFA method)

[1592] 30.2 mg of substrate 16a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. TFA (20 eq.) was added to the solution at room temperature. 4.5 h after the addition of the reagent, a further 10 eq. of TFA was added. One hour after the addition of the reagent, the reaction was analyzed by LCMS, revealing a conversion of 65%. 7.0% of byproducts due to amide bond cleavage were observed.

[1593] (Example 52)

[1594] t-Bu removal reaction of compound 16a (TMSOTf-HMDS method)

[1595] 29.9 mg of substrate 16a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMS (3.6 eq) and TMSOTf (2.4 eq) were subsequently added to the solution at room temperature. The reaction was analyzed by LC-MS four hours after the reagents were added to confirm the disappearance of the starting material.

[1596] At this point, it was confirmed that no amide bonds were broken.

[1597]

[1598] (Example 53)

[1599] t-Bu removal reaction of compound 17a (TFA method)

[1600] 50.0 mg of substrate 17a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. TFA (5 eq.) was added to the solution at 0 °C. Two hours after the addition of the reagent, TFA (5 eq.) was added again. After another 15.5 hours, the reaction solution was warmed to room temperature. Three hours after warming, TFA (10 eq.) was added. After another 1.5 hours, TFA (20 eq.) was added. 1.5 hours after the further addition of reagent, the reaction was analyzed by LCMS, revealing a conversion of 54%. 26% of byproducts due to amide bond cleavage were observed.

[1601] (Example 54)

[1602] t-Bu removal reaction of compound 17a (TMSOTf-HMDS method)

[1603] 30.0 mg of substrate 17a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (5.4 eq.) and TMSOTf (3.6 eq.) were added sequentially to the solution at 0 °C. Four hours after the addition of reagents, the reaction solution was warmed to room temperature. Three hours after warming, the reaction was analyzed by LCMS to confirm the disappearance of the starting material. At this point, no amide bond cleavage was confirmed.

[1604]

[1605] (Example 55)

[1606] t-Bu removal reaction of compound 18a (TFA method)

[1607] 29.9 mg of substrate 18a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. TFA (20 eq.) was added to the solution at 0 °C. 4.5 h after the addition of reagents, a further 10 eq. of TFA was added, and the reaction solution was warmed to room temperature. Two h after the further addition of reagents, the reaction was analyzed by LCMS, revealing a conversion of 82%. 34% of byproducts due to amide bond cleavage were observed.

[1608] (Example 56)

[1609] t-Bu removal reaction of compound 18a (TMSOTf-HMDS method)

[1610] 29.8 mg of substrate 18a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (7.2 eq.) and TMSOTf (4.8 eq.) were added sequentially to the solution at 0 °C. Three hours after the addition of reagents, the reaction solution was warmed to room temperature. 3.5 hours after warming, the reaction was analyzed by LC-MS to confirm the disappearance of the starting material. At this point, no amide bond cleavage was confirmed.

[1611]

[1612] (Example 57)

[1613] t-Bu removal reaction of compound 19a (TFA method)

[1614] 50.0 mg of substrate 19a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. TFA (5 eq.) was added to the solution at 0 °C. Two hours after the addition of the reagent, TFA (5 eq.) was added. After another 15.5 hours, the reaction solution was warmed to room temperature. Three hours after warming, TFA (10 eq.) was added. After another 1.5 hours, TFA (20 eq.) was added. 1.5 hours after the further addition of reagent, the reaction was analyzed by LCMS, revealing a conversion of 82%. 14% of byproducts due to amide bond cleavage were observed.

[1615] (Example 58)

[1616] t-Bu removal reaction of compound 19a (TMSOTf-HMDS method)

[1617] 30.0 mg of substrate 19a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (3.6 eq.) and TMSOTf (2.4 eq.) were added sequentially to the solution at 0 °C. 3.5 h after the addition of reagents, the reaction solution was warmed to room temperature, and HMDS (3.6 eq.) and TMSOTf (2.4 eq.) were further added. One hour after the further addition of reagents, the reaction was analyzed by LCMS to confirm the disappearance of the starting material. At this point, no amide bond cleavage was confirmed.

[1618] As shown in Examples 45 to 58, it was found that in the Bu removal reaction, the TMSOTf-HMDS method using a combination of silylating agents and electrophilic species scavengers did not cause main chain destruction and allowed the deprotection reaction to proceed more efficiently compared to the conventional TFA method.

[1619] [Table 113]

[1620] Reaction conditions and experimental results

[1621]

[1622]

[1623] (Product identification)

[1624] [Table 114]

[1625] (HPLC Method 1)

[1626] MS (major peak) and retention time of the target product (in the TMSOTf / HMDS method embodiment),

[1627]

[1628] [Table 115]

[1629] MS and retention time of decomposition products

[1630]

[1631] The structures of compounds 13c to 19h are provided below.

[1632]

[1633]

[1634]

[1635] (Example 59)

[1636] t-Bu removal reaction of Fmoc-MeAsp(OtBu)-pip (compound 12a) (1-mer: TFA method)

[1637]

[1638] 48.0 mg of the starting 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. Nineteen hours after the addition of the reagents, the reaction was analyzed by LCMS (HPLC method 4), and the conversion (target product / (target product + starting material)) was confirmed to be 77%. At this point, rearrangement product 12c and hydrolysate 12d, representing compounds in which the amide bond was broken, were observed. Impurities of unknown structure were also generated.

[1639] [Table 116]

[1640] Weight (mg) Yield (%) Raw material (compound 12a) 48.0 - Product (compound 12b) Not separated Not separated

[1641] Raw material purity analysis (HPLC method 1)

[1642] [Table 117]

[1643] Analysis (HPLC Method 1)

[1644] MW m / z rt Purity LC A% Raw material (compound 12a) 492.26 493.24([M+H]+) 5.527 98.268

[1645] [Table 118]

[1646] Analysis (HPLC Method 4)

[1647]

[1648] (Example 60)

[1649] t-Bu removal reaction of Fmoc-MeAsp(OtBu)-pip (compound 12a) (1-mer: TMSOTf-HMDS method)

[1650]

[1651] The experiment was conducted according to Example 2.

[1652] [Table 119]

[1653] Weight (mg) Yield (%) Raw material (compound 12a) 59.9 - Product (compound 12b) 55.8 Quantitative

[1654] [Table 120]

[1655] Analysis (HPLC Method 1)

[1656] MW m / z rt Purity LC A% Raw material (compound 12a) 492.26 493.24([M+H]+) 5.527 98.268

[1657] [Table 121]

[1658] Analysis (HPLC Method 4)

[1659]

[1660] E. Comparative experiments between the TFA method and the TMSOTf-HMDS method in the t-Bu removal reaction (Table 122)

[1661]

[1662] (Example 61)

[1663] t-Bu removal reaction of compound 20a (TFA method)

[1664] 27.1 mg of substrate 20a was weighed into a reaction vessel and dissolved in 10 v / w dichloromethane. TFA (10 eq.) was added to the solution at room temperature. Eight hours after the addition of the reagent, the reaction was analyzed by LCMS, revealing a conversion of 76%. Purity decreased by 11%, and 8.1% of byproducts due to amide bond cleavage were observed. The same reaction was performed for substrate 21a (Table 122).

[1665] (Example 62)

[1666] t-Bu removal reaction of compound 20a (TMSOTf-HMDS method)

[1667] 27.6 mg of substrate 20a was weighed into a reaction vessel and dissolved in 10 v / w ethyl acetate. HMDS (2.4 eq) and TMSOTf (2.4 eq) were added sequentially to the solution at room temperature. Two hours after the reagents were added, the reaction was analyzed by LCMS to confirm the disappearance of the starting material. At this point, no amide bond cleavage was confirmed.

[1668] The same reaction was carried out for substrate 21a (Table 122).

[1669] [Table 122]

[1670]

[1671] (Product identification)

[1672] [Table 123]

[1673] (HPLC Method 1)

[1674] Major peaks and retention times of the product and target product

[1675]

[1676]

[1677] F. Comparative experiment between the TFA method and the TMSOTf-HMDS method in resin removal reaction

[1678] (Table 124)

[1679]

[1680] (Example 65)

[1681] Resin removal reaction of resin 22a (TFA method)

[1682] 30.2 mg of resin 22a was weighed into a reaction vessel, and the resin was swollen by adding 10 v / w of dichloromethane. After removing the dichloromethane from the reaction solution, 10 v / w% TFA (5% dichloromethane solution) was added at room temperature, and the vessel was shaken at 25°C. One hour after the start of shaking, the reaction was analyzed by LCMS, and 7.8% of byproducts due to amide bond cleavage were found. The same reaction was performed for resins 23a to 24a (Table 124).

[1683] (Example 66)

[1684] Resin removal reaction of resin 22a (TMSOTf-HMDS method)

[1685] 23.0 mg of substrate 22a was weighed into a reaction vessel, and the resin was swollen by adding 10 v / w of 1,2-dichloroethane. After removing the 1,2-dichloroethane from the reaction solution, a solution of HMDS (3.6 eq.) and TMSOTf (2.4 eq.) in 10 v / w of 1,2-dichloroethane was added to the reaction vessel. After stirring at 25 °C for four hours, the reaction was analyzed by LCMS and no amide bond cleavage was confirmed. The same reaction was performed for resins 23a to 24a (Table 124).

[1686] [Table 124]

[1687]

[1688] (Product identification)

[1689] HPLC Method A

[1690] Instrument: Waters ACQUITY UPLC H-Class

[1691] Column: Ascentis Express C18 (2.7μm, 4.6mm x50mm), Supelco

[1692] Eluents: A) 0.05% TFA / water, B) 0.05% TFA / CH3CN

[1693] Gradient (B):

[1694] Flow rate: 1.0 mL / min.

[1695] Detection: 210nm

[1696] Injection volume: 5μL

[1697] Sample preparation: 25 μL / 0.975 mL MeCN

[1698] HPLC Method B

[1699] Instrument: Waters ACQUITY UPLC H-Class

[1700] Column: Ascentis Express C18 (2.7μm, 4.6mm x 50mm), Supelco

[1701] Eluents: A) 0.05% TFA / water, B) 0.05% TFA / CH3CN

[1702] Gradient (B):

[1703] Flow rate: 1.0 mL / min.

[1704] Detection: 210nm

[1705] Injection volume: 5μL

[1706] Sample preparation: 5 μL / 1.00 mL (MeCN 0.950 mL + 0.1 M phosphate buffer (pH 8.0) 0.050 mL)

[1707] HPLC method C

[1708] Instrument: Waters ACQUITY UPLC H-Class

[1709] Column: Ascentis Express C18 (2.7μm, 4.6mm x 50mm), Supelco

[1710] Eluents: A) 0.05% TFA / water, B) 0.05% TFA / CH3CN

[1711] Gradient (B):

[1712] Flow rate: 1.0 mL / min.

[1713] Detection: 210nm

[1714] Injection volume: 5μL

[1715] Sample preparation: 5 μL / 1.00 mL MeCN

[1716] HPLC method D

[1717] Instrument: Shimadzu LCMS-2020

[1718] Column: Ascentis Express C18 (2.7μμm, 2.1mm x 50mm), Supelco

[1719] Eluents: A) 0.1% FA / water, B) 0.1% FA / CH3CN

[1720] Gradient (B):

[1721] Flow rate: 1.0 mL / min.

[1722] Detection: 210nm-400nm

[1723] Injection volume: 1 μL

[1724] HPLC method E

[1725] Instrument: SHIMADZU LCMS-2020

[1726] Column: Ascentis Express C182.1mm x 50mm, Supelco

[1727] Eluents: A) 0.1% FA / water, B) 0.1% FA / CH3CN

[1728] Gradient (B):

[1729] Flow rate: 1.0 mL / min.

[1730] Testing: PDA 210nm-400nm

[1731] Injection volume: 1 μL

[1732] HPLC method F

[1733] Instrument: Waters Acquity UPLC / SQD2

[1734] Column: Ascentis Express C18 (2.7μm, 2.1mm x 50mm), Supelco

[1735] Eluents: A) 0.1% FA / water, B) 0.1% FA / CH3CN

[1736] Gradient (B):

[1737] Flow rate: 1.0 mL / min.

[1738] Detection: 210nm-400nm

[1739] Injection volume: 1 μL

[1740] HPLC method G

[1741] Instrument: Waters Acquity UPLC / SQD2

[1742] Column: Ascentis Express C18 (2.7μm, 2.1mm x 50mm), Supelco

[1743] Eluents: A) 0.1% FA / water, B) 0.1% FA / CH3CN

[1744] Gradient (B):

[1745] Flow rate: 1.0 mL / min.

[1746] Detection: 210nm-400nm

[1747] Injection volume: 1L

[1748] HPLC method H

[1749] Instrument: Waters Acquity UPLC / SQD

[1750] Column: Ascentis Express C18 (2.7μm, 2.1mm x 50mm), Supelco

[1751] Eluents: A) 0.1% FA / water, B) 0.1% FA / CH3CN

[1752] Gradient (B):

[1753] Flow rate: 1.0 mL / min.

[1754] Detection: 210nm-400nm

[1755] Injection volume: 2μL

[1756] [Table 125]

[1757]

[1758]

[1759] Comparative experiment of G between the TFA method and the TMSOTf-HMDS method in resin removal reaction (Table 126)

[1760]

[1761] (Example 71)

[1762] CTC and t-Bu removal reactions of resin 25a (TFA method)

[1763] 20.0 mg of resin 25a was weighed into a reaction vessel, and the resin was swollen by adding 10 v / w dichloromethane. After removing the dichloromethane from the reaction solution, 10 v / w% TFA (10% dichloromethane solution) was added at room temperature, and the vessel was shaken at 25°C. One hour after the start of shaking, the reaction was analyzed by LCMS, and the conversion rate was found to be 17%. 3.8% of byproducts were generated due to amide bond cleavage. The same reaction was performed for resin 26a (Table 126).

[1764] (Example 72)

[1765] CTC resin removal and tBu deprotection reaction of resin 25a (TMSOTf-HMDS method)

[1766] 23.0 mg of substrate 25a was weighed into a reaction vessel, and the resin was swollen by adding 10 v / w of 1,2-dichloroethane. After removing the 1,2-dichloroethane from the reaction solution, a solution of HMDS (10.7 eq.) and TMSOTf (7.1 eq.) in 10 v / w of 1,2-dichloroethane was added to the reaction vessel. After shaking at 25 °C for four hours, the reaction was analyzed by LCMS, and the disappearance of t-Bu ester was confirmed. The same reaction was performed for resin 26a (Table 126).

[1767] [Table 126]

[1768]

[1769] (Product identification)

[1770] [Table 127]

[1771] (HPLC Method 1)

[1772] Major peaks and retention times of the product and target product

[1773]

[1774]

[1775] H. Synthesis of raw materials used in Boc removal, t-Bu removal, and resin removal reactions.

[1776] (Example 75)

[1777] Synthesis of 3-mer starting material for Boc removal reaction (Boc-Asp(OBn)-pip)

[1778]

[1779] The synthesis was carried out according to Example 88.

[1780] [Table 128]

[1781] Weight (g) Yield (%) Raw materials (27) 34.6 - Product (28) 37.6 90

[1782] [Table 129]

[1783] Analysis (HPLC Method 1)

[1784] MW m / z rt Purity LC A% Product (28) 390.48 291.19([M-Boc+H]+) 4.530 97.619

[1785] (Example 76)

[1786] Synthesis of 2-mer(Boc-MeVal-Asp(OBn)-pip)

[1787]

[1788] 5.714 g of the starting material was weighed into a reaction vessel and 29 ml of MeCN was added. After adding 2.3 ml of methanesulfonic acid, the oil bath was set at 45 °C and the reaction vessel was heated. After 70 minutes, the reaction vessel was allowed to return 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 the addition of the reagents, the reaction solution was concentrated. The reaction was quenched by adding ethyl acetate and a 5% potassium carbonate aqueous solution to the concentrate. The organic layer was separated by liquid separation, followed by washing twice with a 5% potassium carbonate aqueous solution, once with water, once with a 5% potassium bisulfate aqueous solution, once with a 10% sodium chloride aqueous solution, and once with brine. The organic layer was concentrated under reduced pressure to give 7.055 g (96% yield) of a pale yellow solid.

[1789] [Table 130]

[1790] Weight (g) Yield (%) Raw materials (28) 5.714 - Product (29) 7.055 96

[1791] [Table 131]

[1792] Analysis (HPLC Method 1)

[1793] MW m / z rt Purity LC A% Product (29) 503.64 526.29([M+Na]+) 5.178 96.889

[1794] (Example 77)

[1795] Synthesis of 3-mer(Boc-MePhe-MeVal-Asp(OBn)-pip)

[1796]

[1797] 7.055 g of the starting material was weighed into a reaction vessel and 35 mL of MeCN was added. After adding 2.2 mL of methanesulfonic acid, the oil bath was set at 45 °C and the reaction vessel was heated. After 70 minutes, the reaction vessel was allowed to return 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 then 9.466 g of sodium bicarbonate was added. Then 35 mL of water was added, followed by 4.61 g of Boc-MePhe-OH and 7.73 g of DMT-MM. After six hours, the reaction was monitored by LCMS, confirming that the starting material consumption was 99%. One hour after analysis, liquid-liquid separation was performed by adding ethyl acetate and water to obtain the organic layer. The organic layer was washed three times with 5% potassium carbonate aqueous solution, once with water, three times with 5% potassium bisulfate aqueous solution, and once with brine. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain 6.9757 g (75% yield) of the target product as a white solid.

[1798] [Table 132]

[1799] Weight (g) Yield (%) Raw materials (29) 7.055 - Product (9a) 6.9757 75

[1800] [Table 133]

[1801] Analysis (HPLC Method 1)

[1802] MW m / z rt Purity LC A% Product (9a) 664.84 687.43([M+Na]+) 5.684 99.206

[1803] (Example 78)

[1804] Synthesis of Boc-MeGly-O allyl

[1805]

[1806] 9.286 g of the starting material was weighed into a reaction vessel and 46 ml of DMF was added. The reaction vessel was cooled with ice, and then 10.20 g of potassium carbonate and 4.15 ml of allyl bromide were added. After 15 minutes, the reaction vessel was brought to room temperature and stirred overnight. MTBE was added to the reaction vessel, and the reaction was quenched with water. After liquid separation, the organic layer was washed once with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 10.083 g (90% yield) of the target product 31 as a clear oily liquid.

[1807] [Table 134]

[1808] Weight (g) Yield (%) Raw materials (30) 9.286 - Product (31) 10.083 90

[1809] (Example 79)

[1810] Synthesis of Boc-Thr(OBn)-MeGly-O allyl

[1811]

[1812] Deprotection and condensation reactions were carried out according to Example 76.

[1813] [Table 135]

[1814] Weight (g) Yield (%) Raw materials (31) 6.5224 - Product (32) 13.5594 Quantitative

[1815] [Table 136]

[1816] Analysis (HPLC Method 1)

[1817] MW m / z rt Purity LC A% Product (Compound 32) 420.51 321.10([M-Boc+H]+) 4.770 98.54

[1818] (Example 80)

[1819] Synthesis of Boc-MeLeu-Thr(OBn)-MeGly-O allyl

[1820]

[1821] The deprotection and condensation reactions are carried out using the same method as described above.

[1822] (Example 80a)

[1823] Teoc-MeLeu-OPfp was synthesized by esterification of Teoc-MeLeu-OH with pentafluorophenol (Pfp-OH).

[1824]

[1825] 926 mg of the starting material and 736 mg of pentafluorophenol (Pfp-OH) were weighed into separate reaction vessels, and 7.8 mL of isopropyl acetate was added. 767 mg of EDCI hydrochloride was added, and the reaction solution was stirred at room temperature for two 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, a clear oily liquid. The obtained compound was used in the next reaction without purification.

[1826] [Table 137]

[1827] Analysis (HPLC Method G)

[1828] MW m / z Retention time (min) Product (80a) 455.16 428.3([M-C2H4+H]+) 1·19

[1829] (Example 80b)

[1830] Synthesis of Teoc-MeLeu-Thr(OBn)-MeGly-O allyl

[1831]

[1832] Compound 80b can be synthesized via a condensation reaction using the method of Meneses et al. (J. Org. Chem., 2010, 75, 564-569), in which the terminal protecting group of compound 33 is removed and then reacted with pentafluorophenyl ester (compound 80a) to form an amide bond.

[1833] [Table 138]

[1834] Weight (g) Yield (%) Raw materials (33) 13.4338 - Product (8a) 15.5319 100

[1835] [Table 139]

[1836] Analysis (HPLC Method 1)

[1837] MW m / z rt Purity LC A% Product (8a) 660.41 561.28([M-Boc+H]+) 5.657 95.36

[1838] (Example 81)

[1839] Synthesis of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-O allyl

[1840]

[1841] The reaction was carried out according to Example 88.

[1842] [Table 140]

[1843] Weight (g) Yield (%) Raw materials (4b) 5.0118 - Product (3a) 5.68 90

[1844] [Table 141]

[1845] Analysis (HPLC Method 1)

[1846] MW m / z rt Purity LC A% Product (3a) 906.55 807.58([M-Boc]+H)+ 5.974 93.06

[1847] (Example 82)

[1848] Synthesis of Boc-MeAla-MePhe-Leu-MeLeu-Thr(OBn)-MeGly-OH

[1849]

[1850] 1.1180 g of the starting material was weighed into a reaction vessel, and 2.2 ml each of THF, methanol, and water were added. Then, 102.8 mg of lithium hydroxide monohydrate was added, and the reaction solution was stirred at room temperature for five hours. The reaction was confirmed to be complete by LC, and the reaction solution was then concentrated under reduced pressure. After adding ethyl acetate to the concentrate, 0.5 N hydrochloric acid was added to quench the reaction. The organic layer was separated by liquid chromatography, followed by washing twice with 0.5 N hydrochloric acid and twice with a 5% sodium chloride aqueous solution. The solvent was evaporated by concentration under reduced pressure to give 918.8 mg (86% yield) of a white solid.

[1851] [Table 142]

[1852] Weight (g) Yield (%) Raw material (3a) 1.1180 - Product (34) 0.9188 86

[1853] [Table 143]

[1854] Analysis (HPLC Method 1)

[1855]

[1856] (Example 83)

[1857] Synthesis of Fmoc-Asp(OtBu)-pip

[1858]

[1859] The reaction was carried out according to Example 88.

[1860] [Table 144]

[1861] Weight (g) Yield (%) Raw materials (11) 40 - Product (12) 47 Quantitative

[1862] [Table 145]

[1863] Analysis (HPLC Method 1)

[1864]

[1865] (Example 84)

[1866] Synthesis of FmocAsp(OH)pip

[1867]

[1868] 45.4 g of the starting material was weighed into a reaction vessel and 454 ml of trifluoroethanol was added. Then 24 ml of trimethylchlorosilane was added, and the reaction solution was stirred at room temperature. 2.5 hours after the start of the reaction, 910 ml of water was added in two portions, allowing crystals to precipitate. The crystals were filtered and then dried to give 25.8 g (61% yield) of the target product 36.

[1869] [Table 146]

[1870] Weight (g) Yield (%) Raw materials (35) 40 - Product (36) 25.8 61

[1871] [Table 147]

[1872] Analysis (HPLC Method 1)

[1873] MW m / z rt Purity LC A% Product (36) 422.18 423.21([M]+H)+ 3.101 98.259

[1874] (Example 85)

[1875] Fmoc-Asp(OH)-pip was loaded onto CTC resin.

[1876]

[1877] Perform the same loading steps as described in Example 112. Analyze the product after 5-mer elongation and subsequent resin removal steps.

[1878] [Table 148]

[1879] Weight (g) Raw materials (36) 4.09

[1880] (Example 86)

[1881] Solid-phase synthesis (2-mer elongation)

[1882]

[1883] The reaction is carried out in a solid-phase synthesis column.

[1884] 1) Deprotection step: Add 104 mL of DMF to Fmoc-MeAla-OCTC resin (37, theoretical amino acid loading: 9.49 mmol). Add 104 mL of a 20% solution of piperidine in DMF at 30 °C and shake the column for 15 min at 30 °C. After draining the solution, add another 104 mL of a 20% solution of piperidine in DMF and shake the column for 15 min at 30 °C. After draining the solution, wash the resin with 130 mL of DMF for 2 min x 7.

[1885] 2) Elongation Step: In a separate reactor from the solid-phase synthesis column, 6.62 g of Fmoc-MeVal-OH and 2.93 g of Oxyma were dissolved in 52 ml of DMF, followed by the addition of 5.87 ml of DIC. The container was shaken at 30°C for 30 minutes. This solution was then added to the solid-phase synthesis column, which was shaken at 30°C for two hours. After draining the solution, the resin was washed with 130 ml of DMF for 2 min x 6.

[1886] (Example 87)

[1887] Solid-phase synthesis (sequential elongation and resin removal reactions from 2-mer to 5-mer)

[1888]

[1889] The deprotection and elongation steps were repeated according to the method described in Example 86 to provide Boc-MeIle-Ala-MePhe-MeVal-Asp(OCTC)-pip. 147 ml of a mixed solvent of diisopropylethylamine, trifluoroethanol, and dichloromethane (2% diisopropylethylamine, 1:1 volume ratio) was added to the resulting resin, followed by shaking at 30°C for 2.5 hours. The discharged peptide solution was collected. After the resin-deprotected solution was discharged, the resin was washed twice with 25 ml of a mixed solvent of trifluoroethanol and dichloromethane (1:1 volume ratio), and the solution was concentrated. The concentrate was dissolved in 130 ml of ethyl acetate and washed twice with aqueous potassium carbonate solution, twice with potassium bisulfate solution, and once with aqueous sodium chloride solution. The organic layer was then concentrated under reduced pressure. After drying, 4.9821 g (69% yield) of a white solid was obtained.

[1890] [Table 149]

[1891] Weight (g) Yield (%) Fmoc-MeAsp(OH)-pip(37) 4.09 - Product (38) 4.9821 69

[1892] [Table 150]

[1893] Analysis (HPLC Method 1)

[1894] MW m / z rt Purity LC A% Product (38) 772.47 795.5([M+Na]+) 4.856 96.471

[1895] (Example 88)

[1896] Synthesis of Fmoc-MeAsp(OtBu)-pip

[1897]

[1898] 49.6 g of EDCI hydrochloride was weighed into a reaction vessel and 400 mL of DMF was added. The reaction vessel was cooled to 0 °C, and then 100.050 g of Fmoc-MeAsp(OtBu)-OH was added. Next, using a dropping funnel, 40.1 g of Oxyma in 100 mL of DMF was added, followed by 34.9 mL of piperidine. Four hours and 30 minutes after the completion of the dropwise addition of piperidine, the reaction was analyzed by LCMS to confirm the disappearance of the starting material. The reaction solution was diluted with ethyl acetate, and then 500 mL of 0.5 N hydrochloric acid was added to quench the reaction. The organic layer was separated and washed twice with water, twice with 5% sodium carbonate aqueous solution, and twice with 5% sodium chloride aqueous solution. The obtained organic layer was concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate and heptane to give 86.230 g (75% yield) of the target product.

[1899] [Table 151]

[1900] Analysis (HPLC Method 1)

[1901] MW m / z rt Purity LC A% Product (Compound 11) 492.26 493.24([M+H]+) 5.527 98.268

[1902] (Example 89)

[1903] The synthesis intermediate for the synthesis of the 11-residue peptide (tBu form, Cbz-MeAla-MePhe-Leu-MeLeu-Val-MeGly-MeIle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(22)) (Cbz-Asp(OtBu)-pip(41))

[1904]

[1905] 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, and then 175 mL of a 5% potassium carbonate aqueous solution was added. The aqueous layer was removed, and the organic layer was washed twice with 175 mL of a 5% potassium bisulfate aqueous solution. The resulting organic layer was concentrated under reduced pressure and dried to give 20 g of Cbz-Asp(OtBu)-pip (41) in 100% yield.

[1906] (Example 90)

[1907] Synthesis of H-Asp(OtBu)-pip(42)

[1908]

[1909] 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. 10% Pd / C (20 w / w%) was added to both vessels, and the reaction was carried out at 30 °C under a 3 bar hydrogen atmosphere. Three 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 under reduced pressure and dried to give 12.3 g of H-Asp(OtBu)-pip(42) in 99% yield.

[1910] 11-mer (22) is synthesized from H-Asp(OtBu)-pip (42) via 19 steps as described below. The intermediates for synthesis are provided below.

[1911] H-Asp(OtBu)-pip(42)

[1912] Cbz-MeVal-Asp(OtBu)-pip(43)

[1913] H-MeVal-Asp(OtBu)-pip(44)

[1914] Cbz-MePhe-MeVal-Asp(OtBu)-pip(45)

[1915] H-MePhe-MeVal-Asp(OtBu)-pip(46)

[1916] Cbz-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(13)

[1917] H-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(47)

[1918] Cbz-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(14)

[1919] H-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(48)

[1920] Cbz-MeGly-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(49)

[1921] H-MeGly-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(50)

[1922] Cbz-Val-MeGly-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(15)

[1923] H-Val-MeGly-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(51)

[1924] Cbz-MeLeu-Val-MeGly-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(16)

[1925] H-MeLeu-Val-MeGly-Melle-Ser(otBu)-MePhe-MeVal-Asp(OtBu)-pip(52)

[1926] Cbz-Leu-MeLeu-Val-MeGly-Me‖e-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(17)

[1927] H-Leu-MeLeu-Val-MeGly-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(53)

[1928] Cbz-MePhe-Leu-MeLeu-Val-MeGly-Me‖e-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(18)

[1929] H-MePhe-Leu-MeLeu-Val-MeGly-Melle-Ser(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(54)

[1930] Cbz-MeAla-MePhe-Leu-MeLeu-Val-MeGly-Me‖e-Se r(OtBu)-MePhe-MeVal-Asp(OtBu)-pip(19)

[1931] (Example 91)

[1932] Peptide chain elongation (elongation method A)

[1933] 8.6 g of 42 was weighed into a reaction vessel and 108 mL of CPME was added. Cbz-MeVal-OH (1.1 eq.) and diisopropylethylamine (3 eq.) were added, followed by a solution of BEP (1.5 eq.) in 21.5 mL of MeCN. After stirring at room temperature for three minutes, 15 mL of a 10% sodium bisulfate aqueous solution was added. The aqueous layer was removed, and then 15 mL of a 5% potassium carbonate aqueous solution and trimethylamine hydrochloride (3 eq.) were added to the organic layer at room temperature. The mixture was heated to 40 °C and then stirred at 40 °C for 90 minutes. After cooling to room temperature, the aqueous layer was removed, and the resulting organic layer was washed with 15 mL of a 5% potassium carbonate aqueous solution. The resulting organic layer was concentrated under reduced pressure and dried to quantitatively yield 17 g of 43.

[1934] (Example 92)

[1935] Removal of N-terminal Cbz (Deprotection Method A)

[1936] 9.5 g of 43 was weighed into each of 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 3 bar hydrogen atmosphere. 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 under reduced pressure and dried to give 14 g of 44 in 100% yield.

[1937] (Example 93)

[1938] Peptide chain elongation (elongation method B)

[1939] 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 sequentially at room temperature. After stirring at room temperature for one hour, 140 ml of a 5% potassium hydrogen sulfate aqueous solution was added. The aqueous layer was removed, and then 140 ml of a 5% potassium carbonate aqueous 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 then washed with 140 ml of a 5% potassium carbonate aqueous solution. The resulting organic layer was concentrated under reduced pressure and dried to give 24.1 g of 45 in 96% yield.

[1940] (Example 94)

[1941] Removal of N-terminal Cbz (Deprotection Method B)

[1942] 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 at 35 °C under a 5 bar hydrogen atmosphere. Six hours after the start of the reaction, the reaction vessels were cooled to room temperature and stored overnight at room temperature under air. The reaction was further carried out at 45 °C under a 5 bar hydrogen atmosphere for four hours. The two reaction solutions were mixed, filtered, and washed with 92 ml of CPME. The resulting mixture was concentrated under reduced pressure and dried to give 15.9 g of 51 in 98% yield.

[1943] Peptides ranging from 2-mer to 11-mer are synthesized using the same technique. Aside from the reaction time and the quality of the starting materials used, the different reaction conditions described above are further described in the "Reaction Methods" column.

[1944] [Table 152]

[1945] (HPLC Method 1)

[1946]

[1947] Of the synthesized intermediates, 13a, 14a, 15a, 16a, 17a, 18a, and 19a were used in tBu removal experiments. The compounds used in the tBu removal reaction were analyzed by LC-MS as described in Table 153.

[1948] [Table 153]

[1949] analyze

[1950]

[1951] Synthesis of tBu-protected peptides at the IC-terminus

[1952]

[1953] (Example 110)

[1954] Synthesis of Fmoc-MeAla-MeAla-OtBu(20a)

[1955] 99.7 mg of H-MeAla-OtBu hydrochloride and 710 mg of dipotassium hydrogen phosphate were weighed into separate reaction vessels, and 2-MeTHF and water were added at a ratio of 10 v / w each relative to H-MeAla-OtBu hydrochloride. Fmoc-MeAla-OH (167 mg) and DMT-MM (211 mg) were added sequentially at 0 °C, and the reaction solution was then warmed to room temperature. After shaking at room temperature for 16 hours, the reaction was analyzed by LCMS to confirm the disappearance of Fmoc-MeAla-OH. 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 resulting organic layer was washed with brine (3 mL), 15% sodium bisulfate aqueous solution (3 mL), and 5% sodium carbonate aqueous solution (3 mL), respectively, and the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography under the conditions described below. The fraction containing the target product was then concentrated and dried under reduced pressure to give 227.6 mg of 20a in 96% yield and 99.5% purity.

[1956] (Example 111)

[1957] Synthesis of Fmoc-MePhe-MeAla-OtBu(21a)

[1958] H-MeAla-OtBu hydrochloride (99.8 mg) and Fmoc-MePhe-OH (205 mg) were weighed into a reaction vessel, and isopropyl acetate (8 v / w), acetonitrile (2 v / w), and diisopropylethylamine (4 eq.) were added sequentially relative to H-MeAla-OtBu hydrochloride. A 1.7 M solution of T3P in ethyl acetate (2.5 eq.) was added at room temperature. After stirring at room temperature for four hours, a 1.7 M solution of T3P in ethyl acetate (0.5 eq.) and diisopropylethylamine (0.8 eq.) was added. The reaction was analyzed by LCMS 30 minutes after the addition of the reagents, and the conversion rate was found to be 98.5%. NMI (2 eq.) was added at room temperature, and the reaction solution was stirred at 50 °C for five minutes. The reaction solution was transferred to a separatory funnel using 6 mL of ethyl acetate, and the aqueous layer was removed. The resulting organic layer was washed with 3 mL of 5% sodium carbonate aqueous solution, 3 mL of 5% potassium bisulfate aqueous solution, and 3 mL of 5% sodium carbonate aqueous solution, respectively. The organic layer was dehydrated with sodium sulfate for 30 minutes, then filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography under the conditions described below, and the fraction containing the target product was then concentrated under reduced pressure and dried to give 227.6 mg of 21a in 96% yield and 99.5% purity.

[1959] [Table 154]

[1960] Analysis (HPLC Method 1)

[1961]

[1962] J.CTC resin-loaded dipeptide synthesis

[1963]

[1964] (Example 112)

[1965] Fmoc-MeAla-OH was loaded onto CTC resin.

[1966] 4.47 g of C1-CTC resin was weighed into a reaction column, and dichloromethane (36 mL) was added. The column was shaken at 30 °C for 60 min. After evacuating the dichloromethane, a solution of Fmoc-MeAla-OH (1.24 g) and diisopropylethylamine (1.4 mL) in dichloromethane (36 mL) was added at room temperature. After stirring at 30 °C for 3 h, the reaction was analyzed by LCMS, and the conversion rate was found to be 96.0%. After evacuating the reaction solution, a solution of methanol (3.6 mL) and diisopropylethylamine (1.8 mL) in DMF (30 mL) was added at room temperature. After shaking at 30 °C for 1.5 h, the reaction solution was evacuated. The resin was washed four times with 36 mL of DMF and then dried under reduced pressure to obtain 4.80 g of 55. 56 was also synthesized using the same technique. The products were analyzed in the next step.

[1967] [Table 155]

[1968] Analysis (HPLC Method 1)

[1969]

[1970]

[1971] (Example 114)

[1972] Synthesis of Fmoc-MeAla-MeAla-OCTC (22a), Fmoc-MeVal-MeAla-OCTC (23a) and Fmoc-Pro-MeAla-OCTC (24a)

[1973] Dipeptides 22a to 24a were synthesized simultaneously using a solid-phase peptide synthesizer, Prelude X. 676 mg, 687 mg, and 705 mg of resin Fmoc-MeAla-OCTC (55) were weighed into three reaction vessels, respectively. DMF (8 mL) was added, and the resin was allowed to swell by standing at room temperature for one hour. After draining the DMF, a 20% solution of piperidine in DMF (8 mL) was added, and the solution was shaken at room temperature for 15 minutes. After draining the solution, another 20% solution of piperidine in DMF (8 mL) was added, and the vessel was shaken at room temperature for 15 minutes. Mixtures 1 to 3 described below were added to RV 1 to RV 3, respectively, followed by a 12.5% ​​solution of DIC in DMF (4 eq.). The vessel was shaken at room temperature for three hours under nitrogen bubbling. After draining the solution, the resin was washed with DMF (8 v / w) for 2 min x 5 and with MTBE (8 v / w) for 2 min x 4, each wash performed by shaking at room temperature. The obtained resins were dried under reduced pressure to obtain compounds 30a, 31a, and 32a, respectively. The obtained compounds were identified by the resin removal reactions in Examples 65, 67, and 69.

[1974] Approximately 20 mg of each of the three obtained resins was weighed into three reaction vessels, and a 20% solution (100 mL) of piperidine in DMF was added to each vessel. The reaction solutions were stirred at room temperature for two hours. Diphenylene was quantitatively determined from the absorbance of the solution to calculate the loading rate of each dipeptide (Table 156).

[1975] (Example 115)

[1976] Synthesis of Fmoc-MeAla-MeAsp(OtBu)-OCTC(25a) and Fmoc-MeLeu-MeAsp(OtBu)-OCTC(26a)

[1977] Dipeptides 25a to 26a were synthesized simultaneously using a solid-phase peptide synthesizer, Prelude X. 340 mg of resin Fmoc-MeAsp(OtBu)-OCTC(10) was weighed into each of two reactors. DMF (8 mL) was added, and the resin was allowed to swell by standing at room temperature for 30 minutes. After draining the DMF, a 20% solution of piperidine in DMF (8 v / w) was added, and the container was shaken at room temperature for 5 minutes. After draining the solution, another 20% solution of piperidine in DMF (8 v / w) was added, and the container was shaken at room temperature for 20 minutes. After draining the solution, mixtures 1 and 2 described below were added to the respective reaction vessels, followed by a 12.5% ​​solution of DIC in DMF (4 eq.), and the containers were shaken at room temperature for three hours under nitrogen bubbling. After draining the solution, the resin was washed with DMF (8 v / w) for 2 min x 4 times and with MTBE (8 v / w) for 2 min x 4 times, each wash performed by shaking at room temperature. The resulting resin was dried under reduced pressure to give 994 mg of 25a and 1.00 g of 26a, respectively. The obtained compounds were identified by the resin removal reactions in Examples 71 and 73.

[1978] Approximately 20 mg of each of the two obtained resins were weighed into two reaction vessels. A 20% solution (100 mL) of piperidine in DMF was added to each vessel, and the reaction solution was stirred at room temperature for two hours. Diphenylene was quantitatively determined from the absorbance of the solution to calculate the loading rate of each dipeptide (Table 156).

[1979] [Table 156]

[1980] Analysis (HPLC Method 1)

[1981]

[1982] (Example 116)

[1983] Synthesis of Fmoc-MeAsp(O-allyl)-mor

[1984]

[1985] Fmoc-MeAsp(O-allyl)-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 one hour. Further water (180 ml) was added, and the reaction solution was stirred at ambient temperature for 1.75 hours. The resulting solid was collected by filtration using a Kiriyama funnel and washed twice with water (450 ml). After washing with water, the solid was dried under reduced pressure to give 86.8 g (85% yield) of the target product as a colorless solid.

[1986] (Example 117)

[1987] Synthesis of Fmoc-MeAsp(O-allyl)-NMe2

[1988]

[1989] Under a nitrogen stream, EDCI hydrochloride (27.4 g) and DMF (217 ml) were added to the reaction vessel, followed by the addition of HOBt (17.7 g) and a solution of Fmoc-MeAsp(O-allyl)-OH (56, 48.8 g) in dichloromethane-DMF (90 ml-90 ml) at 0 °C. After stirring the reaction solution at 0 °C for 30 minutes, dimethylamine-THF solution (2 N, 65.6 ml) was added dropwise over two minutes, followed by stirring at 0 °C for another 30 minutes. The reaction solution was diluted with ethyl acetate (488 ml), and the organic layer was washed with 1 N hydrochloric acid (twice, 391 ml), water (488 ml), 5% sodium bicarbonate aqueous solution (twice, 488 ml), and 18% sodium chloride aqueous solution (488 ml), and then dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was then concentrated under reduced pressure to obtain 51.2 g (98% yield) of the target product, which was a colorless oil.

[1990] (Example 118)

[1991] Synthesis of Fmoc-MeAsp(OH)-mot

[1992]

[1993] Under a nitrogen stream, Fmoc-MeAsp(O-allyl)-mor (57, 22.8 g) and dichloromethane (50 mL) were added to a reaction vessel, followed by tetrakis(triphenylphosphine)palladium (0.55 g) at ambient temperature. Phenylsilane (3.61 g) was added dropwise, and the reaction solution was stirred at ambient temperature for 30 minutes. The reaction solution was diluted with MTBE (228 mL) and then removed with a 5% sodium bicarbonate aqueous solution (228 mL). The aqueous layer was acidified to approximately pH 3 with an 85% phosphoric acid aqueous solution (12 mL) and extracted with MTBE (228 mL). The organic layer was washed twice with an 18% sodium chloride aqueous solution (228 mL) and then dried with sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give 20.3 g (97% yield) of the target product as colorless amorphous crystals.

[1994] (Example 119)

[1995] Synthesis of Fmoc-MeAsp(OH)-NMe2

[1996]

[1997] Under a nitrogen stream, Fmoc-MeAsp(O-allyl)-NMe2 (58, 32.0 g) and tetrakis(triphenylphosphine)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, and the mixture was stirred at ambient temperature for 30 minutes. The reaction solution was diluted with MTBE (320 ml) and then extracted with a 5% sodium bicarbonate aqueous solution (308 ml). The aqueous layer was acidified to approximately pH 2 with an 85% phosphoric acid aqueous solution (30.1 ml) and extracted with MTBE (320 ml). The organic layer was extracted twice with an 18% sodium chloride aqueous solution (320 ml) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give 25.1 g (86% yield) of the target product as pale brown amorphous crystals.

[1998] [Table 157]

[1999] analyze

[2000]

[2001] (Example 120)

[2002] Synthesis of Fmoc-MeAsp(OtBu)-mor(61)

[2003]

[2004] 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) and morpholine (0.74 mL) were added to the reaction solution, while maintaining the temperature below 10 °C and stirring for three hours. AcOEt (15 mL) and 0.5 N hydrochloric acid (15 mL) were added to the reaction solution. The organic layer was washed with water (15 mL) and further washed with a 5% sodium carbonate aqueous solution (15 mL). The organic layer was washed with a 5% sodium chloride aqueous solution (15 mL) and then concentrated under reduced pressure to give 3.50 g (100%) of the target product as yellow amorphous crystals. The obtained compound was used in the next reaction without purification.

[2005] (Example 121)

[2006] Synthesis of Fmoc-MeAsp(OtBu)-NMe2(62)

[2007]

[2008] Under a nitrogen stream, Fmoc-MeAsp(OtBu)-OH (39 g, 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 below 10 °C and stirring for three hours. Ethyl acetate (15 mL) was added to the reaction solution, followed by 0.5 N hydrochloric acid (15 mL). The organic layer was washed with water (15 mL) and further washed with a 5% sodium carbonate aqueous solution (15 mL). The organic layer was washed with a 5% sodium chloride aqueous solution (15 mL) and then concentrated under reduced pressure to give 3.17 g (95%) of the target product as a colorless oil. The obtained compound was used in the next reaction without purification.

[2009] (Example 122)

[2010] Synthesis of Fmoc-MeAsp(OH)-mor(59)

[2011]

[2012] 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 HMDS (0.86 mL). The reaction vessel was cooled to 0 °C, TMSOTf (0.81 mL) was added, and the reaction solution was stirred at 25 °C for one hour. The reaction vessel was cooled to 0 °C, and a 5% potassium dihydrogen phosphate aqueous solution (9.2 mL) was added to the reaction solution, and the organic layer was separated. A 5% sodium carbonate aqueous solution (9.2 mL) was added, and the aqueous layer was separated. MTBE (9.2 mL) and 2N hydrochloric acid (5.0 mL) were added to the aqueous layer, and the organic layer was separated. The organic layer was washed with a 5% potassium dihydrogen phosphate aqueous solution (9.2 mL), followed by a 10% sodium chloride aqueous solution (9.2 mL). The organic layer was concentrated under reduced pressure to give 1.31 g (97%) of the target product as yellow amorphous crystals.

[2013] (Example 123)

[2014] Synthesis of Fmoc-MeAsp(OH)-NMe2(60)

[2015]

[2016] 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 HMDS (0.80 mL). The reaction vessel was cooled to 0 °C, TMSOTf (0.75 mL) was added, and the reaction solution was stirred at 25 °C for one hour. A 5% potassium dihydrogen phosphate aqueous solution (7.9 mL) was added to the reaction solution, and the organic layer was separated. A 5% sodium carbonate aqueous solution (7.9 mL) was added, and the aqueous layer was separated. MTBE (7.9 mL) and 2N hydrochloric acid (5.0 mL) were added to the aqueous layer, and the organic layer was separated. The organic layer was washed with a 5% potassium dihydrogen phosphate aqueous solution (7.9 mL), followed by a 10% sodium chloride aqueous solution (7.9 mL). The organic layer was concentrated under reduced pressure to give 1.31 g (95%) of the target product, a colorless oily substance.

[2017] [Table 158]

[2018] analyze

[2019]

[2020] [Industrial Applicability]

[2021] This invention provides a method for producing peptide compounds by using novel deprotection and / or resin removal methods with silylating agents. This invention provides an industrially applicable and efficient technique for peptide synthesis.

Claims

1. An amide compound represented by the following general formula (A) or a salt thereof: in R 1' Selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc and trifluoroacetyl; R 17A and R 17B All are methyl, or R 17A and R 17B Together with the nitrogen atom to which they are attached, they form piperidine or morpholine; and R 18 Is hydrogen or PG 10 , of which PG 10 Selected from the group consisting of t-Bu, trityl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl.

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

3. A method for producing a peptide compound in which a protecting group removable by a silylating agent has been removed, the method comprising the following steps: contacting a starting peptide compound comprising a natural amino acid residue and / or an amino acid analog residue with the silylating agent in a solvent, and thereby removing the protecting group from the starting peptide compound, wherein the silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger, wherein the starting peptide compound comprises at least one protecting group which can be removed by the silylating agent, and The starting peptide compound comprises at least one N-substituted amino acid residue.

4. A method for producing a peptide compound from which a solid phase synthesis resin removable by a silylating agent has been removed, the method comprising the following steps: contacting a starting peptide compound comprising a natural amino acid residue and / or an amino acid analog residue with the silylating agent in a solvent, thereby removing the solid phase synthesis resin from the starting peptide compound, wherein the silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger, wherein the starting peptide compound is connected to the removable solid phase synthesis resin, and The starting peptide compound comprises at least one N-substituted amino acid residue.

5. A method for producing an amide compound in which a protecting group that can be removed by a silylating agent has been removed, the method comprising the following steps: contacting a starting amide compound with the silylating agent in a solvent, and thereby removing the protecting group from the starting amide compound, wherein the silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger, The starting amide compound is represented by the following general formula (II): in R 1' is a hydrogen atom or PG7; R 12 and R 12' Independently selected from the group consisting of: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 , -(CH2) n COO-RES and -(CH2) n CONH-RES; RES is a resin for solid phase synthesis; n is 0, 1, or 2; R6 is selected from the group consisting of hydrogen and C1-C6 alkyl; R 13 is C1-C4 alkyl or -(CH2) m CON(R 17A )(R 17B ); m is 0, 1, or 2; R 17A and R 17B are independently hydrogen or C1-C4 alkyl, or R 17A and R 17B Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered ring optionally containing one or more additional heteroatoms; PG7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc and trifluoroacetyl; and PG 10 is selected from the group consisting of t-Bu, trityl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl, and The starting amide compound comprises at least one protecting group which can be removed by the silylating agent.

6. A method for producing an amide compound from which a resin for solid phase synthesis has been removed, the method comprising the following steps: contacting the starting amide compound with the silylating agent in a solvent, thereby removing the starting amide compound from the resin for solid phase synthesis, wherein the silylating agent is prepared by mixing a silyl compound or an acid with an electrophilic species scavenger, and The starting amide compound is represented by the following general formula (II): in R 1' is a hydrogen atom or PG7; R 12 and R 12' Independently selected from the group consisting of: hydrogen, PG 10 -O-methyl, -(CH2) n COO-PG 10 , -(CH2) n COO-RES and -(CH2) n CONH-RES; RES is a resin for solid phase synthesis, in which R 12 and R 12' At least one of them is -(CH2) n COO-RES or -(CH2) n CONH-RES; RES is a resin for solid phase synthesis; n is 0, 1, or 2; R6 is selected from the group consisting of hydrogen and C1-C6 alkyl; R 13 is C1-C4 alkyl or -(CH2) m CON(R 17A )(R 17B ); m is 0, 1, or 2; R 17A and R 17B are independently hydrogen or C1-C4 alkyl, or R 17A and R 17B Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered ring optionally containing one or more additional heteroatoms; PG7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc and trifluoroacetyl; and PG 10 Selected from the group consisting of t-Bu, trityl, cumenyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl and 2-(trimethylsilyl)ethyl.

7. A deprotecting agent for removing a protecting group, comprising a silyl compound or an acid and an electrophilic species scavenger.

8. A resin stripping agent for cleaving a peptide compound from a resin in a solid phase reaction, comprising a silyl compound or an acid and an electrophilic species scavenger.

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