Iodotyrosine derivative and method for preparing iodotyrosine derivative

Abstract

The present invention relates to a compound of the general formula I, and, (Chemical Formula I) In the above formula, A is selected from the group consisting of an unbranched or branched alkyl group having 1 to 12 carbon atoms, -R1-O-R2 group, -R1-Si(R3R4R5) group, -R1-O-Si(R3R4R5) group, -C(O)-O-R9-Si(R3R4R5) group, -CH(O-R6)(O-R7) group, -R1-CH(O-R6)(O-R7) group, and R1-OC(O)-O-R8 group; SG is a protector; R1 is a divalent hydrocarbon residue having 1 to 12 carbon atoms; R2 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R3, R4, and R5 are each independently monovalent hydrocarbon residues having 1 to 12 carbon atoms; R6 and R7 are each independently monovalent hydrocarbon residues having 1 to 12 carbon atoms; R8 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R9 is a divalent hydrocarbon residue having 1 to 12 carbon atoms.

Description

Technology Field

[0001] The present invention relates to iodotyrosine derivatives, in particular Fmoc-3-Iod-tyrosine derivatives and Boc-3-Iod-tyrosine derivatives. The present invention also relates to a method for preparing iodotyrosine derivatives, in particular Fmoc-3-Iod-tyrosine derivatives and Boc-3-Iod-tyrosine derivatives. The present invention also relates to the use of iodotyrosine derivatives, in particular Fmoc-3-Iod-tyrosine derivatives and Boc-3-Iod-tyrosine derivatives, in the synthesis of peptides. Background Technology

[0002] Modifying peptides with 3-iodotyrosine (D / L) is used to have a positive effect on the properties of peptides containing iodotyrosine. In many cases, iodotyrosine is introduced primarily at the N-terminal ends of peptides or small molecules [4]. Due to the lipophilic properties of iodotyrosine, binding properties are improved, which often improves receptor affinity. Examples of peptides or peptide compounds containing iodotyrosine include the theranostic peptide pairs pentissader / pentissapho [5], HA-DOTA-TATE [6], or PSMA I&T [7]. Additionally, substituting tyrosine with iodotyrosine improves the properties of hormones, for example [8].

[0003] In most cases, iod-tyrosine is introduced using commercially available ingredients such as Fmoc-3-Iod-L-tyrosine, Fmoc-3-Iod-D-tyrosine, Boc-3-Iod-D-tyrosine, or Boc-3-Iod-L-tyrosine. The notation "Fmoc" signifies the protecting group fluorenylmethyloxycarbonyl. The notation Boc signifies the protecting group tert-butyloxycarbonyl. However, the use of Fmoc-3-Iod-L-tyrosine, Fmoc-3-Iod-D-tyrosine, Boc-3-Iod-D-tyrosine, or Boc-3-Iod-L-tyrosine can be associated with undesirable side reactions because the hydroxyl function at the para position is still sufficiently nucleophilic and can be acylated by the C-terminal activated amino acid. In most cases, this results in the loss of the amino acid, rendering it unusable for binding. In this regard, due to the high reactivity of the nucleophilic hydroxyl function of tyrosine, binding with Fmoc-3-Iod-L-tyrosine, Fmoc-3-Iod-D-tyrosine, Boc-3-Iod-D-tyrosine, or Boc-3-Iod-L-tyrosine has been proven impossible if little or no conversion occurs at this reaction step.

[0004] One way to overcome these disadvantages is to iodide the tyrosine in the final peptide product. This method generally results in two different products consisting of monoiodinated tyrosine residue and diiodinated tyrosine residue [9]. Both products must be separated by reverse-phase chromatography, which makes industrial use difficult. Additionally, this method is not suitable when there is more than one tyrosine unit in the peptide. Furthermore, this method is not suitable for industrial use because the scale of synthesis is clearly limited. Also, the starting materials must be separated.

[0005] Cobb et al.

[10] proposed the direct iodination of fully protected Fmoc-Tyr(tBu)-OH in the presence of Ag2SO4 in methanol, which, following saponification, primarily leads to Fmoc-3-Iod-Tyr(tBu)-OMe. This method is considered unsuitable for the larger scale required for industrial use. Amedio et al.

[11] proposed the use of Boc-3-Iod-Tyr(PMB)-OH. In another example, Kiyoyuki et al. used Boc-3-Iod-Tyr(Boc)-OH for the synthesis of cyclic peptides

[12] . Both protected iod-tyrosine derivatives are suitable only for Boc chemistry. Martiny et al. synthesized Fmoc-3-Iod-Tyr(TBDMS)-OH, which proved suitable for introducing iodinated tyrosine into peptides using Fmoc / tBu chemistry

[13] . A disadvantage of this particular compound is its vulnerability to (weak) acids (e.g., hexafluoroisopropanol (HFIP)). Due to this vulnerability, the peptide cannot be separated from the resin (e.g., using HFIP) while in a completely protected state. The notation "tBu" means the protecting group "tert-Butyl", the notation "Me" means Metyhl, the notation "boc" means the protecting group tert-Butoxycarbonyl, the notation "PMB" means the protecting group p-Methoxybenzyl, and the notation "TBDMS" means the protecting group "tert-Butyldimethylsilyl". The problem to be solved

[0006] The objective of the present invention is to eliminate the disadvantages according to the prior art. Iod-tyrosine derivatives, in particular Fmoc-3-Iod-tyrosine derivatives and Boc-3-Iod-tyrosine derivatives, must be provided such that the modification of the peptide by the introduction of iodoc-tyrosine units is prevented without the aforementioned side reactions, and the separation of the peptide thus modified from the resin is not achieved in a protected state. means of solving the problem

[0007] The above problem is solved by the features of claims 1, 9, and 12. Preferred embodiments of the present invention are presented in the features of the dependent claims.

[0008] According to the present invention, a compound of formula I is provided, and

[0009]

[0010] (Chemical Formula I)

[0011] In the above formula, A is an unbranched or branched alkyl group having 1 to 12 carbon atoms, -R 1 -OR 2 Gi, -R 1 -Si(R 3 R 4 R 5 ) energy, -R 1 -O-Si(R 3 R 4 R 5 ) Gi, -C(O)-OR 9 -Si(R 3 R 4 R 5 ) Gi, -CH(OR 6 )(OR 7 ) energy, -R 1 -CH(OR 6 )(OR 7 ) Gi, R 1 -OC(O)-OR 8 Selected from a group consisting of;

[0012] SG is a protector;

[0013] R 1 It is a divalent hydrocarbon residue having 1 to 12 carbon atoms;

[0014] R 2 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms;

[0015] R 3 , R 4 and R 5Each is a monovalent hydrocarbon residue having 1 to 12 carbon atoms independently;

[0016] R 6 and R 7 Each is a monovalent hydrocarbon residue having 1 to 12 carbon atoms independently;

[0017] R 8 It is a monovalent hydrocarbon residue having 1 to 12 carbon atoms;

[0018] R 9 is a divalent hydrocarbon residue having 1 to 12 carbon atoms.

[0019] The protecting group SG is preferably selected from the group consisting of a fluorenylmethyloxycarbonyl group (Fmoc), a tert-butoxycarbonyl group (Boc), and a benzyloxycarbonyl group. More preferably, the protecting group SG is fluorenylmethyloxycarbonyl (Fmoc) or tert-butoxycarbonyl. Particularly preferably, the protecting group SG is fluorenylmethyloxycarbonyl (Fmoc). The protecting group SG serves to protect the amino function of the tyrosine unit. The compound of General Formula I is also hereinafter referred to as SG-iodo-tyrosine.

[0020] A compound of general formula I in which SG is a fluorenylmethyloxycarbonyl group (Fmoc) is a compound of general formula Ia, and a compound of general formula I in which SG is a tert-butoxycarbonyl group (Boc) is a compound of general formula Ib:

[0021]

[0022] Chemical formula Ia Chemical formula Ib

[0023] The compound of general chemical formula Ia is hereinafter also referred to as Fmoc-iodine-tyrosine. The compound of general chemical formula Ib is hereinafter also referred to as Boc-iodine-tyrosine.

[0024] The compound according to the present invention of General Formula I comprises not only the individual enantiomers themselves but also a mixture of these enantiomers. Accordingly, the tyrosine units of the compound of General Formula I may exist in a D-configuration, an L-configuration, or a mixture of D-configuration and L-configuration. The notation "D / L" refers to a compound existing in a D-configuration, an L-configuration, or a mixture of D-configuration and L-configuration.

[0025] The compound according to the present invention of general chemical formula I has an iodine atom bonded to the phenyl group of a tyrosine unit.

[0026] The compound according to the present invention enables the introduction of SG-3-iod-D-tyrosine(A)-OH or SG-3-iod-L-tyrosine(A)-OH into a peptide. Protection of the phenol hydroxyl group by protecting group A can prevent undesirable side reactions associated with the unprotected hydroxyl function according to the prior art. Thus, unit A prevents acylation by the C-terminal activated amino acid. Consequently, loss of amino acid is prevented. Furthermore, since the phenol hydroxyl function is protected by unit A, difficult binding with SG-3-iod-D-tyrosine(A)-OH or SG-3-iod-L-tyrosine(A)-OH can be performed. The present invention particularly enables the introduction of Fmoc-3-Iod-D-tyrosine(A)-OH or Fmoc-3-Iod-L-tyrosine(A)-OH into a peptide. The present invention also enables the introduction of Boc-3-Iod-D-tyrosine(A)-OH or Boc-3-Iod-L-tyrosine(A)-OH into a peptide. The notation "(A)-OH" indicates that the phenol hydroxyl group of the tyrosine unit is protected by the protecting group A, but the hydroxyl group of the carboxyl group is not protected. After introducing SG-3-iod-D-tyrosine(A)-OH or SG-3-iod-L-tyrosine(A)-OH into a peptide, the protecting group A can be removed.

[0027] It can be provided that the compound of general formula I is a compound of general formula IA, and

[0028]

[0029] (Chemical formula IA)

[0030] In the above formula, A has the meaning specified in Claim 1. A compound of general formula IA corresponds to a compound of general formula I, except that the iodine atom is at the 3-position. A compound of formula IA in which SG is a fluorenylmethyloxycarbonyl group (Fmoc) is a compound of formula Ia-A, and a compound of general formula I in which SG is a tert-butoxycarbonyl group (Boc) is a compound of general formula Ib-A:

[0031]

[0032] Chemical formula Ia-A Chemical formula Ib-A

[0033] Unit A is a protecting group for protecting the phenol hydroxyl group of SG-iodo-tyrosine. Unit A is preferably an ether group, a silyl ether group, an acetal group, or a carbonate group. In the case of Fmoc-iodo-tyrosine, Unit A is preferably selected to be compatible with the Fmoc / tBu strategy used in non-iodinated Fmoc-D / L-tyrosine(tBu)-OH. In Fmoc-D / L-tyrosine(tBu)-OH, the phenol hydroxyl function is protected by a tert-butyl group (tBu). Unit A is also selected to enable the use of the compound according to the present invention depending on the production scale.

[0034] R 1 is preferably an unbranched alkylene group having 1 to 6 methylene units. Preferably, R 1 It is methylene, ethylene, or n-propylene.

[0035] R 2The is preferably an unbranched or branched alkyl group or aryl group having 1 to 12 carbon atoms, wherein an unbranched or branched alkyl group having 1 to 12 carbon atoms is preferred.

[0036] Preferably R 3 , R 4 and R 5 Each is an unbranched or branched alkyl group or aryl group having one or two carbon atoms independently.

[0037] Preferably R 6 and R 7 Each is an unbranched or branched alkyl group or aryl group having one or two carbon atoms independently.

[0038] R 8 The is preferably an unbranched or branched alkyl group or aryl group having 1 to 12 carbon atoms, wherein an unbranched or branched alkyl group having 1 to 12 carbon atoms is preferred.

[0039] R 9 is preferably an unbranched alkylene group having 1 to 6 methylene units. Preferably, R 1 It is methylene, ethylene, propylene, or butylene.

[0040] Unit A is an unbranched or branched alkyl group having 1 to 12 carbon atoms, -R 1 -OR 2 Gi, -R 1 -Si(R 3 R 4 R 5 )gi and -C(O)-OR 9 -Si(R 3 R 4 R 5 A selection from a group consisting of ) units may be provided. Unit A is -R 1 -OR 2 Gi, -R 1 -Si(R 3 R 4 R5 )gi, -R 1 -O-Si(R 3 R 4 R 5 )gi, -C(O)-OR 9 -Si(R 3 R 4 R 5 )gi, -CH(OR 6 )(OR 7 )gi, -R 1 -CH(OR 6 )(OR 7 )gi, -R 1 -OC(O)-OR 8 It may be provided to be selected from a group consisting of. Additionally, Unit A may be provided to be selected from a group consisting of the following:

[0041] An alkyl group having 1 to 6 carbon atoms; -R 1 -OR 2 Gi, here R 1 is an alkylene group having 1 to 6 carbon atoms, and R 2 is an unbranched or branched alkyl group having 1 to 6 carbon atoms;

[0042] -R 1 -Si(R 3 R 4 R 5 )gi, here R 1 is an alkylene group having 1 to 6 carbon atoms, and R 3 , R 4 and R 5 Each is an unbranched or branched alkyl group or aryl group having 1 to 6 carbon atoms independently; and

[0043] -C(O)-OR 9 -Si(R 3 R 4 R 5 )gi, here R 9 is an alkylene group having 1 to 6 carbon atoms, and R 3 , R 4 and R 5Each is an unbranched or branched alkyl group or aryl group having 1 to 6 carbon atoms independently.

[0044] A compound of general chemical formula I may be provided, wherein A is -R 1- OR 2기 , -R 1 -Si(R 3 R 4 R 5 )gi, -R 1 -O-Si(R 3 R 4 R 5 )gi, -C(O)-OR 9 -Si(R 3 R 4 R 5 )gi, -CH(OR 6) (OR 7 )gi, -R 1 -CH(OR 6 )(OR 7 )gi, R 1 -OC(O)-OR 8 Selected from a group consisting of;

[0045] SG is a protector;

[0046] R 1 It is a divalent hydrocarbon residue having 1 to 12 carbon atoms;

[0047] R 2 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms;

[0048] R 3 , R 4 and R 5 Each is a monovalent hydrocarbon residue having 1 to 12 carbon atoms independently;

[0049] R 6 and R 7 Each is a monovalent hydrocarbon residue having 1 to 12 carbon atoms independently;

[0050] R 8 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; and

[0051] R 9 is a divalent hydrocarbon residue having 1 to 12 carbon atoms.

[0052] Additionally, Unit A may be provided to be selected from the following group:

[0053] -R 1 -OR 2 Gi, here R 1 is an alkylene group having 1 to 6 carbon atoms, and R 2 is an unbranched or branched alkyl group having 1 to 6 carbon atoms;

[0054] -R 1 -Si(R 3 R 4 R 5 )gi, here R 1 is an alkylene group having 1 to 6 carbon atoms, and R 3 , R 4 and R5 are each independently an unbranched or branched alkyl group or an aryl group having 1 to 6 carbon atoms; and

[0055] -C(O)-OR 9 -Si(R 3 R 4 R 5 )gi, here R 9 is an alkylene group having 1 to 6 carbon atoms, and R 3 , R 4 and R5 are each independently unbranched or branched alkyl or aryl groups having 1 to 6 carbon atoms.

[0056] Preferred examples of compounds of the general chemical formula Ia-A are as follows:

[0057] (i) 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid, which is also referred to as Fmoc-D / L-Tyr(MOM)-OH, wherein Fmoc-D-Tyr(MOM)-OH is particularly preferred;

[0058] (ii) 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, which is also referred to as Fmoc-D / L-Tyr(TEOC)-OH, wherein Fmoc-D-Tyr(TEOC)-OH is particularly preferred;

[0059] (iii) 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid, which is also referred to as Fmoc-D / L-Tyr(TBDPSE)-OH, wherein Fmoc-D-Tyr(TBDPSE)-OH is particularly preferred; and

[0060] (iv) 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid, which is also referred to as Fmoc-D / L-Tyr(tBu)-OH, in which case Fmoc-D-Tyr(tBu)-OH is particularly preferred.

[0061] Preferred examples of compounds of the general chemical formula Ib-A are as follows:

[0062] (i) 2-((tert-butoxycarbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid, which is also referred to as Boc-D / L-Tyr(MOM)-OH, wherein Boc-D-Tyr(MOM)-OH is preferred;

[0063] (ii) 2-((tert-butoxycarbonyl)amino)-3-(3-iod-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, which is also referred to as Boc-D / L-Tyr(TEOC)-OH, wherein Boc-D-Tyr(TEOC)-OH is preferred;

[0064] (iii) 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid, which is also referred to as Boc-D / L-Tyr(TBDPSE)-OH, and Boc-D-Tyr(TBDPSE)-OH is preferred; and

[0065] (iv) 2-((tert-butoxycarbonyl)amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid, which is also referred to as Boc-D / L-Tyr(tBu)-OH, in which case Boc-D-Tyr(tBu)-OH is preferred.

[0066] According to the present invention, a method for preparing a compound according to the present invention of general formula I is also provided. To this end, SG comprises a compound of general formula II having a specified meaning in relation to general formula I,

[0067]

[0068] (Chemical Formula II),

[0069] X is a halogen or ammonium, and A is reacted with a compound of general formula XA having the meaning specified in relation to general formula I, so that SG and A form a compound of general formula I having the meaning specified in relation to general formula 1.

[0070]

[0071] (Chemical Formula I)

[0072] By compound XA, protecting group A is introduced into the compound of general formula II. If SG in the compound of general formula II is Fmoc, the compound is Fmoc-iodine-D / L-tyrosine, which is systematically referred to as 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxy-iodophenyl)propionic acid. Preferably, the compound of general formula II is Fmoc-iodine-D-tyrosine. If SG in the compound of general formula II is Boc, the compound is Boc-iodine-D / L-tyrosine, which is systematically referred to as 2-(tert-butoxycarbonyl)amino)-3-(4-hydroxy-iodophenyl)propionic acid, in which case Boc-iodine-D-tyrosine is preferred.

[0073] A particularly preferred compound of General Formula II is Fmoc-3-Iod-D / L-tyrosine, which is systematically referred to as 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid. In this compound, the phenol iodine atom is at the 3-position. Fmoc-3-Iod-D-tyrosine is particularly preferred. Another preferred compound of General Formula II is Boc-3-Iod-D / L-tyrosine, which is systematically referred to as 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid. In this compound, the phenol iodine atom is at the 3-position. Boc-3-Iod-D-tyrosine is particularly preferred.

[0074] A compound of general chemical formula II can be prepared as a compound of general chemical formula IV.

[0075]

[0076] (Chemical Formula IV)

[0077] The amine function of the compound of General Formula IV is protected by the introduction of the protecting group SG. To this end, the compound of General Formula IV may react with, for example, a 9-fluorenylmethoxycarbonyl reagent or a tert-butoxycarbonyl reagent. The 9-fluorenylmethoxycarbonyl compound may be, for example, (9-fluorenylmethoxycarbonyloxy)-succinimide (Fmoc-OSu). The tert-butoxycarbonyl reagent may be, for example, di-tert-butyldicarbonate (Boc2O). The compound of General Formula IV is D / L-iodotyrosine, in which case D-iodotyrosine is preferred.

[0078] A compound of general formula II is combined (reacted) with a compound of general formula XA to obtain a compound of general formula III, and

[0079]

[0080] (Chemical Formula III)

[0081] Compounds of general chemical formula III are linked (reacted) to be converted into compounds of general chemical formula I. Brief explanation of the drawing

[0082] Figure 1 shows the preparation of a compound according to the present invention of general formula I from a compound of general formula II. Fig. 1 FIG. 1a illustrates the preparation of a compound according to the present invention of the general formula Ia from a compound of the general formula IIa. Compound IIa is a compound of the general formula II, where SG is Fmoc. The method illustrated in FIG. 1a is an example of the method illustrated in FIG. 1. Fig. 1a FIG. 2 shows the preparation of a compound according to the present invention of the general formula Ia-A from 3-iodine-D / L-tyrosine. The method illustrated in FIG. 2 is a preferred embodiment of the method illustrated in FIG. 1a. Fig. 2 Step (a) of the method illustrated in FIG. 1 involves reacting a compound of General Formula IV to form a compound of General Formula II. In this case, a protecting group is introduced to the N-terminus of the compound of General Formula IV to protect the amine function. To this end, the compound of General Formula IV may react with, for example, (9-fluorenylmethoxycarbonyloxy)-succinimide (Fmoc-OSu) (see FIG. 1a) or di-tert-butyldicarbonate (Boc2O). The compound of General Formula II is identical to the compound of General Formula IV except that the N-terminus of the compound of General Formula IV is protected by the protecting group SG. Ambient temperature refers to a temperature of 18 to 25°C. In the case where Fmoc is introduced as a protecting SG in step (a) of FIG. 1, step (a) can be performed under a protecting gas, for example, an argon atmosphere, at ambient pressure and ambient temperature. To introduce Fmoc as a protecting SG, step (a) is preferably performed in this case in a mixture of an aqueous sodium carbonate solution and 1,4-dioxane. In the case where Boc is introduced as a protecting SG in step (a) of FIG. 1, step (a) can be performed in air at ambient pressure and ambient temperature. A protecting gas is not required. In this case, step (a) is preferably performed in a mixture of water, tetrahydrofuran, and triethylamine. Step (b) of the method illustrated in FIG. 1 provides for reacting a compound of General Formula II to form a compound of General Formula III. In this case, the hydroxyl group and phenol hydroxyl group at the C-terminus of the compound of General Formula II are protected by unit A. To this end, the compound of General Formula II is reacted with compound XA. The reaction may be carried out in an aprotic solvent such as dichloromethane (DCM) with an auxiliary base such as diisopropylethylamine (Hunig base, DIPEA) and a phase transition catalyst such as tetrabutylammonium chloride (TBACl). The reaction may be carried out in a temperature range from 0°C to ambient temperature. The reaction may be carried out under ambient pressure under a protective gas, for example, an argon atmosphere. The compound of General Formula III is identical to the compound of General Formula II except that the hydroxyl group and phenol hydroxyl group at the C-terminus of the compound of General Formula II are protected by unit A. Step (c) of the method illustrated in FIG. 1 provides for reacting a compound of General Formula III to form a compound of General Formula I. In this case, Unit A protecting the hydroxyl group at the C-terminus of the compound of General Formula III is separated, while Unit A protecting the phenol hydroxyl group is retained. Separation is carried out in a basic range, for example, in a pyridine / water mixture. The reaction can be performed in a temperature range from 0°C to ambient temperature. The reaction can be performed at ambient pressure. A protective gas is not required. The compound of General Formula I is identical to the compound of General Formula III except that the compound of General Formula I has a hydroxyl group at the C-terminus. Other details of the method according to the present invention have already been described in relation to the compound according to the present invention of general formula I. Reference is made to the above description. Specific details for implementing the invention

[0083] According to the present invention, the use of a compound according to the present invention of General Formula I is provided for the preparation of a peptide. The prepared peptide has at least one iodine-tyrosine unit. The prepared peptide may correspond to a disclosed peptide except that at least one, preferably exactly one, tyrosine unit is replaced by a 3-iodine-tyrosine unit. The 3-iodine-tyrosine unit may be prepared by reacting a compound of General Formula I with an amino acid or an amino acid sequence to obtain a peptide. The preparation of the peptide may be carried out using a disclosed synthesis method, such as Merrifield synthesis, for example. A method for peptide synthesis is described in the literature [Robert Bruce Merrifield, Solid phase peptide Synthesis Journal of the American Chemical Society, Volume 85, Issue 14 pp. 2149-2154]. After the preparation of the peptide, unit A derived from the compound of general chemical formula I is isolated, and as a result, a peptide having a 3-iodo-tyrosine unit in which the phenol OH group is not protected is obtained.

[0084] Figure 3 shows the preparation of a peptide of general formula V having an iodine-tyrosine unit using a compound of general formula I.

[0085]

[0086] Fig. 3

[0087] Figure 3a shows the preparation of a peptide of the general formula Va having an iodine-tyrosine unit using a compound of the general formula Ia. The peptide of the general formula Va is a peptide of the general formula V in which SG is Fmoc.

[0088]

[0089] Fig. 3a

[0090] Subsequently, the protecting group SG can be separated, and as a result, as described in FIGS. 4 and 4a, the compound of general formula V can be converted into the compound of general formula VI.

[0091]

[0092] Fig. 4

[0093]

[0094] Fig. 4a

[0095] When the iodine-tyrosine unit is not the terminal unit of the peptide, another amino acid is attached to the N-terminus of the compound of general formula VI, and as a result, the compound of general formula VII is obtained, as shown in Fig. 5.

[0096]

[0097] Fig. 5

[0098] One or more additional amino acids may be attached to other amino acids, and as a result, a peptide of general formula VIII may be obtained, and

[0099]

[0100] In the above formula, A has the specified meaning in relation to the compound of General Formula I, and under the condition that R10 is hydrogen and R11 is a hydroxyl, or R11 is a hydroxyl and R10 is not hydrogen, R10 is hydrogen or one or more amino acid units, and R11 is a hydroxyl or one or more amino acid units. The amino acid units have an NH group or NR at the N-terminus. 12 It may be a unit having a device, in this case R 12 It can be a methyl group.

[0101] The compound of general formula VIII can be converted into a peptide of general formula IX by separating unit A, as shown in Fig. 6.

[0102]

[0103] Fig. 6

[0104] The separation of unit A is carried out in an acidic range, for example, during the process of total removal of the protecting group of the peptide. For the total removal of the protecting group of the peptide, an aqueous solution of trifluoroacetic acid (TFA), for example, a 95% TFA solution, is preferably used. The reaction can be carried out in a temperature range of 0°C to ambient temperature. The reaction can be carried out at ambient pressure. A protecting gas is not required. The compound of general formula IX is identical to the compound of general formula VIII, except that unit A is separated to obtain a hydroxyl group.

[0105] Unless otherwise specified, the designation "alkyl" relates to a monovalent saturated aliphatic hydrocarbon group comprising a branched or unbranched carbon chain having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc.

[0106] Unless otherwise specified, the designation "alkylene" relates to a divalent saturated aliphatic hydrocarbon group comprising a branched or unbranched carbon chain having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene.

[0107] Unless otherwise specified, the designation "aryl" relates to a cyclic aromatic hydrocarbon group comprising a monocyclic, bicyclic, or tricyclic aromatic ring system having 5 to 18 ring atoms, preferably 5 to 6 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, indenyl, azulenyl, biphenyl, methylenediphenyl, etc., and partially hydrogenated derivatives thereof. Unless otherwise specified, the aryl group may be monovalent or polyvalent, for example, monovalent or divalent.

[0108] The present invention is described in more detail below with reference to the embodiments, but these embodiments are not intended to limit the invention.

[0109] Examples of compounds according to the present invention are presented in Table 1. Compounds 1D, 2D, 3D, and 4D have an R-configuration and are derivatives of D-tyrosine. Compounds 1L, 2L, 3L, and 4L have an S-configuration and are derivatives of L-tyrosine.

[0110] compound structure Name (Short name) 1D (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid(Fmoc-3-Iod-D-Tyr(MOM)-OH)) 1L (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid(Fmoc-3-Iod-L-Tyr(MOM)-OH)) 2D (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(((2-trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid(Fmoc-3-Iod-D-Tyr(TEOC)-OH) 2L (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid(Fmoc-3-Iod-L-Tyr(TEOC)-OH) 3D (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid(Fmoc-3-Iod-D-Tyr(TBDPSE)-OH) 3L (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid(Fmoc-3-Iod-L-Tyr(TBDPSE)-OH) 4D (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid(Fmoc-3-Iod-D-tyr(tBu)-OH) 4L (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid(Fmoc-3-Iod-L-Tyr(tBu)-OH)

[0111] The compounds specified in Table 1 are exemplary compounds of General Formula I and General Formula Ia. Compounds 1D and 1L are compounds of General Formula Ia, wherein A is -R 1 -OR 2 It is, and here R 1 is a methylene group, and R 2 is a methyl group. Compounds 2D and 2L are compounds of the general formula Ia, where A is -R 1 -Si(R 3 R 4 R 5 ) is and, here R 1 is -CH2-CH2- and R 3 , R 4 and R 5are each methyl groups. Compounds 3D and 3L are compounds of the general formula Ia, where A is -R 1 -Si(R 3 R 4 R 5 ) is and, here R 1 is -CH2-CH2-CH2- and R 3 and R 4 are each phenyl groups, and R 5 is a tert-butyl group. Compounds 4D and 4L are compounds of the general formula Ia, where A is a tert-butyl group.

[0112] Other examples of compounds according to the present invention are presented in Table 1a. Compounds 5D, 6D, 7D, and 8D have an R-configuration and are derivatives of D-tyrosine. Compounds 5L, 6L, 7L, and 8L have an S-configuration and are derivatives of L-tyrosine.

[0113]

[0114]

[0115] The compounds specified in Table 1a are exemplary compounds of General Formula I and General Formula Ib. Compounds 5D and 5L are compounds of General Formula Ib, where A is -R 1 -OR 2 It is, and here R 1 is a methylene group, and R 2 is a methyl group. Compounds 6D and 6L are compounds of the general chemical formula Ib, where A is -R 1 -Si(R 3 R 4 R 5 )-and, and here R 1 -CH 2 -CH 2 - and, R 3 , R 4 and R 5 are each methyl groups. Compounds 7D and 7L are compounds of the general chemical formula Ib, where A is -R 1 -Si(R3 R 4 R 5 )-and, and here R 1 -CH 2 -CH 2 -CH 2 - and, R 3 and R 4 are each phenyl groups, and R 5 is a tert-butyl group. Compounds 8D and 8L are compounds of the general formula Ib, where A is a tert-butyl group.

[0116] The abbreviations used in short names have the following meanings:

[0117] Boc tert-butoxycarbonyl

[0118] Fmoc 9-Fluorenylmethyloxycarbonyl

[0119] MOM methoxymethyl

[0120] hydroxyl group of the OH carboxyl unit

[0121] TBDPSE tert-butyldiphenylsilylethyl

[0122] TEOC 2-(trimethylsilyl)ethoxycarbonyl

[0123] D-Tyr D-tyrosine

[0124] L-Tyr L-tyrosine

[0125] Example 1

[0126] Fmoc-3-Iod- Synthesis of D-Tyr(MOM)-OH(1D)

[0127] The synthesis of Fmoc-3-Iod-D-Tyr(MOM)-OH was carried out as described in Fig. B1:

[0128]

[0129] Figure B1

[0130] In step (a), (R)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid (11; also called 3-iodo-D-tyrosine or 3-iodo-D-Tyr-OH) is reacted with N-(9-fluorenylmethoxycarbonyloxy)-succinimide (Fmoc-OSu) to obtain (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid (12; also called Fmoc-3-Iod-D-Tyr-OH). The reaction is carried out in a mixture of an aqueous sodium carbonate solution and 1,4-dioxane. In step (b), compound (12) is reacted with methoxymethyl bromide (CH3-O-CH2-Br) to obtain methoxymethyl-(R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propanoate (13; also known as Fmoc-3-Iod-D-Tyr(MOM)-OMOM). The reaction is carried out in dichloromethane (DCM) containing diisopropylethylamine (DIPEA) and tetrabutylammonium chloride (TBACl). Then, in step (c), compound (13) is reacted to produce the target compound (1D). The reaction is carried out in a mixture of tetrahydrofuran (THF), water, and pyridine.

[0131] The analysis of the prepared compounds was performed by HPLC analysis and LC-MS analysis.

[0132] a) Synthesis of Fmoc-3-Iod-D-Tyr-OH (12)

[0133] 3-iod-D-Tyr-OH (11) (5 g, 16.28 mmol) was suspended in 50 ml of aqueous Na2CO3 solution (1.726 g, 16.28 mmol) under an argon atmosphere. 10 ml of dioxane was added, and the yellow solution was cooled in an ice bath. Fmoc-OSu (5.492 g, 16.28 mmol) dissolved in 50 ml of 1,4-dioxane was added dropwise through a dropping funnel under an argon atmosphere. After addition, the reaction mixture was stirred in an ice bath at room temperature for 1 hour. After 17 hours, thin-layer chromatography (DC using DCM / methanol (MeOH), 9:1 as the eluent) confirmed that the desired product Fmoc-3-Iod-D-Tyr-OH was completely converted. 100 ml of H2O was added, and the mixture was cooled in an ice bath. 30% HCl (approx. 4 ml) was added until the pH reached 2 to 3. The mixture was extracted with ethyl acetate (3 x 150 ml), the combined organic phase was washed with H2O (2 x 150 ml) and a salt solution (1 x 150 ml), dried with Na2SO4, and filtered (filter pore size 4). The solvent was removed by rotary evaporation, and the residue was dried under high vacuum. Yield: 9.5 g of white, foamy solid (110%, quantified). The raw product was used without purification in the next step.

[0134] HPLC: t R = 7.26 min. LC-MS: t R = 12.57 min, m / z = 530.05 [M+H] + , 1059.16 [2M+H] + . 1 H NMR(DMSO-d 6, 500MHz): 12.70(br, 1H), 10.12 (s, 1H), 7.88 (m, 2H), 7.72-7.60(m, 4H), 7.43-7.39(m, 2H), 7.34-7.28(m, 2H), 7.09(m, 1H), 6.79 (m, 1H), 4.21-4.18 (m, 3H), 4.10-5.05 (m, 1H), 2.97-2.93 (m, 1H), 2.75-2.70 (m, 1H).

[0135] b) Synthesis of Fmoc-3-Iod-D-Tyr(MOM)-OMOM (13)

[0136] Fmoc-3-Iod-D-Tyr-OH(12) (9.5 g, i.e., 8.62 g, 16.28 mmol ≡ 100%) was suspended in 120 ml of anhydrous DCM under an argon atmosphere. DIPEA (5.673 ml, 32.57 mmol, 2 eq.) was added, and after stirring at room temperature for 10 minutes, a yellow solution was produced. TBACl (453 mg, 1.628 mmol, 0.1 eq.) was added, and the mixture was cooled in an ice bath. Methoxymethyl bromide (MOMBr) (2.658 ml, 32.57 mmol, 2 eq.) diluted in 30 ml of anhydrous DCM was added dropwise through a dropping funnel under an argon atmosphere (gas generation). After addition, the reaction mixture was stirred under ice cooling. After one hour, the mixture was stirred for an additional 18 hours at room temperature. DC (DCM / MeOH, 50:1) showed complete conversion. 100 ml H2O was added, and the mixture was vigorously stirred at room temperature. After one hour, the phases were separated from each other in a separation funnel. The aqueous phase was extracted several times with 150 ml DCM. The combined organic phase was washed with 1N HCl (2 x 150 ml) and a salt solution (150 ml), dried with Na2SO4, and filtered (filter pore size 4). The solvent was removed under vacuum, and the remaining residue was dried under high vacuum. Yield: 11 g of white, foamy solid (109%, quantified). The raw product was used in the next step without purification.

[0137] HPLC: t R = 8.97 min. LC-MS: tR = 14.76 min, m / z = 618.12 [M+H] + , 1235.32 [2M+H] + .

[0138] c) Synthesis of Fmoc-3-Iod-D-thyr(MOM)-OH (1D)

[0139] Fmoc-3-Iod-D-Tyr(MOM)-OMOM (13) was dissolved in 140 ml THF (pa). A mixture consisting of 400 ml H2O and 10 ml pyridine was added while stirring. About 100 ml THF (pa) was added until a clear mixture was formed. The mixture was heated and refluxed in an oil bath (70°C) while stirring vigorously. After 64 hours, the starting material (t) was analyzed by HPLC (214 nm) to produce the product Fmoc-3-Iod-D-Tyr(MOM)-OH. R A complete conversion of (= 8.96 min) was observed. The solvent (THF) was evaporated under vacuum. The mixture was mixed with 2N HCl (approx. 120 ml) under ice cooling. The pH of the solution was between pH 4 and pH 5. The mixture was extracted with DCM (3 x 150 ml), the combined organic phase was washed with 0.5 N HCl (2 x 150 ml) and a saturated salt solution (150 ml), dried with Na2SO4, and filtered. The solvent was evaporated under vacuum, and the remaining residue was dried under high vacuum. Yield: 9.7 g of white, foamy solid (104%, quantified). The raw product was purified by column chromatography (Yield: 4.6 g, purity by HPLC (214 nm): > 95%).

[0140] m / z = 574.11 [M + H] + , 1147.26 [2M + H] + . 1H NMR (400MHz, CDCl3) δ(ppm): 7.752 (d, 2H), 7.610 (s, 1H), 7.549 (m, 2H), 7.387 (t, 2H), 7.307 (m, 2H), 7.042 (d, 1H), 6.960 (d, 2H), 5.185 (s, 2H), 4.697 (m, 1H), 4.444 (m, 1H), 4.336 (m, 1H), 4.201 (m, 1H), 3.483 (s, 3H), 3.131 (m, 1H), 3.004 (m, 1H).

[0141] Example 2

[0142] Synthesis of Boc-3-Iod-D-Tyr(MOM)-OH (5D)

[0143] The synthesis of Boc-3-Iod-D-Tyr(MOM)-OH was carried out as described in Fig. B2:

[0144]

[0145] Figure B2

[0146] In step (a), (R)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid (11; also called 3-iodo-D-tyrosine or 3-iodo-D-Tyr-OH) is reacted with di-tert-butyldicarbonate (Boc2O) to obtain (R)-2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid (22; also called Boc-3-Iod-D-Tyr-OH). The reaction is carried out in a mixture of water, tetrahydrofuran, and triethylamine. In step (b), compound (22) is reacted with methoxymethyl bromide (CH3-O-CH2-Br) to obtain methoxymethyl-(R)-2-((tert-butoxycarbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propanoate (23; also called Boc-3-Iod-D-Tyr(MOM)-OMOM). The reaction is carried out in dichloromethane (DCM) containing diisopropylethylamine (DIPEA) and tetrabutylammonium chloride (TBACl). Then, in step (c), compound (23) is reacted to produce the target compound (5D). The reaction is carried out in a mixture of tetrahydrofuran (THF), water, and pyridine.

[0147] a) Synthesis of Boc-3-Iod-D-Tyr-OH (22)

[0148] 3-iodine-D-Tyr-OH (11) (16.28 mmol) was dissolved in 150 ml of a THF / H2O (1:1) mixture, and TEA (4.44 ml, 32.56 mmol, 2 eq.) was added dropwise. The mixture was cooled to 0°C over ice. Boc2O (3.63 ml, 17.9 mmol, 1.1 eq.) was melted in a water bath at 30°C and then dissolved in 20 ml of THF. The solution was transferred to a dropping funnel and added dropwise over 30 minutes. After 1 hour, the ice bath was removed, and the reaction mixture was stirred overnight at room temperature. The completeness of the conversion was confirmed by HPLC. The THF was removed under vacuum. The aqueous solution was adjusted to pH 3-4 using 1 M HCl and extracted three times with 150 ml of ethyl acetate each time. The combined organic phase was dried with sodium sulfate, and the solvent was removed under vacuum. The product was dried under high vacuum. The purity of the synthesized product (Boc-3-Iod-D-Tyr-OH 22) was determined by HPLC (> 95%).

[0149] b) Synthesis of Boc-3-Iod-D-Tyr(MOM)-OMOM (23)

[0150] Boc-3-Iod-D-Tyr-OH 22 (16.28 mmol) was dissolved in 120 ml of dry DCM. DIPEA (5.67 ml, 32.56 mmol, 2 eq.) and tetrabutylammonium chloride (0.453 g, 1.63 mmol, 0.1 eq.) were added. A methoxymethyl bromide solution (2.657 ml, 32.56 mmol, 2 eq.) dissolved in 30 ml of anhydrous DCM was slowly added dropwise to an ice-cooled solution of Boc-3-Iod-D-Tyr-OH over 30 minutes. After 1 hour, the ice bath was removed, and the mixture was stirred overnight at room temperature. Water was added, and the organic phase was separated and dried; subsequently, the organic phase was evaporated under vacuum. The completeness of the conversion was confirmed by HPLC. The product Boc-3-Iod-D-Tyr(MOM)-OMOM(23) was confirmed by HPLC (> 95%).

[0151] c) Synthesis of Boc-3-Iod-D-thyr(MOM)-OH(5D)

[0152] Boc-ID-Tyr(MOM)-OMOM was dissolved in 20 ml of THF. 20 ml of a 2 M LiOH solution was added to water and stirred at room temperature for 2 hours. The THF was removed under vacuum. 300 ml of DCM and 150 ml of a 5% KHSO4 solution were added and stirred for 5 minutes. After phase separation, the aqueous phase was extracted once with 150 ml of DCM. The combined organic phase was dried with Na2SO4, and the solvent was removed under vacuum. The obtained product was freeze-dried.

[0153] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 7.619 (s, 1H), 7.103 (d, 1H), 6.993 (d, 1H), 5.216 (s, 2H), 4.968; 4.54 (m, 1H), 3.504 (s, 3H), 3.138 (m, 1H), 2.993 (m, 1H), 1.440 (s, 9H).

[0154] Example 3

[0155] a) Synthesis of tripeptides

[0156] A tripeptide was prepared to demonstrate the improved binding properties of the compound according to the present invention of general chemical formula IA. The prepared tripeptide is presented in Table 2, where Ac represents acetyl, Me represents methyl, Amb represents aminomethylbenzoyl, and Pbf represents a 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group.

[0157] Fmoc-3-Iod-D-Tyr(MOM)-OH (Compound 1D) or Boc-3-Iod-D-Tyr(MOM)-OH (Compound 5D) was used to prepare tripeptides P1 and P2 according to the present invention. Additionally, tripeptides V1 and V2 were prepared for comparison. Tripeptides V1 and V2 are distinguished from tripeptides P1 and P2 by the protection of the phenol hydroxyl group. In tripeptides P1 and P2, the phenol hydroxyl group is protected by the -CH2-O-CH3 group (MOM), whereas in tripeptides V1 and V2, it is not protected.

[0158] compound structure designation (order) P1 Fmoc-3-Iod-D-Tyr(MOM)- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH V1 Fmoc-3-Iod-D-Tyr- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH P2 Boc-3-Iod-D-Tyr(MOM)- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH V2 Boc-3-Iodide-D-Tyr- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH

[0159] Tripeptides are precipitated protective peptide fragments using chlorotrityl resin, also known as "Barlos resin" (Barlos, K., et al., substituted triphenylmethyl resin). Tetrahedron Letters It was prepared using the Fmoc / tBu strategy developed by Merrifield in *, 1989, 30(30), pp. 3943-3946). This enables the separation of a fully protected peptide fragment using a weak acidic compound such as hexafluoroisopropanol (HFIP). The binding of all amino acid-like components was performed using diisopropylcarbodiimide (DIC) and ethyl cyanohydroxyiminoacetate (Oxyma). Separation of the Fmoc protecting group was performed in DMF with 20% piperidine. The peptide was separated in DCM with 20% 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP).

[0160] b) Comparative experiment

[0161] Tripeptides V1 and V2 used for comparison with tripeptides P1 and P2 according to the present invention were bound within 60 minutes using diisopropylcarbodiimide (DIC) and ethyl cyanohydroxyiminoacetate (Oxyma).

[0162] To prepare tripeptide P1, Fmoc-3-Iod-D-Tyr(MOM)-OH(1D) was H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotrityl resin was bound. The binding was tracked kinetically. The results are presented in Table 3.

[0163] Fmoc-3-Iod-D-Tyr(MOM)-OH(1D) and H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-Fmoc-3-Iod-D-Tyr(MOM)- chlorotrityl resin N Synthesis of -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(P1) Hours (minutes) Reactants*(%) Product P1(%)** by-product(%)*** 0 100 0 0 15 73 26 0 60 40 60 0 120 14 86 0 720 6 94 0

[0164] Since the reduction of Fmoc-3-Iod-D-Tyr(MOM)-OH can be determined with only a little effort, the reactant is H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH.

[0165] ** Fmoc-3-Iod-D-Tyr(MOM)- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (P1)

[0166] *** It has not been determined in detail what kind of byproduct it is.

[0167] To prepare tripeptide V1, Fmoc-3-Iod-D-Tyr-OH H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotrityl resin was bound. The binding was tracked kinetically. The results are presented in Table 4.

[0168] Fmoc-3-Iod-D-Tyr-OH and H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-Fmoc-3-Iod-D-Tyr- chlorotrityl resin N Synthesis of -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (V1) Hours (minutes) Reactants*(%) Product P1(%)** by-product(%)*** 0 100 0 0 15 81 14.2 4.7 60 65.8 21.9 12.2 120 59.8 26 14.1 720 51.5 29 19.5

[0169] Since the reduction of Fmoc-3-Iod-D-Tyr-OH requires significant effort to measure, the reactant is HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH.

[0170] ** Fmoc-3-Iod-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (V1)

[0171] *** It has not been determined in detail what kind of byproduct it is.

[0172] To prepare tripeptide P2, Boc-3-Iod-D-Tyr(MOM)-OH(5D) was used H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotrityl resin was bound. The binding was tracked kinetically. The results are presented in Table 5.

[0173] Boc-3-Iod-D-Tyr(MOM)-OH and H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-Chlorotrityl resin as Boc-3-Iod-D-Tyr(MOM)- N Synthesis of -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (P2) Hours (minutes) Reactants*(%) Product P1(%)** by-product(%)*** 0 100 0 0 15 87.3 12.17 0 60 37.16 62.84 0 120 13.37 86.63 0 720 0.68 99.32 0

[0174] * Since the reduction of Boc-3-Iod-D-Tyr(MOM)-OH can be measured with only a little effort, the reactant H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH.

[0175] ** Boc-3-Iod-D-Tyr(MOM)- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (P2)

[0176] *** It has not been determined in detail what kind of byproduct it is.

[0177] To prepare tripeptide V2, Boc-3-Iod-D-Tyr-OH H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotrityl resin was bound. The binding was tracked kinetically. The results are presented in Table 6.

[0178] Boc-3-Iod-D-Tyr-OH and H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-Chlorotrityl resin Boc-3-Iod-D-Tyr- N Synthesis of -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (V2) Hours (minutes) Reactants*(%) Product P1(%)** by-product(%)*** 0 100 0 0 15 93.2 5.7 1.06 60 73.3 16.1 10.6 120 65.2 19.8 15 720 53.74 18.56 27.7

[0179] Since the reduction of Boc-3-Iod-D-Tyr-OH can be determined with only a little effort, the reactant is H- N -Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH.

[0180] ** Boc-3-Iod-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH

[0181] *** It has not been determined in detail what kind of byproduct it is.

[0182] The preparation of tripeptides V1 and V2, used for comparison with tripeptides P1 and P2 according to the present invention, demonstrates that target compounds of high purity and yield are produced when both Fmoc-3-Iod-D-Tyr(MOM)-OH(1D) and Boc-3-Iod-D-Tyr(MOM)-OH(5D) are used. When iod-tyrosine derivatives that are not protected in the side chain are used, the yield is significantly reduced or non-specific by-products are formed. Tripeptides P1 and P2 demonstrate increased efficiency in peptide synthesis due to the use of tyrosine derivatives according to the present invention having protected phenol hydroxyl functions.

[0183] Example 4

[0184] Synthesis of Penticather

[0185] While pentisader can be manufactured very efficiently using the amino acid Fmoc-3-Iod-D-Tyr(MOM)-OH(1D), conversion was almost non-existent when using the unprotected amino acid Fmoc-3-Iod-D-Tyr-OH.

[0186] Example 5

[0187] Synthesis of PSMAI&T

[0188] Synthesis of the compound Glu-CO-Lys[(Sub)DLys-DPhe-DTyr(3I)-DOTAGA]trifluoracetat (PSMAI&T) (Wirtz, M., et al., Synthesis and in vitro and in vivo evaluation of urea-based PSMA inhibitors with increased lipophilicity.EJNMMI Research, 2018. 8 (1): p. 84) was synthesized with Boc-3-Iod-D-tyrosine (MOM)-OH (1D) instead of an unprotected derivative, similar to the synthesis of pentisader, and proceeded with significantly improved purity and higher efficiency.

[0189] [Cited Literature]

[0190] 1. Sadri, K., et al., Synthesis and biodistribution studies of iodine-131 D-amino acid YYK peptide as a potential therapeutic agent for labeling an anti-CD20 antibody. 2009. 52 (7): p. 289-294.

[0191] 2. Hallaba, E., H. El-Asrag, and Y. Abou Zeid, 131I-labelling of tyrosine by iodine monochloride. The International Journal of Applied Radiation and Isotopes, 1970. 21 (2): p. 107-110.

[0192] 3. Martin, EB, et al., Evaluation of the effect of D-amino acid incorporation into amyloid-reactive peptides. Journal of translational medicine, 2017. 15 (1): p. 247-247.

[0193] 4. Assoian, RK, et al., Iodotyrosylation of peptides using tertiary-butyloxycarbonyl-l-[125I]iodotyrosine N-hydroxysuccinimide ester. Analytical Biochemistry, 1980. 103 (1): p. 70-76.

[0194] 5. Schottelius, M., et al., [(177)Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent. Theranostics, 2017. 7 (9): p. 2350-2362.

[0195] 6. Brogsitter, C., et al., Twins in spirit part II: DOTATATE and high-affinity DOTATATE―the clinical experience. European journal of nuclear medicine and molecular imaging, 2014. 41 .

[0196] 7. Weineisen, M., et al., 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. J Nucl Med, 2015. 56 (8): p. 1169-76.

[0197] 8. A, W.M., IODINATED INSULIN ANALOGUES WITH FORESHORTENED SIGNALING . 14.12.2016.

[0198] 9. Schottelius, M., et al., An optimized strategy for the mild and efficient solution phase iodination of tyrosine residues in bioactive peptides. Tetrahedron Letters, 2015. 56 (47): p. 6602-6605.

[0199] 10. Steer, A.M., et al., A direct route for the preparation of Fmoc / OtBu protected iodotyrosine. Tetrahedron Letters, 2018. 59 (27): p. 2644-2646.

[0200] 11. White, J.D. and J.C. Amedio, Total synthesis of geodiamolide A, a novel cyclodepsipeptide of marine origin. The Journal of Organic Chemistry, 1989. 54 (4): p. 736-738.

[0201] 12. Ishiwata, H., et al., Total Synthesis of Doliculide, a Potent Cytotoxic Cyclodepsipeptide from the Japanese Sea Hare Dolabella auricularia. The Journal of Organic Chemistry, 1994. 59 (17): p. 4712-4713.

[0202] 13. Pedersen, M.H.F. and L. Martiny, Homogeneous deuteriodeiodination of iodinated tyrosine in angiotensin-I using synthesized triethyl[2H]silane and Pd(0). 2011. 54 (4): p. 191-195.

Claims

Claim 1 delete Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 delete Claim 7 As a compound of general chemical formula I, (Chemical Formula I) In the above formula, A is -R 1 -OR 2 Gi, -R 1 -Si(R 3 R 4 R 5 ) energy, -R 1 -O-Si(R 3 R 4 R 5 ) Gi, -C(O)-OR 9 -Si(R 3 R 4 R 5 ) Gi, -CH(OR 6 )(OR 7 ) energy, -R 1 -CH(OR 6 )(OR 7 ) Gi, R 1 -OC(O)-OR 8 Selected from the group consisting of groups; SG is a protecting group selected from the group consisting of a fluorenylmethyloxycarbonyl group (Fmoc), a tert-butoxycarbonyl group (Boc), and a benzyloxycarbonyl group; R 1 is a divalent hydrocarbon residue having 1 to 12 carbon atoms; R 2 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R 3 , R 4 and R 5 are each independently monovalent hydrocarbon residues having 1 to 12 carbon atoms; R 6 and R 7 Each is a monovalent hydrocarbon residue having 1 to 12 carbon atoms independently; R 8 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R 9 is a divalent hydrocarbon residue having 1 to 12 carbon atoms, and is characterized by the following compounds: 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid, 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, or 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodphenyl)propionic acid Claim 8 As a compound of general chemical formula I, (Chemical Formula I) In the above formula, A is -R 1 -OR 2 Gi, -R 1 -Si(R 3 R 4 R 5 ) energy, -R 1 -O-Si(R 3 R 4 R 5 ) Gi, -C(O)-OR 9 -Si(R 3 R 4 R 5 ) Gi, -CH(OR 6 )(OR 7 ) energy, -R 1 -CH(OR 6 )(OR 7 ) Gi, R 1 -OC(O)-OR 8 Selected from the group consisting of groups; SG is a protecting group selected from the group consisting of a fluorenylmethyloxycarbonyl group (Fmoc), a tert-butoxycarbonyl group (Boc), and a benzyloxycarbonyl group; R 1 is a divalent hydrocarbon residue having 1 to 12 carbon atoms; R 2 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R 3 , R 4 and R 5 are each independently monovalent hydrocarbon residues having 1 to 12 carbon atoms; R 6 and R 7 Each is a monovalent hydrocarbon residue having 1 to 12 carbon atoms independently; R 8 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R 9 is a divalent hydrocarbon residue having 1 to 12 carbon atoms, and is characterized by the following compounds: 2-((tert-butoxycarbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid, 2-((tert-butoxycarbonyl)amino)-3-(3-iod-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodphenyl)propionic acid, or 2-((tert-butoxycarbonyl)amino)-3-(4-(tert-butoxy)-3-iodphenyl)propionic acid Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 A compound of claim 7 or 8 characterized by being used for the production of a peptide. Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 A compound characterized by the following: 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid, 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iod-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, or 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodphenyl)propionic acid. Claim 17 A compound characterized by the following: 2-((tert-butoxycarbonyl)amino)-3-(3-iod-4-(methoxymethoxy)phenyl)propionic acid, 2-((tert-butoxycarbonyl)amino)-3-(3-iod-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodphenyl)propionic acid, or 2-((tert-butoxycarbonyl)amino)-3-(4-(tert-butoxy)-3-iodphenyl)propionic acid Claim 18 A compound of claim 16 or 17 characterized by being used for the production of a peptide.

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