Iodotyrosine derivatives and methods of making iodotyrosine derivatives

Abstract

The present invention relates to a compound of the general formula I wherein A is selected from the group consisting of unbranched or branched alkyl groups having 1 to 12 carbon atoms, -R 1 -O-R 2 groups, -R 1 -Si(R 3 R 4 R 5 groups, -R 1 -O-Si(R 3 R 4 R 5 groups, -C(O)-O-R 9 -Si(R 3 R 4 R 5 groups, -CH(O-R 6 )(O-R 7 ) groups, -R 1 -CH(O-R 6 )(O-R 7 ) groups, -R 1 -O-C(O)-O-R 8 groups; SG is a protecting 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 a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R 6 and R 7 are each independently a monovalent hydrocarbon residue having 1 to 12 carbon atoms; R 8 is a monovalent hydrocarbon residue having 1 to 12 carbon atoms; and R 9 is a divalent hydrocarbon residue having 1 to 12 carbon atoms.

Description

Technical Field

[0001] This invention relates to iodotyrosine derivatives, particularly Fmoc-3-iodotyrosine and Boc-3-iodotyrosine derivatives. It also relates to a method for preparing iodotyrosine derivatives, particularly Fmoc-3-iodotyrosine and Boc-3-iodotyrosine derivatives. Furthermore, this invention relates to the use of iodotyrosine derivatives, particularly Fmoc-3-iodotyrosine and Boc-3-iodotyrosine derivatives, in synthetic peptides. Background Technology

[0002] Modification of peptides with 3-iodotyrosine (D / L) is primarily intended to positively influence the properties of peptides containing iodotyrosine. In many cases, iodotyrosine is introduced primarily at the N-terminus of the peptide or small molecule [4]. Due to the lipophilic nature of iodotyrosine, binding properties are improved, which typically results in improved receptor affinity. Examples of peptides or peptide compounds containing iodotyrosine include the therapeutic diagnostic peptide pair Pentixather / Pentixafor [5], HA-DOTA-TATE [6], or PSMA I&T [7]. In addition, substitution of tyrosine with iodotyrosine produces, for example, improved properties in hormones [8].

[0003] In most cases, iodotyrosine is introduced when using commercially available building blocks Fmoc-3-iodo-L-tyrosine, Fmoc-3-iodo-D-tyrosine, Boc-3-iodo-D-tyrosine, or Boc-3-iodo-L-tyrosine. The term "Fmoc" here refers to the protecting group fluorenylmethoxycarbonyl. The term "Boc" refers to the protecting group tert-butoxycarbonyl. However, the use of Fmoc-3-iodo-L-tyrosine, Fmoc-3-iodo-D-tyrosine, Boc-3-iodo-D-tyrosine, or Boc-3-iodo-L-tyrosine may involve undesirable side reactions because the hydroxyl functional groups at the para position are always nucleophilic enough that they can be acylated by C-terminal activated amino acids. In most cases, this results in the loss of the amino acid, which is no longer available for coupling. In this case, due to the high reactivity of the nucleophilic hydroxyl functional group of tyrosine, coupling Fmoc-3-iodo-L-tyrosine, Fmoc-3-iodo-D-tyrosine, Boc-3-iodo-D-tyrosine or Boc-3-iodo-L-tyrosine may prove infeasible when there is only a small or no conversion in this reaction step.

[0004] One approach to overcome this drawback is to iodinate the tyrosine residues in the peptide product. This typically results in two distinct products: monoiodinated tyrosine residues and diiodinated tyrosine residues [9]. Both must be separated by reversed-phase chromatography, which makes industrial applications difficult. Furthermore, this method is not suitable when there are more than one tyrosine unit in the peptide. Moreover, this method is not suitable for industrial applications because the scale of synthesis is significantly limited. Additionally, the starting material must be separated.

[0005] Cobb et al.

[10] proposed direct iodination of fully protected Fmoc-Tyr(tBu)-OH in methanol in the presence of Ag2SO4 (which mainly produces Fmoc-3-iodo-Tyr(tBu)-OMe), followed by saponification. This method was considered unsuitable for the large-scale applications required in industrial settings. Amedio et al.

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

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

[13] . A disadvantage of this particular compound is its susceptibility to (weak) acids (e.g., hexafluoroisopropanol (HFIP)). This susceptibility makes it impossible to remove the peptide from the resin under complete protection (e.g., in the case of using HFIP). The term "tBu" here refers to the protecting group "tert-butyl", the term "Me" refers to methyl, the term "boc" refers to the protecting group "tert-butoxycarbonyl", the term "PMB" refers to the protecting group "p-methoxybenzyl", and the term "TBDMS" refers to the protecting group "tert-butyldimethylsilyl". Summary of the Invention

[0006] The object of this invention is to overcome the shortcomings of the prior art. Iodotyrosine derivatives, particularly Fmoc-3-iodotyrosine and Boc-3-iodotyrosine derivatives, should be provided, which do not prevent the modification of peptides by introducing iodotyrosine units without the aforementioned side reactions, and do not prevent the such modified peptides from being excised from the resin in a fully protected state.

[0007] This objective is achieved through the features of claims 1, 9, and 12. The convenient design of the invention is derived from the features of the dependent claims.

[0008] According to the present invention, a compound of general formula I is proposed.

[0009]

[0010] in

[0011] A is selected from unbranched or branched alkyl groups having 1 to 12 carbon atoms, -R 1 -OR 2 Group, -R 1 -Si(R 3 R 4 R 5 ) group, -R 1 -O-Si(R 3 R 4 R 5 ) group, -C(O)-OR 9 -Si(R 3 R 4 R 5 ) group, -CH(OR) 6 (OR) 7 ) group, -R 1 -CH(OR 6 (OR) 7 ) group, -R 1 -OC(O)-OR 8 Group;

[0012] SG is a protecting group;

[0013] R 1 These are divalent hydrocarbon residues having 1 to 12 carbon atoms;

[0014] R 2 These are monovalent hydrocarbon residues having 1 to 12 carbon atoms;

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

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

[0017] R 8 It consists of monovalent hydrocarbon residues having 1 to 12 carbon atoms; and

[0018] R 9 These are divalent hydrocarbon residues having 1 to 12 carbon atoms.

[0019] The protecting group SG is preferably selected from fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), and benzyloxycarbonyl. More preferably, the protecting group SG is fluorenylmethoxycarbonyl (Fmoc) or tert-butoxycarbonyl. Particularly preferably, the protecting group SG is fluorenylmethoxycarbonyl (Fmoc). The protecting group SG is used to protect the amino function of the tyrosine unit. Compounds of general formula I are also referred to below as SG-iodotyrosine.

[0020] Compounds of general formula I with SG being fluorenylmethoxycarbonyl (Fmoc) are compounds of general formula Ia; compounds of general formula I with SG being tert-butoxycarbonyl (Boc) are compounds of general formula Ib.

[0021]

[0022] Compounds of general formula Ia are also referred to below as Fmoc-iodotyrosine. Compounds of general formula Ib are also referred to below as Boc-iodotyrosine.

[0023] Compounds of general formula I according to the invention include both each enantiomer individually and mixtures of these enantiomers. The tyrosine unit of a compound of general formula I can therefore exist in the D configuration, L configuration, or a mixture of D and L configurations. The term "D / L" refers to a compound existing in the D configuration, L configuration, or a mixture of D and L configurations.

[0024] The compounds of general formula I according to the present invention have iodine atoms bonded to the phenyl group of the tyrosine unit.

[0025] The compounds according to the invention enable the introduction of SG-3-iodo-D-tyrosine (A)-OH or SG-3-iodo-L-tyrosine (A)-OH into peptides. Protecting the phenolic hydroxyl group with protecting group A prevents undesirable side reactions associated with unprotected hydroxyl functional groups according to the prior art. Unit A thus prevents the acylation of C-terminal activated amino acids. This prevents the loss of amino acids. Furthermore, because the phenolic hydroxyl functional group is protected by unit A, coupling that is difficult to perform with SG-3-iodo-D-tyrosine (A)-OH or SG-3-iodo-L-tyrosine (A)-OH can now be carried out. The invention particularly enables the introduction of Fmoc-3-iodo-D-tyrosine (A)-OH or Fmoc-3-iodo-L-tyrosine (A)-OH into peptides. The invention also enables the introduction of Boc-3-iodo-D-tyrosine (A)-OH or Boc-3-iodo-L-tyrosine (A)-OH into peptides. The term "(A)-OH" should be understood as meaning that the phenolic hydroxyl group of the tyrosine unit is protected by the protecting group A, but the hydroxyl group of the carboxyl group is not protected. Introducing SG-3-iodo-D-tyrosine (A)-OH or SG-3-iodo-L-tyrosine (A)-OH into the peptide can cleave the protecting group A.

[0026] It can be proposed that compounds of general formula I are compounds of general formula IA.

[0027]

[0028] Wherein A has the meaning as described in claim 1. Compounds of general formula IA correspond to compounds of general formula I, except that the iodine atom is located at the 3-position. Compounds of general formula IA where SG is fluorenylmethoxycarbonyl (Fmoc) are compounds of general formulas Ia-A; compounds of general formula I where SG is tert-butoxycarbonyl (Boc) are compounds of general formulas Ib-A.

[0029]

[0030] Unit A is a protecting group for protecting the phenolic hydroxyl group of SG-iodotyrosine. Unit A is preferably an ether group, a silyl ether group, an acetal group, or a carbonate group. In the case of Fmoc-iodotyrosine, unit A is preferably selected to be compatible with the Fmoc / tBu strategy, as in the case of uniodinated Fmoc-D / L-tyrosine (tBu)-OH. In Fmoc-D / L-tyrosine (tBu)-OH, the phenolic hydroxyl functional group is protected by a tert-butyl group (tBu). Furthermore, unit A is selected so that the compound according to the invention can be used on a production scale.

[0031] Preferably, R 1 It is a non-branched alkylene group having 1 to 6 methylene units. Preferably, R 1It is methylene, ethylene, or n-propylene.

[0032] Preferably, R 2 It is an unbranched or branched alkyl group having 1 to 12 carbon atoms or an aryl group, wherein an unbranched or branched alkyl group having 1 to 12 carbon atoms is preferred.

[0033] Preferably, R 3 R 4 and R 5 Each of the following is an alkyl group, which is unbranched or branched and has 1 to 2 carbon atoms, or an aryl group.

[0034] Preferably, R 6 and R 7 Each is independently an alkyl group, either unbranched or branched, having one or two carbon atoms, or an aryl group.

[0035] Preferably, R 8 It is an unbranched or branched alkyl group having 1 to 12 carbon atoms or an aryl group, wherein an unbranched or branched alkyl group having 1 to 12 carbon atoms is preferred.

[0036] Preferably, R 9 It is a non-branched alkylene group having 1 to 6 methylene units. Preferably, R 1 It can be methylene, ethylene, propylene, or butylene.

[0037] It can be proposed that unit A is selected from unbranched or branched alkyl groups having 1 to 12 carbon atoms, -R 1 -OR 2 Group, -R 1 -Si(R 3 R 4 R 5 ) group and -C(O)-OR 9 -Si(R 3 R 4 R 5 () group. It can be proposed that unit A is selected from -R 1 -OR 2 Group, -R 1 -Si(R 3 R 4 R 5 ) group, -R 1 -O-Si(R 3 R 4 R 5 ) group, -C(O)-OR 9 -Si(R 3 R 4 R 5 ) group, -CH(OR) 6(OR) 7 ) group, -R 1 -CH(OR 6 (OR) 7 ) group, -R 1 -OC(O)-OR 8 Group. It can also be proposed that unit A is selected from:

[0038] Alkyl groups having 1 to 6 carbon atoms; -R 1 -OR 2 Group, wherein R 1 R is an alkylene group having 1 to 6 carbon atoms. 2 It is an alkyl group, either unbranched or branched, having 1 to 6 carbon atoms;

[0039] -R 1 -Si(R 3 R 4 R 5 ) group, wherein R 1 R is an alkylene group having 1 to 6 carbon atoms. 3 R 4 and R 5 Each is independently an alkyl group having 1 to 6 carbon atoms, either unbranched or branched, or an aryl group; and

[0040] -C(O)-OR 9 -Si(R 3 R 4 R 5 ) group, wherein R 9 R is an alkylene group having 1 to 6 carbon atoms. 3 R 4 and R 5 Each can be an alkyl group or an aryl group, which are either unbranched or branched and have 1 to 6 carbon atoms.

[0041] A compound of general formula I can be proposed, wherein

[0042] A is selected from -R 1 -OR 2 Group, -R 1 -Si(R 3 R 4 R 5 ) group, -R 1 -O-Si(R 3 R 4 R 5 ) group, -C(O)-OR 9 -Si(R 3 R 4 R 5 ) group, -CH(OR)6 (OR) 7 ) group, -R 1 -CH(OR 6 (OR) 7 ) group, -R 1 -OC(O)-OR 8 Group;

[0043] SG is a protecting group;

[0044] R 1 These are divalent hydrocarbon residues having 1 to 12 carbon atoms;

[0045] R 2 These are monovalent hydrocarbon residues having 1 to 12 carbon atoms;

[0046] R 3 R 4 and R 5 Each is an independent monovalent hydrocarbon residue having 1 to 12 carbon atoms;

[0047] R 6 and R 7 Each is an independent monovalent hydrocarbon residue having 1 to 12 carbon atoms;

[0048] R 8 For monovalent hydrocarbon residues having 1 to 12 carbon atoms; and

[0049] R 9 These are divalent hydrocarbon residues having 1 to 12 carbon atoms.

[0050] It can also be suggested that Unit A is selected from:

[0051] -R 1 -OR 2 Group, wherein R 1 R is an alkylene group having 1 to 6 carbon atoms. 2 It is an alkyl group, either unbranched or branched, having 1 to 6 carbon atoms;

[0052] -R 1 -Si(R 3 R 4 R 5 ) group, wherein R 1 R is an alkylene group having 1 to 6 carbon atoms. 3 R 4 and R 5 Each is independently an alkyl group having 1 to 6 carbon atoms, either unbranched or branched, or an aryl group; and

[0053] -C(O)-OR 9 -Si(R 3R 4 R 5 ) group, wherein R 9 R is an alkylene group having 1 to 6 carbon atoms. 3 R 4 and R 5 Each can be an alkyl group or an aryl group, which are either unbranched or branched and have 1 to 6 carbon atoms.

[0054] Preferred examples of compounds of general formula Ia-A are:

[0055] (i) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid, also known as Fmoc-D / L-Tyr(MOM)-OH, wherein Fmoc-D-Tyr(MOM)-OH is particularly preferred;

[0056] (ii) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iodo-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxo)phenyl)propionic acid, also known as Fmoc-D / L-Tyr(TEOC)-OH, wherein Fmoc-D-Tyr(TEOC)-OH is particularly preferred;

[0057] (iii) 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid, also known as Fmoc-D / L-Tyr(TBDPSE)-OH, wherein Fmoc-D-Tyr(TBDPSE)-OH is particularly preferred; and

[0058] (iv)2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid, also known as Fmoc-D / L-Tyr(tBu)-OH, of which Fmoc-D-Tyr(tBu)-OH is particularly preferred.

[0059] Preferred examples of compounds of the general formula Ib-A are:

[0060] (i) 2-((tert-butoxycarbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid, also known as Boc-D / L-Tyr(MOM)-OH, wherein Boc-D-Tyr(MOM)-OH is preferred;

[0061] (ii) 2-((tert-butoxycarbonyl)amino)-3-(3-iodo-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxo)phenyl)propionic acid, also known as Boc-D / L-Tyr(TEOC)-OH, wherein Boc-D-Tyr(TEOC)-OH is preferred;

[0062] (iii) 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid, also known as Boc-D / L-Tyr(TBDPSE)-OH, wherein Boc-D-Tyr(TBDPSE)-OH is preferred; and

[0063] (iv) 2-((tert-butoxycarbonyl)amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid, also known as Boc-D / L-Tyr(tBu)-OH, wherein Boc-D-Tyr(tBu)-OH is preferred.

[0064] According to the present invention, a method for preparing a compound of general formula I according to the present invention is also provided. For this purpose, a compound of general formula II is reacted with a compound of general formula XA to generate a compound of general formula I.

[0065]

[0066] Where SG has the meaning described in Formula I, X is a halogen or ammonium, and A has the meaning described in Formula I.

[0067]

[0068] Wherein SG and A have the meanings described in Formula I. Protecting group A is introduced into the compound of formula II by means of compound XA. If SG in the compound of formula II is Fmoc, then this compound is Fmoc-iodo-D / L-tyrosine, and according to systematic nomenclature, it is called 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxy-iodophenyl)propionic acid. Preferably, the compound of formula II is Fmoc-iodo-D-tyrosine. If SG in the compound of formula II is Boc, then this compound is Boc-iodo-D / L-tyrosine, and according to systematic nomenclature, it is called 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-iodophenyl)propionic acid, wherein Boc-iodo-D-tyrosine is preferred.

[0069] A particularly preferred compound of general formula II is Fmoc-3-iodo-D / L-tyrosine, systematically named 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid. In this compound, the phenolic iodine atom is located at the 3-position. Fmoc-3-iodo-D-tyrosine is particularly preferred. Another preferred compound of general formula II is Boc-3-iodo-D / L-tyrosine, systematically named 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid. In this compound, the phenolic iodine atom is located at the 3-position. Boc-3-iodo-D-tyrosine is particularly preferred.

[0070] Compounds of general formula II can be prepared from compounds of general formula IV.

[0071]

[0072] The amine functional group of the compound of general formula IV is protected by introducing a protecting group SG. For this purpose, the compound of general formula IV can be reacted with a 9-fluorenylmethoxycarbonyl reagent or a tert-butoxycarbonyl reagent. The 9-fluorenylmethoxycarbonyl compound can be, for example, (9-fluorenylmethoxycarbonyloxo)succinimide (Fmoc-OSu). The tert-butoxycarbonyl reagent can be, for example, di-tert-butyl dicarbonate (Boc2O). The compound of general formula IV is D / L-iodotyrosine, with D-iodotyrosine being preferred.

[0073] It can be proposed that a compound of general formula II be reacted with a compound of general formula XA to obtain a compound of general formula III, and then the compound of general formula III be reacted to generate a compound of general formula I.

[0074]

[0075] Scheme 1 demonstrates the preparation of a compound of general formula I according to the present invention from a compound of general formula II.

[0076]

[0077] Option 1

[0078] Scheme 1a illustrates the preparation of a compound of general formula Ia according to the present invention from a compound of general formula IIa. Compound IIa is a compound of general formula II in which SG is Fmoc. The method shown in Scheme 1a is an embodiment of the method shown in Scheme 1.

[0079]

[0080] Option 1a

[0081] Scheme 2 illustrates the preparation of compounds of general formula Ia-A according to the invention from 3-iodo-D / L-tyrosine. The method shown in Scheme 2 is a preferred embodiment of the method shown in Scheme 1a.

[0082]

[0083] Option 2

[0084] Step (a) of the method shown in Scheme 1 proposes to react the compound of general formula IV to generate the compound of general formula II. Here, a protecting group is introduced at the N-terminus of the compound of general formula IV to protect the amine functional group. For this purpose, the compound of general formula IV can be reacted, for example, with (9-fluorenylmethoxycarbonyloxo)succinimide (Fmoc-OSu) (see Scheme 1a) or di-tert-butyl dicarbonate (Boc2O). The compound of general formula II corresponds 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 is understood to be in the range of 18 to 25 °C.

[0085] If Fmoc is introduced as a protecting group SG in step (a) of scheme 1, step (a) can be carried out under ambient pressure and temperature, and under a protective gas, such as an argon atmosphere. To introduce Fmoc as the protecting group SG, step (a) is preferably carried out in a mixture of aqueous sodium carbonate and 1,4-dioxane in this case.

[0086] If Boc is introduced as a protecting group SG in step (a) of scheme 1, step (a) can be carried out in air under ambient pressure and temperature. No protective gas is required. In this case, step (a) is preferably carried out in a mixture of water, tetrahydrofuran, and triethylamine.

[0087] Step (b) of the method shown in Scheme 1 proposes to react a compound of general formula II to generate a compound of general formula III. Here, the hydroxyl group at the C-terminus and the phenolic hydroxyl group of the compound of general formula II are protected by unit A. For this purpose, the compound of general formula II is reacted with compound XA. This reaction can occur in an aprotic solvent such as dichloromethane (DCM) in the presence of an auxiliary base such as diisopropylethylamine (Hünig base, DIPEA) and a phase transfer catalyst such as tetrabutylammonium chloride (TBACl). This reaction can be carried out in a temperature range between 0°C and ambient temperature. This reaction can be carried out under ambient pressure and under a protective gas, such as an argon atmosphere. The compound of general formula III corresponds to the compound of general formula II, except that the hydroxyl group at the C-terminus and the phenolic hydroxyl group of the compound of general formula II are protected by unit A.

[0088] Step (c) of the method shown in Scheme 1 proposes to react a compound of general formula III to generate a compound of general formula I. Here, the unit A protecting the hydroxyl group at the C-terminus of the compound of general formula III is cleaved, while the unit A protecting the phenolic hydroxyl group remains unchanged. The cleavage occurs in a basic range, for example in a pyridine / water mixture. This reaction can be carried out in a temperature range between 0°C and ambient temperature. This reaction can be carried out under ambient pressure. No protective gas is required. The compound of general formula I corresponds to the compound of general formula III, except that the compound of general formula I has a hydroxyl group at its C-terminus.

[0089] Further details of the method according to the invention have been described in conjunction with compounds of general formula I according to the invention. Please refer to the description therein.

[0090] According to the present invention, the use of compounds of general formula I for the preparation of peptides is proposed. The prepared peptide has at least one iodotyrosine unit. The prepared peptide may correspond to a known peptide, except that at least one, preferably exactly one, tyrosine unit has been replaced by a 3-iodotyrosine unit. The 3-iodotyrosine unit can 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 can be carried out by synthetic methods known per se, such as Merrifield synthesis. A route for synthesizing peptides is described in the Solid phase peptide synthesis journal of the American Chemical Society (Robert Bruce Merrifield, Solid phase peptide synthesis Journal of the American Chemical Society, Volume 85, Heft 14S. 2149–2154). After the preparation of the peptide, unit A of the compound derived from general formula I is cleaved, thereby obtaining a peptide with a 3-iodotyrosine unit whose phenolic OH group is unprotected.

[0091] Scheme 3 demonstrates the use of compounds of general formula I to prepare peptides of general formula V containing iodotyrosine units.

[0092]

[0093] Option 3

[0094] Scheme 3a demonstrates the preparation of peptides of general formula Va containing iodotyrosine units using compounds of general formula Ia. Peptides of general formula Va are peptides of general formula V in which SG is Fmoc.

[0095]

[0096] Option 3a

[0097] Then, the protecting group SG can be cleaved, thereby transforming a compound of general formula V into a compound of general formula VI, as shown in schemes 4 and 4a.

[0098]

[0099] Option 4

[0100]

[0101] Option 4a

[0102] If the iodotyrosine unit is not the terminal unit of the peptide, another amino acid can be coupled to the N-terminus of the compound of formula VI, thereby obtaining the compound of formula VII, as shown in scheme 5.

[0103]

[0104] Option 5

[0105] One or more additional amino acids can be bonded to the other amino acid, thereby obtaining a peptide of general formula VIII.

[0106]

[0107] Where A has the meaning described in compounds of general formula I, R 10 R is a hydrogen or one or more amino acid units. 11 It can be hydrogen or one or more amino acid units, provided that R 10 When it is hydrogen, R 11 Not hydrogen, when R 11 When it is hydrogen, R 10 Not hydrogen. The amino acid unit can have an NH group or NR group at the N-terminus. 12 The unit of the group, wherein R 12 It is a methyl group.

[0108] Compounds of general formula VIII can be converted into peptides of general formula IX by breaking unit A, as shown in scheme 6.

[0109]

[0110] Option 6

[0111] In an acidic range, unit A is cleaved, for example, during the complete deprotection of the peptide. For complete deprotection of the peptide, an aqueous solution of trifluoroacetic acid (TFA), such as a 95% TFA solution, is preferred. This reaction can be carried out in a temperature range between 0°C and ambient temperature. This reaction can be carried out under ambient pressure. No protective gas is required. Compounds of general formula IX correspond to compounds of general formula VIII, except that unit A has been cleaved to obtain a hydroxyl group.

[0112] Unless otherwise stated, the term "alkyl" specifically refers to a monovalent saturated aliphatic hydrocarbon group having a carbon chain of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and particularly preferably 1 to 6 carbon atoms, whether branched or unbranched. 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.

[0113] Unless otherwise stated, the term "alkylene" specifically refers to a divalent saturated aliphatic hydrocarbon group having a carbon chain of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and particularly preferably 1 to 6 carbon atoms, whether branched or unbranched. Examples of alkylene groups include, but are not limited to, methyl, ethyl, propyl, butyl, etc.

[0114] Unless otherwise stated, the term "aryl" specifically refers to a cyclic aromatic hydrocarbon group composed of a monocyclic, dicyclic, or tricyclic aromatic ring system having 5 to 18 ring atoms, preferably 5 or 6 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, fluorenyl, indene, azulel, biphenyl, methylene biphenyl, and their partially hydrogenated derivatives. Unless otherwise stated, aryl groups can be monovalent or polyvalent, for example, monovalent or divalent.

[0115] The present invention will be explained in detail below with the aid of embodiments, but the invention should not be limited to these embodiments.

[0116] Examples of compounds according to the invention are given in Table 1. Compounds 1D, 2D, 3D and 4D have the R configuration and are derivatives of D-tyrosine. Compounds 1L, 2L, 3L and 4L have the S configuration and are derivatives of L-tyrosine.

[0117] Table 1:

[0118]

[0119]

[0120] The compounds mentioned in Table 1 are exemplary compounds of general formulas I and Ia. Compounds 1D and 1L are compounds of general formula Ia, wherein A is -R. 1 -OR 2 Group, wherein R1 It is methylene, R 2 It is a methyl group. Compounds 2D and 2L are compounds of general formula Ia, where A is -R. 1 -Si(R 3 R 4 R 5 ) group, wherein R 1 It is -CH2-CH2-, R 3 R 4 and R 5 They are methyl groups, respectively. Compounds 3D and 3L are compounds of general formula Ia, where A is -R. 1 -Si(R 3 R 4 R 5 ) group, wherein R 1 It is -CH2-CH2-CH2-, R 3 and R 4 They are phenyl, R 5 It is tert-butyl. Compounds 4D and 4L are compounds of general formula Ia, where A is tert-butyl.

[0121] Other examples of compounds according to the invention are given in Table 1a. Compounds 5D, 6D, 7D and 8D have the R configuration and are derivatives of D-tyrosine. Compounds 5L, 6L, 7L and 8L have the S configuration and are derivatives of L-tyrosine.

[0122] Table 1a:

[0123]

[0124]

[0125]

[0126] The compounds mentioned in Table 1a are exemplary compounds of general formulas I and Ib. Compounds 5D and 5L are compounds of general formula Ib, wherein A is -R. 1 -OR 2 Group, wherein R 1 It is methylene, R 2 It is a methyl group. Compounds 6D and 6L are compounds of general formula Ib, where A is -R. 1 -Si(R 3 R 4 R 5 ) group, wherein R 1 It is -CH2-CH2-, R 3 R 4 and R 5They are methyl groups, respectively. Compounds 7D and 7L are compounds of general formula Ib, where A is -R. 1 -Si(R 3 R 4 R 5 ) group, wherein R 1 It is -CH2-CH2-CH2-, R 3 and R 4 They are phenyl, R 5 It is tert-butyl. Compounds 8D and 8L are compounds of general formula Ib, where A is tert-butyl.

[0127] The abbreviations used in abbreviations have the following meanings:

[0128] Boc: tert-butoxycarbonyl

[0129] Fmoc: 9-fluorenylmethoxycarbonyl

[0130] MOM: Methoxymethyl

[0131] OH: hydroxyl group of the carbonyl unit

[0132] TBDPSE: tert-butyldiphenylsilylethyl

[0133] TEOC: 2-(trimethylsilyl)ethoxycarbonyl

[0134] D-Tyr: D-Tyrosine

[0135] L-Tyr: L-tyrosine

[0136] Example 1

[0137] Synthesis of Fmoc-3-Iod-D-Tyr(MOM)-OH(1D)

[0138] The synthesis of Fmoc-3-Iod-D-Tyr(MOM)-OH was carried out as described in Scheme B1:

[0139]

[0140] Option B1

[0141] In step (a), (R)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid 11 (also known as 3-iodo-D-tyrosine or 3-Iod-D-Tyr-OH) is reacted with N-(9-fluorenylmethoxycarbonyloxo)succinimide (Fmoc-OSu) to give (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid 12 (also known as Fmoc-3-Iod-D-Tyr-OH). The reaction occurs in a mixture of aqueous sodium carbonate and 1,4-dioxane. Then, in step (b), compound 12 is reacted with methoxybromomethyl (CH3-O-CH2-Br) to generate methoxymethyl-(R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid 13 (also known as Fmoc-3-Iod-D-Tyr(MOM)-OMOM). The reaction occurs in dichloromethane (DCM) in the presence of diisopropylethylamine (DIPEA) and tetrabutylammonium chloride (TBACl). Then, in step (c), compound 13 is reacted to generate target compound 1D. The reaction is carried out in a mixture of tetrahydrofuran (THF), water, and pyridine.

[0142] The prepared compounds were analyzed by HPLC and LC-MS.

[0143] a) Synthesis of Fmoc-3-Iod-D-Tyr-OH(12)

[0144] 3-Iod-D-Tyr-OH 11 (5 g, 16.28 mmol) was suspended in 50 mL of Na₂CO₃ aqueous 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-water bath. Fmoc-OSu (5.492 g, 16.28 mmol) in 50 mL of 1,4-dioxane solution was added dropwise via a dropping funnel under an argon atmosphere. After the addition, the reaction mixture was stirred in an ice-water bath for 1 hour, then stirred at room temperature. After 17 hours, thin-layer chromatography (using DC with DCM / methanol (MeOH) 9:1 as eluent) showed complete conversion to the desired product Fmoc-3-Iod-D-Tyr-OH. 100 mL of H₂O was added, and the mixture was cooled in an ice-water bath. 30% HCl (approximately 4 mL) was added until a pH of 2 to 3 was achieved. The mixture was extracted with ethyl acetate (3 × 150 ml), and the combined organic phases were washed with H₂O (2 × 150 ml) and salt solution (1 × 150 ml). The mixture was dried over 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 (110%, quantitative) of a white, foamy solid. The crude product was used in the next step without further purification.

[0145] HPLC:t R =7.26min.LC-MS:t R =12.57min, m / z=530.05[M+H] + 1059.16 [2M+H] + . 1 HNMR (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).

[0146] b) Synthesis of Fmoc-3-Iod-D-Tyr(MOM)-OMOM(13)

[0147] 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 equivalents) was added, and a yellow solution was formed after stirring at room temperature for 10 minutes. TBACl (453 mg, 1.628 mmol, 0.1 equivalents) was added, and the mixture was cooled in an ice-cooled water bath. Methoxybromomethyl (MOMBr) (2.658 g, 32.57 mmol, 2 equivalents) diluted in 30 mL of anhydrous DCM was added dropwise using a dropping funnel under an argon atmosphere (gas generation). After the addition, the reaction mixture was stirred while ice-cooled. After one hour, stirring was continued for another 18 hours at room temperature. DC (DCM / MeOH, 50:1) showed complete inversion. Add 100 ml of H₂O and stir the mixture vigorously at room temperature. After 1 hour, separate the phases in a separatory funnel. Extract the aqueous phase repeatedly with 150 ml of DCM. Wash the combined organic phases with 1N HCl (2 × 150 ml) and salt solution (150 ml), dry through Na₂SO₄ and filter (filter pore size 4). Remove the solvent under vacuum; dry the remaining residue under high vacuum. Yield: 11 g (10⁹%, quantitative) of white frothy solid. The crude product was used in the next step without further purification.

[0148] HPLC:t R =8.97min.LC-MS:t R=14.76 min, m / z = 618.12 [M+H] + 1235.32[2M+H] + .

[0149] c) Synthesis of Fmoc-3-Iod-D-Tyr(MOM)-OH(1D)

[0150] Fmoc-3-Iod-D-Tyr(MOM)-OMOM 13 was dissolved in 140 mL of THF (Pa). While stirring, a mixture of 400 mL H₂O and 10 mL pyridine was added. Approximately 100 mL of THF (Pa) was added until a clear mixture was formed. The mixture was heated to reflux in an oil bath (70 °C) with vigorous stirring. After 64 hours, the starting material (t) was observed in HPLC (214 nm). R =8.96 min) completely converted to the product Fmoc-3-Iod-D-Tyr(MOM)-OH. The solvent (THF) was evaporated under vacuum. The mixture was mixed with 2N HCl (approximately 120 ml) while ice-cooled. The pH of the solution was between pH 4 and pH 5. The mixture was extracted with DCM (3 × 150 ml), the combined organic phases were washed with 0.5N HCl (2 × 150 ml) and saturated salt solution (150 ml), dried over Na2SO4 and filtered. The solvent was evaporated under vacuum, and the remaining residue was dried under high vacuum. Yield: 9.7 g (104%, quantitative) of white foamy solid. The crude product was purified by column chromatography (yield: 4.6 g, purity achieved by HPLC (214 nm): >95%).

[0151] m / z = 574.11 [M+H] + 1147.26 [2M+H] + . 1 H-NMR (400MHz, CDCl3) (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),5.1 85(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).

[0152] Example 2

[0153] Synthesis of Boc-3-Iod-D-Tyr(MOM)-OH(5D)

[0154] The synthesis of Boc-3-Iod-D-Tyr(MOM)-OH was carried out as described in Scheme B2:

[0155]

[0156] Option B2

[0157] In step (a), (R)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid 11 (also known as 3-iodo-D-tyrosine or 3-Iod-D-Tyr-OH) is reacted with di-tert-butyl dicarbonate (Boc2O) to give (R)-2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid 22 (also known as Boc-3-Iod-D-Tyr-OH). The reaction occurs in a mixture of water, tetrahydrofuran, and triethylamine. Then, in step (b), compound 22 is reacted with methoxybromomethyl (CH3-O-CH2-Br) to generate methoxymethyl-(R)-2-((tert-butoxycarbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid 23 (also known as Fmoc-3-Iod-D-Tyr(MOM)-OMOM). The reaction takes place in dichloromethane (DCM) in the presence of diisopropylethylamine (DIPEA) and tetrabutylammonium chloride (TBACl). Then, in step (c), compound 23 is reacted to generate the target compound 5D. The reaction is carried out in a mixture of tetrahydrofuran (THF), water, and pyridine.

[0158] a) Synthesis of Boc-3-Iod-D-Tyr-OH(22)

[0159] 16.28 mmol of 3-Iod-D-Tyr-OH 11 was dissolved in 150 mL of a 1:1 THF / H₂O mixture, and TEA (4.44 mL, 32.56 mmol, 2 equivalents) was added dropwise. The mixture was cooled to 0 °C on ice. Boc₂O (3.63 mL, 17.9 mmol, 1.1 equivalents) was melted in an aqueous solution at 30 °C, and then dissolved in 20 mL of THF. The solution was transferred to a dropping funnel and added dropwise over a 30-minute period. After one hour, the ice bath was removed, and the reaction mixture was stirred overnight at room temperature. The degree of conversion was controlled by HPLC. THF was removed under vacuum. The aqueous solution was adjusted to pH 3–4 with 1 M HCl and extracted three times with 150 mL of ethyl acetate. The combined organic phases were dried over 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%).

[0160] b) Synthesis of Boc-3-Iod-D-Tyr(MOM)-OMOM(23)

[0161] 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 equivalents) and tetrabutylammonium chloride (0.453 g, 1.63 mmol, 0.1 equivalents) were added. Over a 30-minute period, a solution of methoxybromomethyl (2.657 mL, 32.56 mmol, 2 equivalents) in 30 mL of anhydrous DCM was slowly added dropwise to the ice-cooled Boc-3-Iod-D-Tyr-OH solution. After one hour, the ice bath was removed, and the mixture was stirred overnight at room temperature. After adding water and subsequently separating and drying the organic phase, the organic phase was evaporated under vacuum. The degree of conversion was controlled by HPLC. The product Boc-3-Iod-D-Tyr(MOM)-OMOM 23 was identified by HPLC (>95%).

[0162] c) Synthesis of Boc-3-Iod-D-Tyr(MOM)-OH(5D)

[0163] Boc-ID-Tyr(MOM)-OMOM was dissolved in 20 mL of THF. 20 mL of 2M LiOH aqueous solution was added and the mixture was stirred at room temperature for 2 hours. The THF was removed under vacuum. 300 mL of DCM and 150 mL of 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 phases were dried over Na2SO4 and the solvent was removed under vacuum. The obtained product was lyophilized.

[0164] 1 H-NMR(400MHz, CDCl3)(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).

[0165] Example 3

[0166] a) Synthetic tripeptide

[0167] To demonstrate the improved coupling properties of the compound of general formula IA according to the present invention, a tripeptide was prepared. The prepared tripeptides are shown in Table 2, wherein Ac represents acetyl, Me represents methyl, Amb represents aminomethylbenzoyl, Pbf represents 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl, and Iod represents iodide.

[0168] To prepare the tripeptides P1 and P2 according to the present invention, Fmoc-3-Iod-D-Tyr(MOM)-OH (compound 1D) or Boc-3-Iod-D-Tyr(MOM)-OH (compound 5D) was used. Additionally, tripeptides V1 and V2 were prepared for comparative purposes. Tripeptides V1 and V2 differ from tripeptides P1 and P2 in the protection of the phenolic hydroxyl group. In tripeptides P1 and P2, the phenolic hydroxyl group is protected by a -CH2-O-CH3 group (MOM), while in tripeptides V1 and V2 it is unprotected.

[0169] Table 2

[0170]

[0171]

[0172] Tripeptides were prepared on chlorotriphenylmethyl resin (also known as "Barlos resin") using the Fmoc / tBu strategy developed by Merrifield (using substituted triphenylmethyl resin to protect peptide fragments, Barlos, K., et al., Darstellung geschützter Peptid-Fragmente unter Einsatz substituierter Triphenylmethylharze, Tetrahedron Letters, 1989, 30(30), pp. 3943-3946). This allows for the cleavage of fully protected peptide fragments using weakly acidic compounds such as hexafluoroisopropanol (HFIP). Coupling of all amino acid components was performed using diisopropylcarbodiimide (DIC) and ethyl hydroxyimide cyanocyanate (Oxyma). The Fmoc protecting group was cleaved in DMF using 20% ​​piperidine. Peptide cleavage is performed in DCM using 20% ​​1,1,1,3,3,3-hexafluoroprop-2-ol (HFIP) to cleave peptides from the resin.

[0173] b) Comparative Experiment

[0174] The tripeptides P1 and P2 according to the invention, as well as tripeptides V1 and V2 for comparative purposes, are coupled within 60 minutes using diisopropylcarbodiimide (DIC) and ethyl hydroxyimide cyanocyanate (Oxyma).

[0175] To prepare the tripeptide P1, Fmoc-3-Iod-D-Tyr(MOM)-OH(1D) was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenylmethyl resin. The coupling was carried out kinetically. The results are shown in Table 3.

[0176] Table 3

[0177] Composed of Fmoc-3-Iod-D-Tyr(MOM)-OH(1D) and HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenyl Synthesis of methyl resins: Fmoc-3-Iod-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(P1)

[0178] Time (minutes) Reactants* (%) Product P1 (%)** Byproducts (%)*** 0 100 0 0 15 73 26 0 60 40 60 0 120 14 86 0 720 6 94 0

[0179] *The reactant is HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, because the determination of the reduction of Fmoc-3-Iod-D-Tyr(MOM)-OH requires higher costs.

[0180] **Fmoc-3-Iod-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(P1)

[0181] ***No specific byproducts were detected.

[0182] To prepare the tripeptide V1, Fmoc-3-Iod-D-Tyr-OH was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenylmethyl resin. The coupling was performed kinetically. The results are shown in Table 4.

[0183] Table 4

[0184] Composed of Fmoc-3-Iod-D-Tyr-OH and HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenylmethyl resin into Fmoc-3-Iod-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(V1)

[0185] Time (minutes) Reactants* (%) Product V1 (%)** Byproducts (%)*** 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

[0186] *The reactant is HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, because the determination of the reduction of Fmoc-3-Iod-D-Tyr-OH requires higher costs.

[0187] **Fmoc-3-Iod-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(V1)

[0188] ***No specific byproducts were detected.

[0189] To prepare the tripeptide P2, Boc-3-Iod-D-Tyr(MOM)-OH(5D) was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenylmethyl resin. The coupling was carried out kinetically. The results are shown in Table 5.

[0190] Table 5

[0191] Composed of Boc-3-Iod-D-Tyr(MOM)-OH and HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenylmethyl resin Liposynthesis Boc-3-Iod-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(P2)

[0192] Time (minutes) Reactants* (%) Product P2 (%)** Byproducts (%)*** 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

[0193] *The reactant is HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, because the determination of the reduction of Boc-3-Iod-D-Tyr(MOM)-OH requires higher costs.

[0194] **Boc-3-Iod-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(P2)

[0195] ***No specific byproducts were detected.

[0196] To prepare the tripeptide V2, Boc-3-Iod-D-Tyr-OH was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenylmethyl resin. The coupling was performed kinetically. The results are shown in Table 6.

[0197] Table 6

[0198] Composed of Boc-3-Iod-D-Tyr-OH and HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-chlorotriphenylmethyl resin into Boc-3-Iod-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH(V2)

[0199] Time (minutes) Reactants* (%) Product V2 (%)** Byproducts (%)*** 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

[0200] *The reactant is HN-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, because the determination of the reduction of Boc-3-Iod-D-Tyr-OH requires higher costs.

[0201] **Boc-3-Iod-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH

[0202] ***No specific byproducts were detected.

[0203] The preparation of tripeptides P1 and P2 according to the invention, and tripeptides V1 and V2 for comparative purposes, showed that the target compounds were produced with high purity and yield using both Fmoc-3-Iod-D-Tyr(MOM)-OH (1D) and Boc-3-Iod-D-Tyr(MOM)-OH (5D). The use of iodotyrosine derivatives with unprotected side chains resulted in significantly reduced yields or the formation of unspecified byproducts. Tripeptides P1 and P2 demonstrated improved peptide synthesis efficiency, obtained by using tyrosine derivatives with protected phenolic hydroxyl groups according to the invention.

[0204] Example 4

[0205] Synthetic Pentixather

[0206] Pentixather can be prepared with high efficiency using the amino acid Fmoc-3-Iod-D-Tyr(MOM)-OH(1D), while using the unprotected amino acid Fmoc-3-Iod-D-Tyr(MOM)-OH results in no conversion or only low conversion.

[0207] Example 5

[0208] synthesis PSMAI&T

[0209] Similar to the Pentixather synthesis, the compound Glu-CO-Lys[(Sub)DLys-DPhe-DTyr(3I)-DOTAGA]trifluoroacetate (PSMAI&T) was synthesized with higher efficiency and significantly improved final product purity when Boc-3-Iod-D-tyrosine (MOM)-OH(1D) was used to replace the unprotected derivative. (Synthesis and in vitro and in vivo evaluation of urea-based PSMA inhibitors with increased lipophilicity. EJNMMIResearch, 2018.8(1):p.84).

[0210] References

[0211] 1.Sadri,K.,et al.,Synthesis and biodistribution studies of iodine-131D-amino acid YYK peptide as a potential therapeutic agent for labeling ananti-CD20 antibody.2009.52(7):p.289-294.

[0212] 2.Hallaba,E.,H.El-Asrag,and Y.Abou Zeid,131I-labelling of tyrosine byiodine monochloride.The International Journal of Applied Radiation andIsotopes,1970.21(2):p.107-110.

[0213] 3.Martin,E.B.,et al.,Evaluation of the effect of D-amino acidincorporation into amyloid-reactive peptides.Journal of translationalmedicine,2017.15(1):p.247-247.

[0214] 4.Assoian,R.K.,et al.,Iodotyrosylation of peptides using tertiary-butyloxycarbonyl-l-[125I]iodotyrosine N-hydroxysuccinimideester.AnalyticalBiochemistry,1980.103(1):p.70-76.

[0215] 5.Schottelius,M.,et al.,[(177)Lu]pentixather:ComprehensivePreclinical Characterizationof a First CXCR4-directed EndoradiotherapeuticAgent.Theranostics,2017.7(9):p.2350-2362.

[0216] 6.Brogsitter,C.,et al.,Twins in spirit part II:DOTATATE and high-affinity DOTATATE—theclinical experience.European journal of nuclearmedicine and molecular imaging,2014.41.

[0217] 7.Weineisen,M.,et al.,68Ga-and 177Lu-Labeled PSMA I&T:Optimization ofaPSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies.JNucl Med,2015.56(8):p.1169-76.

[0218] 8.A,W.M.,IODINATED INSULIN ANALOGUES WITH FORESHORTENEDSIGNALING.14.12.2016.

[0219] 9.Schottelius,M.,et al.,An optimized strategy for the mild andefficient solution phaseiodination of tyrosine residues in bioactivepeptides.Tetrahedron Letters,2015.56(47):p.6602-6605.

[0220] 10.Steer,A.M.,et al.,A direct route for the preparation of Fmoc / OtBuprotected iodotyrosine.Tetrahedron Letters,2018.59(27):p.2644-2646.

[0221] 11.White,J.D.and J.C.Amedio,Total synthesis of geodiamolide A,a novelcyclodepsipeptideof marine origin.The Journal of Organic Chemistry,1989.54(4):p.736-738.

[0222] 12.Ishiwata,H.,et al.,Total Synthesis of Doliculide,a PotentCytotoxic Cyclodepsipeptidefrom the Japanese Sea Hare Dolabellaauricularia.The Journal of Organic Chemistry,1994.59(17):p.4712-4713.

[0223] 13.Pedersen,M.H.F.and L.Martiny,Homogeneous deuteriodeiodination ofiodinated tyrosinein angiotensin-I using synthesized triethyl[2H]silane andPd(0).2011.54(4):p.191-195.

Claims

1. A compound of general formula I, (Formula I), in A is selected from -R 1 -OR 2 Group; SG is a protecting group, selected from fluorenylmethoxycarbonyl and tert-butoxycarbonyl; R 1 These are divalent hydrocarbon residues having 1 to 12 carbon atoms; R 2 These are monovalent hydrocarbon residues having 1 to 12 carbon atoms.

2. The compound according to claim 1, characterized in that, The compound is a compound of general formula IA. (Form IA) Wherein A and SG have the meanings described in claim 1.

3. The compound according to claim 1 or 2, characterized in that, A is selected from: -R 1 -OR 2 Group, wherein R 1 R is an alkylene group having 1 to 6 carbon atoms. 2 It is an alkyl group that is either unbranched or branched and has 1 to 6 carbon atoms.

4. The compound according to claim 1 or 2, characterized in that, A is selected from: -R 1 -OR 2 Group, wherein R 1 R is an alkylene group having 1 to 4 carbon atoms. 2 It is an alkyl group that is either unbranched or branched and has 1 to 6 carbon atoms.

5. The compound according to claim 1 or 2, characterized in that, The compound is 2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid.

6. The compound according to claim 1 or 2, characterized in that, The compound is 2-((tert-butoxycarbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid.

7. A method for preparing the compound according to any one of claims 1 to 6, characterized in that, A compound of general formula II reacts with a compound of general formula XA to form a compound of general formula I. (Formula II) Wherein SG is a protecting group, selected from fluorenylmethoxycarbonyl and tert-butoxycarbonyl; Where X is a halogen or ammonium. A is selected from -R 1 -OR 2 Group; R 1 These are divalent hydrocarbon residues having 1 to 12 carbon atoms; R 2 Monovalent hydrocarbon residues having 1 to 12 carbon atoms (Formula I), Where A and SG have the meanings described in Equation II.

8. The method according to claim 7, characterized in that, The compound of general formula II is reacted with the compound of general formula XA to give the compound of general formula III, and then the compound of general formula III is reacted to give the compound of general formula I. (Formula III).

9. The method according to claim 7 or 8, characterized in that, Compounds of general formula II are prepared from compounds of general formula IV by introducing a protecting group SG at the amino group of the compound of general formula IV. (Formula IV).

10. Use of the compound according to any one of claims 1 to 6 for the preparation of peptides.

11. The use according to claim 10, characterized in that, The peptide is a compound of general formula IX. (Form IX) in R 10 It is hydrogen or one or more amino acid units; and R 11 It can be a hydroxyl group or one or more amino acid units; The prerequisite is that when R 10 When it is hydrogen, R 11 Not a hydroxyl group, when R 11 When R is a hydroxyl group 10 It is not hydrogen.

12. The use according to claim 10 or 11, characterized in that, React compounds of general formula VIII to form compounds of general formula IX. (Formula VIII) in A is selected from -R 1 -OR 2 Group; R 1 These are divalent hydrocarbon residues having 1 to 12 carbon atoms; R 2 These are monovalent hydrocarbon residues having 1 to 12 carbon atoms; R 10 and R 11 It has the meaning described in the compound of general formula IX.

13. The use according to claim 12, characterized in that, The reaction is carried out in an acidic range.

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