TWI352699B - - Google Patents

Description

1352699 IX. Description of the Invention: The present invention relates to a difunctional compound and a method for producing the same, and more particularly to a bifunctional compound containing a carboxylic acid s- and a nitrogen-disulfide complex. In the method for producing the same, the bifunctional compound containing a ligand of a diacid and a diazo disulfide can be used to bond a target substance containing an amino group with chromium or ruthenium to form a nuclear medicine, so that it can be applied to a body tissue contrast agent. 'The target of therapeutic agents for diseases or the field of nuclear medicine for assisting in the correct diagnosis of diseases. [Prior Art] There are special receptors on human cells that can accept certain amines, amino acids, peptides or proteins. If this kind of money base is combined with the nucleus of the nucleus, then the amino group-containing compound will accumulate in a specific organ or tissue and can reach the nuclear medicine angiography diagnosis or Hezhi _ purpose. For example, because the fine death (talking t〇sis) is closely related to the silk of the family disease, the egg is self-proclaimed by the hybridization standard of Annexin V, and is applied to the study of cell growth. If you want to secrete the protein or peptide, you must use a bifunctional compound to bind the protein _99m. S-Hynic contains an activated 峨 _ which can be produced with protein or viscous _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ However, the solution of s_Hynic is a light-sensitive substance, and it is easy to see light decomposition. In addition, the number of chelation of S-_ic is insufficient, and an auxiliary chelating agent is additionally added. For example, it is convenient to use it, so it is easy to find another property, and it is convenient to make (4) a bifunctional compound necessary. The book f knows the technical form, so it provides a double s & sigma sigma and its sputum method, and the bismuth diazo disulfide ligand Functional group compounds - can bond alcohols and amines, on the other hand can be bonded + or Tc (f, can be applied to the chain of proteins and peptides or sputum, and the ugly diazo The dihetero compound of the disulfide ligand has a _-determination, (d) operation and one; and 1352699 the difunctional compound containing a carboxylate and a diazodisulfide ligand does not require an additional auxiliary chelating agent. Therefore, the main steps of the present invention are to provide a bifunctional compound containing a carboxylate and a diazodisulfide complex, and a method for producing the same, the carboxylate-containing compound The difunctional compound with the diazo disulfide ligand can bond the alcohol to the amine on the one hand, and the other It can be bonded to 1^〇3+ or 〇3+, which can be applied to the 铢 mark or chrome label of protein and peptide. The second object of the present invention is to provide a carboxylic acid ester and diazo disulfide. The bifunctional compound of a ligand and a method for producing the same, wherein the bifunctional compound containing a carboxylate and a diazo disulfide ligand is light-stable, and thus is easy to handle and use in an environment having a light source. Another object of the present invention is to provide a bifunctional compound containing a carboxylate and a diazodisulfide complex, and a method for producing the same, wherein the bifunctional compound containing a carboxylate and a diazodisulfide complex is not An additional chelating agent is added, so that the steps and costs of the reaction can be reduced. The present invention provides a bifunctional compound containing a carboxylate and a diazodisulfide complex and a process for producing the same. Difunctional compounds of disulfide ligands, including:

Where R1 = H, CH3; R2 = H, ch3; R3 = CPh3, ch2C6H4 〇 CH3, COC6H5;

;n =1~3 ; m =1~9 and Ph is a phenyl group. 6 1352699 The method for producing a bifunctional compound containing a carboxylate and a diazodisulfide complex, the steps comprising: (1) reacting N^CR^CRtSH with a protective agent to form N^CR^CR^SR3; The NI^CRSCR^SR3 and X(CH2)nC0X are subjected to a guanidation reaction to form

Ov -(CHA NH W1 yRl

R (4) will

Substitution reaction with Br<CH2>nCOOH

; and 7 1352699

N,N,-dicyclohexyldicarbodiamine (N,N-dicycl〇hexyldiearbodiimide)

Wherein R1 = H, CH3; R2 = H, CH3; R3 = CPh3, CH2C6H4 〇 CH3, COC6H5;

; 11 = 1 to 3; 111 = 1 to 9; ? 11 is a phenyl group and the parent is a halogen atom. [Embodiment] For a better understanding and understanding of the features and method steps of the present invention, the detailed principles and preferred embodiments of the present invention are described below. The invention relates to a bifunctional compound containing a carboxylate and a diazodisulfide complex, comprising:

(CH2)? / (CH^-C - 0 -R4 N R1 v ,

Where R1 = H, CH3; R2 = H, CH3; R3 = CPh3, CH2C6H4〇CH3, COC6H5; 1352699 r4=

; n = 1 to 3; m = 1 to 9 and Ph is a phenyl group. Where η and m=l, and R4 =

The difunctional compound containing a carboxylate and a diazodisulfide ligand is butyreneimine 3,6-bisazino-5-oxo-3-[2-((triphenylmethyl)) Thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (Succinimidyi 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl]-8- [(triphenylmethyl)thio] octanoate, referred to as SOCTA) compound. The invention relates to a method for producing a difunctional compound (DFL) containing a carboxylate and a diazodisulfide complex, the steps of which include (as shown in the first figure): (1) NI^CR^CR^SH and a protective agent The reaction forms NI^CR^CRiSR3; (2) the NHsCR^CRiSR3 and X(CH2)nCOX are subjected to amidization reaction.

(CH2)nX

9 1352699

VCCHA 1 HN r1 (4) is substituted with Br(CH2)mCOOH to produce r2 (^sr3 r3s r2

Ru R2- R2

Q. -(CH2)n ^ (CH2)m-COOH Nv ^R1 R1 , SR3 R3S' ' R ; and '(CH2)n (5)

R2y\ R2

SR3 rV .(CH2)nrCOOH .R1 R1 -R2 and team 1^'-bicyclohexyl bis-carbocalamine (1^,1^'-(^0>^1〇116乂71(^汪1>1) 0€^11^06) Dehydration reaction is obtained to obtain ο 〇-(CHjJn ^ (CHj^-CO-R4 N R1 R1- R2- R1 R2 R2

, SR3 R3s wherein R1 = H, CH3; RZ=H, CH3; RJ=CPh3, CH2C6H4〇CH3, COC6H5; ;11=1~3; 111=1~9; ?11 is a phenyl group and is also a halogen atom. Wherein the protective agent is triphenylmethanol in the step (1), and the step (1) further comprises a step of dissolving in the chloroform and heating to reflux, and the step of heating and refluxing further comprises dropping the trifluoride paste. Catalyst for ethyl ether complex. The step (2) further comprises a step of washing the organic phase after dissolving in trimethyl methane and concentrating under reduced pressure. The step (3) further comprises the steps of dissolving and diluting the dichloro chloride 135.2699 methane, adding triethylamine to reflux, and separating and purifying by liquid chromatography. The step (4) further comprises a step of adding bromoacetic acid, triethylamine and acetonitrile, heating to reflux, concentration under reduced pressure, and separation and purification by liquid chromatography. Further, the step (5) further comprises the step of adding N-hydroxammonium imine, 1,3-bicyclohexanecarbalamine and anhydrous tetrahydrofuran to form the N,N'-dicyclohexyldicarbocene.

In the step (5), when η and m=l, and R4=j, the bifunctional compound containing the ligand of the sulphuric acid ester and the diazodisulfide is succinic acid, 6-bisaza-5- Oxy-3-[2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (Succinimidyl 3,6-diaza-5-oxo-3 -[2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)thio] octanoate, abbreviated as SOCTA) compound. A representative difunctional compound 8110 (; 丨11丨111丨(1>^13,6-£11323-5-〇\〇-3-[2-((triphenylmethyl)thio)ethyl)-8-) [(triphenylmethyl)thio] octanoate (referred to as SOCTA) as an example, detailing the synthesis method of SOCTA (as shown in the second figure) and its amide reaction with amines and subsequent mismatch reactions: (1) 1,2- [(Triphenylmethyl)thio]ethylamine 9] 2-thioethylamine hydrochloride (10 g, 88.4 mmol) , triphenylmethanol (22 g, 85 mmol) and triethylamine (triethylamine) (14 mL, 99.7 mmol), co-dissolved in trimethylamine (100 mL). Force σ heat (75 ° C) After refluxing, the catalyst was slowly added dropwise to a boron trifluoride ethyl ether complex (30 mL, 239 mmol), and the mixture was further heated under reflux for 4 hours, concentrated under reduced pressure, dissolved in methanol and then concentrated. The aqueous solution of sodium hydrogen was stirred and immediately precipitated as a white solid. The mixture was filtered off with suction, taken and washed with water and dried to give a solid product 9 (27.9 g, 990/ IR (neat) v 3381 (NH2) cm-i. NMR (CDC13) δ 7.42 (m, 3 H, Ph), 7.30 (m, 12 H, Ph), 2.58 (t, J = 6.6 Hz, 2 H, CH2N), 2.32 (t, J = 6.6 Hz, 2 H, CH2S), 1.45 (br, 2H, NH2). 13C NMR (CDC13) δ 144.80, 192.52, 127.81 11 1352699 and 126.60 (Ph), 66.51 ( CPh), 40.94 (CH2N), 36.09 (CH2S). MS m/z 319 (M"), 243 (IVT - CeHs + 1). (2) N-[2-((triphenylmethylthio)) Synthesis of ethyl] chloroacetamido N-[2-((Triphenylmethyl)thio)ethyl]chloroacetamide) 10 Compound 9 (10.63 g, 33.3 mmol) co-dissolved with triethylamine triethylamine (5.6 mL, 39.9 mmol) To trichlorodecane (80 mL). Under ice cooling, slowly dilute a solution of chloroacetyl chloride (3.18 mL, 39.9 mmol) in trimethylamine (10 mL). After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, and the following organic phases were washed sequentially with the following: 1 aqueous solution of NHC1 (120 mL), saturated aqueous sodium carbonate (100 mL) and water (100 mL). The organic phase was concentrated under reduced pressure EtOAc (EtOAc)EtOAc. φ IR (neat) ν 3413 and 3306 (ΝΗ), 1662 (CO) cm·1· *H NMR (CDC13) δ 7.41 (m, 3 H, Ph), 7.24 (m, 12 H, Ph), 6.48 ( Br, 1 Η, NH), 3.97 (s, 2 H, CH2C1), 3.12 (q, J = 6.3 Hz, 2 H, CH2N), 2.43 (t, J = 6.3 Hz, 2 H, CH2S). 13CNMR( CDC13) δ 165.63 (CO), 144.47, 129.48, 127.97 and 126.81 (Ph), 66.52 (CPh), 42.54 (CH2C1), 38.35 (CH2N), 31.67 (CH2S). MS m/z 397 and 395 243 &CPh3&gt ;+>. (3) N-[2-((Triphenylmethyl)thio)ethyl][2-((triphenylmethyl)thio)ethylamino]acetamide (N-[2 -((Triphenylmethyl)thio)ethyl] [2-((triphenylmethyl)thio)ethyl-amino]acetamide) 11 Synthesis of Compound 10 (12.7 g, 32 mmol) and Compound 9 (10.2 g, 32 mmol) Trichloromethane (60 mL) was added to triethylamine triethyamine (6.7 mL, 48 mmol) and heated to reflux for two days. After cooling, it was washed with an aqueous solution of sodium hydrogencarbonate (NaHC03) (60 mL) and then washed with water (60 mL). The organic phase was dried (MgSO4) (EtOAc m. %). IR (neat) v 3330 (NH), 1670 (CO) cm·'. 'H NMR (CDC13) δ 7.42 (m, 4 H, HNCO and Ph), 7.20 (nU2H, Ph), 3.07 (m, 4H, CH2NCO and CH2CO), 8 12 1352699 2.38 (m,6 H,CH2NHCH2CO and CH2S), 1.94 (br,1 H,NHCH2CO). I3C NMR (CDC13) δ 170.84 (CO), 144.61, 129.47, 127.88 and 126.69 (Ph ), 66.72 and 66.65 (CPh3), 51.62 (£H2CO), 48.19 (CH2NHCH2CO), 37.70 (QH2NHCO), 32.12 and 31.97 (CH2S). MS m/z 243 ((CPH3)+). (4) 3,6·diazepine -5-oxo-3-[2-((triphenylsulfonyl)thio)ethyl]-8-[(triphenyl-methyl)thio]octanoic acid 3,6-01〇23-5- 〇乂〇-3-[2-((出卩)1611)41116仇)你111〇)6出)4]-8-[扣卩1111)4-methyl) thio]octanoic acid) 12 synthesis of compounds 11 (10.1 g, 14.9 mmol), bromacetic acid (2.2 g, 15.8 mmol) and triethylamine (3.13 mL, 22.3 mmol) and acetonitrile (30 mL), then heated to reflux (85 °) C) overnight. After cooling, it was concentrated under reduced pressure. EtOAc m. The organic phase was separated with EtOAc (EtOAc)EtOAc. IR (neat) v 3327 (NH), 1726 and 1634(0)) 011-1. !H NMR (CD3OD) δ 7.40 (m, 3 Η, Ph), 7.25 (m, 12 H, Ph), 3.21 ( s, 2 H, CH2), 3.11 (s, 2 H, CH2), 2.30 (t, J = 6.6 Hz, 2 H, CHjNH), 2.52 (t, J = 6.6 Hz, 2 H, CH2N), 2.34 ( t, J = 6.6 Hz, 4, H, CH2S). 13C NMR (CD3OD) δ 173.89 and 172.97 (CO), 146.11, 130.72, 128.96, 127.87 and 127.81 (Ph), 68.09 and 67.84 (CPh3), 59.0, 55.86 And 55.13 (CH2), 39.12 (CH2NH), 32.70 and 31.01 (CH2S). MS m/z 243 ((CPh3)+). (5) Dibutylenimine 3,6-diazo-5-oxy- 3-[2-((triphenylsulfonyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (Succinimidyl 3,6-diaza-5-oxo-3-[ Synthesis of 2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanoate, SOCTA) Compound 12 (1.65 g, 2.1 mmol) was added to N-hydroxysuccinimide. (0.3 g, 2.52 mmol), 1,3-dicyclohexylcarbodiimide (0.7 g, 31.5 mmol) and anhydrous tetrahydrofuran 13 1352699 (tetrahydrofliran) (30 mL), at Mix overnight at room temperature. A gassing transition was carried out to remove the precipitated solid, and the solution was concentrated under reduced pressure. Separation and purification using liquid chromatography (si s 2, ethyl acetate) gave the oily product SOCTA (1.79 g, 60.2%). IR (neat) v 3360 (NH), 1815, 1786, 1741 and 1674(0)) 011-1. 'HNMR (CDC13) δ 7.37 (m, 4 H, NH and Ph), 7.21 (m, 12 H, Ph), 3.49 (s, 2 H, CH2), 3.31 (s, 2 H, CH2), 3.02 (q, J = 6.6 Hz, 2 H, CH2NH), 2.75 (s, 4 H, CH2CH2CO), 2.58 ( t, J = 6.6 Hz, 2 H, CH2N), 2.36 (t, J = 6.6 Hz, 2 H, CH2S), 2.31 (t, J = 6.6 Hz, 2 H, CH2S). , 3C NMR (CDC13) δ 169.68, 168.56 ^ 165.63 (CO), 144.68, 144.50 129.52, 129.47, 127.96, 127.88, 126.78 and 126.65 (Ph), 66.94 and 66.68 (CPh3), 57.96, 53.31 and 52.41 _ (CH2), 38.07 (CH2NH), 31.89 And 29.93 (CH2S), 25.50 (CH2CH2CO). MS m/z 243 ((CPh3)+). Experiment of SOCTA and amine and radionuclear bond bonding (as shown in the second figure) (1) Ν, Ν-Dimethyl Synthesis of 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanamide 13 Compound 80 (: Ding Ba (1.67 & 2. 〇) 111111〇1) and diamine (1〇1111^18.2111111〇1) were co-dissolved in tri-gas methane (30 mL), stirred at room temperature overnight, evaporated to dryness under reduced pressure and eluted with diethyl ether. (Si02, three gas methane) Purification afforded the oily product 13 (1.22 g, 80%). ❿ IR (neat) v 3341 (NH), 1673 and 1651 (CO) cm·1.]H NMR (CDC13) δ 7.87 (t, J = 6.6 Hz, 1, NH), 7.21-7.06 (m, 30 H, Ph), 3.19 (s, 2 H, CH2CO), 3.09 (s, 2 H, CH2C0), 3.04 (q, J = 6.6 Hz, 2 H, CHjNHCO), 2.82 (s, 3 H, NCH3), 2.77 (s, 3, H, NCH3), 2.64 (t, J = 6.6 Hz, 2 H, CH2 CH2NCH2CO), 2.39 (t, J = 6.6 Hz) , 2 H, CH2CH2NHCO), 2.26 (t, J = 6.6 Hz, 2 H, CH2CH2NCH2CO). 13C NMR (CDC13) δ 171.17 and 169.67 (CO), 144.74, 144.70, 129.52, 129.49, 127.83, 126.63 and 126.60 (Ph ), 66.69 and 66.54 (CPh), 58.39, 54.58, 53.97 and 37.98 (CH2), 36.16 and 8 14 1352699 35.38 (NCH3), 31.88 and 30.23 (CH2). MS m/z 243 ((CPh3)+). 2) [N-(2-thioethy l)-N-(2-thioethy l)-N-(N,N-dimethy carbamoylmethyl) aminoacetimido] Synthesis of oxorhenium(V) 14 Compound 13 (0.63 g, 0.83 mmol) 'ReO(PPh3)2Cl3 (0.87 g, 1.0 mmol) and triethylamine (0.4 mL, 2.9 mmol) were dissolved in methanol (50 mL) and heated at 55 ° C for 16 hours. Dry, use three gas The residue was dissolved alkoxy, washed with water liquid chromatography (Si〇2, three gas Yue chloride: methanol = 100: 5) separation and purification, to give a red-brown product viscosity of 14 (0.18 g, 45%). IR (neat) v 1639 and 1614 (CO), 961 (ReO) cm-1. NMR (CDC13) δ 5.62 _ (d, J = 15.0 Hz, 1 H, NCOCH2N), 4.83 (dd, J = 12.0 and 4.8 Hz, 1 Η,

CONCHjCHz), 4.66 (dd, J = 15.0 and 2.4 Hz, 1 H, NCOCH2N), 4.32 (m, 1 H, COCH2NCH2CH2), 3.76 (m, 1 H, COCH2NCH2C£i2), 3.60 - 3.30 (m, 3 H , CONCH2CH2), 3.26 - 3.05 (m, 3 H, COCH2NCH2CH2), 2.89 (s, 3 H, CH3), 2.72 (s, 3 H, CH3), 2.42 (d, J = 17.1 Hz, 1 H, NCOCH2N) 13C NMR (CDCI3) δ 184.88 and 163.64 (CO), 68.29, 63.58, 54.28, 53.40, 47.98 and 40.69 (CH2), 36.65 and 35.67 (CH3). MS m/z 479 and 477 (ΐνΓ). SOCTA and amine The experiments of the base and the radioactive nucleus bond prove that the SOCTA compound in the bifunctional compound containing the carboxylate and the di-disulfide ligand in the present invention can bond with the peptide of the amino acid, peptide or protein®, and Re〇3+ or Tc03+ and other radioactive nucleus linkages, so it can be applied to the labeling of proteins and peptides, or for the treatment of diseases, and the combination of carboxylate and diazodisulfide ligands The functional group compound is light stable, so it is easy to operate and use in an environment with a light source. Moreover, the bifunctional compound containing a carboxylate and a diazo disulfide ligand does not require additional auxiliary chelation. 'It is possible to reduce the reaction steps and costs. However, the above is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. The structure, features, and spirit of the present invention are equally varied and modified. All should be included in the scope of the patent application of the present invention. 15 1352699 BRIEF DESCRIPTION OF THE DRAWINGS The first figure is a schematic view showing the steps of producing a bifunctional compound containing a carboxylate and a diazodisulfide complex. Fig. 2 is a schematic view showing the steps of producing a SOCTA compound, a SOCTA compound, an amine group and a radioactive nucleus bond of a bifunctional compound containing a carboxylate and a diazodisulfide ligand. [Main component symbol description]

Ph phenyl X dentate atom

Claims (1)

.1352699 Patent Application: Public! A bifunctional compound containing a carboxylate and a diazodisulfide ligand, including: 〇. Wherein R1 = H, CH3; R2 = H, CH3; R3 = CPh3, CH2C6H4〇CH3, COCeHj; q R4: N; n = l~3; m = l~9 and Ph is phenyl O 2 · as claimed The bifunctional fluorenyl compound containing a carboxylate and a diazodisulfide ligand according to the above item 1, wherein when η and m=l, and R4=, the sulphur-containing acid ester is combined with diazodisulfide The difunctional compound of the position is butyl succinimide 3,6-bisaza-5-oxy•3-[2-((triphenylmethyl)thio)ethyl]-8-[(three Phenylmethyl)thio]octanoate (Succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl)-8-[(triphenylmethyl)thio]octanoate, S0CTA) . 3. A method for producing a bifunctional compound containing a carboxylate and a diazodisulfide ligand, the steps comprising: (1) reacting N^CI^CI^SH with a protective agent to form ni^CR^CR^SR3; (2) The nitrile formation of NI^CRSCR^SR3 and X(CH2)nC0X (CH2)nX 17 1352699 Ο, (CH2)nX (3)The R1 R1 R2 R2 Substitution reaction with NHsCR'CR^SR3 to generate SRJ V-(CHA HN NH R1 RfsR3 o. (4) The R R2y\SRJ -(CHA and B<C:H2>naX)H for the substitution reaction, oyster? ο. -(CH2)?/(CH2)m_c〇〇H Ν R1 ; and r27\ R2 SR3 R3S/ R1 R2 O. •(CH2)n (5) The center of the COOH VRR; and the R;^SR3 team 1^'-dicyclohexyldicarbodiamine (>^,1''1'-<11.>^1〇116\54<^31'1)〇(1111111(16) is obtained by dehydration reaction •(CH2^/(CH^-t!-〇-R4 N ! R2-^ R2 SR3 R3S R1 R2 8 18 4. 4. Wherein CH3; R2=H, CH3; R3=CPh3, CH2C6H4〇CH3, COCeHs; n =1~3 ; m =1~9 ; Ph is a phenyl group and X is a halogen atom. A method for producing a bifunctional compound containing a carboxylate and a diazodisulfide complex as described in claim 3, wherein the protecting agent in the step (1) is triphenylmethanol. The method for producing a bifunctional compound containing a carboxylate and a diazodisulfide ligand as described in claim 3 of the patent scope, wherein the step (1) further comprises a dissolution. The step of heating the reflux after the three gas methane. A method for producing a bifunctionalized soiled material containing a tetastereate and a diazodisulfide complex according to the fifth aspect of the patent, wherein the step of heating and refluxing further drops boron trifluoride ethyl ether Catalyst for the compound. The method for producing a bifunctional f compound containing a carboxylate and a diazodisulfide complex as described in claim 3, wherein the step (2) further comprises: washing the organic phase after dissolving in three gas methane; The step of concentration under reduced pressure. The method for producing a bifunctional compound containing a carboxylate and a diazodisulfide complex as described in claim 3, wherein the step (3) further comprises dissolving in a dichloromethane and then adding the triethyl group. The amine is heated to reflux and the step of purification is separated by liquid chromatography. The method for producing a bifunctional compound containing a carboxylate and a diazodisulfide complex as described in claim 3, wherein the step (4) further comprises adding bromoacetic acid, triethylamine and acetonitrile. Thereafter, the mixture was heated under reflux and concentrated under reduced pressure and purified by liquid chromatography. 10. The method for producing a bifunctional compound containing a tetacid S and a dioxodisulfide complex as described in claim 3, wherein the step (5) further comprises adding a hydrazine azoxide. Imine, 1,3-bicyclohexene carbon diamine and anhydrous tetrahydrogen. The step of forming the N,N,_dicyclohexyldicarbodiamine. 11. A method for producing a difunctional 1352699-based compound containing a tickacid and a diazodisulfide ligand as described in claim 3, wherein in step (5), η and m=l, and R4 = , the bifunctional compound containing a carboxylate and a diazodisulfide ligand is dibutyl quinone imino 3,6-diazo-5-oxy-3-[2-((triphenyl) Thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (Succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl]- 8-[(triphenylmethyl)thio]octanoate, abbreviated as SOCTA) compound. 20