[ CAS No. 188715-40-4 ] {[proInfo.proName]}

Name: 188715-40-4|Fmoc-4-Amc-OH|95%
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Quality Control of [ 188715-40-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 188715-40-4 ]

SDS Specification

Alternatived Products of [ 188715-40-4 ]

Product Details of [ 188715-40-4 ]

CAS No. :	188715-40-4	MDL No. :	MFCD01862347
Formula :	C₂₃H₂₅NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MLMIBGARTUSGND-UHFFFAOYSA-N
M.W :	379.45	Pubchem ID :	2756125
Synonyms :

Calculated chemistry of [ 188715-40-4 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.39
Num. rotatable bonds :	7
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	107.09
TPSA :	75.63 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.05
Log Po/w (XLOGP3) :	4.05
Log Po/w (WLOGP) :	4.42
Log Po/w (MLOGP) :	3.44
Log Po/w (SILICOS-IT) :	3.63
Consensus Log Po/w :	3.72

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-4.6
Solubility :	0.00955 mg/ml ; 0.0000252 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.34
Solubility :	0.00173 mg/ml ; 0.00000455 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.03
Solubility :	0.000358 mg/ml ; 0.000000944 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.15

Safety of [ 188715-40-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 188715-40-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 188715-40-4 ]
Downstream synthetic route of [ 188715-40-4 ]

[ 188715-40-4 ] Synthesis Path-Upstream 1~2

1
[ 1197-17-7 ]
[ 28920-43-6 ]
[ 188715-40-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: With sodium carbonate In 1,4-dioxane; water at 20℃; for 2.5 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water	Step 1: Dissolve 4-Aminomethyl-cyclohexanecarboxylic acid ((39); 1.15g, 7.30mmol) in 1,4-dioxane (12.0mL) and 10percent aqu. Na2CO3 (23.2mL) and add Fmoc-Cl (2.26g, 8.76mmol). Stir the reaction mixture for 2.5h at rt. Add 1M aqu HCl (42.0mL) to the mixture and extract with EtOAc (3 times). Wash the combined organic layers with 1M aqu HCl, water and brine, extract the combined aqu layers once again with EtOAc, dry the combined organic layers with Na2SO4 and remove solvent under reduced pressure. The left crude product is washed with ice cold EtOAc and dried in oil pump vacuum to obtain (40) as a white solid (2.28g, 83percent). No further purification. [M. Nichifor; E. H. Schacht; Tetrahedron;1994; 50; 12; 3747-3760]. 1H NMR (400MHz, CDCl3): 0.87-1.02 (br.m, 2 H); 1.34-1.52 (br.m, 4 H); 1.81 (br.d, 2 H, J 6Hz); 1.90-2.11 (br.s, 1 H); 2.12-2.35 (br.m, 1 H); 3.03 (Ψt, 2 H, J = 6.2Hz); 4.19 (br.Ψt, 1 H, J = 6.5Hz); 4.42 (br.Ψd, 2 H, J = 6.5Hz); 4.74 (br.s, 1 H); 7.30 (Ψt, 2 H, J = 7.4Hz); 7.38 (Ψt, 2 H, J = 7.4Hz); 7.57 (d, 2 H, J = 7.4Hz); 7.75 (d, 2 H, J = 7.4Hz).

Reference： [1] Patent: EP1577289, 2005, A1, . Location in patent: Page/Page column 23
[2] Organic Letters, 2008, vol. 10, # 10, p. 1881 - 1884

2
[ 1197-17-7 ]
[ 82911-69-1 ]
[ 188715-40-4 ]

Reference： [1] Patent: US2004/14763, 2004, A1, . Location in patent: Page 17; 18

[ 188715-40-4 ] Synthesis Path-Downstream 1~23

1
[ 112883-29-1 ]
[ 135273-01-7 ]
[ 188715-40-4 ]
(4R,9R)-9-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-2,10-dioxo-6,7-dithia-3,11-diaza-bicyclo[11.2.2]heptadecane-4-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3359 - 3368

2
[ 1197-17-7 ]
[ 82911-69-1 ]
[ 188715-40-4 ]

Yield	Reaction Conditions	Operation in experiment
		Aminomethylcyclohexane carboxylic acid (1) (20 g, 127 mmol) and sodium carbonate (13.6 g, 128 mmol) were dissolved in 600 mL of water, then a solution of FmocOSu (40 g, 118 mmol) was added over a period of 30 min with stirring. The mixture was stirred overnight, during which a large amount of white precipitate formed. The mixture was acidified to pH=3 with 1N HCl, then diluted with 2L of ethyl acetate. The organic layer was separated, washed with 5percent aqueous citric acid, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and cooled in a freezer overnight. The solid was filtered off, then the filtrate was concentrated to ca. 1L and cooled overnight. The solid was filtered and combined with the previously collected solid (2) then dried in a desiccator.

Reference： [1]Patent: US2004/14763,2004,A1 .Location in patent: Page 17; 18

3
[ 188715-40-4 ]
C₂₃H₂₅N₂O₄Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The Fmoc aminomethylcyclohexyl carboxylic acid (2) was taken up in 1L of dichloromethane. Oxalyl chloride (39 mL, 450 mmol) was added, followed by DMF (10 drops) and the mixture was stirred for 1 h. The mixture was concentrated under vacuum and the residue was dissolved in 1L of toluene, and a solution of sodium azide (18.4 g, 280 mmol) in 30 mL of water was added along with 3.4 g (12 mmol) of tetrabutylammonium azide. Due to low solubility, an additional 2L of toluene was added, and the mixture was stirred vigorously until the IR spectrum of an aliquot showed a peak for the acyl azide (2120 cm-1). The mixture was filtered, and the solid set aside (unreacted acid chloride). The filtrate was extracted with 5% aqueous citric acid (2×200 mL) and brine (200 mL) then the toluene solution was dried over anhydrous sodium sulfate and filtered. The solution was heated to reflux until the IR spectrum of an aliquot of the solution showed an isocyanate peak (2230 cm-1) and loss of the acyl azide peak. The solution was evaporated to give 31 g of solid. The solid was dissolved in dichloromethane (800 mL) and stirred with Wang resin (57 g, 54 mmol) and 4N HCl in dioxane (1.5 mL) was added. The mixture was stirred overnight then filtered. The resin (3) was washed with DMF (3×800 mL), dichloromethane (3×800 mL) and diethyl ether (3×800 mL) then dried in a vacuum desiccator.

Reference： [1]Patent: US2004/14763,2004,A1 .Location in patent: Page 18

4
[ 1197-17-7 ]
[ 28920-43-6 ]
[ 188715-40-4 ]

Yield	Reaction Conditions	Operation in experiment
83%		Step 1: Dissolve 4-Aminomethyl-cyclohexanecarboxylic acid ((39); 1.15g, 7.30mmol) in 1,4-dioxane (12.0mL) and 10percent aqu. Na2CO3 (23.2mL) and add Fmoc-Cl (2.26g, 8.76mmol). Stir the reaction mixture for 2.5h at rt. Add 1M aqu HCl (42.0mL) to the mixture and extract with EtOAc (3 times). Wash the combined organic layers with 1M aqu HCl, water and brine, extract the combined aqu layers once again with EtOAc, dry the combined organic layers with Na2SO4 and remove solvent under reduced pressure. The left crude product is washed with ice cold EtOAc and dried in oil pump vacuum to obtain (40) as a white solid (2.28g, 83percent). No further purification. [M. Nichifor; E. H. Schacht; Tetrahedron;1994; 50; 12; 3747-3760]. 1H NMR (400MHz, CDCl3): 0.87-1.02 (br.m, 2 H); 1.34-1.52 (br.m, 4 H); 1.81 (br.d, 2 H, J 6Hz); 1.90-2.11 (br.s, 1 H); 2.12-2.35 (br.m, 1 H); 3.03 (Psit, 2 H, J = 6.2Hz); 4.19 (br.Psit, 1 H, J = 6.5Hz); 4.42 (br.Psid, 2 H, J = 6.5Hz); 4.74 (br.s, 1 H); 7.30 (Psit, 2 H, J = 7.4Hz); 7.38 (Psit, 2 H, J = 7.4Hz); 7.57 (d, 2 H, J = 7.4Hz); 7.75 (d, 2 H, J = 7.4Hz).

Reference： [1]Patent: EP1577289,2005,A1 .Location in patent: Page/Page column 23
[2]Organic Letters,2008,vol. 10,p. 1881 - 1884

5
2-chlorotrityl chloride polystyrene resin [ No CAS ]
[ 188715-40-4 ]
C₄₂H₃₇ClNO₄Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 14h;	Step 2: Dissolve (40) (190mg, 0.5mmol) in DCM (0.5mL) and DMF (0.25mL) at rt in a pre-dried tube, add DIEA (0.52mL, 1.5mmol) and add this solution to 2-chlorotritylchlorid-polystyrene (82mg, 0.13mmol) which is preswollen before in DCM (0.15mL). Shake the reaction suspensions for 14h at rt. The resin is (41) washed with DCM/MeOH/DIEA (17+2+1, 3 times), DCM (once), DMF (3 times) and again DCM (twice) and dried in vacuum. [i.e. Novabiochem2000 Catalog;2000; S15-S18].

Reference： [1]Patent: EP1577289,2005,A1 .Location in patent: Page/Page column 24

6
[ 188715-40-4 ]
C₂₃H₂₄ClNO₃ [ No CAS ]

Reference： [1]Organic Letters,2008,vol. 10,p. 1881 - 1884

7
C₂₉H₃₇N₂O₃Pol [ No CAS ]
[ 29022-11-5 ]
[ 802294-64-0 ]
[ 188715-40-4 ]
[ 188970-92-5 ]
C₅₆H₇₇N₈O₁₂Pol [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 1492 - 1495

8
N,N'-(9,10-dioxo-9,10-dihydroanthracene-2,6-diyl)bis(3-aminopropanamide) bistrifluoroacetate [ No CAS ]
[ 188715-40-4 ]
C₆₆H₆₆N₆O₁₀ [ No CAS ]

Reference： [1]MedChemComm,2013,vol. 4,p. 1388 - 1393

9
[ 84793-07-7 ]
[ 104091-08-9 ]
[ 88574-06-5 ]
[ 188715-40-4 ]
(S)-6-[(Diphenyl-p-tolyl-methyl)-amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid [ No CAS ]
C₄₆H₇₄N₁₀O₂₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		PSMA-i was synthesized manually using standard Fmoc chemistry. Generally, peptide was synthesized at 0.2 mmol scale starting from C-terminal Fmoc-rink amide MBHA resin. Fmoc-deprotection at each cycle was carried out using 20% pipperidine in DMF. Coupling reactions were caffied out using 3.3 equiv of Fmoc-amino acids in DMF activated with 3.3 equiv of HCTU and 5 equiv of diisopropylethylamine (DIPEA) in DMF. These steps were repeated each time with an amino acid added. After the peptide sequence Fmoc-Glu?-Amc-Ahx-Glu-Glu-Glu-Lys(Mtt) was built on the resin, the Fmoc group of Nterminal amino acid Glu? was deprotected by 20% pipperidine. Then, a chloroform solution containing 3 eq of H-Glu(OtBu)-OtBu mixed with 2.5eq of DIPEA were prepared. The solution is then added slowly to 0.25 eq triphosgene in chloroform over 10 minutes at room temperature. After 15 minute incubation to allow for isocyanate formation, the reaction mixture was mixed with Glu?-Amc-Ahx-Glu-Glu-Glu-Lys on rink amide resin pre-swollen in chloroform with 2.5 eq of DIPEA. After the reaction was complete, the resin was washed with DMF and then dichloromethane and dried. The peptide was cleaved from resin by TFA/water/triisopropylsilane (950:25:25). The cleaved peptide was purified by preparative HPLC. The products were ascertained by high resolution matrix-assisted laser desorption/ionization mass (MALDI-MS) spectra from an Applied Biosystem 4800 MALDI TOF/TOF Analyzer in positive ion mode. Retention time: 19.0 mm. MALDI MS:C48H74N10020, 1087.5 (found); 1087.1 (calculated).

Reference： [1]Patent: WO2014/127365,2014,A1 .Location in patent: Paragraph 00123

10
[ 84793-07-7 ]
[ 188715-40-4 ]
[ 234081-98-2 ]
[ 166108-71-0 ]
C₄₅H₈₀N₄O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		2-Chlorotrityl resin 100-200 mesh 1.8 mmol/g (1, 11.9 g, 21.4 mmol) was left to swell in dry dichloromethane (80 ml) for 20 minutes. A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 5.50 g, 14.3 mmol) and N,N-diisopropylethylamine (9.44 ml, 54.2 mmol) in dry dichloromethane (70 ml) was added to resin and the mixture was shaken for 4 hours. Resin was filtered and 10 treated with a solution of N,N-diisopropylethylamine (4.97 ml, 28.5 mmol) in methanol/dichloromethane mixture (4: 1, 2 x 5 min, 2 x 57 ml). Then resin was washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,Ndimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was 15 washed with N,N-dimethylformamide (3 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 11.0 g, 28.5 mmol), 0-( 6-chloro-benzotriazol-1-yi)-N,N,N', N'-tetramethyluronium tetrafluoroborate (TCTU, 10.1 g, 28.5 mmol) and N,N-diisopropylethylamine (9.93 ml, 57.0 mmol) in N,N20 dimethylformamide (80 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-N,N-dimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 225 propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of (S)-2-(9Hfluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiu OtBu, 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 5 ml), dichloromethane (2 x 80 ml) and N,N-dimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of 4-[(9Hfluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 10 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-dimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of dodecanedioic acid mono-tert-butyl ester (C12(0tBu)-OH, 6.13 g, 21.4 mmol), 0-(6chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.61 g, 20 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 38.5 mmol) in dichloromethane/N,N-dimethylformamide mixture (4: 1, 80 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,Ndimethylformamide (6 x 80 ml), dichloromethane (4 x 80 ml), methanol (4 x 80 ml) and dichloromethane (7 x 80 ml). The product was cleaved from resin by treatment with 25 2,2,2-trifluoroethanol (80 ml) for 18 hours. Resin was filtered off and washed with dichloromethane (4 x 80 ml), dichloromethane/2-propanol mixture (1:1, 4 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (6 x 80 ml). Solutions were combined; solvent evaporated and crude product was purified by column chromatography (Silicagel 60, 0.040-0-063 mm; eluent: dichloromethane/methanol 1:0-9:1). The pure product (2) 30 was dried in vacuo and obtained as oil. Yield: 5.40 g (42%). RF (Si02, dichloromethane/methanol 9: 1): 0.30. 1H NMR spectrum (300 MHz, CDC13, dH): 7.45-7.31 (m, 1 H); 7.10-6.97 (m, 1 H); 6.716.60 (m, 1 H); 5.70-5.58 (m, 1 H); 4.43-4.31 (m, 1 H); 4.15 (s, 2 H); 4.01 (s, 2 H); 35 3.79-3.31 (m, 16 H); 3.13-3.08 (m, 2 H); 2.28-1.79 (m, 11 H); 1.71-1.51 (m, 4 H); 1.46 (s, 9 H); 1.44 (s, 9 H); 1.25 (bs, 12 H); 1.05-0.88 (m, 2 H).LC-MS purity: 100%. LC-MS Rt (Sunfire 4.6 mm x 100 mm, acetonitrile/water 50:50 to 100:0 + 0.1% FA): 2.16 min. LC-MS m/z: 903.0 (M+H)+.

Reference： [1]Patent: WO2017/220706,2017,A1 .Location in patent: Page/Page column 61; 62; 63; 64

11
[ 843666-27-3 ]
[ 84793-07-7 ]
[ 188715-40-4 ]
[ 166108-71-0 ]
C₄₉H₈₈N₄O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		2-Chlorotrityl resin 100-200 mesh 1.8 mmol/g (1, 11.9 g, 21.4 mmol) was left to swell in dry dichloromethane (80 ml) for 20 minutes. A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 5.50 g, 14.3 mmol) and N,N-diisopropylethylamine (9.44 ml, 54.2 mmol) in dry dichloromethane (70 ml) was added to resin and the mixture was shaken for 4 hours. Resin was filtered and 20 treated with a solution of N,N-diisopropylethylamine (4.97 ml, 28.5 mmol) in methanol/dichloromethane mixture (4: 1, 2 x 5 min, 2 x 57 ml). Then resin was washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,Ndimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 11.0 g, 28.5 mmol), 0-( 6-chloro-benzotriazol-1-yi)-N,N,N', N'-tetramethyluronium tetrafluoroborate 5 (TCTU, 10.1 g, 28.5 mmol) and N,N-diisopropylethylamine (9.93 ml, 57.0 mmol) in N,Ndimethylformamide (80 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-N,N-dimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 10 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of (S)-2-(9Hfluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiuOtBu, 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 15 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-dimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 220 propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of Fmoctranexamic acid (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,Ndiisopropylethylamine (6.71 ml, 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with 25 N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,Ndimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of hexadecanedioic acid mono-tert-butyl ester (C16(0tBu)-OH, 7.33 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'tetramethyluronium tetrafluoroborate (TCTU, 7.61 g, 21.4 mmol) and N,Ndiisopropylethylamine (6.71 ml, 38.5 mmol) in dichloromethane/N,N-dimethylformamide mixture (4: 1, 80 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (6 x 80 ml), dichloromethane (4 x 35 80 ml), methanol (4 x 80 ml) and dichloromethane (7 x 80 ml). The product was cleaved from resin by treatment with 2,2,2-trifluoroethanol (80 ml) for 18 hours. Resin was filtered off and washed with dichloromethane (4 x 80 ml), dichloromethane/2propanol mixture (1: 1, 4 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (6 x 80 ml). Solutions were combined; solvent evaporated and crude product was purified by column chromatography (Silicagel 60, 0.040-0-063 mm; eluent: 5 dichloromethane/methanol 1:0-9:1).Intermediate (2) was dried in vacuo and obtained as oil. Yield: 8.20 g (80%). RF (Si02, dichloromethane/methanol 9: 1): 0.20. lH NMR spectrum (300 MHz, CDC13, dH): 7.44-7.33 (m, 1 H); 7.07-6.97 (m, 1 H); 6.7210 6.63 (m, 1 H); 5.70-5.59 (m, 1 H); 4.44-4.33 (m, 1 H); 4.15 (s, 2 H); 4.01 (s, 2 H); 3.76-3.32 (m, 16 H); 3.14-3.07 (m, 2 H); 2.38-1.77 (m, 11 H); 1.71-1.50 (m, 4 H); 1.46 (s, 9 H); 1.44 (s, 9 H); 1.25 (bs, 20 H); 1.05-0.87 (m, 2 H). LC-MS purity: 100%. LC-MS Rt (Sunfire 4.6 mm x 100 mm, acetonitrile/water 50:50 to 100:0 + 0.1% FA): 15 3.56 min. LC-MS m/z: 959.0 (M+H)+.

Reference： [1]Patent: WO2017/220706,2017,A1 .Location in patent: Page/Page column 66; 67; 68

12
[ 843666-40-0 ]
C₄₉H₄₇N₂O₆Pol [ No CAS ]
[ 84793-07-7 ]
[ 79-08-3 ]
[ 188715-40-4 ]
[ 166108-71-0 ]
18-[[4-[[(1S)-4-[2-[2-[2-[2-[2-[2-[[(1S)-5-[(2-bromoacetyl)amino]-1-carboxypentyl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-1-carboxy-4-oxobutyl]carbamoyl]cyclohexyl]methylamino]-18-oxooctadecanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		Synthetic protocol: Wang Fmoc-Lys(Mtt) resin 0.26 mmol/g (1, 11.7 g, 3.05 mmol) was left to swell in 5 dichloromethane (100 ml) for 45 minutes. Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.35 g, 6.09 10 mmol), 0-( 6-chlorobenzotriazol-1-yi)-N, N,N', N' -tetramethyluronium tetrafluoroborate (TCTU, 2.17 g, 6.09 mmol) and N,N-diisopropylethylamine (2.12 ml, 12.2 mmol) in N,Ndimethylformamide (100 ml) was added to resin and the mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was 15 removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of {2-[2-(9Hfluoren-9-ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.35 g, 6.09 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium 20 tetrafluoroborate (TCTU, 2.17 g, 6.09 mmol) and N,N-diisopropylethylamine (2.12 ml, 12.2 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml) to obtain intermediate 1. Fmoc group was removed by treatment with 20% piperidine in N,N25 dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiu-OtBu, 1.94 g, 4.57 mmol), 0-(6-chloro-benzotriazol-1-yi)N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 1.62 g, 4.57 mmol) and N,N30 diisopropylethylamine (1.43 ml, 8.23 mmol) in N,N-dimethylformamide (100 ml) was wo 2017/220706 PCT/EP2017/065342 72 added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90ml) and N,Ndimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). 5 Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of 4-[(9H-fluoren-9ylmethoxycarbonylamino )methyl]cyclohexanecarboxylic acid (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 1. 73 g, 4. 57 mmol), 0-( 6-chloro-benzotriazol-1-yi)-N,N,N', N'-tetramethyluronium tetrafluoroborate (TCTU, 1.62 g, 4.57 mmol) and N,N-diisopropylethylamine (1.43 ml, 8.23 mmol) in N,N10 dimethylformamide (100 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90ml) and N,N-dimethylformamide (3 x 90 ml) to obtain intermediate2. Fmoc group was removed by treatment with 20% piperidine in N,Ndimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 50 ml). Resin was washed 15 with N,N-dimethylformamide (3 x 50 ml), 2-propanol (3 x 50 ml) and dichloromethane (3 x 30 ml). Solution of octadecanedioic acid mono-tert-butyl ester (C18(0tBu)-OH, 0.85 g, 2.28 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 0.81 g, 2.28 mmol) and N,N-diisopropylethylamine (0. 72 ml, 4.11 mmol) in N,N-dimethylformamide (50 ml) was added to resin and mixture was 20 shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 50 ml), dichloromethane (3 x 50 ml) and N,N-dimethylformamide (3 x 50 ml). Mtt group was removed by treatment with 80% 1,1,1,3,3,3-hexafluoro-2-propanol in dichloromethane (2 x 10 min, 2 x 30 min, 4 x 50 ml). Resin was washed with dichloromethane (6 x 50 ml). Solution of bromoacetic acid (4.24 g, 30.5 mmol) and 25 N,N '-diisopropylcarbodiimide (DIC, 4.01 ml, 25.9 mmol) in N,N-dimethylformamide (50 ml) was added to resin and mixture was shaken for 45 minutes. Resin was filtered and washed with N,N-dimethylformamide (5 x 50 ml) and dichloromethane (10 x 50 ml). The product was cleaved from resin by treatment with trifluoroacetic acid (50 ml) for 1 hour. Resin was filtered off and washed with trifluoroacetic acid (1 x 25 ml) and 30 dichloromethane (2 x 30 ml). Solutions were combined and solvents were evaporated to dryness giving the compound as thick brownish oil. Yield: 2.18 mg (64%). 1H NMR spectrum (300 MHz, Ac0D-d4, 80C, dH): 4.72-4.55 (m, 2 H); 4.16 (s, 2 H); 4.12 (s, 2 H); 3.80-3.62 (m, 12 H); 3.58-3.44 (m, 4 H); 3.32 (t, J=6.8 Hz, 2 H); 3.15 35 (d, J=6.8 Hz, 2 H); 2.51-2.07 (m, 8 H); 2.01-1.77 (m, 6 H); ...

Reference： [1]Patent: WO2017/220706,2017,A1 .Location in patent: Page/Page column 70; 71; 72; 73

13
[ 683239-16-9 ]
C₄₉H₄₇N₂O₆Pol [ No CAS ]
[ 84793-07-7 ]
[ 79-08-3 ]
[ 188715-40-4 ]
[ 166108-71-0 ]
20-[[4-[[(1S)-4-[2-[2-[2-[2-[2-[2-[[(1S)-5-[(2-bromoacetyl)amino]-1-carboxypentyl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-1-carboxy-4-oxobutyl]carbamoyl]cyclohexyl]methylamino]-20-oxoicosanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		Synthetic protocol: Wang Fmoc-Lys(Mtt) resin 0.26 mmol/g (1, 11.2 g, 2.90 mmol) was left to swell in dichloromethane (100 ml) for 45 minutes. Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 15 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.23 g, 5.80 mmol), 0-(6-chlorobenzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 2.06 g, 5.80 mmol) and N,N-diisopropylethylamine (2.02 ml, 11.6 mmol) in N,N20 dimethylformamide (100 ml) was added to resin and the mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 25 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of {2-[2-(9Hfluoren-9-ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.23 g, 5.80 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 2.06 g, 5.80 mmol) and N,N-diisopropylethylamine (2.02 ml, 11.6 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was 30 shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of (S)-2-(9H5 fluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiuOtBu, 1.85 g, 4.35 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 1.55 g, 4.35 mmol) and N,N-diisopropylethylamine (1.36 ml, 7.82 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 10 ml), dichloromethane (3 x 90ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of <strong>[188715-40-4]4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid</strong> 15 (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 1.65 g, 4.35 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'tetramethyluronium tetrafluoroborate (TCTU, 1.55 g, 4.35 mmol) and N,Ndiisopropylethylamine (1.36 ml, 7.82 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90ml) and N,N20 dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of icosanedioic acid mono-tert-butyl ester (C20(0tBu)-OH, 1. 73 g, 4.35 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'25 tetramethyluronium tetrafluoroborate (TCTU, 1.55 g, 4.35 mmol) and N,Ndiisopropylethylamine (1.36 ml, 7.82 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml), N,Ndimethylformamide (3 x 90 ml) and dichloromethane (3 x 90 ml). Mtt group was 30 removed by treatment with 80% 1,1,1,3,3,3-hexafluoro-2-propanol in dichloromethane (2 x 10 min, 2 x 30 min, 4 x 100 ml). Resin was washed with dichloromethane (6 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Solution of bromoacetic acid (8.06 g, 58.0 mmol) and N,N '-diisopropylcarbodiimide (DIC, 7.60 ml, 49.3 mmol) in N,Ndimethylformamide (100 ml) was added to resin and mixture was shaken for 40 35 minutes. Resin was filtered and washed with N,N-dimethylformamide (5 x 90 ml) and dichloromethane (12 x 90 ml). The product was cleaved from resin by treatment with trifluoroacetic acid (100 ml) for 1 hour. Resin was filtered off and washed with trifluoroacetic acid (1 x 50 ml) and dichloromethane (7 x 70 ml). Solutions were combined and solvents were evaporated to dryness giving a thick brownish oil. Yield: 3.28 g (98%). 5 1H NMR spectrum (300 MHz, Ac0D-d4, 80 C, dH): 4.68 (dd, J=8.0 and 5.4 Hz, 1 H); 4.60 (dd, J=7.9 and 5.3 Hz, 1 H); 4.16 (s, 2 H); 4.12 (s, 2 H); 3.94 (s, 2 H); 3.81-3.61 (m, 12 H); 3.59-3.44 (m, 4 H); 3.32 (t, J=6.8 Hz, 2 H); 3.14 (d, J=6.8 Hz, 2 H); 2.491.79 (m, 15 H)...

Reference： [1]Patent: WO2017/220706,2017,A1 .Location in patent: Page/Page column 81; 82; 83

14
C₂₀H₂₀N₄O₄*2C₂HF₃O₂ [ No CAS ]
[ 188715-40-4 ]
C₆₆H₆₆N₆O₁₀ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2018,vol. 29,p. 2195 - 2207

15
C₁₄H₂₃NO₅ [ No CAS ]
[ 146982-27-6 ]
N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine [ No CAS ]
[ 188715-40-4 ]
[ 137076-54-1 ]
C₇₅H₁₂₂N₁₁O₁₇Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (S)-6-allyloxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid With N-ethyl-N,N-diisopropylamine In dichloromethane Stage #2: With piperidine In N,N-dimethyl-d<SUB>6</SUB>-formamide Stage #3: C₁₄H₂₃NO₅; (S)-6-allyloxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid; N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine; 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid; 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-10-acetic acid Further stages;

Reference： [1]Current Patent Assignee: ITM ISOTOPEN TECHNOLOGIEN MUENCHEN AG - WO2020/109523, 2020, A1 Location in patent: Page/Page column 81; 96

16
C₃₄H₄₈N₃O₈Pol [ No CAS ]
[ 143824-78-6 ]
[ 188715-40-4 ]
[ 133081-25-1 ]
PSMA-LTrp-4Amc-HYNIC [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl]indole-1-carboxylic acid tert-butyl ester With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.0833333h; Stage #2: C₃₄H₄₈N₃O₈Pol In dichloromethane; N,N-dimethyl-formamide for 1h; Stage #3: 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid; 6-([(tert-butoxy)carbonyl]amino}amino)pyridine-3-carboxylic acid Further stages;	2 Example 2. Synthesis of PSMA-T4 (PSMA-LTrp-4Amc-HYNIC) Polystyrene Wang resin with Glu(tBu)-urea-Lys-NH2 was used in the reaction. To the free amine group of Lysine, the Fmoc-L-Trp(Boc) was attached using 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminemorpholino)]uronium hexafluorophosphate (COMU) in the manner described previously [8,9]. The resin was placed in a vessel for peptide synthesis and swollen by stirring with dichloromethane. In a separate vessel, threefold molar excess of Fmoc-L-Trp(Boc), threefold molar excess of COMU and N,N-dimethylformamide were placed and stirred until dissolved. Then N,N-diisopropylethylamine was added and stirred for 5 minutes. Dichloromethane was added and stirred. The activated amino acid solution prepared in such a manner was transferred to the vessel with swollen resin and stirred for 1 hour. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and dichloromethane. The Fmoc protection group was removed in the manner usually used in peptide synthesis [10]. To the vessel with swollen resin, 20% piperidine solution in N,N-dimethylformamide was poured and stirred for 30 minutes After that time, pyridine solution was changed for the fresh one and the mixture was stirred for another 30 minutes. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and at the end with dichloromethane. Fmoc-4Amc attachment and detachment of the Fmoc protection group were carried out in the manner analogous to the one used in the previous synthetic step. The resin was swollen by stirring in dichloromethane for at least 20 minutes. Threefold molar excess of Fmoc-4Amc, threefold molar excess of COMU and N,N-dimethylformamide were placed in a separate vessel and stirred until dissolved. Then N,N-diisopropylethylamine was added and stirred for 5 minutes. Dichloromethane was added and stirred. The activated amino acid solution prepared in such a way was transferred into the vessel with the swollen resin and stirred for 1 hour. The support was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and, finally, with dichloromethane. To the vessel with swollen support, 20% piperidine solution in N,N-dimethylformamide was poured and stirred for 30 minutes After that time, piperidine solution was changed for the fresh one and the mixture was stirred for another 30 minutes. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and dichloromethane. HYNIC-Boc attachment was carried out in the manner analogous to the one used in the previous synthetic step, but with longer reaction time. The resin was swollen by stirring in dichloromethane for at least 20 minutes. Threefold molar excess of HYNIC-Boc, threefold molar excess of COMU and N,N-dimethylformamide were placed in a separate vessel and stirred until dissolved. Then N,N-diisopropylethylamine was added and stirred for 5 minutes. Dichloromethane was added and stirred. The solution of activated amino acid prepared in such a way was transferred into the vessel with swollen resin and stirred for 2 hours. The resin was washed with: N,N-dimethylformamide, 50% N,N-dimethylformamide solution in dichloromethane and with dichloromethane and dried in vacuum. In a separate vessel, the solution of trifluoroacetic acid with addition of triisopropylsilane, phenol, thioanisole, water and 1,2-ethanedithiole was prepared in order to detach the product from the resin and to remove the protection groups. The ready solution was transferred to the vessel comprising the resin and stirred for 3 hours. The product was precipitated with diethyl ether. The precipitate was centrifuged and washed with diethyl ether. After it had been dissolved in 0.1% trifluoroacetic acid solution, it was heated on a vacuum evaporator up to 60°C at 800 mbar for 1 hour. The obtained solution was lyophilized. The lyophilized product was dissolved in acetonitrile/water solvent mixture with addition of 0.1% trifluoroacetic acid and then purified on a preparative polymeric HPLC reversed phase column . Collected fractions containing the compound (PSMA-T4) fulfilling the purity requirements were combined and lyophilized.

Reference： [1]Current Patent Assignee: NARODOWE CENTRUM BADAN JADROWYCH; NARODOWE CENTRUM BADAN JADROWYCH OSRODEK RADIOIZOT - EP3721907, 2020, A1 Location in patent: Paragraph 0029-0036

17
[ 74124-79-1 ]
[ 940941-43-5 ]
[ 32677-01-3 ]
[ 56491-86-2 ]
[ 150629-67-7 ]
[ 133464-46-7 ]
[ 188715-40-4 ]
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine [ No CAS ]
C₆₂H₉₀N₁₂O₂₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Fmoc-Lys(Dde)-OH With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3.5h; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #3: di(succinimido) carbonate; Nα-fluorenylmethyloxycarbonyl-L-lysine-tert-butyl ester; L-glutamic acid di-tert-butyl ester hydrochloride; 1,4,7-triazacyclononane-1,4,7-triacetic acid; (S)-2-[((9H-fluoren-9-yl)methoxy)carbonylamino]-5-(allyloxy)-5-oxopentanoic acid; 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid; N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine Further stages;	1.1-1.8 1) Preparation of compound of formula (1) Soak CTC resin (471mL, 0.5mmol, substitution degree of 1.06mmol/g) in dichloromethane (20mL) for 30 minutes, add Fmoc-Lys(Dde)-OH (533mg, 1mmol) and DIPEA ( 359μl, 2mmol) was stirred at room temperature for 3 hours, then methanol (0.5 mL) was added and stirring continued for 30 minutes, the dichloromethane was removed, and washed with DMF 3 times, and then piperidine DMF solution (20 mL) with a volume percentage of 20% was added. After stirring at room temperature for 30 minutes, the solvent was removed, and then washed with DMF 5 times to obtain the compound of formula (1).2) Preparation of compound of formula (2)Take the compound of formula (1) obtained in step 1), add DSC (256mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 3 hours, remove DMF, wash with DMF 3 times, and add H-Glu (OtBu)-OtBu-HCl (296mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20 mL) were stirred at room temperature for 2 hours, DMF was removed, washed with DMF 3 times, and then 2% hydrazine hydrate DMF was added by volume The solution (20 mL) was stirred at room temperature for 30 minutes, the solvent was removed, and then washed with DMF 5 times to obtain the compound of formula (2).3) Preparation of compound of formula (3)Take the compound of formula (2) obtained in step 2), add Fmoc-D-2-Nal-OH (658mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20 mL), Stir at room temperature for 1.5 hours, remove DMF, wash with DMF 3 times, add piperidine DMF solution (20 mL) with a volume percentage of 20%, stir at room temperature for 30 minutes, remove the solvent, and wash with DMF 5 times to obtain formula (3 ) Compounds.4) Preparation of compound of formula (4)Take the compound of formula (3) obtained in step 3), add Fmoc-D-2-Nal-OH (658mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL) at room temperature Stir for 1.5 hours, remove DMF, and wash with DMF 3 times, then add 20% piperidine DMF solution (20 mL), stir at room temperature for 30 minutes, remove the solvent, and wash with DMF 5 times to obtain the compound of formula (4) .5) Preparation of compound of formula (5)Take the compound of formula (4) obtained in step 4), add Fmoc-D-2-Nal-OH (658mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL) at room temperature Stir for 1.5 hours, remove DMF, and wash with DMF 3 times, add 20% piperidine DMF solution (20 mL), stir at room temperature for 30 minutes, remove the solvent, and wash with DMF 5 times to obtain the compound of formula (5) .6) Preparation of compound of formula (6)Take the compound of formula (5) obtained in step 5), add NOTA (623mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL), stir at room temperature for 1.5 hours, remove DMF, and use DMF wash 3 times, then add H-Glu(OtBu)-OtBu-HCl (296mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 2 hours, remove DMF, and then wash the resin 3 times with DMF , The compound of formula (6) is obtained.7) Preparation of compound of formula (7)Take the compound of formula (6) obtained in step 6), add Pd(PPh3)4 (1.16g, 1mmol) and CHCl3 (30mL), stir at room temperature for 1.5 hours, remove DMF, wash with DMF 3 times, and add Fmoc-Lys-OtBu (638mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL), stirred at room temperature for 30 minutes, removed DMF, and washed with DMF five times to obtain the compound of formula (7).8) Preparation of NOTA-Bi-PSMA compoundTake the compound of formula (7) obtained in step 7), add DSC (256mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 3 hours, remove DMF, wash with DMF 3 times, and add H-Glu (OtBu)-OtBu-HCl (296mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 2 hours, remove DMF, wash with DMF 3 times, and then wash with dichloromethane and methanol twice , Dry under reduced pressure, then add 10ml of the mixture of TFA:TIS:water volume ratio 95:2.5:2.5, stir at room temperature for 2.5 hours and then filter, pour the filtrate into cold ether, a large amount of solid initial product precipitates, and then half-prep The NOTA-Bi-PSMA compound was separated by separation method. A proper amount of NOTA-Bi-PSMA compound was detected by mass spectrometry and high performance liquid chromatography, and the mass spectrometry results were measured: the molecular formula was C62H90N12O23, [M+2H]2+=686.8; the high performance liquid chromatography results were measured: purity>98%.

Reference： [1]Current Patent Assignee: NANFANG HOSPITAL - CN112190722, 2021, A Location in patent: Paragraph 0067-0084

18
C₂₀H₃₆N₃O₇Pol [ No CAS ]
[ 96402-49-2 ]
[ 188715-40-4 ]
C₃₃H₄₅N₅O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₂₀H₃₆N₃O₇Pol; N^α-Fmoc-3-(1'-naphthyl)alanine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid Further stages;

Reference： [1]Stemler, Tobias; Hoffmann, Caroline; Hierlmeier, Ina M.; Maus, Stephan; Krause, Elmar; Ezziddin, Samer; Jung, Gregor; Bartholomä, Mark D. [ChemMedChem, 2021, vol. 16, # 16, p. 2535 - 2545]

19
C₁₃H₁₂NOPol [ No CAS ]
[ 188715-40-4 ]
C₂₁H₂₅N₂O₂Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₁₃H₁₂NOPol; 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In methanol; N,N-dimethyl-formamide for 0.333333h; Stage #2: With piperidine In methanol; N,N-dimethyl-formamide	1.2 (2) The synthetic route of intermediate compound B is as follows: The resin was added to the peptide synthesis tube (load: 1.106 mmol/g, 1 eqv, 0.5 mmol), and swelled with dichloromethane solution (10 mL) for 30 minutes. Fmoc-3-(2-naphthyl)-L-alanine (1.25eqv, 0.625mmol) and N'N-dimethylformamide (8mL) were added to the peptide synthesis tube. The pH of the reaction mixture was adjusted to 8-9 by N,N-diisopropylethylamine. After shaking for 3 hours, use N'N-dimethylformamide reaction mixture (N'N-dimethylformamide: methanol: N, N-diisopropylethylamine = 17: 2: 1, v/ v/v) (10 mL) and N'N-dimethylformamide (10 mL) wash the reaction mixture in the synthesis tube and shake it twice (10 min/time). The color tested by Kaiser is light yellow. After the Kaiser test was completed, the reaction mixture was eluted with 20% piperidine (7 mL) 3 times (10 mL/time). Then it was washed five times with DMF. The Kaiser test is dark purple, and the peptide synthesis tube containing compound 1 is obtained, and you can proceed to the next step. In the second step, N-Fmoc-4-aminomethylcyclohexanecarboxylic acid (1.25eqv, 0.625mmol) and oxybenzotriazole-N,N,N',N'-tetramethylhexafluoro Phosphate (2eqv, 1mmol) and N'N-dimethylformamide (10mL) were added to the peptide synthesis tube. The pH of the reaction mixture was adjusted to 8-9 by N,N-diisopropylethylamine. Then use the reaction mixture of N'N-dimethylformamide (N'N-dimethylformamide: methanol: N, N-diisopropyl Ethylethylamine=17:2:1) (10mL) and N'N-dimethylformamide (10mL) wash the reaction mixture in the synthesis tube and shake it twice (10min/time). The color tested by Kaiser is Light yellow. After the Kaiser test is completed, the reaction mixture is eluted with 20% piperidine (7 mL) 3 times (10 mL/time). Then it is washed with DMF five times. The Kaiser test is dark purple, and then proceed to the next step) Process the reactants of the second step. After the second step of the reaction is completed, add the contents of the third step Fmoc-L-propargylglycine (1.25eqv, 0.625mmol), oxybenzotriazole-N, N, to the peptide synthesis tube containing compound 2. N',N'-tetramethylhexafluorophosphate (2eqv, 1mmol) and N'N-dimethylformamide (10mL). The pH of the reaction mixture was adjusted to 8-9 with N,N-diisopropylethylamine. Then, the reactant of the third step is processed according to the reaction treatment method of the first step. In the fourth step, add 2,3,5-triiodobenzoic acid (1 equivalent, 0.625mmol), oxybenzotriazole-N,N,N',N'-tetramethyl to the peptide synthesis tube containing compound 3 Hexafluorophosphate (2 equivalents, 1 mmol) and N'N-dimethylformamide (10 mL). The pH was adjusted to 8-9 with N,N-diisopropylethylamine, and the reaction was shaken for 3 hours. After the fourth step, use N'N-dimethylformamide reaction mixture (N'N-dimethylformamide: methanol: N, N-diisopropylethylamine = 17: 2: 1) (10mL ) And N'N-dimethylformamide (10 mL) to wash the reaction mixture in the synthesis tube and shake twice. The color tested by Kaiser is light yellow. After the Kaiser test was completed, the reactants in the peptide synthesis tube were washed twice with dichloromethane (10 mL). The 1% trifluoroacetic acid in the resin was removed, and the reaction mixture was taken out and dried to obtain Intermediate Compound B (410 mg, 88.2%).

Reference： [1]Current Patent Assignee: AFFILIATED HOSPITAL OF JIANGSU UNIVERSITY - CN112961173, 2021, A Location in patent: Paragraph 0070; 0079-0081

20
[ 60239-18-1 ]
[ 188715-40-4 ]
[ CAS Unavailable ]
[ 164470-64-8 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
24.4 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid; N-(9-fluorenylmethyloxycarbonyl)-4-(aminomethyl)benzoic acid Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.
24.4 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid; N-(9-fluorenylmethyloxycarbonyl)-4-(aminomethyl)benzoic acid Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.

Reference： [1]Sui, Yu; Duan, Xiaojiang; Zhang, Jingming; Chu, Yingming; Yang, Xing [Bioorganic and Medicinal Chemistry Letters, 2023, vol. 91]
[2]Sui, Yu; Duan, Xiaojiang; Zhang, Jingming; Chu, Yingming; Yang, Xing [Bioorganic and Medicinal Chemistry Letters, 2023, vol. 91]

21
[ 60239-18-1 ]
[ 188715-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
27.8 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.
27.8 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.

22
[ 60239-18-1 ]
[ 188715-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
26.4 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.
26.4 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.

23
[ 60239-18-1 ]
[ 188715-40-4 ]
[ 35661-40-6 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
16 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid; N-Fmoc L-Phe Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.
16 %	Stage #1: C₄₂H₅₁BrN₄O₁₀ With 2-chlorotrityl chloride polystyrene resin In dichloromethane; N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid; N-Fmoc L-Phe Further stages;	1.3 Synthesis of ligand-1~ligand-7 General procedure: The synthetic route of synthesizing seven ligands from resin 9 is shown in Figure S4. Resin 9 (0.02 mmol based onloading) was placed into a 10 mL solid phase synthesis tube, and 2 mL dichloromethane was added to swell the resin forthree times, each time for 5 minutes. Then the resin was washed with 2 mL DMF for three times, each time for 5 minutes.DMF solution containing 20% piperidine (v/v) was used to remove the Fmoc protecting group. 2 ml of DMF solutioncontaining 20% piperidine reacted with the resin for three times (2 minutes, 10 minutes, and 10 minutes), and then 2 ml ofDMF was used to wash 3-5 times, each time for 2 minutes. 0.06 mmol Fmoc amino acid was activated by 0.072 mmolHBTU in the presence of 0.144 mmol DIPEA. Then the mixture was added into the synthetic tube and reacted for 1 hour.Activation and coupling of DOTA tri-tert-butyl ester were carried out according to the above method. Product cleavagefrom the resin and removal of tert-butyl esters were completed by stirring in 5 mL trifluoroaceticacid/triisopropylsilane/water (95:2.5:2.5, v/v/v) for 2 hours. The resin was washed with 2 mL trifluoroacetic acid, and allfiltrates were collected. After trifluoroacetic acid was removed under reduced pressure, the crude product was purified byreverse phase chromatography. Seven target ligands were obtained after freeze-drying.

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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 188715-40-4 ] {[proInfo.proName]}

Quality Control of [ 188715-40-4 ]

Related Doc. of [ 188715-40-4 ]

Product Details of [ 188715-40-4 ]

Calculated chemistry of [ 188715-40-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 188715-40-4 ]

Application In Synthesis of [ 188715-40-4 ]

[ 188715-40-4 ] Synthesis Path-Upstream 1~2

[ 188715-40-4 ] Synthesis Path-Downstream 1~23

Related Functional Groups of [ 188715-40-4 ]

Amino Acid Derivatives

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 188715-40-4 ]