161552-03-0

Basic information

• Product Name: CYCLO (ARG-GLY-ASP-D-PHE-LYS)
• Synonyms: CYCLO(-RGDFK);CYCLO (ARG-GLY-ASP-D-PHE-LYS);cyclo (Arg-Gly-Asp-Phe-Lys);c(RGDfK);Cyclic RGDFK peptide;Cyclo(L-arginylglycyl-L-alpha-aspartyl-D-phenylalanyl-L-lysyl);Cyclo(-Arg-Gly-Asp-D-Phe-Lys) Trifluoroacetate salt
• CAS NO: 161552-03-0
• Molecular Formula: C₂₇H₄₁N₉O₇
• Molecular Weight: 603.67
• Product Categories: peptide
• Mol File: 161552-03-0.mol
• Article Data: 14

Chemical Properties

• Melting Point: 191℃ (decomposition)
• Appearance: /
• Density: 1.47±0.1 g/cm3(Predicted)
• Solubility: ≥30.19 mg/mL in DMSO; insoluble in EtOH; ≥59.2 mg/mL in H2O
• PKA: 4.01±0.10(Predicted)
• CAS DataBase Reference: CYCLO (ARG-GLY-ASP-D-PHE-LYS)(CAS DataBase Reference)
• NIST Chemistry Reference: CYCLO (ARG-GLY-ASP-D-PHE-LYS)(161552-03-0)
• EPA Substance Registry System: CYCLO (ARG-GLY-ASP-D-PHE-LYS)(161552-03-0)

Safety Data

• Hazardous Substances Data: 161552-03-0(Hazardous Substances Data)

Usage

Biological Activity

in one study where this peptide was labeled with 125i, it was found to bind specifically and with high affinity to αvβ3 receptors on neovascular blood vessel sections of different major human cancers. the integrin alpha(iib)beta(3)-specific cyclic hexapeptide contains an arg-gly-asp (rgd) sequence.

Synthetic route

C42H51ClN10O11 → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol; acetic acid at 20℃; for 18h;	100%

Fmoc-Asp(OAll)-Pol + N-(fluoren-9-ylmethoxycarbonyl)glycine (29022-11-5) + Fmoc-Lys(tert-butoxycarbonyl) (71989-26-9) + Fmoc-D-Phe-OH (86123-10-6) + Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Stage #1: Fmoc-Asp(OAll)-Pol Stage #2: N-(fluoren-9-ylmethoxycarbonyl)glycine Stage #3: Fmoc-Lys(tert-butoxycarbonyl); Fmoc-D-Phe-OH; Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine Further stages;	43%

2-chlorotrityl resin + Fmoc-dPhe-OH + Fmoc-(tBu)Asp-OH (71989-14-5) + Nα-Fmoc-Nε-Trt-Lys (111061-54-2) + Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Stage #1: H-Gly-(2-Cl)-Trt-pol; Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine With N-ethyl-N,N-diisopropylamine; [ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate at 20℃; for 1h; 2-CT Cl resin; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 0.1h; Stage #3: Fmoc-dPhe-OH; Fmoc-(tBu)Asp-OH; Nα-Fmoc-Nε-Trt-Lys Further stages;

43%

2-chlorotrityl resin + Fmoc-dPhe-OH + Fmoc-(tBu)Asp-OH (71989-14-5) + Fmoc-Lys(OAc)-OH (159766-56-0) + Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Stage #1: H-Gly-(2-Cl)-Trt-pol; Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine With N-ethyl-N,N-diisopropylamine; [ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate at 20℃; for 1h; 2-CT Cl resin; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 0.1h; Stage #3: Fmoc-dPhe-OH; Fmoc-(tBu)Asp-OH; Fmoc-Lys(OAc)-OH Further stages;

43%

C45H67N9O10S (388633-54-3) → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
With chlorotriisopropylsilane; water; trifluoroacetic acid for 2h;

Fmoc-(tBu)Asp-OH (71989-14-5) + Fmoc-D-Phe-OH (86123-10-6) + Alloc-L-Lys(N-Fmoc)-OH (186350-56-1) + R(Pmc)-G linear peptide bound to resin → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multistep reaction;

Fmoc-(tBu)Asp-OH (71989-14-5) + Fmoc-Asn-OHFmoc-Leu-OH → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: Pd(PPh3)4; PhSiH3 2: TFA; triisopropylsilane; water / 2 h View Scheme

Fmoc-D-Phe-OH (86123-10-6) + bis-1,4-aminomethylcyclohexane on chlorotrityl resin → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: Pd(PPh3)4; PhSiH3 2: TFA; triisopropylsilane; water / 2 h View Scheme

(S)-6-allyloxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid (146982-27-6) → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: Pd(PPh3)4; PhSiH3 2: TFA; triisopropylsilane; water / 2 h View Scheme

cyclo(-D(tBu)-f-K(Aloc)-R(Pmc)-G-) (343312-39-0) → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: Pd(PPh3)4; PhSiH3 2: TFA; triisopropylsilane; water / 2 h View Scheme

C39H56N10O11 (1035105-00-0) → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
for 2h; UV-irradiation;

C74H84N9O12PolS → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
With chlorotriisopropylsilane; trifluoroacetic acid In dichloromethane at 20℃; for 3h; solid phase reaction;	0.45 mg

C39H56N10O11 (1035105-00-0) → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
for 1.5h; Irradiation;	92 %Chromat.

N-(fluoren-9-ylmethoxycarbonyl)glycine (29022-11-5) + Fmoc-Lys(tert-butoxycarbonyl) (71989-26-9) + Fmoc-D-Phe-OH (86123-10-6) + N-alpha-(9-fluorenylmethyloxycarbonyl)-L-aspartic acid beta-allyl ester (146982-24-3) + Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Stage #1: N-alpha-(9-fluorenylmethyloxycarbonyl)-L-aspartic acid beta-allyl ester With N-ethyl-N,N-diisopropylamine In dichloromethane for 3h; 2-chlorotrityl chloride polystyrene resin; Stage #2: With piperidine In 1-methyl-pyrrolidin-2-one for 0.416667h; Stage #3: N-(fluoren-9-ylmethoxycarbonyl)glycine; Fmoc-Lys(tert-butoxycarbonyl); Fmoc-D-Phe-OH; Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine Further stages;

c[R]GDfK → 7-(diethylamino)-4-(hydroxymethyl)-2H-chromen-2-one (54711-38-5) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
With water In aq. buffer pH=7.4; Irradiation;

C21H29BrN8O8 → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: dichloromethane / 20 °C 2.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 2.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 3.1: hydrogenchloride / 1,4-dioxane / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 4.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 5.1: hydrogenchloride / 1,4-dioxane / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 6.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 7.1: hydrogenchloride / 1,4-dioxane / 0.67 h / 20 °C 8.1: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 9.1: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

C16H21BrN8O6*C2HF3O2 → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 1.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 2.1: hydrogenchloride / 1,4-dioxane / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 3.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 4.1: hydrogenchloride / 1,4-dioxane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 5.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 6.1: hydrogenchloride / 1,4-dioxane / 0.67 h / 20 °C 7.1: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 8.1: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

C35H46BrClN10O11 → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: hydrogenchloride / 1,4-dioxane / 20 °C 2.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 2.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 3.1: hydrogenchloride / 1,4-dioxane / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 4.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 5.1: hydrogenchloride / 1,4-dioxane / 0.67 h / 20 °C 6.1: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 7.1: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

C30H38BrClN10O9*ClH → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 1.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 2.1: hydrogenchloride / 1,4-dioxane / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 3.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 4.1: hydrogenchloride / 1,4-dioxane / 0.67 h / 20 °C 5.1: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 6.1: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

C44H55BrClN11O12 → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: hydrogenchloride / 1,4-dioxane / 20 °C 2.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 2.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 3.1: hydrogenchloride / 1,4-dioxane / 0.67 h / 20 °C 4.1: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 5.1: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

C39H47BrClN11O10*ClH → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; bis(trichloromethyl) carbonate / N,N-dimethyl-formamide; acetonitrile / 0 h / 20 °C / Flow reactor 1.2: 0 h / 20 °C / pH 8 - 9 / Flow reactor 2.1: hydrogenchloride / 1,4-dioxane / 0.67 h / 20 °C 3.1: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 4.1: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

C55H66BrClN12O15 → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane / 0.67 h / 20 °C 2: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 3: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

C50H58BrClN12O13 → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetonitrile / 0.08 h / 20 °C / UV-irradiation; Flow reactor 2: hydrogen; palladium 10% on activated carbon / methanol; acetic acid / 18 h / 20 °C View Scheme

Fmoc-Asp(OtBu)-D-Phe-Lys(Boc)-Arg(Pbf)-Gly-OH → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 3 h / 0 - 20 °C 2: sodium hydroxide; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C / pH 8 3: trifluoroacetic acid; methyl-phenyl-thioether; chlorotriisopropylsilane; phenol / 3 h / 20 °C View Scheme

H-Asp(OtBu)-D-Phe-Lys(Boc)-Arg(Pbf)-Gly-OH (942132-29-8) → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C / pH 8 2: trifluoroacetic acid; methyl-phenyl-thioether; chlorotriisopropylsilane; phenol / 3 h / 20 °C View Scheme

cyclized H2N-Asp(OtBu)-D-Phe-Lys(Boc)-Arg(Pbf)-Gly-OH (545376-68-9) → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
With chlorotriisopropylsilane; methyl-phenyl-thioether; trifluoroacetic acid; phenol at 20℃; for 3h;
With chlorotriisopropylsilane; water; trifluoroacetic acid at 20℃; for 24h;

Gly-Arg(Pbf)-Lys(Boc)-D-Phe-Asp(OtBu)-OH → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; diphenyl phosphoryl azide / N,N-dimethyl-formamide / 24 h / 20 °C 2: trifluoroacetic acid; water; chlorotriisopropylsilane / 24 h / 20 °C View Scheme

C45H67N9O13S → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; diphenyl phosphoryl azide / N,N-dimethyl-formamide 2: trifluoroacetic acid; chlorotriisopropylsilane / water / 2 h / 20 °C View Scheme

C45H65N9O12S → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
With chlorotriisopropylsilane; trifluoroacetic acid In water at 20℃; for 2h;

C56H67ClN11O8Pol → [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0)

Conditions	Yield
Stage #1: C56H67ClN11O8Pol With hydrazine hydrate In N,N-dimethyl-formamide for 0.0833333h; CTC-resin; Stage #2: With methyl-phenyl-thioether; ethane-1,2-dithiol; methoxybenzene; trifluoroacetic acid CTC-resin;

C14H21N5O7 (1145938-00-6) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C37H57N13O11 (1145938-02-8)

Conditions	Yield
In dimethyl sulfoxide; acetonitrile	99%

ADIBO-PEG5-N-succinimidyl ester (1378531-80-6) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C59H79N11O15 (1415001-59-0)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃;	90%

C26H39NO13 (1422540-83-7) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C47H75N9O17 (1422541-06-7)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere;	86%

1,3-bis[4, 10-bis(carboxymethyl)-1,4,10-triaza-7-oxacyclododec-1-ylmethyl]-5-isothiocyanatobenzene hydrochloride salt + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C60H92N16O17S

Conditions	Yield
In aq. buffer at 20℃; for 24h; pH=9;	84%

2,5-dioxopyrrolidin-1-yl (E)-3-(2-(2-(4-(dicyanomethylene)-6-methyl-4H-pyran-2-yl)vinyl)-7-(diphenylamino)-9-(2-(2-ethoxyethoxy)ethyl)-9H-fluoren-9-yl)propanoate + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C72H80N12O11

Conditions	Yield
In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;	82%

6-[(2-ethylcarbamothioyl)hydrazinyl]-3-pyridinecarboxylic acid + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C36H51N13O8S

Conditions	Yield
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 In N,N-dimethyl-formamide at 20℃;	80%

C52H50N12O10Si + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C79H89N21O16Si

Conditions	Yield
Stage #1: C52H50N12O10Si With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 4h; Stage #2: [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	78%

cholesterol-tetraethylene glycol-DSC + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → cholesterol-cRGDfK

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 16h;	74%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 16h;	74%

2,5-dioxopyrrolidin-1-yl pent-4-ynoate (132178-37-1) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → cyclo(L-arginylglycyl-L-α-aspartyl-D-phenylalanyl-N6-pent-4-ynoyl-L-lysyl) (1076242-17-5)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide	70%

[(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) + Chloroacetic anhydride (541-88-8) → cyclo[Lys(ClAc)-Arg-Gly-Asp-D-Phe]

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 10h;	65%

6-maleimidohexanoic acid N-hydroxylsuccinimide ester (55750-63-5) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C37H52N10O10

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 4h;	64.1%

C48H60N5O8S(1+)*I(1-)*Na(1+) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C75H99N14O14S(1+)*I(1-)*Na(1+)

Conditions

Yield

Stage #1: C48H60N5O8S(1+)*I(1-)*Na(1+) With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: With O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide for 3h; Inert atmosphere; Stage #3: [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 18h;

60%

2,5-dioxopyrrolidin-1-yl 3-iodobenzoate (91487-18-2) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C34H44IN9O8

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide for 3h;	59%

C18H18N6O5 + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C41H54N14O9

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.5h;	57%

succinimidyl 4-formylbenzoate (60444-78-2) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C35H45N9O9 (1261036-91-2)

Conditions	Yield
In N,N-dimethyl-formamide for 1h; pH=7.5; aq. phosphate buffer;	56%

6-[2-(phenylcarbamothioyl)hydrazinyl]-3-pyridinecarboxylic acid + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C40H51N13O8S

Conditions	Yield
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 In N,N-dimethyl-formamide at 20℃;	55%

rel-(1R-4E-pS)-cyclooct-4-ene-1-yl (4-nitrophenyl) carbonate + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C36H53N9O9

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 6h;	52%

C42H48N6O10Pd + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2,3-dihydroxypropyl)amide-173-(cycloRGDfK)amide

Conditions	Yield
With triethylamine In 1-methyl-pyrrolidin-2-one for 1.25h;	50%

2,5-dioxopyrrolidin-1-yl-6-(4-(dimethylamino)phenoxy)hexanoate (1338496-56-2) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C41H60N10O9 (1338496-53-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 20℃;	50%

[Ru(2,2′:6′,2″-terpyridine)(2,2′-bipyridine)(D-biotin)](Cl)2 + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C62H74N16O9RuS(2+)*2Cl(1-)

Conditions

Yield

Stage #1: [Ru(2,2′:6′,2″-terpyridine)(2,2′-bipyridine)(D-biotin)](Cl)2 With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-hydroxy-2,5-dioxopyrrolidine-3-sulfonic acid In dimethyl sulfoxide at 20℃; for 24h; Darkness; Stage #2: [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid With triethylamine pH=7; Darkness;

50%

11-azido-3,6,9-trioxaundecanoic acid (172531-37-2) + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → 2-((2S,5R,8S,11S)-8-(1-azido-11-oxo-3,6,9-trioxa-12-azahexadecan-16-yl)-5-benzyl-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid

Conditions	Yield
Stage #1: 11-azido-3,6,9-trioxaundecanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dimethyl sulfoxide at 20℃; Stage #2: [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid In dimethyl sulfoxide at 20℃;	48.3%

[(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) + (3R,4R,5R,6S)-6-((((9H-fluoren-9-yl)methoxy)carbonylamino)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (655246-28-9) → C49H62N10O14

Conditions

Yield

Stage #1: (3R,4R,5R,6S)-6-((((9H-fluoren-9-yl)methoxy)carbonylamino)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 6h;

43%

5,5′,5″-(((1,4,7-triazonane-1,4,7-triyl)tris(methylene))tris(1H-imidazole-2,1-diyl))tripentanoic acid + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C114H168N36O24

Conditions

Yield

Stage #1: 5,5′,5″-(((1,4,7-triazonane-1,4,7-triyl)tris(methylene))tris(1H-imidazole-2,1-diyl))tripentanoic acid 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 In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid In N,N-dimethyl-formamide for 2h;

41%

C16H22Cl2N4O12Pt (1542144-06-8) + C54H61N9O11Si + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C89H114Cl2N20O24PtSi

Conditions	Yield
Stage #1: C54H61N9O11Si; [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 0.166667h; Stage #2: C16H22Cl2N4O12Pt In dimethyl sulfoxide at 20℃; for 24h;	40%

C49H49N3O10S2*2H3N + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C72H85N11O14S2

Conditions	Yield
Stage #1: [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.00833333h; Stage #2: C49H49N3O10S2*2H3N In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;	36%

N-succinimidyl 3-bromobenzoate + [(2S,5R,8S,11S)-8-(4-Amino-butyl)-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid (161552-03-0) → C34H44BrN9O8

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide for 3h;	35%

Upstream product

• 1035105-00-0 C₃₉H₅₆N₁₀O₁₁ 
• 545376-68-9 cyclized H₂N-Asp(OtBu)-D-Phe-Lys(Boc)-Arg(Pbf)-Gly-OH 
• 942132-29-8 H-Asp(O^tBu)-D-Phe-Lys(Boc)-Arg(Pbf)-Gly-OH 
• 71989-14-5 Fmoc-(tBu)Asp-OH 
• 159766-56-0 Fmoc-Lys(OAc)-OH 
• 187618-60-6 Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine 
• 111061-54-2 N^α-Fmoc-N^ε-Trt-Lys 

Downstream Products

• 1261036-91-2 C₃₅H₄₅N₉O₉ 
• 1261036-93-4 C₅₁H₇₇N₁₁O₁₆S 
• 909024-55-1 DOTA-cyclo-RGDfK 
• 1415001-59-0 C₅₉H₇₉N₁₁O₁₅ 
• 696660-84-1 [(2S,5R,8S,11S)-8-[4-((S)-2-Amino-3-hydroxy-propionylamino)-butyl]-5-benzyl-11-(3-guanidino-propyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid 

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