* 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.
(S)-2-{(S)-2-[(S)-2-((S)-2-Amino-3-benzyloxycarbonyl-propionylamino)-propionylamino]-3-benzyloxycarbonyl-propionylamino}-succinic acid dibenzyl ester[ No CAS ]
(S)-2-((S)-3-Benzyloxycarbonyl-2-{(S)-2-[(S)-3-benzyloxycarbonyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionylamino]-propionylamino}-propionylamino)-succinic acid dibenzyl ester[ No CAS ]
(S)-3-[((S)-2-Amino-hexanoyl)-methyl-amino]-N-((S)-1-carbamoyl-2-phenyl-ethyl)-succinamic acid benzyl ester; compound with trifluoro-acetic acid[ No CAS ]
EXAMPLE 23 N-Fmoc-Aspartic Acid-beta-Benzyl Ester 2-Aminoaspartic acid-beta-benzyl ester (150 mmol) and diisopropylethylamine (66.3 ml, 49.1 g, 380 mmol) are suspended in 150 ml H2 O+300 ml dioxane. Fluorenylmethyl chloroformate (43.25 g, 1.1 eq) in 100 ml dioxane is added dropwise. The temperature of the reaction is not allowed to rise above 10 C. during the addition. The mixture is stirred vigorously overnight, and most of the solvent removed in vacuo. Water and satd bicarbonate solution are added (250 ml each), and the solution extracted with 250 ml diethyl ether, which is discarded. The aqueous layer is acidified to pH 1 with conc HCl, and extracted twice with ethyl acetate (2*300 ml), and the organic extracts washed with brine. The solution is dried with MgSO4, filtered and the solvent removed in vacuo to give the title compound.
2.89 g (65.0%)
REFERENCE EXAMPLE 2 Synthesis of N-alpha-9-fluorenylmethoxycarbonyl-aspartic acid-alpha-benzyl ester (referred as Fmoc-Aso-OBzl) Dissolved in 50 ml of tetrahydroguran was 3.55 g (0.010 mole) of N-alpha-9-fluorenylmethoxycarbonyl-aspartic acid (referred as Fmoc-Asp-OH) and DCC was added to the mixture as it was cooled with ice. After one hour, it was gradually returned to room temperature and it was stirred continuously for a total of five hours. The generated precipitate of DCC-urea was filtered away and 1.08 g (0.01 mole) of benzyl alcohol was added to the filtrate and it was stirred at room temperature for 24 hours. Insoluble substances were removed by filtration and the filtrate was removed by evaporation. The residue was dissolved in 10 ml of ether and 2.72 g (0.015 mole of dicyclohexylamine was added. After the mixture was stirred for ten minutes, 20 ml of n-hexane was added and the generated precipitate was collected by filtering. The obtained powder was suspended in 40 ml of ethyl acetate and the mixture was stirred after 40 ml of 5% solution of potassium hydrogensulfate was added. The ethyl acetate layer was washed carefully with water and dried and the solvent was removed by evaporation. To the residue, n-hexane was added for crystallization. Ethanol and water were then used for recrystallization. The test results were as follows: Yield: 2.89 g (65.0%). Melting Point: 113-115 C. Angle of Rotation: [alpha]25 +4.0 (C=1.0, methanol). TLC: Rf6 (chloroform:methanol:water = 200:75:13) = 0.80.
EXAMPLE 39 N-Fmoc-Aspartic Acid-beta-Benzyl Ester Aspartic acid-beta-benzyl ester (150 mmol) and diisopropyl-ethylamine (66.3 ml, 49.1 g, 380 mmol) are suspended in 150 ml H2O+300 ml dioxane. Fluorenylmethyl chloroformate (43.25 g, 1.1 eq) in 100 ml dioxane is added dropwise. The temperature of the reaction is not allowed to rise above 10 C. during the addition. The mixture is stirred vigorously overnight, and most of the solvent removed in vacuo. Water and satd bicarbonate solution are added (250 ml each), and the solution extracted with 250 ml diethyl ether, which is discarded. The aqueous layer is acidified to pH 1 with conc HCl, and extracted twice with ethyl acetate (2*300 ml), and the organic extracts washed with brine. The solution is dried with MgSO4, filtered and the solvent removed in vacuo to give the title compound.
EXAMPLE 39 N-Fmoc-Aspartic Acid-beta-Benzyl Ester Aspartic acid-beta-benzyl ester (150 mmol) and diisopropylethylamine (66.3 ml, 49.1 g, 380 mmol) are suspended in 150 ml H2O+300 ml dioxane. Fluorenylmethyl chloroformate (43.25 g, 1.1 eq) in 100 ml dioxane is added dropwise. The temperature of the reaction is not allowed to rise above 10 C. during the addition. The mixture is stirred vigorously overnight, and most of the solvent removed in vacuo. Water and satd bicarbonate solution are added (250 ml each), and the solution extracted with 250 ml diethyl ether, which is discarded. The aqueous layer is acidified to pH 1 with conc HCl, and extracted twice with ethyl acetate (2*300 ml), and the organic extracts washed with brine. The solution is dried with MgSO4, filtered and the solvent removed in vacuo to give the title compound.
31
2-chlorotrityl chloride polystyrene resin[ No CAS ]
[ 29022-11-5 ]
[ 35661-39-3 ]
[ 86060-82-4 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 132327-80-1 ]
[ 150009-58-8 ]
[ 119831-72-0 ]
C151H185ClN17O32PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
fully automated peptide synthesizer;
The resin used for solid synthesis of the peptide was a 2-chlorotrisyl chloride resin, which will not impair the protective groups on various amino acid residues and from which the peptide can be cleaved with a weak acid. A 0.25-mmol (368-mg) portion of the resin was weighed and used. The peptide synthesis was carried out according to the Fmoc (9-fluorenylmethoxycarbonyl) chemistry and a Fmoc-side chain-protected peptide-resin was obtained by starting the synthesis from the C terminus on a fully automated peptide synthesizer using the following Fmoc-side chain-protected amino acids 1) to 12) (1.0 mmol each).1) Fmoc-Gly-OH 1.0 mmol2) Fmoc-L-Arg(Pmc)-OH 1.0 mmolPmc: 2,2,5,7,8-pentamethylchroman-6-sulfonyl3) Fmoc-L-Asp(OtBu)-OH 1.0 mmolOtBu: O-t-butyl4) Fmoc-L-Asp(OtBu)-OH 1.0 mmol5) Fmoc-L-Ala-OH 1.0 mmol6) Fmoc-L-Glu(OtBu)-OH 1.0 mmol7) Fmoc-Gly-OH 1.0 mmol8) Fmoc-L-Glu(OtBu)-OH 1.0 mmol9) Fmoc-L-Lys(Boc)-OH 1.0 mmolBoc: benzyloxycarbonyl10) Fmoc-L-Gln(Trt)-OH 1.0 mmolTrt: trityl11) Fmoc-L-Ser(tBu)-OH 1.0 mmoltBu: t-butyl12) Fmoc-L-Asp(OBzl)-OH 1.0 mmolOBzl: O-benzyl
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
One bag of resin 1 (100 mg, 0.115 mmol) was put into a small polyethylene bottle and the Fmoc group was deprotected with 15 mL of a solution of 20% piperidine in DMF (2 × 10 min). The resin was then washed with 15 mL DMF (3×) and 15 mL DCM (3×). L-Fmoc-Asp(Bzl)-OH (6 equiv, 0.307 g, 0.69 mmol) was coupled in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.094 g, 0.69 mmol) and diisopropylcarbodiimide (DIC, 6 equiv, 0.101 mL, 0.69 mmol) in 15 mL anhydrous DMF for 2 h at room temperature. The resin-bound dipeptide was washed with DMF (3×) and DCM (3×). Completion of the coupling was monitored by the ninhydrin test. The Fmoc group was deprotected with 15 mL 20% piperidine in DMF (2 × 10 min) and followed by the coupling of L-Fmoc-Gly-OH (6 equiv, 0.205 g, 0.69 mmol) using the same reaction conditions. The Fmoc group was deprotected and the resin-bound tripeptide was coupled to L-Fmoc-Arg(Pmc)-OH (6 equiv, 0.457 g, 0.69 mmol) in the same conditions to yield following Fmoc deprotection the corresponding resin-bound protected linear peptide 2a. The resulting N-terminal free amine of resin-bound linear peptide 2a was treated with Fmoc-isothiocyanate (6 equiv, 0.193 g, 11.04 mmol) in 15 mL DMF anhydrous overnight at room temperature. Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal thiourea was treated with 1,3-dichloroacetone (10 equiv, 0.145 g, 18.4 mmol) in DMF anhydrous overnight at 70 C to afford following Hantzsch?s cyclocondensation the resulting resin-bound chloro methyl thiazolyl peptide 4a. The Trt group was removed in the presence of TFA/(But)3SiH/DCM (5:5:90) for 30 min. The resin was washed with DCM (5×) and DIEA/DCM (5:95) and was treated overnight with a solution of Cs2CO3 (10 equiv, 0.325 g) in 15 mL DMF at room temperature to undergo an SN2 intramolecular thioalkylation. The resin was treated with HF/anisole for 90 min at 0 C, and the desired thiazolyl thioether cyclic peptides 5a was obtained following extraction with 95% acetic acid in water and lyophilization as a white powder (61.9 mg). The cyclic peptide 5a was purified by preparative reverse-phase HPLC.
With 2,4,6-trimethyl-pyridine; dicyclohexyl-carbodiimide; ethyl cyanoglyoxylate-2-oxime; In dichloromethane; at 20℃; for 3h;
A solution of 8a (1.7 g, 4.99 mmol) in DCM (40 ml, anhydrous, mol. sieve) was added to a solution of DCC (1.34 g, 6.50 mmol), Oxyma pure (995 mg, 7.00 mmol), Fmoc-L-Asp(OBn)OH (2.22 g, 4.98 mmol) and 2,4,6-collidine (1.24 mL, 9.53 mmol) in DCM (40 ml, anhydrous, mol. sieve). The reaction mixture was stirred for 3 h at RT. The precipitate wasfiltered off and the filtrate was washed with 0.1 M HC1, sat. NaHCO3 and brine. Organic phase was dried over Na2SO4 and solvents were removed in vacuo. The crude material was purified by flash chromatography to give 8b (3.19 g, 4.15 mmol, 83%) as off white solid. MS:m/z 768.35 = [M+H], (calculated = 768.35).
83%
With 2,3,5-trimethyl-pyridine; dicyclohexyl-carbodiimide; ethyl cyanoglyoxylate-2-oxime; In dichloromethane; at 20℃; for 3h;Molecular sieve;
A solution of 6a (1.7 g, 4.99 mmol) in DCM (40 ml, anhydrous, mol. sieve) was added to a solution of DCC (1.34 g, 6.50 mmol), Oxyma pure (995 mg, 7.00 mmol), Fmoc-Z-Asp(OBn)- OH (2.22 g, 4.98 mmol) and collidine (1.24 mL, 9.53 mmol) in DCM (40 ml, anhydrous, mol. sieve). The reaction mixture was stirred for 3 h at RT. The precipitate was filtered off and the filtrate was washed with 0.1 M HCl, sat. NaHC03 and brine. Organic phase was dried over Na2S04 and solvents were removed in vacuo. The crude material was purified by flash chromatography to give 6b (3.19 g, 4.15 mmol, 83%) as off white solid. MS:m/z 768.35 = [M+H]+, (calculated = 768.35).
With 4-methyl-morpholine; In tetrahydrofuran; at -15℃; for 0.333333h;
General procedure: To a solution of Nalpha-protected amino acid (10 mmol) in THF (10 mL), NMM(11 mmol) and ethyl chloroformate (11 mmol) were added at -15 C followed by stirring for 20 min NH3 solution (0.4 mL) was added and stirring was continued for another 4 h. After completion of the reaction (TLC), the solvent was removed in vacuo andthe residue was dissolved in EtOAc (30 mL), washed twice with 10% HCl (10 mL)(in case of Fmoc, Z-amino acids), or 10% citric acid (10 mL) (in case of Boc-amino acids), brine solution (10 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the crude product was purified by recryastallization from EtOAc:hexane (3:8). The solution of amino acid amide (10mmol) in dry THF (10 mL) was treated with pyridine (20 mmol) and TFAA (12 mmol)and the reaction mixture was stirred at 0 C for 3 h. After completion of the reaction (TLC), the solvent was evaporated and residue wasdissolved in EtOAc (30 mL), washed twice with 10% HCl (10 mL) (in case of Fmoc,Z-amino acids), or 10% citric acid (10 mL) (in case of Boc-amino acids), saturatedNaHCO3 (10 mL), brine solution (10 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (hexane:EtOAc 9:1).
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
LYRAD(Bn)-NHNH<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: General procedure for LYRAXaa-NHNH2: 250mg CTC-NHNH2 resin (loading capacity is 0.25 mmol) was added into the reaction flask of peptide synthesizer. The scale of amino acid is 1 mmol. In each coupling reaction, 2.5 mL of 0.4 M HATU, 2.5 mL of 0.8 DIPEA and 2.5 mL DMF were added and the mixture was kept shaking for 70 minutes. The resin was then treated with 20% piperidine in DMF and the removed Fmoc was monitored by a UV detector until completion. Then, the resin was washed with DMF and subject to next synthetic cycle with another amino acid and repeated above procedures. After completion of peptide synthesis, we finished deprotection and cleavage. When the first amino acid is Asp, Gln and Asp(Bn), the peptide resins were cleaved and deprotected with 95% TFA in water for 1 hour. When the first amino acid is Asn, complete cleavage with 1% TFA in DCM for1 hour then carry out deprotection with 95% TFA in water for 1 hour. Then, filtered and removed most of TFA by N2 gas blowing, then ethyl ether was added to precipitate the crude peptide. The crude peptide was subject to the HPLC analysis and purification by semi-preparativeHPLC.
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