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Stage #1: C21H23N2O2PolS; (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid With 1-hydroxy-7-aza-benzotriazole; 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 for 2h; Inert atmosphere;
Stage #2: With 4-methylpiperidine In N,N-dimethyl-formamide Inert atmosphere;
Stage #3: (2S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(adamantan-1-yl)acetic acid Further stages; |
S20
4-Formy1-3-methoxy-phenyloxymethyl polystyrene resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL 1,2-Dichloroethane were added and the resin was allowed to swell for 30 min under nitrogen. The resin was drained under vacuum. (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (3.0 equiv.) was added to the plastic reactor. A solution of triethylamine (10.0 equiv.) solution in 1,2-Dichloroethane (1 mL) was prepared. The solution was drawn into the plastic reactor and reacted for 2 hr at room temperature. The reactor was opened, and sodium cyanoborohydride (10.0 equiv.) and acetic acid (2 equiv.) were added to the reactor. The reactor was left opened on manifold, mixed by pipetting, and reacted overnight at RT. The resin was washed by lOmL methanol, 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (3.0 equiv.), 1-hydroxy-7-azabenzotriazole (3.0 equiv.), and N,N-Diisopropylethylamine (6.0 equiv.) in 10 mL N,N-Dimethylformamide was added; then, the mixture was drawn into the synthesis vessel and reacted for 2 hr under nitrogen. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-Dimethylformamide were drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect Fmoc group. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. A mixture of (2S)-2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-2-(adamantan-1-yl)acetic acid (3.0 equiv.), Ethyl cyano(hydroxyimino) acetate (3.0 equiv.) and N,N'- Diisopropylcarbodiimide (3.0 equiv.) in 10 mL N,N-Dimethylformamide was added; then, the mixture was drawn into the synthesis vessel and reacted for 2 hr under nitrogen. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-Dimethylformamide were drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect Fmoc group. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 1H- imidazole- 1 -sulfonyl azide hydrochloride (3.0 equiv.) and N,N-Diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was drawn into the reaction vessel and reacted under nitrogen for 1 hr to convert amine to azide. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly into the peptide synthesis vessel to perform on-resin "click" reaction. The mixture of ethynylcyclopropane (5.0 equiv.), N,N-Diisopropylethylamine (10.0 equiv.) in 10 mL N,N-Dimethylformamide (nitrogen purged) was drawn into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. A cleavage solution was prepared by mixing 5% Triisopropylsilane in 95% Trifluoroacetic acid. The solution was drawn into the reaction vessel and reacted for 1 hr. The Trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse phase HPLC (30% - 60% Acetonitrile). The desired product was freeze dried and characterized by LC-MS. ESI-MS: m/z [M+H]+ calculated: 615.3, found: 615.3. [0374] 1H NMR (400 MHz, MeOH-d4) 5 8.98 (s, 1H), 7.97 (d, J = 6.7 Hz, 1H), 7.50 - 7.34 (m, 4H), 5.30 (s, 1H), 5.12 - 4.96 (m, 2H), 4.54 (dd, J = 9.3, 7.6 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.85 (dd, 7 = 11.1, 3.8 Hz, 1H), 3.79 - 3.66 (m, 1H), 2.49 (d, 7 = 3.6 Hz, 3H), 2.20 (ddt, 7 = 11.3, 7.6, 2.0 Hz, 1H), 2.04 - 1.91 (m, 5H), 1.85 - 1.58 (m, 14H), 1.55 (d, 7 = 7.0 Hz, 3H), 1.02 - 0.93 (m, 2H), 0.79 (ddt, 7 = 6.4, 4.9, 2.2 Hz, 2H). |
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Stage #1: C21H23N2O2PolS; (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid With 1-hydroxy-7-aza-benzotriazole; 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 for 2h; Inert atmosphere;
Stage #2: With 4-methylpiperidine In N,N-dimethyl-formamide Inert atmosphere;
Stage #3: (2S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(adamantan-1-yl)acetic acid Further stages; |
S20
4-Formy1-3-methoxy-phenyloxymethyl polystyrene resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL 1,2-Dichloroethane were added and the resin was allowed to swell for 30 min under nitrogen. The resin was drained under vacuum. (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (3.0 equiv.) was added to the plastic reactor. A solution of triethylamine (10.0 equiv.) solution in 1,2-Dichloroethane (1 mL) was prepared. The solution was drawn into the plastic reactor and reacted for 2 hr at room temperature. The reactor was opened, and sodium cyanoborohydride (10.0 equiv.) and acetic acid (2 equiv.) were added to the reactor. The reactor was left opened on manifold, mixed by pipetting, and reacted overnight at RT. The resin was washed by lOmL methanol, 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (3.0 equiv.), 1-hydroxy-7-azabenzotriazole (3.0 equiv.), and N,N-Diisopropylethylamine (6.0 equiv.) in 10 mL N,N-Dimethylformamide was added; then, the mixture was drawn into the synthesis vessel and reacted for 2 hr under nitrogen. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-Dimethylformamide were drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect Fmoc group. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. A mixture of (2S)-2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-2-(adamantan-1-yl)acetic acid (3.0 equiv.), Ethyl cyano(hydroxyimino) acetate (3.0 equiv.) and N,N'- Diisopropylcarbodiimide (3.0 equiv.) in 10 mL N,N-Dimethylformamide was added; then, the mixture was drawn into the synthesis vessel and reacted for 2 hr under nitrogen. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-Dimethylformamide were drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect Fmoc group. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 1H- imidazole- 1 -sulfonyl azide hydrochloride (3.0 equiv.) and N,N-Diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was drawn into the reaction vessel and reacted under nitrogen for 1 hr to convert amine to azide. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly into the peptide synthesis vessel to perform on-resin "click" reaction. The mixture of ethynylcyclopropane (5.0 equiv.), N,N-Diisopropylethylamine (10.0 equiv.) in 10 mL N,N-Dimethylformamide (nitrogen purged) was drawn into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. A cleavage solution was prepared by mixing 5% Triisopropylsilane in 95% Trifluoroacetic acid. The solution was drawn into the reaction vessel and reacted for 1 hr. The Trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse phase HPLC (30% - 60% Acetonitrile). The desired product was freeze dried and characterized by LC-MS. ESI-MS: m/z [M+H]+ calculated: 615.3, found: 615.3. [0374] 1H NMR (400 MHz, MeOH-d4) 5 8.98 (s, 1H), 7.97 (d, J = 6.7 Hz, 1H), 7.50 - 7.34 (m, 4H), 5.30 (s, 1H), 5.12 - 4.96 (m, 2H), 4.54 (dd, J = 9.3, 7.6 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.85 (dd, 7 = 11.1, 3.8 Hz, 1H), 3.79 - 3.66 (m, 1H), 2.49 (d, 7 = 3.6 Hz, 3H), 2.20 (ddt, 7 = 11.3, 7.6, 2.0 Hz, 1H), 2.04 - 1.91 (m, 5H), 1.85 - 1.58 (m, 14H), 1.55 (d, 7 = 7.0 Hz, 3H), 1.02 - 0.93 (m, 2H), 0.79 (ddt, 7 = 6.4, 4.9, 2.2 Hz, 2H). |
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Stage #1: C21H23N2O2PolS; (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid With 1-hydroxy-7-aza-benzotriazole; 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 for 2h; Inert atmosphere;
Stage #2: With 4-methylpiperidine In N,N-dimethyl-formamide Inert atmosphere;
Stage #3: (2S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(adamantan-1-yl)acetic acid Further stages; |
S20
4-Formy1-3-methoxy-phenyloxymethyl polystyrene resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL 1,2-Dichloroethane were added and the resin was allowed to swell for 30 min under nitrogen. The resin was drained under vacuum. (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (3.0 equiv.) was added to the plastic reactor. A solution of triethylamine (10.0 equiv.) solution in 1,2-Dichloroethane (1 mL) was prepared. The solution was drawn into the plastic reactor and reacted for 2 hr at room temperature. The reactor was opened, and sodium cyanoborohydride (10.0 equiv.) and acetic acid (2 equiv.) were added to the reactor. The reactor was left opened on manifold, mixed by pipetting, and reacted overnight at RT. The resin was washed by lOmL methanol, 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (3.0 equiv.), 1-hydroxy-7-azabenzotriazole (3.0 equiv.), and N,N-Diisopropylethylamine (6.0 equiv.) in 10 mL N,N-Dimethylformamide was added; then, the mixture was drawn into the synthesis vessel and reacted for 2 hr under nitrogen. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-Dimethylformamide were drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect Fmoc group. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. A mixture of (2S)-2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-2-(adamantan-1-yl)acetic acid (3.0 equiv.), Ethyl cyano(hydroxyimino) acetate (3.0 equiv.) and N,N'- Diisopropylcarbodiimide (3.0 equiv.) in 10 mL N,N-Dimethylformamide was added; then, the mixture was drawn into the synthesis vessel and reacted for 2 hr under nitrogen. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-Dimethylformamide were drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect Fmoc group. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N-Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. 1H- imidazole- 1 -sulfonyl azide hydrochloride (3.0 equiv.) and N,N-Diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was drawn into the reaction vessel and reacted under nitrogen for 1 hr to convert amine to azide. The solvent was drained under vacuum and the deprotection was repeated. The resin was washed with 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. The washing procedure was repeated 3 times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly into the peptide synthesis vessel to perform on-resin "click" reaction. The mixture of ethynylcyclopropane (5.0 equiv.), N,N-Diisopropylethylamine (10.0 equiv.) in 10 mL N,N-Dimethylformamide (nitrogen purged) was drawn into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL N,N- Dimethylformamide, then 10 mL dichloromethane, and drained under vacuum. A cleavage solution was prepared by mixing 5% Triisopropylsilane in 95% Trifluoroacetic acid. The solution was drawn into the reaction vessel and reacted for 1 hr. The Trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse phase HPLC (30% - 60% Acetonitrile). The desired product was freeze dried and characterized by LC-MS. ESI-MS: m/z [M+H]+ calculated: 615.3, found: 615.3. [0374] 1H NMR (400 MHz, MeOH-d4) 5 8.98 (s, 1H), 7.97 (d, J = 6.7 Hz, 1H), 7.50 - 7.34 (m, 4H), 5.30 (s, 1H), 5.12 - 4.96 (m, 2H), 4.54 (dd, J = 9.3, 7.6 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.85 (dd, 7 = 11.1, 3.8 Hz, 1H), 3.79 - 3.66 (m, 1H), 2.49 (d, 7 = 3.6 Hz, 3H), 2.20 (ddt, 7 = 11.3, 7.6, 2.0 Hz, 1H), 2.04 - 1.91 (m, 5H), 1.85 - 1.58 (m, 14H), 1.55 (d, 7 = 7.0 Hz, 3H), 1.02 - 0.93 (m, 2H), 0.79 (ddt, 7 = 6.4, 4.9, 2.2 Hz, 2H). |
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