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CAS No. : | 63628-63-7 | MDL No. : | MFCD22581338 |
Formula : | C18H28N2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AKFVZALISNAFRA-HNNXBMFYSA-N |
M.W : | 336.43 | Pubchem ID : | 1581102 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With perchloric acid In water at 20℃; for 18h; | |
63% | With perchloric acid | 25 tert-Butyl N6-((benzyloxy)carbonyl)-1-lysinate (8). Nε-((benzyloxy)carbonyl)-1-lysine (12.03 g, 42.92 mmol) was mixed with t-butyl acetate (120 mL) in a 250 mL round bottom flask and concentrated HClO4 (3.90 mL) added to this mixture, producing a clear solution. This solution was stirred for 12 h before extracting with 200 mL H2O, 200 mL 5% HCl, then 200 mL, H2O. The aqueous extracts were combined and extracted with diethyl ether (3×200 mL) after addition of 30% NaOH solution until the aqueous layer was pH 11. The ether extracts were combined and dried over anhydrous MgSO4. The ether was then filtered and concentrated under reduced pressure and dried under a 50 μm vacuum overnight giving a colorless oil. Yield: 9.25 g (63%). 1H NMR (400 MHz, CDCl3): δ 1.30 (s 9H), 1.23-1.50 (m 8H), 2.99 (t 2H), 3.11 (t 1H), 4.91 (s 2H), 5.61 (br 1H), 7.14-7.16 (m 5H), 13C NMR (101 MHz, CDCl3): δ 175.18, 156.34, 142.38, 136.60, 128.31, 127.88, 108.60, 80.74, 77.46, 77.14, 76.82, 66.29, 54.66, 40.66, 34.36, 31.08, 29.53, 27.90, 22.64. |
With perchloric acid |
With perchloric acid at 23℃; for 14h; | ||
With perchloric acid at 22℃; for 14h; Inert atmosphere; | HClO4 (3.01 mL) was slowly added to a stirred solution of Z-Lys 1 (6.5 g, 23.18 mmol) in t-butyl acetate (80 mL). The mixture was stirred at 22° C. for 14 h before extracting with H2O (150 mL) and 0.5N HCl solution (150 mL). The combined aqueous solutions were treated with 10% K2CO3 to give a solution of pH 9; the basic solution was then extracted with CH2Cl2 (3*100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and then concentrated to give 2 as a colorless oil. The oil was dissolved in CH3CN (150 mL) before addition of NaHCO3 (4.29 g, 51.07 mmol) and t-butyl bromoacetate (13.58 g, 69.64 mmol). The mixture was heated at reflux for 15 h, then cooled to 22° C. before concentration of the mixture under reduced pressure and extraction of the residue with ethyl acetate (2*150 mL). The combined organic layers were washed with saturated NaCl solution (2*100 mL), dried over anhydrous MgSO4, and evaporated. The crude residue was purified by silica gel flash chromatography using 4:1 hexane:EtOAc as eluent to give compound 3 (11.62 g, 91%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.30-7.35 (m, 5H), 5.08 (s, 2H), 3.44 (dd, J=17.4, 11.1 Hz, 4H), 3.30 (t, J=7.35 Hz, 1H), 3.20 (m, 2H), 1.62 (m, 2H), 1.53 (m, 4H), 1.45 (s, 9H), 1.43 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 172.2, 171.2, 157.0, 137.34, 128.9, 128.6, 128.4, 81.64, 81.2, 66.9, 65.6, 54.4, 41.3, 30.6, 29.8, 28.7, 28.6, 23.5; HRMS (ESI): (M+H)+m/z calc'd for C30H48N2O8=564.7107. found 565.0643. The NMR spectra are in agreement with previously published data. (Huang et al., Bioconjugate Chem. 2006, 17, 1592-1600). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dicyclohexyl-carbodiimide | |
With 2-hydroxyethanethiol; papain In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sulfuric acid In 1,4-dioxane at -78 - 20℃; Inert atmosphere; | |
73% | With sulfuric acid In 1,4-dioxane for 18h; | |
55% | With sulfuric acid In 1,4-dioxane for 4h; Ambient temperature; |
With sulfuric acid In 1,4-dioxane | ||
With sulfuric acid In 1,4-dioxane for 6h; dry ice-acetone cold; | ||
16.7 gm (64%) | With sodium hydroxide; sulfuric acid In 1,4-dioxane | IV EXAMPLE IV EXAMPLE IV Into two separate 500 ml hydrogenation vessels each containing 100 ml of dioxane and 9.0 ml (160 mmol) of concentrated sulfuric acid was placed 11.0 gm (39.2 mmol) and 10.6 gm (37.8 mmol) of Nε-benzyloxycarbonyl-L-lysine. The two solutions were cooled to -78° C. and 140 ml of condensed (-78° C.) isobutylene was added to each vessel. The mixtures were then mechanically shaken (Parr shaker) at room temperature for 4 hours (26 psi). The reaction mixtures were combined and poured into 1000 ml (1.0 mol) of an ice cold solution of 1.0N aqueous sodium hydroxide and subsequently extracted three times with ether. The organic portions were combined (ca. 3000 ml), washed once with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 16.7 gm (64%) of t-butyl Nε-benzyloxycarbonyl-L-lysinate (IV-A) as an oil. |
16.7 gm (64%) | With sodium hydroxide; sulfuric acid In 1,4-dioxane | IV EXAMPLE IV EXAMPLE IV Into two separate 500 ml hydrogenation vessels each containing 100 ml of dioxane and 9.0 ml (160 mmol) of concentrated sulfuric acid was placed 11.0 gm (39.2 mmol) and 10.6 gm (37.8 mmol) of Nε-benzyloxycarbonyl-L-lysine. The two solutions were cooled to -78° C. and 140 ml of condensed (-78° C.) isobutylene was added to each vessel. The mixtures were then mechanically shaken (Parr shaker) at room temperature for 4 hours (26 psi). The reaction mixtures were combined and poured into 1000 ml (1.0 mol) of an ice cold solution of 1.0N aqueous sodium hydroxide and subsequently extracted three times with ether. The organic portions were combined (ca. 3000 ml), washed once with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 16.7 gm (64%) of t-butyl Nε-benzyloxycarbonyl-L-lysinate (IV-A) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium carbonate In acetonitrile for 18h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 2.79 g 2: 3.24 g | With triethylamine In N,N-dimethyl-formamide at 70℃; for 44h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 44% 2: 42% | With triethylamine; potassium iodide In acetonitrile for 72h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With triethylamine In dichloromethane 1.) RT, 1 h, 2.) reflux, 2.5 h; | |
28% | With triethylamine In dichloromethane 1.) RT, 1 h, 2.) reflux, 2.5 h; Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In methanol Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With hydrogenchloride In ethyl acetate | Synthesis of 14 A solution of 13 (1.16 g, 2.65 mmol) in 2 M HCl-AcOEt (13.2 mL, 26.4 mmol) was stirred for 3 hat rt. After neutralization with sat. NaHCO3 aq. on ice-cooling, the mixture was extracted withAcOEt. The organic layer was dried over MgSO4. The solution was concentrated by evaporation togive 14 (705 mg, 79%) as a colorless oil. |
74% | With nitric acid In dichloromethane at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogen; acetic acid In methanol for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-methylmaleimide; N-ethyl-N,N-diisopropylamine In 1,4-dioxane; water; N,N-dimethyl-formamide at 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 65℃; for 18h; | Synthesis of 15 To a solution of 14 (705 mg, 2.09 mmol) in dry DMF (9 mL) was added DIEA (2.20 mL, 12.6mmol) and tert-Bu bromoacetate (1.60 mL, 10.5 mmol) and the solution was stirred for 18 h at 65 °C.After dilution with water, the mixture was extracted with AcOEt. The organic layer was washed withsat. NaHCO3 aq. and brine followed by drying over MgSO4. After removal of the solvent byevaporation, the residue was purified by column chromatography on SiO2 (Hexane : AcOEt = 4 : 1)to give 15 (1.18 g, 100 %) as a yellow oil. |
99% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 55℃; for 24h; Inert atmosphere; | |
98% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 55℃; |
91% | With sodium hydrogencarbonate In acetonitrile for 15h; Reflux; | |
87% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; Inert atmosphere; | 25 Di-t-butyl 2,2′-((6-(((benzyloxy)carbonyl)amino)-1-(t-butoxy)-1-oxohexan-2-yl)azanediyl)diacetate (9). Nε-Benzyloxycarbonyl-L-lysine-t-butyl ester (8, 9.25, 27.5 mmol) was dissolved in DMF (70 mL) prior to the addition of t-butyl bromoacetate (12.2 mL, 16.10 g, 82.6 mmol) and DIEA (16.8 mL, 11.9 g, 92.1 mmol) by syringe. The solution was stirred under N2 at 70° C. for 72 h. The solvent was evaporated under reduced pressure and the residue was extracted with 200 mL of ethyl acetate and filtered. The ethyl acetate extract was purified by flash chromatography on silica (4:1 hexane:EtOAc) to give 9 as a slightly yellow oil. Yield: 12.56 g (87%); TLC: Rf=0.48 (4:1 hexane:EtOAc); 1H NMR (CDCl3): δ 1.25-1.50 (m 6H), 1.30 (s 18H), 1.32 (s 9H), 3.04 (m 2H), 3.16 (t 1H), 3.33 (q 4H), 4.93 (s 2H), 5.39 (br 1H), 7.15-7.19 (m 5H), 13C NMR (101 MHz, CDCl3) δ 172.07, 170.41, 156.32, 136.69, 128.15, 127.79, 127.64, 80.70, 80.33, 77.54, 77.22, 76.90, 66.03, 64.91, 60.04, 53.62, 40.56, 29.93, 29.02, 27.97, 27.86, 27.73, 22.80, 20.71, 13.97. |
85% | With EDIAP In N,N-dimethyl-formamide at 55℃; | |
85% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 55℃; for 12h; | |
70% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 55℃; for 18h; Inert atmosphere; | |
65% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 55 - 60℃; Inert atmosphere; | 3 EXAMPLE 3 Synthesis of histidine tagged protein sensor based on thiazole orange (Figure 5, protein sensor 26) 2-(Bis-ter -butoxycarbonylmethyl-amino)-6-carboxyamino-hexanoic acid terf-butyl ester (23). [00118] 7rt-Butyl bromoacetate (1.59 mL, 10.8 mmol) and DIPEA (2.30 mL, 13.5 mmol) were added sequentially to a solution of N-benzyloxycarbonyl-L-lysine tert-butyl ester (21) (1.00 g, 2.7 mmol) in DMF (25 mL). The reaction mixture was purged with argon and then continuously stirred overnight at 55°C. The reaction mixture was evaporated in vacuum at 60°C. Hexane:ethylacetate (3:1, 15 mL) mixture was added to the partially solidified reaction mixture. The reaction mixture was filtered over a sintered glass funnel and the precipitate was washed three times with the same solvent (3 x 10 mL). The filtrate was concentrated under reduced pressure and purified by combiflash(9% hexane/ethylacetate). Yield: 0.572 g (65%).1HNMR (300 MHz, CDC13); 5=1.42 (s, 18 H), 1.44 (s, 9 H), 1.52 (m, 4H), 1.61 (m, 2H), 3.17 (m, 2H), 3.28 (t,J = 6 Hz, 1H), 3.44 (q,J = 18 Hz, 4 H), 5.07 (s, 2H), 5.13 (t, 1H), 7.33 (m, 5H). ES-MS (m/z): calcd.: 564.71, found: 587.36 (M+Na), 1151.69 (2M+Na). Benzyl deprotection was obtained by dissolving the intermediate (0.572 g, 1.01 mmol) in methanol (28.6 ml); the resulting solution was purged with argon followed by addition of 10% Pd/C (11 mg). The reaction mixture was stirred overnight under a H2 atmosphere at room temperature. Pd/C was removed by filtration over celite and the reaction mixture was evaporated under reduced pressure, yielding compound 23. Yield: 0.420 g(96%). 1NMR (300 MHz, CDC13); 5=1.42 (s, 18H), 1.44 (s, 9H), 1.52 (m, 4H), 1.64 (m, 2H), 2.55 (bs, 2H), 2.73 (t, J = 6 Hz, 2H), 3.31 (t, J = 6 Ηζ,ΙΗ), 3.47 (q,J = 14 Hz, 4H).ES-MS (m/z): calcd: 430.58, found: 431.35 (MH+), 453.36 (M+Na), 861.61 (2M+1), 883.61 (2M+ Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1% | With bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 21h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 85 percent / EDIPA / dimethylformamide / 12 h / 55 °C 2: 94 percent / H2 / Pd/C / methanol / 6 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 85 percent / EDIAP / dimethylformamide / 55 °C 2: 94 percent / H2 / Pd/C / methanol / 6 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 85 percent / EDIAP / dimethylformamide / 55 °C 2: 94 percent / Pd/C; H2 / methanol / 6 h / 20 °C |
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / acetonitrile / 15 h / Reflux 2: 10% palladium on activated carbon; hydrogen / methanol / 3 h / 23 °C / 760.05 Torr | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 55 - 60 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 18 h / 65 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 12 h / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 61.1 percent / PyBrop / dimethylformamide / 21 h / 20 °C 2: TFA; acetic acid / 3.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: 61.1 percent / PyBrop / dimethylformamide / 21 h / 20 °C 2.1: TFA; acetic acid / 3.5 h 3.1: WSC*HCl / dimethylformamide / 2.5 h 3.2: 14 mg / dimethylformamide; H2O / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: 61.1 percent / PyBrop / dimethylformamide / 21 h / 20 °C 2.1: TFA; acetic acid / 3.5 h 3.1: WSC*HCl / dimethylformamide / 2.5 h 3.2: 7 mg / dimethylformamide; H2O / 24 h / 20 °C 4.1: 100 percent / TFA; m-cresol; thioanisol / trimethylsilyl trifluoromethanesulfonate / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 61.1 percent / PyBrop / dimethylformamide / 21 h / 20 °C 2.1: TFA; acetic acid / 3.5 h 3.1: WSC*HCl / dimethylformamide / 2.5 h 3.2: 14 mg / dimethylformamide; H2O / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 61.1 percent / PyBrop / dimethylformamide / 21 h / 20 °C 2.1: TFA; acetic acid / 3.5 h 3.1: WSC*HCl / dimethylformamide / 2.5 h 3.2: 7 mg / dimethylformamide; H2O / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 85 percent / EDIAP / dimethylformamide / 55 °C 2: 94 percent / H2 / Pd/C / methanol / 6 h / 20 °C 3: 90 percent / TBTU; EDIAP / CH2Cl2 / 20 °C 4: 94 percent / H2 / Pd/C / methanol / 6 h / 20 °C | ||
Multi-step reaction with 4 steps 1: 85 percent / EDIAP / dimethylformamide / 55 °C 2: 94 percent / Pd/C; H2 / methanol / 6 h / 20 °C 3: 90 percent / TBTU; EDIAP / CH2Cl2 / 12 h / 20 °C 4: 94 percent / Pd/C; H2 / methanol / 6 h / 20 °C | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 55 - 60 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere 4: palladium 10% on activated carbon; hydrogen / methanol / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 85 percent / EDIAP / dimethylformamide / 55 °C 2: 94 percent / H2 / Pd/C / methanol / 6 h / 20 °C 3: 90 percent / TBTU; EDIAP / CH2Cl2 / 20 °C | ||
Multi-step reaction with 3 steps 1: 85 percent / EDIAP / dimethylformamide / 55 °C 2: 94 percent / Pd/C; H2 / methanol / 6 h / 20 °C 3: 90 percent / TBTU; EDIAP / CH2Cl2 / 12 h / 20 °C | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 55 - 60 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 77 percent / DMAP / 2-methyl-propan-2-ol / 12 h / 20 °C 2: 74 percent / HNO3 / CH2Cl2 / 2 h / 0 °C | ||
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 1.5 h / 20 °C 2: hydrogenchloride / ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: EDC; HOAt; DIEA / CH2Cl2 2: MeSO3H / methanol 3: EDC; DIEA / CH2Cl2 4: H2 / 10 percent Pd/C / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: EDC; HOAt; DIEA / CH2Cl2 2: MeSO3H / methanol 3: EDC; DIEA / CH2Cl2 4: H2 / 10 percent Pd/C / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: EDC; HOAt; DIEA / CH2Cl2 2: MeSO3H / methanol 3: EDC; DIEA / CH2Cl2 4: H2 / 10 percent Pd/C / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: EDC; HOAt; DIEA / CH2Cl2 2: MeSO3H / methanol 3: EDC; DIEA / CH2Cl2 4: H2 / 10 percent Pd/C / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 3.24 g / NEt3 / dimethylformamide / 44 h / 70 °C 2: 3.07 g / trifluoroacetic acid / 3 h / Ambient temperature 3: 4.25 g / N-methylmorpholine, diphenyl phosphorazidate / dimethylformamide / 18 h / Ambient temperature 4: 1.29 g / HBr/glacial acetic acid / Ambient temperature 5: 1.18 g / 1 N aq. NaOH / 16 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 3.24 g / NEt3 / dimethylformamide / 44 h / 70 °C 2: 3.07 g / trifluoroacetic acid / 3 h / Ambient temperature 3: 4.25 g / N-methylmorpholine, diphenyl phosphorazidate / dimethylformamide / 18 h / Ambient temperature 4: 1.29 g / HBr/glacial acetic acid / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 3.24 g / NEt3 / dimethylformamide / 44 h / 70 °C 2: 3.07 g / trifluoroacetic acid / 3 h / Ambient temperature 3: 4.25 g / N-methylmorpholine, diphenyl phosphorazidate / dimethylformamide / 18 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 3.24 g / NEt3 / dimethylformamide / 44 h / 70 °C 2: 3.07 g / trifluoroacetic acid / 3 h / Ambient temperature 3: 4.25 g / N-methylmorpholine, diphenyl phosphorazidate / dimethylformamide / 18 h / Ambient temperature 4: 1.29 g / HBr/glacial acetic acid / Ambient temperature 5: 1.0539 g / Bio-Rad AG 50W-X2 (100-mesh, hydrogen form) / H2O; pyridine; ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 3.24 g / NEt3 / dimethylformamide / 44 h / 70 °C 2: 3.07 g / trifluoroacetic acid / 3 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 73 percent / DCC 2: 567 mg / H2 / 10percent Pd/C / methanol / 4 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / 10percent Pd/C / methanol 2: 85 percent / subtilisin Carlsberg / 2-methyl-butan-2-ol / 24 h / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 73 percent / DCC 2: 567 mg / H2 / 10percent Pd/C / methanol / 4 h 3: 77 percent / subtilisin Carlsberg / 2-methyl-butan-2-ol / 38 h / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 28 percent / K2CO3 / acetonitrile / 18 h / Heating 2: 91 percent / pyridine / tetrahydrofuran / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 28 percent / K2CO3 / acetonitrile / 18 h / Heating 2: 91 percent / pyridine / tetrahydrofuran / 2 h 3: 100 percent / 4 M HCl / dioxane / -5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine for 12h; | XXII To improve the solubility of the copolymers at higher pH, acidic moieties were included in the following hydrophilic polymer design. For this purpose, Scheme XXII below shows the synthesis of a KK monomer that has a cleavable acid group: EPO Reaction Conditions: i) EDC, HOBt5 DIPEA, 12h, 90% yield. ii) Pd/C, 2 equiv. TFA, 12 h, 95% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.1 gm (78%) | With pyridine; sodium hydrogencarbonate; trifluoroacetic anhydride In tetrahydrofuran | IV EXAMPLE IV To a solution containing 20.1 gms (59.7 mmol) of compound (IV-A) and 4.80 ml (59.3 mmol) of pyridine in 150 ml of dry tetrahydrofuran at -5° C. and under an atmosphere of nitrogen was added dropwise over a 15 minute period 8.50 ml (60.2 mmol) of trifluoroacetic anhydride. The reaction mixture was slowly allowed to warm to room temperature. After 16 hours the mixture was concentrated in vacuo. The residue was taken up in ether and washed twice with 1.0N aqueous hydrochloric acid, twice with a saturated aqueous solution of sodium bicarbonate, and once with brine. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a solid which was recrystallized from ether/hexanes to give 20.1 gm (78%) of t-butyl Nε-benzyloxycarbonyl-Nα-trifluoroacetyl-L-lysinate (IV-B): mp 77°-79° C. |
20.1 gm (78%) | With pyridine; sodium hydrogencarbonate; trifluoroacetic anhydride In tetrahydrofuran | IV EXAMPLE IV To a solution containing 20.1 gms (59.7 mmol) of compound (IV-A) and 4.80 ml (59.3 mmol) of pyridine in 150 ml of dry tetrahydrofuran at -5° C. and under an atmosphere of nitrogen was added dropwise over a 15 minute period 8.50 ml (60.2 mmol) of trifluoroacetic anhydride. The reaction mixture was slowly allowed to warm to room temperature. After 16 hours the mixture was concentrated in vacuo. The residue was taken up in ether and washed twice with 1.0N aqueous hydrochloric acid, twice with a saturated aqueous solution of sodium bicarbonate, and once with brine. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a solid which was recrystallized from ether/hexanes to give 20.1 gm (78%) of t-butyl Nε-benzyloxycarbonyl-Nα-trifluoroacetyl-L-lysinate (IV-B): mp 77°-79° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.37 g | In 1,2-dichloro-ethane at 40℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.0 g | With N-ethyl-N,N-diisopropylamine In dichloromethane for 0.75h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; | |
87.5% | Stage #1: N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester With anhydrous sodium carbonate In dichloromethane for 1h; Reflux; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran; dichloromethane | |
With triethylamine In methanol for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester; bromoacetic acid With sodium hydroxide at 20 - 55℃; for 19h; Stage #2: With hydrogenchloride In water at 20℃; | 2; III Nε-benzyloxycarbonyl-L-lysine (I), 2 g (15.1 mmol), was dissolved in 25 mL of 1.5 MNaOH, to which was added dropwise a solution of bromoacetic acid (II), 4.15 g (30.2 mmol) in 15 mL of 1.5 M NaOH. The mixture was allowed to stand 16 h at room temperature and then heated at 55° C. for 3 h. The near neutral solution was cooled to room temperature and mixed with 4 M HCl (12 mL), whereupon copious white precipitate appears. The precipitate was filtered and washed with cold water, and dried in a desiccator containing NaOH pellets overnight. The dry crystals (2.5 g, 40% yield) showed correct structure (III) by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; for 16h; Inert atmosphere; | (9S,13S)-tri-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15 tricarboxylate (12): 11(1.0 g, 3.38 mmol, 1.0 equiv.) and triethylamine (1.54 mL, 11.09 mmol, 3.28 equiv.) were dissolved in dichloromethane (30 mL) and cooled to -78° C. Triphosgene (341 mg, 1.15 mmol, 0.34 equiv.) in dichloromethane (10 mL) was added dropwise to the reaction mixture. Upon complete addition, the reaction was allowed to warm to room temperature and stirred for 30 minutes. 12 (757 mg, 2.03 mmol, 0.6 equiv) was added, followed by the addition of triethylamine (283 μL, 2.03 mmol, 0.6 equiv.). The reaction was allowed to stir at room temperature overnight for 16 hours. The reaction was then diluted with dichloromethane (50 mL), and washed with water (100 mL×2). The crude mixture was dried over Na2SO4 and concentrated under reduced pressure. Column chromatography (Silica 1.5:1 hexane:ethyl acetate) yielded 4 (1.09 g, 86%) as a colorless oil with the following spectral characteristics: IR (thin film/KBr) 3342, 2976, 1731, 1650, 1552, 1454, 1368, 1255, and 1153 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J=3.75 Hz, 4H), 7.33-7.30 (m, 1H), 5.10 (d, J=4.55 Hz, 2H), 5.06-5.01 (m, 2H), 4.99 (s, 1H), 4.34-4.31 (m, 2H), 3.20-3.18 (m, 2H), 2.36-2.23 (m, 2H), 2.10-2.03 (m, 1H), 1.88-1.75 (m, 2H), 1.65-1.57 (m, 1H), 1.57-1.45 (m, 2H), 1.453 (s, 9H), 1.446 (s, 9H), 1.43 (s, 9H), 1.40-1.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 172.6, 172.5, 172.2, 136.8, 128.6, 128.5, 128.2, 82.2, 82.0, 80.7, 66.7, 53.4, 53.2, 40.7, 32.8, 31.7, 29.4, 28.5, 28.2, 28.1, 22.3; HRMS (EI+) m/z 622.3695 [calc'd for C32H51N3O9 (M+H)+ 622.3698]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: bis(trichloromethyl) carbonate; 2-[2-(tert-butoxycarbonyl)hydrazino]benzoic acid benzyl ester With 4-methyl-morpholine In dichloromethane at -10℃; for 1h; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester In dichloromethane at -10 - 20℃; for 22h; | 1.c c) To a solution of 250 mg of hydrazinoester (IVA.1) (0.73 mmol, 1 eq.) in distilled DCM (4 mL/mmol) is added 0.35 eq. of triphosgene. The temperature of the reaction medium is reduced to -10° C. and a solution of NMM (1.08 eq.) in distilled DCM (0.5 mL/mmol) is then introduced. The reaction medium is stirred at -10° C. for 1 hour. 270 mg of H-Lys(Z)-OtBu (0.73 mmol, 1 eq.) and a solution of NMM (1.08 eq.) in distilled DCM (0.5 mL/mmol) are then added. The temperature is maintained for 2 hours at -10° C. and then gradually warmed to room temperature. After 20 hours at room temperature, the medium is diluted by adding DCM (30 mL/mmol of hydrazinoester) and then filtered. The organic phase is washed with 0.5M KHSO4 solution and then with water, dried over sodium sulfate, filtered and evaporated. Purification of the crude product is performed by flash chromatography on silica gel, eluting with an EtOAc/P.E. mixture (1/2 by volume). 250 mg of a yellow oil are obtained (yield 45%).1H NMR 300 MHz (CDCl3): δ (ppm)=0.87 (m, 2H, CH2-CHα); 1.44 (s, 9H, C(CH3)3); 1.48 (s, 9H, C(CH3)3); 1.7 (m, 4H, CH2-(CH2)2-CH2); 3.18 (m, 2H, CH2-NHZ); 4.46 (m, 1H, CHα); 5.02 (s, broad, 1H, NH); 5.08 (s, 2H, CH2-C6H5); 5.36 (s, 2H, CH2-C6H5); 6.12 (s, broad, 1H, NH); 7.12 (s, broad, 1H, NH); 7.38-8.2 (m, 14H, Harom).13C NMR 75 MHz (CDCl3): δ (ppm)=11.37; 14.61; 21.45; 22.39; 28.42; 29.6; 30.1; 33.1; 41.19; 53.92; 60.78; 66.83; 67.58; 77.1; 77.53; 77.73; 77.95; 82.27; 127.6; 128.36; 128.44; 128.65; 128.75; 128.85; 129.1; 132.01; 133.98; 135.8; 137.18; 141.64; 155.08; 156.61; 156.86; 166.13; 171.53; 172.13.IR (NaCl) : νNH=3349.2 cm-1; νCsp2-H=3066.1 cm-1 and 3033.8 cm-1; νCsp3-H=2978.3 cm-1 and 2934.1 cm-1; νCO=1725.6 cm-1, 1713.6 cm-1, 1700.9 cm-1 and 1681.7 cm-1; νCC=1599.8 cm-1 and 1578.2 cm-1.[α]D25° C.=+1.68° (16.8 g.L-1, DCM).HRMS-ESI (m/z): [M+Na] calc. for C38H48N4O9, 727.3319; exp., 727.3324. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With calcium(II) trifluoromethanesulfonate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: bis(trichloromethyl) carbonate; L-glutamic acid di-tert-butyl ester hydrochloride With triethylamine In dichloromethane at -78 - 20℃; for 0.5h; Stage #2: N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester With triethylamine In dichloromethane at 20℃; for 12h; | {9S 13S)-tri-tert-btttyI 3 l~dioxo-l-phei>yl-2-o:xa-4,ie,12-trtazapeiitad caie-9, 13,15- cteHw -"^ co:(.& trica r boxy la te (12): 1 .1 (1.0g, 3.38 mtaai, 1.0 equiv.) ami triethylamine f f ( (1 .54 fflL, 1 1.09 mmoU 3.28 equiv.) were dissolved in dichloromethane n (30 mL) and cooled to -78' C, Triphosgeiie i'341 tag, 1.15 mmol, 0,34 equiv.) in dichloromethane (10 mL) was added clropwtse to the reaction mixture. Upon complete addition, the reaction was allowed to warm to room temperature and stirred for 30 minutes. 12 (757 mg, 2.03 mmol, 0.6 equiv) was added, followed by the addition of riethyamine (283 pjL, 2.03 mmo'l, 0,6 equiv.). The reaction was allowed to stir at room temperature overnight for 1 hours. The reaction was then diluted with dichloromethane (50 mL), and washed with water (1.00 mL x. 2). The crude mixture was dried over Na?SQt and concentrated under reduced pressure. Column chromatography (Silica 1 .5:1 hexane: ethyl acetate) yielded 4 (1 .09g, 86%) as a colorless oil with the following spectral characteristics: IR (thin film/ Br) 3342 . 2976 , 1731 5 1650 , 1552 . 1454 , 1368 , 1255 , and 1153 cm" 5; lH NMR (500 MHz, CD() δ 7.35 ( 9H), 1.40-1.30 |
68.5% | Stage #1: bis(trichloromethyl) carbonate; N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2.5h; Stage #2: L-glutamic acid di-tert-butyl ester hydrochloride In dichloromethane for 12h; | 2.2.9. Synthesis of (S)-2-[3((S)-(5-Benzyloxycarbonylamino)-1-tertbutoxycarbonylpent-ylureido]pentanedioic acid Di-tert-butyl ester (9) In a round-bottom flask triphosgene (0.58 g, 2 mmol) was suspendedin DCM (20 mL) and stirred at 0 C. A solution of Cbz-Lys-OtBu (1.82 g,5.4 mmol) and DIPEA (2.1 mL, 12 mmol) in DCM (20 mL) was addeddropwise to the triphosgene solution over 2.5 h. A solution of L-glutamicacid di-tert-butyl ester hydrochloride (1.6 g, 5.4 mmol) containingDIPEA (2.1 mL, 12 mmol) and DCM (20 mL) was then added in oneportion and allowed to stir for 12 h. The mixture was concentrated todryness, diluted with 150 mL of ethyl acetate, washed with 2 N NaHSO4(2 × 200 mL), brine (150 mL), and dried over sodium sulfate to yield ayellow oil. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give 9 (2.35 g, 3.7 mmol, 68.5%) as colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 5H), 5.40-5.27 (m, 3H), 4.98(q, J = 12 Hz, 2H), 4.23 (d, J = 16 Hz, 2H), 3.05 (dp, 2H), 2.22-2.09 (m,3H), 1.97-1.59 (m, 4H), 1.32 (d, J = 8 Hz, 27H). 13C NMR (101 MHz,CDCl3) δ 172.87, 172.58, 172.40, 172.34, 172.17, 157.12, 156.66,136.75, 128.43, 128.01, 127.94, 82.13, 81.97, 81.58, 80.45, 66.45,53.45, 53.26, 52.98, 52.85, 40.69, 32.61, 31.57, 29.33, 28.42, 28.32,28.06, 28.00, 27.98, 22.37. TOF-HRMS calculated for C32H52N3O9,[M+H]+ m/z 622.3698, found 622.3690. |
68.5% | Stage #1: bis(trichloromethyl) carbonate; N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2.5h; Stage #2: L-glutamic acid di-tert-butyl ester hydrochloride In dichloromethane for 12h; | 2.2.9. Synthesis of (S)-2-[3((S)-(5-Benzyloxycarbonylamino)-1-tertbutoxycarbonylpent-ylureido]pentanedioic acid Di-tert-butyl ester (9) In a round-bottom flask triphosgene (0.58 g, 2 mmol) was suspendedin DCM (20 mL) and stirred at 0 C. A solution of Cbz-Lys-OtBu (1.82 g,5.4 mmol) and DIPEA (2.1 mL, 12 mmol) in DCM (20 mL) was addeddropwise to the triphosgene solution over 2.5 h. A solution of L-glutamicacid di-tert-butyl ester hydrochloride (1.6 g, 5.4 mmol) containingDIPEA (2.1 mL, 12 mmol) and DCM (20 mL) was then added in oneportion and allowed to stir for 12 h. The mixture was concentrated todryness, diluted with 150 mL of ethyl acetate, washed with 2 N NaHSO4(2 × 200 mL), brine (150 mL), and dried over sodium sulfate to yield ayellow oil. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give 9 (2.35 g, 3.7 mmol, 68.5%) as colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 5H), 5.40-5.27 (m, 3H), 4.98(q, J = 12 Hz, 2H), 4.23 (d, J = 16 Hz, 2H), 3.05 (dp, 2H), 2.22-2.09 (m,3H), 1.97-1.59 (m, 4H), 1.32 (d, J = 8 Hz, 27H). 13C NMR (101 MHz,CDCl3) δ 172.87, 172.58, 172.40, 172.34, 172.17, 157.12, 156.66,136.75, 128.43, 128.01, 127.94, 82.13, 81.97, 81.58, 80.45, 66.45,53.45, 53.26, 52.98, 52.85, 40.69, 32.61, 31.57, 29.33, 28.42, 28.32,28.06, 28.00, 27.98, 22.37. TOF-HRMS calculated for C32H52N3O9,[M+H]+ m/z 622.3698, found 622.3690. |
Stage #1: bis(trichloromethyl) carbonate; L-glutamic acid di-tert-butyl ester hydrochloride With triethylamine In dichloromethane at -78℃; Stage #2: N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / -78 °C 2: hydrogen; palladium 10% on activated carbon / methanol / 20 °C | ||
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.5 h / -78 - 20 °C 1.2: 12 h / 20 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / 13 h | ||
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.5 h / 20 °C 1.2: 16 h / 20 °C 2.1: palladium on activated charcoal; hydrogen / ethyl acetate / 16 h / 20 °C / 760.05 Torr |
Multi-step reaction with 2 steps 1.1: bis(trichloromethyl) carbonate; triethylamine / dichloromethane / 3 h / 0 °C 1.2: 20 °C 2.1: hydrogen; palladium on activated charcoal / methanol | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2.5 h / 0 °C 1.2: 12 h 2.1: hydrogen; palladium 10% on activated carbon; ammsnium formate / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.4 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.49 g | With 2,4,6-trimethyl-pyridine; HATU In N,N-dimethyl-formamide at 20℃; for 0.666667h; | 1.a Step a) Preparation of fMLF-(N-Z-Lysine) tert-Butyl Ester A solution of N-Z-Lysine tert-butyl ester 0.852 g, 2.29 mmol) and fMLF (1.00 g, 2.29 mmol) in DMF (20 mL) was charged with HATU (0.869 g, 2.29 mmol) and 2,4,6-collidine (0.554 g, 4.57 mmol). After stirring at room temperature for 40 mm, the reaction was diluted with EtOAc (200 mL) and washedsequentially with saturated LiCI (3 x 50 mL), saturated NaHCO3 (2 x 50 mL), and saturated NaCI (2 x 50mL), then dried over Na2504, filtered, and concentrated under reduced pressure. The crude product waschromatographed on a 40 g Isco RediSep silica cartridge eluting with a gradient from 100% heptane to100% EtOAc, and then to 100% MeOH Yield: 1.49 gas a white solid. 1H NMR (400 MHz, Chloroform-ceo ppm 0.84 (d, J=5.22 Hz, 3 H) 0.87 (d, J=6.20 Hz, 3 H) 1.20 - 2.06 (m, 9 H) 1 .44 (s, 9 H) 2.08 (s, 3 H)2.50 (t, J=7.35 Hz, 2 H) 2.81 (s, 1 H) 2.92 - 3.37 (m, 4 H) 4.30 - 4.75 (m, 4 H) 5.04 - 5.19 (m, 2 H) 5.22 -5.29 (m, 1 H) 6.32-6.52 (m, 1 H) 6.74 (d, J=7.13 Hz, 1 H) 6.83-7.00 (m, 2 H) 7.10-7.47 (m, 10 H) 7.69- 7.85 (m, 1 H) 8.04 - 8.20 (m, 1 H). MS (M+H) 756.2. |
1.49 g | With 2,4,6-trimethyl-pyridine; 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 0.666667h; | 1.a Step a) Preparation of fMLF-(NE-Z-Lysine) ferf-Butyl Ester Step a) Preparation of fMLF-(NE-Z-Lysine) ferf-Butyl EsterA solution of NE-Z-Lysine ferf-butyl ester 0.852 g, 2.29 mmol) and fMLF (1 .00 g, 2.29 mmol) in DMF (20 mL) was charged with HATU (0.869 g, 2.29 mmol) and 2,4,6-collidine (0.554 g, 4.57 mmol). After stirring at rt for 40 min, the reaction was diluted with EtOAc (200 mL) and washed sequentially with saturated LiCI (3 x 50 mL), saturated NaHC03 (2 x 50 mL), and saturated NaCI (2 x 50 mL), then dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was then chromatographed on a 40 g Isco RediSep silica cartridge eluting with a gradient from 1 00% heptane to 100% EtOAc, and then to 1 00% MeOH Yield: 1 .49 g as a white solid. 1 H NM R (400 MHz, Chloroform-d) δ ppm 0.84 (d, J=5.22 Hz, 3 H) 0.87 (d, J=6.20 Hz, 3 H) 1 .20 - 2.06 (m, 9 H) 1 .44 (s, 9 H) 2.08 (s, 3 H) 2.50 (t, J=7.35 Hz, 2 H) 2.81 (s, 1 H) 2.92 - 3.37 (m, 4 H) 4.30 - 4.75 (m, 4 H) 5.04 - 5.19 (m, 2 H) 5.22 - 5.29 (m, 1 H) 6.32 - 6.52 (m, 1 H) 6.74 (d, J=7.13 Hz, 1 H) 6.83 - 7.00 (m, 2 H) 7.1 0 - 7.47 (m, 10 H) 7.69 - 7.85 (m, 1 H) 8.04 - 8.20 (m, 1 H). MS (M+H) 756.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
452 mg | With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; | 1.a Step a) Preparation of tert-Butyl Ester N-Z-Lysine tert-butyl ester (300 mg, 0.81 mmoles) and FMOC-OSu (299 mg, 0.89 mmoles, 1.1 eq) were dissolved in 3mL dry DMF and TEA (112 jiL, 0.81 mmoles, 1 eq) was added. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with 10% aqueous LiCI and extracted 3times with 10% heptanes in ethyl acetate. The organic extractions were combined and back extracted with 10% aqueous LiCI. The organic solution was dried over sodium sulfate, filtered, and evaporated. Yield 519 mg. Target Yield 452 mg. LC/MS, 559.0 [M÷H]. 1H NMR d6-DMSO is consistent with the desired product and indicated trace amounts of DMF and ethyl acetate. 1H NMR (400 MHz, DMSO-d6) ö ppm 1.38 (s, 10 H) 1.50-1.72 (m, 1 H) 2.92-3.05 (m, 1 H) 3.79-3.90 (m, 1 H) 4.16-4.25 (m, 1 H) 4.26-4.33 (m, 1 H) 5.00 (s, 1 H) 7.20 - 7.26 (m, 1 H) 7.29 - 7.37 (m, 7 H) 7.41 (s, 2 H) 7.59 - 7.66 (m, 1 H)7.72 (d, J=7.42 Hz, 2 H) 7.89 (d, J=7.42 Hz, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (S)-2-[(imidazole-1-carbonyl)amino]pentanedioic acid di-tert-butyl ester With triethylamine; methyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester In 1,2-dichloro-ethane at 40℃; | 5.2.2. Tri-tert-butyl (9S,13S)-3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate (4) 2 (780 mg, 2.208 mmol) was dissolved in EtCl2 (7.8 mL) andcooled to 0 C. Triethylamine (0.615 mL, 4.417 mmol) and MeOTf(0.252 mL, 2.230 mmol) were added to the solution and stirredfor 30 min at room temperature. (S)-tert-butyl 2-amino-6-(((benzyloxy)carbonyl)amino)hexanoate (743 mg, 2.208 mmol) wasadded to the reaction mixture. The mixture was heated to 40 Cand stirred overnight. After the reaction was complete, the solventwas evaporated under reduced pressure. The compound was solidifiedwith diethylether and n-hexane. Finally, compound 4 wasobtained as a white solid. Yield: 1.18 g, 86%. MS (ESI+), (M+H)+calcd for C32H51N3O9, 622.36; found 622. |
80% | With triethylamine In 1,2-dichloro-ethane at 0 - 40℃; | 8 tBuO-L-Glu(OtBu)-u-L-Lys(Cbz)-OtBu (VIII) A solution of (S)-di-ferf-butyl 2-(1 H-imidazole-1-carboxamido)pentanedioate (V) (3.57 g, 10.1 mmol, 1 .0 eq.) in DCE (45 mL) was cooled to 0°C and TEA (2.82 mL, 20.2 mmol, 2.0 eq.) as well as H-L-l_ys(Cbz)-OiBu-HCI (4.14 g, 1 1.1 mmol, 1.1 eq.) were added under stirring. The reaction mixture was heated to 40°C overnight, subsequently washed with water (45 mL) and sat. aq. NaCI (45 mL), dried over MgSC , filtered, and concentrated in vacuo. The resulting crude product was purified by flash column chromatography (silica, 40% EtOAc in n-hexane, v/v) affording VIII (5.04 g, 8.11 mmol, 80%) as a colourless oil. |
78% | Stage #1: (S)-2-[(imidazole-1-carbonyl)amino]pentanedioic acid di-tert-butyl ester With triethylamine; methyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0℃; for 0.75h; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester In 1,2-dichloro-ethane at 40℃; for 2h; | Preparation of Cbz-Lys ureido Glu tris-t-butyl ester (PSMA4) Preparation of Cbz-Lys ureido Glu tris-t-butyl ester (PSMA4)To an ice cold solution of glutamic di-tert-butyl ester (1 .06 g, 3.58 mmol), DMAP (27 mg), and TEA (1 .25 m L, 8.95 mmol) in CH2CI2 (10.0 mL) was added CDI (638 mg, 3.94 mmol) in one portion. After 30 min, the reaction was removed from the ice bath and stirred overnight. The reaction was diluted with CH2CI2 and washed with sat. NaHC03 (aq.), water, and brine. After drying over Na2S04, the organic layer was concentrated in vacuo and dried under high vacuum to give PSMA2. A solution of PSMA2 in DCE (10 m L) was cooled to 0 °C and treated sequentially with MeOTf (0.59 g, 3.58 mmol) and TEA (1 .00 mL, 7.16 mmol). After 45 min, Cbz-Lys t- butyl ester PSMA3 (1 .34 g, 3.58 mmol) in DCE (2 mL) was added, and the mixture was heated to 40 °C. After 2 h, the reaction was diluted with CH2CI2 and washed with sat. NaHC03 (aq.), water, and brine. The organic layer was dried over Na2S04 and concentrated in vacuo to thick syrup. The crude material was purified through Si02 gel chromatography to afford PSMA4 (1 .73 g, 78%) as a white foam. AP-ESI+ Mass calcd C32H5i N309: 621 .36, Found: 622.4 [M+H]+, 644.4 [M+Na]+ |
78% | Stage #1: (S)-2-[(imidazole-1-carbonyl)amino]pentanedioic acid di-tert-butyl ester With triethylamine; methyl trifluoromethanesulfonate In trans-1,2-dichloroethylene at 0℃; for 0.75h; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester In trans-1,2-dichloroethylene at 40℃; for 2h; | Preparation of Cbz-Lys ureido Glu tris-t-butyl ester (PSMA4). To an ice cold solution of glutamic di-tert-butyl ester (1 .06 g, 3.58 mmol), DMAP (27 mg), and TEA (1 .25 ml_, 8.95 mmol) in CH2CI2 (10.0 mL) was added CDI (638 mg, 3.94 mmol) in one portion. After 30 min, the reaction was removed from the ice bath and stirred overnight. The reaction was diluted with CH2CI2 and washed with sat. NaHC03 (aq.), water, and brine. After drying over Na2S04, the organic layer was concentrated in vacuo and dried under high vacuum to give PSMA2. A solution of PSMA2 in DCE (10ml_) was cooled to 0 °C and treated sequentially with MeOTf (0.59 g, 3.58 mmol) and TEA (1 .00 mL, 7.16 mmol). After 45 min, Cbz-Lys t- butyl ester PSMA3 (1 .34 g, 3.58 mmol) in DCE (2 mL) was added, and the mixture was heated at 40 °C. After 2 h, the reaction was diluted with CH2CI2 and washed with sat. NaHCCb (aq.), water, and brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford a thick syrup. The crude material was purified through S1O2 gel chromatography to afford PSMA4 (1 .73 g, 78%) as a white foam. AP-ESI+ Mass calcd C32H51 N3O9: 621 .36, Found: 622.4 [M+H]+, 644.4 [M+Na]+ |
1.73 g | Stage #1: (S)-2-[(imidazole-1-carbonyl)amino]pentanedioic acid di-tert-butyl ester With triethylamine; methyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0℃; for 0.75h; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester In 1,2-dichloro-ethane at 40℃; for 2h; | 1.PSMA4 Preparation of Cbz-Lys ureido Glu tris-t-butyl ester (PSMA4). To an ice cold solution of glutamic di-tert-butyl ester (1.06 g, 3.58 mmol), DMAP (27 mg), and TEA (1.25 mL, 8.95 mmol) in CH2CI2 (10.0 mL) was added CDI (638 mg, 3.94 mmol) in one portion. After 30 min, the reaction was removed from the ice bath and stirred overnight. The reaction was diluted with CH2CI2 and washed with sat. NaHC03 (aq ), water, and brine. After drying over Na2S04, the organic layer was concentrated in vacuo and dried under high vacuum to give PSMA2. A solution of PSMA2 in DCE (10mL) was cooled to 0 °C and treated sequentially with MeOTf (0.59 g, 3.58 mmol) and TEA (1.00 mL, 7.16 mmol). After 45 min, Cbz-Lys t- butyl ester PSMA3 (1.34 g, 3.58 mmol) in DCE (2 mL) was added, and the mixture was heated at 40 °C. After 2 h, the reaction was diluted with CH2CI2 and washed with sat. NaHC03 (aq.), water, and brine. The organic layer was dried over Na2S04 and concentrated in vacuo to afford a thick syrup. The crude material was purified through Si02 gel chromatography to afford PSMA4 (1.73 g, 78%) as a white foam. AP-ESI+ Mass calcd C32H51N309: 621.36, Found: 622.4 [M+H]+, 644.4 [M+Na]+ |
733.7 mg | Stage #1: (S)-2-[(imidazole-1-carbonyl)amino]pentanedioic acid di-tert-butyl ester With triethylamine; methyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 0℃; for 0.5h; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester In 1,2-dichloro-ethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 55℃; Inert atmosphere; | di-tert-butyl 2,2'-((6-(((benzyloxy)carbonyl)amino)-1-(tert-butoxy)-1-oxohexan-2-yl)azanediyl)diacetate t-butyl bromo acetate (2.39ml, 16mmol) and DIPEA (3.5ml, 20mmol) were added to a solution of N-benzyloxycarbonyl-L-lysine tert-butyl ester (1.5g, 4.02mmol) in 25ml DMF. The reaction was purged with argon and then heated to 55 °C and stirred overnight. The excess solvent was removed under high vacuum and 15ml hexane:ethyl acetate 3:1 was added to the solidified mixture. The mixture was filtered over sinter glass and washed with the same solvent (3X10ml). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (80:20 hexane/EtOAc) to yield the purified product (2.2g, 97% yield). 1H NMR (CDCl3, 300 MHz): δ 1.44 (s, 18H); 1.47 (s, 9H); 1.50 (m, 2H); 1.54 (m, 2H); 1.65 (m, 2H); 3.21 (m, 2H); 3.31 (t, J=6Hz, 1H); 3.46 (dd, 4H); 5.09 (s, 2H); 7.33 (s, 5H). ES-MS (m/z): Calcd: 564.34; Found: 587.32 (M+Na). |
11.62 g | With sodium hydrogencarbonate In acetonitrile for 15h; Inert atmosphere; Reflux; | Di-t-butyl 2,2'-((6-(((benzyloxy)carbonyl)amino)-1-(t-butoxy)-1-oxohexan-2-yl)azanediyl)diacetate (3) HClO4 (3.01 mL) was slowly added to a stirred solution of Z-Lys 1 (6.5 g, 23.18 mmol) in t-butyl acetate (80 mL). The mixture was stirred at 22° C. for 14 h before extracting with H2O (150 mL) and 0.5N HCl solution (150 mL). The combined aqueous solutions were treated with 10% K2CO3 to give a solution of pH 9; the basic solution was then extracted with CH2Cl2 (3*100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and then concentrated to give 2 as a colorless oil. The oil was dissolved in CH3CN (150 mL) before addition of NaHCO3 (4.29 g, 51.07 mmol) and t-butyl bromoacetate (13.58 g, 69.64 mmol). The mixture was heated at reflux for 15 h, then cooled to 22° C. before concentration of the mixture under reduced pressure and extraction of the residue with ethyl acetate (2*150 mL). The combined organic layers were washed with saturated NaCl solution (2*100 mL), dried over anhydrous MgSO4, and evaporated. The crude residue was purified by silica gel flash chromatography using 4:1 hexane:EtOAc as eluent to give compound 3 (11.62 g, 91%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.30-7.35 (m, 5H), 5.08 (s, 2H), 3.44 (dd, J=17.4, 11.1 Hz, 4H), 3.30 (t, J=7.35 Hz, 1H), 3.20 (m, 2H), 1.62 (m, 2H), 1.53 (m, 4H), 1.45 (s, 9H), 1.43 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 172.2, 171.2, 157.0, 137.34, 128.9, 128.6, 128.4, 81.64, 81.2, 66.9, 65.6, 54.4, 41.3, 30.6, 29.8, 28.7, 28.6, 23.5; HRMS (ESI): (M+H)+m/z calc'd for C30H48N2O8=564.7107. found 565.0643. The NMR spectra are in agreement with previously published data. (Huang et al., Bioconjugate Chem. 2006, 17, 1592-1600). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
519 mg | With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; | 1.a Step a) Preparation of Na-F OC-NE-Z-Lysine tert-Butyl Ester Step a) Preparation of Na-F OC-NE-Z-Lysine tert-Butyl EsterNE-Z-Lysine tert-butyl ester (300 mg, 0.81 mmoles) and FMOC-OSu (299 mg, 0.89 mmoles, 1 .1 eq) were dissolved in 3ml_ dry DM F and TEA (1 12 μΙ_, 0.81 mmoles, 1 eq) was added. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with 1 0% aqueous LiCI and extracted 3 times with 10% heptanes in ethyl acetate. The organic extractions were combined and back extracted with 10% aqueous LiCI. The organic solution was dried over sodium sulfate, filtered, and evaporated. Yield 51 9 mg. Target Yield 452 mg. LC/MS, 559.0 [M+H]+. 1 H NM R d6-DMSO is consistent with the desired product and indicated trace amounts of DMF and ethyl acetate. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .38 (s, 10 H) 1 .50 - 1 .72 (m, 1 H) 2.92 - 3.05 (m, 1 H) 3.79 - 3.90 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.26 - 4.33 (m, 1 H) 5.00 (s, 1 H) 7.20 - 7.26 (m, 1 H) 7.29 - 7.37 (m, 7 H) 7.41 (s, 2 H) 7.59 - 7.66 (m, 1 H) 7.72 (d, J=7A2 Hz, 2 H) 7.89 (d, J=7.42 Hz, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,6-dimethylpyridine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With triethylamine In N,N-dimethyl acetamide at 100℃; for 12h; | Synthesis of N-(2-acetamidopurin-6-yl)substituted amino-acid tert-butyl esters 3a-h (general procedure). General procedure: Amino acid tert-butyl ester hydrochloride or hydrogen acetate (3.0 mmol,3 equiv.) and TEA (0.56 mL, 4.0 mmol) were added to a suspension of 2-acetamido-6-chloropurine (1) (0.212 g, 1.0 mmol) in DMA (2.5 mL). When amino acid tert-butyl esters were used as free bases (3 equiv.), the amount of TEA was decreased to 1 equiv. The mixture was allowed to stand at 100 C for 12 h and quenched with water (25 mL), a precipitate formed was separated and dried in vacuo. Compounds 3a, 3b, and 3e were isolated by recrystallization, 3c, 3d, and 3f-h by flash chromatography onsilica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | DCE was cooled to -78 (70mL) L-Glu (OBn) -OtBu hydrochloride in(3.13mg, 9.49mmol) and triphosgene (923mg, 3.13mmol) triethylamine undernitrogen soluble, including (2 .80mL) was added. After the mixture was stirredfor 2 hours at -78 , was L-Lys in DCE (10mL) (Z) -OtBu (3.88g, 10.40mmol) asolution containing and TEA (1.5mL) was added. The mixture period of 1 hour,then allowed to come to room temperature and stirred overnight at roomtemperature. The reaction was quenched with 1N HCl, and extracted with DCM. Theorganic layer was dried and concentrated under reduced pressure, the residuewas purified using Biotage SP4, (9S, 13S) -15- benzyl 13,9- di tert- methyl3,11- dioxo-1-phenyl - 2-oxa -4,10,12- triazacyclononane pentadecane -9,13,15-bird carboxylate as a colorless oil (4.71g, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: L-glutamic acid di-tert-butyl ester hydrochloride; 4-Nitrophenyl chloroformate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Inert atmosphere; | EC1380 In a dry flask, H-Glu(0u)-0u.HCl (2.48g , 8.41 mmol) and 4-nitrophenyl chloroformate (1.86 g, 9.25 mmol, 1.1 eq) were added, dissolved in CH2CI2 (30ml) under Argon atmosphere. The stirring solution was chilled to 0 °C, followed by the dropwise addition of DIPEA (4.50 ml, 25.2 mmol, 3 eq). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. To the stirring solution was added H-Lys-(Z)-0u (4.39 g, 11.8 mmol, 1.4 eq), DIPEA (4.50 ml, 25.2 mmol, 3 eq) and stirred for 1 hr. Upon completion, the reaction was quenched with saturated NaHCC and extracted with CH2CI2 three times. The organic extracts were combined, dried over Na2S04, filtered and the solvent was removed via reduced pressure. The product was purified using silica gel chromatography with petroleum ether and ethyl acetate. The Cbz protected amine was transferred to a round bottom flask with 10% Pd/C (10% wt eq), dissolved in MeOH (30 ml) under Hydrogen atmosphere (latm) and stirred for 3 hr. Upon completion, the reaction mixture was filtered through celite and the solvent was removed via reduced pressure to yield the crude amine. The amine was taken up in CH2CI2 (30ml) under Argon atmosphere and chilled to 0 °C. To the chilled solution was added 4-nitrophenyl chloroformate (2.2 g, 10.9 mmol, 1.3 eq) and DIPEA (6.0 ml, 33.6 mmol, 4 eq) subsequently and stirred for 2 hr at room temperature. The reaction mixture was quenched with saturated NH4CI and extract three times with ethyl acetate. The organic extracts were combined, dried over Na2S04, filtered, and solvent was removed under vacuum and purified using silica gel chromatography to yield the desired activated amine, EC1380 (2.54 g, 46%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Step 1. (9S,13S)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate To a solution of L-Glu(OBn)-OtBu hydrochloride (3.13 mg, 9.49 mmol) and triphosgene (923 mg, 3.13 mmol) in DCE (70 mL) cooled to -78 C was added triethylamine (2.80 mL) under nitrogen. After stirring at -78 C for 2 h, a solution of L-Lys(Z)-OtBu (3.88 g, 10.40 mmol) and TEA (1.5 mL) in DCE (10 mL) was added. The mixture was allowed to come to room temperature over a period of 1 h and stirred at room temperature overnight. The reaction was quenched with IN HCl, and extracted with DCM. The organic layer was dried and concentrated under reduced pressure and the residue was purified utilizing a Biotage SP4 to afford (9S,13S)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate as a colorless oil (4.71 g, 76%). 1H NMR (400 MHz, CDCl3) delta 7.34-7.29 (m, 10H), 5.13-5.04 (m, 6H), 4.97 (brs, 1H), 4.38-4.28 (m, 2H), 3.18-3.14 (m, 2H), 2.50-2.35 (m, 2H), 2.19-2.10 (m, 1H), 1.94-1.85 (m, 1H), 1.79-1.72 (m, 1H), 1.58-1.33 (m, 21H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 24 h / 55 °C / Inert atmosphere 2: trifluoroacetic acid; triethylsilane / dichloromethane / 5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 20℃; for 16.0h; | NaHCO3 (0.41 g, 4.83 mmol) was added to a mixture of <strong>[843666-34-2]1-tert-butyl 18-(2,5-dioxopyrrolidin-1-yl) octadecanedioate</strong> (29) (1.13 g, 2.416 mmol), and Lys(Nepsilon-CBZ)-OtBu hydrochloride (1.17 g, 3.14 mmol) in DME (60 mL) and water (20 mL). The resulting light suspension was stirred at RT overnight. DME was removed under vacuum, and then aqueous HCl (1 M, 4.83 mL, 4.83 mmol) was added to adjust the pH to 2-3. The mixture was extracted with EtOAc (200 mL, 100 mL*2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated under vacuum and subjected to flash chromatography eluting with EtOAc/CH2Cl2 to afford (S)-tert-butyl 18-((6-(((benzyloxy)carbonyl)amino)-1-(tert-butoxy)-1-oxohexan-2-yl)amino)-18-oxooctadecanoate (30) (1.66 g, 2.42 mmol, 100% yield) as a colorless, viscous liquid. 1H-NMR (400 MHz, CDCl3) delta ppm 7.29-7.38 (m, 5H), 6.08 (br d, J=7.34 Hz, 1H), 5.06-5.19 (m, 2H), 4.84-5.02 (m, 1H), 4.48 (td, J=7.70, 5.14 Hz, 1H), 3.07-3.27 (m, 2H), 2.15-2.24 (m, 4H), 1.75-1.88 (m, 1H), 1.49-1.70 (m, 7H), 1.46 (s, 9H), 1.44 (s, 9H), 1.20-1.34 (m, 26H). 13C-NMR (101 MHz, CDCl3) delta ppm 173.30, 172.87, 171.81, 171.05, 156.49, 136.67, 128.47, 128.03, 82.03, 79.82, 66.55, 60.35, 52.24, 40.66, 36.65, 35.64, 32.35, 29.67, 29.64, 29.61, 29.50, 29.48, 29.44, 29.33, 29.29, 29.10, 28.13, 28.00, 25.63, 25.13, 22.25, 21.00, 14.19. [MH]+ 689.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: bis(trichloromethyl) carbonate; di-tert-butyl L-glutamate; Nε-benzyloxycarbonyl-L-lysine tert-butyl ester With triethylamine In dichloromethane at 0 - 25℃; for 6h; Stage #2: With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.4% | Stage #1: bis(trichloromethyl) carbonate; di-tert-butyl L-glutamate With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester With triethylamine In dichloromethane at 20℃; for 16h; | 1 This example discloses the synthesis of compound S-1, and the reaction formula is Specifically: Add triethylamine (4.11g, 40.7mmol) in a solution of S (6.0g, 20.3mmol) in dichloromethane (50mL) at room temperature, then add triphosgene (2.00g, 6.71mmol), and react 30 After minutes, add R1 (5.30 g, 14.2 mmol) and triethylamine (1.44 g, 14.2 mmol). The mixture was stirred at room temperature for 16 hours. TLC tracks the reaction,The reaction mixture was poured into 200 mL ice water and extracted with ethyl acetate (3×60 mL),After washing with brine 3 times, drying with anhydrous sodium sulfate for two hours. Under reduced pressure, the organic solvent was removed by rotary evaporation, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1)7.5 g of yellow oily compound was obtained, and the yield was 59.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.5% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 6.1 Step 1: preparation of N6-((benzyloxy) carbonyl)-N2-(2-bromoacetyl)-L-lysine tert-butyl ester (6-2) Under condition of N2, compound N6-((benzyloxy) carbonyl)-L-lysine tert-butyl ester (6-1, 1.68 g, 5 mmol) wasdissolved in DCM (10 mL). DIPEA (1.94 g, 15 mmol), HATU (2.85 g, 7.5 mmol) and 2-bromoacetic acid (5-2, 759 mg,5.5 mmol) were added at 0 °C. Then the reaction was warmed up to room temperature, and the reaction was monitoredby LC-MS. After the completion of the reaction, water (5 mL) was added to quench the reaction, reaction mixture isextracted with DCM (3 3 20 mL). The organic phase was concentrated and the residue obtained was separated bycolumn chromatography to obtain the title compound (6-2, 1.38 g, yield: 60.5%).MS m/z (ESI): 457 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With triethylamine In acetonitrile at 20℃; for 4.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester With bis(trichloromethyl) carbonate; triethylamine In dichloromethane at 0℃; for 3h; Stage #2: L-glutamic acid di-tert-butyl ester hydrochloride In dichloromethane at 20℃; | 2-[3-(5-benzyloxycarbonylamino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioicacid di-tert-butyl ester (10) Triphosgene (420 mg, 1.40 mmol) was dissolved in dichloromethane (5 mL) and cooledto 0 C. A solution of N(")-benzoyloxycarbonyl-L-lysine (1.42 g, 3.80 mmol) and triethylamine(1.05 mL, 765 mg, 7.60 mmol) in dichloromethane (25 mL) was added dropwiseover a period of 3 hours at 0 C. The reaction mixture was stirred for 40 minutes andL-glutamic acid di-tert-butyl ester hydrochloride (1.13 g, 3.80 mmol) and triethylamine(1.05 mL, 765 mg, 7.60 mmol) in dichloromethane (20 mL) was added. The solution wasstirred over night at room temperature. The solution was evaporated under reducedpressure. Ethyl acetate (25 mL) was added. The organic layer was washed with saturatedNaHCO3-solution (2 10 mL) and brine (2 10 ml), dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by column chromatography(hexane/ethyl acetate; 20:1, Rf = 0.26) and the product was obtained as a colorless oil(357.6 mg, 0.58 mmol, 41%).1H-NMR (300 MHz, CDCl3): [ppm] = 7.38-7.22 (m, 5H), 5.16 (d, J = 13.5 Hz, 1H),5.09 (d, J = 3.2 Hz, 2H), 4.32 (dt, J = 7.5, 5.2 Hz, 2H), 3.16 (s, 2H), 2.40-2.15 (m, 2H), 1.93-1.68(m, 2H), 1.43 (m, 29H).13C-NMR (300 MHz, CDCl3): [ppm] = 172.54, 172.25, 172.15, 157.09, 156.61, 136.67,128.47, 128.04, 128.01, 82.29, 81.84, 80.65, 77.24, 66.56, 53.38, 53.03, 40.63, 32.53, 31.52, 29.36,28.28, 28.07, 28.00, 22.26.MS (ESI+): 622.4 [M + H]+, 644.4 [M + Na]+, calculated for C32H51N3O9: 621.36 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: bis(trichloromethyl) carbonate; triethylamine / dichloromethane / 3 h / 0 °C 1.2: 20 °C 2.1: hydrogen; palladium on activated charcoal / methanol 3.1: aq. phosphate buffer; ethyl acetate / pH 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: bis(trichloromethyl) carbonate; triethylamine / dichloromethane / 3 h / 0 °C 1.2: 20 °C 2.1: hydrogen; palladium on activated charcoal / methanol 3.1: aq. phosphate buffer; ethyl acetate / pH 7 4.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: bis(trichloromethyl) carbonate; triethylamine / dichloromethane / 3 h / 0 °C 1.2: 20 °C 2.1: hydrogen; palladium on activated charcoal / methanol 3.1: aq. phosphate buffer; ethyl acetate / pH 7 4.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 5.1: aq. phosphate buffer / 48 h / 20 °C / pH 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With diisopropyl-carbodiimide In dichloromethane at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With diisopropyl-carbodiimide In dichloromethane at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogenchloride; hydrogen / lithium hydroxide monohydrate; ethanol / 22 h / 20 °C / 7500.75 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogenchloride; hydrogen / lithium hydroxide monohydrate; ethanol / 22 h / 20 °C / 7500.75 Torr 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 2.1: palladium 10% on activated carbon; hydrogenchloride; hydrogen / lithium hydroxide monohydrate; ethanol / 22 h / 20 °C / 7500.75 Torr 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.17 h / 0 °C / Inert atmosphere 4.2: 20 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 2.1: palladium 10% on activated carbon; hydrogenchloride; hydrogen / lithium hydroxide monohydrate; ethanol / 22 h / 20 °C / 7500.75 Torr 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.17 h / 0 °C / Inert atmosphere 4.2: 20 h / 20 °C / Inert atmosphere 5.1: triethylsilane / dichloromethane / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 2.1: palladium 10% on activated carbon; hydrogenchloride; hydrogen / lithium hydroxide monohydrate; ethanol / 22 h / 20 °C / 7500.75 Torr 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.17 h / 0 °C / Inert atmosphere 4.2: 20 h / 20 °C / Inert atmosphere 5.1: triethylsilane / dichloromethane / 0 - 20 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 2.1: palladium 10% on activated carbon; hydrogenchloride; hydrogen / lithium hydroxide monohydrate; ethanol / 22 h / 20 °C / 7500.75 Torr 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 0 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.17 h / 0 °C / Inert atmosphere 4.2: 20 h / 20 °C / Inert atmosphere 5.1: triethylsilane / dichloromethane / 0 - 20 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 h / 0 - 20 °C / Inert atmosphere 7.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: (S)-N-(tert-butoxycarbonyl)alanine methyl ester With PivOH In neat (no solvent) at 20℃; for 0.166667h; Stage #2: N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester In neat (no solvent) at 70℃; for 2h; |
Tags: 63628-63-7 synthesis path| 63628-63-7 SDS| 63628-63-7 COA| 63628-63-7 purity| 63628-63-7 application| 63628-63-7 NMR| 63628-63-7 COA| 63628-63-7 structure
[ 5978-22-3 ]
(S)-tert-Butyl 2-amino-6-(((benzyloxy)carbonyl)amino)hexanoate hydrochloride
Similarity: 0.98
[ 133170-57-7 ]
(S)-Benzyl 2-amino-6-((tert-butoxycarbonyl)amino)hexanoate hydrochloride
Similarity: 0.98
[ 161234-80-6 ]
tert-Butyl (S)-2-amino-5-(((benzyloxy)carbonyl)amino)pentanoate hydrochloride
Similarity: 0.98
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Code | Phrase |
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Code | Phrase |
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P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
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H260 | In contact with water releases flammable gases which may ignite spontaneously |
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H303 | May be harmful if swallowed |
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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 |
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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 |
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H351 | Suspected of causing cancer |
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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 |
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