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CAS No. : | 13726-84-6 | MDL No. : | MFCD00038257 |
Formula : | C14H25NO6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YGSRAYJBEREVRB-VIFPVBQESA-N |
M.W : | 303.35 | Pubchem ID : | 6993432 |
Synonyms : |
|
Num. heavy atoms : | 21 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.79 |
Num. rotatable bonds : | 10 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 77.02 |
TPSA : | 101.93 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.93 cm/s |
Log Po/w (iLOGP) : | 2.48 |
Log Po/w (XLOGP3) : | 1.72 |
Log Po/w (WLOGP) : | 2.09 |
Log Po/w (MLOGP) : | 1.34 |
Log Po/w (SILICOS-IT) : | 1.22 |
Consensus Log Po/w : | 1.77 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.14 |
Solubility : | 2.18 mg/ml ; 0.00717 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.48 |
Solubility : | 0.101 mg/ml ; 0.000334 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.95 |
Solubility : | 3.4 mg/ml ; 0.0112 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.41 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
With sodium hydrogencarbonate; In 1,4-dioxane; at 20℃; for 20h; | To a solution of Glu (O-t-Bu) in saturated sodium bicarbonate solution was added a solution of di-t-butyl pyrocarbonate in dioxane and the mixture was stirred at room temperature for about 20 hrs. Dioxane was removed from the reaction mixture. The aqueous solution was acidified with 10% KHSO4 solution and the liberated Boc-Glu (O-t-Bu) was extracted into ethyl acetate. The ethyl acetate solution was washed with water, dried and concentrated. Precipitation was done using petroleum ether (60-800). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.1 18.2 l,l-Dimethylethyl (4i)-4-([(l,l-dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate: [00220] Triethylamine (11.49 mL, 82.4 mmol) and ethyl chloroformate (8.27 niL, 86.5 mmol) were added successively by syringe to 2V-t-BOC-D-glutamic acid 5-tert-bviotatyl ester (25 g, 82.4 mmol) in THF (588 mL) at <0 0C (ice-salt bath). After stirring in the cold bath for 40 min, solids were filtered and washed with THF (150 mL). The filtrate was transferred to a 250-mL addition funnel and added to a solution of sodium borohydride (8.42 g, 222.5 mmol) in H2O (114 mL) at 00C over 1 hour. The reaction mixture was maintained at 0 0C for 1.5 h and then stirred for 16 h (00C to room temperature). After the bulk of solvents were removed by rotary evaporation, the concentrate was quenched with ice water (50 mL) and 1 N HCl (50 mL). After extraction with EtOAc (4 x 100 mL), the extracts were washed with 100 mL: 0.5 M citric acid, saturated NaHCO3, H2O, and brine and concentrated in vacuo to give the title compound, which was used directly in the next step. ESMS [M+H]+ = 290.4, [2M+H]+ = 579.4. (Literature prep: J. Med. Chan, 1999, 42(1), 95-108 for other isomer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | GENERAL PROCEDURE FOR THE COUPLING OF AMINES WITH CARBOXYLIC ACIDS: The compound is dissolved in an appropriate amount of dichloromethane and the carboxylic acid (1.1 equiv.) added followed by PS-CDI (2 equiv.) and DIEA (10 equiv.). The reaction is shaken at room temperature until the starting material has been consumed. Once complete, the reaction is filtered and the filtrate concentrated in vacuo to obtain the crude product. In most cases, the crude product is pure enough for further transformations. If the crude product is not sufficiently pure, it can be purified using normal or reverse phase chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | A solution of Boc-D-Glu(But)-OH (37.2 mg, 0.123 mmol) and HOAt (14.0 mg, 0.103 mmol) in dry DMF (1.00 mL) was successively treated with collidine (75.5 muL, 0.571 mmol) and DIC (16.0 muL, 0.102 mmol) then stirred 5 minutes at 22 C. The product of Example 3 A (30.0 mg, 62.3 mumol) was added in one portion and the resulting solution stirred 1.5 hours at 22 C. All volatiles were then removed in vacuo, and the resulting oil treated with a solution of tris(2-aminoethyl)amine in DMF (1:4 v/v, 4.00 mL). The solution was stirred 0.5 hours, then concentrated in vacuo and the crude residue purified by HPLC on a Phenomenex Luna Cl 8 column (21.2 x 250 mm) using a 1.0%/min gradient of 15-45% acetonitrile containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 17 minutes was lyophilized to a white solid (24.3 mg, 44.6 mumol; 71.6%). 1H NMR (DMSO-J6, 600 MHz): delta 8.77 (IH, s), 8.68 (IH, s), 7.32 (3H, br s), 5.76 (IH, br s), 4.11 (IH, br s), EPO <DP n="73"/>2.96 (2H, t, J= 6.8 Hz), 2.22 (2H, t J= 6.8 Hz), 2.02-1.97 (IH, m), 1.85-1.80 (IH, m), 1.70 (2H, tt, J= 7.6, 7.5 Hz), 1.65 (2H, tt, J= 7:0, 6.9 Hz), 1.54 (2H, m), 1.44 (9H, s), 1.42 (9H, s). MS (ESI): 431.3 (100, M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). 1H NMR (400 MHz, CD3OD): delta = 7.24 (dd, J = 5.0, 1.4 Hz, 1H), 7.20 (dd, J = 5.0, 1.4 Hz, 1H), 6.97-6.90 (m, 4H), 4.72 (dd, J = 9.6, 4.4 Hz, 1H), 4.50 (dd, J = 7.5, 2.1 Hz, 1H), 4.42 (d, J = 7.8, 5.0 Hz, 1H), 4.33 (d, J = 7.6 Hz, 1H), 4.13 (d, J = 2.4 Hz, 1H), 3.97 (d, J = 6.4 Hz, 1H), 3.31 (d, J = 4.0 Hz, 1H), 3.21 (dd, J = 14.8, 7.6 Hz, 1H), 3.12 (dd, J = 15.2, 9.6 Hz, 1H), 3.05 (dd, J = 14.6, 7.4 Hz, 1H), 2.50-2.40 (m, 2H), 2.10 (d, J = 3.2 Hz, 1H), 2.06 (d, J = 8.4 Hz, 1H), 1.91-1.71 (m, 3H), 1.58-1.52 (m, 1H), 1.45-1.37 (m, 2H), 1.20-1.13 (m, 1H), 0.99-0.91 (m, 9H); HRMS (FAB) Calcd for C31H46N5O9S2 [M+H]+: 696.2737. Found: 696.2740. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: After agitating 2-chlorotrityl resin (500 mg) in DMF for 20 min, <strong>[135112-28-6]Fmoc-Nva-OH</strong> (407 mg, 1.20 mmol) and DIPEA (0.21 mL, 1.20 mmol) was added with DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, MeOH and DIPEA (0.41 mL, 2.40 mmol) in DMF was added to the resin. After agitating for 30 min, the resin was washed with DMF, CHCl3, and DMF to give protected Nva on resin (575 mg). After washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. After agitating in DMF, CHCl3, and DMF for 20 min, R-10 (34.9 mg, 0.0827 mmol), HOBt·H2O (25.3 mg, 0.165 mmol), EDCI·HCl (31.7 mg, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF were added to this resin (114 mg, 0.0532 mmol). The mixture was agitated for 18 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. To this resin were added Fmoc-AA-OH (0.0827 mmol), HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.099 mmol) in DMF. The mixture was agitated for 2 h. After the resin was washed with DMF, piperidine (20%) in DMF was added to the resin. After agitating for 20 min, the deprotected resin was washed with DMF. Completion of each coupling reaction was ascertained using the Kaiser Ninhydrin test. Finally, coupling of Boc-Glu(Ot-Bu)-OH (25.1 mg, 0.0827 mmol) was carried out with HOBt·H2O (25.2 mg, 0.165 mmol), DIC (26 muL, 0.165 mmol), and DIPEA (28 muL, 0.165 mmol) in DMF. The mixture was agitated for 2 h, and the resin was washed with DMF. The resin was dried under reduced pressure. TFA/H2O/thioanisole (95:2.5:2.5) was added to the resin and the mixture was agitated for 2 h. The mixture was filtered, and solvents of the filtrate were removed under reduced pressure. Ether was added to the residue to form the precipitate. The precipitate was washed with ether and purified by preparative HPLC to yield R-14 (28.0 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2 (0042) FIG. 2 depicts a synthesis of Pt-LHRH conjugate in accordance with a preferred embodiment of the present invention. The Mal-LHRH decapeptide was synthesized using Fmoc solid phase chemistry techniques and then chelated to activated cisplatin. Fmoc-Rink Amide-AM resin was placed onto a reaction vessel and washed with DMF and DCM in continuous-flow mode using a PS3 peptide synthesizer. The side chain protected amino acids derivatives used were Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, <strong>[214750-75-1]Fmoc-DLys(Aloc)-OH</strong>, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-His(Trt)-OH and Boc-Glu(OtBu)-OH. Moreover, the use of Boc protecting group instead of Fmoc in the last amino acid (Boc-Glu(OtBu) allows for a straightforward synthesis because it reduces the number of synthetic steps and avoids unwanted side chain reactions. The acid labile Boc protecting group is conveniently removed in the end during cleavage of the peptide from the resin. The amino acid couplings employed four equivalents of amino acid and (2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU) and sometimes (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphoniumhexafluorophosphate (PyAOP) or other known coupling reagents dissolved in 0.4 M N-methylmorpholine (NMM) in DMF at room temperature. The allyloxycarbonyl (aloe) protecting group on the D-lys was selectively removed using palladium. The amine end of the D-lys was coupled with the mal linker (see FIG. 2) and the conjugate cleaved from the resin using TFA-Tips-H2O-Phenol or TFA-Tips-H2O or TFA-Thioanisole-H2O or TFA-Thioanisole-H2O cocktail to yield of LHRH-mal. Activated cisplatin was formed using cisplatin, silver nitrate and water in accordance with known methods as described in Berners-Price, et al., ?Hydrolysis products of cisplatin: pKa determinations via [1H, 15N] NMR spectroscopy,? Journal of the Chemical Society, Chemical Communications (1992) 789-791; Appleton et al., ?NMR study of acid-base equilibria and other reactions of ammineplatinum complexes with aqua and hydroxo ligands,? Inorganic Chemistry, (1989) 28, 1989-1993. Reaction of LHRH-mal and activated cisplatin yielded Pt-LHRH. (0043) FIG. 3 depicts a mass spectrum of Pt-LHRH conjugate in accordance with a preferred embodiment of the present invention. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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