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CAS No. : | 133852-23-0 | MDL No. : | MFCD20264831 |
Formula : | C28H29NO5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VJSGNJOUWWMJDE-VWLOTQADSA-N |
M.W : | 459.53 | Pubchem ID : | 15295906 |
Synonyms : |
|
Num. heavy atoms : | 34 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 10 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 130.46 |
TPSA : | 84.86 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.13 cm/s |
Log Po/w (iLOGP) : | 3.27 |
Log Po/w (XLOGP3) : | 5.6 |
Log Po/w (WLOGP) : | 5.18 |
Log Po/w (MLOGP) : | 3.69 |
Log Po/w (SILICOS-IT) : | 5.01 |
Consensus Log Po/w : | 4.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.95 |
Solubility : | 0.000517 mg/ml ; 0.00000112 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -7.14 |
Solubility : | 0.000033 mg/ml ; 0.0000000717 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -8.26 |
Solubility : | 0.00000252 mg/ml ; 0.0000000055 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.47 |
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 |
---|---|---|
100% | Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 18 h; Stage #2: With hydrogenchloride; water In 1,4-dioxane |
[00284] tButyl N-(9-fluorenylmethoxycarbonyl)-L-tyrosine (83): To a stirring suspension of L-tyrosine O-f-butyl ester (LOOg, 4.21 mmol) and NaHCO3 (354 mg, 4.21 mmol) in 1 ,4-dioxane/water (1 :1 , 20 ml_) was added 9-fluorenylmethyl-N-succinimidyl carbonate (1.42 g, 4.21 mmol) and the resulting mixture was stirred for 18 hr at room temperature. The solvent was reduced to 10 ml. followed by the addition of 50 ml. of cold 1 N HCl. The product was extracted with ethyl acetate (3x). The organic extracts were washed with H2O and saturated aqueous NaCl then dried over Na2SO4. The solution was then concentrated after filtration to give the colourless solid 83 (1.94 g, 100percent) which was used without purification: 1H NMR (400 MHz, CDCI3) δ 1.43 (s, 9H), 2.97-3.06 (m, 2H), 4.21 (bt, J=7.1 , 1 H), 4.33 (dd, J=7.1 , 10.5, 1 H), 4.41-4.53 (m, 2H), 5.01 (bs, 1 H), 5.30, (d, J=8.2, 1 H), 6.73 (d, J=8.5, 2H), 7.00 (d, J=8.5, 2H), 7.31 (t, J=7.5, 2H), 7.40 (t, J=7.5, 2H), 7.57 (dd, J=3.3, 7.3, 2H), 7.76 (d, J=7.5, 2H). |
95.8% | With N-ethyl-N,N-diisopropylamine In acetone at 20℃; for 12 h; | 10 mmol of L-tyrosine tert-butyl ester and10 molecules of N, N-diisopropylethylamine were dissolved in 75 mL of acetone,A 75 mL portion of acetone solution containing 9.8 mmol of Fmoc-OSu was added under stirring,Stirred at room temperature for 12 hours,And then separated by silica gel column chromatography,To obtain 4.4 g of product Fmoc-L-Tyr-OtBu (i.e., compound 3 in the above synthesis step)The yield was 95.8percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | [00284] tButyl N-(9-fluorenylmethoxycarbonyl)-L-tyrosine (83): To a stirring suspension of L-tyrosine O-f-butyl ester (LOOg, 4.21 mmol) and NaHCO3 (354 mg, 4.21 mmol) in 1 ,4-dioxane/water (1 :1 , 20 ml_) was added 9-fluorenylmethyl-N-succinimidyl carbonate (1.42 g, 4.21 mmol) and the resulting mixture was stirred for 18 hr at room temperature. The solvent was reduced to 10 ml. followed by the addition of 50 ml. of cold 1 N HCl. The product was extracted with ethyl acetate (3x). The organic extracts were washed with H2O and saturated aqueous NaCl then dried over Na2SO4. The solution was then concentrated after filtration to give the colourless solid 83 (1.94 g, 100%) which was used without purification: 1H NMR (400 MHz, CDCI3) delta 1.43 (s, 9H), 2.97-3.06 (m, 2H), 4.21 (bt, J=7.1 , 1 H), 4.33 (dd, J=7.1 , 10.5, 1 H), 4.41-4.53 (m, 2H), 5.01 (bs, 1 H), 5.30, (d, J=8.2, 1 H), 6.73 (d, J=8.5, 2H), 7.00 (d, J=8.5, 2H), 7.31 (t, J=7.5, 2H), 7.40 (t, J=7.5, 2H), 7.57 (dd, J=3.3, 7.3, 2H), 7.76 (d, J=7.5, 2H). | |
95.8% | With N-ethyl-N,N-diisopropylamine; In acetone; at 20℃; for 12h; | 10 mmol of L-tyrosine tert-butyl ester and10 molecules of N, N-diisopropylethylamine were dissolved in 75 mL of acetone,A 75 mL portion of acetone solution containing 9.8 mmol of Fmoc-OSu was added under stirring,Stirred at room temperature for 12 hours,And then separated by silica gel column chromatography,To obtain 4.4 g of product Fmoc-L-Tyr-OtBu (i.e., compound 3 in the above synthesis step)The yield was 95.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The sequence Glu(OtBu)-Tyr(tBu)-Arg(Pbf)-DArg(Pbf)-2Nal-Gly-Dap(Boc)-Arg(Pbf) (SEQ ID NO:11) is assembled by standard Fmoc chemistry utilizing an ABI 431 instrument as outlined in Scheme 3 below. The automated assembly is carried out by using the standard Applied Biosystems DCC/HOBt chemistry protocol or FastMoc chemistry (HBTU/DIEA) protocol following the supplier's directions (PE Applied Biosystems Inc., Foster City, Calif.). The solid support is Rink amide resin for C-terminal amides or indole resin [3-({ethyl-Fmoc-amino}-methyl)-indol-1-yl]-acetyl AM resin for C-terminal ethyl amides. Stepwise chain assembly starts from the C-terminal end of the linear peptide and is accomplished in 9 major steps. In step 1, four equivalents of protected amino acid Fmoc-Arg(Pbf) are activated with DCC/HOBt (or HBTU/DIEA for FastMoc chemistry) in NMP, and coupled to deprotected Rink Amide resin. In step 2, four equivalents of Fmoc-Dap(Boc) are activated and coupled to the deprotected resin from step 1. Appropriate steps are carried out until step 8, the coupling of Fmoc-Glu(OtBu). For step 9, Fmoc at the N-terminal end is removed using 20percent piperidine in DMF and acetylation of the alpha-amino group is carried out off-line with 5 equivalents acetic anhydride, 10 equivalents DIEA in dry DMF or NMP, for 1 h at room temperature. The finished peptide is simultaneously deprotected and cleaved from the resin using a scavenger cocktail of TFA/H2O/TIS/EDT (95/2/1/2, v/v/v/v), or TFA/H2O/TIS/anisole (92/2/4/2, v/v/v/v) for 2 hours at room temperature (Scheme 4). The solvents are then evaporated under vacuum, and the peptide is precipitated and washed three times with cold diethyl ether to remove the scavengers. The crude product is used directly in the cyclization reaction. MW cal.: 1142.30; MW obs.: 1142.83. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The sequence Ac-Dap(Alloc)-Tyr(tBu)-Arg(Pbf)-DArg(Pbf)-2Nal-Gly-Glu(Oallyl)-Arg(Pbf) (SEQ ID NO:3) is assembled by standard Fmoc chemistry utilizing an ABI 431 Peptide Synthesizer (Applied Biosystems) as outlined in Scheme 1 below. The automated assembly is carried out by using the standard Applied Biosystems DCC/HOBt chemistry protocol or FastMoc chemistry HBTU/DIEA protocol following the supplier's directions (PE Applied Biosystems Inc., Foster City, Calif.). The solid support is Rink amide resin (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxy resin) for C-terminal amides or indole resin [3-({ethyl-Fmoc-amino}-methyl)-indol-1-yl]-acetyl AM resin for C-terminal ethyl amides (NovaBiochem, EMD Biosciences, Inc., San Diego, Calif.). The stepwise chain assembly starts from the C-terminal end of the linear peptide and is accomplished in 9 major steps. In step 1, four equivalents of protected amino acid Fmoc-Arg(Pbf) are activated with DCC/HOBt (or HBTU/DIEA for FastMoc chemistry) in NMP, and coupled to deprotected Rink Amide resin using 20% piperidine. In step 2, four equivalents of Fmoc-Glu(Oallyl) are activated and coupled to the deprotected peptide resin from step 1. Appropriate steps are carried out until step 8, the coupling of Fmoc-Dap(Alloc). Then, Fmoc at the N-terminal end is removed using 20% piperidine in DMF and acetylation of the alpha-amino group is carried out off-line using 5 equivalents of acetic anhydride, 10 equivalents of DIEA in dry DMF or NMP, for 1 h at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The sequence Gly-Tyr(tBu)-Lys(iPr)(Boc)-DArg(Pbf)-2Nal-Gly-DGlu(Oallyl)-Arg(Pbf) (SEQ ID NO:33) is assembled by standard Fmoc chemistry utilizing an ABI 431 instrument as outlined in Scheme 5 below. The automated assembly is carried out by using the standard Applied Biosystems DCC/HOBt chemistry protocol or FastMoc HBTU/DIEA chemistry protocol following the supplier's directions (PE Applied Biosystems Inc., Foster City, Calif.). The solid support is Rink amide resin for amides or indole resin [3-({ethyl-Fmoc-amino}-methyl)-indol-1-yl]-acetyl AM resin for C-terminal ethyl amides. Stepwise chain assembly starts from the C-terminal end of the linear peptide and is accomplished in 8 major steps (Scheme 5). In step 1, four equivalents of protected amino acid Fmoc-Arg(Pbf) are activated with DCC/HOBt (or HBTU/DIEA for FastMoc chemistry) in NMP, and are coupled to deprotected Rink amide resin. In step 2, four equivalents of Fmoc-DGlu(Oallyl) are activated and coupled to the deprotected peptide resin from step 1. Appropriate steps are carried out until step 8, the coupling of Fmoc-Gly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 57 discloses the synthesis of SEQ ID NO:70 via Fmoc solid phase peptide synthesis chemistry employing the commercially available building block Fmoc-Lys(iPr)Boc, which is expensive and difficult to obtain in large quantity. The process described in this example permits the synthesis of SEQ ID NO:70 using less expensive Fmoc-Lys(Boc), solution cyclization, and lysine alkylation through reductive amination using sodium cyanoborohydride, providing a more economical route to this end product. Additional advantages are that the reaction media (acetic acid, acetone, and methanol) are relatively inexpensive, the reaction conditions are easily controlled, the ratio of solvents can vary significantly without affecting the alkylation reaction, and the recovery yield is 90% or higher.The sequence Phe-Tyr(tBu)-Lys(Boc)-DArg(Pbf)-2Nal-Gly-DGlu(Oallyl)-Lys(Boc) (SEQ ID NO:100) is assembled on Rink Amide Resin by standard Fmoc chemistry utilizing an ABI 431 Peptide Synthesizer as outlined in Scheme 7. The automated assembly is carried out using the standard Applied Biosystems DCC/HOBt chemistry protocol or FastMoc chemistry (HBTU/DIEA) protocol following the supplier's directions (PE Applied Biosystems Inc., Foster City, Calif.). The side chain protecting group scheme is: Lys(Boc), DGlu(Oallyl), DArg(Pbf), Tyr(tBu). The stepwise chain assembly starts from the C-terminal end of the linear peptide and is accomplished in 8 steps. In step 1, four equivalents of protected amino acid Fmoc-Lys(Boc) are activated with DCC/HOBt (or HBTU/DIEA for FastMoc chemistry) in NMP, and coupled to deprotected Rink amide resin. In step 2, four equivalents of Fmoc-DGlu(Oallyl) are activated and coupled to the deprotected peptide resin from step 1. These steps are repeated appropriately until step 8, the coupling of Fmoc-Phe. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | [00285] tButyl N-(9-fluorenylmethoxycarbonyl)-O-(4,4-bis(diethylphosphoryl)butyl)- L-tyrosine (84): A solution of 83 (664 mg, 1.44 mmol) and PPh3 (454 mg, 1.73 mmol) in THF (20 ml.) was cooled in an ice-bath followed by the addition of diisopropyl azodicarboxylate (336 mg, 1.74 mmol). After a further 10 min a solution of 81 (500 mg, 1.44 mmol) in THF (5 ml.) was added and the resulting solution was stirred while warming to room temperature overnight. The solvent was removed at reduced pressure and the crude material was purified by silica gel chromatography (0 to 10% methanol in ethyl acetate over 10 column volumes then 10 to 20% over 5 column volumes) using a Biotage Horizon apparatus resulting in the colourless liquid 84 (491 mg, 43%): 1H NMR (400 MHz, CDCI3) delta 1.33 (t, J=7.1 , 6H), 1.34 (t, J=7.1 , 6H), 1.43 (s, 9H), 2.04-2.18 (m, 4H), 2.37 (tt, J=6.3, 24.2, 1 H), 2.98-3.07 (m, 2H), 3.92 (t, J=5.8, 2H), 4.14-4.22 (m, 8H), 4.33 (dd, J=IA , 10.4, 1 H), 4.43 (dd, J=7.2, 10.5, 1 H), 4.50 (dd, J=6.0, 8.4, 1 H), 5.24, (d, J=8.1 , 1 H), 6.78 (d, J=8.5, 2H), 7.04 (d, J=8.4, 2H), 7.28-7.33 (m, 2H), 7.40 (t, J=7.6, 2H), 7.77 (d, J=7.6, 2H): 31P (162 MHz, CDCI3) delta 24.74 (s, 2P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Cys-Tyr-Cys(Acm)-Pro-Thr-Cys(Acm)-Tyr-Gln-Met-Cys 13? was synthesized as described above. A solution of the crude peptide 13? (11 mg) in an ammonium bicarbonate buffer (50 mL, pH 8.0) was stirred in air at 25 C, and the reaction was monitored as above. After 47 h, the solution was lyophilized to yield 10 mg (91%) of a cyclized peptide 13?: MALDI-TOF MS; found 1376.24 for [M+Na]+, calcd 1376.45 for C55H79N13O17S5Na. The obtained peptide 13? (3.1 mg) was mixed with 0.1 M I2 in 50% AcOH (2.5 mL, 100 equiv) and the solution was stirred for 1 min at 25 C. Two drops of 1 M ascorbic acid solution in H2O were added and the solution was concentrated in vacuo. The product was purified by preparative RP-HPLC as above to yield 0.36 mg (12%) of 13 as a white amorphous powder: HPLC rt, 25.13 min (single peak) [YMC-Pack ODS-AM (4.6 × 150 mm), 0.9 ml/ min, CH3CN (0-50%)/50 min], FAB-MS; found 1232.3312 for [M+Na]+, calcd. 1232.3319 for C49H67N11O15S5Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
fx3 8 First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
fx3 8 First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
fx3 8 First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: First, 400 mg (0.52 mmol) of 2-chlorotrityl chloride resin (1.3 mmol/g) was agitated in CH2Cl2 (3.0 mL) at 25 C for 10 min. Next, Fmoc-Cys(Trt)-OH (150 mg, 0.26 mmol) and diisopropylethylamine (DIPEA) (91 muL, 0.52 mmol) were added and the mixture was stirred for 150 min at 25 C. The resin was washed with DMF, CHCl3, and MeOH, and dried in vacuo. To the resulting resin (150 mg, 0.050 mmol) were added 2% (v/v) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2% (v/v) piperidine in DMF (1.0 mL) and the mixture was stirred for 5 min at 25 C then washed with DMF (5*) and CHCl3 (2*). Fmoc-Gln(Trt)-OH (74 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (19 mg, 0.12 mmol), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) (39 mg, 0.12 mmol), and DIPEA (42 muL, 0.24 mmol) in DMF (2.0 mL) were added, the mixture was stirred for 1 h at 25 C, and the resin was washed with DMF (5*). Successive condensation of the corresponding Fmoc amino acid derivatives was carried out by repeating the same deprotection/coupling protocol. The N-terminal Fmoc-Cys(Trt)-OH (71 mg, 0.12 mmol) was condensed using DIC (diisopropylcarbodiimide) (19 muL, 0.12 mmol) and HOBt (19 mg, 0.12 mmol) in DMF (2.0 mL) at 25 C for 1 h. The protected peptide-resin (84 mg) was treated with trifluoroacetic acid (TFA)-ethandithiol-triisopropylsilane-H2O (94.5:2.5:1:2.5, 2.0 mL) at 25 C for 90 min. The mixture was filtered and the filtrate was concentrated in vacuo. Cold diethyl ether (30 mL) was added to the residue. The product was suspended in distilled H2O and lyophilized to give 19 mg (27%) of crude product. HPLC retention time (rt), 22.96 min [YMC-Pack ODS-AM (4.6 * 150 mm), 0.9 ml/min, CH3CN (0-100%)/100 min], MALDI-TOF-MS; found 1114.1617 for [M+Na]+, calcd 1114.3950 for C46H65N11O16S2Na. The crude peptide (12 mg) in an ammonium bicarbonate buffer (120 mL, pH 8.1, peptide concentration of 0.1 mg/mL) was stirred in air at 25 C. An aliquot (50 muL) was subjected to analytical reversed-phase HPLC [YMC-Pack ODS-AM (4.6 * 150 mm), 40 C, 0.1% TFA/CH3CN (0-100%/100 min) in H2O, 0.9 ml/min]. After 10 h, the solution was lyophilized to yield a white powder containing ammonium bicarbonate (70 mg): MALDI-TOF-MS; found 1112.3088 for [M+Na]+, calcd 1112.3793 for C46H63N11O16S2Na. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The resin-supported Fmoc -protected peptide A (0.25 mmol) was sequentially deprotected and coupled with (25,45)- 1-(((9H- fluoren-9-yl)methoxy)carbonyl)-4- azidopyrrolidine-2-carboxylic acid (1 mmol, 1 h), followed by (5)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3,3-dimethylbutanoic acid (1 mmol, 3 h), and then (S)-2- ((tert-butoxycarbonyl)(methyl)amino)propanoic acid (1 mmol, 1 h) to give the resin- supported product. LC-MS analysis was performed on peptide cleaved from the resin using the following protocol: analytical amount of the resin was treated with TFA (1% solution in DCM, 0.2 mL) at room temperature for 1 min and then filtered through a syringe filter to give a solution of the free peptide. MS(ESI+) m/z 652.5 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.5% | 8 mmol of triethyl phosphite was dissolved in 80 mL of dichloromethane,Adding 7.5 mmol of iodine,Placed in an ice bath,After 10 min reaction, the temperature was returned to room temperature,And then added dropwise to 50 mL of dichloromethane containing 5.0 mmol of the compound 3 synthesized in the first step and 20.0 mmol of pyridine,Placed in an ice bath,Reaction 2h,Then extracted with 100 mL of ether and 300 mL of ethyl acetate,The organic phase was washed three times with 100 mL of 5% potassium bisulfate,And then washed with saturated sodium chloride again,The organic phase was then dried over anhydrous magnesium sulfate,filter,concentrate,Silica gel column separation,To obtain Fmoc-L-Tyr (PO (OEt) 2) -OtBu (i.e., compound 4 in the above synthesis step)The yield was 85.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.03 g | L-tyrosine (2 g, 11.04 mmol) and Na2CO3 (2.93 g, 27.6 mmol) were dissolved in H2O (50 mL) and added dropwise to a stirred solution of Fmoc-Chloride (2.86 g, 11.04 mmol) in dioxane (60 mL) cooled in ice to 0C. The solution was allowed to warm to room temperature overnight. Dioxane was removed by evaporation and the residue was washed with diethyl ether (50 mL). The aqueous layer was acidified with 2N HCl and the solution was extracted with EtOAc (60 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated to give crude compound which was used next step directly. DCC (7.5 g, 36.43 mmol), tert-butyl alcohol (4.43 mL, 46.37 mmol), and CuCl (76.5 mg, 0.77 mmol) were placed in an argon-purged, three-necked, round-bottom flask fitted with a magnetic stirrer and a condenser. The suspension was stirred at room temperature for 72 h. The dark green suspension was diluted in anhydrous DCM (20 mL), and crude acid obtained above (11.04 mmol) was added. The resulting suspension was purged with argon and was stirred at room temperature for 4 h. The reaction mixture was then filtered, and the white dicyclohexylurea precipitate was washed with DCM (10 mL). The filtrate was combined and concentrated, which was diluted with ethyl acetate (50 mL). The organic layer was washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL). The ethyl acetate layer was dried over anhydrous Na2SO4, and evaporated under reduced pressure to give crude product which was purified by column chromatography on silica gel using 7:3 petroleum ether-EtOAc as eluent to give the compound D (2.03 g, 4.42 mmol, 40%) as a white sticky solid. NMR spectra were identical to that reported.[2] 1H NMR (300 MHz, CDCl3): delta = 7.76 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.73 (d, J = 8.1 Hz, 2H), 5.36 (d, J = 8.1 Hz, 1H), 4.55 - 4.40 (m, 2H), 4.34 (m, 1H), 4.20 (t, J = 6.9 Hz, 1H), 3.08 - 2.95 (m, 2H), 1.44 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): delta = 171.0, 155.9, 155.2, 143.9, 141.4, 130.7, 127.84, 127.2, 125.3, 125.2, 120.1, 115.5, 82.7, 67.2, 55.5, 47.3, 37.7, 28.1 ppm; HRMS (ESI): m/z [M+Na]+ calcd for C28H29NO5Na: 482.1943; found: 482.1945. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; In N,N-dimethyl-formamide; at 20℃; for 0.166667h; | L-Fmoc-Tyr-OtBu (85 mg, 0.184 mmol) was treated with 20% piperidine-DMF (2 ml) and stirred at room temperature for about 10 min. Piperidine and DMF were then removed in vacuo and a white solid obtained which was directly used in the next step without further purification. |
Tags: 133852-23-0 synthesis path| 133852-23-0 SDS| 133852-23-0 COA| 133852-23-0 purity| 133852-23-0 application| 133852-23-0 NMR| 133852-23-0 COA| 133852-23-0 structure
[ 82911-79-3 ]
(S)-Methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate
Similarity: 0.95
[ 72594-77-5 ]
(S)-Ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate
Similarity: 0.95
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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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