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CAS No. : | 115186-31-7 | MDL No. : | MFCD00076966 |
Formula : | C26H32N2O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JYEVQYFWINBXJU-JOCHJYFZSA-N |
M.W : | 468.54 | Pubchem ID : | 14019424 |
Synonyms : |
|
Num. heavy atoms : | 34 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.42 |
Num. rotatable bonds : | 14 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 128.14 |
TPSA : | 113.96 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.99 cm/s |
Log Po/w (iLOGP) : | 3.49 |
Log Po/w (XLOGP3) : | 4.46 |
Log Po/w (WLOGP) : | 4.67 |
Log Po/w (MLOGP) : | 2.8 |
Log Po/w (SILICOS-IT) : | 3.8 |
Consensus Log Po/w : | 3.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.89 |
Solubility : | 0.00601 mg/ml ; 0.0000128 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.57 |
Solubility : | 0.000125 mg/ml ; 0.000000268 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -6.95 |
Solubility : | 0.0000526 mg/ml ; 0.000000112 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.51 |
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 methanol; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 3h; | EXAMPLE 4 This Example describes the synthesis of Compounds 1 and 13 to 16. Synthesis of Compound 1 al Synthesis of Intermediate A Intermediate A TFA (2 mL) was added to Boc-D-Lys (Fmoc) -OAllyl (2.86 g, 5.6 mmol) and left to stand for 5 min. The TFA was then removed by a stream of dry nitrogen to afford H-D- Lys (Fmoc) -OAllyl which was dried on a high vacuum line for 2 h to remove all traces of TFA. 2-Chlorotrityl resin (1 g, 1.4 mmol) was pre-swelled in DCM (10 mL) for 1 h. The resin was drained and a solution of H-D-Lys (Fmoc) -OAllyl (2.30 g, 5.64 mmol) and DIEA (729 mg, 982 82 LL, 5.64 mmol) in DCM (10 mL) was added and the reaction mixture shaken for 1 h. Further DIEA (1.46 g, 1.95 mL, 11.3 mmol) was added to the resin and the reaction mixture shaken for a further Ih. Methanol (1 mL) was added to end-cap any unreacted resin and the reaction mixture shaken for a further 1 h. The resin was filtered and washed with DMF (2 x 5 mL), DCM (2 x 5 mL) and DMF (2 x 5 mL). The resin was subjected to Fmoc- solid phase peptide synthesis (SPPS) using the following conditions: (i) Fmoc deprotection: 20 % piperidine in DMF (2 x 10 mL) for 2 min followed by washing with DMF (4 x 5 mL), DCM (4 x 5 mL) and DMF (4 x 5mL). (ii) Coupling conditions: In all couplings the solution of the coupling reagent in DMF is added to the Fmoc-amino acid. This solution is added to the resin followed by DIEA. (a) Fmoc-Trp (Boc) -OH (2.95 g, 5.6 mmol), HBTU (0.5 M solution, 11.2 mL) and DIEA (0.975 mL, 5.6 mmol) 20 min. (b) Fmoc-N-Me- Leu-OH (2.06 g, 5.6 mmol), HBTU (0.5 M solution, 11.2 mL) and DIEA (0.975 mL, 5.6 mmol) 20 min. (c) Fmoc-Leu-OH (1.98 g, 5.6 mmol), HOBt (756 mg, 5.6 mmol), HATU (2.13 g, 5.6 mmol) and DIEA (314 pLL, 1.8 mmol) in DMF (10 mL) 3 h. (d) Fmoc-Ala-OH (1.74 g, 5.6 mmol), HBTU (0.5 M solution, 11.2 mL) and DIEA (0.975 mL, 5.6 mmol) 20 min. Following all couplings the resin was filtered and washed with DMF (4 x 5 mL), DCM (4 x 5 mL) and DMF (4 x 5mL). All couplings except for (c) were monitored using the ninhydrin test, coupling (c) was monitored using a bromophenol blue test. All couplings were also monitored by MS by cleaving a small amount of resin (5 mg) with 100 % TFA for 5 min, the filtrate from the resin was then analysed by MS. A solution of Pd (PPh3) 4 (1.62 g, 1.4 mmol) and dimedone (1.96 g, 14 mmol) in THF: DCM (1: 1, 50 mL) was sparged with nitrogen gas for 10 min. , added to the resin and the mixture shaken for 16 h. The reaction mixture was filtered and washed with DCM (3 x 5 mL), DMF (3 x 5 mL) a solution of 0.5% DIEA and 0.5% diethyldithiocarbamic acid sodium salt in DMF (3 x 5 mL) and DMF (3 x 5mL). The resin was treated with 20 % piperidine in DMF (2 x 10 mL) for 2 min. followed by washing with DMF (4 x 5 mL), DCM (4 x 5 mL), 10% pyridinium hydrochloride in DCM: DMF (1: 1, 4 x 5 mL) and DMF (4 x 5 mL). A solution of PyBroP (718 mg, 1.54 mmol) and DIEA (1 mL, 5.74 mmol) in DCM: DMF (1: 1,10 mL) was added to the resin and the mixture shaken for 3 h after which a ninhydrin test was negative. The cyclic peptide was cleaved from the resin by treatment with 50% TFA in DCM (20 mL) for 1 h. The resin was filtered, washed with TFA (2 x 5 mL) and DCM (2 x 5 mL), concentrated to dryness, re-dissolved in MeCN: H20 (0. 1% TFA) and lyophilised to afford crude Intermediate A (435 mg, 50% based on the 2-chlorotrityl resin). Purification by RPHPLC (95: 5 H20 (1% TFA): MeCN (1% TFA) to 2: 3 H20 (1% TFA): MeCN (1% TFA)) over 60 min afforded Intermediate A (0.417 g, 3.6 %). b) lyl-N2-[(9H-fluoren-9-ylmethoxy)carbonyl]-N5-{imino[(2,2,4,6,7-pentamethyl-2,3- dihvdro-1-benzofuran-5-yl) aminolmethvl ornithinate N2-[(9H-fluoren-9-ylmethoxy) carbonyl]-N5- {imino [ (2, 2,4, 6,7-pentamethyl-2, 3- dihydro-l-benzofuran-5-yl) amino] methyl} ornithine (l. Og, 1.54 mmol) was dissolved in DMF (5 mL). Caesium carbonate (377 mg, 1.16 mmol) was added and the reaction mixture stirred for 1 h. Allyl bromide (0.913 mL, 10.8 mmol) was then added and stirring was continued for a further 1 h resulting in a milky white solution. Water (25 mL) was added and the reaction mixture acidified with 2M KHS04. DCM (50 mL) was added and the phases separated. The aqueous phase was washed with DCM (2 x 50 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), filtered and concentrated to dryness to afford allyl-N2- [ (9H- fluoren-9-ylmethoxy) carbonyl]-N5- {imino [(2, 2,4, 6, 7-pentamethyl-2, -dihydro-l-benzofuran- 5-yl) amino] methyl} ornithinate as colourless foam (857 mg, 81%). lHNMR (CDC13, 500 MHz): D 1.43 (s, 6H), 1.59 (m, 2H), 1.73 (m, 1H), 1.86 (m, 1H), 2.09 (s, 3H), 2.52 (s, 3H), 2.61 (s, 3H), 2.91 (s, 2H), 3.22 (m, 2H), 4.17 (t, J7 Hz, 1H), 4.32 (m, 1H), 4. 37 (m, 1H), 4. 59 (br d, J4. 5 Hz, 2H), 5.21 (d, J 10.5 Hz, 1H), 5. 30 (d, J 17 Hz, 1H), 5.83 (m, 1H), 5.88 (m, 1H), 6.26 (br s, 1H), 6.35 (br s, 2H), 7.26 (t, J 7. 5 Hz, 2H), 7.37 (t, J 7.5 Hz, 2H), 7.57 (m, 2H), 7.74 (d, J7. 5 Hz, 2H). 13CNMR (CDC13,125 MHz): 0 12.68, 18.... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 3: the GHK analogue As an example, compound 9 was used for the solid phase synthesis of a Gly-His-Lys analogue, an endogenous tripeptide known as a growth-modulating factor, as a strong activator of wound healing and as a copper chelator. The synthesis was performed on a chlorotrityl resin using Fmoc-glycine, compound 9 (D enantiomer) and Fmoc-D-lysine(Boc). After cleavage of the peptide from the resin using TFA, the two remaining protecting groups (id est Fmoc on the glycine and POM on the azahistidine side chain) were removed using NaOH in MeOH. After trituration in cold ether, GHK analogue 14 was obtained as a single isomer. [Show Image] Synthesis of Gly-D-azaHis-D-Lys 14 The synthesis of the tripeptide was achieved according to a literature protocol using DIC and HOBt as coupling reagents. Fmoc-Lys(Mtt)-OH and Fmoc-His(Mtt)-OH were replaced by Fmoc-D-Lys(Boc)-OH and Fmoc-D-azaHis(POM)-OH, respectively. Cleavage from the resin was performed using 10 mL of a cocktail composed of TFA/TIS/H2O (9.5/0.3/0.2) for 4 hours at room temperature. After filtration, TFA was removed by evaporation, the resulting solid was dissolved in water and the solution was lyophilized. 100 mg of the peptide TFA salt was then subjected to deprotection (Fmoc and POM) by addition of 650 muL of a 1 M NaOH aqueous solution (2.2 eq.) in 3.5 mL of MeOH for 5 hours at room temperature. After addition of HCl (1M) to reach pH 4, the solution was evaporated and the solid was taken up in MeOH. NaCl was filtrated and the resulting solution was evaporated. The resulting solid was triturated in cold diethyl ether yielding peptide 14 (yield 36 %) as a white solid with a purity of 90% (estimated by LC/MS and 1H NMR). Configuration of the compound 14 was checked by HPLC and 1H NMR. As previously mentionned, no epimerisation of the azahistidine moiety was noticed, and no epimerisation of the lysine moiety was noticed.Analytical Data: 1H NMR (400 MHz; D2O): delta 1.19-1.31 (m, 2H, CH2 delta Lys), 1.50-1.80 (m, 4H, CH2 beta and gamma Lys), 2.88 (t, 2H, J = 7.2 CH2 epsilon Lys), 3.13 (dd, 1H, J = 7.7, J = 15.2, CH2 beta azaHis), 3.20 (dd, 1H, J = 6.2, J = 15.2, CH2 beta azaHis), 3.74 (AB system, 2H, J = 16.1, CH2 Gly), 4.13 (dd, 1H, J = 5.4, J = 7.5, CH alpha Lys), 4.51-4.82 (m, 1H superimposed with water, CH alpha azaHis), 7.68 (s, 1H, CH triazol). 13C NMR {1H} (100 MHz, D2O): delta 21.84, 26.14, 26.69, 30.36, 39.08, 40.24, 53.26, 53.84, 127.29, 140.06, 166.8, 171.58, 176.73. HRMS (ES-) calcd for C13H22N7O4 : 340.1733; found : 340.1723. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | <strong>[115186-31-7]Boc-D-Lys(Fmoc)-OH</strong> (260 mg, 0.555 mmol) was treated with a solution of piperidine in DMF (1:4 v/v, 4.00 mL). The solution was maintained for 0.5 hours, then concentrated in vacuo and dried on the vacuum manifold for 18 hours to insure complete removal of excess piperidine. The resulting solid material was taken up in DMF (2.00 mL) and transferred to a previously prepared solution of Boc-Leu-OH (193 mg, 0.830 mmol) in DMF (2.00 mL) containing HBTU (263 mg, 0.694 mmol), HOBt (106 mg, 0.692 mmol) and U--Pr2NEt (483 muL, 2.77 mmol). The resulting solution was maintained at 22 0C for 1 hour, then concentrated in vacuo. The residue was purified by HPLC on a Phenomenex Luna Cl 8 column (21.2 X 250 mm) using a 2.0%/min gradient of 35-75% acetonitrile containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 15 minutes was lyophilized to a white solid (203 mg, 0.442 mumol; 79.6%). MS (ESI): 482.4 (30, M+Na), 460.4 (14, M+H), 360 (100, M-Boc). This material was used without further purification in the subsequent step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were synthesized by manual solid-phase procedure as described before, using techniques for Boc-protected amino acids on MBHA resin (100-200 mesh, 0.8 mM/g, Novabiochem).refPreviewPlaceHolder14 Nepsilon-amino group of Lys and d-Lys was protected by 9-fluorenylmethyloxycarbonyl (Fmoc), beta-carboxy group of Asp and d-Asp by fluorenylmethyl ester (OFm), and hydroxy group of Tyr by 2-bromo-benzyloxycarbonyl (2-Br-Z). 50% trifluoroacetic acid (TFA) in dichloromethane (DCM) was used for deprotection of Boc-groups and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) was employed to facilitate coupling. Fully assembled Boc-protected peptides were treated with 20% piperidine in dimethylformamide (DMF) to remove base-labile groups (Fmoc and OFm), followed by cyclization (TBTU). Simultaneous deprotection and cleavage of peptides from the resin was accomplished using TFA in a microwave-assisted procedure, described elsewhere.refPreviewPlaceHolder20 Shortly, a sample of the resin (50 mg) in a 2 ml polypropylene syringe reactor was treated with TFA/TIS/H2O (95:2.5:2.5; 1 ml) for 15 min at room temperature. The reactor was then transferred into the microwave synthesizer and irradiated with gas cooling at 30 W with magnetic stirring and temperature limit of 50 C for 30 s at a time (total irradiation time 32.5 min). Between irradiations, the resin was cooled in an ice-water bath for 2 min. Every 10 cycles the solution was removed, the resin washed with TFA, and a new portion of cleavage mixture added to the syringe. The combined filtrates were evaporated in a stream of nitrogen. Crude peptides were purified by RP-HPLC using the solvent system of 0.1% TFA in water (A)/80% acetonitrile in water containing 0.1% TFA (B) and a linear gradient of 0-100% B over 15 min. The purity of peptides was verified by analytical RP-HPLC, employing the solvent system of 0.1% TFA in water (A) and 80% acetonitrile in water containing 0.1% TFA (B). A linear gradient of 0-100% of solvent B over 25 min was used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were synthesized by manual solid-phase procedure as described before, using techniques for Boc-protected amino acids on MBHA resin (100-200 mesh, 0.8 mM/g, Novabiochem).refPreviewPlaceHolder14 Nepsilon-amino group of Lys and d-Lys was protected by 9-fluorenylmethyloxycarbonyl (Fmoc), beta-carboxy group of Asp and d-Asp by fluorenylmethyl ester (OFm), and hydroxy group of Tyr by 2-bromo-benzyloxycarbonyl (2-Br-Z). 50% trifluoroacetic acid (TFA) in dichloromethane (DCM) was used for deprotection of Boc-groups and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) was employed to facilitate coupling. Fully assembled Boc-protected peptides were treated with 20% piperidine in dimethylformamide (DMF) to remove base-labile groups (Fmoc and OFm), followed by cyclization (TBTU). Simultaneous deprotection and cleavage of peptides from the resin was accomplished using TFA in a microwave-assisted procedure, described elsewhere.refPreviewPlaceHolder20 Shortly, a sample of the resin (50 mg) in a 2 ml polypropylene syringe reactor was treated with TFA/TIS/H2O (95:2.5:2.5; 1 ml) for 15 min at room temperature. The reactor was then transferred into the microwave synthesizer and irradiated with gas cooling at 30 W with magnetic stirring and temperature limit of 50 C for 30 s at a time (total irradiation time 32.5 min). Between irradiations, the resin was cooled in an ice-water bath for 2 min. Every 10 cycles the solution was removed, the resin washed with TFA, and a new portion of cleavage mixture added to the syringe. The combined filtrates were evaporated in a stream of nitrogen. Crude peptides were purified by RP-HPLC using the solvent system of 0.1% TFA in water (A)/80% acetonitrile in water containing 0.1% TFA (B) and a linear gradient of 0-100% B over 15 min. The purity of peptides was verified by analytical RP-HPLC, employing the solvent system of 0.1% TFA in water (A) and 80% acetonitrile in water containing 0.1% TFA (B). A linear gradient of 0-100% of solvent B over 25 min was used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 50℃; for 1h; | In a 50 mL flask were added 3,4-dimethoxy-N-methyl-aniline (Intermediate la)(500 mg, 2.99 mmol), 6 mL of ethyl acetate, <strong>[115186-31-7](2R)-2-(tert-butoxycarbonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid</strong> (1681.33 mg, 3.59mmol), DIEA (1.57 mL, 8.97 mmol) and T3P (2.64 mL, 4.49 mmol). The reaction mixture was then stirred at 50C for 1 hour. The reaction mixture was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHCO3 and with brine, and the organic phase was dried over MgSO4 and evaporated to dryness to give 1.85 g of 9H-fluoren-9-ylmethyl N-[(5S)-5-(tert-butoxycarbonylamino)-6- (3 ,4-dimethoxy-N-methyl-anilino)-6-oxo- hexyl]carbamate as a dark red oil, leading to a 100% yield. It was used without further purification in the next step of the synthesis.MS: [M-t-H]niJz = 618. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; at 100℃; for 10h; | To a solution of compound 291 (500 mg, 1.07 mmol) in propan-2-ol (10 mL) was added SOCl 2 (0.5 mL). The mixture was stirred at 100 for 10 h, then concentrated under vacuum to obtain the titled compound 292 (439 mg, 100%) as a white solid. MS (ESI) : [M+H +] 411.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h; | EDC.HCl (0.77 g, 4.0 mmol) was added to a mixture of Boc-D-Lys (fluorenylmethyloxycarbonyl,Fmoc)-OH (1.4 g, 3.0 mmol) and amine 2 (1.3 g, 1.0 mmol)in anhydrous dichloromethane (DCM) (20.0 ml) and stirred for 20 hours at roomtemperature (RT). The reaction mixture was concentrated under reduced pressure,and the residue was purified over 100.0 g of prepacked flash silica gel column(25-50.0 mm). Elution with 0%-10% MeOH in DCM eluted the required peptideat 8% MeOH concentration. The LC fractions with the pure product were pooledand concentrated to yield the fully protected linear peptide as a colorless foam.Yield was 0.97 g (55%, 0.55 mmol); HPLC conditions were I, tR 5.3 minutes, andMS was [M 1 Na] 1771.1. |
Tags: 115186-31-7 synthesis path| 115186-31-7 SDS| 115186-31-7 COA| 115186-31-7 purity| 115186-31-7 application| 115186-31-7 NMR| 115186-31-7 COA| 115186-31-7 structure
[ 159751-47-0 ]
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-6-(tert-butoxy)-6-oxohexanoic acid
Similarity: 0.97
[ 104091-08-9 ]
(R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid
Similarity: 0.97
[ 71989-26-9 ]
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-6-((tert-butoxycarbonyl)amino)hexanoic acid
Similarity: 0.97
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