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CAS No. : | 71989-20-3 | MDL No. : | MFCD00037137 |
Formula : | C20H20N2O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IZKGGDFLLNVXNZ-KRWDZBQOSA-N |
M.W : | 368.38 | Pubchem ID : | 2724775 |
Synonyms : |
Fmoc-L-glutamine
|
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 97.69 |
TPSA : | 118.72 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.21 cm/s |
Log Po/w (iLOGP) : | 1.87 |
Log Po/w (XLOGP3) : | 1.89 |
Log Po/w (WLOGP) : | 2.24 |
Log Po/w (MLOGP) : | 1.5 |
Log Po/w (SILICOS-IT) : | 2.04 |
Consensus Log Po/w : | 1.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.05 |
Solubility : | 0.329 mg/ml ; 0.000892 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.01 |
Solubility : | 0.0364 mg/ml ; 0.0000987 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.87 |
Solubility : | 0.00496 mg/ml ; 0.0000135 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.84 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
85% | With potassium carbonate In acetonitrile at 20℃; for 2 h; | General procedure: To a solution of H-Phe-OH (100 mg, 60.5 mmol) in 50 percent MeCN (6.1 mL)were added Fmoc-OPhth (233 mg, 60.5 mmol) and K2CO3 (167 mg, 121 mmol) and stirred at room temperature. After 2 h of stirring saturated sodium bicarbonate solution and H2O were added and the resulting solution was washed with diethyl ether. The aqueous phase is acidified to pH 1 with 1M HCl and extracted with diethyl ether. The organic phase was washed with 1 M HCl, H2O, brine, dried over MgSO4. The filtrate was evaporatedevaporated under reduced pressure to give yellow solid as crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium carbonate In tetrahydrofuran; water | To a stirred solution of L-glutamine (1.75 g, 12 mmole) and sodium carbonate (1.27 g, 12 mmole) in 30 ml of water, was added a solution of Fmoc-OSu (3.0 g, 8.9 mmole) in 60 ml of THF. After stirring overnight the mixture was concentrated under reduced pressure to remove the THF. The residue was diluted with 100 ml of 1 N hydrochloric acid . The white solid was collected by filtration and recrystallized in DMF-0.1 N hydrochloric acid aqueous solution to afford a white powder (38, 2.76 g). Yield: 84percent. 1H-NMR (90 MHz, DMSO-d6) ppm: 12.47 (1H, s), 7.89-7.20 (10 H, m), 6.68 (1H, s, br), 4.22-3.90 (4H, m), and 2.25-1.86 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | With [bis(acetoxy)iodo]benzene In water; ethyl acetate; acetonitrile at 20 - 30℃; for 72 h; | A. The suspension 100g271 . 5nmolFmoc-Gln-OH with 2L ethyl acetate: acetonitrile: water = 2:1: mixed solution 1(v/v/v), in 20-30 °C add 105.1g325 . 9nmolDipa, reaction 72 hours, post-processed to obtain product Fmoc-Dab-OH80g. Yield of 86.5percent, HPLC: 99.6percent. The infrared, nuclear magnetic resonance confirmed correct structure, see Figure 1, Figure 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;Combinatorial reaction / High throughput screening (HTS); | Split & Mix Procedure for the Resin Bound HexapeptideP-Glu (OAll)-Gly-X1X2X3X4-H sublibrary The resin was suspended in 3:1 mixture of 1,2-dichloroethane (DCE) and DMF and equally partitioned into 17 4 mL Alltech tubes. Each tube thus contained 0.1/17 mmol=5.88 10-6 mol of resin-bound dipeptide. Excess solvent was removed in vacuo, and the resin was suspended in DMF (200 mL) and agitated for 30 minutes. The 17 amino acids (1.76 10-5 mmol, 3 eq for each step, 7.04 10-5 mmol for 4 steps) were weighed into 17 vials: 1. Fmoc-Ala-OH 22 mg 2. Fmoc-Asn-OH 25 mg 3. Fmoc-Asp(OtBu)-OH 29 mg 4. Fmoc-Gln-OH 26 mg 5. <strong>[104091-08-9]Fmoc-Glu(OtBu)-OH</strong> 30 mg 6. Fmoc-Gly-OH 21 mg 7. Fmoc-Ile-OH 25 mg 8. Fmoc-Leu-OH 25 mg 9. Fmoc-Lys(BOC)-OH 33 mg 10. Fmoc-Met-OH 26 mg 11. Fmoc-Phe-OH 27 mg 12. Fmoc-Pro-OH 24 mg 13. Fmoc-Ser(tBu)-OH 27 mg 14. Fmoc-Thr(tBu)-OH 28 mg 15. Fmoc-Trp(BOC)-OH 37 mg 16. Fmoc-Tyr(tBu)-OH 32 mg 17. Fmoc-Val-OH 24 mg Each amino acid was dissolved in DMF (2 mL); an aliquot of each solution (0.5 mL, corresponding to 1.76 10-5 mmol, 3 eq of each amino acid) was added to the appropriate tube. TBTU (1.76 10-5 mmol×17=2.99 10-4, 96 mg) and DIPEA (1.76 10-5 mmol×17=2.99 10-4, 52 mL) were separately dissolved in DMF (1.7 mL) and each solution was evenly distributed, delivering 3 eq of each reagent, to each one of the 17 tubes.The reaction tubes were agitated at room temperature for 12 hours, then the reagents and solvents were removed in vacuo and the resin was rinsed with DMF (2×1 mL each tube), DCM (2×1 mL each tube) and methanol (2×1 mL each tube). The resin was then suspended in 3:1 mixture of 1,2-dichloroethane and DMF and recombined. The recombined resin was acetylated (3 mL of acetylating reagent, 1 hour, room temperature) and deprotected (3 mL of 20% piperidine in DMF, 2 hours, room temperature).The procedure was repeated 3 more times. At the end of the 4th amino acid coupling the deprotection step was not executed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The peptides are manufactured using Fmoc (9-fluorenylmethyloxycarbonyl) chemistry. Peptides are made using a polystyrene resin, functionalized with an appropriate linker, and the peptides are then manufactured using an lntavis Peptide Synthesizer. A 4-fold excess of amino acid is added relative to the resin and either HATU (O-(7-azabenzotriazol-1 -yl)-N, N, N?, N?-tetramethyluronium hexafluorophosphate)or HCTU (2-(6-Chloro-1 H-benzotriazole-1 -yl)-1 , 1, 3,3-tetramethylaminium hexafluorophosphate) were used at a 3.95-fold excess to create the active ester. Along with an 8-fold excess of DIPEA (N,N-Diisopropylethylamine) as the base, these reagents catalyze the addition of the next amino acid. Once the amino acid is coupled (each cycle includes a double coupling cycle to insure efficient coupling) theresin is exposed to 20% acetic anhydride to terminate (?cap-off?) any peptide chains that have not added the next amino acid.The amino acids are dissolved in NMP (N-Methyl-2- pyrrolidone) or DMF (Dimethylformamide) For washing. Piperidine is used to remove the Fmoc group at theend of each coupling cycle which allows the next amino acid to be added. Similarly the synthesis of BAP modified a-MSH peptide analogues (Example 1)peptides were synthesized using standard Fmoc chemistry using 1-[Bis(dimethylamino)methylene]-1 H-i ,2, 3-triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate (HATU) or 2-(6-Chloro-i H-benzotriazole-1 -yl)-l ,1,3,3- tetramethylaminium hexafluorophosphate (HCTU) as the coupling reagents with Hunig?s Base (N,N-diisopropylethylamine, DIPEA). For the lysine branching asdescribed in more detail below, combination of orthogonally protected lysines were used including Fmoc-Lys(MTT)-OH, <strong>[204777-78-6]Fmoc-Lys(ivDde)-OH</strong> , and Fmoc-Lys(Boc)-OH.Peptides were cleaved with standard cleavage cocktails including trifluoroacetic acid, triisoproproylsilane, and water and precipitated with ice-cold ether. All crude peptides were purified by reversed-phase chromatography on columns with C-18 functionalityand using gradients of acetonitrile, deionized water, and trifluoroacetic acid as running buffers. Purity was determined by high-pressure liquid chromatography and mass (MS) and sequence (tandem MS) information was obtained using a nanospray mass spectrometer. BAP attached to lysines in the sequence between the N- and C-terminiMETHOD 2: N - a - Fmoc - N - E - 4 - methyltrityl - L - lysine was added to the peptide sequence, methytrityl was removed after finalizing the sequence and optionally N-terminal acetylation. Appropriate lysine analogues such as Fmoc-Lys(MTT)-OH, FmocLys(ivDde)-OH and Fmoc-Lys(Boc)-OH were sequentially added and selectively deprotected, before acetylation to ensure appropriate side chain and acetyl addition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Solid phase peptide synthesis was performed on a CEM Liberty Peptide Synthesizer using standard Fmoc chemistry. TentaGel S Ram resin (1 g; 0.25 mmol/g) was swelled in NMP (10 ml) prior to use and transferred between tube and reaction vessel using DCM and NMP. Coupling (0148) An Fmoc-amino acid in NMP/DMF/DCM (1:1:1; 0.2 M; 5 ml) was added to the resin in a CEM Discover microwave unit together with HATU/DMF or COMU/DMF (0.5 M; 2 ml) and DIPEA/NMP (2.0 M; 1 ml). The coupling mixture was heated to 75° C. for 5 min while nitrogen was bubbled through the mixture. The resin was then washed with NMP (4×10 ml). Deprotection (0149) Piperidine/DMF (20percent; 10 ml) was added to the resin for initial deprotection and the mixture was heated by microwaves (30 sec; 40° C.). The reaction vessel was drained and a second portion of piperidine/NMP (20percent; 10 ml) was added and heated (75° C.; 3 min.) again. The resin was then washed with DMF (6×10 ml). Side Chain Acylation (0150) Fmoc-Lys(ivDde)-OH or alternatively another amino acid with an orthogonal side chain protective group was introduced at the position of the acylation. The N-terminal of the peptide backbone was then Boc-protected using Boc2O or alternatively by using a Boc-protected amino acid in the last coupling. While the peptide was still attached to the resin, the orthogonal side chain protective group was selectively cleaved using freshly prepared hydrazine hydrate (2-4percent) in NMP for 2×15 min. The unprotected lysine side chain was first coupled with Fmoc-Glu-OtBu or another spacer amino acid, which was deprotected with piperidine and acylated with a lipophilic moiety using the peptide coupling methodology as described above. Alternatively, the acylation moiety was introduced as a premade building block e.g. Fmoc-Lys(hexadecanoyl-gamma-Glu)-OH where gamm-Glu is the coupling of Glutamic acid through the side-chain. Abbreviations employed are as follows: COMU: 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholinomethylene)]methanaminium hexaflourophosphate ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)3-methyl-butyl Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl DCM: dichloromethane DMF: N,N-dimethylformamide (0151) DIPEA: diisopropylethylamine EtOH: ethanol Et2O: diethyl ether HATU: N-[(dimethylamino)-1H-1,2,3-triazol[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide MeCN: acetonitrile NMP: N-methylpyrrolidone (0152) TFA: trifluoroacetic acid TIS: triisopropylsilane Cleavage (0153) The resin was washed with EtOH (3×10 ml) and Et2O (3×10 ml) and dried to constant weight at room temperature (r.t.). The crude peptide was cleaved from the resin by treatment with TFA/TIS/water (95/2.5/2.5; 40 ml, 2 h; r.t.). Most of the TFA was removed at reduced pressure and the crude peptide was precipitated and washed three times with diethylether and dried to constant weight at room temperature. HPLC Purification of the Crude Peptide (0154) The crude peptide was purified to greater than 90percent by preparative reverse phase HPLC using a PerSeptive Biosystems VISION Workstation equipped with a C-18 column (5 cm; 10 mum) and a fraction collector and run at 35 ml/min with a gradient of buffer A (0.1percent TFA, aq.) and buffer B (0.1percent TFA, 90percent MeCN, aq.). Fractions were analyzed by analytical HPLC and MS and relevant fractions were pooled and lyophilized. The final product was characterized by HPLC and MS. (0155) The synthesized compounds are shown in Table 1 and Table 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Peptide monomers of the present invention were synthesized using the Merrifield solid phase synthesis techniques on Protein Technology's Symphony multiple channel synthesizer. The peptides were assembled using HBTU (0-Benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluoro-phosphate), Diisopropylethylamine(DIEA) coupling conditions. For some amino acid couplings PyAOP(7-Azabenzotriazol- 1 -yloxy)tripyrrolidinophosponium hexafluorophosphate) and DIEA conditions were used. Rink Amide MB HA resin (100-200 mesh, 0.57 mmol/g) was used for peptide with C-terminal amides and pre-loaded Wang Resin with N-a-Fmoc protected amino acid was used for peptide with C-terminal acids. The coupling reagents (HBTU and DIEA premixed) were prepared at lOOmmol concentration. Similarly amino acids solutions were prepared at 100 mmol concentration. Peptide inhibitors of the present invention were identified based on medical chemistry optimization and/or phage display and screened to identify those having superior binding and/or inhibitory properties.[00611] The peptides were assembled using standard Symphony protocols. The peptide sequences were assembled as follows: Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4ml of DMF followed by treatment with 2.5ml of 20% 4-methyl piped dine (Fmoc de- protection) for lOmin. The resin was then filtered and washed two times with DMF (4ml) and re -treated with N-methyl piperifine for additional 30 minute. The resin was again washed three times with DMF (4 ml) followed by addition 2.5ml of amino acid and 2.5ml of HBTU-DIEA mixture. After 45min of frequent agitations, the resin was filtered and washed three timed with DMF (4 ml each). For a typical peptide of the present invention, double couplings were performed. After completing the coupling reaction, the resin was washed three times with DMF (4 ml each) before proceeding to the next amino acid coupling. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: tGLP-1 and its analogues 2?13 were all synthesized using general solid-phase peptide synthesis of N-Fmoc/tBu chemistry. 63Fmoc Rink Amide-MBHA resin (0.1 mmol) was added to a 25 ml peptide synthetic vessel and swollen with DMF for 40 min. After deprotected by 25percent piperidine in DMF, a solution of Fmoc-AA-OH (0.4 mmol), HATU (0.4 mmol), HoAt (0.4 mmol) and DIPEA (0.8 mmol) in DMF was added to the vessel. After reacted for 1 h, the resin was washed three times with DMF and three times with CH2Cl2, then qualitative ninhydrin testing was performed to monitor whether some free amino groups still existed on the resin ornot. If not, the resin was washed three times with DMF again and repeated the procedures of deprotection and coupling. Forthe coupling of some unnatural amino acids, NMM instead of DIPEA and NMP instead of DMF were used. Besides, the reaction time was prolonged to 4 h. Following the final deprotection of N-terminus, the target peptide was cleaved from resin with Reagent K (TFA/thioanisole/water/phenol/EDT, 82.5:5:5:5:2.5) for 2 h atroom temperature. After filtration, the residue solution was concentrated, precipitated with cold diethyl ether and centrifuged for three times. The residue was dissolved in water and purified by Waters 2545 preparative RP-HPLC system. Sephadex G-25 was used for the further purification to remove some short peptide impurities. The molecular mass of the target peptide was confirmed by MALDI-TOF. The purity of peptide was tested with analytical RP-HPLC, and the conditions were as follows: a linear gradient of 20percent mobile phase A and 80percent mobile phase B to 80percent mobile phase A and 20percent mobile phase B (A: acetonitrile containing 0.1percent TFA; B: H2O containing 0.1percent TFA) in 30 min, at a flow rate of 1 mL/minute with UV detection at 214 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: tGLP-1 and its analogues 2-13 were all synthesized using general solid-phase peptide synthesis of N-Fmoc/tBu chemistry. 63Fmoc Rink Amide-MBHA resin (0.1 mmol) was added to a 25 ml peptide synthetic vessel and swollen with DMF for 40 min. After deprotected by 25% piperidine in DMF, a solution of Fmoc-AA-OH (0.4 mmol), HATU (0.4 mmol), HoAt (0.4 mmol) and DIPEA (0.8 mmol) in DMF was added to the vessel. After reacted for 1 h, the resin was washed three times with DMF and three times with CH2Cl2, then qualitative ninhydrin testing was performed to monitor whether some free amino groups still existed on the resin ornot. If not, the resin was washed three times with DMF again and repeated the procedures of deprotection and coupling. Forthe coupling of some unnatural amino acids, NMM instead of DIPEA and NMP instead of DMF were used. Besides, the reaction time was prolonged to 4 h. Following the final deprotection of N-terminus, the target peptide was cleaved from resin with Reagent K (TFA/thioanisole/water/phenol/EDT, 82.5:5:5:5:2.5) for 2 h atroom temperature. After filtration, the residue solution was concentrated, precipitated with cold diethyl ether and centrifuged for three times. The residue was dissolved in water and purified by Waters 2545 preparative RP-HPLC system. Sephadex G-25 was used for the further purification to remove some short peptide impurities. The molecular mass of the target peptide was confirmed by MALDI-TOF. The purity of peptide was tested with analytical RP-HPLC, and the conditions were as follows: a linear gradient of 20% mobile phase A and 80% mobile phase B to 80% mobile phase A and 20% mobile phase B (A: acetonitrile containing 0.1% TFA; B: H2O containing 0.1% TFA) in 30 min, at a flow rate of 1 mL/minute with UV detection at 214 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were obtained by a stepwise elongation of the peptide chain according to procedures described previously by Kuczer et al. [9]. In brief, the analogs were synthesized by the classical solid phase method using the Fmoc procedure starting from an Fmoc-Gly-Wang resin. Synthesis was performed in disposable plastic reactors (Intavis AG). Fmoc protecting groups were removed using 20% piperidine in DMF. Subsequently, Fmoc-protected amino acids (3equiv) were attached by using 3equiv of HBTU as the coupling agent in the presence of HOBt (3equiv) and NMM (6equiv) for 2h at room temperature. (0016) The completeness of each coupling reaction was monitored by the Kaiser test [18]. (0017) Final cleavage of the peptides was achieved with TFA, TIS, and water (95:2.5:2.5 v/v) for 2h at room temperature. The crude peptides were precipitated from cold diethyl ether, washed with diethyl ether, dissolved in water, and lyophilized. The peptides were purified by semipreparative HPLC using a Varian ProStar chromatograph equipped with a TOSOH Bioscience C18 column (21.5mm×300mm) (Tosoh, Tokyo, Japan) and a 210/254nm dual-wavelength UV detector. Water-acetonitrile gradients containing 0.1% TFA at a flow rate of 7ml/min were used for purification. The final purity of the lyophilized peptides was >95% according to analytical HPLC (Thermo Separation Product; column: Vydac Protein RP C18 (4.6mm×250mm) (Grace, Deerfield, IL, USA); linear gradient 0-100% B in 60min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water, UV detection at 210nm). Additional HPLC analyses were performed, using a Varian Microsorb-MV 100-5 CN column (4.6mm×250mm) (Varian, Palo Alto, CA, USA) with a linear gradient from 0% to 100% B for 40min, flow rate 1.0ml/min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were obtained by a stepwise elongation of the peptide chain according to procedures described previously by Kuczer et al. [9]. In brief, the analogs were synthesized by the classical solid phase method using the Fmoc procedure starting from an Fmoc-Gly-Wang resin. Synthesis was performed in disposable plastic reactors (Intavis AG). Fmoc protecting groups were removed using 20% piperidine in DMF. Subsequently, Fmoc-protected amino acids (3equiv) were attached by using 3equiv of HBTU as the coupling agent in the presence of HOBt (3equiv) and NMM (6equiv) for 2h at room temperature. (0016) The completeness of each coupling reaction was monitored by the Kaiser test [18]. (0017) Final cleavage of the peptides was achieved with TFA, TIS, and water (95:2.5:2.5 v/v) for 2h at room temperature. The crude peptides were precipitated from cold diethyl ether, washed with diethyl ether, dissolved in water, and lyophilized. The peptides were purified by semipreparative HPLC using a Varian ProStar chromatograph equipped with a TOSOH Bioscience C18 column (21.5mm×300mm) (Tosoh, Tokyo, Japan) and a 210/254nm dual-wavelength UV detector. Water-acetonitrile gradients containing 0.1% TFA at a flow rate of 7ml/min were used for purification. The final purity of the lyophilized peptides was >95% according to analytical HPLC (Thermo Separation Product; column: Vydac Protein RP C18 (4.6mm×250mm) (Grace, Deerfield, IL, USA); linear gradient 0-100% B in 60min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water, UV detection at 210nm). Additional HPLC analyses were performed, using a Varian Microsorb-MV 100-5 CN column (4.6mm×250mm) (Varian, Palo Alto, CA, USA) with a linear gradient from 0% to 100% B for 40min, flow rate 1.0ml/min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were obtained by a stepwise elongation of the peptide chain according to procedures described previously by Kuczer et al. [9]. In brief, the analogs were synthesized by the classical solid phase method using the Fmoc procedure starting from an Fmoc-Gly-Wang resin. Synthesis was performed in disposable plastic reactors (Intavis AG). Fmoc protecting groups were removed using 20% piperidine in DMF. Subsequently, Fmoc-protected amino acids (3equiv) were attached by using 3equiv of HBTU as the coupling agent in the presence of HOBt (3equiv) and NMM (6equiv) for 2h at room temperature. (0016) The completeness of each coupling reaction was monitored by the Kaiser test [18]. (0017) Final cleavage of the peptides was achieved with TFA, TIS, and water (95:2.5:2.5 v/v) for 2h at room temperature. The crude peptides were precipitated from cold diethyl ether, washed with diethyl ether, dissolved in water, and lyophilized. The peptides were purified by semipreparative HPLC using a Varian ProStar chromatograph equipped with a TOSOH Bioscience C18 column (21.5mm×300mm) (Tosoh, Tokyo, Japan) and a 210/254nm dual-wavelength UV detector. Water-acetonitrile gradients containing 0.1% TFA at a flow rate of 7ml/min were used for purification. The final purity of the lyophilized peptides was >95% according to analytical HPLC (Thermo Separation Product; column: Vydac Protein RP C18 (4.6mm×250mm) (Grace, Deerfield, IL, USA); linear gradient 0-100% B in 60min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water, UV detection at 210nm). Additional HPLC analyses were performed, using a Varian Microsorb-MV 100-5 CN column (4.6mm×250mm) (Varian, Palo Alto, CA, USA) with a linear gradient from 0% to 100% B for 40min, flow rate 1.0ml/min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were obtained by a stepwise elongation of the peptide chain according to procedures described previously by Kuczer et al. [9]. In brief, the analogs were synthesized by the classical solid phase method using the Fmoc procedure starting from an Fmoc-Gly-Wang resin. Synthesis was performed in disposable plastic reactors (Intavis AG). Fmoc protecting groups were removed using 20% piperidine in DMF. Subsequently, Fmoc-protected amino acids (3equiv) were attached by using 3equiv of HBTU as the coupling agent in the presence of HOBt (3equiv) and NMM (6equiv) for 2h at room temperature. (0016) The completeness of each coupling reaction was monitored by the Kaiser test [18]. (0017) Final cleavage of the peptides was achieved with TFA, TIS, and water (95:2.5:2.5 v/v) for 2h at room temperature. The crude peptides were precipitated from cold diethyl ether, washed with diethyl ether, dissolved in water, and lyophilized. The peptides were purified by semipreparative HPLC using a Varian ProStar chromatograph equipped with a TOSOH Bioscience C18 column (21.5mm×300mm) (Tosoh, Tokyo, Japan) and a 210/254nm dual-wavelength UV detector. Water-acetonitrile gradients containing 0.1% TFA at a flow rate of 7ml/min were used for purification. The final purity of the lyophilized peptides was >95% according to analytical HPLC (Thermo Separation Product; column: Vydac Protein RP C18 (4.6mm×250mm) (Grace, Deerfield, IL, USA); linear gradient 0-100% B in 60min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water, UV detection at 210nm). Additional HPLC analyses were performed, using a Varian Microsorb-MV 100-5 CN column (4.6mm×250mm) (Varian, Palo Alto, CA, USA) with a linear gradient from 0% to 100% B for 40min, flow rate 1.0ml/min, solvent A=0.1% TFA in water, solvent B=0.1% TFA in 80% acetonitrile/water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Phenethylamine-AMEBA resin (Sigma Aldrich, 0.25 mmol, 1.0 mmol/g) was subjected to solid phase peptide synthesis on an automatic peptide synthesizer (CEM Liberty Blue Microwave) with standard double Arg for the Arg residues and D-Nle andAzidolysine coupled double time. Amino acids were prepared as 0.2 M solution in DMF. A standard coupling cycle was defined as follows:Amino acid coupling: AA (5 eq.), HATU (5 eq.), DIEA (25 eq.)Washing: DMF (3x7 mL)Fmoc Deprotection: 20% Piperidine/0.1 M HOBt (2x7 mL)Washing: DMF (4x7 mL then 1x5 mL) After the assembly of the peptide, the resin was washed with DMF (2x50 mL) and DCM (2x50 mL) then dried under vacuum to give Intermediate 42a (770 mg, 0.250 mmol). Intermediate 42a (770mg, 0.250 mmol) was divided inhalf and each sample was combined with 6 mE TFA solution (37 mE TFA, 1 mE R20, 1 mE TIPS, 2.569 g (20 eq.) DTT) and shaken at ri. for 3 hours. The solution was removed from the resin and precipitated into 40 mE cold Et20. The solution wasvortexed and let stand over ice for 10 minutes before centrifuging at 4000 rpm for 5 minutes. The solvent was removed and the white solid was washed twice more with cold Et20 (40 mE each time), centrifuged (5 minutes each time) and decanted. The solid was dried under vacuum overnight andpurified via M-triggered RPEC yielding Intermediate 43b as a white powder (80 mg, 0.045 mmol, 80%). ECMS (5Q2 ProductAnalysis-Acidic-Peptide-Polar, Acquity UPEC HER C18 column, 130 A, 1.7 tm, 2.1 mmx50 mm, 50 C.):R=2.32 minutes, MS [M+R+2/2] 888.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | General procedure: Peptides were synthesised on a MultiSynTech Syro Peptide Synthesiser (model MP-60). The peptide synthesiser contains an agitation block which held 5mL syringes with frits connected to a vacuum pump to remove solvents. Pre-loaded Rink amide resins (100-200 mesh) and Fmoc protected amino acids were purchased from Merck KGaA/Novabiochem, and were used in all cases of automated peptide synthesis. The total volume of all reagents in each step was 1.5mL and all reagents were dissolved in HPLC grade DMF. (0024) Fmoc deprotection: A solution of piperidine in DMF (40% v/v, 1.5mL) was added to the syringe containing an N-terminal Fmoc-protected peptide. The mixture was agitated for 20s every minute for a total of 3min. The reagents were removed by vacuum filtration and the resin was washed with DMF (6×1.5mL). A second portion of piperidine in DMF (40% v/v, 0.75mL) was added to the syringe followed by DMF (0.75mL) to give a final solution of 20% v/v of piperidine in DMF. The mixture was agitated for 20s every minute for a total of 10min. The reagents were removed by vacuum filtration and the resin washed with DMF (6×1.5mL). (0025) Amino acid coupling: Fmoc protected amino acid (4eq.), HBTU (4eq.) and DIPEA (10eq.) were added to the reaction syringe. The mixture was agitated for 20s every minute for a total of 40min. The reagents were removed by vacuum filtration and the resin was washed with DMF (4×1.5mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To 9H-fluoren-9-ylmethyl carbamate Rink Amide Resin ChemPep Inc. (0.575 g, 0.5 mmol, 1 eq) was added 20% piperidine/DMF (10 mL). The mixture was bubbled with N2 for 5 min at 25 C. The mixture was filtered, then DMF (10 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (10 mL). The procedure was repeated for 4 times. A solution of Na-Fmoc-S-trityl-L- cysteine 9 (1.17 g, 2.0 mmol, 4 eq), HATU (0.76 g, 2.00 mmol, 4 eq) and DIPEA (0.5 g, 4.00 mmol, 0.69 mL, 8 eq) in DMF (12 mL)was added to the resin. The mixture was bubbled for 30 min at 25 C.Coupling with of N-(9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (0.85 g, 2.00 mmol, 4 eq), Na-Fmoc-N(in)-Boc- L-tryptophan 18 (0.85 g, 2.00 mmol, 4 eq ), Na-Fmoc-Nd-trityl-L-glutamine 11 (1.2 g, 2.0 mmol, 4 eq), Fmoc-b-alanine 12 (0.625 g, 2.00 mmol, 4 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran- 5-sulfonyl)-L-arginine 13 (1.3 g, 2.0 mmol, 4 eq), Fmoc-O-tert-butyl-L-tyrosine 15 (0.9 g, 2.0 mmol, 4eq), Fmoc-L-valine 15 (0.7 g, 2.0 mmol, 4eq), Na-Fmoc-S-trityl-L-cysteine 9 (1.17 g, 2.00 mmol, 4 eq),O-tert-butyl-L-tyrosine 14 (0.9 g, 2.0 mmol, 4eq), Fmoc-L-proline 17 (0.7 g, 2.0 mmol, 4eq). The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 C).Scheme 20 To intermediate peptide A (0.22 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N2 for 5 min at 25 C. The mixture was filtered, then DMF (5 mL) was added and the resulting mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated for 4 times giving intermediate peptide B.General coupling procedure for EXAMPLES 24-26 (procedure A)Corresponding acids (0.40 mmol, 4 eq) were dissolved in 5 mL of DMF. The amounts are given in Table 3 below.Table 3 To the solutions, DIC (0.05 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) were added sequentially. Intermediate peptide B (0.1 mmol, 1 eq) was added to each solution. The mixtures were bubbled for 30 min at 25 C, then filtered and DMF (15 mL) were added to each resin. The mixtures were bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptides C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The peptide backbone of Example 1 is synthesized using Fluorenylmethyloxycarbonyl (Fmoc)/tert-Butyl (t-Bu) chemistry on a Symphony X peptide synthesizer (Gyros Protein Technologies. Tucson, Ariz.). The resin consists of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) at a substitution of 0.3-0.4 meq/g. Standard side-chain protecting groups were used. Fmoc-Lys(Mtt)-OH is used for the lysine at position 17 and Boc-Tyr(tBu)-OH) was used for the tyrosine at position 1. Fmoc groups are removed prior to each coupling step (2×7 minutes) using 20% piperidine in DMF. All standard amino acid couplings are performed for 1 hour to a primary amine and 3 hour to a secondary amine, using an equal molar ratio of Fmoc amino acid (0.3 mM), diisopropylcarbodiimide (0.9 mM) and Oxyma (0.9 mM), at a 9-fold molar excess over the theoretical peptide loading. Exceptions are couplings to Calpha-methylated amino acids, which are coupled for 3 hours. After completion of the synthesis of the peptide backbone, the resin is thoroughly washed with DCM for 6 times to remove residual DMF. The Mtt protecting group on the lysine at position 17 is selectively removed from the peptide resin using two treatments of 300 hexafluoroisopropanol (Oakwood Chemicals) in DCM (2×40-minute treatment). Subsequent attachment of the fatty acid-linker moiety is accomplished by coupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fmoc-glutamic acid alpha-t-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.), mono-OtBu-eicosanedioic acid (WuXi AppTec, Shanghai, China). 3-Fold excess of reagents (AA:PyAOP:DIPEA=1:1:1 mol/mol) are used for each coupling that is 1-hour long. After the synthesis is complete, the peptide resin is washed with DCM, and then thoroughly air-dried. The dry resin is treated with 10 mL of cleavage cocktail (trifluoroacetic acid:water:triisopropylsilane, 95:2.5:2.5 v/v) for 2 hours at room temperature. The resin is filtered off, washed twice each with 2 mL of neat TFA, and the combined filtrates are treated with 5-fold excess volume of cold diethyl ether (-20 C.) to precipitate the crude peptide. The peptide/ether suspension is then centrifuged at 3500 rpm for 2 min to form a solid pellet, the supernatant is decanted, and the solid pellet is triturated with ether two additional times and dried in vacuo. The crude peptide is solubilized in 20% acetonitrile/20% Acetic acid/60% water and purified by RP-HPLC on a Luna 5 mum Phenyl-Hexyl preparative column (21*250 mm, Phenomenex) with linear gradients of 100% acetonitrile and 0.1% TFA/water buffer system (30-50% acetonitrile in 60 min). The purity of peptide is assessed using analytical RP-HPLC and pooling criteria is >95%. The main pool purity of compound 1 is found to be 98.0%. Subsequent lyophilization of the final main product pool yielded the lyophilized peptide TFA salt. The molecular weight is determined by LC-MS (obsd. M+3=1657.2; Calc M+3=1657.0). |
Tags: 71989-20-3 synthesis path| 71989-20-3 SDS| 71989-20-3 COA| 71989-20-3 purity| 71989-20-3 application| 71989-20-3 NMR| 71989-20-3 COA| 71989-20-3 structure
[ 71989-16-7 ]
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-amino-4-oxobutanoic acid
Similarity: 0.97
[ 204320-60-5 ]
(R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-methylhexanoic acid
Similarity: 0.97
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