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CAS No. : | 112883-41-7 | MDL No. : | MFCD00155639 |
Formula : | C21H23NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VCFCFPNRQDANPN-LJQANCHMSA-N |
M.W : | 353.41 | Pubchem ID : | 2756111 |
Synonyms : |
|
Num. heavy atoms : | 26 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 99.59 |
TPSA : | 75.63 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.28 cm/s |
Log Po/w (iLOGP) : | 2.85 |
Log Po/w (XLOGP3) : | 4.48 |
Log Po/w (WLOGP) : | 4.17 |
Log Po/w (MLOGP) : | 3.0 |
Log Po/w (SILICOS-IT) : | 3.72 |
Consensus Log Po/w : | 3.64 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -4.6 |
Solubility : | 0.00886 mg/ml ; 0.0000251 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.79 |
Solubility : | 0.000575 mg/ml ; 0.00000163 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.08 |
Solubility : | 0.000292 mg/ml ; 0.000000826 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 3.86 |
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 |
---|---|---|
With PS-carbodiimide; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16.5h; | Example 111 [2- [ (2R)-2-BUTYL-4- (3-TRIFLUOROMETHYL-PYRIDIN-2-YL)-PIPERAZIN-1-YL]-5-] [TRIFLUOROMETHYL-7- (3,] 4, [5-TRIFLUORO-PHENYL)-LH-BENZOIMIDAZOLE,] trifluoroacetic acid salt. (a) Methyl N- [{ [ (9H-FLUOREN-9-YHNETHYL)] oxy] cqarbonyl}-d-norleucy6lglycinate. A mixture [OF FINOC-D-NLE-OH (LOG, 28.] 3 mmol, Novabiochem) and PS- carbodiimide (33 g, 42.45 mmol, 1.28 mmol/g, Argonaut Technologies [INC.)] in dichloromethane (250 mL) was stirred at room temperature for 0.5 h. Then, glycine methyl ester hydrochloride (5.3 g, 42.45 mmol, Aldrich), [HOAT] (3.8g, 28. 3 mmol, Perseptive Biosystems) and diisopropylethylamine (16 mL, 84.9 mmol, Aldrich) were added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the resin was washed with dichloromethane (2 x 70 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography, eluting with EtOAc/hexane (1: 2) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 425 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS); | EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; NaCO3; water; | EXAMPLE 3 Fmoc-D-Nle-OH D-Nle-OH (1.01 g) was dissolved in 30 ml of 10% NaCO3 and 10 ml of dioxan. While stirring, a solution of Fmoc-Cl (2.0 g) in 10 ml of dioxan was added to the solution. After stirring at room temperature for 2 hours, 400 ml of water was added to the mixture. The reaction mixture was extracted twice with 200 ml of ether to remove by-products. Ice was added to the aqueous phase and the mixture was neutralized with conc. hydrochloric acid. After extracting with ethyl acetate, the extract was washed with water. Crystallization from ether gave 933 mg of Fmoc-D-Nle-OH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.4 mg | Phenethylamine-AMEBA resin (Sigma Aldrich, 0.1 mmol, 1.0 mmol/g) was subjected to solid phase peptidesynthesis on an automatic peptide synthesizer (CEM Liberty Blue Microwave) with standard double Arg for the Arg residues and DNIe coupled double time. Amino acids were prepared as 0.2 M solutions in DMF. A standard coupling cycle was defined as follows:Amino acid coupling: AA (5 eq.), HA11J (5 eq.), DIEA (25 eq.)Washing: DMF (3x7 mE)Fmoc Deprotection: 20% Piperidine/0. 1 M HOBt (2x7 mE)Washing: DMF (4x7 mE then 1 x5 mE) 55Intermediate 41a (276 mg, 0.1 mmol) was combined with 4 mE TFA solution (37 mE TFA, 1 mE H20, 1 mE TIPS, 3.06 g DTT) and shaken at r.t. for 3 hours. The solution was removed from the resin and precipitated into 40 mE cold Et20. The solution was vortexed and let stand over ice for 10 minutes before centriffiging at 4000 rpm for 5 minutes. Thesolvent was removed and the white solid was washed twice 60 more with cold Et20 (40 mE each time), centrifuged (5 minutes each time) and decanted. The solid was dried under vacuum overnight yielding Intermediate 41b-batch 1 (17.4 mg, 0.012 mmol). ECMS (5Q2 ProductAnalysis-AcidicPeptide-Polar, Acquity UPEC HER C18 column, 130 A, 1.7 65 pm, 2.1 mmx50 mm, 50 C.): R=1.83 minutes, MS [M+R]1513.5. |
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 |
---|---|---|
11% | After the assembly of the peptide, the resin was washed with DMF (3x10 mE), DCM (3x10 mE). The peptide resin was dried under vacuum at room temperature to give Intermediate 43a (0.622 g, 0.25 mmol). After the assembly of the peptide, the resin was washed with DMF (3x10 mE), DCM (3x10 mE). The peptide resin was dried under vacuum at room temperature to give Intermediate 43a (0.622 g, 0.25 mmol). 1) Cleavage and Protecting Group RemovalTo intermediate 43a (0.622 g, 0.25 mmol) was added 3 mE solution of 95% TFA2.5% H20/2.5% TIPS and DTT (771 mg, 5.00 mmol), the resulting mixture was shaked at room temperature for 3 hours, then filtered. The filtrate wasdropped into 40 mE of cold ether, then centrifuged at 4000 rpm for 5 minutes. The solvent was removed and the white solid was washed with ether (3x40 mE), vortexed and centrifuged. The solid was dried under high vacuum at 25 C. forhour.2) PurificationThe above white solid was then purified by preparative HPEC (SunfireTM Prep C18 OI3DTM 30x50 mm Sum column ACN/H20 w/ 0.1% TFA 75 ml/min, 10-30% ACN 8 mmgradient). The product fraction was lyophilized to give intermediate 43b as TFA salt (44 mg, 11%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.6 g | (Loading of 2-Chlorotrityl Chloride Resin with Fmoc-D30 Nle-OH, Fmoc Removal and Determination ofthe Loading ofthe Resin)2-Chlorotrityl chloride resin (50.0 g, 85.0 mmol) was suspended in of DCM (400 mL) the suspension was stirred for 10mm and then the solvent was drained, the resin was washed with DCM (3x200 mL). Then a solution of Fmoc-D-Nle-OH(24.0 g, 68.0 mmol) and DIPEA (96.5 ml, 552.5 mmol) in DCM (120.0 mL) was added to the resin, the suspension wasflushed with nitrogen and stirred at it for 5 mm. Anotherportion of DIPEA (22.7 ml, 127.5 mmol) was added and thereaction mixture was stirred at it overnight.The reaction mixture was drained and the resin was washed with DCM (3x250 mL) for 2 mm each time. The resin wasquenched with of a mixture DCM/MeOH/DIPEA (70:15:15)(2x250 mL) for 10 mm each time.g).The Fmoc group was cleaved by treating the resin with piperidine/DMF (1:3) (1x300 mL) for 5 mm. the resin was drained then (1x300 mL) for 15 mm, followed by washingsteps: DMF (6x250 mL, 2 mm each time), isopropanol(2x250 mL, 2 mm each time) and TBME (6x250 mL, 2 mmeach time). The resin was dried under vacuum at 35 C. for 24hours to afford Intermediate 32a (57.8 g, loading=1 .08 mmol/ (Assembly of Linear Peptide)Amino acid coupling: AA (3.0 eq.), DIC (3.0 eq.), HOBt(3.0 eq.), DMF (see table below)Intermediate 32a (18.5 g, 20.0 mmol) was subjected tosolid phase peptide synthesis on an automatic peptide synthesizer (CSBIO536TM). A coupling cycle was defined as follows:Washing: DMF (4x150 mL, 2 mm each time). Fmoc deprotection: Piperidine/DMF (1:3) (150 mE for 5 mm then 150 mE for 15 mm).Washing: DMF (6x150 mE, 2 mm each time). Afier the assembly of the peptide, the resin was washed with DMF (6x1 SOmE, 2 mm each time), isopropanol (6x1 50mE, 2 mm each time) and TBME (6x150 mE, 2 mm each time). The peptide resin was dried overnight under high vacuum at 35 C. to give Intermediate 32b (57.6 g, 20.0 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Linear Peptide Synthesis on Solid Support: (0330) Fmoc-D-Tyr(tBu) Chlorotrityl resin (Substitution: 1.1 mmol/g) was subjected to manual solid phase peptide synthesis via standard Fmoc chemistry. 0.3 mmol resin was swelled in DMF for 30 minutes; DMF was drained and the resin was treated with 20% piperidine in DMF for 30 min to remove Fmoc group. The resin was washed by DMF 3 times and coupled with a pre-activated Fmoc amino acid solution (Fmoc amino acid/HBTU/HOBt/NMM=3:3:3:6eq) for 2 hours. Ninhydrin test was performed after each coupling to check the coupling efficiency. (0331) The peptide chain was assembled on resin by repetitive removal of the Fmoc protecting group and coupling of protected amino acid till N-term end. After the coupling of the last amino acid, peptide resin was washed with DMF and ethyl ether, and dried under vacuum. The dried peptide resin was treated with TFA cleavage cocktail (TFA/thiolanisole/phenol/EDT/H2O=87.5:5:2.5:2.5:2.5, v/v) for cleavage and removal of the side chain protecting groups. Crude peptides were precipitated from cold ether, collected by filtration and dried under high vacuum. Crude peptides was purified on HPLC (Column: 2?-inch Delta Pak C18, Wavelength: 215 nm) to afford desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Examples 45, 188, 189 and 192 are shown in Table 1. Procedure D as described above, was used for the preparation of the peptides. The peptides were synthesized starting with the amino acid Fmoc-Thr(tBu)-OH, which 15 was grafted to the resin (Fmoc-Thr(tBu)-2-chlorotrityl resin). The linear peptides were synthesized on the solid support according to method B, as described above, in the following sequence: Subsequently, ivDde deprotection at Q1, cleavage of the peptide from the resin, 20 macrolactam cycle formation (module B) by an amide bond between the a-carboxyl group of Thr at Q7 and the gamma-amino group of Dab at Q1, formation of the disulfide interstrand linkage between P2 and P11, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 45, 188, 189 and 192 25 r Table 2. 1.1.1.1 Coupling to the resin via a carboxyl group In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1% crosslinked; loading: 1.4 mMol/g) was swollen in dry CH2CI2 for 30 min (7 mL CH2CI2 per g resin). A solution of 0.8 eq of the Fmoc-protected amino acid and 6 eq of DIPEA in dry CH2CI2/DMF (4/1, v/v) (10 mL per g resin) was added. After shaking for 2-4 h at rt the resin was filtered off and washed successively with CH2CI2, DMF, CH2CI2, DMF and CH2CI2. Then a solution of dry CH2CI2/MeOH/DIPEA (17:2:1, v/v/v) was added (10 mL per g resin). After shaking for 3 x 30 min the resin was filtered off in a pre-weighed sinter funnel and washed successively with CH2CI2, DMF, CH2CI2, MeOH, CH2CI2, MeOH, CH2CI2 (2x) and Et20 (2x). The resin was dried under high vacuum overnight. The final mass of resin was calculated before the qualitative control. Loading was typically 0.6 - 0.7 mMol/g. The following preloaded resins were prepared: Fmoc-Thr(tBu)-2-chlorotrityl resin, Fmoc-DThr(tBu)-2-chlorotrityl resin, Fmoc-Val-2-chlorotrityl resin, Fmoc-DVal-2- chlorotrityl resin, Fmoc-Arg(Pbf)-2-chlorotrityl resin and Fmoc-DArg(Pbf)-2-chlorotrityl resin. 1.1.2 Methods for synthesis on solid support of the fully protected peptide fragment and of fully protected peptide fragments for fragment coupling The synthesis was carried out on a Syro-peptide synthesizer (MultiSynTech GmbH) using 24 to 96 reaction vessels. Unless otherwise indicated, in each vessel were placed 0.05 mMol of the resin, obtained from procedure 1.1.1.1 as described above, and the resin was swelled in CH2CI2 and DMF for 15 min, respectively. The following reaction cycles were programmed and carried out as described in the methods A - L, as described herein below: Step Reagent Time 1 CH2CI2, wash and swell (manual) 1 x 3 min 2 DMF, wash and swell 2 x 30 min 3 20% piperidine/DMF 1 x 5 min and 1 x 15 min 4 DMF, wash 5 x 1 min 5 a) 3.6 eq appropriately protected amino acid and 3.6 eq HOAt in DMF or NMP + 3.6 eq DIC in DMF 1 x 40 min 6 3.6 eq appropriately protected amino acid and 3.6 eq HOAt in DMF or NMP + 3.6 eq HATU + 7.2 eq DIPEA in NMP l x 40 min 7 DMF, wash 5 x 1 min 8 20% piperidine/DMF 1 x 5 min and 1 x 15 min or 2 x 2 min b) 9 DMF, wash 5 x 1 min 10 CH2CI2, wash (at the end of the synthesis) 3 x 1 min a) In the coupling cycle following coupling of an N-alkyl amino acid residue and for coupling of the first protected amino acid residue to Sieber amide resin, step 5 was omitted and step 6 was performed twice instead, b) Reduced times were used for Fmoc deprotection of an amino acid residue having a carboxyl group protected as allyl ester, and for the Fmoc deprotection step of the following coupling cycle. 1.1.2.2 Method B The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide fragment, using appropriately protected Fmoc amino acid building blocks, except for the last coupling. For the latter an appropriately protected Boc amino acid building block was used. Steps 5 to 9 are repeated to add each amino acid residue, except for the last amino acid residue, which was added by steps 5 to 7, followed by step 10. 1.1.3.3 Procedure D: Preparation of a peptide having a disulfide interstrand linkage(s) in module A and having a free N-terminal amino group The linear peptide was assembled on solid support according to Method B, as described above. Appropriately protected amino acid building blocks with a thiol group protected as trityl thioether were used for addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage. For addition of the last amino acid residue of the peptide chain an appropriately protected Boc amino acid building block was used. Subsequent ivDde deprotection (module B), cleavage, macrolactam cycle formation (module B), formation of a disulfide interstrand linkage(s) (module A), and full deprotection were performed as described in the corresponding sections of procedure C, following the same order. Finally, the peptide was purified ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Examples 199 to 205 are shown in Table 1. Procedure D, as described above, was used for the preparation of the peptides. The peptides were synthesized starting with the amino acid Fmoc-Thr(tBu)-OH, which was grafted to the resin (Fmoc-Thr(tBu)-2-chlorotrityl resin). The linear peptides were synthesized on the solid support according to method B, as described above, in the following sequence: Subsequently, deprotection at Q1, cleavage of the peptide from the resin, macrolactam cycle formation (module B) by an amide bond between the a-carboxyl group of Thr at Q7 and the gamma-amino group of Dab at Q1, formation of the disulfide interstrand linkage between P13 and P14, and full deprotection were performed as indicated in procedure D above. Finally, the peptides were purified, as described above, and characterized by HPLC-MS. For analytical data, see Ex. 199 to 205 in Table 2. 1.1.1.1 Coupling to the resin via a carboxyl group In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1% crosslinked; loading: 1.4 mMol/g) was swollen in dry CH2CI2 for 30 min (7 mL CH2CI2 per g resin). A solution of 0.8 eq of the Fmoc-protected amino acid and 6 eq of DIPEA in dry CH2CI2/DMF (4/1, v/v) (10 mL per g resin) was added. After shaking for 2-4 h at rt the resin was filtered off and washed successively with CH2CI2, DMF, CH2CI2, DMF and CH2CI2. Then a solution of dry CH2CI2/MeOH/DIPEA (17:2:1, v/v/v) was added (10 mL per g resin). After shaking for 3 x 30 min the resin was filtered off in a pre-weighed sinter funnel and washed successively with CH2CI2, DMF, CH2CI2, MeOH, CH2CI2, MeOH, CH2CI2 (2x) and Et20 (2x). The resin was dried under high vacuum overnight. The final mass of resin was calculated before the qualitative control. Loading was typically 0.6 - 0.7 mMol/g. The following preloaded resins were prepared: Fmoc-Thr(tBu)-2-chlorotrityl resin, Fmoc-DThr(tBu)-2-chlorotrityl resin, Fmoc-Val-2-chlorotrityl resin, Fmoc-DVal-2- chlorotrityl resin, Fmoc-Arg(Pbf)-2-chlorotrityl resin and Fmoc-DArg(Pbf)-2-chlorotrityl resin. 1.1.2 Methods for synthesis on solid support of the fully protected peptide fragment and of fully protected peptide fragments for fragment coupling The synthesis was carried out on a Syro-peptide synthesizer (MultiSynTech GmbH) using 24 to 96 reaction vessels. Unless otherwise indicated, in each vessel were placed 0.05 mMol of the resin, obtained from procedure 1.1.1.1 as described above, and the resin was swelled in CH2CI2 and DMF for 15 min, respectively. The following reaction cycles were programmed and carried out as described in the methods A - L, as described herein below: Step Reagent Time 1 CH2CI2, wash and swell (manual) 1 x 3 min 2 DMF, wash and swell 2 x 30 min 3 20% piperidine/DMF 1 x 5 min and 1 x 15 min 4 DMF, wash 5 x 1 min 5 a) 3.6 eq appropriately protected amino acid and 3.6 eq HOAt in DMF or NMP + 3.6 eq DIC in DMF 1 x 40 min 6 3.6 eq appropriately protected amino acid and 3.6 eq HOAt in DMF or NMP + 3.6 eq HATU + 7.2 eq DIPEA in NMP l x 40 min 7 DMF, wash 5 x 1 min 8 20% piperidine/DMF 1 x 5 min and 1 x 15 min or 2 x 2 min b) 9 DMF, wash 5 x 1 min 10 CH2CI2, wash (at the end of the synthesis) 3 x 1 min a) In the coupling cycle following coupling of an N-alkyl amino acid residue and for coupling of the first protected amino acid residue to Sieber amide resin, step 5 was omitted and step 6 was performed twice instead, b) Reduced times were used for Fmoc deprotection of an amino acid residue having a carboxyl group protected as allyl ester, and for the Fmoc deprotection step of the following coupling cycle. 1.1.2.2 Method B The reaction cycles, as described herein above, were applied for the assembly of the fully protected peptide fragment, using appropriately protected Fmoc amino acid building blocks, except for the last coupling. For the latter an appropriately protected Boc amino acid building block was used. Steps 5 to 9 are repeated to add each amino acid residue, except for the last amino acid residue, which was added by steps 5 to 7, followed by step 10. 1.1.3.3 Procedure D: Preparation of a peptide having a disulfide interstrand linkage(s) in module A and having a free N-terminal amino group The linear peptide was assembled on solid support according to Method B, as described above. Appropriately protected amino acid building blocks with a thiol group protected as trityl thioether were used for addition of amino acid residues that are involved in the formation of a disulfide interstrand linkage. For addition of the last amino acid residue of the peptide chain an appropriately protected Boc amino acid building block was used. Subsequent ivDde deprotection (module B), cleavage, macrolactam cycle formation (module B), formation of a disulfide interstrand linkage(s) (module A), and full deprotection were performed as described in the corresponding sections of procedure C, following the same order. Finally, the peptide was purified by preparative reverse phase LC-... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72 mg | 2-Chlorotrityl chloride resin loaded with D-phenylalanine H-f-O-Pol (0.100 mmol) was subjected to solid phase peptide synthesis on the Liberty microwave peptide synthesizer. Coupling was performed as follows: A mixture of 95% aq. TFA/EDT/DTT (92.5:2.5:5) (3 mL) was added to Intermediate 1a (0.1 mmol) and the suspension was shaken at rt for 3 h, and filtered. The cleavage solution was dropped onto cold diethyl ether (20 mL), giving a precipitate. The suspension was centrifuged and the supernatant poured off. Diethyl ether (20 mL) was added to the residue. The suspension was vortexed for 3 min, centrifuged, and the supernatant was poured off. The washing process was repeated twice. The solid was dried in high vacuum. The crude was purified by preparative HPLC and lyophilized from ACN/H2O to afford Intermediate 2b (72 mg, 0.037 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | Phenethylamine-AMEBA-PS-resin (Aldrich, 0.100 mmol) was subjected to solid phase peptide synthesis on the Liberty microwave peptide synthesizer. Coupling was performed as follows: A mixture of 95% aq. TFA/EDT/DTT (92.5:2.5:5) (3 mL) was added to Intermediate 3a (0.1 mmol) and the suspension was shaken at rt for 3 h, and filtered. The cleavage solution was dropped onto cold diethyl ether (20 mL), giving a precipitate. The suspension was centrifuged and the supernatant poured off. Diethyl ether (20 mL) was added to the residue. The suspension was vortexed for 3 min, centrifuged, and the supernatant was poured off. The washing process was repeated twice. The solid was dried in high vacuum. The crude was purified by preparative HPLC and lyophilized from ACN/H2O to afford Intermediate 3b (30 mg, 0.016 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The synthesis of peptides 2-12 was performed in a stepwise fashion via solid-phase peptide strategy (SPPS) as elsewhere reported [45]. In particular, each peptide was constructed on the Rink amide resin (0.1mmol from 0.64mmol/g of loading substitution) as solid support. The resin, stored as Fmoc-protected on the primary amine of the rink amide linker, was first swollen in DMF for 30min, then treated with 20% piperidine in DMF solution (5min×1, 25min×1). Peptide bond formation by the coupling with the first residue Nalpha-Fmoc-Leu (3 equiv) was achieved by using 3-fold excess of HBTU and HOBt, in the presence of a 6-fold excess of DIEA. Deprotection of the Nalpha-Fmoc was carried out by treatment with 20% piperidine in DMF solution (5min×1, 25min×1) as described above. After each coupling and Fmoc-deprotection step, the peptide resin was washed with DMF (3×2mL), DCM (3×2mL) and DMF (3×2mL), and reactions were monitored by the Kaiser and Chloranil tests as colorimetric assays for the detection of solid-phase bound primary and secondary amines, respectively. The peptide sequences of 1 and its derivatives 2-12 were thereby assembled. The N-terminal Fmoc group was deblocked, as previously explained, and the peptide-resin was thoroughly washed with DCM (5×2mL) and dried under argon to yield dried peptide-resin. Peptides 2-12 were released from the resin and cleaved by their protecting groups simultaneously by using a cocktail of 95:2.5:2.5 TFA/TIS/H2O at rt for 3h. The resin was removed by filtration and crude peptides were recovered by precipitation with chilled anhydrous Et2O as white to pale beige-colored amorphous solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In hexane; isopropyl alcohol; at 25℃;Resolution of racemate; | Analysis was performed usingan HP series 1100 HPLC system (Palo Alto, CA, USA),consisting of a G1310A iso pump, an automatic sample injector, and an HP 1046A programmable fluorescencedetector. The chromatographic analysis was performedunder simultaneous UV 262 nm and fluorescence [excitation(Ex.) 264 and emission (Em.) 312 nm] detection. Allenantiomeric separations of alpha-amino acids and methyl estersas N-FMOC derivatives were performed using isocraticmobile phases [10 or 20% 2-propanol/hexane (v/v) with orwithout 0.1% TFA] at an ambient temperature (approximately25 C) with a flow rate of 1 mL/min. Three covalentlybonded CSPs, CSP 1 (Chiralpak ID), CSP 2 (Chiralpak IE),and CSP 3 (Chiralpak IF) (250 mm × 4.6 mm, I.D., 5 mum)having chiral selectors of amylose tris (3-chlorophenylcarbamate),amylose tris (3,5-dichlorophenylcarbamate), and amylosetris (3-chloro-4-methylphenylcarbamate), respectively,were purchased from the Daicel Company (Tokyo, Japan). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General method for preparation of the peptide and introduction of the substituent The preparation of the peptide was carried out with SPPS using Fmoc based chemistry on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 U.S.A.). The Fmoc-protected amino acids used in the methods were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(Mmt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Boc-Lys(Fmoc)-OH Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc- Tyr(tBu)-OH, Fmoc-Val-OH and Fmoc-Lys(Mtt)-OH supplied from e.g. Anaspec, Bachem, Iris Biotech or NovabioChem. A Wang resin preloaded with an amino acid such as Fmoc-Phe-Wang resin or the like was used (for derivatives containing Nphe, 4-CI-Nphe, or alpha-Me-Phe, a 2-Chlorotrityl resin was used). Fmoc- deprotection was achieved with 20% piperidine in NMP. Peptide couplings were performed by using DIC/Oxyma Pure with collidine. Amino acid/Oxyma Pure solutions (0.3 M/0.3 M in DMF at a molar excess of 3-10 fold) was added to the resin followed by the same molar equivalent of DIC (3 M in NMP) followed by collidine (3 M in NMP). Fmoc-Cys(Trt)-OH was used for peptides prepared for methylene bridge introduction according to method A, while Fmoc-Cys(Mmt)-OH was used for peptides prepared for methylene bridge introduction according to method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General method for preparation of the peptide and introduction of the substituent The preparation of the peptide was carried out with SPPS using Fmoc based chemistry on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 U.S.A.). The Fmoc-protected amino acids used in the methods were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(Mmt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Boc-Lys(Fmoc)-OH Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc- Tyr(tBu)-OH, Fmoc-Val-OH and Fmoc-Lys(Mtt)-OH supplied from e.g. Anaspec, Bachem, Iris Biotech or NovabioChem. A Wang resin preloaded with an amino acid such as Fmoc-Phe-Wang resin or the like was used (for derivatives containing Nphe, 4-CI-Nphe, or alpha-Me-Phe, a 2-Chlorotrityl resin was used). Fmoc- deprotection was achieved with 20% piperidine in NMP. Peptide couplings were performed by using DIC/Oxyma Pure with collidine. Amino acid/Oxyma Pure solutions (0.3 M/0.3 M in DMF at a molar excess of 3-10 fold) was added to the resin followed by the same molar equivalent of DIC (3 M in NMP) followed by collidine (3 M in NMP). Fmoc-Cys(Trt)-OH was used for peptides prepared for methylene bridge introduction according to method A, while Fmoc-Cys(Mmt)-OH was used for peptides prepared for methylene bridge introduction according to method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General method for preparation of the peptide and introduction of the substituent The preparation of the peptide was carried out with SPPS using Fmoc based chemistry on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 U.S.A.). The Fmoc-protected amino acids used in the methods were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(Mmt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Boc-Lys(Fmoc)-OH Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc- Tyr(tBu)-OH, Fmoc-Val-OH and Fmoc-Lys(Mtt)-OH supplied from e.g. Anaspec, Bachem, Iris Biotech or NovabioChem. A Wang resin preloaded with an amino acid such as Fmoc-Phe-Wang resin or the like was used (for derivatives containing Nphe, 4-CI-Nphe, or alpha-Me-Phe, a 2-Chlorotrityl resin was used). Fmoc- deprotection was achieved with 20% piperidine in NMP. Peptide couplings were performed by using DIC/Oxyma Pure with collidine. Amino acid/Oxyma Pure solutions (0.3 M/0.3 M in DMF at a molar excess of 3-10 fold) was added to the resin followed by the same molar equivalent of DIC (3 M in NMP) followed by collidine (3 M in NMP). Fmoc-Cys(Trt)-OH was used for peptides prepared for methylene bridge introduction according to method A, while Fmoc-Cys(Mmt)-OH was used for peptides prepared for methylene bridge introduction according to method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General method for preparation of the peptide and introduction of the substituent The preparation of the peptide was carried out with SPPS using Fmoc based chemistry on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 U.S.A.). The Fmoc-protected amino acids used in the methods were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(Mmt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Boc-Lys(Fmoc)-OH Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc- Tyr(tBu)-OH, Fmoc-Val-OH and Fmoc-Lys(Mtt)-OH supplied from e.g. Anaspec, Bachem, Iris Biotech or NovabioChem. A Wang resin preloaded with an amino acid such as Fmoc-Phe-Wang resin or the like was used (for derivatives containing Nphe, 4-CI-Nphe, or alpha-Me-Phe, a 2-Chlorotrityl resin was used). Fmoc- deprotection was achieved with 20% piperidine in NMP. Peptide couplings were performed by using DIC/Oxyma Pure with collidine. Amino acid/Oxyma Pure solutions (0.3 M/0.3 M in DMF at a molar excess of 3-10 fold) was added to the resin followed by the same molar equivalent of DIC (3 M in NMP) followed by collidine (3 M in NMP). Fmoc-Cys(Trt)-OH was used for peptides prepared for methylene bridge introduction according to method A, while Fmoc-Cys(Mmt)-OH was used for peptides prepared for methylene bridge introduction according to method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General method for preparation of the peptide and introduction of the substituent The preparation of the peptide was carried out with SPPS using Fmoc based chemistry on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 U.S.A.). The Fmoc-protected amino acids used in the methods were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(Mmt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Boc-Lys(Fmoc)-OH Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc- Tyr(tBu)-OH, Fmoc-Val-OH and Fmoc-Lys(Mtt)-OH supplied from e.g. Anaspec, Bachem, Iris Biotech or NovabioChem. A Wang resin preloaded with an amino acid such as Fmoc-Phe-Wang resin or the like was used (for derivatives containing Nphe, 4-CI-Nphe, or alpha-Me-Phe, a 2-Chlorotrityl resin was used). Fmoc- deprotection was achieved with 20% piperidine in NMP. Peptide couplings were performed by using DIC/Oxyma Pure with collidine. Amino acid/Oxyma Pure solutions (0.3 M/0.3 M in DMF at a molar excess of 3-10 fold) was added to the resin followed by the same molar equivalent of DIC (3 M in NMP) followed by collidine (3 M in NMP). Fmoc-Cys(Trt)-OH was used for peptides prepared for methylene bridge introduction according to method A, while Fmoc-Cys(Mmt)-OH was used for peptides prepared for methylene bridge introduction according to method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General method for preparation of the peptide and introduction of the substituent The preparation of the peptide was carried out with SPPS using Fmoc based chemistry on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 U.S.A.). The Fmoc-protected amino acids used in the methods were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(Mmt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Boc-Lys(Fmoc)-OH Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc- Tyr(tBu)-OH, Fmoc-Val-OH and Fmoc-Lys(Mtt)-OH supplied from e.g. Anaspec, Bachem, Iris Biotech or NovabioChem. A Wang resin preloaded with an amino acid such as Fmoc-Phe-Wang resin or the like was used (for derivatives containing Nphe, 4-CI-Nphe, or alpha-Me-Phe, a 2-Chlorotrityl resin was used). Fmoc- deprotection was achieved with 20% piperidine in NMP. Peptide couplings were performed by using DIC/Oxyma Pure with collidine. Amino acid/Oxyma Pure solutions (0.3 M/0.3 M in DMF at a molar excess of 3-10 fold) was added to the resin followed by the same molar equivalent of DIC (3 M in NMP) followed by collidine (3 M in NMP). Fmoc-Cys(Trt)-OH was used for peptides prepared for methylene bridge introduction according to method A, while Fmoc-Cys(Mmt)-OH was used for peptides prepared for methylene bridge introduction according to method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General method for preparation of the peptide and introduction of the substituent The preparation of the peptide was carried out with SPPS using Fmoc based chemistry on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 U.S.A.). The Fmoc-protected amino acids used in the methods were the standard recommended : Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(Mmt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Boc-Lys(Fmoc)-OH Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc- Tyr(tBu)-OH, Fmoc-Val-OH and Fmoc-Lys(Mtt)-OH supplied from e.g. Anaspec, Bachem, Iris Biotech or NovabioChem. A Wang resin preloaded with an amino acid such as Fmoc-Phe-Wang resin or the like was used (for derivatives containing Nphe, 4-CI-Nphe, or alpha-Me-Phe, a 2-Chlorotrityl resin was used). Fmoc- deprotection was achieved with 20% piperidine in NMP. Peptide couplings were performed by using DIC/Oxyma Pure with collidine. Amino acid/Oxyma Pure solutions (0.3 M/0.3 M in DMF at a molar excess of 3-10 fold) was added to the resin followed by the same molar equivalent of DIC (3 M in NMP) followed by collidine (3 M in NMP). Fmoc-Cys(Trt)-OH was used for peptides prepared for methylene bridge introduction according to method A, while Fmoc-Cys(Mmt)-OH was used for peptides prepared for methylene bridge introduction according to method B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: All reactions were carried out in polypropylene empty reservoirs (15mL) fitted with polyethylene frits and polytetrafluoroethylene stopcock at room temperature.Loading of first amino acid: 2-chlorotrityl chloride resin (75mg, 1.0mmol/g) was swelled in DCM (3.0mL) for 30min. DCM was removed then a solution of Fmoc-protected amino acid (3.0 equiv.) and DIPEA (4.0 equiv.) in DCM (1.3mL) was added. The reservoir was shaken for 240min, the reaction mixture was filtered, the coupling repeated once and the resin was washed with DMF (3x2.5mL, 0.5min). A mixture of DCM/MeOH/DIPEA (80/15/5, 2.5mL) was added to the resin, the reservoir was shaken for 10min, the reaction mixture was filtered, the capping repeated once and the resin was washed with DMF (3x2.5mL, 0.5min), MeOH (1x2.5mL, 0.5min) and DCM (6x2.5mL, 0.5min).Fmoc removal was achieved with a solution DMF/piperidine (80:20, 4.0mL, 20 minx2) then the resin was washed with DMF (5x2.5mL, 0.5min), MeOH (1x2.5mL, 0.5min), DCM (1x2.5mL) and DMF (2x2.5mL, 0.5min) .Addition of next amino acids was achieved using the following conditions: Fmoc-protected amino acid (3.0 equiv.), DMF (1.3mL) then DIPEA (4.0 equiv.) were added to the resin and the reservoir was shaken until full dissolution. HBTU (2.9 equiv.) was added and the reservoir was shaken for 120min. The reaction mixture was filtered, the coupling repeated once and the resin was washed with DMF (3x2.5mL, 0.5min), MeOH (1x2.5mL, 0.5min) and DCM (6x2.5mL, 0.5min).Cleavage from the resin and global deprotection was achieved using the following conditions: after the last Fmoc removal the resin was rinsed carefully with DCM (5x2.5mL, 2min) and dried overnight (18h) at room temperature. 2.0mL of cleavage cocktail were freshly prepared (TFA/H2O/TIS, 85/7.5/7.5) and added to the resin. The mixture was shaken for 3h and the solution was added dropwise to tubes containing 30mL of cold (0C) TBME. This step was repeated once, the cold mixture was stirred at 0C for 30min and the tubes were centrifuged (2,200 g, 5min). The supernatant was discarded, the solid was washed with cold TBME (10mL) and then centrifuged again (2,200 g, 5min). The crude product obtained was air-dried (3h) at room temperature, dissolved in water and freeze dried.Crude peptides were purified on semi preparative HPLC. Pure fractions were combined, lyophilized. TFA salt was exchanged for HCl salt by dissolving the pure peptide in aqueous HCl solution (0.05M) at a concentration of 20mg/mL. The solution obtained was freeze dried and this step was repeated twice. HCl salt of the peptide was analysed on analytical LC-MS. All peptides were of purity>95%. |
[ 371770-32-0 ]
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-cyclopentylpropanoic acid
Similarity: 0.99
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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