Structure of 4-Fluorobenzoic acid
CAS No.: 456-22-4
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Ramirez, Eduardo ; Min, Sehong ; Ganegamage, Susantha K. ; Shimanaka, Kazuma ; Sosa, Magaly Guzman ; Dettmer, Ulf , et al.
Abstract: Alzheimer's disease (AD) is a multifactorial, chronic neurodegenerative disease characterized by the presence of extracellular beta-amyloid (Abeta) plaques, intraneuronal neurofibrillary tangles (NFTs), activated microglial cells, and an inflammatory state (involving reactive oxygen species production) in the brain. NFTs are comprised of misfolded and hyperphosphorylated forms of the microtubule-binding protein tau. Interestingly, the trimeric form of the 2N4R splice isoform of tau has been found to be more toxic than the trimeric 1N4R isoform in neuron precursor cells. Few drug discovery programs have focused on specific tau isoforms. The present drug discovery project is centered on the anti-aggregation effect of a series of seventeen 4- or 5-aminoindole carboxamides on the 2N4R isoform of tau. The selection of the best compounds was performed using alpha-synuclein (alpha-syn). The anti-oligomer and -fibril activities of newly synthesized aminoindole carboxamide derivatives were evaluated with biophys. methods, such as thioflavin T fluorescence assays, photo-induced crosslinking of unmodified proteins, and transmission electron microscopy. To evaluate the reduction of inclusions and cytoprotective effects, M17D neuroblastoma cells expressing inclusion-forming alpha-syn were treated with the best amide representatives. The 4-aminoindole carboxamide derivatives exhibited a better anti-fibrillar activity compared to their 5-aminoindole counterparts. The amide derivatives 2, 8, and 17 exerted anti-oligomer and anti-fibril activities on alpha-syn and the 2N4R isoform of tau. At a concentration of 40 μM, compound 8 reduced inclusion formation in M17D neuroblastoma cells expressing inclusion-prone alphaSynuclein3K::YFP. Our results demonstrate the potential of 4-aminoindole carboxamide derivatives with regard to inhibiting the oligomer formation of alpha-syn and tau (2N4R isoform) for further optimization prior to pre-clin. studies.
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Keywords: Alzheimer's disease ; Amide ; Alpha-synuclein ; Fibril ; Oligomer
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Purchased from AmBeed: 527-72-0 ; 5192-23-4 ; 586-38-9 ; 456-22-4 ; 5192-03-0 ; 6019-39-2 ; 153-78-6 ; 455-24-3 ; 182564-41-6 ; 708987-59-1
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CAS No. : | 456-22-4 |
Formula : | C7H5FO2 |
M.W : | 140.11 |
SMILES Code : | C1=CC(=CC=C1C(O)=O)F |
MDL No. : | MFCD00002530 |
InChI Key : | BBYDXOIZLAWGSL-UHFFFAOYSA-N |
Pubchem ID : | 9973 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 33.36 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.24 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.07 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.94 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.04 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.64 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.79 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.39 |
Solubility | 0.57 mg/ml ; 0.00407 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.48 |
Solubility | 0.461 mg/ml ; 0.00329 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.02 |
Solubility | 1.33 mg/ml ; 0.00948 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.68 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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 |
---|---|---|
96% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC·HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79%). |
92% | General procedure: To a solution of acid 1 (1.0g, 8.9 mmol) in THF (15 mL) was added Et3N (3.1 mL, 22.2 mmol), and T3P (50% solution in EtOAc, 10.6mL, 17.7 mmol) at 0-5 C and the solution was stirred for about 10 min under a nitrogen atmosphere. Then N,O-dimethylhydroxylaminehydrochloride salt (1.1g, 13.3 mmol) was added to the reaction mixture at 0-5 C and the heterogeneous mixture was allowed to stir at room temperature till the completion of the reactionas indicated by TLC (see Table S-1). The mixture was then diluted with water(20 mL) followed by ethyl acetate (20 mL) and stirred for about 10 min. The separated organic layer was collected, washed with 5% citric acid (2 x10 mL),5% Na2CO3 (2 x 10 mL), and then brine solution. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The crude product obtainedwas purified by flash column chromatography over silicagel (100-200 mesh) using 12-15% EtOAc / n-hexane as eluent to affordthe desired compound. | |
79% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; at 20℃; for 2h; | Step 4a: 4-Fluoro-N-methoxy-N-methyl-benzamide (4a)To a solution of 4-fluorobenzoic acid (6.8 g, 48.57 mmole) in 100 mL of DMF at room temperature, is added diisopropylethylamine (25.3 mL, 145.7 mmole). After stirring at room temperature for 20 minutes, HOBT (7.22 g, 53.43 mmole), HBTU (20.26 g, 53.43 mmole) and N,O-dimethyl hydroxylamine hydrochloride (5.69 g, 58.29 mmole) are added to the reaction solution. After stirring at room temperature for 2 hours, the reaction solution is diluted with 200 mL of EtOAc and washed with 4×50 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70%, EtOAc 30%) to yield 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (7.0 g, yield 79%). |
77% | Method C: a solution of ethyl chloroformate (3.40mL, 35.68mmol) in anhydrous dichloromethane (6mL) was added dropwise at 10C to a solution of 4-fluorobenzoic acid (5.00g, 35.68mmol) and triethylamine (5mL, 35.68mmol) in anhydrous dichloromethane (50mL). This reaction mixture was stirred at 10C for 50min, and then N,O-dimethylhydroxylamine hydrochloride (3.48g, 35.68mmol) and triethylamine (5mL, 35.68mmol) were added. The resulting mixture was stirred for 1h at 10C and the suspension was taken up in water (150mL) and extracted with CH2Cl2 (150mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was finally chromatographed on silica gel eluting with ethyl acetate:petroleum ether (gradient from 0/100 to 20/80 v/v) to give 77% of 3a as clear oil. 1H NMR (300MHz, CDCl3) delta 7.69 (m, 2H, F-Ph-2,6), 7.02 (m, 2H, F-Ph-3,5), 3.47 (d, 3H, J=1.2Hz, OCH3), 3.29 (d, 3H, J=1.2Hz, NCH3). 13C NMR (75MHz, CDCl3) delta 168.7, 164.0 (J=249Hz), 130.8 (2×C, J=9Hz), 129.8 (J=3Hz), 115.0 (2×C, J=22Hz), 61.0, 33.6. | |
75% | General procedure: A. To a mixture of benzoic acid (50 mg, 0.41 mmol, 1 equiv), PPh3 (160 mg, 0.61 mmol, 1.5 equiv) and NBS (108.5 mg, 0.61 mmol, 1.5 equiv), CH2Cl2 (2 ml) was added and the reaction was stirred at 0 C for 15 min. The reaction was brought to room temperature and N,O-dimethylhydroxylamine hydrochloride (59.5 mg, 0.61 mmol, 1.5 equiv) and Et3N (45.5 mg, 63 mul, 0.45 mmol, 1.1 equiv) were added and reaction was stirred for 1 h at room temperature. The reaction mixture was quenched with aqueous sodium bicarbonate solution and diluted with CH2Cl2. The bicarbonate washings were again extracted with CH2Cl2 and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Column chromatography was performed using EtOAc/Petroleum ether (1:5). | |
57% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0 C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57%). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90% (UV254). |
53.9% | Thecompound10bcanbesynthesizedaccordingtotherouteoftheabovescheme(Scheme11).Toamixtureofcompound134-fluorobenzoicacid(3g,21.42mmol,1.0eq.)inDCM(30mL)andDMF(0.3mL)wasaddedoxaloylchloride(2.99g,23.55mmol,1.1eq.)slowly.Thenthereactionmixturewasstirredatroomtemperaturefor1hour.AfterthatN,O-Dimethylhydroxylaminehydrochloride(2.5g,25.69mmol,1.2eq.)andEt 3N(9.0mL,62.4mmol,1.2eq.)wereaddedintothereactionmixture.Andthemixturewasstirredatroomtemperatureforadditional2hours.TLC(petroleumether/EtOAc=10/1)showedthestartingmaterialwasconsumedcompletely.Themixturewaspouredintowater(100mL),extractedwithEtOAc(100mL×3).Thecombinedorganiclayerswerewashedwithbrine(100mL×1),driedoverNa 2SO 4,filtered,andconcentratedinvacuotogivethecrudecompound14.Thecrudeproductwaspurifiedbygelchromatography(petroleumether/EtOAc=20/1)togivecompound8b(2.1g,53.9%yield)asacolorlessoil.MS:184(M+H +). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; | A. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c. A solution of 1.0 g (4.9 mmol) of <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> 9a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c, which was used without purification. MS m/z (M+H+) 290.1. | |
With triethylamine; HATU; In N,N-dimethyl-formamide; | A solution of 1.0 g (4.9 mmol) of <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> 8a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 8b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 8c, which was used without purification. MS m/z (M+H+) 290.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | To a flask containing 4-fluorobenzoic acid (385 mg, 2.75 mmol) was added DMF (9 mL). CDI (446 mg, 2.75 mmol) was added and the reaction was stirred at room temperature for 15 min. At this point, 12 (391 mg 2.50 mmol) and additional DMF (4 mL) were added. The reaction was heated to 100 oC and stirred overnight. A solution of 1 M NaOH was added (10 mL), the mixture was poured into 100 mL of ice water, and the precipitate was collected by filtration. The crude material was absorbed onto celite using DMF and then purified by flash column chromatography (1% DMF in dichloromethane) to afford 17 (77 mg, 0.277 mmol, 11%) as an orange solid; MS (ESI) m/z calcd. 278.05, found 279.06 [M + H]+; Purity was determined to be 94.01% by HPLC analysis. Compound 17 was used immediately without full characterization. See 9 for characterization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With di-tert-butyl peroxide; copper(II) bis(trifluoromethanesulfonate); In 1,2-dichloro-ethane; at 130℃; for 12h;Sealed tube; | General procedure: A 50 mL sealed tube (with a Teflon high pressure valve) equipped with a magnetic stir bar was charged with Cu(OTf)2 (0.05 mmol), followed by carboxylic acid (0.5 mmol), formamide (2.0 mmol), tert-butyl peroxide (DTBP, 1 mmol), and DCE (1 mL). After the reaction mixture was stirred at 130 C for 12 h, it was allowed to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate, and then filtered through a small pad of Celite. The filtrate was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL, twice). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 23℃; for 3.0h; | General procedure: To a suspension of 3-chloro-4-fluorobenzoic acid (25.0 g, 143 mmol), Methylamine hydrochloride (11.60 g, 172 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (41.2 g, 215 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (32.9 g, 215 mmol) in DMF (Volume: 150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23 C. The reaction was stirred at 23 C for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23C affording a suspension. The suspension was filtered, washed with H2O (3 x 100 mL), and the resulting solid was dried in vacuo at 30 C to provide 3-chloro-4-fluoro-N-methylbenzamide ( 14.24 g, 76 mmol, 53.0 % yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dmap; In tert-butyl alcohol; at 0 - 20℃; for 4h; | Tert-butyl 4-fluorobenzoate. To the solution of 4-fluorobenzoic acid (10 g, 0.07 mol) in tert-Butanol (200 ml) was added 4-di methylaminopyridine (4.36 g, 35.7 mmol), then Pyrocarbonic acid di-tert-butyl ester (31.1 g, 0.14 mol) was added at C, the solution was stirred for 4h at room temperature, then water (200 ml) was added and extracted with dichloromethane, evaporated the solvent purified by column chromatography (silica gel, Petroleum ether / ethyl acetate = 20: 1) to give tert-butyl 4-fluorobenzoate (10.2 g, 74%) H- NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) delta 7.98(m, 2H), 7.15 (m, 2H), 1.59 (s, 9H) |
74% | With dmap; In tert-butyl alcohol; at 0 - 20℃; for 4h; | To the solution of 4-fluorobenzoic acid (10 g, 0.07 mol) in tert-Butanol (200 ml) was added 4-di methylaminopyridine (4.36 g, 35.7 mmol), then Pyrocarbonic acid di-tert-butyl ester (31.1 g, 0.14 mol) was added at 0 C., the solution was stirred for 4 h at room temperature, then water (200 ml) was added and extracted with dichloromethane, evaporated the solvent purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give tert-butyl 4-fluorobenzoate (10.2 g, 74%) H-NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) delta 7.98 (m, 2H), 7.15 (m, 2H), 1.59 (s, 9H) |
15 g | With dmap; In tert-butyl alcohol; at 0 - 20℃; for 16h; | 35.0 g of p-fluorobenzoic acid and 15.0 g of dimethylaminopyridine were dissolved in 500 mL of t-butanol and cooled to 0 C.107.50 g of di-tert-butyl dicarbonate was added to the mixture, followed by stirring at room temperature for 16 h.Purification by column chromatography to obtain a colorless oily product.The oily product was combined with 15.0 g of the intermediate product represented by formula (III).60.0 g of cesium carbonate was dissolved in 300 mL of dimethyl sulfoxide and heated continuously at 110 C for 16 h.Dimethyl sulfoxide was removed by distillation under reduced pressure. Add 200 mL of water to the residue.It was extracted with dichloromethane, dried over sodium sulfate and concentrated, and the residue was purified by column chromatography eluting with methanol/dichloromethane (50:1 by volume).The product of 6.0 g of a white solid was obtained at room temperature with hydrochloric acid/tetrahydrofuran (12 mol/L concentrated hydrochloric acid)A mixture of 10 ml and tetrahydrofuran (90 ml) was stirred for 16 h.The pH was adjusted to pH 9 with sodium bicarbonate and the mixture was filtered to give a crude material. The crude product was further crystallized three times with methanol to give 2.6 g of the pure product as a white solid, which was the ribavirin hapten of the formula (I), yield 55%. The specific synthetic route is shown in Figure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With di-tert-butyl dicarbonate; potassium carbonate; magnesium chloride; nickel dichloride; zinc; In tetrahydrofuran; at 20℃; for 20h; | Weigh 1mmol of p-fluorobenzoic acid and 0.5mmol of p-methylbenzeneboronic acid in the reaction flask, With tetrahydrofuran as solvent, 6.5 mg of nickel chloride (0.05 mmol) 98 mg zinc powder (1.5 mmol), 8 mg of bipyridine (0.05 mmol), 138 mg of potassium carbonate (1.0 mmol), 143 mg of magnesium chloride (1.5 mmol), 109 mg of di-tert-butyl dicarbonate (0.5 mmol), The reaction was stirred at room temperature for 20h, to give the desired product isolated 58mg, yield 54percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | General procedure: The compounds were synthesized manually by SPPS following theFmoc/tert-butyl (Fmoc/tBu) strategy and using 2-chlorotrityl resin (IrisBiotech) in polypropylene syringes, each fitted with a polyethyleneporous disk. Solvents and soluble reagents were removed by suction.Prior to starting the synthesis, the resin was conditioned by swelling indichloromethane (DCM, 15 min) and washings with dimethylformamide(DMF, 3×30 s). The incorporation of hydroxylamine linker wasperformed by adding N-Fmoc-hydroxylamine (1.5 eq) and N,N-diisopropylethylamine(10 eq) to the resin in DCM for 24 h [50]. After this,the unreacted points of the resin were capped with methanol (0.8 mL/ gresin, 10 min). The Fmoc protecting groups were removed using 20%piperidine (Carlo Erba) solution in DMF (Carlo Erba) (2x1 min, 1x10min). The coupling reactions were performed in DMF using Fmocaminoacids (3 eq) and oxyma pure (3 eq, Iris Biotech) in the presenceof diisopropylcarbodiimide (3 eq) for 90 min. This mixture is known toproduce couplings with high efficiency and extremely low or null racemization[51]. The reaction was monitored by colorimetric tests: theKaiser colorimetric test [52] was used for the detection of primaryamines, while the chloranil test was used for secondary amines boundto the solid-phase [53]. The Alloc group was removed by adding phenylsilane(10 eq) and Pd(PPh3)4 (0.1 eq) in DCM (3×15 min). Peptideswere cleaved from the resin using 30% trifluoroacetic acid (TFA,Fluorochem) in DCM (3×15 min). After cleavage, filtrates and DCMwashes (3×5 min) were evaporated and lyophilized. The crude productobtained was purified by reverse-phase column chromatographyusing a Combi flash ISCO RF provided with dual ultraviolet detectionusing a high performance RediSep Rf Gold C18 column (Teledyne isco).The purity of the purified compounds was determined at lambda=220 nmby analytical HPLC (Waters Alliance 2695 separation module equippedwith a 2487 photodiode array detector, a Sunfire C18 column(100×4.6mm×5 mum, 100 A, Waters), and Empower software). Flowrate 1 mL/min, mobile phase H2O (0.036% TFA) and acetonitrile(0.045% TFA). Compound identity was assessed by analytical HPLC-MS(Waters Alliance 2695 separation module system equipped with aWaters 2998 photodiode array detector electrospray ionization (ESI)-MS micromass ZQ and a Sunfire C18 column (2.1×100mm×3.5 mum,100 A, Waters), and Masslynx software. Flow rate 0.3 mL/min, mobilephase H2O (0.1% formic acid (FA)) and acetonitrile (0.07% FA). Thepurity of all final compounds was 95% or higher, as measured by HPLC.The exact mass for compound 40 was measured in a LCT-Premier XE(Waters-Micromass) coupled to UPLC (Acquity, Waters). |
Tags: 456-22-4 synthesis path| 456-22-4 SDS| 456-22-4 COA| 456-22-4 purity| 456-22-4 application| 456-22-4 NMR| 456-22-4 COA| 456-22-4 structure
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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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