Structure of 4-Fluorophenol
CAS No.: 371-41-5
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Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors
Kaustav Khatua ; Yugendar R. Alugubelli ; Kai S. Yang ; Veerabhadra R. Vulupala ; Lauren R. Blankenship ; Demonta Coleman , et al.
Abstract: The main protease (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like protease and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic cysteine and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19.
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Keywords: COVID-19 ; SARS-CoV-2 ; Main protease ; Azapeptide ; Covalent inhibitor
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Purchased from AmBeed: 371-41-5 ; 1187431-43-1 ; 60-00-4 ; 3483-12-3
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Berg, Kaja ; Hegde, Pooja ; Pujari, Venugopal ; Brinkmann, Marzena ; Wilkins, David Z. ; Parish, Tanya , et al.
Abstract: The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H+) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC50 = 13-22 μM, GIC50 = 8-10 μM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.
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Keywords: 1,4-dihydroxy-2-naphthoate prenyltransferase ; MenA ; MenA inhibitors ; Menaquinone ; Mtb ; Mycobacterium tuberculosis ; Piperidine derivatives ; SAR
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Purchased from AmBeed: 25952-53-8 ; 90719-32-7 ; 872-85-5 ; 6457-49-4 ; 3769-41-3 ; 10338-57-5 ; 135-19-3 ; 135-19-3 ; 28177-48-2 ; 22246-18-0 ; 122334-37-6 ; 91914-06-6 ; 10040-98-9 ; 161975-39-9 ; 150-76-5 ; 371-41-5 ; 63754-96-1 ; 288-32-4 ; 3380-34-5 ; 1677-46-9 ; 166815-96-9 ; 700-57-2 ; 1204-86-0 ; 21725-69-9 ; 367-12-4 ; 1003-29-8 ; 627-35-0 ; 27292-49-5 ; 104324-16-5 ; 123855-51-6 ; 180847-23-8 ; 4328-13-6 ; 875401-70-0 ; 405272-71-1 ; 63614-86-8 ; 1420942-13-7 ; 25952-53-8 ; 1420895-21-1 ; 1078-18-8 ; 32363-45-4 ; 69564-68-7 ; 31519-22-9 ; 22246-18-0 ; 189618-33-5 ; 180847-24-9 ; 6264-98-8 ; 946680-75-7 ; 63608-38-8 ; 713-68-8 ; 62810-39-3 ; 189618-32-4 ; 63608-31-1 ; 15789-05-6 ; 63712-27-6 ; 63608-33-3 ; 63608-35-5
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CAS No. : | 371-41-5 |
Formula : | C6H5FO |
M.W : | 112.10 |
SMILES Code : | OC1=CC=C(F)C=C1 |
MDL No. : | MFCD00002316 |
InChI Key : | RHMPLDJJXGPMEX-UHFFFAOYSA-N |
Pubchem ID : | 9732 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 28.42 |
TPSA ? Topological Polar Surface Area: Calculated from | 20.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.36 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.77 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.95 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 1.9 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 1.84 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.76 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.21 |
Solubility | 0.699 mg/ml ; 0.00624 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -1.81 |
Solubility | 1.73 mg/ml ; 0.0154 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -2.04 |
Solubility | 1.02 mg/ml ; 0.0091 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 | -5.73 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 | 2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
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 |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; | Example 1 A specific procedure for the synthesis of: N-[(4-fluoro)-5-phenoxythien-2-yl]methanesulfonamide (1) STR10 <strong>[13195-50-1]2-Nitro-5-bromothiophene</strong> (2.97 g, 14.2 mmol) was dissolved in dimethyl-formamide (40 mL). To this was added 4-fluorophenol (1.59 g, 14.2 mmol) and potassium carbonate (3.92 g, 28.4 mmol). This was stirred at 70° C. for 5 hours after which time the mix was poured into water and the crude solid was filtered and washed with water to give 2-Nitro-5(4-fluoro)phenoxythiophene 2.67 g (78percent), mp=69°-70° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 15 If the procedure is as described in Example 13, except that 50.1 g (0.175 mol) of 2,3-dichloro-4,4'-difluorobenzophenone and 10 g of 90 percent hydrogen peroxide, solution are used, 11.8 g (0.105 mol, 60%) of 4-fluorophenol and 28.3 g (0.136 mol, 78%) of 2,3-dichloro-4-fluorobenzoic acid are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In benzene; | Step A A mixture of 40 g (0.36 mole) of 4-fluorophenol, 80.3 g (0.36 mole) of 3-methyl-alpha-bromoacetophenone, 83 g (0.6 mole) of potassium carbonate in 500 ml of benzene is heated to its reflux temperature and maintained at reflux for 20 hours while removing water into a Dean-Stark trap. The reaction mixture is then washed with water, 10% sodium hydroxide solution, 3N hydrochloric acid and saturated sodium chloride solution, then dried over magnesium sulfate. Evaporation of the solvent provides alpha-(4-fluorophenoxy)-3-methylacetophenone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-fluorophenol (224 mg, 2.0 mmol) in DMF (5.0 mL) was added sodium hydride (48 mg, 2.0 mmol) at room temperature. After stirring for 10 min, methyl <strong>[59782-86-4]2-chloro-5-iodonicotinate</strong> (J. Org. Chem. 1989, 54, 3618-3624, 594 mg, 2.0 mmol) was added to the reaction mixture. The reaction mixture was stirred under reflux for 16 h. Then the reaction mixture was poured into water (50 mL) and extracted with ether (50 mL x 3). The combined organic extracts were washed with brIne (50 m(at)-) and dr*(at)--d, (sod.uTY: s.1l(at)a(at)e). After removal o4 the 3ci'.3(at)f:(at) t'e (at)3(at):::(at)(at) <";zs ;'.(at)-Z?"(at)'(at)(at)3(at) hy7 '(at):(at):1B(at)(at) xt(at)l:r- :-;(at)(at)(at)(at)(at).(at)5..t:;,?"£;:(at).;/ 8(at)(at)(at)0E. £ ,q], L .-.."I.: -'-(at)2(at)::'(at)0/;:/::*-(at),(at)(at) ::_=J'(at)(at)'(at)(at)- (J.>,'. ] .:: ilf=No.= (at):<.No...---'(at) (I? lflXJ i:.: ..:.:,i .::":.1 compound: (at)H-NMR (CDCl3) No. 8.51 (1 H, d, J=2.3 Hz), 8.41 (1 H, s), 7.09 (4H, d, J=6.2 Hz), 3.95 (3H, s) ; MS (ESI) m/z 374 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Example 24. Synthesis of Compounds 344 and 317.TBSCl, DMAP imidazole, CH2Cl2 Synthesis of Compound 493. A mixture of 4-fluorophenol (491; 2.36 g, 21.1 mmol) and sodium hydroxide (1.05 g, 26.3 mmol) in ethanol was heated at reflux for 15 minutes and then (^-S-chloro-l^-propanediol (492; 2.80 g, 25.3 mmol) was added and the mixture stirred at reflux for 16 h. After this time, the reaction was cooled to room temperature and concentrated. The residue was dissolved in diethyl ether (200 mL) and washed with water (75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated. The residue was crystallized from hexanes/diethyl ether and afforded 493 (3.30 g, 84%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; | Methyl 4-(l-(4-fluorophenoxy)ethyl)benzoate. To a solution of methyl 4-(l- hydroxyethyl)benzoate (0.9 g, 5 mmol), 4-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0C. The mixture was stirred at 20C for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL x 3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5: 1) to give methyl 4-(l-(4-fluorophenoxy)ethyl)benzoate (490 mg, 35%). |
35% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; | To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 4-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0 C. The mixture was stirred at 20 C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(4-fluorophenoxy)ethyl)benzoate (490 mg, 35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.3% | With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 20 - 200℃; for 0.3h;Inert atmosphere; Microwave irradiation; | A solution of <strong>[21560-29-2]1-chloro-6,7-dimethoxyisoquinoline</strong> (50 mg, 0.22 mmol) and 4-fluorophenol (25.06mg, 0.22 mmol) in DMA (3 mL) was stirred under a nitrogen atmosphere for 5 minutes.Sodium hydride (22.35 mg, 0.56 mmol; 60% in mineral oil) was added to the reaction mixture and stirred at ambient temperature for 15 minutes. Next the mixture was stirred and heated at 200C for 3 minutes under microwave irradiation. The reaction mixture was quenched with methanol (0.5 mL) and the crude material was purified by flash column chromatography eluting with a gradient of ethyl acetate and methanol (1:0 to 1:1) to give a gum. The product was purified by reverse phase chromatography and the desired product (33.0 mg,49.3%) was obtained as a solid. HPLC purity:>99% (215 nM), >99% (254 nM), >99% (280 nM). 1H NMR (400MHz, DMSO-d6) d ppm 3.94 (s, 3 H), 3.92 (s, 3 H), 7.23- 7.31 (m, 4 H), 7.36 - 7.43 (m, 2 H), 7.58 (s, 1 H), 7.76 (d, J=5.5 Hz, 1 H).HRMS m/z calcd for C17H14FNO3 [M+H]+300.1031, found 300.1030. |
49.3% | A solution of <strong>[21560-29-2]1-chloro-6,7-dimethoxyisoquinoline</strong>(50 mg, 0.22 mmol) and 4-fluorophenol (25.06 mg, 0.22 mmol) in DMA (3 mL) wasstirred under a nitrogen atmosphere for 5 minutes. Sodium hydride (22.35 mg,0.56 mmol; 60% in mineral oil) was added to the reaction mixture and stirred atambient temperature for 15 minutes. Next the mixture was stirred and heated at 200C for 3 minutes undermicrowave irradiation. The reaction mixture was quenched with methanol (0.5 mL)and the crude material was purified by flash column chromatography eluting witha gradient of ethyl acetate and methanol (1:0 to 1:1) to give a gum. Theproduct was purified by reverse phase chromatography and the desired product (33.0mg, 49.3%) was obtained as a solid. HPLCpurity: >99% (215 nM), >99% (254 nM), >99% (280 nM). 1H NMR(400 MHz, DMSO-d6) dppm 3.94 (s, 3 H), 3.92 (s, 3 H), 7.23 - 7.31 (m, 4 H), 7.36- 7.43 (m, 2 H), 7.58 (s, 1 H), 7.76 (d, J=5.5 Hz, 1 H). HRMS m/z calcd for C17H14FNO3[M+H]+ 300.1031, found 300.1030. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 150℃; for 24h; | Chemical compound4-fluorophenol (2mmol)With the compound 4-fluoroiodobenzene (6mmol)Dissolve in N, N-dimethylformamide (20mL) solution,After adding sodium carbonate, it was stirred at 150 C for 24h.The formed compound was extracted with ethyl acetate and washed with saturated brine to obtain compound 1a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 0 - 20℃;Inert atmosphere; | Preparation of intermediate EV A solution of DIAD (0.74 mL, 3.75 mmol) in toluene (5 mL) was added to a solution of 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1147557-97-8], 0.8 g, 3.75 mmol), 4-fluorophenol (0.421 g, 3.75 mmol) and triphenylphosphine (1.48 g, 5.63 mmol) in toluene (35 mL) at 0 °C under N2. The reaction mixture was then allowed to warm up to room temperature slowly overnight. Additional 4-fluorophenol (0.21 g, 1.88 mmol) was added and the reaction was stirred further at room temperature for 3d. The reaction mixture was evaporated to dryness, then dissolved in a minimum of diethyl ether and cooled to 0 °C. A large excess of heptane was added and the resulting mixture was evaporated under vacuum which induced the precipitation of PPh30, which was filtered off and washed with diethyl ether. The filtrate was evaporated to dryness and purified by preparative LC (irregular SiOH, 15-40 muiotaeta, 40 g, Grace, dry loading (silica), mobile phase gradient: Heptane/EtOAc from 90/10 to 50/50) to give 1.07 g of intermediate EV as a yellow solid (not obtained pure but engaged as such in the next step). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 10.0h;Inert atmosphere; | General procedure: NaH (12.0mmol) was added to a solution of 1 or 722 (1.88g, 10.0mmol) and substituted phenol (12.0mmol) in DMF (50mL) at room temperature under N2, and the mixture was stirred at 80C for 10h. Water was added to the cooled mixture, and the mixture was extracted with EtOAc several times. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain purified compound 2, or crude 2 was used directly for the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.13% | With potassium carbonate; In acetone; for 4h;Reflux; | General procedure: To a solution of various substituted phenols (1 mmol) in dry acetone (30 mL) K2CO3 (1 mmol)and compound 3 or 4 (1 mmol) were added. After being stirred for 4 h at reflux temperature, thereaction mixture was cooled, filtered, and concentrated under vacuum. Then the residue was dilutedwith 30 mL ethyl acetate and sequentially washed with 30 mL 1 M HCl, aq. NaHCO3 solution andbrine in order. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of theresidue by chromatography on silica gel furnished target compounds. 1H-NMR, 13C-NMR and massspectroscopy (MS) of compounds 5a-m and 6a-m are shown in Supplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium fluoride; In acetone; at 0℃; for 0.5h; | In a 50 ml reactor, 7 g of <strong>[1835-65-0]tetrafluorophthalonitrile</strong>,2.25 g of potassium fluoride and 30 g of acetone were added and stirred at 0 ° C. A solution prepared by mixing 3.9 g of 4-fluorophenol with 5 g of acetone was dropped there, and kept at 0 ° C. for 30 minutes.After raising the temperature to 25 ° C., the reaction solution is suction filtered.The solvent was distilled off from the filtrate under reduced pressure, and then crystallization was performed by adding methanol.The crystallized material is collected by filtration and then dried under reduced pressure.5.72 g (yield 56 molpercent based on <strong>[1835-65-0]tetrafluorophthalonitrile</strong>) of 4- (4-fluorophenoxy) -3,5,6-trifluorophthalonitrile was obtained.5 g of 4- (4-fluorophenoxy) -3,5,6-trifluorophthalonitrile thus obtained,2.61 g of potassium carbonate, 1.56 g of ethyl 3,4-dihydroxybenzoate and 50 g of acetonitrile were charged into a 100 ml reactor and reacted at 80 ° C. for 2 hours.Thereafter, 3.84 g of 4-fluorophenol and 5.21 g of potassium carbonate were further added, and reacted at 80 ° C. for about 7 hours.The reaction solution is filtered while hot to remove inorganic components,The solvent was distilled off under reduced pressure from the filtrate to obtain 9.21 g of phthalonitrile mixture (A) (yield: 98 molpercent based on 4- (4-fluorophenoxy) -3,5,6-trifluorophthalonitrile). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | Dissolve <strong>[52092-47-4]2-nitro-5-chloropyridine</strong> (3.17g, 20mmol), p-fluorophenol (2.24g, 20mmol), and potassium carbonate (4.14g, 30mmol) in 50mL of DMF solution. The reaction was carried out at 100 C for 12 hours. The reaction was cooled to room temperature, and 100 mL of ice water was added and stirred. A solid precipitated out, filtered with suction, washed with water, and dried.The target compound was obtained (brown solid, 4.03 g, yield: 86%). |
Tags: 371-41-5 synthesis path| 371-41-5 SDS| 371-41-5 COA| 371-41-5 purity| 371-41-5 application| 371-41-5 NMR| 371-41-5 COA| 371-41-5 structure
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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 |
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