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CAS No. : | 53473-36-2 | MDL No. : | MFCD00674032 |
Formula : | C10H9F3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OEIUMLSCWINLBB-UHFFFAOYSA-N |
M.W : | 218.17 | Pubchem ID : | 3588736 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.8 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.7 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | 2.72 |
Log Po/w (WLOGP) : | 3.87 |
Log Po/w (MLOGP) : | 2.99 |
Log Po/w (SILICOS-IT) : | 2.95 |
Consensus Log Po/w : | 2.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.94 |
Solubility : | 0.251 mg/ml ; 0.00115 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.16 |
Solubility : | 0.152 mg/ml ; 0.000697 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.47 |
Solubility : | 0.0732 mg/ml ; 0.000336 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
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 |
---|---|---|
100% | With hydrogen In ethanol for 21 h; | A mixture of 4-(trifluoromethyl)cinnamic acid (commercially available, 10.0 g, 46.3 mmol) and Pd/C (10 wtpercent, 250 mg) in EtOH (100 mL) was stirred under a hydrogen atmosphere (6 bar) for 21 h. After filtration through Celite and removal of the solvents in vacuo, the desired product was obtained as a white solid (10.1 g, 46.1 mmol, 100percent yield). 1H-NMR (CDCl3) δ: 2.73 (t, J = 7.6 Hz, 2H); 3.03 (t, J = 7.6 Hz, 2H); 7.33 (d, J = 8.0 Hz, 2H); 7.56 (d, J = 8.1 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;5%-palladium/activated carbon; In methanol; under 1500.15 Torr; | A solution of 4-thfluoromethylcinnamic acid (commercial available) in methanol is hydrogenated with Pd/C (5 wt%) at 2 bar until 4-trifluoromethylcinnamic acid has reacted completely. After removal of the catalyst by filtration the 4-thfluoromethylhydrocinnamic acid is further reacted in step 2 to compound 2. | |
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 20℃; for 10h; | (11-1) Synthesis of 3-(4-trifluoromethylphenyl)-1-propanol (compound 11-1) 4-Trifluoromethylcinnamic acid (10.0 g) was dissolved in methanol (20 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (5.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a colorless powder (10.5 g). The colorless powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane tetrahydrofuran solution (1 mol/l, 59.5 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 16 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.53 g) as a colorless oil. 1H-NMR(CDCl3) delta (ppm): 1.54(1H, brs), 1.87-1.94(2H, m), 2.78(2H, t, J=7.7Hz), 3.68(2H, t, J=6.3Hz), 7.31(2H, d, J=8.0Hz), 7.54(2H, d, J=8.0Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0℃; for 1.75h; | DCC (41.3 g, 200. mmol) was added in portions to a stirred 0 C solution of 3- (4-trifluoromethylphenyl) propionic acid (43.6 g, 200. mmol), Meldrum's acid (28.8 g, 200. mmol) and DMAP (24.4 g, 200. mmol) in 500 mL DCM. After stirring at 0 C for 1.75 h, the reaction mixture was filtered through Celite, the filtrate was washed with 1N HCl (2x), water and brine and dried over MgS04. Filtration and concentration provided the acyl Meldrum's acid derivative as a yellow solid :'H NMR (400 MHz, CDCl3) 8 7.52 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 3.39 (t, J = 7.6 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 1.63 (s, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In diethyl ether; hexane; at 20℃; for 1h; | Example R; Compound 38; {4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; To a solution of R1 (1.00 g, 4.59 mmol) in Et2O (20 mL) and MeOH (1U mL) was added 1.0 M (trimethylsilyl) diazomethane (9.16 mL, 9.16 mmol) in hexane. After stirring at room temperature for 1 h, the solvents were removed under reduced pressure. The residue was dissolved in Et20, washed with saturated NaHC03 and brine, dried, and concentrated to give 1.04 g (98%) of R2; 1 H NMR (300 MHz, CDCI3) 6 7. 54 (d, J = 8. 1 Hz, 2 H), 7.31 (d, J = 8. 1 Hz, 2 H), 3.67 (s, 3 H), 3.01 (t, J = 7. 7 Hz, 2 H), 2.65 (t, J = 7.7 Hz, 2 H); MS (ES) m/z: 255 (M+Na+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-chloro-1,3-dimethylimidazolinium chloride; triethylamine; In methanol; at 0 - 20℃; for 15h; | (2) To a solution of said N-{2-[isopropyl(methyl)amino]-6-nitro-1H-benzimidazole (1.00 g) as obtained in Example 1-(1) in methanol (30 ml), 20% palladium hydroxide-carbon (200 mg) was added and stirred at room temperature under atmospheric pressure for 5 hours. The reaction solution was filtered through Celite, and the filtrate was condensed under reduced pressure. Thus obtained 6-amino-N-{2-isopropyl(methyl)amino]-1H-benzimidazole was dissolved in chloroform (15 ml), followed by successive addition of triethylamine (1.8 ml) and <strong>[53473-36-2]3-[4-(trifluoromethyl)phenyl]propionic acid</strong> (930 mg) and dropwise addition, under cooling with ice, of 2-chloro-1,3-dimethyl-2-imidazolinium chloride (2M chloroform solution, 2.6 ml). After 15 hours' stirring at room temperature, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure, the resultant residue was purified on silica gel column chromatography, (methanol/ethyl acetate = 1/10) and washed with ether to provide the title compound (1.00 g). 1H-NMR(400MHz,DMSO-d6,deltappm):1.14(6H,d,J=6.8Hz), 2.62(2H,t,J=7.6Hz),2.84(3H,s),3.00(2H,t,J=7.6Hz),4.42(1H,m), 6.96(1H,d,J=8.4Hz),7.01(1H,d,J=8.4Hz),7.48(2H,d,J=8.1Hz) 7.55(1H,s),7.64(2H,d,8.1Hz),9.69(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; for 1h;Heating / reflux; | To a solution of 3- [4- (trifluoromethyl) phenyl] propanoic acid (4.36 g, 20.0 mmol) in THF (100ml) was added carbonyldiimidazole (3.89 g, 24.0 mmol) and the mixture was refluxed for 1 h. Into a separate flask was placed nitromethane (4.5 ml, 80.0 mmol), THF (40 ml) and sodium hydride (0.96 g, 24.0 mmol) and the mixture was stirred for 10 min. To this was added slowly the imidazolide from the first reaction and the mixture was refluxed for 16 h. To the reaction mixture was added water (100 ml) and the pH was adjusted to 3 with HCI. The THF was removed by rotary evaporation. The product was extracted with ethyl acetate. The product was purified by silica gel column chromatography (silica gel/30% ethyl acetate in petroleum ether) giving A as an oil (3.70 g, 71%).'H NMR (300 MHz, CDC13) S 7.53 (dd, 2H), 7.28 (dd, 2H), 5.20 (s, 2H), 3.03 (m, 2H), 2.87 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In toluene; for 90h;Reflux;Product distribution / selectivity; | A solution of homoveratrylamine (18.5 niL, 110 mmol) in toluene (350 mL) was treated with intermediate Li (23.9 g, 110 mmol), refluxed for 90 h in the presence of a Dean-Stark and cooled slowly to RT. The precipitate was filtered off and dried under vacuum to give the desired amide as a white solid (36.5 g, 95.7 mmol, 87% yield).1H-NMR (CDCl3) delta: 2.44 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 3.49 (dt, J = 6.2, 6.7 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 5.34 (bs, IH), 6.61 (dd, J = 1.8, 8.1 Hz, IH), 6.67 (d, J = 1.8 Hz, IH), 6.77 (d, J = 8.1 Hz, IH), 7.29 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H). |
In toluene; for 90h;Heating / reflux; | E. Synthesis of phenylethylamides (general procedure):; A solution of the respective phenylethylamine (110 mmol) in toluene (350 mL) is treated with the respective propionic acid derivative (110 mmol), refluxed for 90h in the presence of a Dean-Stark trap and cooled slowly to RT. The precipitate is filtered off and dried under vacuum to give the desired amide.; 1. Synthesis of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-(4-trifluoromethyl-phenyl)- propionamide:; This compound is prepared by reaction of 3,4-dimethoxyphenylethylamine and 4-(tri- fluoromethyl) -hydrocinnamic acid. LC-MS: rt= 0.97 min, 382 (M+1, ES+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.40 g (100%) | With thionyl chloride; In ISOPROPYLAMIDE; benzene; | Example 2 2-[3-(4-Trifluoromethyl-phenyl)-propionylamino]-benzoic acid A mixture of 3-(4-trifluoromethylphenyl)-propionic acid (2.14 g, 10.0 mmol) and thionyl chloride (0.80 mL, 11.0 mmol) was heated to reflux in benzene (100 mL) until all starting material was consumed as indicated by TLC. This mixture was concentrated via rotary evaporation providing the crude acid chloride, which was combined with anthranilic acid (1.37 g, 10.0 mmol) in dimethylacetamide (100 mL) and then refluxed for 12 h. The reaction mixture was cooled to RT, and partitioned between water and ether. The organic phase was dried over Na2 SO4, concentrated, triturated repeatedly with MeOH, then dried to yield 3.40 g (100%) of a white solid: mp 169-171 C.; 1 H NMR (DMSO-d6) delta 13.4-13.7 (br s, 1 H), 11.12 (s, 1 H), 8.45 (dd, 1 H), 7.63 (d, 2 H), 7.57 (ddd, 1 H), 7.50 (d, 2 H), 7.13 (ddd, 1 H), 3.03 (t, 2 H), 2.77 (t, 2 H); IR (KBr) 3124, 3036, 2983, 1711, 1661, 1609, 1585, 1335, 1315, 1224, 1192, 1163, 1145, 1122, 1107, 1070, 791, 760 cm-1; MS (m/z) 379 [M+ ]. Elemental analysis for C17 H14 F3 NO3: Calc'd: C, 60.54; H, 4.18; N, 4.15. Found: C, 60.27; H, 4.26; N, 4.19. |
3.40 g (100%) | With thionyl chloride; In ISOPROPYLAMIDE; benzene; | Example 2 2-[3-(4-Trifluoromethyl-phenyl)-propionylamino]-benzoic acid A mixture of 3-(4-trifluoromethylphenyl)-propionic acid (2.14 g, 10.0 mmol) and thionyl chloride (0.80 mL, 11.0 mmol) was heated to reflux in benzene (100 mL) until all starting material was consumed as indicated by TLC. This mixture was concentrated via rotary evaporation providing the crude acid chloride, which was combined with anthranilic acid (1.37 g, 10.0 mmol) in dimethylacetamide (100 mL) and then refluxed for 12 h. The reaction mixture was cooled to RT, and partitioned between water and ether. The organic phase was dried over Na2 SO4, concentrated, triturated repeatedly with MeOH, then dried to yield 3.40 g (100%) of a white solid: mp 169-171 C.; 1 H NMR (DMSO-d6) delta13.4-13.7 (br s, 1 H), 11.12 (s, 1 H), 8.45 (dd, 1 H), 7.63 (d, 2 H), 7.57 (ddd, 1 H), 7.50 (d, 2 H), 7.13 (ddd, 1 H), 3.03 (t, 2 H), 2.77 (t, 2 H); IR (KBr) 3124, 3036, 2983, 1711, 1661, 1609, 1585, 1335, 1315, 1224, 1192, 1163, 1145, 1122, 1107, 1070, 791, 760 cm-1; MS (m/z) 379 [M+ ]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; at 20℃; | Step 1 : Synthesis of 3-[4-(trifluoromethyl)phenyl]-N-[3-fluoro-4-(methane sulfonylamino)benzyl]propionamide; Under the same condition as Scheme 10, 3-fluoro-4-(methanesulfonylamino)benzylaminehydrochloride (164 mg), 4-trifluoromethylphenyl propionic acid (418 mg), DMTMM (276 mg) and TEA (0.3 mL) were dissolved in THF(20mL) and the solution was stirred overnight at room temperature. The THF was removed under reduced pressure and the residue was extracted three times with water (30 ml) and MC (30ml). Water was removed from the extracted MC solution, the organic phase was concentrated under reduced pressure. The concentrated organic solution was purified by column chromatography (hexane/ethyl acetate = 1/2, 10OmL) to obtain the purposed compound (213mg, 79%).1U NMR (300 MHz, CDCl3): 2.50 (t, J = 7.2 Hz, 2H), 2.99 (s, 3H), 3.02 (t, 2H), 4.33 (d, J = 6 Hz, 2H), 5,68 (br, IH, NH), 6,87 (m, 2H), 7.21 (m, 2H), 7.42 - 7.50 (m, 3H) ; IR (KBr, cm"1): 3274 (NH), 1652, 1512, 1325, 1158. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100%; 100%; 93%; 98%; 93%; 96%; 78%; 98%; 56%; 87% | With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h; | Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88%; 79%; 67%; 66%; 84%; 94%; 76%; 100%; 100%; 100% | With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h; | Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92 - 94%; 96%; 96%; 92%; 83%; 81%; 83 - 97%; 97%; 83%; 100% | With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h; | Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.0 g 4-(Trifluoromethyl)hydrocinnamic acid were heated under reflux in 150 ml thionyl chloride for three hours. The thionyl chloride was removed in vacuo and the residue dissolved in 150 ml tetrahydrofuran and added dropwise to a stirred solution of concentrated ammonia in water. The reaction mixture was stirred at room temperature. After 15 minutes the organic layer was separated and the aqueous layer was extracted two times with portions of 100 ml ethyl acetate. The combined organic layers were EPO <DP n="144"/>dried over MgSO4. The solvent was removed in vacuo to obtain 18.6 g 3-(4- trifluoromethyl-phenyl)-propionamide as white solid. C10H10F3NO (217,19), MS(ESI): 218.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To an ice-cooled homogeneous solution of 4-(trifluoromethyl)hydrocinnamic acid (9.800 g; 44.918 mmol) in anhydrous THF (250 ml) was added dropwise a solution of 1 M BH3THF (67.4 ml; 67.4 mmol) over 20 min. The resulting homogeneous solution was further stirred at 00C, under nitrogen, for 1 h, and then at rt for 14h. The colorless homogeneous reaction mixture was cooled to 00C, and MeOH (100 ml) was carefully added followed by water (100 ml). MeOH and THF were then removed under vacuum. After extraction with DCM (3 x 100 ml), the combined organic extracts were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM / MeOH = 9 / 1 ) to give the pure product 3-(4-trifluoromethyl-phenyl)- propan-1-ol as a colorless oil which was further dried under HV (9.180 g; 100%). LC-MS: tR = 0.89 min.; [M+H]+: no ionisation. | |
100% | With sodium tetrahydroborate; iodine; In tetrahydrofuran; at 70℃; for 16h;Cooling with ice; | The carboxylic acid (1 equiv) and sodium borohydride (5 equiv) were suspended in dry tetrahydrofuran. The mixture was cooled in an ice bath and a solution of iodine (2 equiv) in THF was added dropwise over 30 minutes. The mixture was warmed to room temperature and when the solution became clear, it was heated to 70 C for 16 hours. Upon cooling, aqueous 2M sodium hydroxide solution was slowly added and stirred for 1 hour. The mixture was transferred to a seperatory funnel and diluted with ethyl acetate. The aqueous layer was discarded and the organic layer was washed with brine, dried over Na2S04, and filtered. Celite was added and the solvent was evaporated under reduced pressure. The resulting powder was subjected to flash chromatography on silica gel. |
99% | In an inert atmosphere, 3-(4-Trifluoromethyl-phenyl)-propionic acid (10 g, 45.8 mmol) was dissolved in anhydrous THF (250 ml) and cooled to 0 C. followed by the addition of a 1 M solution of borane in THF (69 ml, 69 mmol). Stirring was continued at 0 C. for 1 h and 16 h at rt followed by slow addition of methanol (100 ml) and water (100 ml). The organic solvents were evaporated under reduced pressure. The remaining water phase was extracted with DCM (3×100 ml) and the combined organic layers were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silicagel, DCM/methanol=9/1 to give 9.25 g (99%) of 3-(4-Trifluoromethyl-phenyl)-propan-1-ol. LC-MS: tR=0.89 min; [M+H]+=no ionisation. |
99% | With borane; In tetrahydrofuran; at 0 - 20℃; for 17h;Inert atmosphere; | In an inert atmosphere, 3-(4-trifluoromethyl-phenyl)-propionic acid (10 g, 45.8 mmol) was dissolved in anhydrous THF (250 ml) and cooled to 0C followed by the addition of a 1 M solution of borane in THF (69 ml, 69 mmol). Stirring was continued at 0C for 1 h and 16 h at rt followed by slow addition of methanol (100 ml) and water (100 ml). The organic solvents were evaporated under reduced pressure. The remaining water phase was extracted with DCM (3 x 100 ml) and the combined organic layers were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silicagel, DCM / methanol = 9/1 to give 9.25 g (99%) of 3-(4-trifluoromethyl-phenyl)-propan-1-ol. LC-MS: tR = 0.89 min; [M+H]+ = no ionisation. |
(11-1) Synthesis of 3-(4-trifluoromethylphenyl)-1-propanol (compound 11-1) 4-Trifluoromethylcinnamic acid (10.0 g) was dissolved in methanol (20 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (5.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a colorless powder (10.5 g). The colorless powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane tetrahydrofuran solution (1 mol/l, 59.5 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 16 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.53 g) as a colorless oil. 1H-NMR(CDCl3) delta (ppm): 1.54(1H, brs), 1.87-1.94(2H, m), 2.78(2H, t, J=7.7Hz), 3.68(2H, t, J=6.3Hz), 7.31(2H, d, J=8.0Hz), 7.54(2H, d, J=8.0Hz). | ||
With borane; In tetrahydrofuran; at 0 - 20℃; | To an ice-cooled homogeneous solution of 4-(trifluoromethyl)hydrocinnamic acid (20 g, 91.7 mmol 1 eq.) in anhydrous THF (500 ml), a solution of 1M BH3 in THF (137.5 ml, 137.5 mmol, 1.5 eq.) was added dropwise over ca. 20 min. The resulting homogeneous solution was stirred at 0 C. for 1 hour, and further at r.t. for 16 hours. The colorless homogenous reaction mixture was cooled to 0 C., and methanol (200 ml) was carefully added, followed by water (200 ml). Methanol and THF were then removed under vacuum. The product was extracted with dichloromethane (3×200 ml). The combined organic extracts were washed with sat. aq. NaCl soln. (1×100 ml), dried over MgSO4, and concentrated in vacuo. The residue was purified by CC (DCM/MeOH 9:1) to yield the desired alcohol as a colorless oil.LC-MS (A1): tR=0.94 min; no ionization. | |
To an ice-cooled homogeneous solution of 4-(trifluoromethyl)hydrocinnamic acid (20 g, 91.7 mmol 1 eq.) in anhydrous TetaF (500ml), a solution of IM BH3 in THF (137.5 ml, 137.5 mmol, 1.5 eq.) was added dropwise over ca. 20 min. The resulting homogeneous solution was stirred at 00C for 1 hour, and further at r.t. for 16 hours. The colorless homogenous reaction mixture was cooled to 00C, and methanol (200ml) was carefully added, followed by water (200ml). Methanol and THF were then removed under vacuum. The product was extracted with dichloromethane (3 x 200ml). The combined organic extracts were washed with sat. aq. NaCl soln. (1 x 100ml), dried over MgSO4, and concentrated in vacuo. The residue was purified by CC (DCM/MeOH 9:1) to yield the desired alcohol as a colorless oil. LC-MS (Al): tR = 0.94 min; no ionization. | ||
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; for 18h; | General procedure: To a stirred solution of 3- or 4-substituted phenylpropanoic acid 51-63 (7.0 mmol) in dry THF (35 ml), borane dimethyl sulfide (21.0 mmol) was added dropwise at 0 oC. The reaction mixture was stirred for 18h at room temperature, quenched with H2O and concentrated in vacuo. The resulting residue was re-dissolved in diethyl ether (25 ml), and washed with 10%NaOH (30ml) and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo to give 3-phenylpropan-1-ol derivatives that were used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | EXAMPLE 27 N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-4-methoxyphenyl}-3-[4-(trifluoromethyl)phenyl]propanamide 5-(5-Amino-2-methoxy-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 19) (0.17 g), <strong>[53473-36-2]3-[4-(trifluoromethyl)phenyl]propionic acid</strong> (0.17 g), HATU (0.32 g) and DIPEA (0.25 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5-5.0% MeOH in DCM as eluent gave the title compound as a white solid (119 mg, 39%); 1H NMR (300.132 MHz, DMSO) 9.85 (s, 1H), 8.39 (s, 2H), 7.72 (s, 1H), 7.65 (d, 2H), 7.50-7.43 (m, 3H), 7.10 (s, 2H), 7.01 (d, 1H), 3.81 (s, 3H), 3.01 (t, 2H), 2.65 (t, 2H); MS m/e MH+441. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | EXAMPLE 28 N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-6-methylpyridin-3-yl}-3-[4-(trifluoromethyl)phenyl]propanamide 5-(5-Amino-2-methyl-pyridin-3-ylethynyl)-pyrimidin-2-ylamine (Intermediate 21) (0.17 g), <strong>[53473-36-2]3-[4-(trifluoromethyl)phenyl]propionic acid</strong> (0.22 g), HATU (0.38 g) and DIPEA (0.27 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5-5.0% MeOH in DCM as eluent gave the title compound as a white solid (182 mg, 56%); 1H NMR (300.132 MHz, DMSO) 10.17 (s, 1H), 8.48 (s, 3H), 8.15 (s, 1H), 7.66 (d, 2H), 7.49 (d, 2H), 7.19 (s, 2H), 3.02 (t, 2H), 2.71 (t, 2H), 2.57 (s, 3H); MS m/e MH+426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | EXAMPLE 29 N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2-methoxyphenyl}-3-[4-(trifluoromethyl)phenyl]propanamide 5-(5-Amino-6-methoxy-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 23) (0.17 g), <strong>[53473-36-2]3-[4-(trifluoromethyl)phenyl]propionic acid</strong> (0.20 g), HATU (0.35 g) and DIPEA (0.33 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5-5.0% MeOH in DCM as eluent gave the title compound as a white solid (123 mg, 39%); 1H NMR (300.132 MHz, DMSO) 9.36 (s, 1H), 8.44 (s, 2H), 7.99 (d, 1H), 7.66 (d, 2H), 7.51 (d, 2H), 7.20 (d, 1H), 7.15 (s, 2H), 7.07 (t, 1H), 3.84 (s, 3H), 3.02 (t, 2H), 2.81 (t, 2H); MS m/e MH+441. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | EXAMPLE 30 N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-2-methylpyridin-3-yl}-3-[4-(trifluoromethyl)phenyl]propanamide 5-(5-Amino-6-methyl-pyridin-3-ylethynyl)-pyrimidin-2-ylamine (Intermediate 27) (0.17 g), <strong>[53473-36-2]3-[4-(trifluoromethyl)phenyl]propionic acid</strong> (0.22 g), HATU (0.38 g) and DIPEA (0.27 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. The solid was added to 50% MeOH/DCM and sonicated for 20 minutes, the title compound was filtered and dried (129 mg, 40%); 1H NMR (300.132 MHz, DMSO) 9.50 (s, 1H), 8.45 (s, 2H), 8.36 (s, 1H), 7.94 (s, 1H), 7.67 (d, 2H), 7.51 (d, 2H), 7.17 (s, 2H), 3.03 (t, 2H), 2.77 (t, 2H), 2.35 (s, 3H); MS m/e MH+426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | EXAMPLE 31 N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-2-methoxyphenyl]-3-[4-(trifluoromethyl)phenyl]propanamide 5-(5-Amino-4-methoxy-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 29) (0.17 g), <strong>[53473-36-2]3-[4-(trifluoromethyl)phenyl]propionic acid</strong> (0.19 g), HATU (0.35 g) and DIPEA (0.33 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5-10% MeOH in DCM as eluent gave the title compound as a white solid (159 mg, 51%); 1H NMR (300.132 MHz, DMSO) 9.22 (s, 1H), 8.41 (s, 2H), 8.12 (s, 1H), 7.64 (d, 2H), 7.51 (d, 2H), 7.21 (s, 1H), 7.06 (s, 3H), 3.85 (s, 3H), 3.06-2.94 (m, 2H), 2.85-2.71 (m, 2H); MS m/e MH+441. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.03333h; | c) step 3:N-[2-(5-Methyl-thiophen-2-yl)-ethyl]-3-(4-trifluoromethyl-phenyl)-propionamide To a solution of 3 g (13 mmol) 4-(trifluoromethyl)hydrocinnamic acid (commercially available) in 30 mL DMF under argon were added 4.7 g (14.37 mmol) TBTU and 11.2 mL (65.3 mmol) N-ethyldiisopropylamine. A solution of 1.85 g (13 mmol) 2-(5-methyl-thiophen-2-yl)-ethylamine in 5 mL DMF was added drop wise over a period of 2 minutes. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with water and with a sat. NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The solid was stirred in 30 mL ether, filtered and dried. The mother liquor was concentrated in vacuo and purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated. 3.75 g (84%) of the title compound was yielded as white solid.MS (m/e): 342.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | a) step 1:N-[2-(5-Methoxy-1H-indol-3-yl)-ethyl]-3-(4-trifluoromethyl-phenyl)-propionamide A mixture of 0.3 g (1.57 mmol) 5-methoxytryptamine, 0.34 g (1.57 mmol) 4-(trifluoromethyl)hydrocinnamic acid (commercially available), 0.6 g (1.8 mmol) TBTU and 0.6 g (4.6 mmol) DIPEA in 6 mL DMF was shaken for 3 h at room temperature. 50 mL water was added and the mixture was extracted with DCM. The combined organic phases were washed with water, dried with MgSO4 and evaporated to dryness to yield the title compound which was used without further purification in the consecutive step.MS (m/e): 391.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
sulfuric acid;Heating; | To the methanolic reaction mixture obtained from step 1 is added 5 mol% sulfuric acid and the mixture is heated. The formed water is distilled off until the esterification is complete. Then, methanol is completely removed. | |
With sulfuric acid;Heating; | To the methanolic reaction mixture obtained from step 1 is added 5 mol% sulfuric acid and the mixture is heated. The formed water is distilled off until the esterification is complete. Then, methanol is completely removed. | |
With sulfuric acid;Heating; | Step 2: synthesis of 3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester (compound 2) To the methanolic reaction mixture obtained from step 1 is added 5 mol % sulfuric acid and the mixture is heated. The formed water is distilled off until the esterification is complete. Then, methanol is completely removed. |
sulfuric acid;Heating; | To a solution of intermediate Li in MeOH (as obtained in Preparation I, step Li, method 3) was added 5 mol% sulfuric acid and heated. The formed water was distilled off together with MeOH until the esterification was complete. MeOH was then completely removed to yield the desired product.1H-NMR (CDCl3) delta: 7.5 (d, J = 8.0 Hz, 2H), 7.3 (d, J = 8.0 Hz, 2H), 3.7 (s, 3H), 3.0 (t, J = 7.6 Hz, 2H), 2.6 (t, J = 7.6 Hz, 2H) | |
With sulfuric acid;Heating; | To the methanolic reaction mixture obtained from step 1 is added 5 mol % sulfuric acid and the mixture is heated. The formed water is distilled off until the esterification is complete. Then, methanol is completely removed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen;palladium 10% on activated carbon; In ethanol; under 4500.45 Torr; for 21h;Product distribution / selectivity; | A mixture of 4-(trifluoromethyl)cinnamic acid (commercially available, 10.0 g, 46.3 mmol) and Pd/C (10 wt%, 250 mg) in EtOH (100 mL) was stirred under a hydrogen atmosphere (6 bar) for 21 h. After filtration through Celite and removal of the solvents in vacuo, the desired product was obtained as a white solid (10.1 g, 46.1 mmol, 100% yield). 1H-NMR (CDCl3) delta: 2.73 (t, J = 7.6 Hz, 2H); 3.03 (t, J = 7.6 Hz, 2H); 7.33 (d, J = 8.0 Hz, 2H); 7.56 (d, J = 8.1 Hz, 2H). |
With hydrogen;5% palladium over charcoal; In methanol; under 1500.15 Torr; | Step 1: synthesis of 3-(4-trifluoromethyl-phenyl)-propionic acid (compound 1); A solution of 4-trifluoromethylcinnamic acid (commercial available) in methanol is hydrogenated with Pd/C (5 wt %) at 2 bar until 4-trifluoromethylcinnamic acid has reacted completely. After removal of the catalyst by filtration the 4-trifluoromethylhydrocinnamic acid is further reacted in step 2 to compound 2. | |
With hydrogen;5% Pd(II)/C(eggshell); In methanol; under 1500.15 Torr; | A solution of 4-trifluoromethylcinnamic acid (commercial available) in methanol is hydrogenated with Pd/C (5 wt %) at 2 bar until 4-trifluoromethylcinnamic acid has reacted completely. After removal of the catalyst by filtration the 4-trifluoromethylhydrocinnamic acid is further reacted in step 2 to compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; | Caesium carbonate (19.0 g, 58.3 mmol) was added in one portion to a solution of intermediate Li (10.2 g, 46.8 mmol) in anhydrous DMF (150 ml). The suspension was stirred at RT for 15 min, cooled to 00C and treated dropwise with iodomethane (4.4 mL, 70.5 mmol). The mixture was stirred at 00C for 10 min and at RT for 18 h. EA (400 mL), water (300 mL), and brine (100 mL) were added to the reaction mixture and the layers were separated. The org. layer was washed with a mixture of water (100 mL) and brine (10O mL), dried over anhydrous MgSO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil which was purified by flash chromatography (DCM/MeOH 200/1). The desired product was obtained as a slightly yellow oil (10.7 g, 98% yield).1H-NMR (CDCl3) delta: 2.66 (t, J = 7.5 Hz, 2H), 3.01 (t, J = 7.8 Hz, 2H), 3.67 (s, 3H), 7.32 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Step 3 : (z)-3 - [4-(t-butyl)phenyl] -2-fluoro-N- { 3 -fluoro-4- [(methanesulfonyl) aminojbenzyl} -2-butenamide; (z)-3-[4-(t-butyl)phenyl]-2-fluoro-2-butenoic acid (60mg, 0.25mmol), 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methylmol phlinium chloride (DMTMM) (470 mg, 1.7 mmol) and Et3N (85 fd, O.betalmmol) were added in the THF (10 mL). The reaction mixture was stirred for 2 hr. 3-Fluoro-4-methanesulfonylbenzylamine HCl (77.6mg, 0.30 mmol) was added into the reaction mixture. The mixture was stirred for 3hr at room temperature. The reaction mixture was concentrated in vacuo. The residue was extracted with EtOAc. A combined organic layer was washed with H2O and brine, dried with MgSO4, concentrated in vacuo. The residue was purified with column chromatography (EtOAc: Tz-hexane = 1: 1) to yield (z)-3-[4-(t-wty/)phenyl]-2-fluoro-N- {3 -fluoro-4- [(methanesulfonyl) aminojbenzyl} -2-butenamide (238 mg, 79%).1H-NMR (300MHz, CDCl3) : delta 1.32 (s, 9H), 2.15 (d, 3H, J = 4.4 Hz,), 3.05 (s, 3H), 4.39 (d, 2H, J= 5.9 Hz)5 6.44 (s, NH), 6.81 (s, NH), 7.04 (s, IH), 6.99-7.04 (m, 2H), EPO <DP n="97"/>7.20-7.25 (m, 2H)5 7.38-7.41 (m, 2H), 7.50-7.56 (m, IH) ; IR (neat) cm"1: 2962, 1651, 1516, 1455, 1333 ; Mass (EI+) 436.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: All linear peptides were assembled using standard Fmoc peptide synthesisprotocol with the Rink amide resin on 433A Peptide Synthesizer (Applied Biosystems).For each coupling reaction, 10 equiv of Fmoc-amino acid, 0.45 Msolution of HOBt/HBTU (9 equiv) in DMF, 2 M solution of DIEA in NMP wereused. The coupling reaction was allowed to proceed for 9 min. Fmoc deprotectionwas performed by treating the resin-bound peptide with 20% piperidinein DMF for 10 min. The peptide was cleaved from the resin by treating the resin with a cleavage cocktail containing 94% TFA, 2% water, 2% triisopropylsilane,2% phenol for 3 hr. All protecting groups were also removedduring this cleavage reaction. TFA was removed under reduced pressureand the peptides were precipitated in diethyl ether, centrifuged, and washedwith diethyl ether before drying in high vacuum. The crude peptides werepurified by preparative reverse phase high-performance liquid chromatography(HPLC). The final compound was characterized by NMR and MALDIMS.All compounds were > 95% purity. The synthetic approaches for123B9-L2-PTX and the scrambled XDP-L2-PTX are similar to what we haverecently reported |
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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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