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CAS No. : | 3300-51-4 | MDL No. : | MFCD00010220 |
Formula : | C8H8F3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PRDBLLIPPDOICK-UHFFFAOYSA-N |
M.W : | 175.15 | Pubchem ID : | 76804 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 39.12 |
TPSA : | 26.02 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) : | -5.96 cm/s |
Log Po/w (iLOGP) : | 1.7 |
Log Po/w (XLOGP3) : | 1.98 |
Log Po/w (WLOGP) : | 3.16 |
Log Po/w (MLOGP) : | 2.61 |
Log Po/w (SILICOS-IT) : | 2.44 |
Consensus Log Po/w : | 2.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.41 |
Solubility : | 0.679 mg/ml ; 0.00388 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.15 |
Solubility : | 1.23 mg/ml ; 0.00704 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.33 |
Solubility : | 0.0827 mg/ml ; 0.000472 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
93.6% | With hydrogenchloride In methanol | 5.00 g (26.4 mmol) of this 4-trifluoromethylbenzaldehyde oxime were dissolved in methanol followed by the addition of 4.0 g (109.7 mmol) of hydrogen chloride gas and 252 mg of the same catalyst as that of Example 1 and stirring for 3 hours in a hydrogen atmosphere at 10 atm and room temperature (approx. 250° C.). After removing the catalyst, ether was added to the reaction liquid, and the reaction liquid was neutralized with aqueous sodium hydroxide solution. As a result of analyzing the separated ether layer by gas chromatography, 4-trifluoromethylbenzylamine was formed at a yield of 93.6percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogen In methanol; ammonia at 120℃; for 6h; | |
99% | With ammonia; hydrogen In water; isopropyl alcohol at 100℃; for 24h; Autoclave; | |
94% | With C28H29Cl2CoNP2; hydrogen; sodium triethylborohydride In 1,4-dioxane at 80℃; for 6h; |
90% | With borane-ammonia complex; C15H30Cl2CoN3P In hexane at 50℃; for 16h; Sealed tube; Inert atmosphere; chemoselective reaction; | |
90% | With ammonia; hydrogen In toluene at 120℃; for 16h; Autoclave; | |
89% | With [Ru(H)(BH4)(CO)(PPh3)(3-(di-tert-butylphosphino)-N-((1-methyl-1H-imidazol-2 yl)methyl)propylamine)]; hydrogen In isopropyl alcohol at 50℃; for 3h; Inert atmosphere; Autoclave; | |
88% | With C46H49CoN3P4(2+)*2BF4(1-); potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 120℃; for 16h; | |
82% | With sodium tetrahydroborate; [κ3-(1-pz)2HB(N=CHCH3)]Ru(cymene)}+ TfO-; sodium t-butanolate In d(4)-methanol at 70℃; for 12h; | |
82% | With methanol; sodium tetrahydroborate; C18H25BN5Ru(1+)*CF3O3S(1-); sodium t-butanolate for 12h; Reflux; | |
80% | With hydrogen In glycerol at 100℃; for 24h; Autoclave; | |
57% | With C19H34Cl2CoN2P; hydrogen; sodium ethanolate; sodium triethylborohydride In benzene at 135℃; for 36h; Autoclave; | |
50% | With [RuH(tBu-PNP(-))(CO)]; hydrogen In benzene at 110℃; for 40h; | |
With lithium aluminium tetrahydride In diethyl ether Heating; | ||
With borane | ||
With diborane In tetrahydrofuran | ||
92 %Chromat. | With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); 1,1'-bis(diphenylphosphino)ferrocene; potassium <i>tert</i>-butylate; hydrogen In toluene at 140℃; for 1h; Inert atmosphere; Autoclave; chemoselective reaction; | |
93 %Chromat. | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; 1,4-di(diphenylphosphino)-butane; iso-butanol; sodium hydroxide at 120℃; for 0.333333h; Inert atmosphere; | |
98 %Chromat. | With formic acid; 5%-palladium/activated carbon; triethylamine In tetrahydrofuran at 40℃; for 1h; | |
With carbonylhydrido(tetrahydroborato)[bis(2-diphenylphosphinoethyl)amino]ruthenium(II); hydrogen In isopropyl alcohol at 100℃; for 3h; Autoclave; chemoselective reaction; | ||
88 %Chromat. | With Fe-<SUP>Cy</SUP>MACHO; hydrogen In isopropyl alcohol at 100℃; for 3h; Autoclave; chemoselective reaction; | |
75 %Chromat. | With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); [(phenylphosphinediyl)bis(2,1-phenylene)]bis(methylene)}bis(di-tert-butylphosphine); hydrogen In isopropyl alcohol at 50℃; for 17h; Inert atmosphere; Autoclave; | |
99 %Chromat. | Stage #1: 4-CF3C6H4CN With cobalt(III) acetylacetonate; tris(2-(dicyclohexylphosphanyl)ethyl)phosphane In <i>tert</i>-butyl alcohol Sealed tube; Inert atmosphere; Stage #2: With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol Sealed tube; Inert atmosphere; Stage #3: With hydrogen In <i>tert</i>-butyl alcohol at 100℃; for 18h; Autoclave; | |
With C43H38Cl2CoN5; potassium <i>tert</i>-butylate; hydrogen; sodium triethylborohydride In toluene at -196.16 - 115℃; for 8h; | ||
91 %Chromat. | With ammonium hydroxide; hydrogen In isopropyl alcohol at 120℃; for 15h; Autoclave; | |
95.6 %Chromat. | With ammonium hydroxide; hydrogen In methanol for 18h; Autoclave; Heating; | |
99 %Chromat. | With hydrogen In water at 20℃; for 1.5h; Green chemistry; chemoselective reaction; | |
98 %Chromat. | With formic acid; triethylamine at 40℃; for 3h; | |
72 %Chromat. | With hydrogenchloride; oxalic acid In water at 20℃; for 2h; UV-irradiation; chemoselective reaction; | |
With hydrogen In ethanol at 30℃; for 4h; | ||
81 %Chromat. | With ammonium hydroxide; hydrogen; nano-dicobalt phosphide on hydrotalcite In isopropyl alcohol at 150℃; for 20h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,4-dibromoisoquinoline; p-Trifluoromethylbenzylamine In butan-1-ol at 90℃; for 36h; Stage #2: pyridine-4-thiol With caesium carbonate at 180℃; for 1h; Stage #3: In methanol at 20℃; for 0.166667h; Sonication; | 83 Dibromoisoquinoline (5, 29 mg, 0.1 mmol) Example 1, step 1, and M-NH2 (0.2 mmol) in 8-mL vial were heated in 1 mL of n-butanol at 90 0C for 36 hrs. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. 4-Mercaptopyridine (23 mg, 0.2 mmol) and cesium carbonate (67 mg, 0.2 mmol) were added to the vial. The mixture was heated at 180 0C for 1 hr and was allowed to cool to room temperature. Methanol (2 mL) was added to the vial and the mixture was sonicated for 10 min and filtered. The methanol solution of reaction mixture was collected and evaporated under reduced pressure. The formation of product was confirmed by LC/MS. The invention compounds of Examples 83 - 92 as shown in the below table were prepared by method B-I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 18h; | 2-Methyl-l,3-benzothiazole-5-carboxylic acid (150 mg, 0.660 mmol) was mixed with 4- i5 trifluoromethylbenzylamine (228 mg, 1.30 mmol), EDC (249 mg, 1.30 mmol) and DMAP (158 mg, 1.30 mmol) in DCM (5.00 mL) and DMF (2.00 mL) for 18 hours. The mixture was concentrated, and the product was purified by flash chromatography on silica gel, eluting with mixtures of heptanes and EtOAc (95/5 to 50/25), to yield the product (114 mg, 0.325 mmol, 49.2%). 1H NMR (600 MHz, MeOD) delta ppm 2.84 (s, 3 H) 4.56 (s, 2 H) 7.43 20 (d, J=7.94 Hz, 2 H) 7.51 (d, J=8.19 Hz, 2 H) 7.88- (d, J=8.45 Hz, 1 H) 8.02 (dd, J=8.45, 2.30 Hz, 1 H) 8.27 - 8.33 (m, J=1.02 Hz, 1 H); MS [M+H] calcd. 351.0, found 351.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With 4-methyl-morpholine; In dichloromethane; | EXAMPLE 49 N-(4-trifluoromethyl-phenylmethyl)-3-(4'-trifluoromethyl-biphenyl-2-carbonylamino)-benzoic acid amide Prepared analogously to Example 7 from 3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid and 4-trifluoromethyl-benzylamine in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine. Yield:48% of theory Rf value:0.63 (silica gel; dichloromethane/ethanol=9:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; water; | Referential Example 1 5-Formyl-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide Publicly known [e.g. E. J. Wayne et al, J. Chem. Soc., 1022(1922)] <strong>[84923-70-6]5-formyl-2-methoxybenzoic acid</strong> (4.05 g, 22.5 mmol) was dissolved in 80 ml of dichloromethane, which was cooled with ice. Triethylamine (7.94 ml, 56.2 mmol) was added under stirring. Next, ethyl chlorocarbonate (2.44 ml, 24.8 mmol) was added and, after stirring for 10 minutes, 4-(trifluoromethyl)benzylamine (3.31 ml, 22.5 mmol) was added dropwise, which was allowed to stand overnight. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and concentrated. Water was added to the residue, which was made acidic with dilute hydrochloric acid. Then, the precipitates were filtered and dried to quantitatively obtain the title compound as milky white crystals. Mass analysis m/z 337(M+). | |
With triethylamine; In dichloromethane; | (Example 1) 4-Methoxy-3-[N-(4-trifluoromethylbenzyl)carbamoyl]benzoic acid To a suspension of 1.00g of <strong>[84923-70-6]5-formyl-2-methoxybenzoic acid</strong> in 50ml of methylene chloride were added 1.00ml of triethylamine and 0.60ml of ethyl chlorocarbonate, and the mixture was stirred for 15 minutes at room temperature. Then, a solution of 1.17g of 4-trifluoromethylbenzylamine in 10ml of methylene chloride was added and the mixture was stirred further for 3 hours at room temperature. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue obtained was purified by means of column chromatography (silica gel, hexane:ethyl acetate=1:1) and then recrystallized from a mixed solvent of diethyl ether-ethyl acetate-hexane to obtain 1.46g of 5-formyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals. Melting point 116-117C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | Referential Example 2 2-Methoxy-5-nitro-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide Publicly known [e.g. De.Paulis et al, J. Med. Chem., 1022(1922)]<strong>[40751-89-1]2-methoxy-5-nitrobenzoic acid</strong> (9.00 g, 45.7 mmol) was dissolved in 450 ml of dichloromethane and, after triethylamine (8.11 ml, 58.4 mmol) and ethyl chlorocarbonate (4.70 ml, 49.3 mmol) were added, the mixture was stirred for 45 minutes at room temperature. Next, 4-trifluoromethylbenzylamine (9.59 g, 54.8 mmol) was added dropwise, which was stirred for 30 minutes at room temperature. The reaction mixture was poured into water. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain 12.5 g of the aimed compound as yellow powder. Further, the filtrate was concentrated and recrystallized from ethyl acetate to obtain 2.13 g of the second crystals. Total 14.6 g (91%). Mass analysis m/z 354(M+); 1H-NMR (400 MHz, CDCl3) delta4.09(3H,s), 4.75(2H,d,J=5.9 Hz), 7.11(1H,d,J=8.8 Hz), 7.47(2H,d,J=7.8 Hz), 7.61 (2H,d,J=7.8 Hz), 8.05(1H,brs), 8.36(1H,dd,J=8.8, 3.0 Hz), 9.12(1H,d, J=3.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N-methyl-acetamide; dichloromethane; | (Example 3) 5-[2-Carbamoyl-2-(methylthio)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide To a suspension of 17.2g of <strong>[40751-89-1]2-methoxy-5-nitrobenzoic acid</strong> in 35ml of methylene chloride were added 35ml of oxalyl chloride and one drop of dimethylformamide, and the mixture was stirred for 1 hour at room temperature. Solvent was distilled off under reduced pressure, 150ml of dimethylformamide, 15ml of triethylamine and 16.9g of 4-trifluoromethylbenzylamine were added to the residue, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and extracted (150ml*3) with ethyl acetate. The organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was crystallized from hexane:ethyl acetate=3:1, then the crystals were collected by filtration to obtain 26.6g of 2-methoxy-5-nitro-N-(4-trifluoromethylbenzyl)benzamide as pale yellow crystals. Melting point 108-109C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; ethyl acetate; | P23 N-trifluoromethlybenzy 3-methylisoxazole-4-carboxamide A solution of 3 grams of <strong>[17153-20-7]3-methylisoxazole-4-carboxylic acid</strong> and 4.8 grams of 1,3-dicyclohexylcarbodimide in 30 ml of dichloromethane was stirred at room temperature for 30 minutes. This was then added with 8 ml of 4-trifluoromethylbenzylamine dropwise and the mixture stirred at room temperature overnight. The mixture was then diluted in ethyl acetate (100 ml) and worked up with diluted hydrochloride solution, saturated sodium bicarbonate and sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude was then crystallized with ethanol and water to provide 1.5 grams of N-trifluoromethlybenzyl 3-methylisoxazole-4-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 140℃; for 3h;Microwave irradiation; | A solution of 1.0 g (3.4 mmol) <strong>[78686-83-6]methyl 5-iodo-2-chloronicotinate</strong> and 1.05 mL (7.4 mmol) of 4-(trifluoromethyl)benzylamine in 7.0 mL of ethanol was irradiated in the microwave for a total of 3 h at 1400C. The solvent was evaporated, the residue was triturated with EtOAc and the resulting solid formed was filtered off. The filtrate was concentrated in vacuo to afford a thick oil. The oil was dissolved in minimum amount of EtOAc and filtered through a plug of silica gel washing with 10 % EtOAc / hexane. The filtrated was concentrated in vacuo to afford 1.3 g of the title compound: 1H NMR (500 MHz, CDCl3) delta 8.43 (d, IH, J = 1.8 Hz), 8.39 (d, IH, J = 1.9 Hz), 7.59 (d, 2H, J = 7.8 Hz), 7.46 (d, 2H, J = 7.7 Hz), 4.80 (d, 2H, J = 5.7Hz), 3.91 (s, 3H); MS: m/z 437.17 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; for 48h;Heating / reflux; | A mixture of 1.0 g (5.0 mmol) of the compound of Step B and 4-(trifluoromethyl)- benzylamine (1.82 g, 10.4 mmol) in DME (25 mL) was refluxed for 48 h. The resulting mixture was filtered and washed with DME. The combined filtrate was evaporated followed by the purification silica column (combiflash, ISCO) and eluted with hexane + EtOAc (0 to 10% gradient) to give 1.49 g of the title compound as an off white solid: 1H NMR (500 MHz, CDCl3) delta 8.63 (br s, IH), 8.04 (d, IH, J = 8.5 Hz), 7.59 (d, 2H, J = 7.3 Hz), 7.48 (d, 2H, J = 7.2 Hz), 6.02 (d, IH, J = 8.5 Hz), 4.81 (d, 2H, J = 5.5 Hz), 3.86 (s, 3H), 3.81 (s, 3H); MS: m/z 341 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: cis,trans-2,5-dimethoxytetrahydrofuran With hydrogenchloride In water at 75℃; for 1.5h; Stage #2: acetonedicarboxylic acid; p-Trifluoromethylbenzylamine With hydrogenchloride; sodium acetate In water at 10 - 40℃; for 2h; Stage #3: With sodium hydroxide In water | 8 Description 8 : { [4- (Triftuoromethyt) phenyt] methyt}-8-azabicycio [3. 2.1] octan-3-one 2,5 Dimethoxytetrahydrofuran (27.7g, 210mmol) was dissolved in water (65ml) and conc hydrochloric acid (3ml), and the reaction mixture was heated 1.5hr at 75°C. The resulting solution was added drop-wise to a mixture of 4-trifluoromethyl benzylamine (40g, 230mmol), sodium acetate tri-hydrate (113g, 830mmol), and 1,3 acetonedicarboxylic acid (33.6g, 295mmol) in water (200ml) and conc hydrochloric acid (20ml) at 10°C (pH 5.0-5. 2). The reaction mixture was stirred 1hr at 25°C then heated 1 hr at 40C. After basification with 50% sodium hydroxide solution to pH 10 sodium chloride (50g) was added to the reaction mixture and the aqueous phase extracted with diethylether (300ml). The organic phase was dried (Na2SO4) and evaporated in vacuo and the organic residue was filtered through a silica pad eluting with Cyclohexane/EtOAc (7/3) to give the title product (36.1g, 61% yield).'HNMR (CDCI3) 8 : 1.45-1. 85 (2H, m), 2.00- 2.15 (2H, m), 2.3 (2H, d), 2.75 (2H, d), 3.45 (2H, bs), 4.82 (2H, bs), 7.5-7. 7 (4H, m), Mass spectrum (API+) : Found 284 (MH+). C15H16F3NO requires 283. |
Stage #1: cis,trans-2,5-dimethoxytetrahydrofuran With hydrogenchloride; water at 20℃; for 1h; Stage #2: acetonedicarboxylic acid; p-Trifluoromethylbenzylamine With sodium acetate In water at 60℃; for 2h; | 6 Example 6; 8-(4-Tr ifluoromethy 1-benzy l)-8-aza-bicy clo [3.2.1] octan-3 -one (compound 07-82)A mixture of 2,5-dimethoxytetrahydrofuran (l,36g 10,3 mmol) and hydrochloric acid (2,25g, 37%,22,8 mmol) in water 20 mL were stirred at 200C for 1 h. Then 3-oxo-pentanedioic acid (1,5Og 10,3 mmol), 4-trifluoromethyl-benzylamine (2,0Og 11,4 mmol) and sodium acetate (2,8 Ig 34,3 mmol) were added and heated to 6O0C for 2 h. After extractive workup with heptane-ethylacetate 1 :1 and water and column chromatography (heptane-ethylacetate 1 :1) an oil was obtained, 1,53, purity >96%, compound 07-82.1H-NMR (ppm): 1,66, 2H; 2,13, 2H; 2,23, 2H; 2,68, 2H; 3,47, 2H; 3,80, 2H, NCH2Ph; 7,55 and 7,60, 4H, PhH; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.5% | With sodium methylate; at 110 - 120℃; for 2h; | The toluenic solution obtained in A) (4.00 Kg of 4-trifluoromethylbenzylamine) was charged in a reactor. After distillation until an oil residue was obtained, 3.20 Kg of <strong>[29006-01-7]methyl 4-methoxybutyrate</strong>, 0.40 kg of 30% sodium methylate were added. The solution was then heated to 1 10-1200C, distilling at atmospheric pressure in order to remove all methanol (also methanol freeing from the reaction) and maintaining such temperature for at lest two hours. The reactor at 1 10-120C was then put under vacuum for at least one hour. At the end of the reaction, 12.0 Kg of toluene, 2.0 Kg of water and 0.40 Kg of 80% acetic acid were added to the mass. After stirring, the lower aqueous phase was separated and removed. The organic phase was then distilled under vacuum to a oil residue. To such a residue, 4.00 Kg of ethylacetate, 12.0 Kg of n-hexane were added and the final mass was heated to 40-60 C until a complete solution was obtained. Then the solution was brought to 20-30 C and so maintained until a good precipitation was obtained. The mass was then cooled to 0C - 10C, centrifuged by washing with a mixture of 0.80 Kg of ethylacetate, 4.00 Kg of n-hexane. The obtained humid product was used as such in the following step.About 3.8 Kg of crude N-[4-(trifluoromethyl)benzyl]-4-methoxybutyramide were obtained. Yield: 60.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dmap; copper(l) iodide; 9-azabicyclo[3.3.1]nonane N-oxyl; oxygen; 4,4'-di-tert-butyl-2,2'-bipyridine In acetonitrile at 20℃; for 15h; | |
89% | With pyridine; 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate In dichloromethane at 20℃; for 12h; Inert atmosphere; | |
86% | With pyridine; Oxone; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy; Pyridine hydrobromide In dichloromethane at 20℃; for 12h; Green chemistry; |
81% | With pyridine; tert.-butylhydroperoxide; iodine; potassium carbonate In water at 80℃; for 0.0833333h; | |
80.5% | With C68H64Cl2N6P2Ru2(4+)*2F6P(1-)*2Cl(1-); caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24h; Inert atmosphere; Green chemistry; | |
76% | With 1-methyl-1H-imidazole; oxygen; copper(ll) bromide In dimethyl sulfoxide at 100℃; for 24h; | 1 Typical procedure for CuBr2/NMI catalyzed aerobic oxidation of primary amines General procedure: To a 100 mL eggplant type Schlenk flask were added CuBr2 (67.0 mg, 0.3 mmol), corresponding amine (3 mmol) and a solution of NMI (73.8 mg, 0.9 mmol) in DMSO (6 mL). The flask was evacuated and purged with oxygen for three times before the flask was attached to a balloon filled with oxygen. Then the flask was heated at 100 °C for 24 h. After the flask was cooled down and the reaction mixture turned into green color, water (15 mL) and dichloromethane (15 mL) was added into the mixture. The water layer was extracted with dichloromethane (5 mL x 3) and the organic layers were combined. After removing the solvent, residue was purified by column chromatography (PE/EA = 100:1) to give the product. |
66% | With tris(2,2’-bipyridine)dichlororuthenium(II) hexahydrate; oxygen; copper(I) bromide; lithium tert-butoxide In dimethyl sulfoxide at 20℃; for 18h; Schlenk technique; Irradiation; | |
50% | With tris(2,2'-bipyridyl)ruthenium dichloride; oxygen; copper(I) bromide; lithium tert-butoxide In dimethyl sulfoxide at 25℃; for 18h; Schlenk technique; Microwave irradiation; | 3 Embodiment 3: catalytic oxidation of 4 - trifluoromethyl benzylamine preparation 4 - trifluoromethyl benzonitrile To the Schlenk reaction tube by adding 7.2 mg (0.05 mmol) of cuprous bromide, 6.4 mg (0.01 mmol) three (2, 2' - bipyridyl) ruthenous, 8.0 mg (0.01 mmol) tert lithium ethoxide, using Schlenk double-row tube vacuum pumping, access oxygen state, adding 71 uL (0.5 mmol) 4 - trifluoromethyl benzylamine, 3.0 ml dimethyl sulfoxide, the use of the Schlenk tube with double row sustained and the oxygen to the reaction system, the temperature control of the reaction system 25 °C, blue light LED lamp (wavelength 450 - 500 nm) irradiation, stirring the reaction 18 hours after the, adding 3 ml saturated sodium acid sulfite aqueous solution and 10 ml ethyl acetate, extraction liquid, anhydrous magnesium sulfate drying, to remove the magnesium sulfate, the resulting organic phase is concentrated, the concentrate with silica gel column chromatography, to obtain 4 - trifluoromethyl benzonitrile, yield 50%; |
41 %Spectr. | With C28H19ClN4Ru(1+)*F6P(1-); oxygen; potassium carbonate In d(4)-methanol at 30℃; for 24h; | |
With cyclohexyl hydroperoxide In acetonitrile at 20℃; for 7h; | 12 Example 12 0.5 millimole of p-trifluoromethylbenzylamine, 0.05 g of MnAPO-5, 2 ml of acetonitrile was added to a pressure-resistant flask,Moles cyclohexyl hydroperoxide, reacted at room temperature under normal pressure for 7 hours. The reaction product was analyzed by GC-MS. The amine conversion was81%, nitriles, i.e., the selectivity to trifluoromethylbenzonitrile was 89%. | |
Multi-step reaction with 2 steps 1: N-chloro-succinimide / 0.17 h / 20 °C / Milling 2: triethylamine / 0.33 h / 20 °C / Milling | ||
With C21H28ClN4Ru(1+)*CF3O3S(1-); ammonia; oxygen In 1,2-dichloro-benzene at 150℃; for 0.666667h; | ||
57.01 %Chromat. | With ammonia; oxygen; silica gel; 11-pyridino[3,2-h]quinoxalino[2,3-f]quinolin-11-ylpyridino[3,2-h]quinoxalino[2,3-f]quinoline In tert-Amyl alcohol; N,N-dimethyl-formamide at 110 - 800℃; for 16h; Sonication; Inert atmosphere; Calcination; | 14 Example 14 The preparation of the catalyst was as described in Example 1. In the reaction flask was added 60 mg of the catalyst with a calcination temperature of 800 , 1 ml of tert-amyl alcohol as a solvent, 0.5 mmol of 4-(trifluoromethyl)benzylamine, and 200 microliters of ammonia (mass The fraction is 28%), the reactor is filled with 0.2MPa O2, reacted at 110°C for 16 hours, and the yield of 4-(trifluoromethyl)benzonitrile obtained by gas chromatography is 57.01%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: p-Trifluoromethylbenzylamine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | A mixture of ethyl 2,6-dichloro-5-fluoro-pyrid-3-yl-3-oxo-propionate (3.0 g, 10.7 mmol), triethylorthoformate (2.4 g, 2.68 mL, 16.1 mmol) and acetic anhydride (2.73 g, 2.38 mL, 26.7 mmol) was heated to reflux for 1 hour at 1400C. The mixture was cooled and then concentrated. The residue was diluted with ethanol (5 mL) and 4-trifluoromethylbenzyl amine (2.25 g, 1.83mL, 12.84 mmol) was added. The mixture was stirred for approximately 12 hours and was filtered to collect a solid material (2.2 g). The filtrate was concentrated and product was purified from the residue by chromatography over silica to give an additional solid material (0.8 g). The solid material was combined to give ethyl 2-(2,6-dichloro-5- fluoropyridine-3-carbonyl)-3-(4-trifluoromethyl-benzylamino)acrylate (3.0 g, 60 %). Rp=.55 (20% EtOAc/hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 54.8% 2: 31.6% | With ammonium hydroxide; oxygen In tert-Amyl alcohol at 110℃; for 16h; | |
1: 38 %Spectr. 2: 10 %Spectr. | With [RuCl(ppy)(tpy)][PF6]; oxygen; potassium carbonate In d(4)-methanol at 30℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: p-trifluoromethylbenzamide With bis(cyclopentadienyl)dihydrozirconium; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane at 20℃; Glovebox; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; water for 2h; Glovebox; Inert atmosphere; | 2. Experimental General procedure: In a nitrogen-filled glovebox, to a 15 mL reaction tube equipped with a magnetic stirrer, were added Cp2ZrH2 (0.01mmol, 2.2 mg) as the catalyst, and the appropriate amide (0.2mmol); solvent was added when necessary. HBpin (3 equiv. peramide functional group) was then added, and the reaction tube was taken out from the glovebox and stirred at room temperature for 12-48 h. The resultant crude amines were either isolated using silica gel flash chromatography, or acidified by stirring with HCl in Et2O (2 mL, 1N) for 2 h, after which time precipitation was observed. Then, the reaction solution was transferred to a centrifuge tube and centrifuged three times. The supernatant was removed and the resulting solid was dried inan oven at 80 °C for several hours to obtain the HCl salt of the amine. |
59% | With 1,10-Phenanthroline; diethoxymethylane; iron(II) acetate In toluene at 100℃; for 28h; Inert atmosphere; chemoselective reaction; | |
With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In neat (no solvent) at 120℃; for 24h; Inert atmosphere; Sealed tube; chemoselective reaction; | General procedure for hydroboration of primary amides General procedure: Benzamide (0.0606 g, 0.5 mmol) was placed in a culture tube (11 mL) at 25 °C, sealed with septum, the air in culture tube was replaced with argon gas (Tables 1 and 2). After adding pinacolborane (0.36 ml, 2.5 mmol 5 equiv), the screw cap was closed, stirred at 120 °C for 24 h. After this time, it was cooled to room temperature, excess HBpin was quenched by adding water (0.5 ml). The mixture was diluted with ethyl acetate (5 ml), 1 M HCl in ether (2 ml) and stir for 1 h. The generated amine salt was filtered using ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 130℃; for 18h;Inert atmosphere; | General procedure: Solid starting materials were placed in a 100 cm3 3-necked flask, evacuated, and flushed with argon three times. Then, the liquid starting materials and, finally, toluene were added through the septum with a syringe. The mixture was heated at 130 °C (oil bath temperature) maintaining the argon atmosphere with a balloon. The reaction was stopped after 18 h (TLC). After cooling to r.t., the solid material was removed by filtration and washed with CH2Cl2.The combined organic layers were evaporated and the resulting crude product was purified by flash column chromatography (LP/EtOAc) starting with 5percent EtOAc to 10percent EtOAc over the course of 20 min. Then, flash column chromatography was continued with 10percent EtOAc. Drying under reduced pressure delivered the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: 4.1.2. General procedure for the synthesis of aromaticsulfamoyl-acetic acid methyl ester (6a-k) The triethylamine (1.2mmol) was added to the solution of aromatic amines 5a-k (1mmol) and chlorosulfonyl acetic acid methyl ester 4 (1mmol) in THF (15mL) and stirred at RT until absence of the aromatic amines (checked by TLC). The reaction mixture was concentrated in vacuo and diluted with H2O, followed by neutralization with 5% HCl to pH 7 and extracting with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. Purification of the crude residue by column chromatography (petroleum ether/ethyl acetate) afforded the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Synthesis Example 1: Synthesis of compounds by reductive animation. Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-trifluoromethylbenzylamine (4.73 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean- Stark trap was removed and the reaction mixture was cooled to 0C on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion- wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.72 g, 74% ). 1H NMR (500 MHz, CDC13) delta: 7.57 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.9 Hz, 2H), 6.82 (d, J = 7.3 Hz, 1H), 6.65 (m, 2H), 5.16-4.42 (br s, 2H), 3.90 (d, J = 13.7 Hz, 1H), 3.84 (s, 3H), 3.80 (d, J = 13.7 Hz, 1H), 2.76-2.70 (m, 1H), 2.67-2.55 (m, 2H), 1.84- 1.77 (m, 1H), 1.69-1.63 (m, 1H), 1.17 (d, J - 6.3 Hz, 3H). 13C NMR (125 MHz, CDC13) delta: 146.7, 144.6, 143.9, 134.0, 129.1, 128.4, 127.5, 125.4, 125.3, 123.2, 120.8, 114.6, 111.0, 55.7, 52.1, 50.6, 38.8, 32.0, 20.1. MS (CI) m/z 353 (M+). | |
74% | Compound Example 2 4-(3-(4-(trifluoromethyl)benzylamino)butyl)-2-methoxyphenol B. Synthesis by Reductive Amination (0258) (0259) Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-trifluoromethylbenzylamine (4.73 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0 C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.72 g, 74%). 1H NMR, 13C NMR, and Mass Spectrum of the product were substantially the same as those in Example 2, A (made by the Conditioned Extraction method). | |
74% | Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-trifluoromethylbenzylamine (4.73 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0 C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.72 g, 74%). 1H NMR (500 MHz, CDCl3) delta: 7.57 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 6.82 (d, J=7.3 Hz, 1H), 6.65 (m, 2H), 5.16-4.42 (br s, 2H), 3.90 (d, J=13.7 Hz, 1H), 3.84 (s, 3H), 3.80 (d, J=13.7 Hz, 1H), 2.76-2.70 (m, 1H), 2.67-2.55 (m, 2H), 1.84-1.77 (m, 1H), 1.69-1.63 (m, 1H), 1.17 (d, J=6.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) delta: 146.7, 144.6, 143.9, 134.0, 129.1, 128.4, 127.5, 125.4, 125.3, 123.2, 120.8, 114.6, 111.0, 55.7, 52.1, 50.6, 38.8, 32.0, 20.1. MS (CI) m/z 353 (M+). (0516) The chemical shift measure by 1H NMR may vary, for example, up to 0.2 ppm. The chemical shift measure by 13H NMR may vary, for example, up to 0.5 ppm. The analytical Mass Spectrum may have an experimental error of +/-0.3. Purity Determination (0517) The purity of the product was measured by HPLC. The major peak of retention time of 2.22 minutes indicating greater than about 80%, 85%, 90, or 95% of purity. The HPLC conditions used are as follows. HPLC Conditions: (0518) Mobile Phase A: 13.3 mM ammonium formate/6.7 mM formic acid in water Mobile Phase B: 6 mM ammonium formate/3 mM formic acid in water/CH3CN (1/9, v/v) Column: Synergi Fusion-RP 100A Mercury, 2×20 mm, 2.5 micron (Phenomenex Part No 00M-4423-B0_CE) Gradient Progam: RT=2.22 minutes [table-us-00017-en] Time, minute % Phase B Flow rate, ml/min 0 100 0.5 1 100 0.5 2.5 40 0.5 3.4 40 0.5 3.5 100 0.5 4.5 100 0.5 (0519) The purity of the product was also measure by 1H NMR indicating it to be a single compound of a purity of greater than 90% or 95%. The synthesis described herein can be modified depending upon the final-product to be synthesized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With (dipyridylamine)Cp*IrOSO3; hydrogen In neat (no solvent) at 110℃; for 16h; Autoclave; chemoselective reaction; | |
88% | With hydrogen In neat (no solvent) at 100℃; for 20h; | |
88% | With hydrogen In methanol at 130℃; for 10h; Autoclave; | 2.4. General procedure for the reductive amination of levulinic acidwith amine General procedure: The catalytic reactions were performed in a 100 mL stainless steel batch autoclave reactor. In a typical reaction, the reactor was loaded with LA (1 mmol), an amine (1 mmol), solvent (5 mL), and catalyst (15 mg). Prior to introducing H2 gas in the reactor vessel, the reactor was flushed with N2 gas twice to ensure removal of air from the reactor vessel. Later, the 15 bar of H2 gas pressure was applied at room temperature and the reactor was heated to 130°C. After completion of reaction, the reactor (autoclave) was cooled to room temperature and the remaining H2 gas was carefully vented off and then the reactor was opened. The catalyst was separated from the reaction mixture by filtration and then reaction mixture was diluted with water (10 mL). Diluted reaction mixture was extracted with ethyl acetate (3 10 mL), dried over Na2SO4 and concentrated on the rotary evaporator. The products in the reaction mixture were identified by GC/MS(Shimadzu GCMS-QP 2010) equipped with Restek column Rtx-5MS. |
80% | With formic acid; C22H29IrN4O4S In water at 60℃; for 17h; Schlenk technique; | |
76% | With formic acid; triethylamine In dimethyl sulfoxide at 100℃; for 15h; Inert atmosphere; | |
With formic acid; C24H22N4*BF4(1-)*Ru(2+)*Cl(1-)*C10H14 In neat (no solvent) at 80℃; for 24h; Green chemistry; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 87% 2: 12% | With manganese(IV) oxide In dichloromethane at 40℃; for 24h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; 2,3-dicyano-5,6-dichloro-p-benzoquinone; In ethyl acetate; at 20℃; for 4h; | General procedure: To a solution of anthranilic acid (1 mmol) in ethyl acetate (3 ml) solvent, triethyl amine (1.5 mmol) and T3P (2 mmol) was added and the resulting reaction mixture was stirred at room temperature for 1-2 hrs. The reaction was monitored by TLC, aldehyde (1 mmol) was added and stirred for 1-2 hrs. DDQ (1 mmol) was added to the reaction mixture and further stirred for 30 mins. After completion of the reaction, the mixture is diluted with (20 ml) water and neutralized with 10% NaHCO3 solution. The product was extracted with ethyl acetate (10 ml) and the combined organic phase was washed with water (10ml) and brine solution. The organic phase was dried over anhydrous Na2SO4. The solvent was dried under reduced pressure to afford a crude product, which was purified on silica gel using ethyl acetate and petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With iron oxide In ethanol at 25℃; for 2h; | |
89% | With copper(I) bromide In 1,2-dichloro-ethane at 25℃; for 6h; Schlenk technique; | |
80% | With manganese oxide octahedral molecular sieve-supported copper hydroxide; air In ethanol at 20℃; for 2h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With silica gel In neat (no solvent) at 150℃; for 26h; Inert atmosphere; Sealed tube; | 7 Conversion of o-diacids to N-substituted phthalimides General procedure: These compounds were prepared using the same procedure as reported above, but at 150°C for 18-26h. Following work up, the crude products were purified on 15cm×2.5cm silica gel columns eluted with 60-80% EtOAc in hexanes. The isolated yields are given in Table 3. Note: Saturated NH4Cl was used for washing the pyridine derivatives instead of 1M HCl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With silica gel In neat (no solvent) at 145℃; for 36h; Inert atmosphere; Sealed tube; | 13 Transamidation of primary arylamides to N-substituted arylamides General procedure: These compounds were prepared using the standard procedure at 130°C (benzamides) or 145°C (nicotinamides) for 18-40h. For each reaction, the catalyst was removed by filtration, the EtOAc filtrate was concentrated with 1-2 g of silica gel, and the crude product was purified on a 15cm×2.5cm silica gel column eluted with 40-60% EtOAc in hexanes. The isolated yields are given in Table 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dihydrogen peroxide; In water; at 120℃; for 20h;Sealed tube; | General procedure: A 15 mL tube was added 2-aminobenzamide (1mmol), benzyl amine (1.5mmol), and a stir bar. Then H2O2 (30 wtpercent in H2O, 5 equiv.) was added by a syringe at room temperature under open air. The tube was closed and kept at 120°C for 20 h. The conversion and yield were determined by GC and GC?MS using hexadecane (0.1 mmol) as the internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With urea; In N,N-dimethyl acetamide; at 250℃; for 0.333333h;Microwave irradiation; | 7-Fluoro-lH-benzo[d][l,3]oxazine-2,4-dione (109 mg; 0.6 mmol), (4- (trifluoromethyl)phenyl)methanamine (127 mg; 0.7 mmol), urea (54 mg; 0.9 mmol), and 0.5 ml of DMA were charged in a microwave tube and heated for 20 min at 250 C. The reaction mixture was cooled to rt, 5 ml of water was added, and the precipitation formed was filtered and dried to give 202 mg of crude product. LC-MS (ES-) [M-l]: 337.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 150℃; for 1h;Microwave irradiation; | To a suspension of 6-chloropyridine-3 -sulfonamide in ethanol (0.3 M) in a microwave compatible vessel was added (4-(trifluoromethyl)phenyl)methylamine. The reaction mixture was heated at 150 C in Biotage Initiator for 1 hour. The reaction mixture was quenched by addition of H20, extracted with EtOAc, dried over MgS04, filtered and concentrated in vacuo to give the title compound as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In ethanol; at 90℃; for 5h; | To a solution of methyl 4-oxotetrahydrofuran-3 -carboxylate (11, 50 g, 350 mmol) in anhydrous EtOH (1000 mL) was added (4-(trifluoromethyl) phenyl)methanamine (64 g, 360 mmol), followed by AcQH (60 mL). The reaction mixture was then heated to 90C and stirred for 5 hours when TLC showed that the reaction completed. The reaction mixture was concentrated under reduced pressure to removemost of the solvent. The residue was partitioned between EtOAc (1000 mL) and H20 (1000 mL), and the organic phase was washed with H20 (1000 mL) and brine (1000 mL), dried over Na2SO4 and concentrated under reduced pressure to afford methyl 4-((4-(trifluoromethyl)benzyl)amino)-2,5- dihydrofuran-3-carboxylate (12) as a solid, which was used directly in next step without further purification. LC/MS (m/z): 302 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With montmorillonite K-10; In ethanol; at 80℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: To a solution of 1 (2.0 mmol) in absolute EtOH (8.0 mL)in a glass tube was added dropwise the appropriate amine(3.6 mmol) and K-10 (0.3 g mmol-1); the quartz tubewas sealed with reaction mixture and introduced intoa microwave oven. The flask was irradiated for 30 min(150 W) the temperature of 80 C. After completion of thereaction the mixture was filtered, the organic phase wasdried with Na2SO4, filtered and the solvent was evaporatedunder reduced pressure to give the crude products. All thecompounds were purified by column chromatographyon silica gel using 2-5% EtOH-CH2Cl2 as eluent to giveanalytically pure products 3a-m. The products werecharacterized by corresponding spectroscopic data (1H and13C NMR, and HRMS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | Synthesis of Intermediates 5 (8) General procedure: To a mixture of benzoic acids 4 (7) (4 mmol),1-ethyl-3-(3-dimethyllaminopropyl) carbodiimide hydrochloride (4.8 mmol) and N-hydroxybenzotrizole (0.48 mmol) wereadded amines (4.8 mmol) at room temperature. The reaction mixture was stirredfor overnight and washed with water successively. The organic layer was driedover anhydrous sodium sulfate. Then the solvent was removed in vacuo to affordcrude compounds 5 (8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 36h;Inert atmosphere; | To a stirred solution of <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> 4a (1.10 g, 6.15 mmol) in dry DMSO (6 mL) was added 4- (trifluoromethyl)benzylamine 3a (1.00 g, 5.60 mmol) followed by Et3N (0.94 mL, 6.71 mmol) and I2 (28 mg, 0.11 mmol). The reaction mixture was heated to 120 C for 36 h, cooled to room temperature, diluted with water (50 mL) and extracted with EtO Ac (3 x 30 mL). The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was recrystallized from acetone/hexanes to afford 5a (1.20 g). The filtrate was concentrated and purified by chromatography on Si02 (acetone/hexanes, 1:8 to 1:4 to 1:3, containing Et3N (1%)) to afford an additional batch of 5a (0.34 g; total amount 1.54 g, 84%) as a yellow solid: Mp 165.4-166.7 C; IR (ATR) 3487, 3377, 1629, 1549, 1480, 1411, 1329, 1275, (0169) 1236, 1200, 1178, 1154, 1090, 1066, 1016, 787, 755 cm 1; NMR (500 MHz, CDCh) d 7.86 (dd, (0170) 1 H, 7 = 9.5, 1.0 Hz), 7.63 (d, 2 H, 7 = 8.0 Hz), 7.44 (d, 2 H, 7 = 8.0 Hz), 6.00-6.12 (m, 3 H), 4.94 (brs, 1 H), 4.55 (d, 2 H, 7 = 6.0 Hz); 13C NMR (100 MHz, acetone-d6) d 144.2 (app d, 7 = 1.0 Hz), 141.5 (d, 7 = 9.0 Hz), 137.6 (d, 7 = 227.0 Hz), 135.8 (d, 7 = 13.0 Hz), 128.8 (q, 7 = 32.0 Hz), 127.6, 125.4 (q, 7 = 4.0 Hz), 124.5 (d, 7 = 4.0 Hz), 124.5 (q, 7 = 269.0 Hz), 122.9 (d, 7 = 2.0 Hz), 100.7 (d, 7 = 4.0 Hz), 45.5; 19F NMR (376 MHz, CDCh) d -62.9 (s, 3 F), -160.7 (s, 1 F); HRMS (HESI) m/z calcd for C14H12N3O2F4 [M+H]+ 330.0860, found 330.0858. |
67.3% | With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 24h; | p-Trifluoromethylbenzylamine (2.43 ml, 16.7 mmol)Dissolved with <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> (3 g, 16.7 mmol) in 70 ml of anhydrous DMSO followed by triethylamine (2.7 ml, 20.1 mmol)And a simple iodine (50 mg) as a catalyst to prepare a reaction mixture;The reaction mixture was reacted at 120 C for 24 h and cooled to room temperature.Diluted with 200 ml of water and extracted with ethyl acetate 3 times (100 ml × 3).The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated.The filter cake was washed with a petroleum ether / ethyl acetate (5:1) mixed solvent.Obtained a yellow solid of 3.71 g, a yield of 67.3%. |
65% | With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 24h; | 2-fluoro-4-nitro-A^l-(4-(trifluoromethyl)benzyl)benzene-l,3-diamine. To a stirred solution of <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> (0.100 g, 0.557 mmol, 1.00 equiv) in dry DMSO (4.6 mL) were added 4-(trifluoromethyl)benzylamine (0.081 mL, 0.557 mmol, 1.00 equiv) followed by Et3N (0.09 mL, 0.669 mmol, 1.20 equiv) and I2 (cat. 1 mg). The reaction mixture was heated to 120 C for 24h. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (3 x 15 mL). The separated organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexanes = 1 : 10 to 1 :5 to 1 :3) to afford the product as a yellow solid (0.120 g, 65 %). 1H NMR (500 MHz, CDCb) delta 7.86 (dd, 7 = 9.5, 1.0 Hz, 1 H), 7.63 (d, 7 = 8.0 Hz, 2 H), 7.44 (d, 7 = 8.0 Hz, 2 H), 6.00-6.12 (m, 3H), 4.94 (br, 1H), 4.55 (d, 7 = 6.0 Hz, 2 H); 13C NMR (100 MHz, acetone-d6) delta 144.15 (d, 7 = 1.0 Hz), 141.45 (d, 7 = 9.0 Hz), 137.61 (d, 7 = 227.0 Hz), 135.80 (d, 7 = 13.0 Hz), 128.75 (q, 7 =32.0 Hz), 127.56, 125.40 (q, 7 = 4.0 Hz), 124.53 (d, 7 = 4.0 Hz), 124.49 (q, 7 = 269.0 Hz), 122.93 (d, 7 = 2.0 Hz), 100.73 (d, 7 = 4.0 Hz), 45.48; 19F NMR (376 MHz, acetone-d6) delta -62.87 (s, 3 F), -160.72 (s, 1 F); IR (neat) 3487.3, 3377.3, 1629.0, 1548.9, 1479.9, 1410.9, 1328.9, 1274.9, 1235.7, 1200.3, 1178.0, 1153.7, 1090.4, 1066.1 , 1015.8, 786.5, 754.9 cm-1 ; HRMS (ESI) m/z calcd for C14H12N3O2F4 [M+H]+ 330.0860, found 330.0858. |
65% | With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | A solution of <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> (0.100 g, 0.557 mmol, 1.00 equiv) in dry DMSO (4.6 mL) was treated with 4-(trifluoromethyl)benzylamine (0.081 mL, 0.557 mmol, 1.00 equiv) followed by Et3N (0.09 mL, 0.669 mmol, 1.20 equiv) and I2 (cat. 1 mg). The reaction mixture was heated to 120 C for 24 h, cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (3 x15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2(EtOAc/hexanes,1:10 to 1:5 to 1:3) to afford the 2-fluoro-4-nitro-N1-(4-(trifluoromethyl)benzyl)benzene-1,3-diamine (0.120 g, 65 %) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: p-Trifluoromethylbenzylamine With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 2-fluoroprop-2-enoate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 4.2.1 General procedure for the synthesis of N-substituted -fluoroacrylamides (2a-i) General procedure: A solution of 2.0 M NaHMDS in THF (7.5 mL, 15.0 mmol) was added to the solution of RNH2 (1.2 equiv) in THF (25 mL) at 0 °C under Ar atmosphere. The reaction solution was then stirred for 30 min at room temperature, after that, methyl 2-fluoroacrylate (0.91 mL, 10.0 mmol) was added dropwise at 0 °C. The resulting solution was then warmed to room temperature and stirred for overnight. After quenched with saturated NH4Cl aqueous solution, the mixture was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with brine (20mL) and dried over NaSO4. After filtration and concentration, the residue was purified by column chromatography, and the isolated yields were shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With iodine; dimethyl sulfoxide at 130℃; for 0.166667h; Microwave irradiation; | |
82% | With iodine In dimethyl sulfoxide at 100℃; for 8h; | (17) General Procedure for the Preparation of 3 General procedure: Iodine (0.25 mmol, 63.4 mg) and 1,2-dibenzyldisulfane (0.5mmol, 123.4 mg) was added to a solution of 1-methylpiperazine(1.2 mmol, 119.1 mg) in DMSO (0.5 mL), and the reactionmixture was stirred for 8 h at 100 °C. The solvent was removedunder vacuum, and the residue was purified by flash silica gelcolumn chromatography with PE-EtOAc (1:1) as eluent to affordthe product 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 24h;Inert atmosphere; | General procedure: To a stirred solution of corresponding amine (1.0 or 2.0 equiv) in CH2Cl2 (0.2 M) were added at 0C DCC (1.3 equiv), DMAP (0.13 equiv) and 3-butenoic acid (1.3 equiv). The reaction mixture was stirred for 10 minutes at 0 C, then for 24 hours at room temperature. The precipitate was filtered off and washed with CH2Cl2 (25 mL). The organic layer was hydrolyzed with saturated aqueous NaHCO3, extracted and dried over MgSO4 and concentrated at reduced pressure. The crude product was purified by silica gel column chromatography to afford the corresponding allyl-amide 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With C19H35Cl2CoN2P; potassium <i>tert</i>-butylate; sodium triethylborohydride In tetrahydrofuran; toluene at 150℃; for 24h; Inert atmosphere; Molecular sieve; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With pyridine; In methanol; at 140℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: Compounds 1-6 were prepared according to conventional organic synthesis methods. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was dissolved in THF (20 mL) in a round bottom flask and after that treated with two equivalents of the corresponding benzylamine and an equimolar amount of triethylamine. The reaction was conducted with continuous stirring and heating (70 C) under reflux in an oil bath for 15 h. Compounds 7-15 were synthesised using a microwave reactor with a focused field. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was put into a thick-walled tube together with the corresponding benzylamine (2.54 mmol), pyridine (1.27 mmol), methanol (approx. 5 mL) and a magnetic stir bar and then sealed with a special cap. The reaction parameters were set according to the previously published paper as follows-140 C, 30 min, 200 W [29]. Reaction progress was checked by TLC (hexane:ethyl acetate-1:1). Regardless of the synthesis method used,all reaction mixtures were adsorbed on silica and subjected to preparative flash chromatography (hexane and ethyl acetate, gradient elution, detection wavelengths 260 nm and 280 nm). Products were recrystallized from ethanol or ethanol and water if necessary. All final substances were chemically characterized (1H-NMR, 13C-NMR, IR, melting point and elemental analysis). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 140℃; for 1.5h;Microwave irradiation; | j00483j A mixture of (4-(trifluoromethyl)phenyl)methanamine (2.0 g, 11 mmol) and methyl 2,2- dimethoxyacetate (1.7 g, 13 mmol) was stirred at 140 C for 1.5 hours in microwave. On completion, the mixture was concentrated in vacuo to give compound B-106 (3.1 g, crude) as a yellow gum. LCMS (B): tR= 0.718 mi, (ES) mlz (M+H) + = 278.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: caffeic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: p-Trifluoromethylbenzylamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 6.33h; | 17 (E)-3-(3,4-dihydroxyphenyl)-N-(4-(trifluoromethyl)benzyl)acrylamide Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-(trifluoromethyl)benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then EtOAc, water,1N-HCl and brine. The organic layer was dried over anhydrous Mg2SO4, concentrated under reduced pressure and purified by column chromatography. Yield 76.0% |
76% | Stage #1: caffeic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: p-Trifluoromethylbenzylamine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #3: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 16h; | 17 17. Synthesis Example 17: (E)-3-(3,4-dihydroxyphenyl)-N-(4-(trifluoromethyl)benzyl)acrylamide Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 20 minutes. After 20 minutes, 4-(trifluoromethyl)benzylamine (0.16 mL, 1.11 mmol) was added, followed by stirring at room temperature for 20 minutes. After 20 minutes, DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 hours, followed by extraction with EtOAc, water, 1N-HCl and brine. The organic layer was dried over anhydrous Mg2SO4, concentrated under reduced pressure, and purified by column chromatography.Yield 76.0% |
Stage #1: caffeic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: p-Trifluoromethylbenzylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #3: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; | General Procedure for Synthesis of CGA Derivatives (5 - 10) General procedure: To a solution of caffeic acid (1.0 equiv.), HOBt (1.0 equiv.) and EDCI (1.0 equiv.) in DMF were stirred at room temperature for 15 min. To this solution was added amine derivative (1.0 equiv.) and the reaction mixture was stirred at room temperature. After 15 min the reaction mixture was treated with DIPEA (2.0 equiv.) stirred at room temperature for 16 h. The reaction progress is monitored by TLC and then it was quenched with 1N HCl and extracted with EtOAc (3 x 15 mL), the organic layer was dried over MgSO4, filtered, concentrated in vacuo. The residue was purified by silica gel column chromatography (10-25% EtOAc/hexanes) to afford desired products in good yields (5-90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With iodine; triethylamine In dimethyl sulfoxide for 1h; Reflux; Inert atmosphere; | 10.1 Step 1: Synthesis of 4-Nitro-N1-(4-(trifluoromethyl)benzyl)benzene-1,3-diamine 5-Fluoro-2-nitroaniline (10.24 g, 58.46 mmole) was dissolved in anhydrous dimethylsulfoxide (90 mL). (4-(trifluoromethyl)phenyl)methanamine (6.1 g, 39.0 mmole) was added followed by triethylamine (13.0 mL) and solid iodine (70 mg). The mixture was heated at reflux for 1 h. under argon. Ethyl acetate (150 mL) was added and the organics were extracted with water (3*150 mL). The combined aqueous layers were washed with dichloromethane (300 mL), all organics were combined, filtered through a 1PS filter and then evaporated to dryness. The crude material was dissolved in boiling ethyl acetate (20 mL) and hexanes were added to cloud point. Upon cooling, crystals formed. The solid was filtered off on a No.54 Whatman filter paper on a Buchner filter and dried under high vacuum to give 4-nitro-N1-(4-(trifluoromethyl)benzyl)benzene-1,3-diamine (8.61 g, 71% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese(IV) oxide; oxygen; In dichloromethane; at 180℃; under 15001.5 Torr; for 24h; | 300 mg of manganese dioxide, 60 mg of 4-(trifluoromethyl)benzylamine (mass concentration in the mixture: 1.0%) was added to 6 g of dichloromethane, and the mixture was uniformly mixed;Filled with 2MPa oxygen, reacted at 180 C for 24 hours,4-(trifluoromethyl)benzylamine conversion rate of 99.0%,The selectivity of the corresponding 4-(trifluoromethyl)benzamide was 99.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran at 20℃; Alkaline conditions; Inert atmosphere; | General method for the preparation of amides 25, 26 General procedure: A mixture of the appropriate acid 9a or 9c (1 eq) and TBTU (1.2 eq.) was suspended in anhydrous THF (5 ml . mmol/eq.) at r.t. under a N2 atmosphere. DiPEA (2.5 eq.) was then added to the reaction, followed by the appropriate benzyl amine (1 eq.). The reaction was stirred at r.t. for 4-8 hours (monitored by T.L.C.), then diluted with EtOAc (50 ml . mmol/eq). The organic phase was washed with 0.5M aq. citric acid solution (2x 30 ml . mmol/eq), sat. aq. NaHCO3 solution (2x 30 ml . mmol/eq), and finally with brine (30 ml . mmol/eq). The organic layer was dried over Na2SO4 concentrated under vacuum. The solid obtained was purified by crystallization or flash column chromatography. |
64% | With 4-(dimethylamino)pyridine N-oxide; phenylboronic acid In neat (no solvent) at 200℃; for 0.5h; Microwave irradiation; chemoselective reaction; | Cinnamamide Derivatives 3 and 5; General Procedure General procedure: A mixture of carboxylic acid 1 (0.5 mmol), amine 2 or 4 (0.5 mmol),phenylboronic acid (5 mol%), and DMAPO (5 mol%) was placed in acylindrical quartz reactor (∅ = 1.1 cm). The reactor was then introducedinto an Anton Paar Monowave 300. The stirred mixture washeated at 200 °C (P = 100 W) for 15 min. After microwave dielectricheating, the crude reaction mixture was allowed to cool down to r.t.and partitioned between CH2Cl2 (5 mL) and sat. aq NaHCO3 (5 mL).The aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combinedorganic layers were washed with aq 1 N HCl (2 CH2Cl2 5 mL),dried (MgSO4), filtered, and concentrated under vacuum. The crudeproduct was purified using cold diisopropyl ether as a trituration solventor by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Diethoxyacetonitrile (15.5 mmol, 1 eq) was added to sodium methoxide solution, 25% w/t in methanol and stirred for 24 hours at rt. Corresponding amine (0.9 eq) was added and stirred for additional 24 hours at rt. The reaction mixture was then concentrated under vacuum. The flask was then placed on ice, followed by addition of concentrated sulfuric acid to reach final concentration as 1 M. The reaction was allowed to stir for additional 48 hours and then neutralized by 4 M potassium hydroxide solution to pH ~ 7. The resulting precipitate was collected and extracted with CH2Cl2 for three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Crude product was subject to purification by silica gel column chromatography. Following the described general procedure, brown solid was obtained. 1H NMR (400 MHz, MeOD) delta 8.84 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.31-7.29 (m, 1H), 6.84 (s, 1H). 13C NMR (100 MHz, MeOD) delta 158.36, 152.70, 139.69, 133.63, 133.32, 133.00, 132.68, 130.74, 126.98, 124.99, 124.28, 123.63, 123.58, 118.73, 118.70, 100.92. LRMS (ESI+) [M+H] calcd for C10H8F3N2213.1, found 213.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine; In acetonitrile;Inert atmosphere; Reflux; | General procedure: To a solution of Boc-protected amine 7 (1 mmol, 1.0 equiv.) in MeCN (5 mL) was added successively TBD (13.9 mg, 0.1 mmol, 0.1 equiv.) and amine 8 (2 mmol, 2.0 equiv.) under nitrogen atmosphere and the solution was refluxed for 6-18 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was extracted with CH2Cl2, washed with water and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | Methyl 2-fluoro-3 -nitrobenzoate (1 eq.), (4-(trifluoromethyl)phenyl) methanamine (1.5 eq.) and potassium carbonate (2 eq.) were combined in DMF (0.24 M) and the suspension was heated at 80C for 2 h. The reaction was cooled to rt, diluted with EtOAc and washed sequentially with 10% aq. NH4C1, water and brine. The organic layer was then dried over MgSO4 and filtered. Concentration of the filtrate in vacuo furnished the crude reaction product as a yellow semi-solid. Purification by column chromatography (Si02, 9:1 (v/v) Hex:EtOAc to 3:7 (v/v) Hex :EtOAc) afforded methyl 3-nitro-2-((4-(trifluoromethyl)benzyl)amino)benzoate as a golden, yellow oil (56% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 120℃; for 0.5h; Microwave irradiation; | 3.2.2. General Procedure B (Used for Compounds 1-2 and 5-20) General procedure: The starting 3-aminopyrazine-2-carboxylic acid (200 mg; 1.44 mmol) was treated with1,10-carbonyldiimidazole (CDI; 303 mg; 1.88 mmol; 1.3 equiv) in DMSO (2 mL) in a special tubeused for microwave reactions. The reaction mixture was left to react for 5-10 min until the bubblingdue to emerging CO2 ceased. Subsequently the corresponding alkylamine/aniline/benzylamine(2.15 mmol, 1.5 equiv) was added. The microwave reactor was used to form the amide bond underfollowed conditions: 120 °C, 30 min, 100 W. The progress of the reaction was checked using TLCon silica desk developed by hexane/ethyl-acetate 2:1 system. Water (6 mL) was poured into thereaction mixture, the precipitate was filtered off, dissolved again in acetone and adsorbed to silica.The prepared sample was subjected to flash chromatography as described in previous section. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 30h;Inert atmosphere; Sealed tube; | A 30-mL microwave vial equipped with a magnetic stir bar was charged with <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> 4b (0.530 g, (0213) 2.98 mmol) and 4-(trifluoromethyl)benzylamine 3a (0.575 g, 3.28 mmol). The vial was evacuated and filled with N2 (3x). Dry DMSO (3 mL) was added followed by Et3N (0.42 mL, 2.98 mmol) and L (0.023 g, 0.089 mmol). The vial was sealed and the reaction mixture was heated to 120 C for 30 h, cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 5 mL), dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by chromatography on S1O2 (acetone/hexanes, 1:4 to 3:7, containing Et3N (1%)) to afford 5d (0.81 g, 82 %) as a yellow solid: Mp 150-151 C; IR (ATR) 3446, 3323, 1641, 1549, 1397, 1325, 1283, 1251, 1105, 867 cm 1; NMR (400 MHz, CDCh) d 7.79 (d, 1 H, 7 = 12.4 Hz), 7.64 (d, 2 H, 7 = 8.0 Hz), 7.44 (d, 2 H, 7 = 8.0 Hz), 6.14 (brs, 2 H), 5.69 (d, 1 H, 7 = 7.6 Hz), 5.12 (s, 1 H), 4.50 (d, 1 H, 7 = 6.0 Hz); 13C NMR (100 MHz, CDCh) d 144.9, 143.8 (d, 7 = 14.0 Hz), 143.5 (d, 7 = 235.0 Hz), 141.0, 130.4 (q, 7 = 32.0 Hz), 127.4, 126.1 (q, 7 = 4.0 Hz), 124.1 (q, 7 = 270.0 Hz), 121.6 (d, 7 = 9.0 Hz), 111.1 (d, 7 = 23.0 Hz), 96.1, 46.7; 19F NMR (376 MHz , CDCh) d -62.6 (s, 3F), -146.8 (s, 1F); HRMS (HESI) m/z calcd for C14H12N3O2F4 [M+H]+ 330.0860, found 330.0856. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In acetonitrile at 80℃; for 8h; | II. General synthetic procedure for the preparation of compounds (3a-u, 5a-i and 7a-g) General procedure: To a stirred solution of a pyridinium salt of phenacyl bromide (1 mmol) and thebenzylamine/benzyl alcohol/amine (1 mmol) was added in CH3CN and allowed to stir. K2CO3was added to the reaction mixture and refluxed for 8 h. The reaction progress was monitoredby using TLC. After complete consumption of the starting materials, the CH3CN wasevaporated under reduced pressure and the crude reaction mixture was diluted with EtOAc (35mL) and washed with water (10 mL) and brine (10 mL), then dried over anhydrous sodiumsulfate and concentrated to yield the crude amide, which was purified by using silica gel columnchromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 3-((tert-butyldimethylsilyl)oxy)cyclobutan-l-one (1.0 g, 5.0 mmol) and (4-(trifluoromethyl)phenyl)methanamine (874 mg, 5.0 mmol) in a RB flask was added MeOH (10 mL). The mixture was stirred at r.t. for 5 min. To this mixture were added (isocyanomethylene)dibenzene (965 mg, 5.0 mmol) and 2-chloroacetic acid (472 mg, 5.0 mmol) sequentially. The resulting mixture was stirred at r.t. for 5 h, diluted with EtOAc (150 mL), washed with saturated aqueous NaHC03 (50 mL), saturated aqueous NH4Cl (50 mL), and brine, dried over sodium sulfate, concentration under reduced pressure, and purified by silica chromatography using 20% EA/Hex to provide 1.2 g (1.8 mmol, 36% yield) of the first eluting Diastereomer 46-1A and 698 mg (1.08 mmol, 21% yield) of the second eluting Diastereomer 46- 1B. Characterization of Diastereomer 46-1 A: LRMS (APCI) m/z 645.3 (M+H). 1 H NMR (400 MHz, Methanol-i/4) d 7.57 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.41 - 7.10 (m, 10H), 6.13 (s, 1H), 4.82 (s, 2H), 4.24 (s, 2H), 4.18 (t, / = 7.0 Hz, 1H), 3.07 (ddd, / = 9.8, 6.8, 3.0 Hz, 2H), 2.26 (t, J = 9.9 Hz, 2H), 0.84 (s, 9H), 0.00 (s, 6H). acterization of Diastereomer 46-1B: LRMS (APCI) m/z 645.3 (M+H). 1 H NMR (400 MHz, Methanol-i/4) d 7.66 (d, / = 8.1 Hz, 2H), 7.51 (d, / = 8.1 Hz, 2H), 7.37 - 7.25 (m, 10H), 6.18 (s, 1H), 4.75 (s, 2H), 4.28 - 4.22 (m, 1H), 4.18 (s, 2H), 2.85 - 2.74 (m, 2H), 2.66 - 2.53 (m, 2H), 0.74 (s, 9H), -0.12 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Stage #1: p-Trifluoromethylbenzylamine; ethyl 3-oxocyclobutanecarboxylate In 2,2,2-trifluoroethanol at 20℃; for 0.166667h; Stage #2: 5-chloro-3-fluoro-2-isocyanopyridine; chloroacetic acid In 2,2,2-trifluoroethanol at 20℃; for 3h; | 61.1 1. Synthesis of Intermediate 61-1 To a solution of (4-(trifluoromethyl)phenyl)methanamine (2.76 g, 15.73 mmol, 1.1 equiv) in 2,2,2-trifluoroethanol (10.0 mL) was added ethyl 3-oxocyclobutane-l- carboxylate (2.03 g, 14.30 mmol, 1.0 equiv). After stirring at r.t. for 10 min, to this resulting mixture were added 5-chloro-3-fluoro-2-isocyanopyridine (2.53 g, 14.30 mmol, 1.0 equiv) and chloroacetic acid (1.49 g, 15.73 mmol, 1.1 equiv). The resulting mixture was stirred at r.t. for 3 h, concentrated under reduced pressure, and purified silica gel chromatography, eluted with EA/HE to afford 1.6 g (20%) of ethyl 3-((5-chloro-3-fluoropyridin-2-yl)carbamoyl)-3- (2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-l-carboxylate (Intermediate 61-1) as a foam. LRMS (ES) m/z 550 (M+H). NMR (400 MHz, Methylene Chloride-*) d 9.55 (s, OH), 9.36 (s, 1H), 8.15 (dd, / = 4.5, 2.1 Hz, 1H), 7.57 (dd, / = 17.6, 8.1 Hz, 2H), 7.46 (dd, / = 9.2, 2.1 Hz, 1H), 7.34 (t, J = 6.6 Hz, 2H), 4.57 (s, 2H), 4.09 - 3.97 (m, 2H), 3.90 (d, / = 10.6 Hz, 2H), 3.07 - 2.97 (m, 3H), 2.83 (p, / = 8.9 Hz, 1H), 2.74 - 2.61 (m, 1H), 2.52 (dd, / = 12.3, 9.6 Hz, 1H), 1.12 (q, 7 = 6.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate In toluene at 110℃; for 16h; Microwave irradiation; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | 1 Step 1 : (R)-tert- butyl 4-(((benzyloxy)carbonyl)amino)-5-oxo-5-((4- (trifluoromethyl)benzyl)amino)pentanoate To a mixture of Z-D-Glu-(0/-Bu)-OH (1.00 g, 2.96 mmol) and 4- trifluoromethylbenzyl amine (0.42 mL, 3.0 mmol) in DCM (10 mL) was added EDAC (680 mg, 3.55 mmol) followed by HOBt H20 (480 mg, 3.55 mmol). The resultant reaction mixture was stirred at ambient temperature for 16 h. The mixture was then concentrated in vacuo and the crude residue was taken up in EtOAc (100 mL). This was washed successively with sat. NaHSCri (aq) (1 X 50 mL), sat. NaHCO3 (aq) (1 X 50 mL) and brine (1 X 50 mL). The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo to provide 1.39 g (95%) of (A)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-5-oxo-5-((4- (trifluoromethyl)benzyl)amino)pentanoate which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 20 %Chromat. 2: 50 %Chromat. | With cobalt(II) bis[bis((trifluoromethyl)sulfonyl)amide]; trimethylsilyl trifluoromethanesulfonate; (p-anisyl)triphos; hydrogen In n-heptane at 145℃; for 24h; Autoclave; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tert.-butylhydroperoxide; sodium chloride; sodium hydroxide In water monomer at 90℃; for 8h; Green chemistry; | General procedure for the synthesis of 4-methoxy benzoicacid from 4-methoxy benzylamines General procedure: A 50 mL of round bottom flask was charged with a magneticbead,0.1 g (0.729 mmol) of 4- methoxy benzyl amine, 0.0084 g ofNaCl (20 mol%), 0.116 g of NaOH (4 equiv) and 0.336 g of aq. TBHP (5equiv) in 0.3 mL of deionised H2O and it was heated at 90 C for 8 h. Afterwards, the reaction mixture was neutralized by aq. HCl and extracted with EtOAc. The organic layer was dried over anhydrousNa2SO4 and after evaporation of the solvent, the crude mixture waspurified by the silica gel column chromatography with EtOAc:Hexane (06:94 v/v) as eluent. 4-methoxy benzoic acid was obtainedin 84% yield (93 mg). |
82.6 mg | Stage #1: p-Trifluoromethylbenzylamine With (4,5-bis(di-isopropylphosphinomethyl)acridine)RuH(CO)Cl; water monomer; sodium hydroxide In 1,4-dioxane at 150℃; for 48h; Inert atmosphere; Sealed tube; Green chemistry; Stage #2: With hydrogenchloride; water monomer Inert atmosphere; Green chemistry; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 2h; | General procedure: To a solution of 12 (80 mg, 0.32 mmol) in 10 mL anhydrous DCM,various benzylamines (0.38 mmol), EDCI (296 mg, 1.6 mmol), HOBt(52 mg, 0.38 mmol) and catalytic amount of DMAP were added. Themixtures were stirred for 2 h, and extracted with DCM (3 25 mL).The combined organic layers were then washed with brine, driedover anhydrous Na2SO4, and concentrated in vacuo to provide thecrude products, which were purified by column chromatographywith petroleum/ethyl acetate (4:1) to give target compounds. Forbenzylamines that containing TBS-protected phenolic hydroxyl, theproducts obtained in above procedure were dissolved into 10 mLTHF, and TBAF (1.2 e.q) was added. The mixtures were stirred for15 min, and extracted with DCM (3 25 mL). The combined organiclayers were then washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuo to provide the crude products, whichwere purified by column chromatography with petroleum/ethylacetate (2:1) to give target compounds 13j and 13n. |
Tags: 3300-51-4 synthesis path| 3300-51-4 SDS| 3300-51-4 COA| 3300-51-4 purity| 3300-51-4 application| 3300-51-4 NMR| 3300-51-4 COA| 3300-51-4 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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