Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 69409-98-9 | MDL No. : | MFCD01631629 |
Formula : | C7H5F4N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ARHDUOQIXLGANT-UHFFFAOYSA-N |
M.W : | 179.11 | Pubchem ID : | 2737674 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 35.81 |
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) : | -5.81 cm/s |
Log Po/w (iLOGP) : | 1.59 |
Log Po/w (XLOGP3) : | 2.23 |
Log Po/w (WLOGP) : | 4.01 |
Log Po/w (MLOGP) : | 2.99 |
Log Po/w (SILICOS-IT) : | 2.55 |
Consensus Log Po/w : | 2.67 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.66 |
Solubility : | 0.392 mg/ml ; 0.00219 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.41 |
Solubility : | 0.694 mg/ml ; 0.00388 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.2 |
Solubility : | 0.112 mg/ml ; 0.000628 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.24 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P210-P261-P262-P271-P280-P301+P310-P302+P352-P304+P340-P305+P351+P338-P312-P330-P403+P235 | UN#: | N/A |
Hazard Statements: | H227-H302-H312-H315-H319-H332 | 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 |
---|---|---|
58% | With diphenyl phosphoryl azide; triethylamine; copper(l) chloride In <i>tert</i>-butyl alcohol at 20 - 85℃; Large scale | To the solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (1 kg, 4.805 mol, 1.00 equivalent “eq.”) and CuCl (14.26 g, 0.144 mol, 0.03 eq.) in t-BuOH (11.7 L) was added triethylamine (TEA, 533.8 g, 5.286 mol, 1.10 eq.) dropwise at room temperature (rt). Then the solution was heated to 50° C. and diphenylphosphoryl azide (DPPA, 1393 g, 5.045 mol, 1.05 eq.) was added dropwise to the solution at 50-60° C. After heating at 80-85° C. overnight the solution was concentrated under vacuum. The residual was dissolved in H2O and filtered. The filtrate was extracted with ethyl acetate. The organic layers was dried with Na2SO4, filtered and concentrated under vacuum. The residual was dissolved in tent-Butyl methyl ether (TBME) and HCl (gas) was bubbled in for 2 hours. The filtrate was collected and dissolved in water and basified with 2 M NaOH. The solution was extracted with TBME. The organic layers were dried and concentrated under vacuum to give 2-fluoro-4-(trifluoromethyl)aniline (498 g, 58percent) as a red oil. [0271] 1H-NMR (300 MHz, CDCl3) δ 7.27 (m, 2H), 6.82 (m, 1H), 4.05 (bs, 2H) [0272] MS: m/z=180 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-chloro-succinimide; In acetonitrile; for 3h;Reflux; | To a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (498 g, 2.783 mmol, 1.00 eq.) in acetonitrile (5 L) was added N-chlorosuccinimide (NCS, 408 g, 3.06 mmol, 1.1 eq.). Then the solution was heated under reflux for 3 hours and then concentrated under vacuum, diluted with petroleum ether (PE 1 L) and filtered. The filtrate was concentrated under vacuum to afford a red oil. The oily product was purified by vacuum distillation to give 2-chloro-6-fluoro-4-(trifluoromethyl)aniline as a yellow liquid (420 g, 71%). 1H-NMR (300 MHz, CDCl3) delta7.37 (s, 1H), 7.20 (dd, J=10.5 Hz, J=1.5 Hz, 1H), 4.43 (bs, 2H) 19F NMR (282 MHz, CDCl3): -63.24 (s, 3F), -111.04 (s, 1F) MS: m/z=214 [M+H]+ |
50% | With N-chloro-succinimide; In acetonitrile; at 90℃; for 5h; | 2-Chloro-6-fluoro-4-(trifluoromethyl)aniline To a mixture of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (1 equiv.) in acetonitrile (10 mL) was added N-chlorosuccinimide (1.15 equiv.) at 90 C. The reaction mixture was stirred at 90 C. for 5 h. The mixture was concentrated to give a residue. The residue was purified via silica gel chromatography to give the desired product 2-chloro-6-fluoro-4-(trifluoromethyl)aniline (50%). |
With N-chloro-succinimide; In acetonitrile; at 75℃; | N-Chlorosuccinimide (4.1 g) was added to a solution of 2-fluoro-4-trifluoromethylaniline in acetonitrile under nitrogen and the mixture heated to 75 C. over night. The mixture was concentrated, diluted with ether, washed with water, saturated sodium bicarbonate solution and brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-6-fluoro-4-trifluoromethylaniline as a liquid (5.9 g). Rf=0.6 (2:8 EA/heptane); 1H NMR: (400 MHz, CDCl3) 4.41 (bs, 2H); 7.20 (dd, 1H, J=10.5, 1.5 Hz) and 7.36 (s, 1H). 19F NMR (376 MHz, CDCl3): -130.78 (s, 1F) and -61.98 (s, 3F). |
With N-chloro-succinimide; In acetonitrile; at 75℃; for 16h; | 2-Fluoro-4-(trifluoromethyl)aniline (from Matrix Scientific; 5 g, 27.9 mmol) was dissolved in acetonitrile (100 mL). To this was added N-chlorosuccinimide (4 g, 30.7 mmol). The reaction was heated to 75 C. for 16 h then poured into water and extracted with ether. The organic layer was separated and washed with saturated aqueous sodium bicarbonate then water, brine and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. 5.2 g of yellow oil was recovered. MS [(+)ESI] m/z=212.8 [M-H]+. | |
With N-chloro-succinimide; In acetonitrile; at 75℃; for 16h; | 2-Fluoro-4-(trifluoromethyl)aniline (5 g, 27.9 mmoi) [Matrix Scientific P.O. Box 25067Columbia, SC 29224-5067 USA] was dissolved in acetonitrle (100 ml_). To this was added N-chlorosuccinamide (4g, 30.7 mmol). The reaction was heated to 75 0C for 16 hrs whcih was then poured into water and extracted with ether. The organic layer was separated, washed with saturated aqueous sodium bicarbonate, washed with water, brined, and dried over MgSO4. The resulting solution was filtered and the solvent removed under reduced pressure. 2-Chloro-6-fluoro-4-(trifluoromethyl)aniline (5.2 g) was recovered as a yellow oil. Mass spectrum [(+)ESI] m/z = 212.8 [M-H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 37: 1 (1 R, 5S/1S, 5R)- [2-Fluoro-4- (trifluoromethyl) phenyl]-3 azabicyclo [3. 1. 0] hexane-2, 4-dione; To a slurry of maleimide (1.7 eq), anhydrous CuCI2 (1.2 eq) and tert-butyl nitrite (1.5 eq) in CH3CN (35 mL) at 0 C a solution of 2-fluoro-4- (trifluoromethyl) aniline (16.3 g) in CH3CN (6.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h and HCI (10%, aqueous, 196 mL) was added. The mixture was extracted with EtOAc, the organic layer was washed with saturated aqueous NaCI and dried over Na2SO4. The solution was filtered and the filtrate was concentrated in vacuo. By NMR analysis the crude mixture resulted a 1: 4 mixture of the arylated maleimide hydrogen chloride adduct (component A) and unreacted maleimide (component B). A DMSO (140 mL) solution of this crude product was added dropwise to a preformed solution of trimethylsulfoxonium iodide (2 eq with respect to component A plus 2 eq with respect to component B) in anhydrous DMSO (412 mL) to which NaH (3 eq with respect to component A plus 2 eq with respect to component B) had been added portionwise. The reaction mixture was stirred for 30 min and AcOH (2 eq) was added followed by water. The reaction mixture was extracted with Et20 and then with EtOAc, the combined organic layers were washed with saturated aqueous NaCI and dried over Na2SO4. The solution was filtered and the filtrate was concentrated in vacuo. The crude product obtained was triturated with water and then with cyclohexanes to give the title compound as light brown solid (5.98 g). NMR ('H, CDCI3) : 8 7.55-7. 3 (m, 3H), 2.8-2. 7 (m, 1H), 2.1 (m, 1H), 2.0 (m, 1H), NH not observed. MS (m/z) : 274 [MH] +. | ||
To a slurry of maleimide (1.7 eq), anhydrous CuCI2 (1.2 eq) and terf-butyl nitrite (1.5 eq) in CH3CN (35 mL) at 0 0C a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (16.3 g) in CH3CN (6.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h and HCI (10%, aqueous, 196 mL) was added. The mixture was extracted with EtOAc, the organic layer was washed with saturated aqueous NaCI and dried over Na2SO4. The solution was filtered and the filtrate was concentrated in vacuo. By NMR analysis the crude mixture resulted a 1 :4 mixture of the arylated maleimide hydrogen chloride adduct (component A) and unreacted maleimide (component B).A DMSO (140 mL) solution of this crude product was added dropwise to a preformed solution of trimethylsulfoxonium iodide (2 eq with respect to component A plus 2 eq with respect to component B) in anhydrous DMSO (412 mL) to which NaH (3 eq with respect to component A plus 2 eq with respect to component B) had been added portionwise. The reaction mixture was stirred for 30 min and AcOH (2 eq) was added followed by water. The reaction mixture was extracted with Et2O and then with EtOAc, the combined organic layers were washed with saturated aqueous NaCI and dried over Na2SO4. The solution EPO <DP n="48"/>was filtered and the filtrate was concentrated in vacuo. The crude product obtained was triturated with water and then with cyclohexanes to give the title compound as light brown solid (5.98 g).NMR (1H, CDCI3): delta 7.55-7.3 (m, 3H), 2.8-2.7 (m, 1 H), 2.1 (m, 1H), 2.0 (m, 1 H) , NH not observed. MS (m/z): 274[MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium bicarbonate; sulfuric acid; | REFERENCE EXAMPLE 1 A reactor was charged with 10.0 g of 2-fluoro-4(trifluoromethyl)acetanilide, 50 ml of 20% aqueous sulfuric acid and 50 ml of methyl alcohol, and the mixture was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature (about 20 C.) and then made weakly alkaline by slowly adding a 5% aqueous solution of sodium hydrogen carbonate. The resultant solution was then extracted with two 200-ml portions of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel column chromatolography (eluent: n-hexane/ethyl acetate = 4/1) to give 7.29 g of 4-amino-3-fluorobenzotrifluoride. Yield 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; | EXAMPLE 1 A stainless steel autoclave was charged with 10.0 g (0.055 mole) of 3,4-difluorobenzotrifluoride and then with 9.34 g (0.55 mole) of anhydrous ammonia. The charge was stirred at an autoclave temperature of 100-110 C. for 38 hours, the pressure being 50 kg/cm2 at its maximum. The autoclave was then cooled to 20 C. and the pressure in the autoclave was allowed to return to ordinary (atmospheric) pressure. The reaction mixture was subjected to distillation at ordinary (atmospheric) pressure to give 7.7 g of 3,4-difluorobenzotrifluoride boiling at 103-105 C. The residue was then purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give 1.97 g of 4-amino-3-fluorobenzotrifluoride. Yield 20% (corrected yield (see note) 87%); | |
With ammonia; | EXAMPLE 2 A stainless steel autoclave was charged with 20.0 g (0.11 mole) of 3,4-difluorobenzotrifluoride and then with 9.35 g (0.55 mole) of anhydrous ammonia. The charge was stirred at an autoclave temperature of 100-120 C. for 40 hours, the pressure being 60 kg/cm2 at its maximum. The autoclave was then cooled to 20 C. and the pressure in the autoclave was allowed to return to ordinary (atmospheric) pressure. The reaction mixture was subjected to distillation at ordinary (atmospheric) pressure to give 15.8 g of 3,4-difluorobenzotrifluoride boiling at 103-105 C. The residue was then subjected to distillation under reduced pressure to give 3.76 g of 4-amino-3-fluorobenzotrifluoride (b.p. 109-111 C./25 mmHg). Yield 19% (corrected yield (see note) 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; | EXAMPLE 1 STR9 (Process variant (a)) A solution of 2.0 g (0.01 mol) of 2-chloro-4-fluorobenzoyl isocyanate in 100 ml of dry toluene is added to a solution of 1.79 g (0.01 mol) of 2-fluoro-4-trifluoromethylaniline in 40 ml of dry toluene, and the mixture is stirred for half an hour at 80 C. and subsequently concentrated in vacuo. The residue is washed with a little toluene and petroleum ether and subsequently dried. 3.4 g (90% of theory) of 1-(2-chloro-4-fluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl-phenyl)-urea of melting point 194 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydrogencarbonate; In ethanol; dichloromethane; water; | (C) Hydrolysis to 2-fluoroaniline A solution of 5.5 parts of 2-fluoro-4-trifluoromethylacetanilide in 41 parts of ethanol was heated to reflux and 14.9 parts of concentrated hydrochloric acid was added. After one hour the reaction mixture was allowed to cool and a white precipitate formed. The solvent was removed under reduced pressure and the remaining crude product was dissolved in water, treated with sodium bicarbonate, extracted with methylene chloride, dried and evaporated to remove the methylene chloride solvent. The remaining product was distilled at 55 C. (0.3 torr) to yield 3.97 parts of 2-fluoro-4-trifluoromethylaniline. The structure of the final product was confirmed by C-13 nuclear nagnetic resonance in comparison with a known sample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; | EXAMPLE 1 STR9 (Process variant (a)) A solution of 1.83 g (0.01 mol) of 2,6-difluorobenzoyl isocyanate in 10 ml of dry toluene is added to a solution of 1.79 g (0.01 mol) of <strong>[69409-98-9]2-fluoro-4-trifluoromethyl-aniline</strong> in 40 ml of dry toluene, and the mixture is stirred at 80 C. for half an hour and subsequently concentrated in vacuo. The precipitated product is separated off, washed with toluene and petroleum ether and dried in vacuo. 3.4 g (93.5% of theory) of 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethylphenyl)-urea of melting point 197 C. are obtained. | |
In hexane; toluene; | Production example 1 [Production of the present compound (1)] 0.50 Gram of 2-fluoro-4-trifluoromethylaniline was dissolved in 10 ml of toluene, and to this solution, a solution of 0.51 g of 2,6-difluorobenzoylisocyanate in 5 ml of toluene was added dropwise with stirring and ice-cooling. After completion of the addition, stirring was continued overnight at room temperature and then 10 ml of hexane was added. The precipitated crystals were collected by filtration and dried to obtain 0.83 g of N-2,6-difluorobenzoyl-N'-2-fluoro-4-trifluoromethylphenylurea as white crystals. m.p. 186.1C Yield 83% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-(2,4-dinitrophenyl)valine is reacted with m-phenoxybenzyl bromide using the procedure of Example 38 to yield the m-phenoxybenzyl ester of N-(2,4-dinitrophenyl)valine. This procedure is repeated using 3-fluoro-4-nitrotoluene in place of 2-fluoro-4-nitrotoluene to prepare 2-fluoro-4-trifluoromethylaniline, which is converted into N-(2-fluoro-4-trifluoromethylphenyl)valine and then esterified to yield the m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine, MS m/e 461.1 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen isocyanide; | EXAMPLE 4 Following the procedure of Example 1, each of 3-chloro-4-aminobenzotrifluoride and 3-fluoro-4-aminobenzotrifluoride is reacted with hydrogen cyanide and isobutyraldehyde, in a neat, initially water-free system, to give the respective nitrile, 2-(2-chloro-4-trifluoro-methylphenylamino)-3-methylbutyronitrile and 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutyronitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 1 : 1 (1 /?,5S/1 S,5/?)-[2-Fluoro-4-(trif luoromethyl)phenyl]-3 azabicyclo[3.1.0]hexane-2,4-dioneTo a slurry of maleimide (1.7 eq), anhydrous CuCI2 (1.2 eq) and terf-butyl nitrite (1.5 eq) in CH3CN (35 mL) at 0 0C a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (16.3 g) in CH3CN (6.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h and HCI (10%, aqueous, 196 mL) was added. The mixture was extracted with EtOAc, the organic layer was washed with saturated aqueous NaCI and dried over Na2SO4. The solution was filtered and the filtrate was concentrated in vacuo. By NMR analysis the crude mixture resulted a 1 :4 mixture of the arylated maleimide hydrogen chloride adduct (component A) and unreacted maleimide (component B). EPO <DP n="29"/>A DMSO (140 mL) solution of this crude product was added dropwise to a preformed solution of trimethylsulfoxonium iodide (2 eq with respect to component A plus 2 eq with respect to component B) in anhydrous DMSO (412 mL) to which NaH (3 eq with respect to component A plus 2 eq with respect to component B) had been added portionwise. The reaction mixture was stirred for 30 min and AcOH (2 eq) was added followed by water. The reaction mixture was extracted with Et2O and then with EtOAc, the combined organic layers were washed with saturated aqueous NaCI and dried over Na2SO4. The solution was filtered and the filtrate was concentrated in vacuo. The crude product obtained was triturated with water and then with cyclohexanes to give the title compound as light brown solid (5.98 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.6% | With tert.-butylnitrite; copper dichloride; In acetonitrile; at 0 - 20℃; | Maleimide (48.6 g) was suspended in acetonitrile (300 mL,) under N2 and tert-butyl nitrite (38 mL) followed by copper (II) chloride (45 g) were added. The resulting suspension was cooled down to 00C and neat 4-amino-2-fluorotrifluorobenzene (5Og, 35.2 mL) was added drop wise in 45min ca. The internal temperature was kept below 10C during the aniline addition and gas developing was observed. The reaction mixture was allowed to stir at 00C for 1 h and then overnight at 200C. Then 10% HCI (300 mL,) was added. The biphasic mixture obtained was extracted with AcOEt (300 mL). The organic layer was washed with water (30OmL, 6vol) and then with 10% NaCI (300 mL). After solvent evaporation to dryness the residue was dissolved in IPA (200 mL) and re-distilled down to dryness. Then IPA (100 mL, 2 vol) and 2,6-Lutidine (17.5 mL) were added and the suspension refluxed for 20 min to obtain a clear dark solution. After cooling down to 200C the suspension was stirred overnight and then the solid filtered by washing upon the filter with water (200 mL). After drying at 500C under vacuum the product was obtained as beige solid in a 30.6% theoretical yield (22.13 g).1 H NMR (DMSO-d6) ppm: 11.29 (br.s., 1 H); 8.21 (t, 1 H); 7.90 (d, 1 H); 7.75 (d, 1 H); 7.15 (s, 1 H) |
30.6% | Maleimide (48.6 g) was suspended in acetonitrile (300 mL,) under N2 and tert-butyl nitrite (38 mL) followed by copper (II) chloride (45 g) were added. The resulting suspension was cooled down to O0C and neat 4-amino-2-fluorotrifluorobenzene (5Og, 35.2 mL) was added drop wise in 45min ca. The internal temperature was kept below 1O0C during the aniline addition and gas developing was observed. The reaction mixture was allowed to stir at O0C for 1h and then overnight at 2O0C. Then 10% HCI (300 mL,) was added. The biphasic mixture obtained was extracted with AcOEt (300 mL). The organic layer was washed with water (30OmL, 6vol) and then with 10% NaCI (300 mL). After solvent evaporation to dryness the residue was dissolved in IPA (200 mL) and re-distilled down to dryness. Then IPA (100 mL, 2 vol) and 2,6-Lutidine (17.5 mL) were added and the suspension refluxed for 20 min to obtain a clear dark solution. After cooling down to 2O0C the suspension was stirred overnight and then the solid filtered by washing upon the filter with water (200 mL). After drying at 4O0C under vacuum the product was obtained as beige solid in a 30.6% theoretical yield (22.13 g). <n="21"/>1 H MMR (DMSO-d6) ppm: 11.29 (br.s., 1 H); 8.21 (t, 1 H); 7.90 (d, 1 H); 7.75 (d, 1 H); 7.15 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
LDA (416 mg, 0.004 mol) was added to a solution of <strong>[69409-98-9]2-fluoro-4-trifluoromethyl-phenylamine</strong> (484 mg, 0.003 mol) in THF (10 mL) at -78 C. and the resulting mixture was stirred for 1 hr at -78 C. This was followed by addition of 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (250 mg, 0.001 mol) in THF (30 mL) at -78 C. and stirring was continued for a further 18 hrs at RT. THF from the reaction mixture was distilled and this was followed by addition of 1N HCl (5 mL) and ether (10 mL). The reaction mixture was stirred for 15 minutes and the precipitate was collected to afford 150 mg (37% yield) of 6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid as the required product.LC-MS purity: 100%, m/z=375, (M+)HPLC: 91.4%1H NMR (DMSO-D6, 300 MHz): delta 13.8-13.6 (br s, 1H), 9.6 (s, 1H), 7.7 (d, 1H), 7.52 (d, 1H), 7.15 (q, 1H), 4.1 (t, 2H), 3.5 (t, 2H), 2.2-2.1 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 110℃; for 1.3h; | Palladium acetate (0.063 g, 0.003 mol), BINAP (0.263 g, 0.0003 mol), cesium carbonate (1.37 g, 0.004 mol) were dissolved in toluene and the resulting mixture was sparged for 30 mins with nitrogen. This was followed by addition of 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-8-carboxyllic acid ethyl ester (1 g, 0.003 mol) and <strong>[69409-98-9]2-fluoro-4-trifluoromethyl aniline</strong> (0.549 g, 0.003 mol) and the reaction flask was again sparged for another 15 mins. The reaction mixture was heated at 110 C. for 1.30 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrate was purified by column chromatography (using silica gel of mesh size 60-120, 70% MeOH in CHCl3 as eluant) to afford 0.4 g (37% yield) of 7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-1,2,3,5-terahydro-indolizine-8-carboxyllic acid ethyl ester as the required product.1H NMR (DMSO-D6): 7.6 (t, 1H), 7.4 (t, 2H), 6.0 (s, 1H), 4.4 (q, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.2 (q, 3H), 1.4 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With boron trifluoride diethyl etherate; In toluene; at 90℃; for 8h;Inert atmosphere; | General procedure: An 8 mL screw-top vial was charged with aniline (1 eq), aldehyde (1 eq), freshly cracked cyclopentadiene (1.5 eq), and toluene (0.2 M). To this mixture, BF3*OEt2 (1.1 eq) was added, and the vial was seals with a Teflon-lined cap, and heated at 90 C for 8 hours. The reaction was cooled, diluted with dichloromethane, then sequentially washed with 1 M aqueous HCl, saturated NaHCO3, and brine. The organic layer was dried over MgSO4, and concentrated. The compound was purified by dissolving in the minimum amount of dichloromethane and precipitated by adding to stirring solution of hexanes and filtering, providing products in >20:1dr by 1H-NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-(2-Fluoro-4-trifluoromethylphenyl)-3-(3-cyano-5-fluorophenyl)urea A solution of 6.15 g (45.18 mmol) of 5-fluoro-3-cyanoaniline in 90 ml of tetrahydrofuran is stirred at ambient temperature under an argon atmosphere. 4.3 ml (36.14 mmol) of diphosgene are added dropwise then 30 ml (135.54 mmol) of triethylamine. After refluxing in the reaction mixture for 3 hours, a solution of 7.10 g (39.64 mmol) of <strong>[69409-98-9]4-amino-3-fluorotrifluoromethylbenzene</strong> in 10 ml of tetrahydrofuran is slowly added. The reflux is maintained for an additional 2 hours. The medium is then stirred into 100 ml of water, then extracted with 100 ml of ethyl acetate. The organic phase is washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness using a rotary evaporator. The solid residue obtained is recrystallized at high temperature in 90 ml of acetonitrile in order to give 10.35 g of 1-(2-fluoro-4-trifluoromethylphenyl)-3-(3-cyano-5-fluorophenyl)urea in the form of a cream solid.1H NMR (400 MHz, DMSO-d6) delta ppm 7.47 (d, J=8.3 Hz, 1H) 7.57 (d, J=8.6 Hz, 1H) 7.69 (s, 1H) 7.70-7.75 (m, 2H) 8.37 (t, J=8.4 Hz, 1H) 9.17 (br. s., 1H) 9.63 (br. s., 1H)MS: Retention time Tr (min)=1.1; [M+H]+: m/z 341.Melting point (Kofler): 253 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With diphenyl phosphoryl azide; triethylamine; copper(l) chloride; In tert-butyl alcohol; at 20 - 85℃;Large scale; | To the solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (1 kg, 4.805 mol, 1.00 equivalent ?eq.?) and CuCl (14.26 g, 0.144 mol, 0.03 eq.) in t-BuOH (11.7 L) was added triethylamine (TEA, 533.8 g, 5.286 mol, 1.10 eq.) dropwise at room temperature (rt). Then the solution was heated to 50 C. and diphenylphosphoryl azide (DPPA, 1393 g, 5.045 mol, 1.05 eq.) was added dropwise to the solution at 50-60 C. After heating at 80-85 C. overnight the solution was concentrated under vacuum. The residual was dissolved in H2O and filtered. The filtrate was extracted with ethyl acetate. The organic layers was dried with Na2SO4, filtered and concentrated under vacuum. The residual was dissolved in tent-Butyl methyl ether (TBME) and HCl (gas) was bubbled in for 2 hours. The filtrate was collected and dissolved in water and basified with 2 M NaOH. The solution was extracted with TBME. The organic layers were dried and concentrated under vacuum to give 2-fluoro-4-(trifluoromethyl)aniline (498 g, 58%) as a red oil. [0271] 1H-NMR (300 MHz, CDCl3) delta 7.27 (m, 2H), 6.82 (m, 1H), 4.05 (bs, 2H) [0272] MS: m/z=180 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With Iodine monochloride; In methanol; dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | To a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (5.1 g, 28.5 mmol) in methanol (25 mL) at 0 C was slowly added a solution of iodine monochloride (6.95 g, 42.7 mmol) in dichloromethane (25 mL). The reaction was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL), andwashed sequentially with a saturated aqueous solution of sodium thosuiate, a saturated aqueous solution of sodurn bicarbonate and with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 5% ethyl acetate in nhexanes) afforded the title compound. Yield: 6.5 g, 75%. 1H NMR (400 MHz, CDCI3) oe7.68 (5, 1 H), 7.24 (d, J= 10.8 Hz, 1 H), 4.49 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With Oxone; In 1,4-dioxane; at 90℃;Schlenk technique; Inert atmosphere; | General procedure: A Schlenk tube was charged with Oxone (0.398 g, 0.648mmol) and trifloroacetic acid (0.099 mL, 1.296 mmol) in anhydrous dioxane (2 mL) under argon. To this mixture was added 2-fluoroaniline (0.06 g, 0.54 mmol), and the reaction mixture was heated to 90 C under argon until starting material was consumed. As the reaction progressed, the color turned from lightred to dark red. The mixture was then cooled to room temperature and washed with a saturated aqueous sodium bicarbonate.The mixture was extracted with EtOAc (2 × 20 mL) and the combined organic layers were dried over Na2SO4. After filtering andremoval of the solvent under reduced pressure in vacuo, theresidue was purified by silica gel (100-200 mesh) column chromatography(hexane-EtOAc, 9:1), to afford a pale-brown solid(65%) of 2-hydroxy-N-trifluoroacetanilides from 2-fluoroaniline(2a). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In 2,2,2-trifluoroethanol; at 80℃; for 6h; | A mixture of compound 17 (300 mg, 0.690 mmol) and <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (148 mg, 0.826 mmol) in 2,2,2-trifluoroethanol (3.5 mL) was stirred at 80 C for 6 h. The reaction mixture was diluted with water and then extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt = 90:10 to 40:60) to give the title compound as a pale yellow amorphous solid (346 mg, 0.599 mmol, 87%). MS (ESI/APCI) m/z 578.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta 1.93-2.06 (2H, m), 2.13-2.28 (2H, m), 3.12 (2H, t, J = 8.1 Hz), 3.66 (2H, t, J = 6.9 Hz), 4.11 (2H, t, J = 8.2 Hz), 5.15 (2H, s), 7.26-7.45 (5H, m), 7.50-7.77 (5H, m), 10.66 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | General procedure: General procedures for compounds 10 and 15 are as follows:a solution of aldehyde (0.50 mmol) and amine (0.50 mmol)in MeOH (1 mL) was stirred at room temperature for 10min in a 5 mL microwave vial. Next, acid (0.50 mmol) andisonitrile (0.50 mmol) were added separately. The mixturewas stirred at room temperature overnight. The reaction wasmonitored by TLC and the solvent was removed under nitrogenblowing. The residue was dissolved in AcOH (3 mL)and NH4AcO (2.5 mmol, 193 mg) was added and thentreated in microwave (MW) at 150 C for 10 min. The solventwas removed under reduced pressure and the residuewas diluted with EtOAc (15 mL) and washed with sat. sodiumcarbonate and brine. The organic layer was dried overMgSO4 and concentrated. The residue was purified by silicagel column chromatography using a gradient of ethylacetate/hexane (1%-100%) to afford the relative products 9and 14a-14h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | General procedure: General procedures for compounds 10 and 15 are as follows:a solution of aldehyde (0.50 mmol) and amine (0.50 mmol)in MeOH (1 mL) was stirred at room temperature for 10min in a 5 mL microwave vial. Next, acid (0.50 mmol) andisonitrile (0.50 mmol) were added separately. The mixturewas stirred at room temperature overnight. The reaction wasmonitored by TLC and the solvent was removed under nitrogenblowing. The residue was dissolved in AcOH (3 mL)and NH4AcO (2.5 mmol, 193 mg) was added and thentreated in microwave (MW) at 150 C for 10 min. The solventwas removed under reduced pressure and the residuewas diluted with EtOAc (15 mL) and washed with sat. sodiumcarbonate and brine. The organic layer was dried overMgSO4 and concentrated. The residue was purified by silicagel column chromatography using a gradient of ethylacetate/hexane (1%-100%) to afford the relative products 9and 14a-14h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; for 1h;Inert atmosphere; Reflux; | General procedure: Anilide synthesis. General method. To a 100 mL flask equipped with a reflux condenser was added 5-chloro-2-hydroxybenzoic acid (1 equiv), the aniline derivative (1 equiv), and dry xylenes(stored over 3A molecular sieves, 40 mL per gram of 5-chloro-2-hydroxybenzoic acid) under an Argon atmosphere. The mixture was heated to reflux, and PCl3 (0.4 equiv) was added rapidly via syringe. The mixture was heated at reflux for 1 h and cooled to room temperature. Water (40 mL per gram of 5-chloro-2-hydroxybenzoic acid) was added and the resultant heterogeneous mixture stirred rapidly for 1 h. Saturated sodium bicarbonate was added to a final pH of 3-4, and the mixture stirred rapidly overnight. The solids were filtered and washed sequentially with water, toluene and hexane. Samples were analyzed by NMR, HPLC/mass spectrometry and TLC. Purification by crystallization or column chromatography on silica gel was performed when purity was less than 95% by LC. Additional experimental procedures and analytical data are provided in Supplemental data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.8% | With triethylamine; In dichloromethane; at 0 - 25℃; | Acid chloride obtained from Step 1, was taken up in dichloromethane (20 mL) and a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (217 mg, 1.21 mmols, 0.950 eq) and triethylamine (0.530 mL, 3.81 mmols, 3.0 eq) in dichloromethane (3 mL) was added dropwise at 0 C. The reaction was stirred at 25 C overnight. The reaction was diluted with dichloromethane, washed successively with saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over Na2504, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 4 / 1) to give the desired product 121 (210 mg, 0.660 mmols, 5 1.8%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With pyridine; In dichloromethane; at 0 - 20℃; for 3h; | Phenyl chloroformate (4.5 mL, 36 mmol) was added slowly to a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl) aniline</strong> (8.0 g, 45 mmol) and pyridine (9.0 mL, 110 mmol) in DCM (80 mL) at 0 C. The reaction mixture was gradually warmed to rt and stirred for 3 h. The reaction mixture was quenched with water and the mixture was extracted with DCM (3*200 mL). The combined organic layers were washed with 0.5 N HCl and 10% sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The solid was stirred in pet. ether (100 mL) for 15 min, filtered and dried to give Intermediate 11 (9.0 g, 30 mmol, 67% yield). MS(ESI) m/z: 317.2 (M+NH4)-. 1H NMR (300 MHz, CHLOROFORM-d) delta=10.43 (s, 1H), 8.04 (br. t., J=8.1 Hz, 1H), 7.75 (br. d., J=10.9 Hz, 1H), 7.60 (br. d., J=8.6 Hz, 1H), 7.52-7.38 (m, 2H), 7.36-7.21 (m, 3H). |
293 mg | With pyridine; In acetonitrile; at 0 - 20℃; | Phenyl chloroformate (215 mg, 1.34 mmol) was added to a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (207 mg,1.16 mmol) and pyridine (101 mg, 1.28 mmol) in ACN (10 mL) at 0C. After stirring thesolution overnight at room temperature, the reaction was quenched with H20. The resulting precipitate was filtered, dried and used without further purification. The product was a white solid (293 mg, mmol, yield). ?H NMR (300 MHz, DMSO-d6) oe 10.40 (s, 1H), 8.04 (t, J= 8.2 Hz, 1H), 7.76 (d, J= 10.9 Hz, 1H), 7.61 (d, J 9.3 Hz, 1H), 7.45 (t, J 7.8 Hz, 2H), 7.32- 7.21 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of compound 22 (0.1 g, 0.26 mmol) in a mixture of DMF (1.0 mL) and THF (5 mL) were added TBTU (0.16 g, 0.51 mmol), Et3N (51.5 g, 0.51 mmol) and stirred at room temperature for 30 mins. Then, cyclopropylmethanamine hydrochloride (0.054 g, 0.51 mmol) was added to the reaction mixture and stirred further at room temperature for 10-14 h. After the reaction completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 50 mL). The organic portion was washed with 10% sodium bisulfite, water, then dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography on neutral alumina using 1-2% of methanol in DCM to afford compound 8d (0.068 g) in 65% yield as off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Example-21a: 2-((2,6-dichlorophenyl)amino)-N-(2,6-difluorophenyl)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxamide Thionyl chloride (5 mL) was added in neat to compound 19 (X = Cl, R1 = H; 0.1 g, 0.27 mmol) at 10 oC and further 3-drops DMF was added. The reaction mixture was refluxed for 3 h. In parallel, 2, 6-difluoroaniline (0.13 g, 0.79 mmol) in THF (5 mL) was added slowly to a solution of 60% NaH (60 mg, 2.38 mmol) in THF (3 mL) under nitrogen atmosphere at 0 oC and further stirred at room temperature for 1 h. Next, thionyl chloride was completely removed under vacuum and further stripped out with THF (couple of times) and then the acid chloride compound was diluted with THF (5 mL) and further transferred to sodium hydride containing flask slowly at room temperature and further stirred for 6-10 h (till reaction completion). The reaction mixture was quenched with ice-water and extracted with ethyl acetate (2 x 50 mL). The organic portion was washed with 10% sodium bicarbonate solution, water, then dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography on neutral alumina using 1-2% of methanol in DCM to afford compound 21a (68 mg) in 24% yield as off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (1 g, 5.6 mmol) was added to a mixture of conc. HCl (4 mL) and acetic acid (3 mL). The mixture was cooled to 10 C and a solution of sodium nitrite (0.42 g, 6.1 mmol) in a minimum amount of water was added dropwise and the mixture stirred at 10 C for 45 min to form the diazonium salt. In a separate reaction flask, sulfur dioxide (0.36 g, 5.6 mmol) was bubbled into acetic acid (8 mL) until saturation. Copper(I) chloride (0.17 g, 1.7 mmol) was added and stirred until the mixture turned green. The flask was cooled in an ice bath, the diazonium salt mixture was added dropwise and the reaction mixture was allowed to warm to rt overnight with stirring. The reaction mixture was poured into ice, the resulting solid collected by filtration, washed well with water and dried to give the title compound (0.70 g, 48% yield).1H NMR (400 MHz, CDCl3) ^: 8.17 (t, J = 7.4 Hz, 1H), 7.61-7.71 (m, 2H). | |
48% | <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (1 g, 5.6 mmol) was added to a mixture of cone. HCI (4 ml_) and acetic acid (3 ml_). The mixture was cooled to 10 C and a solution of sodium nitrite (0.42 g, 6.1 mmol) in a minimum amount of water was added dropwise and the mixture stirred at 10 C for 45 min to form the diazonium salt. In a separate reaction flask, sulfur dioxide (0.36 g, 5.6 mmol) was bubbled into acetic acid (8 ml_) until saturation. Copper(l) chloride (0.17 g, 1 .7 mmol) was added and stirred until the mixture turned green. The flask was cooled in an ice bath, the diazonium salt mixture was added dropwise and the reaction mixture was allowed to warm to rt overnight with stirring. The reaction mixture was poured into ice, the resulting solid collected by filtration, washed well with water and dried to give the title compound (0.70 g, 48% yield). 1H NMR (400 MHz, CDC ) delta: 8.17 (t, J = 7.4 Hz, 1 H), 7.61 -7.71 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | A mixed solution of <strong>[69409-98-9]4-amino-3-fluorobenzotrifluoride</strong> (19.1 g, 106.6 mmol) in 35% hydrochloric acid (30 mL) and water (30 mL) was cooled to -5 C. and sodium nitrite (9.01 g, 138.6 mmol) in water (40 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at -5 C. for 30 minutes, and then an aqueous solution (40 mL) of sodium azide (8.83 g, 128.0 mmol) was added dropwise. The mixture was stirred at -5 C. for 60 minutes and at room temperature for 4 hours. Ethyl acetate was added to the reaction solution for extraction, the organic layer was washed with saturated brine, and dried over sodium sulfate. FiltrationAfter removal of the white precipitate and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1: 20) to give an orange oilThe title compound (17.02 g, yield 78%) was obtained. | |
With sodium azide; acetic acid; sodium nitrite; | Step 3-1 Synthesis of 1-Azido-2-fluoro-4-(trifluoromethyl)benzene Sodium nitrite (1.2 s dissolved in a concentrated sulfuric acid (9 ml), and then acetic acid solution (18 ml) of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl) aniline</strong> (2.8 g) was added dropwise at 0 C. After raising the temperature to room temperature and stirring for 30 minutes, the resulting solution was cooled to 0 C., and then an aqueous solution (3 ml) of sodium azide (0.98 g) was added dropwise, followed by stirring at room temperature overnight. The resulting reaction solution was poured into water and extracted with dichloroether. The obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was used in the next step without purification. | |
Sodium nitrite (1.2 g) was dissolved in concentrated sulfuric acid (9 ml), and a solution of <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl)aniline</strong> (2.8 g) in acetic acid (18 ml) was added dropwise at 0 C. After warming to room temperature and stirring for 30 minutes, it was cooled to 0 C, and an aqueous solution (3 ml) of sodium azide (0.98 g) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with diethyl ether. The obtained organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was used in the next step without purification |
With hydrogenchloride; sodium azide; sodium nitrite; In water; at 0 - 20℃; for 0.5h; | (Step 4-1) Synthesis of 1-azido-2-fluoro-4-(trifluoromethyl)benzene Water (2 ml) and hydrochloric acid (2 ml) were added to <strong>[69409-98-9]2-fluoro-4-(trifluoromethyl) aniline</strong> (1.15 g), and the mixture was stirred at 0 C. Sodium nitrite (0.54 g) dissolved in water (2 ml) was added thereto, and the mixture was stirred at 0 C. for 10 minutes, then sodium azide (0.31 g) dissolved in water (2 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and then the organic phase was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With bromine; iron; sodium hydrogencarbonate; In dichloromethane; at 50℃; | To a suspension of aniline Int-102-1 (5.0 g, 27.9 mmol), iron powder (0.23 g, 4.2 mmol, 15 mol%) and NaHCO3 (2.34 g, 27.9 mmol) in CH2Cl2 (100 mL) was added Br2 (1.73 mL, 33.5 mmol) dropwise. The resulting mixture was refluxed at 50 C overnight. The mixture was partitioned between 2N NaOH and CH2Cl2. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (Hexanes/EtOAc gradient) to give Int-102-2 as a yellow solid (6.35 g, 88% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Diethyl 2-(ethoxymethylene)malonate (13.54 ml, 67.0 mmol) and 2- fluoro-4-(trifluoromethyl)aniline (10 g, 55.8 mmol) were stirred at 100 C for 2 hours. The reaction was then concentrated in vacuo to remove EtOH formed in first step. The crude residue taken up in diphenyl ether (55.8 ml) and refluxed at 250 C for 6 hours. Reaction was then cooled to room temperature and a precipitate forms. The reesutling solid was filtered off and rinsed with 1 : 1 hexanes:EtOAc to give ethyl 8-fluoro-4-hydroxy-6- (trifluoromethyl)quinoline-3-carboxylate Intermediate 44A (7.79 g, 25.7 mmol, 46.0 % yield) as an off white solid. LC-MS Anal. Calc'd for C13H9F4NO3 303.05, found [M+H] 304.1, Tr = 0.75 min (Method A). NMR (400 MHz, DMSO-de) delta 12.80 (br s, 1H), 8.46 (s, 1H), 8.22 (s, 1H), 8.12 (dd, J=10.6, 1.8 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H) |
Tags: 69409-98-9 synthesis path| 69409-98-9 SDS| 69409-98-9 COA| 69409-98-9 purity| 69409-98-9 application| 69409-98-9 NMR| 69409-98-9 COA| 69409-98-9 structure
[ 261944-56-3 ]
2,4-Difluoro-5-(trifluoromethyl)aniline
Similarity: 0.92
[ 535-52-4 ]
2-Fluoro-5-(trifluoromethyl)aniline
Similarity: 0.90
[ 2357-47-3 ]
4-Fluoro-3-(trifluoromethyl)aniline
Similarity: 0.90
[ 454-67-1 ]
3-Amino-5-fluorobenzotrifluoride
Similarity: 0.90
[ 827-20-3 ]
5-Fluoro-2-(trifluoromethyl)aniline
Similarity: 0.88
[ 261944-56-3 ]
2,4-Difluoro-5-(trifluoromethyl)aniline
Similarity: 0.92
[ 535-52-4 ]
2-Fluoro-5-(trifluoromethyl)aniline
Similarity: 0.90
[ 2357-47-3 ]
4-Fluoro-3-(trifluoromethyl)aniline
Similarity: 0.90
[ 454-67-1 ]
3-Amino-5-fluorobenzotrifluoride
Similarity: 0.90
[ 827-20-3 ]
5-Fluoro-2-(trifluoromethyl)aniline
Similarity: 0.88
[ 261944-56-3 ]
2,4-Difluoro-5-(trifluoromethyl)aniline
Similarity: 0.92
[ 535-52-4 ]
2-Fluoro-5-(trifluoromethyl)aniline
Similarity: 0.90
[ 2357-47-3 ]
4-Fluoro-3-(trifluoromethyl)aniline
Similarity: 0.90
[ 454-67-1 ]
3-Amino-5-fluorobenzotrifluoride
Similarity: 0.90
[ 827-20-3 ]
5-Fluoro-2-(trifluoromethyl)aniline
Similarity: 0.88
[ 261944-56-3 ]
2,4-Difluoro-5-(trifluoromethyl)aniline
Similarity: 0.92
[ 535-52-4 ]
2-Fluoro-5-(trifluoromethyl)aniline
Similarity: 0.90
[ 2357-47-3 ]
4-Fluoro-3-(trifluoromethyl)aniline
Similarity: 0.90
[ 454-67-1 ]
3-Amino-5-fluorobenzotrifluoride
Similarity: 0.90
[ 827-20-3 ]
5-Fluoro-2-(trifluoromethyl)aniline
Similarity: 0.88
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :