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CAS No. : | 54962-75-3 | MDL No. : | MFCD00236205 |
Formula : | C7H5BrF3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HJTLKVYOWNTDPF-UHFFFAOYSA-N |
M.W : | 240.02 | Pubchem ID : | 2735880 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 43.55 |
TPSA : | 26.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.76 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | 2.82 |
Log Po/w (WLOGP) : | 4.21 |
Log Po/w (MLOGP) : | 3.3 |
Log Po/w (SILICOS-IT) : | 2.81 |
Consensus Log Po/w : | 2.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.41 |
Solubility : | 0.0937 mg/ml ; 0.00039 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.02 |
Solubility : | 0.227 mg/ml ; 0.000946 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.78 |
Solubility : | 0.0396 mg/ml ; 0.000165 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.65 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | Stage #1: for 0.666667 h; Stage #2: at 80℃; |
DMF (10 mL) was deoxygenated by bubbling with nitrogen for 30 minutes before a solution of 3-amino-5-bromobenzotrifluoride (500 mg, 2.08 mmol) in DMF was added. The solution was bubbled with nitrogen for another 10 minutes fore zinc cyanide (147 mg, 1.25 mmol) and Tetrakis (triphenylphospine) -Pd (96 mg, 0.083 mmol) were added. The mixture was deoxygenated for another 15 minutes before heated to 80 °C in a sealed high pressure tube overnight. The reaction was diluted with ethyl acetate, washed with an ammonia hydroxide solution (2x), and concentrated IN VACUO. The crude product was purified by preparation plates (30/70 ethyl acetate/hexanes) to yield 43-1 (289 mg, 74.5percent). 1H NMR (400 MHz, CDC13) .sect. 7.25 (d, J=0.6 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J=0.9 Hz, 1H). LC-MS: MW calculated 186.13, found 227.8 (M+ACETONITRILE+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 3-Amino-5- bromobenzotrifluoride (4.0 g, 0.0167 mol), 8-hydroxy quinoline (0.362 g, 0.0025 mot), CuI (0.476 g, 0.025 mol), imidazole (1.36 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.0183 mol) in 17 mL of DMSO (degassed with argon for -10 min) was heated at 120°C under an atmosphere of argon for 15 h; the HPLC indicated no starting material. A 14percent aqueous solution of ammonium hydroxide was added to the cooled mixture and this was stirred for 1 h at ambient temperature. Water (50 mL) and EtOAc (200 mL) were added and the aqueous layer was extracted with EtOAc (3x30mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with EtOAc/hexanes) to provide 2.51 g of product. | ||
With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; | General procedure: A mixture of CuI (190mg, 1mmol), 4-methyl-1H-imidazole (1.64g, 20mmol), Cs2CO3(3.25g, 10mmol), <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (2.40g, 10 mmol), 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (350mg, 2mmol) and DMF (30mL) was added to a bottom, the bottom was evacuated and backfilled with argon (this procedure was repeated three times), then the mixture was heated to 130 °C for 24 h under argon. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to afford the crude product. The crude product was recrystallized as a white solid (1.7 g, 71percent) | |
2.51 g | 3-(1H-imidazo1-1-y1)-5-(trfluoromethy1)anh1ine: A mixture of 3-Amino-5- bromobenzotrifluoride (4.0 g, 0.0167 mol), 8-hydroxy quinoline (0.362 g, 0.0025 mol), Cul (0.476 g, 0.025 mol), irnidazole (1.36 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.0183mol) in 17 mL of DMSO (degassed with argon for 10 mm) was heated at 120°C under an atmosphere of argon for 15 h; the HPLC indicated no starting material. A 14percent aqueous solution of ammonium hydroxide was added to the cooled mixture and this was stirred for I h at ambient temperature. Water (50 mL) and EtOAc (200 mL) were added and the aqueous layer was extracted with EtOAc (3x3OmL). The combined organic layers were dried over Na2SO4 andconcentrated, The crude product was purified by silica gel flash chromatography (eluted with EtOAc/hexanes) to provide 2.51 g of product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 18.25h; | Amino-5-bromobenzotrifluoride (6 g, 25 mmol) and 1-(1 H-imidazol-2-yl)-N,N- dimethylmethanamine (3.7 g, 29.6 mmol) were dissolved in anhydrous DMSO (25 mL). To this was added CuI (0.95 g, 7.5 mmol), 8-hydroxy quinoline (0.72 g, 7.5 mmol) and K2CO3 (6.9 g, 50 mmol). The mixture was stirred vigorously and degassed with N2 for 15 minutes. The flask was then equipped with a condenser and heated at 1200C for 18 h. The resultant heterogeneous mixture was cooled to rt, poured into 14% aq. NH4OH (100 mL) and extracted with EtOAc (3*300ml). The combined extracts were dried over NaSO4 and concentrated in <n="57"/>vacuo. The residue was chromatograhed over silica gel eluting with MeOH/DCM (5:95) to furnish 3.5 g of the desired product as a tan colored material: 285 m/z (M+H). | |
3.5 g | With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 18h;Inert atmosphere; | 3-(2-((Dimethylamino)methyl)-1H-imidazol-1-yI)-5-(trifluoromethyl)aniline: 3-Amino-5-bromobenzotrifluoride (6 g, 25 mmol) and 1-(IH-imidazol-2-yl)-N,N-dimethylmethanamine(3.7 g, 29.6 mmol) were dissolved in anhydrous DMSO (25 mL). To this was added Cul (0.95 g,7.5 mmol), 8-hydroxy quinoline (0.72 g, 7.5 mmol) and K2C03 (6.9 g, 50 mmol). The mixture was stirred vigorously and degassed with N2 for 15 minutes. The flask was then equipped with a condenser and heated at 120C for 18 h. The resultant heterogeneous mixture was cooled to rt, poured into 14% aq. NH4OH (100 mL) and extracted with EtOAc (3x300m1). The combinedextracts were dried over NaSO4 and concentrated in vacuo. The residue was chrornatographed over silica gel eluting with MeOHIDCM (5:95) to furnish 3.5 g of the desired product as a tan colored material: 285 m/z (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 3-bromo-5-trifluoromethylaniline (720 mg, 5 mmol) was dissolved in concentrated hydrochloric acid, cooled to -10 C, and an aqueous solution of sodium nitrite (380 mg, 5.5 mmol) was added dropwise to react for 2 h. Cooled to -30 C, dropped into a concentrated hydrochloric acid solution of SnCl2 (3.40g, 15mmol) pre-cooled to -30 C, reacted at -20 C for 1h, warmed to room temperature, filtered, and dried to give 805 mg of a pale yellow solid, yield 100%. | |
31% | Intermediate 66; [3-Bromo-4-(trifluoromethyl)phenyl] hydrazine hydrochloride; A solution OfNaNO2 (949 mg, 13.75 mmol) in water (4 mL) was added drop wise to an ice cold mixture of <strong>[54962-75-3][3-bromo-5-(trifluoromethyl)phenyl]amine</strong> (3.00 g, 12.5 mmol) in cone. HCl/water (8 mL, 1:1). The reaction mixture was stirred at 0 C for Ih. Additional two solutions OfNaNO2 (431 mg, 6.25 mmol) in water (2 mL) were added, with continous stirring Ih after each addition. SnCl2 (8.46 g, 37.5 mmol) in cone. HCl (8 mL) (milky suspension) was added slowly; a brown precipitation was immediately formed. The mixture was diluted with water, basified with W/w 50% aq NaOH and extracted with DCM (x2) together with brine. The water layer was extracted once more with ether and allowed to phase separate over weekend. The organic layers were combined, dried, filtered and concentrated. The crude product was purified by flash column chromatography (DCM- > 2% MeOH in DCM). 2M HCl in ether was added to get the title compound (1.13 g, 31%) as an off white solid. MS (ESI+) for C7H6BrF3N2 m/z 255 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.18% | With copper(l) iodide; (+)-D-glucosamine hydrochloride; caesium carbonate; In water; dimethyl sulfoxide; at 90℃; for 12h; | In a reaction vessel, 24 g (0.1 mol) of 3-bromo-5-trifluoromethylaniline,8.2 g (0.1 mol) of 4-methylimidazole,58.7 g (0.18 mol) Cs2CO3,0.95 g (0.005 mol) CuI, 1.1 g (0.005 mol) D-glucosamine hydrochloride,Then 60 mL DMSO and 80 mL water were added,Stirring to dissolve, the reaction temperature was controlled at 90 ,The reaction was continued for 12 hours. After the reaction was completed, 120 mL of ethyl acetate was added,After centrifugation to take the supernatant,Concentration and drying gave 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline.The HPLC purity was 98.66% and the yield was 96.18% |
91% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;Inert atmosphere; Sealed tube; | In a pressure tube with one end sealed, add 190mg CuI (1mmol), 1.64g 4-methyl-1H-imidazole (20mmol), 3.25g Cs2CO3(10mmol), and after Nitrogen replacement, add 2.40g 3-bromo-5-(trifluoromethyl)aniline (10 mmol), 350mg 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (2mmol) and 30mL DMF was added into a flask. The mixture was stirred at 110C for 18 h under sealing. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography to afford 2.19 g desired product (91 %).; 1H NMR (400 MHz, d-DMSO), delta 8.06 (s, 1H), 7.35 (s, 1 H), 6.97 (s, 1 H), 6.93 (s, 1 H), 6.81 (s, 1H), 5.87 (br, 2H), 2.15 (s, 3H). MS (ESI), m/z: 242 (M+ + H+). |
91% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;Sealed tube; Inert atmosphere; | In a pressure tube with one end sealed, add 190 mg CuI (1 mmol), 1.64 g 4-methyl-1H-imidazole (20 mmol), 3.25 g Cs2CO3 (10 mmol), and after Nitrogen replacement, add 2.40 g 3-bromo-5-(trifluoromethyl)aniline (10 mmol), 350 mg 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (2 mmol) and 30 mL DMF was added into a flask. The mixture was stirred at 110 C. for 18 h under sealing. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography to afford 2.19 g desired product (91%). 1H NMR (400 MHz, d-DMSO), delta 8.06 (s, 1H), 7.35 (s, 1H), 6.97 (s, 1H), 6.93 (s, 1H), 6.81 (s, 1H), 5.87 (br, 2H), 2.15 (s, 3H). MS (ESI), m/z: 242 (M++H+). |
77.3% | With copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | To the solution of Bromo-5-trifluoromethyl-phenylamine (500 mg, 2.1 mmol, 1.0 eq), 4-methyl-1H-imidazole (20.5 mg, 2.5 mmol, 1.2 eq), cuprous iodide (0.14 eq) and 8-hydroxyquinoline (44 mg, 0.3 mmol, 0.14 eq) in 3 mL dimethylsulfoxide was purged with nitrogen 3 times and the solution was heated to 120 C., the mixture was diluted with water after completion of the reaction. Then the organic layer was washed successively with dilute aqueous ammonia solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was isolated by column chromatography to give the title product as a yellow solid (392 mg, 77.3% yield). 1H NMR (400 MHz, CDCl3) delta7.73 (s, 1H), 6.98 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 4.14 (s, 2H), 2.27 (s, 3H). MS m/z (ESI): 242.1 [M+H]. |
71% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; | General procedure: A mixture of CuI (190mg, 1mmol), 4-methyl-1H-imidazole (1.64g, 20mmol), Cs2CO3(3.25g, 10mmol), 3-bromo-5-(trifluoromethyl)aniline (2.40g, 10 mmol), 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (350mg, 2mmol) and DMF (30mL) was added to a bottom, the bottom was evacuated and backfilled with argon (this procedure was repeated three times), then the mixture was heated to 130 C for 24 h under argon. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to afford the crude product. The crude product was recrystallized as a white solid (1.7 g, 71%) |
71% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; | CuI (190 mg, 1 mmol), 4-methyl-1H-imidazole (1.64 g, 20 mmol), Cs2CO3 (3.25 g, 10 mmol), 3-bromo-5- (trifluoromethyl) aniline 2.40 g, 10 mmol), 1- (5,6,7,8-tetrahydroquinoline-8-substituted) ethanone (350 mg, 2 mmol) was dissolved in DMF (30 mL), protected with argon, heated to 130 C., and reacted for 24 hours.After the reaction was completed, it was cooled to room temperature, spin-dried, and separated by silica gel column chromatography. The white solid obtained by recrystallization was the target product (1.7 g, yield: 71%) |
70% | With copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | 3-bromo-5-trifluoromethylaniline (48 g, 0.2 mol) was added to a three-necked flask equipped with argon,4-methylimidazole (19.7 g, 0.24 mol), cuprous iodide (5.7 g, 0.03 mol)8-hydroxyquinoline (4.4 g, 0.03 mol)(30g, 0.22mol) and 300ml of DMSO, stirred and heated to 120 C for 24 h, followed by TLC. After the reaction was completed, the mixture was cooled to 50 C. 200 ml of 14% aqueous ammonia was added and stirring was continued for 1 h. Water and ethyl acetate were extracted three times. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed by rotary distillation.Then, the solvent was cooled in a refrigerator, and the precipitated crystals were filtered and dried to obtain 33.7 g of pale green needle-like crystals in a yield of 70%. |
67% | With copper(l) iodide; copper; potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 48h; | 3-Bromo-5-(trifluoromethyl)aniline (0.2 mL, 1.43 mmol) was stirred in a solvent of dimethylacetamide (10 mL). The reaction solution was added with 4-methyl-1H-imidazole (0.35 g, 4.26 mmol), K2CO3 (0.20 g, 5.23 mmol), Cu (0.022 g, 0.346 mmol) and CuI (0.068 g, 0.115 mmol), and stirred for about 2 days at 140C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, 67%). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 8.06 (s, 1H), 7.36 (s, 1H), 6.96 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 5.86 (s, 2H), 2.14 (s, 3H). MS (ESI+, m/z): 242 [M+H]+ |
67% | With copper(l) iodide; copper; potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 48h; | 3-Bromo-5-(trifluoromethyl)aniline (0.2 mL, 1.43 mmol) was stirred in a solvent of dimethylacetamide (10 mL). The reaction solution was added with 4-methyl-1H-imidazole (0.35 g, 4.26 mmol), K2CO3 (0.20 g, 5.23 mmol), Cu (0.022 g, 0.346 mmol) and CuI (0.068 g, 0.115 mmol), and stirred for about 2 days at 140 C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, 67%). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 8.06 (s, 1H), 7.36 (s, 1H), 6.96 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 5.86 (s, 2H), 2.14 (s, 3H). MS (ESI+, m/z): 242 [M+H]+ |
59.1% | With copper(l) iodide; 8-quinolinol; ammonia; potassium carbonate; In water; dimethyl sulfoxide; at 50 - 120℃; for 16h;Sealed tube; Inert atmosphere; | Step 1. 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), K2CO3 (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol) and 8-hydroxyquinoline (0.44 g, 3 mmol) in 20 mL DMSO was stirred at 120 C. in a sealed tube under Ar2 for 16 hrs. The mixture was cooled down to 50 C. and 28% aq ammonia (10 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, H2O and EtOAc were added. The aqueous layer was extracted with EtOAc (60 mL*3) and the organic layer was washed with brine, dried with Na2SO4, after filtration, the filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3) to give 2.85 g product as pale yellow solid (59.1%). 1H NMR (300 MHz, CDCl3) delta: 7.76 (1H, s), 7.01 (1H, s), 6.94 (1H, s), 6.84 (1H, s), 6.78 (1H, s), 4.11 (2H, brs), 2.29 (3H, s). LCMS: m/z [M+H]+ 242.0966. |
58% | With 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | A suspension of 1(3.0 g, 36 mmol), 2 (4.8 g, 20 mmol), K2C03 (4.5 g, 33 mmol), Cul (1.14 g, 6 mmol) and 8-hydroxyquinoline (0.56 g, 4 mmol) in DMSO (20 mL) was heated at 120 C overnight under nitrogen. After cooling, water was added and the mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gelcolumn chromatography to give 3 (2.8 g, 58%) as a yellow solid. LCMS (m/z: m+1):242.2. |
47.5% | With copper(l) iodide; 8-quinolinol; sodium hydroxide; calcium oxide; In dimethyl sulfoxide; at 120℃; for 69h;Inert atmosphere; | Example 1; Preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I2000 g of 3-bromo-5-trifluoromethylaniline of formula II, 1368 g of 4-methylimidazole of formula III, 181 g of 8-hydroxyquinoline, 238 g of CuI, 666.6 g of NaOH, 933 g of CaO and 7000 ml of DMSO were loaded into a 10 L of 3-neck flask. The reaction mixture was protected with nitrogen and was then stirred at 120 C. for 69 hours while monitoring for the consumption of 3-bromo-5-trifluoromethyaniline by HPLC. Heating was stopped when 3-bromo-5- trifluoromethyaniline/4-methylimidazole is not more than 5%. The reaction mixture was cooled down to 45-50 C. and poured into a 50 L reactor. 8.4 L of 14% ammonia was added dropwise and then stirred for 1 hour at 45-50 C. The mixture was cooled down to room temperature. 16.8 L of water and 10 L of ethyl acetate were added to the extract. The upper organic layer was separated and filtered through the filter aid. The lower aqueous layer was washed with 7.5L of ethyl acetate and combined with the above filtrate. The combined organic layer was washed with 5 L×3 of 5% of brine for three times. The upper organic layer was separated and dried over 1 kg of anhydrous Na2SO4 overnight. The mixture was filtered and concentrated to obtain 2.3 kg of solid. The residue was dissolved in 2 L of ethyl acetate at 45 C. To the solution was then added 8 L of petroleum ether dropwise at 45 C. The mixture was cooled down slowly to 0-15 C. and stirred for 1 hour. A large amount of precipitate was formed and filtered. The filtered cake was dissolved in 2 L of ethyl acetate at 45 C. The solution was then added 8 L of petroleum ether dropwise at 45 C. The mixture was cooled down slowly to 15-0 C. and stirred for 1 hour. A large precipitate was formed and filtered. The filter cake was dried at 45 C. and 954 g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I were obtained. (Yield: 47.5%). The obtained compound of formula I had purity of 99.7% on area by HPLC and contained 0.13% on area by HPLC, of the 5 methyl isomer impurity. |
47.5% | Example 1: Preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I 2000g of 3-bromo-5- trifluoromethylaniline of formula II, 1368g of 4-methylimidazole of formula III , 181 g of 8-hydroxyquinoline, 238g of CuI, 666.6g of NaOH, 933g of CaO and 7000ml of DMSO were loaded into a lOL of 3-neck flask. The reaction mixture was protected with nitrogen and was then stirred at 120C for 69 hours while monitoring for the consumption of 3-bromo-5- trifluoromethyaniline by HPLC. Heating was stopped when 3-bromo-5- trifluoromethyaniline / 4-methylimidazole is not more than 5%. The reaction mixture was cooled down to 45-50C and poured into a 50L reactor. 8.4L of 14% ammonia was added dropwise and then stirred for 1hour at 45-50C. The mixture was cooled down to room temperature.16.8L of water and 10L of ethyl acetate were added to the extract. The upper organic layer was separated and filtered through the filter aid. The lower aqueous layer was washed with 7.5L of ethyl acetate and combined with the above filtrate. The combined organic layer was washed with 5Lx3 of 5% of brine for three times. The upper organic layer was separated and dried over 1kg of anhydrous Na2S04 overnight. The mixture was filtered and concentrated to obtain 2.3kg of solid. The residue was dissolved in 2L of ethyl acetate at 45C. To the solution was then added 8L of petroleum ether dropwise at 45C. The mixture was cooled down slowly to 0-15C and stirred for 1hour. A large amount of precipitate was formed and filtered. The filtered cake was dissolved in 2L of ethyl acetate at 45C. The solution was then added 8L of petroleum ether dropwise at 45C. The mixture was cooled down slowly to 15-0C and stirred for 1hour. A large precipitate was formed and filtered. The filter cake was dried at 45C and 954g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-l-yl)-benzeneamine of formula I were obtained. (Yield: 47.5%). The obtained compound of formula I had purity of 99.7% on area by HPLC and contained 0.13% on area by HPLC, of the 5 methyl isomer impurity. | |
With copper; potassium carbonate; copper(II) iodide; In ISOPROPYLAMIDE; at 140 - 150℃; for 16h; | Preparation 30; [229] Preparation of 3-(4-methyl-imidazol- 1 - yl)-5-trifluoromethyl-phenylamine; [230] 3-amino-5-bromo-benzotrifluoride (17.1g,71.24mmol), 4-methylimidazole (17.6g,213.72mmol), potassium carbonate (9.8g, 71.24mmol), cupper (1. Ig, 17.81mmol), and cupper iode (II) (3.4g, 17.81mmol) were added to N,N-dimethylacetamide (100ml) at room temperature, and mixed therewith at 140~150C for 16 hr. After the reaction was completed, the temperature of the reaction vessel was cooled to RT. Then, ethyl acetate (200ml) was added thereto and mixed therewith for 30 min. The reaction mixture was filtered with Celite, and an organic layer of the filtered solution was washed with water, dried with magnesium sulfate, distilled under vacuum, and washed with n- hexane to give the titled compound as pale white solid.[231] 1H-NMR (CDCl3 delta)= 2.28 (s,3H), 4.04 (br,2H), 6.79 (s,lH), 6.83 (s,lH), 6.92(s,lH), 7.00 (s,lH), 7.77 (s.lH) | |
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃; for 15h; | B) 3-(4-Methyl-1W-imidazol-1-yl)-5-(trifluoromethyl)benzenamine; A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.80 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol), and 8-hydroxyquinoline(0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120 0C (oil bath temperature) for 15 h. The mixture was cooled down to 45- 50 0C and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/biue Cu salt. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was EPO <DP n="39"/>recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles. | |
A suspension of 3- bromo-5-(trifiuoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120 0C (oil bath temperature) for 15 h. The mixture was cooled down to 45- 50 0C and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cu salts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles. | ||
With copper(l) iodide; caesium carbonate; rac-diaminocyclohexane; In diethylene glycol dimethyl ether; at 20 - 150℃; for 24h;Product distribution / selectivity; | Example 9 5-(4-Methyl-1 H-imidazol-1 -yl)-3-trifluoromethyl-phenylamine (I) EPO <DP n="23"/>To a single neck flask fitted with a condenser are added CuI (89.5 mg, 0.47 mmol), cyclohexanediamine (107.3 mg, 0.94 mmol) and diglyme (10 ml_). The mixture is stirred for 10 minutes at ambient temperature. To the purple heterogeneous mixture, 3-bromo-5- trifluoromethyl-phenylamine (XVI) (1.13 g, 4.7 mmol), 4-methyl-1 /-/-imidazole (0.77 g, 9.4 mmol) and Cs2CO3 (1.53 g, 4.7 mmol) are added. The mixture is heated at 1500C and stirred for an additional 24 hours. The mixture is cooled to 250C and purified by column chromatography (silica gel; EtOAc/MeOH 95:5) to afford (I) as the major product (840 mg). | |
With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 40 - 120℃; for 16h;Inert atmosphere; Sealed tube; | 3-(4-MetIzyI-1H-imidazo1-1-y1)5-(trifluorornethy1)ani1ine: A suspension of 3-bromo-5-(trifluorornethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), Cu (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mrnol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10minutes while stirring. The tube was sealed tightly. The mixture was heated at 120 C (oil bath temperature) for 15 h. The mixture was cooled down to 45- 50C and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for I h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cusalts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The motherliquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
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100% | With pyridine; at 0 - 20℃; for 16h; | Reference Example 58 N-[3-bromo-5-(trifluoromethyl)phenyl]acetamide; To a solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (10 g) in pyridine (50 mL) was added acetic anhydride (5.6 g) at 0°C, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (12.9 g, yield quant.) as a white solid. 1H-NMR (300 MHz, CDCl3)delta:2.21 (s, 3 H), 7.36 (br. s, 1 H), 7.49 (s, 1 H), 7.68 (s, 1 H), 7.99 (s, 1 H). |
100% | With pyridine; at 0 - 20℃; for 16h; | To a solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (10 g) in pyridine (50 mL) was added acetic anhydride (5.6 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (12.9 g, yield quant.) as a white solid.1H-NMR (300 MHz, CDCl3) delta: 2.21 (s, 3H), 7.36 (br. s, 1H), 7.49 (s, 1 H), 7.68 (s, 1H), 7.99 (s, 1H). |
Production Example 62N- [3-{2- [4- (hydrazinocarbonylmethyl) phenyl] ethyl}-2-(trifluoromethyl) phenyl] acetamide hydrochlorideUsing N7 [3-bromo-5- (trifluoromethyl) phenyl] acetamide obtained by treating 3-bromo-5- (trifluoromethyl) aniline with acetic anhydride as a starting material, the title compound was synthesized by a method similar to Production Example 1, steps 4 - 6. |
at 20℃; | 3-Bromo-5-(trifluoromethyl)phenylamine (5 g, Alfa-Aesar) was dissolved in AcOH (140 ml) and Ac2O (5.9 ml, Aldrich) was added. The reaction was stirred at RT overnight. The mixture was added slowly to H2O (~700 ml) forming a white precipitate. The solid was isolated by filtration, washed with H2O and dried under vacuum to yield N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide. | |
In acetic acid; at 20℃; | 3-Bromo-5-(trifluoromethyl)phenylamine (5 g, Alfa-Aesar) was dissolved in AcOH (140 ml) and Ac2O (5.9 ml, Aldrich) was added. The reaction was stirred at RT overnight. The mixture was added slowly to H2O (~700 ml) forming a white precipitate. The solid was isolated by filtration, washed with H2O and dried under vacuum to yield N-(3- , . bromo-5-1xifluoromethyl-phenyl)-acetamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) in degassed (argon) tetrahydrofuran (2 mL) is added bis-(tri-o-tolylphosphino)palladium (0.15 g), a solution of dimethylamine in tetra-hydrofuran (2M, 4.2 mL), and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 10.4 mL). The reaction mixture is heated in a sealed vessel to 100°C for approximately 2.5 hours to complete the reaction. The mixture is then cooled to room temperature, quenched by addition of water, and diluted with ethyl acetate. The product is extracted three times into 5percent aqueous hydrochloric acid, and pooled acidic extracts are then basified with cooling by addition of 5N aqueous sodium hydroxide. This basic solution is then extracted with ethyl acetate, and these pooled organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting residue is chromatographed over silica gel (20-30percent ethyl acetate in hexanes is used as the eluant) to provide the desired product as a slightly tinted solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With triethylamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 60℃; | 3-Bromo-5- (trifluoromethyl)aniline (0.5 g, 2.08 mmol) and N,N-dimethylpropargylamine (0.345 g, 4.16 mmol) were dissolved in anhydrous Nu,Nu-dimethylformamide and the solution was purged with nitrogen. Triethylamine (0.585 mL, 4.16 mmol), tetrakis(triphenylphosphine)palladium (0) (0.12 g, 0.104 mmol) and copper (I) iodide (0.08 g, 0.416 mmol) were added and the resulting solution was stirred overnight at 60 °C. After cooling to room temperature, the residue was dissolved in water and ethyl acetate. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, was dried over magnesium sulfate, was filtered and was concentrated. The residue was purified by column chromatography (eluted with dichloromethane:methanol = 20: 1 to 9: 1) to give 3-[3- (dimethylamino)prop-l-yn-l-yl]-5-(trifluoromethyl)aniline (60 mg, 12percent yield) as a sticky brown oil. 3/4 NMR (400 MHz, CDC13): delta 7.08 (s, 1H), 6.89 (s, 1H), 6.83 (s, 1H), 3.87 (br s, 2H), 3.47 (s, 2H), 2.37 (s, 6H). |
bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In triethylamine; at 100℃; for 3h;Heating / reflux; | Step A-Preparation of {3-[3-amino-5-(trifluoromethyl)phenyl]propyn-2-yl}dimethylamine A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol), 1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at 100° C. in a sealed tube for 3 h.The resulting mixture was filtered over Celite.The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the titled compound. MS (ES+): 243 (M+H)+; (ES-): 241 (M-H). Calc'd C12H13F3N2-242.24. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 4h; | N2 was bubbled through a solution of 3-bromo-5-trifluoromethyl-phenylamine (2.38 g), 5,5,5',5'-tetramethyl-[2,2']bi[[l,3,2]dioxaborinanyl] (2.24g, FrontierScientific) and KOAc (2.92 g), dppf (165 mg, Aldrich) inanhydrous dioxane (50 ml) for 2 min. PdCl2 (dppf) (243 mg,Aldrich) was added and the reaction was heated to 80°C for 4h. After cooling to RT, the mix was diluted with 50 mL ofEt20, filtered through Celite.(R)., and the filtrate wasconcentrated in vacua. The residue was dissolved in Et20(100 mL) , washed with sat. NaHC03 aqueous solution (50 mL)followed by brine (50 mL). The organic phase was dried overNa2SO4 and concentrated in vacua. The residue wasdissolved in 3:2 Et20/Hex (100 mL) , filtered through Celite.(R).and the filtrate was concentrated in vacua to afford a darkbrown semi-solid. | |
With 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 4.03333h; | N2 was bubbled through a solution of 3-bromo-5-trifluoromethyl-phenylamine (2.38 g), 5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl](2.24 g, Frontier Scientific) and KOAc (2.92 g), dppf (165 mg, Aldrich) in anhydrous dioxane (50 ml) for 2 min. PdCl2 (dppf) (243 mg, Aldrich) was added and the reaction was heated to 80° C. for 4 h. After cooling to RT, the mix was diluted with 50 mL of Et2O, filtered through Celite.(R)., and the filtrate was concentrated in vacuo. The residue was dissolved in Et2O (100 mL), washed with sat. NaHCO3 aqueous solution (50 mL) followed by brine (50 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in 3:2 Et2O/Hex (100 mL), filtered through Celite.(R). and the filtrate was concentrated in vacuo to afford a dark brown semi-solid. | |
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 4h; | Preparation [LIX-3- (5, 5-DIMETHYL- [1,] 3,2] dioxaborinan-2-yl) - 5-trifluoromethyl-phenylamine N2 was bubbled through a solution of 3-bromo-5- trifluoromethyl-phenylamine (2.38 g), 5,5, 5', 5'-tetramethyl- [[2,] [2APOS;] BI [ [1,] 3, [2] DIOXABORINANYL]] (2.24 g, Frontier Scientific) and KOAc (2.92 g), dppf (165 mg, Aldrich) in anhydrous dioxane (50 mL) for 2 min. [PDCL2] (dppf) (243 mg, Aldrich) was added and the reaction was heated to [80 °C] for 4 h. After cooling to RT, the mix was diluted with 50 mL of [ET20,] filtered through [CELTECOMMAT;, ] and the filtrate was concentrated in vacuo. The residue was dissolved in [ET20] (100 mL), washed with sat. [NAHC03] aqueous solution (50 mL) followed by brine (50 mL). The organic phase was dried over [NA2SO4] and concentrated in vacuo. The residue was dissolved in 3: 2 [ET2O/HEX] (100 mL), filtered through [CELITES] and the filtrate was concentrated in vacuo to afford a dark brown semi-solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With monopotassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h; | To a mixture of 4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane (1.0 g, 4.4 mmol), PdCl2pddf (0.16 g, 0.2 mmol) and K2CO3 (1.8 g, 13.2 mmol) and 3-amino-5-bromobenzotrifluoride (0.8 g, 3.3 mmol) in DMF (25 mL) was heated at 80° C. for 16 h. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, and concentrated. The residue was purified by SiO2 chromatography to give the title intermediate. MS (ES+): 257 (M+H)+. Calc'd C13H15F3N2 - 256.3. |
Yield | Reaction Conditions | Operation in experiment |
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A stirred solution of 3-amino-5-bromo-benzotrifuoride (Apollo, England ; 1.12 g, 5 [MMOL)] and 3- (tri-n-butylstannyl) pyridine (Maybridge Chemical Co. Ltd., England ; 2.0 g, 5.4 [MMOL)] in xylene (30 mL) was purged with argon for 10 minutes at [20°C.] Tetrakis (triphenylphosphine)- palladium (0) (1. 16 g, 1.0 [MMOL)] is then added and the resulting mixture is heated at [140°C] for 36 hours under an argon atmosphere. The mixture is then cooled, treated with an aqueous solution of sodium hydroxide (100 mL of 0.1 M) and purged with air for 2 hours. The resulting mixture is then diluted with ethylacetate (200 mL) and filtered. The orgainic phase is then sequentially washed with water (2 x 80 mL) and saturated aqueous sodium chloride (1 x 80 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent ethyl acetate) to afford the title compound as a brown [OIL. 1H-NMR] (400 MHz, [DMSO-D6,] [8)] : 5.73 (br s, 2H), 6.83 (dd, 1 H), 6.99 (d, 1 H), 7.04 (d, 1 H), 7.39 (dd, 1 H), 7.64 (d, [1 H),] 8.42 (m, 1 H) and 8. 53 (dd, [1 H).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; at 0 - 20℃; for 16h; | Reference Example 65 N-[3-bromo-5-(trifluoromethyl)phenyl]methanesulfonamide; To a solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (10 g) in pyridine (50 mL) was added methanesulfonyl chloride (5.73 g) at 0°C, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (13.4 g, yield quant.) as a pale-yellow solid. 1H-NMR (300 MHz, CDCl3)delta:3.10 (s, 3 H), 6.71 - 7.05 (m, 1 H), 7.39 (s, 1 H), 7.53 - 7.62 (m, 2 H). |
100% | With pyridine; at 0 - 20℃; for 16h; | To a solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (10 g) in pyridine (50 ml) was added methanesulfonyl chloride (5.73 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (13.4 g, yield quant.) as a pale-yellow solid.1H-NMR (300 MHz, CDCl3) delta: 3.10 (s, 3H), 6.71-7.05 (m, 1H), 7.39 (s, 1H), 7.53-7.62 (m, 2H). |
79% | In pyridine; at 0 - 150℃;Microwave irradiation; | To a mixture of 3-amino-5-bromobenzotrifluoride (1.0 g, 4.17 mmol) in pyridine (10 mL) at 0- 5°C was added dropwise methanesulfonyl chloride (0.389 mL, 5 mmol). The reaction mixture was stirred at rt for 4 days. As the reaction was not completed, the reaction mixture was then heated in a microwave oven at 150°C for 15 min. There was no evolution, so the reaction was stopped. The reaction mixture was concentrated until dryness, and the residue was co- evaporated with toluene. The residue was then diluted with a saturated aqueous solution of NaHC03 and extracted with DCM. The organic layer was dried over MgS04 and evaporated. Purification by Flash chromatography using CombiFlash Companion ISCO system (Redisep silica 12g column, eluting with Cyclohexane/EtOAc 100:0 to 70:30) gave the title compound (1.05 g, 79percent yield) as a white solid. 1H-NMR (400 MHz, DMSO-d6, 298 K): ? ppm 3.14 (s, 3H) 7.48 (s, 11-1) 7.64 (s, 11-1) 7.68 (s, 1 H) 10.42 (s, 1 H). MS(10): 316.3-318.2 [M-1]\ |
79% | With pyridine; In dichloromethane; at 20 - 150℃; for 96.25h;Microwave irradiation; | To a mixture of 3-amino-5-bromobenzotrifluoride (1.0 g, 4.17 mmol) in pyridine (10 mL) at 0-5°C was added dropwise methanesulfonyl chloride (0.389 mL, 5 mmol). The reaction mixture was stirred at rt for 4 days. As the reaction was not completed, the reaction mixture was then heated in a microwave oven at 150°C for 15 min. There was no evolution, so the reaction was stopped. The reaction mixture was concentrated until dryness, and the residue was co-evaporated with toluene. The residue was then diluted with a saturated aqueous solution of NaHC03 and extracted with DCM. The organic layer was dried over MgS04 and evaporated. Purification by Flash chromatography using CombiFlash Companion ISCO system (Redisep silica 12g column, eluting with Cyclohexane/EtOAc 100:0 to 70:30) gave the title compound (1.05 g, 79percent yield) as a white solid. 1H-NMR (400 MHz, DMSO-d6, 298 K): delta ppm 3.14 (s, 3H) 7.48 (s, 11-1) 7.64 (s, 11-1) 7.68 (s, 1 H) 10.42 (s, 1 H). MS(10): 316.3-318.2 [M-1] |
79% | With pyridine; at 20 - 150℃; for 240.25h;Microwave irradiation; | N-(3-bromo-5-(trifluoromethyl)phenyl)methane sulfonamide To a mixture of 3-amino-5-bromobenzotrifluoride (1.0 g, 4.17 mmol) in pyridine (10 mL) at 0-5° C. was added dropwise methanesulfonyl chloride (0.389 mL, 5 mmol). The reaction mixture was stirred at rt for 4 days. As the reaction was not completed, the reaction mixture was then heated in a microwave oven at 150° C. for 15 min. There was no evolution, so the reaction was stopped. The reaction mixture was concentrated until dryness, and the residue was co-evaporated with toluene. The residue was then diluted with a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was dried over MgSO4 and evaporated. Purification by Flash chromatography using CombiFlash Companion ISCO system (Redisep silica 12 g column, eluting with Cyclohexane/EtOAc 100:0 to 70:30) gave the title compound (1.05 g, 79percent yield) as a white solid. 1H-NMR (400 MHz, DMSO-d6, 298 K): delta ppm 3.14 (s, 3H) 7.48 (s, 1H) 7.64 (s, 1H) 7.68 (s, 1H) 10.42 (s, 1H). MS(10): 316.3-318.2 [M-1]-. |
With dmap; In pyridine; at 20℃; for 4h; | To a solution of 3-Amino-5-bromobenzotrifluoride (200mg) in pyridine (2mL) was added methane sulphonyl chloride (115mg) and one crystal of 4-(dimethyl- amino) pyridine. The mixture was stirred at room temperature for four hours then diluted with ethyl acetate (50mL) and washed with HCI .(2M, 50mL) and saturated sodium chloride solution (50mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield N-(3- bromo-5-trifluoromethyl-phenyl) -methanesulfonamide (264mg). 1H NMR (MeOD); 6 7.59 (s, 1 H), 7.58 (s, 1 H), 7.40 (s, 1 H), 7.00 (s, 1 H), 3.11 (s, 3H). MS m/z 318.9 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; at 100℃; for 3h; | A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9mmol), l-dimethylamino-2-propyne (1.3 mL, 0.76 mmol),PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and Cul (114 mg, 0.60 mmol)in 10 mL of TEA was heated at 100 °C in a sealed tube for 3h. The resulting mixture was filtered over Celite.(R).. Thefiltrate was concentrated, and the residue was purified byprep-HPLC (reverse phase) to give the aniline. MS (ES+):243 (M+H)+; (ES-) : 241 (M-H)~. Calc' d Ci2H13F3N2 - 242.24. | |
With CuI;PdCl2(PPh3)2; In triethanolamine; | Step A: Preparation of {3-[3-amino-5(trifluoromethyl)phenyl]propynyl}dimethylamine A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol), 1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite.(R).. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the aniline. MS (ES+): 243 (M+H)+; (ES-): 241 (M-H)-. Calc'd C12H13F3N2-242.24. | |
With CuI;PdCl2(PPh3)2; In triethanolamine; | Step A Preparation of {3-[3-amino-5-(trifluoromethyl)phenyl]propynyl}dimethylamine A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol), 1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite.(R).. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the aniline. MS (ES+): 243 (M+H)+; (ES-): 241 (M-H)-. Calc'd C12H13F3N2-242.24. |
With CuI;PdCl2(PPh3)2; In triethanolamine; | Step A Preparation of {3-[3-amino-5-(trifluoromethyl)phenyl]propynyl}dimethylamine A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol), 1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite.(R).. The filtrate was concentrated, and the residue was purified by prep-HPLC(reverse phase) to give the aniline. MS (ES+): 243 (M+H)+; (ES-): 241 (M-H)-. Calc'd C12H13F3N2-242.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 2h;Inert atmosphere; | Example 30: Synthesis of c/s-N-(3-cyclopropyl-5-(trifluoromethyl)phenyl)-3-ethyl-4- methyl-l-(2,6-dimethyIphenyl)-5-oxopyrrolidine-3-carboxamide[0167] a) A 40 mL vial was charged with 3-amino-5-bromobenzotrifluoride (275 mg, 1.15 mmol), cyclopropylboronic acid (128 mg, 1.5 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), triclyclohexylphosphine (38 mg, 0.13 mmol), and K3P04 (488 mg, 2.3 mmol). The vial was subsequently sealed with a septum-lined screw cap and purged with nitrogen, followed by the addition of degassed toluene (4 mL) and degassed water (1 mL). After stirring the reaction mixture for 2 h at 100 °C, the mixture was diluted in ethyl acetate (50 mL) and the organics were washed with brine, dried (MgS04), and concentrated in vacuo. The residue was purified by flash chromatography (Si02, 10-40percent EtOAc/hexanes) to give the desired product in 55percent yield (126 mg). LC-MS Rt (retention time): 2.46 min, MS: (ES) m/z 202 (M+H+). [0168] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; N,N-dimethyl-formamide; at 75℃; for 24h; | A solution of l-allyl-4-methylpiperazine (2.12 g, 14.0 mmol) and 9-BBN (0.5 M in THF, 1.7 g, 28 mL, 14.0 mmol) was EPO <DP n="173"/>heated at reflux for 3 h and then cooled to RT. The solution was added to a mixture of 3-bromo-5- (trifluoromethyl)aniline (3.Oo g, 12.5 ittmol) , potassium carbonate (8.64 g, 62.5 mmol) , PdCl2(PPh3J2-CH2Cl2 adduct (0.457 g, 0.6 mmol) , DMF (30 mL) and water(2 mL) . The mixtre was heated to 75°C for 24. The mixture was concentrated, triturated with dichloromethane, and filtered. The filtrate was concentrated and the residue was purified via column chromatography on silica gel (gradient elution with 0-20percent methanol-dichloromethane) to afford 3- (3- (4-methylpiperazin- 1-yl)propyl) -5- (trifluoromethyl)benzenamine as a brown oil. MS m/z = 302 [M+H]+. CaIc'd for C15H22F3N3: 301. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 17 10-(3-amino-5-triflouro-phenyl)-5,8-Dioxa-10-azadispiro[2.0.4.3]undecane 3-Bromo-5-trifouroaniline (200 mg) was mixed with DIPEA (1.5 eq) in DCM (10 ml) at 0° C. To the reaction was added benzylchloroformate (1.1 eq) and stirred at RT for one hour. The reaction was washed with water, brine and dried over Na2SO4 then evaporated. The residue was purified by column chromatography to give the product (190 mg) that was mixed with 5,8-Dioxa-10-azadispiro[2.0.4.3]undecane (75 mg), Pd(dbda)3 16 mg), X-Phos (28 mg) and t-BuONa (50 mg) in toluene (15 ml). The reaction was heated at 60° C. overnight and evaporated and purified on silica gel column to give the 10-(3-CBZ-amino-5-triflouro-phenyl)-5,8-Dioxa-10-azadispiro[2.0.4.3]undecane (80 mg). This product was mixed with Pd-C (40 mg, 10percent), HCOONH4 (160 mg) and MeOH (10 ml). The reaction was refluxed for one hour and filtered through Celite and evaporated. The residue was mixed with water and extracted with EtOAc then purified with silica gel column to give the titled product. Mass: (M+1), 315 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-iodo-succinimide; acetic acid; at 20℃; for 24h; | 3-Bromo-5-(trifluoromethyl)aniline (20 g, 83 mmol) in acetic acid (150 ml) was treated portionwise with N-iodosuccinimide (20.62 g, 92 mmol). The reaction was stirred 24 h at ambient temperature. The reaction was diluted with ethyl acetate (600 mL) and was washed with aqueous sodium bisulfie (100 mL) and brine (100 mL). The organic layer was dried with magnesium sulfate and evaporated. The residue was purified on a silica gel column with a gradient of ethyl acetate/hexanes from 7percent to 15percent to give 23.5 g (77percent) of slightly impure product. 1H-NMR (CDCl3, 400 MHz) delta 7.21 (d, J=1.3 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 4.57 (bs, 2H); LC/MS (HPLC method 4): tR=3.578 min, 365.80(MH)+. |
5.21 g | With N-iodo-succinimide; acetic acid; at 10 - 35℃;Inert atmosphere; | To a solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (5.00 g) in acetic acid (40 mL) was added N-iodosuccinimide (5.16 g) at 0° C., and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 10percent aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.21 g). 1H NMR (300 MHz, CDCl3) delta 4.58 (2H, brs), 6.84 (1H, d, J=1.1 Hz), 7.23 (1H, d, J=1.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | DMF (10 mL) was deoxygenated by bubbling with nitrogen for 30 minutes before a solution of 3-amino-5-bromobenzotrifluoride (500 mg, 2.08 mmol) in DMF was added. The solution was bubbled with nitrogen for another 10 minutes fore zinc cyanide (147 mg, 1.25 mmol) and Tetrakis (triphenylphospine) -Pd (96 mg, 0.083 mmol) were added. The mixture was deoxygenated for another 15 minutes before heated to 80 °C in a sealed high pressure tube overnight. The reaction was diluted with ethyl acetate, washed with an ammonia hydroxide solution (2x), and concentrated IN VACUO. The crude product was purified by preparation plates (30/70 ethyl acetate/hexanes) to yield 43-1 (289 mg, 74.5percent). 1H NMR (400 MHz, CDC13) .sect. 7.25 (d, J=0.6 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J=0.9 Hz, 1H). LC-MS: MW calculated 186.13, found 227.8 (M+ACETONITRILE+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 29.0% | Example 7; Preparation of Compound of Formula IVThe compound of formula X (50 g), HOBt (26.5 g)/EDCI (37.5 g) and DMF (500 mL) were loaded into a reactor at 25+/-5 C. After being reacted for 3 h, the compound of formula II (39 g) was added to the reactor. The reaction mixture was stirred at 80 C. for about 18 hours while monitoring for the consumption of active ester by HPLC. After being cooled to 25+/-5 C., the mixture was dropped to a solution of half-saturated aqueous solution of sodium hydrogen carbonate, and the product was precipitated as canary yellow solid.The yield of this step was about 29.0% by weight. The purity of the isolated product was 95% (% on area by HPLC method described in Appendix 1). | |
29% | Example 7: Preparation of compound of formula IV The compound of formula X (50 g), HOBt (26.5 g)/ EDCI (37.5 g) and DMF (500 mL) were loaded into a reactor at 25+/-5C. After being reacted for 3h, the compound of formula II (39 g) was added to the reactor. The reaction mixture was stirred at 80C for about 18 hours while monitoring for the consumption of active ester by HPLC. After being cooled to 25+/-5C, the mixture was dropped to a solution of half-saturated aqueous solution of sodium hydrogen carbonate, and the product was precipitated as canary yellow solid. The yield of this step was about 29.0% by weight. The purity of the isolated product was 95% (% on area by HPLC method described in Appendix 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; | To a mixture of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (1 g, 4.17 mmol) in 1,4-dioxane (12 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.164 g, 4.58 mmol), PdCl2(dppf) (0.305 g, 0.417 mmol) and CS2CO3 (2.71 g, 8.33 mmol). The mixture was stirred at 100 °C for 2 h under N2. The mixture was filtered and concentrated, which was purified by silica column chromatography (PE/EA = 5: 1). All fractions found to contain product by TLC (PE/EA = 2: 1, Rf = 0.8) were combined and concentrated to yield a light yellow solid of 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (800 mg, 2.369 mmol, 56.9percent yield): NMR (400 MHz, CD3OD) delta 7.27 (s, 1H), 7.23 (s, 1H), 7.03 (s, 1H), 1.37 (s, 12H). ES-LCMS m/z 287.9 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.6% | With copper(l) iodide; potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 195℃; for 2h; | INTERMEDIATE 13 -( 1 H- 1 ,2,4-Triazol- 1 -yl)-5-(trifluoromethyl)aniline[00146] 3-Bromo-5-(trifluoromethyl)aniline (3.5 g, 14.6 mmol), copper(I) iodide (1.39g, 7.3 mmol), potassium carbonate (6.0 g, 43.7 mmol) and lH-l,2,4-triazole (3.0 g, 43.7 mmol) in NMP (10 mL) were heated at 195 0C for 2 hours. The reaction mixture was filtered through a plug of silica gel, washed with ethyl acetate, and concentrated. The crude residue was purified by silica gel column chromatography (stepwise gradient, from hexanes to 75percent ethyl acetate/hexanes). The fractions were concentrated, dissolved in diethyl ether (150 mL), washed with water (4 x 50 mL), dried over Na2SO4, filtered and concentrated to afford Intermediate 1 (1.95 g, 58.6 percent yield) as a tan solid. HPLC: Rt = 1.193 min. (PHENOMENEX.(R). Luna 5 micron C18 4.6 x 30 mm, 10-90percent aqueous methanol containing 0.1percent TFA, 2 min. gradient, flow rate = 5 mL/min., detection at 254 nm). MS (ES): m/z = 229.01 [M+H]+. 1H NMR (500 MHz, DMSOd6) delta ppm 8.27 (1 H, s), 7.34 (1 H, s), 6.47 (2 H, d, J = 2.29), 6.14 (1 H, s). Intermediate 1 was used in the synthesis of Examples 13, 104, 165, 169, and175. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ferrous(II) sulfate heptahydrate; sulfuric acid; In nitrobenzene; at 130℃; for 4.0h; | 3-bromo-5-(trifluoromethyl)aniline (11.7 g, 48.5 mmol) was taken up in glycerol (7.2 mL) and cone. H2SO4 (13 mL). Nitrobenzene (5.0 mL) and FeSO4»7H2O (800 mg, 2.88 mmol) were added, and the mixture was slowly warmed to 130 0C for 4 h. Isolation led to a 3:2 mixture of regioisomers, which was used without further purification in the subsequent reaction. HPLC method [4], retention time 2.53 and 2.59 min; MS(ESI) 278.0 (MH+ ,81Br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
< 51% | 1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanone. A flask was charged with water (42 ml), cooled to 0 C., and treated with concentrated hydrochloric acid (21.7 ml) and sulfuric acid (5.66 ml). To this was added 3-amino-5-bromobenzotrifluoride (8.77 ml, 62.5 mmol). The reaction was treated with a solution of sodium nitrite (5.39 g, 78 mmol) in water (10 mL). The resulting reaction mixture was stirred for 30 min at 0 C. The reaction was transferred to a solution of acetaldoxime (5.71 ml, 94 mmol) and copper(II) sulfate (0.499 g, 3.12 mmol) in water (30 mL) at room temperature. After stirring for 1 h at room temperature, the reaction was heated to reflux and held there for 3 h. The reaction was cooled and diluted with pentane. It gave an intractable suspension. The reaction mixture was filtered through a sintered glass funnel. The layers were separated. The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated. The crude residue was distilled (high vacuum, 75 C.) to give 3 fractions of varying levels of purity. Total yield was 8.5 g (51%) with purity that ranged from 10:1 to 1:1. 1H NMR (500 MHz, CDCl3) delta ppm 8.25 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 2.63 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃;Inert atmosphere; Microwaves; | A mixture of 3-bromo-5-(trifluoromethyl)aniline (0.48 g, 2.0 mmol), 4-cyclopropyl-lH- imidazole (0.26g, 2.4 mmol), K2CO3 (0.35g, 2.5 mmol), CuI (57 mg, 0.30 mmol), and 8- hydroxyquinoline (44 mg, 0.30 mmol) in dry DMSO (2 mL) in a microwave tube was cooled to -78deg;C, and degassed by vacuum and refilled with N2 for three times. The mixture was heated at1200C overnight. The mixture was cooled to 40-500C and 14percent aq. NH4OH was added. The mixture was stirred at 40-500C for 1 h. After cooling, the mixture was diluted with water, and extracted with ethyl acetate (3x15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (5percent MeOH in CH2Cl2) to afford the crude product (0.41 g). LCMS: (M+H)+= 268.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Reference Example 68 1-[3-bromo-5-(trifluoromethyl)phenyl]pyrrolidin-3-ol; 3-Bromo-5-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (4.83 g) were stirred at 100°C for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 - 50:50) to give the title compound (5.6 g, yield 22percent) as a brown oil. 1H-NMR (300 MHz, CDCl3)delta:1.66 (br. s, 1 H), 2.08 - 2.27 (m, 2 H), 3.23 - 3.32 (m, 1 H), 3.38 (td, J = 8.8, 3.4 Hz, 1 H), 3.44 - 3.59 (m, 2 H), 4.65 (br. s, 1 H), 6.65 (s, 1 H), 6.80 (t, J = 1.9 Hz, 1 H), 7.02 (s, 1 H). | |
22% | at 100℃; for 3h; | 3-Bromo-5-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (4.83 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (5.6 g, yield 22percent) as a brown oil.1H-NMR (300 MHz, CDCl3) delta: 1.66 (br. s, 1H), 2.08-2.27 (m, 2H), 3.23-3.32 (m, 1H), 3.38 (td, J=8.8, 3.4 Hz, 1H), 3.44-3.59 (m, 2H), 4.65 (br. s, 1H), 6.65 (s, 1H), 6.80 (t, J=1.9 Hz, 1 H), 7.02 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; | General procedure: A mixture of CuI (190mg, 1mmol), 4-methyl-1H-imidazole (1.64g, 20mmol), Cs2CO3(3.25g, 10mmol), 3-bromo-5-(trifluoromethyl)aniline (2.40g, 10 mmol), 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (350mg, 2mmol) and DMF (30mL) was added to a bottom, the bottom was evacuated and backfilled with argon (this procedure was repeated three times), then the mixture was heated to 130 C for 24 h under argon. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to afford the crude product. The crude product was recrystallized as a white solid (1.7 g, 71%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate;copper(l) iodide; rac-Pro-OH; In dimethyl sulfoxide; at 20 - 90℃; for 16h; | Example 29: Synthesis of c s-3-ethyl-N-(3-(trifluoromethyl)-5-(pyrrolidin-l-yl)phenyl)- 4-methyl-l-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide[0165] a) 3-Amino-5-bromobenzotrifluoride (1.0 g, 4.2 mmol) was dissolved in DMSO (2 mL). Pyrrolidine (1.0 mL, 13 mmol) was added at room temperature, followed by K3P04 (1.9 g, 8.4 mmol), Cul (80 mg, 0.42 mmol), and proline (97 mg, 0.84 mrnol). After stirring 16 h at 90 °C, LC-MS and TLC indicated the completion of the reaction. The reaction mixture was diluted with EtOAc (50 mL) and washed with aqueous NH4OH (30percent, 60 mL) and brine (20 mL) and the resulting solution was concentrated under reduced pressure. The residue was purified by flash chromatography (Si02, 10-35percent EtOAc/hexanes) to give 800 mg of tan powder (83percent yield). LC-MS Rt (retention time): 2.44 min, MS: (ES) mlz 231 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Bromo-5-(trifluoromethyl)aniline (1.2mL, 8.60mmol) and 2-methylimidazole(847mg, 10.3mmol) were dissolved in dimethyl sulfoxide (8.6mL), and Cul (490mg, 2.58mmol), 8-quinolinol (370mg, 2.58mmol) and potassium carbonate (2.38g, 17.2mmol) were added thereto. The reaction mixture was treated with N2 gas for 10 minutes to remove gas and subjected to a reaction at 120°C for 12 hours. The reaction mixture was cooled to room temperature, and 14percent aqueous ammonium hydroxide solution was added thereto. The reaction mixture was stirred for 1 hours at room temperature, dilluted with ethyl acetate (30mL) and washed with an aqueous sodium hydrogen carbonate solution (30mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was filtered with a silica column using ethyl acetate to remove copper impurities, and the filtrate was distilled under reduced pressure. The concentrated mixture was crystallized with ethyl acetate (3mL) and n-hexane (30mL) to obtain the title compound (1.31g) as a bright green solid..1H NMR (300 MHz, DMSO-d6) delta 7.27 (s, 1H), 6.90 (s, 2H), 6.78 (s, 2H), 5.93 (s, 2H), 2.26 (s, 3H). | ||
1.31 g | 3-Bromo-5-(trifluoromethyl)aniline (1.2 mL, 8.60 mmol) and 2-methylimidazole (847 mg, 10.3 mmol) were dissolved in dimethyl sulfoxide (8.6 mL), and CuI (490 mg, 2.58 mmol), 8-quinolinol (370 mg, 2.58 mmol) and potassium carbonate (2.38 g, 17.2 mmol) were added thereto. The reaction mixture was treated with N2 gas for 10 minutes to remove gas and subjected to a reaction at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, and 14percent aqueous ammonium hydroxide solution was added thereto. The reaction mixture was stirred for 1 hours at room temperature, diluted with ethyl acetate (30 mL) and washed with an aqueous sodium hydrogen carbonate solution (30 mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was filtered with a silica column using ethyl acetate to remove copper impurities, and the filtrate was distilled under reduced pressure. The concentrated mixture was crystallized with ethyl acetate (3 mL) and n-hexane (30 mL) to obtain the title compound (1.31 g) as a bright green solid. 1H NMR (300 MHz, DMSO-d6) delta 7.27 (s, 1H), 6.90 (s, 2H), 6.78 (s, 2H), 5.93 (s, 2H), 2.26 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 20h;Inert atmosphere; | Intermediate 28: 3-amino-5-(trifluoromethyl)benzonitrile; A solution of 3-bromo-5-(trifluoromethyl)aniline (3.24g, 13.5 mmol) in N, N- dimethylformamide (50 mL) was degassed by bubbling argon through the solution for 30 minutes. To the reaction was added zinc cyanide (0.872 g, 7.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.624 g, 0.54 mmol). The reaction was heated to 80°C and stirred for 20 hours. The solvent was removed from the reaction under vacuum and the residue purified by silica chromatography (Biotage SP4, eluting 15percent EtOAc in iso-hexane ( 4 column volumes) then a gradient from 15-30percent (over 6 column volumes)) to yield the title compound as a colourless oil (2.20g). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.98 - 4.29 (m, 2 H) 7.04 (s, 1 H) 7. (s, 1 H) 7.24 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | 3-Amino-5-bromobenzotrifluoride (2.00 g, 8.332 mmol) was dissolved in acetonitrile (80 mL) and the solution was degassed with nitrogen. Pd(OAc)2 (94 mg, 0.417 mmol), tris(2- methylphenyl)phosphine (254 mg, 0.833 mmol) and triethylamine (3.5 mL, 25.0 mmol) were added and the bright orange solution was allowed to stir at room temperature for 1 h. To this solution was added N-vinylphthalimide (1.73 g, 10.0 mmol) and the reaction mixture was degassed and was heated at reflux for 16 h. The reaction was filtered through a Celite pad. The filtrate was washed with water and brine, was dried over magnesium sulfate, was filtered and was concentrated. The residue was purified by column chromatography (eluted with hexanes:ethyl acetate = 3 : 1 to 2: 1 to 1 : 1) to afford 2- {(E)-2-[3-amino-5- (trifluoromethyl)phenyl]vinyl}-lH-isoindole-l,3(2H)-dione (2.02 g, 73percent yield) as a yellow solid. XH NMR (400 MHz, CDC13): delta 7.92-7.90 (m, 2H), 7.78-7.76 (m, 2H), 7.59 (d, 1H), 7.35 (d, 1H), 7.09 (s, 1H), 6.91 (s, 1H), 6.79 (s, 1H), 3.88 (-NH2; br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux; | General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium perchlorate; In acetonitrile; at 20℃; | Add propylene oxide (36 mg, 0.624 mmol) and lithium perchlorate (56 mg, 0.458 mmol) to the solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (100 mg, 0.416 mmol) in acetonitrile (5 mL), stir the resulting mixture overnight at ambient temperature. Upon completion of the reaction, concentrate the mixture under reduced pressure. Purify the residue by flash chromatography (silica gel, PE:EtOAc=5:l) to afford the product (136 mg, 100percent). |
100% | With lithium perchlorate; In acetonitrile; at 25℃; | Add propylene oxide (36 mg, 0.624 mmol) and lithium perchlorate (56 mg, 0.458 mmol) to the solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (100 mg, 0.416 mmol) in acetonitrile (5 mL), stir the resulting mixture overnight at ambient temperature. Upon completion of the reaction, concentrate the mixture under reduced pressure. Purify the residue by flash chromatography (silica gel, PE:EtOAc=5:1) to afford the product (136 mg, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | 4.1.3 N-[3-Bromo-5-(trifluoromethyl)phenyl]-N'-(4-pyridin-3-ylphenyl)urea (L1) Triphosgene (0.14 g, 0.48 mmol) was dissolved in anhydrous CH2Cl2 (15 mL) and the mixture was stirred on the ice-bath for 15 min. 3-Bromo-5-(trifluoromethyl)aniline (0.3 g, 1.2 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise to the above mixture and stirring continued for 20 min. Et3N (0.2 mL, 1.44 mmol) diluted with CH2Cl2 (5 mL) was then added into the mixture. Stirring was continued for 20 min and a solution of Et3N (0.2 mL, 1.44 mmol), 4-pyridin-3-ylaniline (5) (0.2 g, 1.2 mmol) in anhydrous CH2Cl2 (20 mL) was added. After completion of the action, the reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt = 6:1) yielding (L1). yield 73percent, mp: 200-202 °C, 1H NMR (400 MHz, DMSO) delta 9.28 (s, 1H), 9.12 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.53 (m, 1H), 8.08-8.03 (m, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.53 (s, 1H), 7.46 (m, 1H). 13C NMR (101 MHz, DMSO) delta 152.71, 148.39, 147.71, 142.59, 139.77, 135.60, 133.93, 131.84, 131.52, 131.35, 127.72, 124.54, 124.26, 122.81, 121.02, 119.60, 113.97, 113.93. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.2% | 0.8 g (3.33 mmol) of 3-bromo-5-trifluoromethylaniline was weighed out,(0.33 g, 3.33 mmol) of monomethyl Suberate, Boronic acid 0.10 g (1.67 mmol) was placed in a 100 ml three-necked round bottom flask, 30 ml of toluene was added,Nitrogen protection, magnetic stirring, oil bath heated to toluene reflux,With the water separator to separate the water generated during the reaction, before the reaction was filled with toluene,The reaction time was 20 h, during which the reaction was followed by a thin layer chromatography. The developing solvent was ether: petroleum ether = 1: 1.After completion of the reaction, the reaction solution was poured into 300 ml of petroleum ether in the stirred mixture, and after stirring for 0.5 h,The solid was filtered through a sand core funnel and the solid was washed with water to remove the catalyst boric acid,After drying, rinse the solid with petroleum ether and drain the solid. The final solid was 1.11 g, yield: 81.2percent; Weigh KOH 1.21 g (21.6 mmol) was dissolved in 10 ml of methanol,Add NH2OH · HCl 1.58g (22.8mmol), mix 40 degrees Celsius magnetic stirring 0.5h, cooled to room temperature,The addition of the product obtained in the first step was 0.50 g (1.2 mmol)During the period with thin layer chromatography board to track the reaction, 0.5h after the end of the reaction,The reaction solution was poured into 300 ml of ice water in a magnetic stirrer to precipitate a solid,Wash the solid twice with 20 ml of distilled water, each 10ml, vacuum dry after washing with 20ml ether twice,Each 10ml, and then dried and then recrystallized with acetonitrile B123 solid 0.21g, yield: 41.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.2% | With boric acid; In toluene; for 1h;Reflux; Dean-Stark; Inert atmosphere; Green chemistry; | General procedure: (A) To an oven-dried, 100-mL, three-necked, roundbottomedflask equipped with a thermometer, a vacuumjacketed vacuumjacketedDean-Stark trap topped with a reflux condenserfitted with a T-joint inlet, glass stoppers, and a Teflon-coatedmagnetic stirring bar was sequentially charged with 8-methoxy-8-oxooctanoic acid (3.76g, 20 mmol, 1 equiv),30mL of toluene, and boric acid (0.62g, 10 mmol, 0.5 equiv).While stirring vigorously under nitrogen, aniline (1.86g, 20mmol, 1 equiv) was added in one portion. The reaction washeated at reflux for 10h in an oil bath. TLC analysis, usingether: petroleum ether (2:1) as the eluent, indicated the completereaction. The reaction mixture was allowed to cool toroom temperature and then poured into 300mL of hexanewith vigorous stirring leading to the precipitation of a solid.Stirring was continued for an additional 30min, and the resultingsolid was then filtered off with suction through a sinteredglass filter funnel. After having been successivelywashed with water and hexane, the collected solid was furtherdried in vacuo at ambient temperature for 12h to affordmethyl 8-(phenyl amino)-8-oxooctanoate as a white solid(3.82g, 72.5percent). |
81.2% | With boric acid; In toluene; for 10h;Reflux; Inert atmosphere; Dean-Stark; Green chemistry; | (A) Following the part A of the general procedure, the ester intermediate was prepared using 8-methoxy-8-oxooctanoic acid (0.63 g, 3.33 mmol, 1 equiv), 30mL of toluene, boric acid (0.10g, 1.67 mol, 0.5 equiv), and <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (0.80 g, 3.33 mmol, 1equiv). The reaction was heated at reflux for 10h. TLC analysis, using ethyl acetate/petroleum ether (1/1) as the eluent,indicated the complete reaction. The reaction mixture was allowed to cool to room temperature and then poured in300 mL of hexane with stirring leading to the precipitation of a solid. Stirring was continued for an additional 30 min and the solid was then filtered off with suction through a sintered glass filter funnel. After having been The collected solid was successively washed with water and hexane, the crude was further dried in vacuum at ambient temperature for 12h to afford methyl 8-[3-bromo-5-(trifluoromethyl)phenyl]amino}-8-oxooctanoate as a white solid (1.11g, 81.2 percent). (B) Following the part B of the general procedure, the title inhibitor was prepared using potassium hydroxide(1.21g, 21.6mmol), methanol (8 mL), and hydroxylamine hydrochloride (1.67g, 24mmol), and methyl 8-[3-bromo-5-(trifluoromethyl)phenyl]amino}-8-oxooctanoate (the product obtained from the part A. 0.50g, 1.2mmol). The crude product was further purified by recrystallization from acetonitrile to afford N-[3-bromo-5-(trifluoromethyl)phenyl]-N'-hydroxyoctanediamide as a white solid (0.21g, 41.2percent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 1,4-diaza-bicyclo[2.2.2]octane; In toluene; at 20℃; for 8h; | A solution of 2.5 g (10.4 mmol) of 5-bromo-3-trifluoromethylaniline and 1.4 g (12.5 mmol) of DABC (triethylenediamine) was dissolved in 40 mL of toluene,Then, 1.9 mL of carbon disulfide was gradually added dropwise,The reaction was stirred at room temperature for 8 hours. After the reaction,Filter cake is[3-bromo-5- (trifluoromethyl) phenyl] dithioic acid in a yield of about 40percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Under nitrogen protection, 2.2 mL of anhydrous triethylamine was added dropwise to a solution of 2 g (15.4 mmol) of 1,1-cyclopropanedicarboxylic acid in methylene chloride, stirred under ice-cooling for 30 min, and a solution of 1.2 ML SOCl2 in methylene chloride. After stirring for 2 hours, 3.6 g (15.4 mmol) of 5-bromo-3-trifluoromethylaniline in dichloromethane was added dropwise to the reaction mixture, Stir for 2 h. After completion of the reaction, the reaction mixture was 2mol / L NaOH solution was adjusted to pH 10, evaporated to dryness under reduced pressure, water was added q.s. ultrasonic, extracted once with ethyl acetate, the aqueous layer was retained, then 2mol / L HCl aqueous layer adjusted to pH 2, extracted three times with ethyl acetate, the organic solvent under reduced rotation, i.e., to give 1 - ([5-bromo-2- (trifluoromethyl) phenyl] amino} carbonyl) cyclopropanecarboxylic acid about 0.8g, 37percent yield; | |
37% | 1,1-Cyclopropanedicarboxylic acid (2 g, 15.4 mmol) was dissolvedin anhydrous CH2Cl2, anhydrous triethylamine (2.2 mL) wasadded under nitrogen. The mixture was stirred on the ice-bath for30 min. Thionyl chloride (1.2 mL) in anhydrous CH2Cl2 was addeddropwise to the above mixture and stirring for 2 h. 5-bromo-3-(trifluoromethyl)-benzenamine (3.6 g, 15.4 mmol)dissolved inanhydrous CH2Cl2 was added into the mixture. Stirring wascontinued for 2 h and the solution was adjusted to pH 10 withNaOH (2 mol/L), after filtration and concentration in vacuo, anappropriate amount of water was added to the residues.The productwas extracted with ethyl acetate (50 mL), The organic layer wasseparated and the aqueous layer was adjusted to pH 2 with HCl(2 mol/L). The product was extracted with ethyl acetate (50 mL 3)again. The combined organic layer was concentrated in vacuo, totalyielding 1-[[(3,5-dimethylphenyl)amino]carbonyl] (9) (0.8 g, 37percent). | |
37% | Under nitrogen atmosphere, 2.2 mL of anhydrous triethylamine was added dropwise to a solution of 2 g (15.4 mmol) of 1,1-cyclopropanedicarboxylic acid in dichloromethane, and the mixture was stirred for 30 min in an ice bath and then 1.2 mL SOCl2 in dichloromethane,The addition is complete and stirred 2h,Then, a solution of 3.6 g (15.4 mmol) of 5-bromo-3-trifluoromethylaniline in dichloromethane was further added dropwise to the reaction solution,Continue stirring for 2h after the addition is complete. The reaction solution was then adjusted to pH 10 with 2 mol / L NaOH solution,Evaporated to dryness under reduced pressure, adding an appropriate amount of water for sonication, extracting once with ethyl acetate, retaining the aqueous layer,The aqueous layer was further adjusted to pH 2 with 2 mol / L HCl and extracted three times with ethyl acetate.The organic solvent was removed under reduced pressure to obtain 1 - [(3,5-dimethylphenyl) amino] carbonyl} cyclopropanecarboxylic acid, about 0.8 g, yield 37percent |
General procedure: 1,1-Cyclopropanedicarboxylic acid (5) (12.0 g, 15.4 mmol) was dissolved in anhydrous THF (50 mL). Then triethanolamine (2.0 mL,13.9 mmol) was added to the mixture and the mixture was stirred on the ice-bath for 30 min. SOCl2 (1.2 mL, 16.66 mmol) was then added. Stirring was continued for 2h, a solution of 3,5-dimethylaniline 6 (3.6 g, 15.4 mmol) in anhydrous THF (10 mL) was added and continued stirring for 2h, after that, the ice bath was removed, and the mixture was stirred at room temperature overnight. After the completion of the reaction, the mixture was filtered and concentrated in vacuo. The residues was purified by silica gel flash chromatography (PE/AcOEt = 5:1) to yield 7 as white solid (0.8 g, 30.7percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline 600 mg (2.50 mmol: 1.00 eq) of 3-ammo-5-bromo-1-trifluoromethylbenzene, then 1028 mg (12.50 mmol; 5.00 eq) of formaldehyde and finally 4 g of acetonitrile were introduced into a 50 ml round-bottomed flask. The reaction mixture was brought to 30° C. It was left for 30 min,then 314.21 mg (5.00 mmol; 2.00 eq) of sodium cyanoborohydride were added, followed, one minute later, by 900 mul of acetic acid; a strong effervescence was noted. The reaction medium was stirred at 35° C. for 3 h. Next, the initial pH of 10.9 was brought back to 7.9 by adding 1 N hydrochloric acid. ;The medium was evaporated under vacuum and then extracted four times with ether. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by Hash chromatography on silica (Merck column of 30 g of SiO2 15-40 mum) with a 100percent toluene eluent (liquid deposit in the eluent). The fractions containing the targeted product were combined and then evaporated under reduced pressure to give 481 mg of 3-dimethylamino-5-bromo-1-trifluoromethylbenzene in the form of a colorless liquid. Yld: 72percent. 1H NMR (300 MHz, CHCl3-d) deltappm 2.98 (s, 6H) 6.78 (s, 1H) 6.93 (s, 1H) 7.04 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In toluene; at 80℃; for 2.5h; | To a solution of <strong>[54962-75-3]3-bromo-5-(trifluoromethyl)aniline</strong> (5 g, 20.83 mmol, 1.00 equiv) in toluene (60 mL) was added HCOOH (1.25 g, 27.17 mmol, 1.30 equiv). The resulting solution was stirred for 2.5 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column, eluted with ethyl acetate/petroleum ether (1 : 10) to afford 5 g (90percent) of N-[3-bromo-5- (trifluoromethyl)phenyl]formamide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.8% | With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 85℃; Inert atmosphere; | 1.3 (3) Step 3 Synthesis of compound 1-IM5 Put 3-bromo-5-(trifluoromethyl)aniline (Compound 1-IM4, 5g, 20.83mmol) in a 100mL double-necked flask, add 40mL of anhydrous N,N-dimethylformamide after nitrogen substitution, Tributyl allyl tin (8.28 g, 25.0 mmol) and tetratriphenylphosphine palladium (2.40 g, 2.08 mmol) were heated to 85° C. and reacted overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic layer was combined, washed with a saturated solution of sodium chloride (50 mL × 2), and dried over anhydrous sodium sulfate. After filtration, ethyl acetate was distilled off under reduced pressure, and the resulting crude product was separated and purified through a silica gel column to obtain compound 1-IM5 as a yellow oily liquid. Yield 87.8%; |
87.8% | With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 20 - 85℃; for 16h; Inert atmosphere; | General procedure F General procedure: (for the synthesis of compounds 12a-12d) the aniline (20.83 mmol) was dissolved in anhydrous DMF (50 mL), the allyltributyltin (8.28 g, 25.0 mmol) was added under N2 atmosphere at room temperature. Pd(PPh3)4 (2.40 g, 2.08 mmol) were then added and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was then cooled down to room temperature and diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL 3),washed by saturated brine(50 mL 2) and dried over anhydrous sodium sulfate. After solvent removal, the residue was purified by column chromatography to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 39: 5-Bromo-N,N-dimethyl-2-(trifluoromethyl)aniline The title compound was prepared in a manner analogous to Intermediate 38 using <strong>[703-91-3]5-bromo-2-(trifluoromethyl)aniline</strong> instead of 3-bromo-5-(trifluoromethyl)aniline. MS (ESI): mass calcd. for C9H9BrF3N, 267.0; m/z found, 267.8 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (R)-3-(benzyloxy)pyrrolidine hydrochloride; [3-bromo-5-(trifluoromethyl)phenyl]amine With Cs2CO3 In N,N-dimethyl-formamide for 0.166667h; Inert atmosphere; Stage #2: With copper (I) iodide; 8-quinolinol In N,N-dimethyl-formamide at 120℃; for 16h; Inert atmosphere; | Synthesis of compound Int-119.1. A mixture of 3-bromo-5-(trifluoromethyl)aniline (0.9 g, 3.75 mmol, 1.0 equiv), (R)-3-(benzyloxy)pyrrolidine hydrochloride (1.2 g, 5.62 mmol, 1.5 equiv) and cesium carbonate (4.89 g, 15.0 mmol, 4.0 equiv) in DMF (9 mL) was degassed by bubbling argon through for 10 min. Under argon atmosphere copper iodide (0.213 g, 1.125 mmol, 0.3 equiv) and 8-hydroxyquinoline (0.163 g, 1.125 mmol, 0.3 equiv) was then added, again degassed for 5 min. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 20% ethyl acetate in hexane) to afford Int-119.1. MS (ES): m/z 337.3 [M+H]+. |
Tags: 54962-75-3 synthesis path| 54962-75-3 SDS| 54962-75-3 COA| 54962-75-3 purity| 54962-75-3 application| 54962-75-3 NMR| 54962-75-3 COA| 54962-75-3 structure
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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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