| 99% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; |
4-Methyl-3-nitroaniline (5 g, 32.9 mmol) was stirred in a solvent of dichloromethane (150 mL). The reaction solution was added with DIPEA (11.48 mL, 65.7 mmol) and 3-(trifluoromethyl)benzoylchloride (4.86 mL, 32.9 mmol), and stirred for about an hour at room temperature. The reaction mixture was washed with 1M aqueous HCl solution, an aqueous sodium bicarbonate and saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (10.6 g, 99 %). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 10.8(s, 1H), 8.53(s, 1H), 8.32(m, 2H), 8.03(m, 2H), 7.84(t, 1H), 7.53(d, 1H). MS (ESI+, m/z): 325 [M+H]+ |
| 99% |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; |
4-Methyl-3-nitroaniline (5 g, 32.9 mmol) was stirred in a solvent of dichloromethane (150 mL). The reaction solution was added with DIPEA (11.48 mL, 65.7 mmol) and 3-(trifluoromethyl)benzoylchloride (4.86 mL, 32.9 mmol), and stirred for about an hour at room temperature. The reaction mixture was washed with 1M aqueous HCl solution, an aqueous sodium bicarbonate and saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (10.6 g, 99%). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 10.8 (s, 1H), 8.53 (s, 1H), 8.32 (m, 2H), 8.03 (m, 2H), 7.84 (t, 1H), 7.53 (d, 1H). MS (ESI+, m/z): 325 [M+H]+ |
| 97% |
With triethylamine; In dichloromethane; at 20℃; for 3h; |
To a solution of 4-methyl-3-nitroaniline (5.04g, 33.1mmol) and TEA (5.00g, 49.5mmol) in DCM (30mL) was added 3-(trifluoromethyl)benzoyl chloride (6.90g, 33.1mmol) dropwise. After stirring for 3h at rt, the solution was diluted with 1M HCl (30mL). The solids were filtered, washed with water and DCM and dried to obtain the title compound as a white solid (10.4g, 97%). 1H NMR (400MHz, DMSO-d6): δ=10.77 (s, 1H), 8.52 (d, 1H, J=2.3Hz, 8.32 (s, 1H), 8.27 (d, 1H, J=7.9Hz), 7.99 (m, 2H), 7.80 (t, 1H, J=7.8Hz), 7.50 (d, 1H, J=8.9Hz), 2.50 (s, 3H, overlaps with DMSO signal); 13C NMR (101MHz, DMSO-d6): δ=164.3, 148.5, 137.7, 135.1, 133.1, 131.9, 129.8, 129.2 (d, J=32.1Hz), 128.5 (d, J=3.5Hz), 128.0, 125.0, 124.3 (d, J=3.5Hz), 123.4 (d, J=272.6Hz), 115.7, 19.3; ESI-HRMS: m/z calculated for C15H11F3N2NaO3: 347.0619; found: 347.0615 [M+Na]+. |
| 96% |
With triethylamine; In dichloromethane; at 25℃; for 0.5h; |
Example 16: N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)-benzamide A solution of 4-methyl-3-mtro-phenylamine (3.64 g, 24 mmol) and 3-trifluoromethyl benzoyl chloride (5 g, 24 mmol) in DCM (100 ml) was treated with Et3N (6.7 ml, 48 mmol). The mixture was stirred at 25 C for 30 min. The reaction was then quenched with water (50 ml) and stirred for 15 min. The solid was collected by vacuum filtration and washed with hexane. A second crop of solid was collected from the filtrate to give a total yield of 7.78 g (96 %) of white-light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H); 8.51 (d, 1H, J = 1.6 Hz); 8.30 (s, 1H); 8.27 (d, 1H, J=7.8 Hz); 8.00 (m, 2H); 7.80 (t, 1H, J= 7.7 Hz); 7.48 (d, 1H, J- 8.4 Hz); 2.48 (s, 3H). 13C NMR (125 MHz,DMSO-d6) δ 164.7; 148.9; 138.2; 135.6; 133.5; 132.4; 130.3; 129.9; 129.5; 129.0; 128.5; 125.4; 124.7; 116.1; 19.8. HRMS: calcd for C15Hn03N2 F3Na, 347.0619, found 347.0621. |
| 88% |
With triethylamine; In dichloromethane; at 25℃; for 1h; |
Method 70; N-f 4-Methyl-3 -nitrophenyl)- 3 -(trifluoromethyl)benzarnide; 3-(Trifluoromethyl)benzoyl chloride (2.70 g, 12.95 mmol) in 10 ml anhydrous DCM was added to 4-methyl-3-nitroaniline (1.9 g, 12.95 mmol), and TEA (5.4 ml, 38.85 mmol) in DCM (65 ml)and the reaction mixture was allowed to stir at 25 0C for 1 h. The resulting mixture was washed with 1 ν HCl, water and brine. The organic extracts were dried and solvent was removed under reduced pressure to give the title compound as a pale yellow solid (3.70 g, 88%). m/z 325. |
| 88% |
With triethylamine; In dichloromethane; at 25℃; for 1h; |
Method 103; iV-f 4-Methy 1-3 -nitrophenyl)-3 -f trifluoromethvDbenzamide .; 3-(Trifluoromethyl)benzoyl chloride (2.70 g, 12.95 mmol) in 10 ml anhydrous DCM was added to 4-methy 1-3 -nitroaniline (1.9 g, 12.95 mmol), and TEA (5.4 ml, 38.85 mmol) in DCM (65 ml)and the reaction mixture was allowed to stir at 25 C for 1 h. The resulting mixture was washed with 1 N HCl, water and brine. The organic extracts were dried and solvent was removed under reduced pressure to give the title compound as a pale yellow solid (3.7O g, 88%); m/z 325. |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 1 - 1.5h;Product distribution / selectivity; |
N-(4-methyl-3-nitro-phenvl)-3-trifluoromethyl-benzamideTo a solution of 4-methyl-3-nitroaniline (5 g, 32.2 mmol, 1.0 eq.) and triethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) in dichloromethane (100 ml) is added a solution of 3-tri-fluoromethylbenzoyl chloride 33.8 mmol, 1.05 eq.) within 30 min. The suspension formed is stirred for 1h at room temperature. Then, the reaction mixture is diluted with dichloromethane (800 ml) and extracted with water (100 ml), 2M aqueous Na2CO3 (100 ml), 2M HCI (100 ml), water (100 ml). The organic layer is dried over Na2SO4, evaporated to a volume of about 100 ml and diluted with hexanes (100 ml). The precipitate is filtered off, washed with hexanes / dichloromethane 1:1 and hexanes. Vacuum drying over night at room temperatures gives light yellow fine needles: HPLC: tR = 6.72 min (purity: > 99%, gradient A), ESI-MS: 325.2 [MH]+; 4-methyl-3-nitroaniline (3.0 g, 20 mmol) is dissolved in 100ml methylene chloride. 3 mltriethylamine (22 mmol) is added, the solution is cooled to 0C, and 3-trifluorobenziocchloride (4.1g; 20 mmol) is added slowly to the above mixture while stirring. The reactionmixture was allowed raised to room temperature and the reaction was completed in 1 hr. Thereaction mixture was washed with 10% NaHCO3 solution, brine and dried over Na^O^ Thefinal product (3) N-(4-Methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide is a yellow solid,6.28g. |
|
With triethylamine; at 0 - 20℃; for 1h; |
To a stirred solution of 4-methyl-3-nitroaniline (1.00 g, 6.57 mmol) and triethylamine (1.10 mL, 7.89 mmol) at 0 C is added 3-trifluoromethylbenzoyl chloride (4.90 g, 31.0 mmol) and the mixture is stirred for 1 hour at room temperature. The reaction mixture is diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution. The organic layer is dried over MgSO4 and concentrated in reduced pressure to EPO <DP n="25"/>give a crude product. The crude product is dissolved in MeOH and 10% Pd/C is added to the solution. The reaction mixture is stirred for 12 hours at room temperature under hydrogen. The reaction mixture is filtered on Celite plate and the filtrate is concentrated under reduced pressure to give N-(3-amino-4-methylphenyl)-3-trifluoromethyl-benzamide as a dark-gray solid.[0062] To a stirred solution of N-(4-methyl-3-nitrophenyl)-3- trifluoromethylbenzamide (250 mg, 0.85 mmol), 2-bromothiazole-5-carboxylic acid (177 mg, 0.85 mmol), and diisopropylethyl-amine (0.59 mL, 3.4 mmol) in DMF is added O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (355 mg, 0.93 mmol), and the mixture is stirred for 12 hours at room temperature. The reaction mixture is diluted with EtOAc and washed with 10% aqueous sodium thiosulfate solution. The organic layer is dried over MgSO4 and concentrated in reduced pressure. The crude product is purified by preparative HPLC to give 2-bromothiazole-5-carboxylic acid [2-methyl-5-(3- trifluoromethyl-benzoylamino)-phenyl] -amide as a brownish solid.; 2-Bromothiazole-5-carboxylic acid [2-methyl-5-(3- trifluoromethylbenzoyl-amino)-phenyl]-amide (25 mg, 52 μmol) is dissolved in 3- (diethylamino)-proρylamine and the mixture is stirred for 4 hours at 80C . The crude product is diluted with DMSO (1 mL) and purified by preparative HPLC to give 2-(3- diethylaminopropylammo)-thiazole-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl- benzoylamino)-phenyl]-amide in a TFA salt form: 1H ΝMR 400 MHz (DMSO-d6) δ 9.67 (s, IH), 9.43 (br, IH), 8.35 (t, IH), 8.29 (s, IH), 8.26 (d, IH), 7.96 (d, IH), 7.94 (s, IH), 7.80 (d, IH), 7.58 (d, IH), 7.25 (d, IH), 3.35 (q, 2H), 2.89 (m, 6H), 2.19 (s, 3H), 1.93 (m, 2H), 1.20 (t, 6H); MS m/z 534.4(M + 1). |
|
With triethylamine; In chloroform; at -5℃; for 2 - 2.25h; |
Step I: Preparation of novel (3- trifluoromethyl)-N- (4-methyl-3-nitro-phenyl)- benzamide of the formula (XIII) where R represents methyl, X represents CH and n=l : In the first instance , 3-trifluoro methyl benzoyl chloride which is used as one of the starting material is prepared as follows.Tbionyl chloride (312.0 g, 2.63mol) is added over a period of 15 min to a solution of 3- trifluoro methyl benzoic acid (100.0 g, 0.53mol) in chloroform (1000ml) at room temperature. The reaction mixture is heated to reflux temperature for lhour. The excess of tbionyl chloride is removed by co-distillation with chloroform under reduced pressure at 40 C. After the end of the distillation, the resulting trifluoro methyl benzoyl chloride is cooled down to room temperature and dissolved in 100 ml chloroform. A solution of 4-methyl-3-nitroaniline (49.0 g, 0.32mol) in chloroform (600 ml) is cooled to -5 C and triethyl amine (161.0 g, 1.59mol) of is added. Trifluoromethyl benzoyl chloride in chloroform prepared as described above is added drop wise at -5 C over a period of 60-75jnin. The resulting suspension is stirred for 1 hr at -5 C. The suspension is distilled to a residual volume of 800 ml and filtered ,washed with chilled chloroform (250ml) and dried in vacuum to give 85.0 g of novel (3- trifluoromethyl)- N- (4-methyl-3-nitro-phenyl)-benzamide of the formula (TV) where R represents methyl, X represents CH and n=l (83%) as pale yellow crystals (98.0% purity by HPLC) MR-162-164C |
|
With triethylamine; In dichloromethane; at 20℃; |
The compound shown on the left above, N-(3-amino-4-methyl-phenyl)-3-trifluoromethyl- benzamide, is obtained by hydrogenation of the corresponding nitro-compound (N-(4-methyl- 3-nitro-phenyl)-3-trifluoromethyl-benzamide) with Raney-Nickel in methanol at room temperature. The product is obtained in high yield. The intermediate nitro compound (A), N- (3-nitro-4-methyl-phenyl)-3-trifluoromethyl-benzamide, is obtained by reaction of 4-methyl-3- nitro-phenylamine (B) and 3-trifluoromethyl-benzoyl chloride (C) in methylenchloride at room temperature and using triethylamine. The intermediate (A) is obtained in good yield. Similar and different anilines have been described before in the literature and patents (e.g. CAS No. 30069-31-9). For coupling, the corresponding acid chlorides are used. |
|
With triethylamine; In dichloromethane; at 20℃; |
Starting Materials: General procedure for the synthesis of aniline building blocks (illustrated with the formula and educts for N-(3-amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide):; The compound shown on the left above, N-(3-amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide, is obtained by hydrogenation of the corresponding nitro-compound (N-(4-methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide) with Raney-Nickel in methanol at room temperature. The product is obtained in high yield. The intermediate nitro compound (A), N-(3-nitro-4-methyl-phenyl)-3-trifluoromethyl-benzamide, is obtained by reaction of 4-methyl-3-nitro-phenylamine (B) and 3-trifluoromethyl-benzoyl chloride (C) in methylenchloride at room temperature and using triethylamine. The intermediate (A) is obtained in good yield. Similar and different anilines have been described before in the literature and patents (e.g. CAS No. 30069-31-9). For coupling, the corresponding acid chlorides are used. |
|
With triethylamine; In dichloromethane; at 20℃; |
N-(3-amino-4-methyl- phenyl)-3-trifluoromethyl- (A) (B) (C) benzamideThe compound shown on the left above, N-(3-amino-4-methyl-phenyl)-3-tιfluoromethyl- benzamide, is obtained by hydrogenation of the corresponding nitro-compound (N-(4-methyl- 3-nitro-phenyl)-3-trifluorornethyl-benzarnide) (A) with Raney-Nickel in methanol at RT. The product is obtained in high yield. The intermediate (A) is obtained by reaction of 4-methyl-3- nitro-phenylamine (B) and 3-trifluoromethyl-benzoyl chloride (C) in methylene chloride at RT using triethylamine. |
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