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Stage #1: at 5 - 12℃; Stage #2: With hydrogenchloride In methanol; water at 100℃;
Step B4-bromo-2-nitro-6-(trifluoromethyl)aniline[00234] Sulfuric acid (350 ml) was cooled to 5 °C in an ice-bath before V-[4-bromo-2- (trifluoromethyl)phenyl]acetamide (100 g, 355 mmol) was added portion-wise. The observed internal temperature increased from 5 °C to 10 °C. After the solids dissolved and temperature decreased to 5 °C, nitric acid (70percent) (43.8 ml) was added slowly drop-wise at such a rate that the internal temperature did not increase above 10 °C. The temperature was carefully controlled between 8 °C and 12 °C until the reaction was complete. The cold dark solution was carefully poured into stirring ice water (2L, mostly ice). The tan precipitate was collected by filtration and the filter cake washed with 1 L of cold water before being air dried. The tan powder was slurried in methanol (500 mL) in a 3L 3-neck flask, and concentrated hydrochloric acid (37percent) (750 mL, 9130 mmol) was added and the mixture heated with a heating mantel to 100 °C. Excessive frothing occurred. 10OmL of 1 ,4-dioxane and 200mL of tetrahydrofuran were added to help the frothing subside. Frothing did not subside. The reaction temperature was brought down to 80 °C and heated overnight. The mixture was much more manageable and frothing was better controlled. The mixture was slowly heated to 95 °C and was stirred for 72 hours. The mixture was cooled to room temperature and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the title compound (101 g, 99percent). 1H NMR (400 MHz, DMSO-tf6) δ ppm 8.40 (d, 1 H), 7.96 (d, 1 H), 7.44 (br. s 2 H).
Reference：
[1] Patent: WO2011/97491, 2011, A1, . Location in patent: Page/Page column 117-118
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379
[3] Patent: WO2011/97491, 2011, A1,
[4] Patent: US5514680, 1996, A,
Example 474-[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbon[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinoneStep AN-[4-bromo-2-( trifluorom ethyl)phenyl]acetami de[00233] 4-bromo-2-(trifluoromethyl)aniline (553 g, 2.30 mol) was dissolved in acetic anhydride (1087 ml, 11.5 mol) and stirred at room temperature overnight. A thick white solid had formed and was slurried in a mixture of 200 mL of ethyl ether and 400 mL of hexanes. The solids were triturated thoroughly and collected by filtration. The filter cake was washed with a mixture of 200 mL of ethyl ether and 400 mL of hexanes, and was thoroughly air dried to give the title compound (528 g; 81 %) as a white solid. LCMS: m/z 282, 284 (M+1).
Step FN-[4-bromo-2-(tri?luoromethyl)phenyl]acetamide[00313] To a solution of 4-bromo-2-(trifluoromethyl)aniline (5.00 g, 20.8 mmol) in chloroform (60 mL) was added acetyl chloride (2.45 g, 31 .2 mmol) dropwise at 0 C. The mixture was stirred at room temperature overnight. The reaction solution was quenched with sat. NaHC03 (80 mL) and then extracted with dichloromethane (100 mL x 2). The combined organic solutions were washed with brine (100 mL x 2), H20 (100 mL x 2) and then dried over anhydrous Na2S0 . Removal of the solvent gave the title compound (5.68 g, 97%). LCMS; m/z 282, 284 (M+1 ).
93%
With pyridine; In toluene; for 2h;Heating / reflux;
To a solution of [2-AMINO-5-BROMOBENZOTRIFLUORIDE] (1.20g, 5.00 [MMOL)] in toluene (10 [ML)] at [0C] was added acetyl chloride (3.9g, 50 [MMOL)] and pyridine (3. [8] g, 48 [MMOL).] The mixture was then refluxed for two hours. After cooling to room temperature, the mixture was diluted with ethylacetate and washed with [NAHCO3] (saturated), brine and the separated organic layer was then dried over anhydrous Na2SO4. The solvent was removed in vacuo giving the product as a white solid (1.3g, 93%).
EXAMPLE 7 3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0 C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0 C. for 10 min and then allowed to warm to 25 C. The reaction mixture was stirred at 25 C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The crude residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtration and washed with hexanes to afford N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as an amorphous white solid: EI-HRMS m/e calcd for C9H7BrF3NO (M+) 281.8352, found 281.8348.
With acetic anhydride; In tetrahydrofuran;
EXAMPLE 10 1-{3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-urea A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0 C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0 C. for 10 min and then allowed to warm to 25 C. The reaction mixture was stirred at 25 C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The crude residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtrated and washed with hexanes to afford N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as an amorphous white solid: EI-HRMS m/e calcd for C9H7BrF3NO (M+) 281.8352, found 281.8348.
With acetic anhydride; In tetrahydrofuran;
EXAMPLE 19 (E)-3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-acrylamide A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0 C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0 C. for 10 min and then allowed to warm to 25 C. The reaction mixture was stirred at 25 C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The crude residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtrated and washed with hexanes to afford N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as an amorphous white solid: EI-HRMS m/e calcd for C9H7BrF3NO (M+) 281.8352, found 281.8348.
With acetic anhydride; In tetrahydrofuran;
EXAMPLE 21 (E)-4-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid thiazol-2-ylamide A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0 C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0 C. for 10 min and then allowed to warm to 25 C. The reaction mixture was stirred at 25 C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The crude residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtrated and washed with hexanes to afford N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as an amorphous white solid: EI-HRMS m/e calcd for C9H7BrF3NO (M+) 281.8352, found 281.8348.
1.840 g (99.7%)
In acetic anhydride;
A. 2-Acetamido-5-bromobenzotrifluoride A solution of 2-amino-5-bromobenzotrifluoride (1.623 g, 6.76 mmol, Aldrich) in acetic anhydride (10 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.840 g (99.7%) of title compound. Mp: 140-2 C., 1 H-NMR (CDCl3): delta2.212 (s, 3H); 7.358(s, 1H); 7.659(d, 1H, J=8.7 Hz); 7.726(d, 1H, J=1.8 Hz); 8.118 (d, 1H, J=8.4 Hz).
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