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With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane at 20 - 70℃; for 4 h; Inert atmosphere
Fluoro-3-methyl-2-nitrobenzene To a solution of 2-fluoro-6-methylaniline (8.5 g, 67.9 mmol) in DCE (150 mL), m- CPBA (58.6 g, 272 mmol) was added slowly under nitrogen at RT. The reaction mixture was stirred at 70 °C for 4 h. DCM (500 mL) was added. Then it was washed with 1 N NaOH (200 mL x4). The combined organic layers was dried and concentrated under a stream of nitrogen at 50 °C to give 1 1.2 g (65.9percent) of the title compound.
Stage #1: at 0℃; for 0.166667 h; Stage #2: at 0 - 20℃; for 4.08333 h; Stage #3: With sodium hydrogencarbonate In hexanes; dichloromethane; water
l-Bromo-4-fluoro-2-methyl-3-nitrobenzene (C)(C) [00170] A 250 mL single neck flask equipped with magnetic stirrer was charged with 3-fluoro-2-nitrotoluene (4.75 g, 30.6 mmol) and trifluoroacetic acid (20 mL). Sulfuric acid (96percent, 10 mL) was added dropwise over 10 minutes at 0 0C followed by N-bromosuccinimide (8.12 g, 45.6 mmol) in portions over 15 min (causing an exotherm of 3 0C). The reaction was stirred at 0 0C for 20 min and then stirred at room temperature for 3.5 h. After this time, the reaction mixture was poured in to a 1:1 mixture of ice/water (500 mL), diluted with 95:5 hexanes/methylene chloride (250 mL) and the layers were separated. The aqueous layer was extracted with hexanes (100 mL) and the combined organic layers were washed with water (2x100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was suspended in hexanes (40 mL) and heated until dissolved. The solution was evaporated to a volume to 20 mL and allowed to cool to room temperature overnight. The product was filtered and washed with cold hexanes (3x2 mL) to afford (C) (4.29 g, 60percent) as a yellow crystalline solid. The filtrate was concentrated to dryness and the residue was dissolved in hot hexanes (5 mL). After cooling to room temperature, stirring for 2 h, and filtering, an additional 1.30 g of C (18percent) was isolated
68%
at 0 - 20℃; for 5.25 h; Inert atmosphere
To 1-fluoro-3-methyl-2-nitrobenzene 8-1 (5 g, 32.25 mmol) at 0 °C under argonatmosphere was added concentrated sulfuric acid: trifluoroacetic acid (1: 2, 45 mL). To thiswas added N-bromosuccinimide (8.61 g, 48.37 mmol) portion wise for 15 mm; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (200 mL), the precipitated solid was filtered, washed with water (100 mL) and dried in vacuo to afford the crude. The crude waspurified through silica gel flash column chromatography using 1-2percent EtOAc/ hexanes to afford compound 8-2 (5.1 g, 68percent). TLC: 5percent EtOAc/ hexanes (Rj: 0.8); TLC: 30percent EtOAc/ hexanes (Rf: 0.3). 1H NMR (DMSO-d6, 400 MHz): 7.96 (dd, J = 8.9, 5.2 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 22.35 (m, 3H)
67%
at 20℃; for 2 h;
To a solution of l-fluoro-3-methyl-2-nitro-benzene (5 g, 32.24 mmol, 1.0 eq) in TFA (25 mL) and conc.H2S04 (10 mL) at 0°C was added NBS (6.31 g, 35.46 mmol, 1.1 eq) in portions. After addition, the mixture was stirred at room temperature for 2h. The resulting mixture was poured onto ice and the precipitate that formed collected by filtration, washed with water and dried in vacuo to give the title compound as a yellow solid (5 g, 67 percent)..H NMR (400 MHz, DMSO-d6) ? 7.98 (dd, J = 9.0, 5.2 Hz, 1H), 7.48 (app t, J1H), 2.36 (s, 3H)
56%
at 0 - 20℃; for 3 h; Inert atmosphere
To a stirred solution of compound 12 (25 g, 161.2 mmol) in TFA: conc. H2S04 (150 mL: 75 mL) at 0 °C, under argon atmosphere, NBS (43 g, 241.9 mmol) was added portion wiseand stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured in to ice cold water (700 mL); the precipitated solid was collected by filtration and washed with water. The residue was purified by silica gel column chromatography using 2percent EtOAc/ hexane to afford the title compound 13 (21 g, 56percent) as a light yellow solid. TLC: 10percent EtOAc/ hexane (R 0.6); ‘H NMR (400 MHz, DMSO-d6): ö 7.89 —7.86 (m, 1H), 7.48 (t, J = 9.6 Hz, 1H), 2.36 (s, 3H).
27%
Stage #1: at 0 - 1℃; for 0.166667 h; Stage #2: at 0 - 20℃;
[00220] 1-Fluoro-3-methyl-2-nitro-benzene (5 g, 32.2 mmol) was mixed withtrifluoroacetic acid (21 mL, 274.2 mmol) and cooled to 0 °C in a salt/ice bath. Sulphuric acid(10.5 mL, 32.2 mmol) was added portionwise over 10 minutes - the reaction mixture exothermed to 1 °C. The reaction was allowed to cool back to 0 °C and N-bromosuccinimide (8.5 g, 47.8 mmol) was added portionwise over approximately 10 minutes - maintaining the temperature below 2 00. The mixture was stirred overnight - the ice bath was not removed sothe reaction was allowed to slowly warm to ambient temperature. The reaction was poured into ice/water (500mls) - a solid precipitate could be seen on the top of the ice. The mixture was stirred vigorously for 5 minutes then a mixture of isohexane (230m1s) and DCM (2Omls) was added and the mixture stirred vigorously for 10 minutes - the layers were separated and the aqueous further extracted with a mixture of isohexane (230m1s) and DCM (2Omls). The twoorganic phases were washed separately with 2 x Dl water, 1 x saturated sodium bicarbonate, 1x brine and then combined and dried over anhydrous sodium sulphate. The organic solutionwas concentrated down to give crude material, roughly 3:1 ratio of desired product: dibromo HbO 8.38 (d) F 6.6Hz, (TLC 4:1 isohexane/DOM showed no starting material and two spots.)[00221] The crude material was crystallised from isohexane (lOOmis) - stirring used oncooling, then cooling and stirring in ice bath. A white solid was filtered off (0.53g).[00222] 1H NMR (DMSO-d6): 07.99 (dd, J=5.1 and 8.9Hz, 1H), 7.49 (t, J= 9.2 Hz, 1H), 2.37 (5, 3H).[00223] A second crop was obtained on standing, together yielding 2.17g, 27percent.
l-Bromo-4-fluoro-2-methyl-3-nitrobenzene (C)(C) [00170] A 250 mL single neck flask equipped with magnetic stirrer was charged with 3-fluoro-2-nitrotoluene (4.75 g, 30.6 mmol) and trifluoroacetic acid (20 mL). Sulfuric acid (96%, 10 mL) was added dropwise over 10 minutes at 0 0C followed by N-bromosuccinimide (8.12 g, 45.6 mmol) in portions over 15 min (causing an exotherm of 3 0C). The reaction was stirred at 0 0C for 20 min and then stirred at room temperature for 3.5 h. After this time, the reaction mixture was poured in to a 1:1 mixture of ice/water (500 mL), diluted with 95:5 hexanes/methylene chloride (250 mL) and the layers were separated. The aqueous layer was extracted with hexanes (100 mL) and the combined organic layers were washed with water (2x100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was suspended in hexanes (40 mL) and heated until dissolved. The solution was evaporated to a volume to 20 mL and allowed to cool to room temperature overnight. The product was filtered and washed with cold hexanes (3x2 mL) to afford (C) (4.29 g, 60%) as a yellow crystalline solid. The filtrate was concentrated to dryness and the residue was dissolved in hot hexanes (5 mL). After cooling to room temperature, stirring for 2 h, and filtering, an additional 1.30 g of C (18%) was isolated
68%
With N-Bromosuccinimide; trifluoroacetic acid; at 0 - 20℃; for 5.25h;Inert atmosphere;
To 1-fluoro-3-methyl-2-nitrobenzene 8-1 (5 g, 32.25 mmol) at 0 C under argonatmosphere was added concentrated sulfuric acid: trifluoroacetic acid (1: 2, 45 mL). To thiswas added N-bromosuccinimide (8.61 g, 48.37 mmol) portion wise for 15 mm; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (200 mL), the precipitated solid was filtered, washed with water (100 mL) and dried in vacuo to afford the crude. The crude waspurified through silica gel flash column chromatography using 1-2% EtOAc/ hexanes to afford compound 8-2 (5.1 g, 68%). TLC: 5% EtOAc/ hexanes (Rj: 0.8); TLC: 30% EtOAc/ hexanes (Rf: 0.3). 1H NMR (DMSO-d6, 400 MHz): 7.96 (dd, J = 8.9, 5.2 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 22.35 (m, 3H)
67%
With N-Bromosuccinimide; sulfuric acid; at 20℃; for 2h;
To a solution of l-fluoro-3-methyl-2-nitro-benzene (5 g, 32.24 mmol, 1.0 eq) in TFA (25 mL) and conc.H2S04 (10 mL) at 0C was added NBS (6.31 g, 35.46 mmol, 1.1 eq) in portions. After addition, the mixture was stirred at room temperature for 2h. The resulting mixture was poured onto ice and the precipitate that formed collected by filtration, washed with water and dried in vacuo to give the title compound as a yellow solid (5 g, 67 %)..H NMR (400 MHz, DMSO-d6) ? 7.98 (dd, J = 9.0, 5.2 Hz, 1H), 7.48 (app t, J1H), 2.36 (s, 3H)
56%
With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 0 - 20℃; for 3h;Inert atmosphere;
To a stirred solution of compound 12 (25 g, 161.2 mmol) in TFA: conc. H2S04 (150 mL: 75 mL) at 0 C, under argon atmosphere, NBS (43 g, 241.9 mmol) was added portion wiseand stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured in to ice cold water (700 mL); the precipitated solid was collected by filtration and washed with water. The residue was purified by silica gel column chromatography using 2% EtOAc/ hexane to afford the title compound 13 (21 g, 56%) as a light yellow solid. TLC: 10% EtOAc/ hexane (R 0.6); ?H NMR (400 MHz, DMSO-d6): oe 7.89 -7.86 (m, 1H), 7.48 (t, J = 9.6 Hz, 1H), 2.36 (s, 3H).
27%
[00220] 1-Fluoro-3-methyl-2-nitro-benzene (5 g, 32.2 mmol) was mixed withtrifluoroacetic acid (21 mL, 274.2 mmol) and cooled to 0 C in a salt/ice bath. Sulphuric acid(10.5 mL, 32.2 mmol) was added portionwise over 10 minutes - the reaction mixture exothermed to 1 C. The reaction was allowed to cool back to 0 C and N-bromosuccinimide (8.5 g, 47.8 mmol) was added portionwise over approximately 10 minutes - maintaining the temperature below 2 00. The mixture was stirred overnight - the ice bath was not removed sothe reaction was allowed to slowly warm to ambient temperature. The reaction was poured into ice/water (500mls) - a solid precipitate could be seen on the top of the ice. The mixture was stirred vigorously for 5 minutes then a mixture of isohexane (230m1s) and DCM (2Omls) was added and the mixture stirred vigorously for 10 minutes - the layers were separated and the aqueous further extracted with a mixture of isohexane (230m1s) and DCM (2Omls). The twoorganic phases were washed separately with 2 x Dl water, 1 x saturated sodium bicarbonate, 1x brine and then combined and dried over anhydrous sodium sulphate. The organic solutionwas concentrated down to give crude material, roughly 3:1 ratio of desired product: dibromo HbO 8.38 (d) F 6.6Hz, (TLC 4:1 isohexane/DOM showed no starting material and two spots.)[00221] The crude material was crystallised from isohexane (lOOmis) - stirring used oncooling, then cooling and stirring in ice bath. A white solid was filtered off (0.53g).[00222] 1H NMR (DMSO-d6): 07.99 (dd, J=5.1 and 8.9Hz, 1H), 7.49 (t, J= 9.2 Hz, 1H), 2.37 (5, 3H).[00223] A second crop was obtained on standing, together yielding 2.17g, 27%.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 70℃;
Example 13l-[(3S)-l-(Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-(4'-fluoro-4-biphenylyl)-4- methyl-lH-benzimidazole(a) 1,1-Dimethylethyl (35)-3-[(3-methyl-2-nitrophenyl)amino]methyl}-l- pyrrolidinecarboxylate3 -Methyl-2-nitrofluorobenzene, 1 , 1 -dimethylethyl (35)-3 -(aminomethyl)- 1 - pyrrolidinecarboxylate (1 eq) and DIEA (1.4 eq) were dissolved in DMSO and stirred at 70 C overnight. The reaction mixture was allowed to cool, diluted with EtOAc, washed with water and saturated brine, dried over sodium sulfate and evaporated to yield the crude product. Purification by silica gel column chromatography afforded the titled compound.
With 3-chloro-benzenecarboperoxoic acid; In 1,2-dichloro-ethane; at 20 - 70℃; for 4h;Inert atmosphere;
Fluoro-3-methyl-2-nitrobenzeneTo a solution of <strong>[443-89-0]2-fluoro-6-methylaniline</strong> (8.5 g, 67.9 mmol) in DCE (150 mL), m- CPBA (58.6 g, 272 mmol) was added slowly under nitrogen at RT. The reaction mixture was stirred at 70 C for 4 h. DCM (500 mL) was added. Then it was washed with 1 N NaOH (200 mL x4). The combined organic layers was dried and concentrated under a stream of nitrogen at 50 C to give 1 1.2 g (65.9%) of the title compound.
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