* 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.
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 16, p. 4817 - 4821
7
[ 446-30-0 ]
[ 56456-49-6 ]
Yield
Reaction Conditions
Operation in experiment
224 mg
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 16 h;
To a solution of 4-chloro-2-fluorobenzoic acid (300mg) in THF (15m1) was added at 0°CLiAIH4 (130mg). The suspension was stirred at 0°C for 16h. The reaction mixture wasdiluted with EA and aq. solution of potassium sodium tartrate and stirred for lh at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgSO4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in percentB: 0 to 5, flow rate: 6.0 mI/mm) to afford 224mg of colourless oil. LCMS: (A) tR = 0.68 mm; [M+H]: not visible.
224 mg
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 16 h; Inert atmosphere
To a solution of 4-chloro-2-fluorobenzoic acid (300 mg) in THF (15 ml_) was added at 0°C UAIH4 (130 mg). The suspension was stirred at 0°C for 16h. The reaction mixture was diluted with EA and aq. solution of potassium sodium tartrat and stirred for 1 h at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in percentB: 0 to 5, flow rate: 6.0 imL/min) to afford 224 mg of colourless oil. LC-MS (A) tR = 0.68 min; [M+H]+: not visible.
224 mg
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 16 h;
To a solution of 4-chloro-2-fluorobenzoic acid (300mg) in THF (15ml) was added at 0°C UAIH4 (130mg). The suspension was stirred at 0°C for 16h. The reaction mixture was diluted with EA and aq. solution of potassium sodium tartrat and stirred for 1 h at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in percentB: 0 to 5, flow rate: 6.0 ml/min) to afford 224mg of colourless oil. LC-MS (A) tR = 0.68min; [M+H]+: not visible.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 16h;
To a solution of 4-chloro-2-fluorobenzoic acid (300mg) in THF (15m1) was added at 0CLiAIH4 (130mg). The suspension was stirred at 0C for 16h. The reaction mixture wasdiluted with EA and aq. solution of potassium sodium tartrate and stirred for lh at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgSO4, filtrated off and evaporated in vacuo. The crude was purified by CC (Buechi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in %B: 0 to 5, flow rate: 6.0 mI/mm) to afford 224mg of colourless oil. LCMS: (A) tR = 0.68 mm; [M+H]: not visible.
224 mg
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 16h;Inert atmosphere;
To a solution of 4-chloro-2-fluorobenzoic acid (300 mg) in THF (15 ml_) was added at 0C UAIH4 (130 mg). The suspension was stirred at 0C for 16h. The reaction mixture was diluted with EA and aq. solution of potassium sodium tartrat and stirred for 1 h at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in %B: 0 to 5, flow rate: 6.0 imL/min) to afford 224 mg of colourless oil. LC-MS (A) tR = 0.68 min; [M+H]+: not visible.
224 mg
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 16h;
To a solution of 4-chloro-2-fluorobenzoic acid (300mg) in THF (15ml) was added at 0C UAIH4 (130mg). The suspension was stirred at 0C for 16h. The reaction mixture was diluted with EA and aq. solution of potassium sodium tartrat and stirred for 1 h at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 5g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in %B: 0 to 5, flow rate: 6.0 ml/min) to afford 224mg of colourless oil. LC-MS (A) tR = 0.68min; [M+H]+: not visible.
2-(4-[4-(4-chloro-2-fluoro-benzoylamino)-1-methyl-1<i>H</i>-pyrrole-2-carbonyl]-amino}-1-methyl-1<i>H</i>-pyrrol-2-yl)-3<i>H</i>-benzoimidazole-5-carboxylic acid[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-(3-dimethylamino-propyl)-1<i>H</i>-pyrrole-2-carboxylic acid [5-(3<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
2-[4-(4-chloro-2-fluoro-benzoylamino)-1-methyl-1<i>H</i>-pyrrol-2-yl]-3<i>H</i>-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-(3-dimethylamino-propyl)-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-(3-dimethylamino-propyl)-1<i>H</i>-pyrrole-2-carboxylic acid [5-(3<i>H</i>-imidazo[4,5-<i>b</i>]pyridin-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
2-(4-[4-(4-chloro-2-fluoro-benzoylamino)-1-methyl-1<i>H</i>-pyrrole-2-carbonyl]-amino}-1-methyl-1<i>H</i>-pyrrol-2-yl)-3<i>H</i>-benzoimidazole-5-carboxylic acid ethyl ester[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-(3-dimethylamino-propyl)-1<i>H</i>-pyrrole-2-carboxylic acid [1-methyl-5-(9<i>H</i>-purin-8-yl)-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
methanesulfonic acid 3-[2-[5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl]-4-(4-chloro-2-fluoro-benzoylamino)-pyrrol-1-yl]-propyl ester[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-(3-morpholin-4-yl-propyl)-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-(3-thiomorpholin-4-yl-propyl)-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-(3-piperidin-1-yl-propyl)-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-[3-(4-hydroxy-piperidin-1-yl)-propyl]-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
2-(4-[4-(4-chloro-2-fluoro-benzoylamino)-1-methyl-1<i>H</i>-pyrrole-2-carbonyl]-amino}-1-methyl-1<i>H</i>-pyrrol-2-yl)-3<i>H</i>-benzoimidazole-5-carboxylic acid benzotriazol-1-yl ester[ No CAS ]
1-{3-[bis-(2-hydroxy-ethyl)-amino]-propyl}-4-(4-chloro-2-fluoro-benzoylamino)-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
4-(4-chloro-2-fluoro-benzoylamino)-1-[3-(4,4-difluoro-piperidin-1-yl)-propyl]-1<i>H</i>-pyrrole-2-carboxylic acid [5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
2-(4-[4-(4-chloro-2-fluoro-benzoylamino)-1-methyl-1<i>H</i>-pyrrole-2-carbonyl]-amino}-1-methyl-1<i>H</i>-pyrrol-2-yl)-3<i>H</i>-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide[ No CAS ]
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;
Reference Example 8 : 1- (4-chloro-2-fluorophenyl) ethanone To a solution <strong>[446-30-0]4-chloro-2-fluorobenzoic acid</strong> (leq) in CH2C12 (1.6 M) was added N, O-dimethylhydroxylamine hydrochloride (1. 5 eq), EDCI (1.5 eq) and triethylamine (4 eq). The reaction mixture was stirred at rt for 16 hrs, concentrated and 0. 5M aqueous citric acid was added. The mixture was extracted with 1: 1 EtOAc: Et20. The combined organic layers were washed with brine, dried over MgS04 and concentrated to give 4-chloro-2-fluoro-N-methoxy-N- methylbenzamide, which was used as such for the next step. To a solution of the above benzamide (leq) in CHsClz (0.5 M) at 0C was added 3M/EtzO MeMgBr (1.25 eq). The reaction mixture was slowly warmed to rt over a 2 hrs period, quenched with 0.5 M aqueous citric acid and extracted with Et20. The combined organic layers were washed with brine, dried over MgS04 and concentrated. The residue was purified by flash chromatography on silica gel eluted with 20% EtOAc/hexane to give the title compound.
With hydrogenchloride; benzotriazol-1-ol; In dichloromethane;
Example 14 N-t-Butyl-4-chloro-2-fluorobenzamide To a suspension of <strong>[446-30-0]4-chloro-2-fluorobenzoic acid</strong> (0.3494 g, 2.00 mmol) in methylene chloride (10 ml) were added t-butyl amine (0.32 ml, 3.05 mmol) and HOBt (0.3248 g, 2.40 mmol), and then WSC HCl (0.4596 g, 2.40 mmol) was added and stirred for 3 hours. The reaction mixture was added into water and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (0.4403 g; 96%). 1H-NMR(270 MHz, CDCl3) 8.01 (t, 1H, J=8.6 Hz), 7.24 (dd, 1H, J=8.6, 2.0 Hz), 7.13 (dd, 1H, J=11.6, 2.0 Hz), 6.50 (br, 1H), 1.47 (s, 9H)
With pyridine; hydrogenchloride; sodium carbonate; In thionyl chloride; dichloromethane;
EXAMPLE 8 N-Methoxy-N-methyl-4-chloro-2-fluorobenzamide A suspension of 19.7 g of <strong>[446-30-0]4-chloro-2-fluorobenzoic acid</strong> in 80 ml of thionyl chloride was refluxed for 1.5 h. The excess thionyl chloride was removed under reduced pressure to give the crude intermediate acid chloride as an oil. This crude acid chloride was dissolved in 300 ml of methylene chloride and 20 ml of pyridine was added. The solution was cooled to 0 C. and 12.9 g of N,O-dimethylhydroxylamine hydrochoride was added in one portion. The solution was stirred at room temperature overnight then diluted with 200 ml of methylene chloride and washed with 100 ml each of water, 2M hydrochloric acid, 5% sodium carbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated to give 23.5 g of N-Methoxy-N-methyl-4-chloro-2-fluorobenzamide as a gum, GC-M.S. (E.I.) (M/Z): 217 [M]+.
A mixture of <strong>[446-30-0]2-fluoro-4-chlorobenzoic acid</strong> (6.05 g), polyphosphoric acid (62.51 g) and CH3 NO2 (5.1 g) is heated at 130. After about 2.5 hr, the reaction mixture is poured onto ice and made basic by addition of dilute sodium hydroxide. The reaction is then worked up by extracting with ether. The combined ether extracts are washed with water and brine, dried over sodium sulfate, filtered and evaporated to yield 2-fluoro-4-chloroaniline.
With pyridine; hydrogenchloride; sodium carbonate; In thionyl chloride; dichloromethane;
Example 8 N-Methoxy-N-methyl-4-chloro-2-fluorobenzamide A suspension of 19.7 g of <strong>[446-30-0]4-chloro-2-fluorobenzoic acid</strong> in 80 ml of thionyl chloride was refluxed for 1.5 h. The excess thionyl chloride was removed under reduced pressure to give the crude intermediate acid chloride as an oil. This crude acid chloride was dissolved in 300 ml of methylene chloride and 20 ml of pyridine was added. The solution was cooled to 0 C and 12.9 g ofN,O-dimethylhydroxylamine hydrochoride was added in one portion. The solution was stirred at room temperature overnight then diluted with 200 ml of methylene chloride and washed with 100 ml each of water, 2M hydrochloric acid, 5% sodium carbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated to give 23.5 g of N-Methoxy-N-methyl-4-chloro-2-fluorobenzamide as a gum, GC-M.S. (E.I.) (M/Z) 217 [M]+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide;
General procedure: To a solution of corresponding acids (RCOOH, 0.63 mmol), HOBt (170 mg, 1.26 mmol), EDCI (242 mg, 1.26 mmol), and DIPEA (0.208 mL, 1.26 mmol) were added to DMA (60 mL), and then 4 (186 mg, 1.26mmol) were added, the mixture was stirred overnight. The mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-nitrophenethyl)amide (5) in a good yield. And to a solution of 5 in MeOH was added 10% Pd/C under H2 at reflux overnight, then the mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-aminophenethyl)amide (6) in a good yield. Then the mixture of 3 and 6 was added NaCNBH3 in MeOH and the solution was stirred under reflux overnight. After reaction completed, the solvent was removed under reduced pressure and the residue was dissolved in water, the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to afford the corresponding compounds (7-26) in good yields.
With copper (II) nitrate tetrahydrate; oxygen; In acetonitrile; at 180℃; under 18751.9 Torr; for 1.5h;Green chemistry;
<strong>[175711-83-8]2-fluoro-4-chloroacetophenone</strong> 25g (144.9mmol, 1.0eq), Cu(NO3)2·4H2O 7.0g (29.0mmol, 0.2eq), acetonitrile 250mL (10V),The temperature of the outer bath of the reaction coil was raised to 180 C, and the coil pressure was adjusted to 2.5 MPa with oxygen to start the charging. The residence time of the system was 1.5 h and the oxygen was 3 to 5 eq.The system was directly pumped into 375 mL of purified water, and the pH of the system was adjusted to 12-14 with NaOH solids.The aqueous phase was extracted twice with 125 mL MTBE, and the aqueous phase was adjusted to pH 1 with concentrated HCl.A large amount of solid was precipitated, and 19.3 g of the target product was obtained by filtration, yield 77%.
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