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With thionyl chloride;N,N-dimethyl-formamide;Reflux; |
Example 133l-[(3S)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-(3'-hydroxy-4-biphenylyl)- N-methyl-lH-benzimidazole-7-carboxamide(a) 2-Fluoro-3-nitrobenzoyl chlorideTo a mixture of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> (1 g) and thionyl chloride (20 mL) was added 2 drops of DMF. The reaction mixture was heated at reflux overnight, allowed to cool and then evaporated under reduced pressure to afford the titled compounds, which was used without further purification. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; at 20 - 50℃; |
Example I 1.1 : N-r2-bromo-6-chloro-4-(l, 1,1,2,3, 3,3-heptafluoro-prop-2-yl)phenyl1-2- fluoro-3 -nitro-benzamide To a suspension of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> (309 g, 1.67 mol) in dichloroethane (2090 ml) was added N,N-dimethylformamide (1.3 ml, 16.7 mmol) followed by slow addition of oxalyl chloride (150 ml, 1.69 mol) at ambient temperature. The reaction mixture was stirred and heated at 50C until a solution was formed. The reaction mixture was allowed to cool to ambient temperature and then added to a solution of 2-bromo-6-chloro-4- [l,l,l,2,3,3,3-heptafluoro-prop-2-yl]aniline (described in WO/10127926) (125 g, 334 mmol) in dichloroethane (477 ml) followed by addition of triethylamine (564 ml, 4.01 mol). The reaction mixture was stirred at reflux for 4 hours. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (500 ml). The layers were separated and the organic layer was washed with water (500 ml). The combined aqueous layers were extracted twice with dichloroethane (2x 500 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The crude residue was dissolved in THF and a IN solution of sodium hydroxide (2 eq) was added. The mixture was stirred at room temperature until the diacylated product disappeared. Then ethyl acetate (1 L) and saturated aqueous sodium hydrogen carbonate (1 L) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (4x 250 ml). The organic layer was concentrated, filtered through silica gel, and concentrated again. The residue (181 g) was used directly for the next step. 1H NMR (CDCI3, 400 MHz): 8.39 (m, 1H), 8.21 (m, 1H), 8.09 (d, 1H), 7.78 (s 7.67 (s, 1H), 7.43 (t, 1H). |
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With thionyl chloride; for 3h;Reflux; |
Step 6 Methyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate A mixture of 18.51 g (0.10 mol; 1.0 eq) of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> and 100 ml of thionyl chloride was refluxed for 3 hours. The excess thionyl chloride was then concentrated and the residue was co-evaporated twice with toluene. The resulting acid chloride was taken up in 250 ml of dichloromethane. To this mixture, cooled to 0 C., were added 16.56 g (0.10 mol; 1.0 eq) of L-proline methyl ester hydrochloride and then 30.50 ml (0.22 mol; 2.2 eq) of triethylamine. After 30 minutes at 0 C. and one hour at ambient temperature, the reaction medium was diluted and washed with 250 ml of a 1 M aqueous hydrochloric acid solution and then with 250 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. 25.64 g of methyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate were obtained. Yield=87%. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; at 50℃; |
Example I 1.1 : N-|"2-bromo-6-chloro-4-(l, 1,1, 2,3,3, 3-heptafluoro-prop-2-yl)phenyl1-2-fluoro-3- nitro-benzamide To a suspension of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> (309 g, 1.67 mol) in dichloroethane (2090 ml) was added N,N-dimethylformamide (1.3 ml, 16.7 mmol) followed by slow addition of oxalyl chloride (150 ml, 1.69 mol) at ambient temperature. The reaction mixture was stirred and heated at 50C until a solution was formed. The reaction mixture was allowed to cool to ambient temperature and then added to a solution of 2-bromo-6-chloro-4-[l, 1,1, 2,3,3, 3 -heptafluoro-prop-2-yl] aniline (described in WO/10127926) (125 g, 334 mmol) in dichloroethane (477 ml) followed by addition of triethylamine (564 ml, 4.01 mol). The reaction mixture was stirred at reflux for 4 hours. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (500 ml). The layers were separated and the organic layer was washed with water (500 ml). The combined aqueous layers were extracted twice with dichloroethane (2x 500 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The crude residue was dissolved in THF and a IN solution of sodium hydroxide (2 eq) was added. The mixture was stirred at room temperature until the diacylated product disappeared. Then ethyl acetate (1 L) and saturated aqueous sodium hydrogen carbonate (1 L) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (4x 250 ml). The organic layer was concentrated, filtered through silica gel, and concentrated again. The residue (181 g) was used directly for the next step. lH NMR (CDC13, 400 MHz): 8.39 (m, 1H), 8.21 (m, 1H), 8.09 (d, 1H), 7.78 (s, 1H), 7.67 (s 1H), 7.43 (t, 1H). |
12.2 g |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 5.5h; |
To a suspension of 11 g <strong>[317-46-4]2-fluoro-3-nitro-benzoic acid</strong> in 170 ml dichloromethane a drop of Nu,Nu-dimethylformamide was added, followed by 5.55 ml oxalyl dichloride. The resulting yellow suspension was stirred at ambient temperature for 5.5 hours. Then the solution was evaporated to give 12.2 g of 2-fluoro-3-nitro-benzoyl chloride. |
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With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 1h;Reflux; |
To a solution of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> (35a) (5.0 , 27.0 mrnol) in toluene(20.0 rnL) was added thionyl chloride (19.71 mL, 270 rnmol), one drop of DMF and heated at reflux for 1 h. The reaction mixture was concentrated in vacuum to dryness, co-distilledwith toluene (10 mL) once and dried under vacuum to remove traces of thionyl chloride. The acid chloride obtained was dissolved in dichloromethane (40 mL) and to it was added at room temperature N,O-dimethylhydroxylamine hydrochloride (3.95 g, 40.5 mmol) and triethylamine (18.82 m L, 135 mmol). The reaction mixture was stirred at room temperature overnight, washed with water (25 mL), brine (25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography (silica gel 40 g, eluting with 0- 100%, ethyl acetate in hexane) to furnish 2-Fluoro-N-niethoxy-N-methyl- 3-nitrobenzamide (35b) (5.062 g, 82 % yield) as a yellow solid; ?H NMR (300 MHz, DMSO-t/6)oe 8.25 (ddd,J= 8.3, 7.4, 1.7 Hz, JH), 7.93 (ddd,J=7.5, 5.6, 1.7 Hz, H-I), 7.54 (ddd, .1 = 8.5, 7.7, 1.0 Hz, I H), 3.50 (s, 3H), 3.32 (s, 3H); ?9F NMR (282 MHz, DMSO-d6)6-123.00 (t,J= 6.6 Hz); MS (ES+) 251.1 (M+Na). |
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With thionyl chloride; for 5h;Reflux; |
A solution of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> (0.5 g, 2.7 mmol) in 1.6 mL of thionylchloride isheated under reflux for 5 h. The resulting solution is concentrated under reduced pressureThe residue is dissolved in 5 mL toluene and concentrated again under reduced pressure.The crude 2-fluoro-3-nitro-benzoyl chloride is dissolved in 25 mL DCM, the resulting solutionis cooled to 0C and treated with 0.7 mL DIPEA under argon. A solution of cyclopropylmethyl-[2-(4-methoxy-benzyloxy)-ethyl]-amine (636 mg, 2.7 mmol) in 10 mL DCM is added dropwise. The mixture is stirred at RT for 18 h. The reaction mixture is treated with 50 mL aq. sat. NaHCO3 solution. The organic phase is separated. The aqueous phase isextracted twice with 50 mL DCM. The combined organic phase is washed with 100 mL brine, dried over Mg504, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography over 80 g of silica gel with heptane I EtOAc (4:1 to 1:1 gradient) as eluent to yield N-cyclopropylmethyl-2-fluoro-N-[2-(4-methoxy-benzyloxy)-ethyl]- 3-nitro-benzamide as a yellowish oil. LC-A: tR = 0.92 mm; [M+H] = 403.15. |
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With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h; |
General procedure: 4-methyl-3-nitrobenzoic acid (2.7 g, 15 mM), oxalyl chloride (2.5 mL, 30 mM) and N, N-dimethylformamide (DMF, several drops) in dichloromethane (50 mL) were stirred at room temperature for 2 h. Then, the solvent and oxalyl chloride were evaporated under reduced pressure to get 4-methyl-3-nitrobenzoyl chloride. The benzoyl chloride (1 M solution in dichloromethane, 15 mL) in constant pressure funnel was added to a solution of 4-chloro-3-(trifluoromethyl) aniline (2.4 g, 12.5 mM) and triethylamine (5.2 mL, 37.5 mM) in dichloromethane (40 mL) successively, and the reaction mixture was stirred at room temperature for 5 h. Subsequently, the solvent and triethylamine were evaporated under reduced pressure to get nitroaniline. Then, reduction of the nitro group was carried out by using Fe/NH4Cl (50 mM/37.5 mM) in C2H5OH/H2O (75 mL/25 mL), heated to reflux for about 3 h. The reaction mixture was evaporated in vacuo, purified with silica gel column chromatography. Desired aniline (3 g, 72.6%) was afforded as a pale yellow solid. |
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With oxalyl dichloride; In 1,2-dichloro-ethane; N,N-dimethyl-formamide; at 50℃; |
To a suspension of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> (309 g, 1.67 mol) in dichloroethane (2090 ml) was added N,N-dimethylformamide (1.3 ml, 16.7 mmol) followed by slow addition of oxalyl chloride (150 ml, 1.69 mol) at ambient temperature. The reaction mixture was stirred and heated at 50 C. until a solution was formed. The reaction mixture was allowed to cool to ambient temperature and then added to a solution of 2-bromo-6-chloro-4-[1,1,1,2,3,3,3-heptafluoro-prop-2-yl]aniline (described in WO/10127926) (125 g, 334 mmol) in dichloroethane (477 ml) followed by addition of triethylamine (564 ml, 4.01 mol). The reaction mixture was stirred at reflux for 4 hours. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (500 ml). The layers were separated and the organic layer was washed with water (500 ml). The combined aqueous layers were extracted twice with dichloroethane (2*500 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The crude residue was dissolved in THF and a 1N solution of sodium hydroxide (2 eq) was added. The mixture was stirred at room temperature until the diacylated product disappeared. Then ethyl acetate (1 L) and saturated aqueous sodium hydrogen carbonate (1 L) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (4*250 ml). The organic layer was concentrated, filtered through silica gel, and concentrated again. The residue (181 g ) was used directly for the next step. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h; |
General procedure: Analogs 6a-o were synthesized as outlined in Scheme 1: Acid(1.2 eq) was dissolved in anhydrous DCM, oxalyl chloride (1.44eq) was added dropwise at 0C and then one drop DMF was added.The reaction mixture stirred at room temperature for 2 h. The excess oxalyl chloride was removed under reduced pressure, andthe residue dissolved in THF for next transformation.Intermediate 5 (1eq) and triethylamine (1.5 eq) were added sequent to a 25 ml three-neck-bottom flask under a nitrogen atmosphere. Acyl chloride in THF was added dropwise to flask at 0C.The reaction mixture was stirred at 0C. After pale yellow solid appeared, the mixture reacted at room temperature until TLC showed 5 disappeared. Ice water was added to reaction mixtureat 0C, and stirred for another 30 min until no insoluble solid generated.The solid was filtered to get crude product. The crude product further purified by medium pressure column chromatography(C18 padding, ACN: H2O (containing 0.05% TFA) =1:99-99:1) to getproduct as a solid. |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;Reflux; |
Example 12: N-r2-ethyl-4-(l,2,2,3,3,3-hexafluoro-l-trifluoromethylpropyl)-6-methyl- phenyl. -2-fluoro-3 -nitrobenzamidepyridine; To a suspension of <strong>[317-46-4]2-fluoro-3-nitrobenzoic acid</strong> (6.3 g, 34 mmol) in dichloromethane(20 ml) was added oxalyl chloride (4.3 ml) at ambient temperature, followed by Lambda/,Lambda/-dimethylformamide (0.2 ml). The reaction mixture was stirred for 1 hour at ambient temperature and then heated to reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated. The residue was suspended in tetrahydrofuran (50 ml). 2-Ethyl-4-(l,2,2,3,3,3-hexafluoro-l-trifluoromethylpropyl)-6-methylaniline(preparation as described in WO 08/074427) (10 g, 28.3 mmol) was dissolved in tetrahydrofuran (50 ml) and pyridine (6.8 ml, 84.9 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours, then at reflux for 3 hours. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (100 ml) and the mixture extracted twice with ethyl acetate (2x 200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4:1 to 0:1) to give N-[2-ethyl-4-(l,2,2,3,3,3-hexafluoro-l- trifluoromethylpropyl)-6-methylphenyl]-2-fluoro-3-nitrobenzamide (6.32 g, 43% yield).1H NMR (CDCl3, 400 MHz): 8.34 (m, IH), 8.22 (m, IH), 8.02 (bs, IH), 7.45 (t, IH), 7.48 (s, 2H), 2.70 (q, 2H), 1.22 (t, 3H). |
1529 g |
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 75 - 80℃; for 3.91h;Large scale; |
A 10L, four-necked, round-bottomed flask equipped with an internal thermometer, a mechanical stirrer, a dropping funnel, and a reflux condenser was charged with 2-fluoro-3- nitrobenzoic acid (1269 g, 6.86 mol), N,N-dimethylformamide (20.5 g) and toluene (4450 g). The suspension mixture was heated to 75 C, and thionylchloride (1227 g, 10.31 mol) was added dropwisely at 80 C over 1 hr 55 min. The reaction mixture was stirred at 80 C for 2hr. After completion of the reaction, the solution was concentrated under reduced pressure at 40 C. 2-fluoro-3-nitrobenzoyl chloride was obtained as yellow oil (1529 g), and was used for the next step without further purification |
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With thionyl chloride; In dichloromethane; at 60℃; for 12h; |
To a solution of <strong>[317-46-4]2-fluoro-3-nitro-benzoic acid</strong> (10 g, 54 mmol, 1 eq) in (3032) dichloromethane (100 mL) was added thionyl chloride (14 g, 118.85 mmol, 8.6 mL, 2.2 eq) and N,N-dimethylformamide (1 mL). The mixture was stirred at 60 C for 12h. The mixture was concentrated.2-fluoro-3-nitro-benzoyl chloride (11 g, crude) was obtained as a yellow oil. To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (11.7 g, 59.44 mmol, 1.1 eq) in dichloromethane (100 mL) was added Aluminium trichloride (46.1 g, 345.85 mmol, 6.4 eq). Then a solution of 2- fluoro-3-nitro-benzoyl chloride (11 g, 54.04 mmol, 1 eq) in dichloromethane (50 mL) was added into the mixture. The mixture was stirred at 60 C for 12 h. The mixture was added to water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was added ethyl acetate (30 mL) and filtered to give desired product. (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-nitro-phenyl) methanone (12 g, 32.96 mmol, 60% yield) was obtained as a yellow solid. LC/MS (ESI) m/z: 363.8 [M+1] +. |