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Structure of 99368-67-9 * Storage: {[proInfo.prStorage]}
* 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.
With thionyl chloride In N,N-dimethyl-formamide at 100℃; for 10 h;
SOCl2 (18.45 mL, 253 mmol) was added to a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol). DMF (1.957 mL, 25.3 mmol) was added and the mixture was at 100° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86percent yield) was used in the next step without further purification. TLC (PE/EA=5:1, Rf=0.6): 1H NMR (400 MHz, CDCl3) δ: 9.23-9.59 (m, 1H), 8.79 (d, J=2.4 Hz, 1H).
86%
at 100℃; for 10 h;
SOCl2 (18.45 mL, 253 mmol) was added to a solution of 5 -nitro-3 -(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol). DMF (1.957 mL, 25.3 mmol) was added and the mixture was at 100 °C for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCC>3 solution. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated. The resulting 2-chloro-5 -nitro-3 -(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86percent yield) was used in the next step without further purification. TLC (PE/EA = 5: 1, Rf = 0.6): 'HNMR (400 MHz, CDCI3) δ: 9.23-9.59 (m, 1H), 8.79 (d, J = 2.4 Hz, 1H).
77%
at 90℃; for 3 h;
Reference Example 118 2-chloro-5-nitro-3-(trifluoromethyl)pyridine; A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.65 g), phosphorus pentachloride (3.17 g) and phosphorus oxychloride (1.5 mL) was stirred at 90° C. for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-->3:1) to give the title compound as a yellow oil (yield 2.21 g, 77percent). 1H-NMR (CDCl3) δ: 8.79-8.81 (1H, m), 9.40-9.41 (1H, m).
55.1%
at 80℃; for 16 h;
To a mixture of 5-nitro-3- (trifluoromethyl) pyridin-2-ol (2 g 9.61 mmol) was added SOCl2(21.04 mL 288 mmol) and DMF (0.074 mL 0.961 mmol) . Then the mixture was stirred at 80 for 16 h. The mixture was concentrated and extracted with EA (2 x 100 mL) and washed with H2O (100 mL) to give the organic layer. The combined organic extract was washed with brine dried over Na2SO4 concentrated to yield a brown solid of 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (2 g 5.30 mmol 55.1yield) 1HNMR(400 MHz CD3OD) δ 8.91 (d J 2.43 Hz 1H) 9.42 (d J 2.43 Hz 1H)
With copper(l) iodide In N,N-dimethyl-formamide at 70℃; for 19 h;
B. 2-Chloro-5-nitro-3-(trifluoromethyl)pyridineIn a schlenck tube, a mixture of 2-chloro-3-iodo-5-nitropyridine (17.58 mmol, 5.00 g), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (8.79 mmol, 1.12 ml) and CuI (2.64 mmol, 0.5 g) in DMF (30 ml) was heated at 7O0C for 3 hours under argon atmosphere. Methyl 2,2- difluoro-2-(fluorosulfonyl)acetate (4.40 mmol, 0.6 ml) was added and the mixture was heated at 7O0C for 16 hours. The solvent was evaporated and the crude mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting with hexane/DCM mixtures affording 1.19 g (yield 30percent) of the expected product.1H NMR (300 MHz, CDCI3) δ ppm: 8.82 (s, 1 H), 9.41 (s, 1 H). B. 2-ChIoro-5-nitro-3-(trifluoromethyl)pyridineIn a schlenk tube, a mixture of 2-chloro-3-iodo-5-nitropyridine (17.58 mmol, 5.00 g), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (8.79 mmol, 1.12 ml) and CuI (2.64 mmol, 0.5 g) in DMF (30 ml) was heated at 7O0C for 3 hours under argon atmosphere. Methyl 2,2- difluoro-2-(fluorosulfonyl)acetate (4.40 mmol, 0.6 ml) was added and the mixture was heated at 7O0C for 16 hours. The solvent was evaporated and the crude mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting with hexane/DCM mixtures affording 1.19 g (yield 30percent) of the expected product. δ 1H NMR (300 MHz, CDCI3): 8.82 (s, 1H), 9.41 (s, 1 H).
21%
With copper(l) iodide; hydrogen In N,N-dimethyl-formamide at 70℃; for 19 h;
In a 100 mL round bottom flask, a mixture of 2-chloro-3-iodo-5-nitropyridine (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(l) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70 °C for 3h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21 percent).
21%
With copper(l) iodide; hydrogen In N,N-dimethyl-formamide at 70℃; for 19 h;
In a 100 mL round bottom flask, a mixture of 2-chloro-3-iodo-5-nitropyridine (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(l) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70 °C for 3 h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21 percent).
21%
With copper(l) iodide; hydrogen In N,N-dimethyl-formamide at 70℃; for 18 h;
Step 1: In a 100 mL round bottom flask, a mixture of 2-chloro-3-iodo-5-nitropyridine (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(I) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70° C. for 3 h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21percent).
21%
With copper(l) iodide In N,N-dimethyl-formamide at 70℃; for 19 h;
Step 1 In a 100 mL round bottom flask, a mixture of 2-chloro-3-iodo-5-nitropyridine (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(I) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70° C. for 3 h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21percent).
a mixture of 5-nitro-3- (trifluoromethyl) pyridine -2 (1H) -One, 3 (1.50g, 7.21mmol), POCl3 (2.76g, 18.02mmol) and PCl5(1.4g, 10. 09mmol) was heated 8 hours to about 110 ~ 120 and poured into ice water. Themixture was neutralized with solid NaHCO3, and extracted with ethylacetate (3 × 40ml). The organic phases were combined, dried over Na2SO4,all solvents were evaporated under reduced pressure to give 2-chloro-5-nitro-3-(trifluoromethyl) pyridine 4.
96%
at 110 - 120℃; for 8 h;
Synthesis of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine, 4 (0076) (0077) A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3 (1.50 g, 7.21 mmol), POCl3 (2.76 g, 18.02 mmol) and PCl5 (1.4 g, 10.09 mmol) is heated to about 110-120° C. for 8 hours and then poured into ice water. The mixture is neutralized with solid NaHCO3 and extracted with ethyl acetate (3×40 ml). The combined organic phases is dried over Na2SO4 and all solvents removed under reduced pressure to obtain 2-chloro-5-nitro-3-(trifluoromethyl)pyridine 4.
Reference：
[1] Patent: JP2016/11315, 2016, A, . Location in patent: Paragraph 0059-0060
[2] Patent: US9388159, 2016, B2, . Location in patent: Page/Page column 15
[3] Patent: EP1632477, 2006, A1, . Location in patent: Page/Page column 21
With iron; ammonium chloride In ethanol; water at 80℃; for 4 h;
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (10.0 g, 44.1 mmol) in ethanol:water:TH F tin (2:2:1, 150 mL) were added, NH4CI (16.53 g, 309 mmol) and iron powder (17.26 g, 309 mmol). The resulting reaction mixture was stirred at 80eC for 4 h. After completion of the reaction, the reaction mixture was cooled to room temprature, filtered over celite bed and filtrate bed was washed with ethyl acteate (200 mL). Combined filtrate was concentrated to afford 8.0 g (92percent) of the titled product as a brown solid. 1HNMR (400 MHz, DMSO-d6) U7.93 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 6.02 (s, 2H); ESI-MS (m/z) 197.26 (MH)+.
92%
With hydrogen In ethyl acetate for 20 h;
C. 6-Chloro-5-(trifluoromethyl)pyridin-3-amine A mixture of 2-chloro-5-nitro-3-(trifiuoromethyi)pyridine (5.25 rnrnoi, 1.1S g), ZnBr2 (1.05 mmol, 0.200 g) and 5percent Pt (C) (1.58 mmol, 0.31 g) in ethyl acetate (50 ml) was stirred for 20 hours under hydrogen atmosphere. The catalyst was filtered off and the solid was washed with warmed ethanol. The solvent was evaporated affording the expected product (0.95 g, yield 92percent). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.59 (bs, 1 H), 7.37 (s, 1 H), 7.92 (s, 1 H). C. 6-Chloro-5-(trifluoromethyl)pyridin-3-amine <n="71"/>A mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (5.25 mmol, 1.19 g), ZnBr2 (1.05 mmol, 0.200 g) and 5percent Pt .(C). (1.58 mmol, 0.31 g) in ethyl acetate (50 ml) was stirred for 20 hours under hydrogen atmosphere. The catalyst was filtered off and the solid was washed with warmed ethanol. The solvent was evaporated affording the expected product (0.95 g, yield 92percent). δ 1H NMR (300 MHz1 DMSO-d6): 5.59 (bs, 1 H)1 7.37 (s, 1 H), 7.92 (s, 1H).
65%
With water; iron; ammonium chloride In methanol at 20℃; for 4.08333 h;
Reference Example 119 6-chloro-5-(trifluoromethyl)pyridine-3-amine; Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water (40 mL), and the mixture was stirred at room temperature for 5 min. A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.8 g) in methanol (40 mL) was added, and the mixture was stirred at room temperature for 1 hr. Reduced iron (2.3 g) was added, and the mixture was further stirred at the same temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-->1:1) to give the title compound as a solid (yield 1.0 g, 65percent). 1H-NMR (CDCl3) δ: 7.29 (1H, m), 7.99 (1H, m), 2H not detected.
51.9%
at 80℃; for 0.25 h;
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) in acetic acid (10 mL) was added iron (2.465 g, 44.1 mmol) in one portion. The mixture was stirred at 80° C. for 15 min. The mixture was filtered and concentrated and then washed with aq. NaOH and extracted with EA. he crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=8:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (1 g, 4.58 mmol, 51.9percent yield): 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.86 (d, J=8.60 Hz, 1H), 7.53 (d, J=8.60 Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J=6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+H).
51.9%
at 80℃; for 0.25 h;
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) in acetic acid (10 inL) was added iron (2.465 g, 44.1 mmol) in one portion. The mixture was stirred at 80 °C for 15 min. The mixture was filtered and concentrated and then washed with aqueous NaOH and extracted with EA. The crude material was purified by silica column chromatography (PE/EA = 5: 1). All fractions found to contain product by TLC (PE/EA = 8: 1, Rf = 0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5-(trifluoromethyl)pyridin-3 -amine (1 g, 4.58 mmol, 51.9percent yield): lH NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.86 (d, J = 8.60 Hz, 1H), 7.53 (d, J = 8.60 Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J = 6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+H).
51.9%
at 80℃; for 0.25 h;
To a mixture of 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (2 g 8.83 mmol) in AcOH (10 mL) was added iron (2.465 g 44.1 mmol) in one portion. The mixture was stirred at 80 for 15 min. The mixture was filtered and concentrated and then washed with aq. NaOH and extracted with EA. The residue was purified by silica column chromatography (PE/EA 51) . All fractions found to contain product by TLC (PE/EA 81 Rf 0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5- (trifluoromethyl) pyridin-3-amine (1 g 4.58 mmol 51.9yield) 1HNMR(400 MHz CD3OD) δ 8.06 (s 1H) 7.86 (d J 8.60 Hz 1H) 7.53 (d J 8.60 Hz 1H) 7.46-7.26 (m 5H) 4.16-4.11 (m 2H) 3.81 (s 2H) 1.47 (t J 6.62 Hz 3H) ES-LCMS m/z 197.0 (M+H)
A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (15 g, 66.2 mmol) and ammonia solution in MeOH (7 N, 150 mL, 1.05 mol) was stirred at room temperature for 14 h. After completion of the reaction, reaction mixture was concentrated under vacuum and residue was diluted with water (100 mL) and aqueous phase was extracted with ethyl acetate (100 mL x 3), combined organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was rotary evaporated to afford 11 g (80percent) of the titled product as yellow solid.1HNMR (400 MHz, DMSO- d6) U9.06 (d, J = 2.7 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 8.04 (s, 2H); ESI-MS (m/z) 208.33 (MH)+.
5-Nitro-3-(trifluoromethyl)pyridin-2(1H)-one was treated with thionyl chloride and then the resulting <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> was treated with dimethylamine to obtain N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine.
With phosphorus pentachloride; trichlorophosphate; at 110 - 120℃; for 8.0h;
a mixture of 5-nitro-3- (trifluoromethyl) pyridine -2 (1H) -One, 3 (1.50g, 7.21mmol), POCl3 (2.76g, 18.02mmol) and PCl5(1.4g, 10. 09mmol) was heated 8 hours to about 110 ~ 120 and poured into ice water. Themixture was neutralized with solid NaHCO3, and extracted with ethylacetate (3 × 40ml). The organic phases were combined, dried over Na2SO4,all solvents were evaporated under reduced pressure to give 2-chloro-5-nitro-3-(trifluoromethyl) pyridine 4.
96%
With phosphorus pentachloride; trichlorophosphate; at 110 - 120℃; for 8.0h;
Synthesis of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine, 4 (0076) (0077) A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3 (1.50 g, 7.21 mmol), POCl3 (2.76 g, 18.02 mmol) and PCl5 (1.4 g, 10.09 mmol) is heated to about 110-120° C. for 8 hours and then poured into ice water. The mixture is neutralized with solid NaHCO3 and extracted with ethyl acetate (3×40 ml). The combined organic phases is dried over Na2SO4 and all solvents removed under reduced pressure to obtain 2-chloro-5-nitro-3-(trifluoromethyl)pyridine 4.
With thionyl chloride;
5-Nitro-3-(trifluoromethyl)pyridin-2(1H)-one was treated with thionyl chloride and then the resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine was treated with dimethylamine to obtain N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 1.0h;Heating / reflux;
C. To a solution of compound 26c (1.136 g, 5.01 mmol) in 50 mL CH3CN was added imidazole (0.514 g, 7.55 mmol) and iPr2NEt (1.75 mL, 10.0 mmol). The reaction was heated at reflux for 1 hour then concentrated in vacuo to a residue. The residue was purified via silica gel chromatography (40-80percent EtOAc/heptane) to give compound 26d as a waxy yellow solid. MS: M+H+=258, 1H NMR (d6-DMSO): delta 9.66 (s, 1H), 9.13 (s, 1H), 8.13 (s, 1H), 7.65 (s, 1H), 7.21 (s, 1H).
With iron; ammonium chloride; In ethanol; water; at 80℃; for 4.0h;
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (10.0 g, 44.1 mmol) in ethanol:water:TH F tin (2:2:1, 150 mL) were added, NH4CI (16.53 g, 309 mmol) and iron powder (17.26 g, 309 mmol). The resulting reaction mixture was stirred at 80eC for 4 h. After completion of the reaction, the reaction mixture was cooled to room temprature, filtered over celite bed and filtrate bed was washed with ethyl acteate (200 mL). Combined filtrate was concentrated to afford 8.0 g (92%) of the titled product as a brown solid. 1HNMR (400 MHz, DMSO-d6) U7.93 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 6.02 (s, 2H); ESI-MS (m/z) 197.26 (MH)+.
92%
With hydrogen;5 % platinum on carbon; zinc dibromide; In ethyl acetate; for 20.0h;
C. 6-Chloro-5-(trifluoromethyl)pyridin-3-amine A mixture of 2-chloro-5-nitro-3-(trifiuoromethyi)pyridine (5.25 rnrnoi, 1.1S g), ZnBr2 (1.05 mmol, 0.200 g) and 5% Pt (C) (1.58 mmol, 0.31 g) in ethyl acetate (50 ml) was stirred for 20 hours under hydrogen atmosphere. The catalyst was filtered off and the solid was washed with warmed ethanol. The solvent was evaporated affording the expected product (0.95 g, yield 92%). 1H NMR (300 MHz, DMSO-d6) delta ppm: 5.59 (bs, 1 H), 7.37 (s, 1 H), 7.92 (s, 1 H). C. 6-Chloro-5-(trifluoromethyl)pyridin-3-amine <n="71"/>A mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (5.25 mmol, 1.19 g), ZnBr2 (1.05 mmol, 0.200 g) and 5% Pt (1.58 mmol, 0.31 g) in ethyl acetate (50 ml) was stirred for 20 hours under hydrogen atmosphere. The catalyst was filtered off and the solid was washed with warmed ethanol. The solvent was evaporated affording the expected product (0.95 g, yield 92%). delta 1H NMR (300 MHz1 DMSO-d6): 5.59 (bs, 1 H)1 7.37 (s, 1 H), 7.92 (s, 1H).
65%
With water; iron; ammonium chloride; In methanol; at 20℃; for 4.08333h;
Reference Example 119 6-chloro-5-(trifluoromethyl)pyridine-3-amine; Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water (40 mL), and the mixture was stirred at room temperature for 5 min. A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.8 g) in methanol (40 mL) was added, and the mixture was stirred at room temperature for 1 hr. Reduced iron (2.3 g) was added, and the mixture was further stirred at the same temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1?1:1) to give the title compound as a solid (yield 1.0 g, 65%). 1H-NMR (CDCl3) delta: 7.29 (1H, m), 7.99 (1H, m), 2H not detected.
51.9%
With iron; acetic acid; at 80℃; for 0.25h;
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) in acetic acid (10 mL) was added iron (2.465 g, 44.1 mmol) in one portion. The mixture was stirred at 80 C. for 15 min. The mixture was filtered and concentrated and then washed with aq. NaOH and extracted with EA. he crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=8:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (1 g, 4.58 mmol, 51.9% yield): 1H NMR (400 MHz, CD3OD) delta 8.06 (s, 1H), 7.86 (d, J=8.60 Hz, 1H), 7.53 (d, J=8.60 Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J=6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+H).
51.9%
With iron; acetic acid; at 80℃; for 0.25h;
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) in acetic acid (10 inL) was added iron (2.465 g, 44.1 mmol) in one portion. The mixture was stirred at 80 C for 15 min. The mixture was filtered and concentrated and then washed with aqueous NaOH and extracted with EA. The crude material was purified by silica column chromatography (PE/EA = 5: 1). All fractions found to contain product by TLC (PE/EA = 8: 1, Rf = 0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5-(trifluoromethyl)pyridin-3 -amine (1 g, 4.58 mmol, 51.9% yield): lH NMR (400 MHz, CD3OD) delta 8.06 (s, 1H), 7.86 (d, J = 8.60 Hz, 1H), 7.53 (d, J = 8.60 Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J = 6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+H).
51.9%
With iron; acetic acid; at 80℃; for 0.25h;
To a mixture of 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (2 g 8.83 mmol) in AcOH (10 mL) was added iron (2.465 g 44.1 mmol) in one portion. The mixture was stirred at 80 for 15 min. The mixture was filtered and concentrated and then washed with aq. NaOH and extracted with EA. The residue was purified by silica column chromatography (PE/EA 51) . All fractions found to contain product by TLC (PE/EA 81 Rf 0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5- (trifluoromethyl) pyridin-3-amine (1 g 4.58 mmol 51.9yield) 1HNMR(400 MHz CD3OD) delta 8.06 (s 1H) 7.86 (d J 8.60 Hz 1H) 7.53 (d J 8.60 Hz 1H) 7.46-7.26 (m 5H) 4.16-4.11 (m 2H) 3.81 (s 2H) 1.47 (t J 6.62 Hz 3H) ES-LCMS m/z 197.0 (M+H)
With ethanol; water; iron; calcium chloride; for 1.0h;Heating / reflux;
5. 6-Chloro-5-trifluorom.eihyl-pyridin-3-ylam.ine Heat a mixture of 2-chloro-5-nitro-3-trifluoromethyl-pyridine (2.27 g, 10 mmol), calcium chloride (1.1 g, 10 mmol) and iron powder (4.5 g) in ethanol (30 mL) and water (5 mL) at reflux for 1 hour. Cool the mixture and filter through Celite. Evaporate the filtrate, dissolve the residue in EtOAc (200 mL) and wash with saturated NaHCO3(aq) (100 mL) and brine (100 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
With ammonium chloride; zinc; In ethanol; water; for 18.0h;
EXAMPLE 27; N-[6-(3-Hydroxy-phenyl)-5-trifluoromethyl-pyridin-3-yl]-3-(4-trifluoromethyl-phenyl)-propionamide (Cpd 210) A. To a solution of compound 26c (1.478 g, 6.52 mmol) in 20 mL 4:1 EtOH/H2O was added NH4Cl (0.524 g, 9.80 mmol) and Zn powder (3.44 g, 52.6 mmol, <10 micron). The reaction was stirred under a nitrogen atmosphere for 18 hours then partitioned between 75 mL EtOAc and 75 mL H2O. This solvent mixture was filtered over a pad of Celite, 50 mL brine was added to help with the emulsion. The mixture was filtered again over Celite. The organic phase was isolated and dried over Na2SO4, filtered, and evaporated in vacuo to a residue. The residue was purified via silica gel chromatography (30-60% EtOAc/heptane) to give compound 27a as a yellow-orange powder. MS: M+H+=197.0, 1H NMR (d6-DMSO): delta 7.93 (d, 1H), 7.39 (d, 1H), 6.02 (s, 2H).
With Raney-Ni; In tetrahydrofuran; for 24.0h;
2-chloro-5-nitro-3-(trifluoromethyl) pyridine 4 (1.57g, 6.93mmol) was dissolved in tetrahydrofuran(THF) (10 ml), then was added to THF (20 ml) suspension of Raney -Ni (200 mg).Hydrogen gas was gentle foaming passing through a 24 hour stirring solutionusing a balloon. The mixture was filtered throughCelite (registered trademark) (World Minerals Inc., Lompoc, CA) and the solventwas evaporated under reduced pressure to obtain 6-chloro-5- (trifluoromethyl)pyridin-3-amine 5.
With hydrogen; In tetrahydrofuran; at 22℃; for 24.0h;
Synthesis of 6-chloro-5-(trifluoromethyl)pyridin-3-amine, 5 (0078) (0079) 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine 4 (1.57 g, 6.93 mmol) is dissolved in tetrahydrofuran (THF) (10 ml) and added to a suspension of Raney-Ni (200 mg) in THF (20 ml). Hydrogen gas is slowly bubbled through the stirred solution for 24 hours using a balloon. The mixture is filtered through Celite (available from World Minerals, Inc., Lompoc, Calif.) and the solvent is removed under reduced pressure to obtain 6-chloro-5-(trifluoromethyl)pyridin-3-amine 5.
With iron; ammonium chloride; In methanol; water; at 20℃; for 4.0h;
(0875) A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in water (40 ml) was stirred at room temperature for 5 minutes. To this suspension was added Compound 288B in methanol (40 ml). The reaction mixture was stirred at room temperature for 1 hour. More iron (1.8 g) was added to the reaction mixture, and it was stirred for another 3 hours. The solid from the reaction mixture was filtered off, and the filtrate was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 20percent ethyl acetate in hexanes to provide the title compound.
With thionyl chloride; In N,N-dimethyl-formamide; at 100℃; for 10.0h;
SOCl2 (18.45 mL, 253 mmol) was added to a solution of <strong>[99368-66-8]5-nitro-3-(trifluoromethyl)pyridin-2-ol</strong> (2.63 g, 12.64 mmol). DMF (1.957 mL, 25.3 mmol) was added and the mixture was at 100 C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86% yield) was used in the next step without further purification. TLC (PE/EA=5:1, Rf=0.6): 1H NMR (400 MHz, CDCl3) delta: 9.23-9.59 (m, 1H), 8.79 (d, J=2.4 Hz, 1H).
86%
With thionyl chloride; N,N-dimethyl-formamide; at 100℃; for 10.0h;
SOCl2 (18.45 mL, 253 mmol) was added to a solution of 5 -nitro-3 -(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol). DMF (1.957 mL, 25.3 mmol) was added and the mixture was at 100 C for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCC>3 solution. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated. The resulting 2-chloro-5 -nitro-3 -(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86% yield) was used in the next step without further purification. TLC (PE/EA = 5: 1, Rf = 0.6): 'HNMR (400 MHz, CDCI3) delta: 9.23-9.59 (m, 1H), 8.79 (d, J = 2.4 Hz, 1H).
77%
With phosphorus pentachloride; trichlorophosphate; at 90℃; for 3.0h;
Reference Example 118 2-chloro-5-nitro-3-(trifluoromethyl)pyridine; A mixture of <strong>[99368-66-8]5-nitro-3-(trifluoromethyl)pyridin-2-ol</strong> (2.65 g), phosphorus pentachloride (3.17 g) and phosphorus oxychloride (1.5 mL) was stirred at 90 C. for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1?3:1) to give the title compound as a yellow oil (yield 2.21 g, 77%). 1H-NMR (CDCl3) delta: 8.79-8.81 (1H, m), 9.40-9.41 (1H, m).
55.1%
With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 16.0h;
To a mixture of 5-nitro-3- (trifluoromethyl) pyridin-2-ol (2 g 9.61 mmol) was added SOCl2(21.04 mL 288 mmol) and DMF (0.074 mL 0.961 mmol) . Then the mixture was stirred at 80 for 16 h. The mixture was concentrated and extracted with EA (2 x 100 mL) and washed with H2O (100 mL) to give the organic layer. The combined organic extract was washed with brine dried over Na2SO4 concentrated to yield a brown solid of 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (2 g 5.30 mmol 55.1yield) 1HNMR(400 MHz CD3OD) delta 8.91 (d J 2.43 Hz 1H) 9.42 (d J 2.43 Hz 1H)
With trichlorophosphate; at 85℃; for 18.0h;
4. 2-ChlotauO-5-nitro-3-trifluoromethyl-pyridine Heat a mixture of <strong>[99368-66-8]5-nitro-3-trifluoromethyl-pyridin-2-ol</strong> (416 mg, 2.0 mmol) and phosphorus oxychloride (1 mL) at 85C for 18 hours. Cool the mixture and remove the volatiles by rotary evaporation. Dissolve the residue in EtOAc (15 mL) and wash with water (10 mL), saturatedNaHCO3(aq) (10 mL) and brine (10 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
With thionyl chloride; In N,N-dimethyl-formamide; for 4.0h;Heating / reflux;
B. To a mixture of compound 26b (3.84 g, 18.5 mmol) in 20 mL SOCl2 was added 0.5 mL DMF. The mixture was heated to reflux for 4 hours then concentrated in vacuo. The residue was dissolved in benzene and concentrated again in vacuo. This residue was taken up in 50 mL EtOAc and washed with 50 mL saturated NaHCO3, and 50 mL brine, then dried over Na2SO4, and filtered and concentrated in vacuo. The resulting residue was chromatographed over silica gel (0-10% EtOAc/heptane) to give compound 26c as a pale yellow oil. 1H NMR (d6-DMSO): delta 9.52 (s, 1H), 8.92 (s, 1H).
With phosphorus pentachloride; trichlorophosphate; at 90℃; for 3.0h;
(0874) A mixture of Compound 288A (1.69 g), phosphorus pentachloride (2.03 g), and phosphoryl trichloride (0.97 ml) was heated at 90° C. for 3 hours. After cooling, the reaction mixture was poured into ice, and extracted with ethyl acetate three times. The extract was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 10percent ethyl acetate in hexanes to provide the title compound.
5-nitro-N-(pyridin-2-ylmethyl)-3-(trifluoromethyl)-2-pyridinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Preparation 146 A mixture of <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (226mg) and 2-pyridylmethanamine (0.2ml) in tetrahydrofuran (2.0ml) was stirred for 18 hours. The mixture was poured into water and stirred for 1 hour. The precipitated solid was collected by filtration, washed with water, and dried to give 5-nitro-N-(2-pyridylmethyl)-3-(trifluoromethyl)-2-pyridinamine (277mg).
A. 2-Chloro-5-nitro-3-trifluoromethylpyridine (766A) 2-Chloro-3-iodo-5-nitropyridine (1.0 g, 3.5 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.35 g, 1.82 mmol), and copper iodide (0.083 g, 0.44 mmol) were reacted in DMF (10 mL) according to the method described in example 763D. The crude product was purified by silica gel chomatography using 30percent CH2Cl2/hexane as the eluent to give compound 766A (0.278 g, 35percent) as a colorless oil. The product was characterized by 1H NMR and 19F NMR.
8
[ 99368-67-9 ]
[ 7439-89-6 ]
[ 99368-68-0 ]
Yield
Reaction Conditions
Operation in experiment
B. 5-Amino-2-chloro-3-trifluoromethylpyridine (766B) 2-Chloro-5-nitro-3-trifluoromethylpyridine (0.16 g, 0.68 mmol) and iron powder (0.2 g, 3.42 mmol, 325 Mesh) were reacted as described in example 762D. Purification of the crude product by Prep-TLC using 10percent ether/CH2Cl2 as eluent gave compound 766B (0.098 g, 73percent) as a yellow solid. HPLC: 89percent at 2.52 min(YMC S5 ODS column) eluding with 10-90percent aqueous methanol containing 0.2percent phosphoric acid over a 4 min gradient monitoring at 220 nm. MS(ES): m/z 197.01 [M+H]+.
1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 130℃; for 0.333333h;Microwave irradiation;
l-cyano-S-nitro-S-trifluoromethylpyridine muwave 130 0C, 20 min[0066] Zinc cyanide (25 mg, 0.216 mmol, 1.2 eq) is added to the chloride (43 mg,0.180 mmol) solubilized in DMF (1 ml). The solution is degassed for 10 minutes. Then the ligand dppf (20 mg, 0.036 mmol, 0.2 eq) is added. The solution is degassed again for 5 min. The catalyst Pd2(dba)3 (25 mg, 0.027 mmol, 0.15 eq) is added, the solution is degassed for 5 more minutes. The reaction mixture is then heated at 130 0C for 20 min in a microwave. After filtration, the solvent is evaporated and the crude residue is purified by flash chromatography on silica gel (hexane /EtOAc) to afford 16 mg (40percent) of the desired product. [0067] 1H NMR (400 MHz, CDCl3) delta 8.60 (d, J= 2.5, IH); 9.08 (d, J= 2.5, IH),
With copper(l) iodide; In N,N-dimethyl-formamide; at 70℃; for 19.0h;
B. 2-Chloro-5-nitro-3-(trifluoromethyl)pyridineIn a schlenck tube, a mixture of <strong>[25391-60-0]2-chloro-3-iodo-5-nitropyridine</strong> (17.58 mmol, 5.00 g), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (8.79 mmol, 1.12 ml) and CuI (2.64 mmol, 0.5 g) in DMF (30 ml) was heated at 7O0C for 3 hours under argon atmosphere. Methyl 2,2- difluoro-2-(fluorosulfonyl)acetate (4.40 mmol, 0.6 ml) was added and the mixture was heated at 7O0C for 16 hours. The solvent was evaporated and the crude mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting with hexane/DCM mixtures affording 1.19 g (yield 30percent) of the expected product.1H NMR (300 MHz, CDCI3) delta ppm: 8.82 (s, 1 H), 9.41 (s, 1 H). B. 2-ChIoro-5-nitro-3-(trifluoromethyl)pyridineIn a schlenk tube, a mixture of <strong>[25391-60-0]2-chloro-3-iodo-5-nitropyridine</strong> (17.58 mmol, 5.00 g), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (8.79 mmol, 1.12 ml) and CuI (2.64 mmol, 0.5 g) in DMF (30 ml) was heated at 7O0C for 3 hours under argon atmosphere. Methyl 2,2- difluoro-2-(fluorosulfonyl)acetate (4.40 mmol, 0.6 ml) was added and the mixture was heated at 7O0C for 16 hours. The solvent was evaporated and the crude mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting with hexane/DCM mixtures affording 1.19 g (yield 30percent) of the expected product. delta 1H NMR (300 MHz, CDCI3): 8.82 (s, 1H), 9.41 (s, 1 H).
21%
With copper(l) iodide; hydrogen; In N,N-dimethyl-formamide; at 70℃; for 19.0h;
In a 100 mL round bottom flask, a mixture of <strong>[25391-60-0]2-chloro-3-iodo-5-nitropyridine</strong> (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(l) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70 °C for 3h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21 percent).
21%
With copper(l) iodide; hydrogen; In N,N-dimethyl-formamide; at 70℃; for 19.0h;
In a 100 mL round bottom flask, a mixture of <strong>[25391-60-0]2-chloro-3-iodo-5-nitropyridine</strong> (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(l) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70 °C for 3 h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21 percent).
21%
With copper(l) iodide; hydrogen; In N,N-dimethyl-formamide; at 70℃; for 18.0h;
Step 1: In a 100 mL round bottom flask, a mixture of <strong>[25391-60-0]2-chloro-3-iodo-5-nitropyridine</strong> (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(I) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70° C. for 3 h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21percent).
21%
With copper(l) iodide; In N,N-dimethyl-formamide; at 70℃; for 19.0h;
Step 1 In a 100 mL round bottom flask, a mixture of <strong>[25391-60-0]2-chloro-3-iodo-5-nitropyridine</strong> (250 mg, 0.88 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.44 mmol) and Copper(I) iodide (25 mg, 0.13 mmol) in dimethylformamide was heated at 70° C. for 3 h under hydrogen atmosphere. Another 0.03 mL methyl 2,2-difluoro-2-(fluorosulfonyl)acetate was added and the mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (41 mg, 21percent).
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 3.0h;
Example 10: 5-Trifluoromethyl-pyridin-3-ylamine.; A mixture of 2-chloro-5-nitro-3-trifluoromethyl-pyridine (30 mg, 0.13 mmol), 10percent Pd/C (3 mg, 10percent w/w), and MeOH (5 mL) is stirred under 1 arm of hydrogen for 3 h. The mixture is then filtered over Celite.(R). and concentrated in vacuo to give the title compound as an oil. MS (ESI) m/z 162.9 (M+l).
With 18-crown-6 ether; potassium carbonate; In acetonitrile; for 12.0h;Reflux;
<strong>[99368-67-9]2-Chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (41 mg, 0.18 mmol), dimethylamine hydrochloride (18 mg, 0.22 mmol), potassium carbonate (88 mg, 0.63 mmol) and 1 ,4,7, 10,13, 16-hexaoxacyclooctadecane (10 mg) was dissolved in acetonitrile. The reaction mixture was refluxed for 12 h. The reaction mixture was cooled to room temperature and then was concentrated under reduced pressure. Then the mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give N,N-dimethyl-5-nitro-3- (trifluoromethyl)pyridin-2-amine (36 mg, 84 percent).
84%
With 18-crown-6 ether; potassium carbonate; In acetonitrile; for 12.0h;Reflux;
<strong>[99368-67-9]2-Chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (41 mg, 0.18 mmol), dimethylamine hydrochloride (18 mg, 0.22 mmol), potassium carbonate (88 mg, 0.63 mmol) and 1 ,4,7,10, 13, 16-hexaoxacyclooctadecane (10 mg) was dissolved in acetonitrile. The reaction mixture was refluxed for 12 h. The reaction mixture was cooled to room temperature and then was concentrated under reduced pressure. Then the mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give N,N-dimethyl-5-nitro-3- (trifluoromethyl)pyridin-2-amine (36 mg, 84 percent).
84%
With 18-crown-6 ether; potassium carbonate; In acetonitrile; for 12.0h;Reflux;
Step 2: <strong>[99368-67-9]2-Chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (41 mg, 0.18 mmol), dimethylamine hydrochloride (18 mg, 0.22 mmol), potassium carbonate (88 mg, 0.63 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (10 mg) was dissolved in acetonitrile. The reaction mixture was refluxed for 12 h. The reaction mixture was cooled to room temperature and then was concentrated under reduced pressure. Then the mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine (36 mg, 84percent).
84%
With 18-crown-6 ether; potassium carbonate; In acetonitrile; for 12.0h;Reflux;
Step 2 <strong>[99368-67-9]2-Chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (41 mg, 0.18 mmol), dimethylamine hydrochloride (18 mg, 0.22 mmol), potassium carbonate (88 mg, 0.63 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (10 mg) was dissolved in acetonitrile. The reaction mixture was refluxed for 12 h. The reaction mixture was cooled to room temperature and then was concentrated under reduced pressure. Then the mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine (36 mg, 84percent).
tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate; In tetrahydrofuran; at 50℃; for 10.0h;
To a solution of tert-butyl 2-cyanoacetate (523 mg, 3.71 mmol) in THF (15 mL) was added K2CO3 (854 mg, 6.18 mmol). Then <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (700 mg, 3.09 mmol) was added into the mixture and the mixture was at 50° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (DCM/MeOH=20:1, Rf=0.4) to yield a light yellow solid of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (1 g, 3.02 mmol, 98.0percent yield): 1H NMR (400 MHz, CD3OD) delta 8.99 (d, J=2.43 Hz, 1H), 8.36 (d, J=2.43 Hz, 1H), 3.35 (s, 1H), 1.49 (d, J=1.54 Hz, 9H); ES-LCMS m/z 276 (M-55).
98%
With potassium carbonate; In tetrahydrofuran; at 50℃; for 10.0h;
To a solution of tert-butyl 2-cyanoacetate (523 mg, 3.71 mmol) in THF (15 mL) was added K2CO3 (854 mg, 6.18 mmol). Then <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (700 mg, 3.09 mmol) was added into the mixture and the mixture was at 50 °C for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHC03 solution. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated. The crude material was purified by preparative TLC (DCM/MeOH = 20: 1, Rf = 0.4) to yield a light yellow solid of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (1 g, 3.02 mmol, 98.0percent yield): lH NMR (400 MHz, CD3OD) delta 8.99 (d, J = 2.43 Hz, 1H), 8.36 (d, J = 2.43 Hz, 1H), 3.35 (s, 1H), 1.49 (d, J = 1.54 Hz, 9H); ES-LCMS m/z 276 (M-55).
N,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 5.0h;
To a solution of <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (0.5, 2.207 mmol) and 2-(dimethylamino)ethanol (0.393 g, 4.41 mmol) in THF (10 mL) was added NaH (0.177 g, 4.41 mmol) at 0° C. The resulting mixture was stirred at rt. After 5 h, TLC analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (DCM/MeOH=20/1) to yield a white solid of N,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine (0.5 g, 1.717 mmol, 78.0percent yield): 1H NMR (400 MHz, CD3OD) delta 9.25 (d, J=2.4 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H), 4.73 (t, J=5.4 Hz, 2H), 2.88 (t, J=5.4 Hz, 2H), 2.37 (s, 6H); ES-LCMS m/z 280.0 (M+H).
78%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 5.0h;
To a solution of 2-chloro-5 -nitro-3 -(trifluoromethyl)pyridine (0.5 , 2.207 mmol) and 2- (dimethylamino)ethanol (0.393 g, 4.41 mmol) in THF (10 mL) was added NaH (0.177 g, 4.41 mmol) at 0 °C. The resulting mixture was stirred at rt. After 5 h, TLC analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H20 (20 mL) and brine (20 mL). The organic layer was dried over NaaSOzi, filtered and concentrated. The crude product was purified by silica column chromatography (DCM/ Me OH = 20/1) to yield a white solid of N,N-dimethyl-2-((5 -nitro-3 - (trifluoromethyl)pyridin-2-yl)oxy)ethanamine (0.5 g, 1.717 mmol, 78.0percent yield): NMR (400 MHz, CD3OD) delta 9.25 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 4.73 (t, J = 5.4 Hz, 2H), 2.88 (t, J= 5.4 Hz, 2H), 2.37 (s, 6H); ES-LCMS m/z 280.0 (M+H).
N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide dihydrochloride[ No CAS ]
2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.7%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 16.5h;
To a mixture of <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (500 mg, 2.207 mmol) in THF (10 mL) was added ethanol (0.155 mL, 2.65 mmol) and NaH (132 mg, 3.31 mmol). Then the mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred for 16 h. The mixture was added to H2O and extracted with EA (2*50 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4 and concentrated to yield a brown oil of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.457 mmol, 20.7percent yield): 1H NMR (400 MHz, CD3OD) delta 9.27 (d, J=2.5 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H), 4.67 (m, 2H), 1.47 (t, J=7.0 Hz, 3H).
20.7%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 16.5h;
To a mixture of <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (500 mg, 2.207 mmol) in THF (10 mL) was added EtOH (0.155 mL, 2.65 mmol) and NaH (132 mg, 3.31 mmol). Then the mixture was stirred at 0 °C for 30 min, then warmed to rt and stirred for 16 h. The mixture was added to H20 and extracted with EA (2 x 50 mL) to give the organic layer. The combined organic extract was washed with brine, dried over NaaSOzi, filtered, and concentrated to yield a brown oil of 2- ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.457 mmol, 20.7percent yield): lH NMR (400 MHz, CD3OD) delta 9.27 (d, J = 2.5 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 4.67 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H).
With sodium hydride; at 0 - 85℃; for 2.0h;
At 0°C, NaH (141 mg, 3.53 mmol, 2.0 equiv) is added to 2-chloro-5-nitro-3- (trifluoromethyl)pyridine (400 mg, 1.77 mmol, 1.0 equiv) in ethanol (6 mL, 0.3 M), the resulting mixture is stirred at 85°C for 2 h. The mixture is diluted with DCM and water. The aqueous phase is extracted with DCM. The combined organic phase is filtered through a phase separator and concentrated under vacuum to afford the desired compound
5-nitro-2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.6%
With potassium carbonate; In N,N-dimethyl acetamide; at 20℃; for 2.0h;
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.2 g, 6.84 mmol) and 2H-1,2,3-triazole (0.567 g, 8.20 mmol) in anhydrous DMA (5 mL) was added K2CO3 (1.89 g, 13.67 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered and washed with ethyl acetate (10 mL*3). The filtrate was concentrated to dryness to give a crude product.
With potassium carbonate; In tetrahydrofuran; at 20℃; for 1.0h;
To a so?ution of 2-choro-5-nitro-3-(trifluoromethy)pyridine (1 .0 g, 4.41 mmo) and K2CQ3 (1.22 g, 883 mmo) in THF (5 m) was added 2H-l ,2,3-triazoe (0.31 m, 5.30 mmo). The reaction mixture was stirred for lh at RT. Water was added and the mixture was extracted with AcOEt. The organic ayer was washed with brine, dried over Na2SO4, fHtered and concentrated under vacuum. The residue was purified by flash co?umn chromatography on sHica ge (cycohexane/AcOEt: 100/0 to 50/50) to afford 5-nitro-2- (2H-1 ,2,3-triazo-2-y 3-(trifluoromethy)pyridine. Miz = 260 [M+H]+, Rt = 0.88 mm (UPLC Method 81), 1H NMR (400 MHz, DMSO-d6) O ppm: 9.69 (d, IH), 9.17 (d, IH), 8,37 (s, 2H).
2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)isothiazolidine 1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 140℃; for 0.666667h;Inert atmosphere; Microwave irradiation;
To 2-choro-5-nitro-3-trifluoromethypyridine (056 g, 2.48 mmo) and isothiazoHdine 1,1- dioxide (060 g, 496 mmo) in 1,4-dioxane (12 m) were added Cs2003 (0.81 g, 2.48 mmo) and argon was bubbed though the mixture for 10 mm. Then Xantphos (287 mg, 0,50 mrnoD and Pd2(dba)3 (114 mg, 0.124 mmoD were added. The reaction mixture was stirred for 40 mm at 140°C in a microwave oven. The mixture was fi?tered through a pad of C&ite and the sovent was evaporated. The crude product was purified by flash co?umn chromatography on sihca ge (cyciohexane/AcOEt 100/0 to 50/50) to afford 2-(5- nitro-3-(trifluoromethy)pyridmn-2-y)isothiazoidine 1,1-dioxide. M/z = 312 [M+H]+, Rt = 0.87 mm (U PLC Method 32).
With tert.-butylhydroperoxide; hydrogen; In water; toluene; at 160℃; under 30003.0 Torr; for 36.0h;Autoclave;
General procedure: 0.5 mmol nitrobenzene, 4.0 mmol TBH (70percent. aq. soln.), 40 mg Co-Ni/ Lignin catalyst and 10 mL Toluene were added in to an 80 mL autoclave. It was then exchanged with 4.0 MPa H2. The reaction was reacted at 160 °C for 36 h under magnetic stirring. Subsequently, the autoclave was cooled to room temperature, and 70 mg biphenyl and 10 mL ethanol were added for quantitative analysis by GC-FID (Agilent 6890A). Purification Procedure: The crude products were subjected to silica gel column chromatography (60, 230-400 mesh supplied by Qingdao Haiyang Chemical and Special Silica Gel Co, Ltd). Eluting with ~75mL of Petroleum Ether, followed by 100:1 (Petroleum Ether:EtOAc).
(R)-1-methoxy-N-methylpropan-2-amine hydrochloride[ No CAS ]
(R)-N-(1-methoxypropan-2-yl)-N-methyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 16.0h;
To a solution of (R)-1-methoxy-N-methylpropan-2-amine hydrochloride (1.017 g, 7.28 mmol) in DMF (10 mL) was added K2C03 (3.02 g, 21.85 mmol) and <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (1.650 g, 7.28 mmol). The resulting reaction mixture was stirred at 65eC for 16 h. After completion of the reaction as monitored on TLC, reaction mixture was quenched with water (20 mL) and aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was rotary evaporated and residue was purified by flash column chromatography (silica gel) to afford to afford 1.0 g (47percent) of the titled product.1HNMR (400 MHz, DMSO-d6) U9.10 (d, J = 2.6 Hz, 1H), 8.59 (d, J = 2.6 Hz, 1H), 4.90-4.80 (m, 1H), 3.58 (dd, J = 10.5, 8.7 Hz, 1H), 3.40 (dd, J = 10.4, 5.0 Hz, 1H), 3.22 (s, 3H), 3.01 (s, 3H), 1.20 (d, J = 6.8 Hz, 3H); ESI-MS (m/z) 293.93 (MH)+.
A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (15 g, 66.2 mmol) and ammonia solution in MeOH (7 N, 150 mL, 1.05 mol) was stirred at room temperature for 14 h. After completion of the reaction, reaction mixture was concentrated under vacuum and residue was diluted with water (100 mL) and aqueous phase was extracted with ethyl acetate (100 mL x 3), combined organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was rotary evaporated to afford 11 g (80percent) of the titled product as yellow solid.1HNMR (400 MHz, DMSO- d6) U9.06 (d, J = 2.7 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 8.04 (s, 2H); ESI-MS (m/z) 208.33 (MH)+.
N-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3.0h;Inert atmosphere;
To a stirred solution of <strong>[99368-67-9]2-chloro-5-nitro-3-(trifluoromethyl)pyridine</strong> (2.0 g, 8.83 mmol) in 1,4-dioxane (20 mL) was added, cesiu m carbonate (5.75 g, 17.66 mmol) and the contents were purged with nitrogen for 30 min followed by sequential addition of thiazol-2-amine (1.32 g, 13.24 mmol), xantphos (0.511 g, 0.883 mmol) and Pd2(dba)3 (0.808 g, 0.883 mmol). The resulting reaction mixture was heated at 100eC for 3 h. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was rotary evaporated and residue was purified by flash column chromatography (silica gel) to afford 0.850 g (33percent) of the titled product as a colorless gum. 1HNMR (400 MHz, DMSO-d6) U13.32 (s, 1H), 9.32 (d, J = 2.7 Hz, 1H), 8.50 (d, J = 2.7 Hz, 1H), 7.50 (d, J = 4.6 Hz, 1H), 7.12 (d, J = 4.6 Hz, 1H); ESI-MS (m/z) 291.21 (MH)\
diethyl 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.1 g
To a stirred solution of diethylmalonate (5.0 g, 23.5 mmol) in THF (25 mL) was addedpotassium tert-butoxide (1M in THF, 70.5 mmol) at -10 °C and the mixture was stirred 10mm at the same temperature followed by 30 mm at RT. A solution of 2-chloro-S-nitro-3-(trifluoromethyl)pyridine (5.0 g, 23.52 mmol) in THF (25 mL) was added slowly to the mixture at 0 °C and the resultant mixture was stirred for 4-S h at RT. The mixture was quenched with aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to yield 5.1 g of the desired product. The crude amine was as such carried forward to the next step.
With potassium carbonate In N,N-dimethyl acetamide at 80℃; for 12h; Inert atmosphere;
2.1
34.514g (0.2mol) 2-chloro-3-trifluoromethyl-5-nitropyridine, 35.041g (0.1mol) 9,9-bis(4-hydroxyphenyl) fluorene, 20.73g ( 0.15mol) potassium carbonate was mixed with 350mL N,N-dimethylacetamide, heated to 80°C, reacted at a constant temperature for 12h, and then detected by thin layer chromatography (TLC) to confirm the completion of the reaction; then the reaction solution was cooled to room temperature, Pour into 700 mL of water, the solid product was separated out, then filtered, the filter cake was washed with deionized water and dried to obtain 70 g of white solid (that is, crude dinitro compound containing fluorenyl and pyridine heterocyclic structure). The solid was mixed with 630mL N,N-dimethylacetamide, the temperature was raised to 120°C, and then naturally cooled to 90°C. When 126mL of water was added dropwise, solids began to precipitate. Stop the dropwise addition of water, and let it stand for 12h after cooling to room temperature. The solid reaction liquid was filtered, and the obtained solid was washed with a mixture of N,N-dimethylacetamide and water mixed in a volume ratio of 5:1 and dried to obtain 62 g of a heterocyclic structure containing fluorenyl and pyridine The calculated yield of the dinitro compound is 85%;
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