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Structure of 372-47-4 * 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.
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 25℃; for 2 h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; hexane; water
3-Fluoro-4-methylpyridine To a cooled (-780C) solution of Λ/,Λ/-diisopropylamine (15.92mL, 113.4mmol) in THF (14OmL) a solution of BuLi 2.5M in hexane (45.4ml, 113.4 mmol) was added dropwise over 30 minutes under an atmosphere of Argon. The mixture was stirred for 30 min. at - 780C and a solution of 3-fluoropyridine (1 Og1 103.1 mmol) in THF (5ml) was added. After 1h at -780C, the mixture was treated with MeI (7 ml, 113.4mmol) and then was allowed to reach 250C. A solution of NaHCO3 saturated (30ml) was added and the aqueous phase was extracted with diethyl ether. The organic layer was dried (MgSO4) and upon distillation the product was collected as a colourless liquid, bp 1300C, yield 5.3 g (47percent) δ 1 H-NMR (CDCI3): 8.25 (s, 1 H), 8.18 (m, 1 H), 7.02 (m, 1 H). ESI/MS m/e: 112 ([M+H]+, C6H6FN)
Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane; n-butyllithium In diethyl ether; hexane at -65℃; for 1.16667 h; Stage #2: With hexachloroethane In diethyl ether; hexane at -40℃; for 2.25 h;
n-Butyllithium (2.5 M in hexanes; 230 ml, 0.57 mol) was added to a solution of 1, [4-DIAZABICYCLO] [[2.] 2. [2]] octane (pre-dried by azeotropic removal of water with toluene) (63. 8 g, 0.57 mol) in [ET20] (2. [5 1)] holding the temperature between-20 [AND-30°C.] After stirring for 1 h, the temperature was adjusted to-65°C and a solution of [3-FLUOROPYRIDINE] (50.0 g, 0.52 mol) in [ET20] (250 ml) was added dropwise over 10 min and the mixture stirred for a further 1 h. A solution of hexachloroethane (136.5 g, 0.58 mol) in [ET20] (350 ml) was then added dropwise over 15 min, holding the temperature [BELOW-60°C] and the mixture was stirred for 2 h, allowing the temperature to rise [TO-40°C.] The reaction was quenched by addition of saturated aqueous [NH4C1] solution (250 ml), warmed to ambient temperature and separated. The aqueous phase was extracted with [ET20] (2 x 250 ml) and the combined organics washed with further saturated aq. [NH4C1] (250 [ML),] dried over anhydrous [MGS04] and concentrated in vacuo. The residue was diluted with isohexane (150 ml) and washed with 2 N hydrochloric acid (3 x 100 ml), followed by 37percent hydrochloric acid (3 x 50 ml). The acid washings were then extracted with isohexane (3 x 100 ml), basified to pH 14 by careful addition of 4 N aqueous [NAOH] solution (500 ml) and re-extracted with [CH2CL2] (3 x 150 ml). The organic fractions were dried over anhydrous [MGS04] and concentrated in vacuo. The residue was purified by distillation (bp [74-82°C,] 1 atm) to afford 2-chloro-3- fluoropyridine as a straw-coloured oil (42.6 g, 63percent): [8H] (400 MHz, CDC13) 7.25-7. 30 [(1H,] m), 7.47-7. 51 [(1H,] m), 8.24 [(1H,] dd, [J 0.] 8 and 4.7) ; m/z (ES+) 132 (100percent, [[MH] +).] A mixture of 2-chloro-3-fluoropyridine (21.0 g, 0.16 mol), benzophenone imine (32.3 g, 0.18 mol), [CS2CO3] (73.0 g, 0.23 mol), BINAP (5.96 g, 9.6 mmol), palladium (II) acetate (1.45 g, 6.4 mmol) and toluene (370 ml) were heated to [95°C] for 42 h, then cooled, filtered and the residue extracted with further toluene (2 x 210 ml). The filtrate was washed with 0.5 N hydrochloric acid (200 ml) and saturated aqueous [NAHCO3] (200 ml), dried over anhydrous [MGS04] and concentrated in vacuo, affording crude benzhydrylidene [(3-FLUOROPYRIDIN-2-YL) AMINE] as a brown oil (49.4 g) which was used directly without further purification: [N7c/Z] (ES+) 277 (100percent, [[MH] +).] A mixture of crude [BENZHYDRYLIDENE] (3-fluoropyridin-2-yl) amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48percent hydrobromic acid (20 ml) and water (20 ml) were heated to [90°C] for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), NaHCOs [(68] g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 [ML)] and the combined organics were stirred and heated to [50°C] for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2 x 440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear [(11).] The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous NaHCO3 solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2 x 220 ml). The combined organic extracts were dried over anhydrous [MGS04] and concentrated in vacuo affording crude [8-FLUOROIMIDAZO [1, 2-APYRIDINE.] Purification was achieved by dissolving the crude material in EtOAc (1 l) and extracting with 2 N hydrochloric acid (5 x 50 [ML).] The acid washings were back-extracted with EtOAc (3 x 100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5 x 100 [ML).] The combined organic fractions were washed with brine, dried over anhydrous [MGS04] and concentrated [17] vacua to afford 8- [FLUOROIMIDAZO] [[L,] 2-a] pyridine (11.4 [G, 76percent] from 2-chloro-3-fluoropyridine): [No.H ] [(400] MHz, CDCl3) 6.69-6. 74 [(1H,] m), 6.84-6. 87 [(1H,] m), 7.65-7. 66 (2H, m), 7.97 [(1H,] dd, J 1.0 and 6.8) [; M/Z (ES+)] 137 (100percent, [[MH]] +). A solution of bromine in [MEOH,] saturated with [KBR] (0. 86 M, 1.0 ml, 0.86 mmol) was added to a cooled, stirred solution of 8-fluoroimidazo[1, 2- pyridine (118 mg, 0. 86 mmol) and NaOAc (85 mg, 1.04 mmol) in methanol saturated with [KBR] (1.6 ml). After 2 min, the solution was poured into water (50 [ML)] and the resulting yellow solution extracted with [CH2CL2] (3 x 50 ml). The combined organic fractions were dried over anhydrous [NA2SO4] and concentrated in vacuo, yielding 3-bromo-8- [FLUOROIMIDAZO] [1, 2-a] pyridine as a yellow solid (155 mg, 83percent), used without further purification: [5H] (400 MHz, [CD13)] 6. [86-6.] 91 [(1H,] m), 6.95-6. 99 (1H, m), 7.65 [(1H,] s), 7.98 [(1H,] dd, [J 0.] 8 and 6.7) ; [M/Z] (ES+) 217 [(100percent,] [[MH] +),] 215 (100). [3-BROMO-8-FLUOROIMIDAZO] [1, [2-A] PYRIDINE,] 3- [[3- (5,] 5-dimethyl- [1, 3,2] dioxaborinan-2-yl) phenyl] pyridine (prepared as described in WO [01/90108),] tetrakis (triphenylphosphine) palladium [(0)] (42 mg, 0.036 [MMOL),] THF (3.6 ml) and 2 M aqueous [NA2CO3] solution were combined and the vigorously stirred mixture heated to [75°C] for 16 h. After cooling, the mixture was partitioned between 1 N aqueous [NAOH] solution (20 ml) and [CHZCL2] (20 ml) and the aqueous phase extracted with further [CHZCLZ] (20 ml). The combined organics were dried over anhydrous [NA2SO4] and concentrated in vacuo, and the residue purified by column chromatography (silica; 2percent [ETOH/ETOAC)] to afford the title imidazopyridine as a white amorphous solid (96 mg, 47percent): [SN] (400 MHz; DMSO) 6.93-6. 98 [(1H,] m), 7.21-7. 24 [(1H,] m), 7.51-7. 54 [(1H,] m), 7.68-7. 76 (2H, m), 7. 82 [(1H,] t, J [1.] 6), 7.94 [(1H,] s), 8.01 [(1H,] t, J 1.6), 8. 19-8.22 [(1H,] m), 8.54 [(1H,] dd, [J 0.] 8 and 7.0), 8.62 [(1H,] dd, J 1.6 and 4.7), 9.02 [(1H,] dd, J 0. 8 and 2.3) ; [MILZ] (ES+) 290 (30percent, [MH] +), 166 (100).
63%
Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane; n-butyllithium In diethyl ether; hexane at -65℃; for 1.16667 h; Stage #2: With hexachloroethane In hexanes; diethyl ether at -40℃; for 2.25 h;
n-Butyllithium (2.5 M in hexanes; 230 ml, 0.57 mol) was added to a solution of [1,] 4-diazabicyclo [2.2. [2]] octane (pre-dried by azeotropic removal of water with toluene) (63. [8] g, 0. [57] mol) in Et20 (2. [5 1)] holding the temperature between-20 [AND-30°C.] After stirring for 1 h, the temperature was adjusted to-65°C and a solution of 3-fluoropyridine (50.0 g, 0.52 mol) in [ET20] (250 [ML)] was added dropwise over 10 min and the mixture stirred for a further 1 h. A solution of hexachloroethane (136.5 g, 0. 58 mol) in [ET20] (350 [ML)] was then added dropwise over [15 MIN,] holding the temperature [BELOW-60°C] and the mixture was stirred for 2 h, allowing the temperature to rise [TO-40°C.] The reaction was quenched by addition of saturated aqueous [NH4CL] solution (250 ml), warmed to ambient temperature and separated. The aqueous phase was extracted with [ET20] (2 x 250 [ML)] and the combined organics washed with further saturated aq. NH4Cl (250 ml), dried over anhydrous [MGS04] and concentrated in uacuo. The residue was diluted with isohexane (150 ml) and washed with 2 N hydrochloric acid (3 x 100 ml), followed by 37percent hydrochloric acid (3 x 50 ml). The acid washings were then extracted with isohexane (3 x 100 ml), basified to pH 14 by careful addition of 4 N aqueous [NAOH] solution (500 ml) and re-extracted with [CH2CL2] (3 x 150 ml). The organic fractions were dried over anhydrous [MGS04] and concentrated in vacuo. The residue was purified by distillation (bp 74-82°C, 1 atm) to afford 2-chloro-3- fluoropyridine as a straw-coloured oil (42.6 g, 63percent): 8H (400 MHz, [CDCL3)] 7. [25-7. 30 (1H, M), 7.] 47-7.51 [(1H,] m), 8. 24 [(1H,] dd, J 0. 8 and 4.7) ; m/z (ES+) 132 (100percent, [MH] +). A mixture of 2-chloro-3-fluoropyridine (21.0 g, 0.16 mol), benzophenone imine (32.3 g, 0. 18 mol), Cs2CO3 (73.0 g, 0. [23 MOL), BINAP] (5.96 g, 9.6 mmol), palladium (II) acetate (1.45 g, 6.4 mmol) and toluene (370 ml) were heated to [95°C] for 42 h, then cooled, filtered and the residue extracted with further toluene (2 x 210 ml). The filtrate was washed with 0.5 N hydrochloric acid (200 ml) and saturated aqueous [NAHCO3] [(200] ml), dried over anhydrous [MGS04] and concentrated [IN VACUO, AFFORDING] crude benzhydrylidene [(3-FLUOROPYRIDIN-2-YL)] amine as a brown oil (49.4 g) which was used directly without further purification : [M/Z] [(ES+)] 277 (100percent, [
[MH] NU+)-] A mixture of crude benzhydrylidene (3-fluoropyridin-2-yl) amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48percent hydrobromic acid (20 ml) and water (20 [ML)] were heated to [90°C] for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), [NAHCO3] [(68] g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 ml) and the combined organics were stirred and heated to [50°C] for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2 x 440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear [(11).] The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous [NAHCO3] solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2 x 220 ml). The combined organic extracts were dried over anhydrous MgS04 and concentrated in vacuo affording crude [8-FLUOROIMIDAZO [1, 2-A]] pyridine. Purification was achieved by dissolving the crude material in EtOAc [(11)] and extracting with 2 N hydrochloric acid (5 x 50 ml). The acid washings were back-extracted with EtOAc (3 x 100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5 x 100 ml). The combined organic fractions were washed with brine, dried over anhydrous [MGS04] and concentrated in vacuo to afford 8- [FLUOROIMIDAZO] [1, 2-a] pyridine (11.4 g, 76percent from 2-chloro-3-fluoropyridine): 8H (400 MHz, CDCl3) 6.69-6. 74 [(1H,] m), 6. [84-6. 87 (1H,] m), 7.65-7. 66 (2H, m), 7.97 [(1H,] dd, J 1.0 and 6.8) [; M/Z] (ES+) 137 [(100percent,] [[MHJ+).] 8-Fluoroimidazo [1, 2-a] pyridine (68 mg, 0.50 mmol), 2-chloro-6- [TRIFLUOROMETHYLPYRIDINE] (182 mg, 1.0 [MMOL),] [CS2CO3] (326 mg, 1.0 mmol), tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.05 mmol) and 1,4- dioxane (3 ml) were heated to [150°C] for 800 s in a Smith Personal [SYNTHESISERTM] using microwave irradiation. On cooling, the mixture was partitioned between [CH2CL2] (2 ml) and water (2 ml), and the phases separated using a [WHATMAN 5, UM] teflon filter tube. The organics were concentrated in vacuo and purified by column chromatography (silica; 90percent EtOAc/isohexane), yielding the title imidazopyridine as a white amorphous solid [(85] mg, 60percent): 8H (400 MHz; DMSO) 7.19-7. 24 [(1H, M),] 7.38-7. 43 [(1H,] m), 7.83 [(1H,] d, [J 7.] 4), 8. 20 [(1H,] t, J 8. 2), 8.38 [(1H,] s), 8.64 [(1H,] s), 9.64 [(1H,] dd, J 1.2 and 7.0) ; [WIZ] (ES+) 282 (100percent, [. MH]] +).
Reference：
[1] Patent: WO2003/99816, 2003, A1, . Location in patent: Page 42-43
[2] Patent: WO2003/99817, 2003, A1, . Location in patent: Page 35
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 29, p. 9103 - 9107[4] Angew. Chem., 2018, vol. 130, p. 9241 - 9245,5
[5] Journal of Medicinal Chemistry, 2004, vol. 47, # 15, p. 3853 - 3864
11
[ 280-57-9 ]
[ 372-47-4 ]
[ 67-72-1 ]
[ 17282-04-1 ]
Yield
Reaction Conditions
Operation in experiment
52%
With n-butyllithium In tetrahydrofuran; diethyl ether; water
Example 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78° C. The reaction mixture was warmed to -20° C. for 1 hour and then recooled to -78° C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78° C., the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78° C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0° C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10percent ethyl acetate/hexanes) to afford 3.5 g (52percent yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium In tetrahydrofuran; diethyl ether; water
Example 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78° C. The reaction mixture was warmed to -20° C. for 1 hour and then recooled to -78° C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78 C, the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78° C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0° C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10percent ethyl acetate/hexanes) to afford 3.5 g (52percent yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium In tetrahydrofuran; diethyl ether; water
EXAMPLE 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78° C. The reaction mixture was warmed to -20° C. for 1 hour and then recooled to -78° C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78 C., the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78° C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0° C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10percent ethyl acetate/hexanes) to afford 3.5 g (52percent yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium In tetrahydrofuran; diethyl ether; water
EXAMPLE 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78° C. The reaction mixture was warmed to -20° C. for 1 hour and then recooled to -78° C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78C, the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78° C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0° C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10percent ethyl acetate/hexanes) to afford 3.5 g (52percent yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium In tetrahydrofuran; diethyl ether; water
Example 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78° C. The reaction mixture was warmed to -20° C. for 1 hour and then recooled to -78° C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78° C., the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78° C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0° C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10percent ethyl acetate/hexanes) to afford 3.5 g (52percent yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6298 - 6301
13
[ 372-47-4 ]
[ 2546-56-7 ]
Yield
Reaction Conditions
Operation in experiment
70.2%
Stage #1: With 2,3-dimethyl-2,3-diaminobutane; lithium diisopropyl amide In tetrahydrofuran; n-heptane; tert-butyl methyl ether; ethylbenzene at -50 - -40℃; for 74 h; Stage #2: With hexachloroethane In tetrahydrofuran; n-heptane; tert-butyl methyl ether; ethylbenzene at -46 - -40℃; for 68 h;
A 30-gal Hastelloy reactor under nitrogen is charged with 2.5 kg (25.8 mole) of 3-fluoropyridine, 3.4 kg (29.6 mole, 1.2 equiv.) of tetramethylethylenediamine (TMEDA) and 20 L of methyl tert-butyl ether (MTBE). The solution is cooled to-50°C. A total of 15.5 L (12.6 L, 29.6 mole, 1.15 equiv.) of 1.9 M lithium diisopropylamide (LDA) solution (heptane/THF/ethylbenzene) is added over a period of 24 min while maintaining a temperature of-40 to-48 °C. The light-brown suspension is stirred for 50 rnin at-44 to-48°C. A solution of 7 kg (29.6 mole, 1.15 equiv.) of hexachloroethane in 20 L of MTBE is added over a period of 48 min while maintaining a temperature of-40 to-46°C. After stirring for 20 min at-40°C, the reaction is warmed to 0°C, then quenched into a reactor that contained 54 L of cold water. After stirring at 20-25°C for 20 min, the mixture is filtered through Celite to break a minor emulsion. The layers are separated. The aqueous layer is extracted with 5 L of MTBE. The organic layers are combined, then extracted with portions (1 x 21 L, 3 x 13 L) of 2 N HCl. The acidic aqueous phases are combined, partitioned with 16 L of MTBE, then basified to pH 6.19 by adding 6.5 kg of 50percent NaOH while maintaining a temperature of 15- 20 °C. The layers are separated. The aqueous phase is extracted with 10 L of MTBE. The combined organic phase is dried over 3.0 kg of sodium sulfate, then filtered and concentrated (56°C, 575 mbar during most of the concentration, 400 mbar for final concentration) to give 3.7 kg of 4-chloro-3-fluoropyridine, as a brown liquid, 2.4 kg corrected for 31. 2percent solvent by NMR and 95. 5percent purity by HPLC, 70.2percent yield.
Reference：
[1] Patent: WO2005/35496, 2005, A1, . Location in patent: Page/Page column 32
[2] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
[3] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 29, p. 9103 - 9107[5] Angew. Chem., 2018, vol. 130, p. 9241 - 9245,5
14
[ 372-47-4 ]
[ 769-54-0 ]
Reference：
[1] Patent: WO2013/184757, 2013, A1,
15
[ 372-47-4 ]
[ 107-31-3 ]
[ 40273-47-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 13, p. 1435 - 1438
Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane; n-butyllithium In diethyl ether; hexane at -70 - -60℃; for 1.5 h; Stage #2: at -70℃; for 1 h;
To a solution of DABCO (8.8 g, 78.2 mmol) in anhydrous diethyl ether (250 mL) at -25° C. was added n-BuLi (1.6 M in hexanes, 49 mL, 78.2 mmol). The mixture was stirred between -25 to -10° C. for 45 min and then cooled to -70° C. To the above solution was added 3-fluoropyridine (5.9 mL, 71 mmol) dropwise. The reaction was stirred between -70 to -60° C. for 1.5 h before DMF (11.0 mL, 2.0 eq.) was added. After 1.0 h stirring at -70° C., water (150 mL) was added and warmed up to rt. The layers were separated and the aqueous layer was extracted with methylene chloride (5.x.100 mL). The combined organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the crude was purified by silica gel column chromatography using gradient EtOAc in hexanes to give 5.4 g (55-60percent yield) of 65A. 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.57 (m, 2H) 8.61 (d, J=2.20 Hz, 1H) 10.20 (s, 1H).
43%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In diethyl ether; hexane at -78 - -20℃; for 2.41667 h; Stage #2: at -78℃; for 2.16667 h;
n-Butyllithium (2.0 M in hexanes, 27.5 ml, 55 mmol) was added dropwise over 10 minutes at -200C to a solution of Λ/,Λ/,Λ/',Λ/'-tetramethylethylenediamine (7.5 ml, 50 mmol) in anhydrous diethyl ether (200 ml). The reaction mixture was stirred at -200C for 1 hour, then it was cooled to -78°C and 3- fluoropyridine (4.3 ml, 50 mmol), in diethyl ether (10 ml), was added dropwise over 15 minutes at - 78°C. The reaction mixture was stirred at" ι-78°C for 1 hour, after which time N1N- Dimethylformamide (4.3 ml, 55 mmol), in diethyl ether (10 ml), was added dropwise over 10 minutes at -78°C. It was stirred for 2 hours, then poured carefully onto a rapidly stirring ice/water mixture (300 ml). The mixture was stirred for 20 minutes, then diluted with ethyl acetate (200 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (4 x 50 ml). The organic solutions were combined and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel using EPO <DP n="49"/>dichloromethane:pentane as eluant (0:100 to 60:40 v/v) to yield the title compound (2.7 g, 43percent) as a solid.1H NMR (400MHz, CDCI3): δ 7.56-7.60 (m, 2H)1 8.63 (m, 1 H), 10.22 (s, 1 H).
Reference：
[1] Patent: US2010/227894, 2010, A1, . Location in patent: Page/Page column 55
[2] Patent: WO2006/114706, 2006, A1, . Location in patent: Page/Page column 47-48
[3] Tetrahedron, 1983, vol. 39, # 12, p. 2009 - 2021
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 6998 - 7003
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1852 - 1856
[6] Patent: WO2012/177896, 2012, A1, . Location in patent: Page/Page column 89-90
[7] Organic Process Research and Development, 2007, vol. 11, # 4, p. 716 - 720
With n-butyllithium In diethyl ether; hexane; water; N,N-dimethyl-formamide
2-Formyl-3-fluoropyridine Dry ethyl ether (500 mL), n-BuLi (1.6M in hexane, 62.5 mL, 0.1 mol), and dry 1,4-diazabicyclo[2.2.2]octane (DABCO) (11.56 g, 0.1 mol) were introduced into a 1 L flask under a dry N2 stream at -60° C. and the resulting cloudy solution was stirred for 1 hour at -20° C. The mixture was then cooled to -75° C. and an ethyl ether (50 mL) solution of 3-fluoropyridine (9.81 g, 0.1 mol) was added dropwise and stirring continued for 11/2 hours at -60° C. The mixture was recooled to -75° C., dry N,N-dimethylformamide (8.52 mL, 0.11 mol) dissolved in ethyl ether (50 mL) was added dropwise and the mixture stirred for 2 hours at -75° C. Water (175 mL) was introduced slowly at -10° C., the aqueous layer extracted with ethyl acetate (5*200 mL), and the combined extracts were dried over anhydrous sodium sulfate. Solvent removal produced a dark brown oil which after vacuum distillation and purification by chromatography on silica gel provided 4.4 g (35percent) of the titled product as an off-white crystalline solid: mp 48°-49° C.; IR (CHCl3, cm-1) 3071, 3020, 2873, 2842, 1720, 1588, 1461, 1441; 1 H NMR (300 MHz, CDCl3) δ10.21 (s, 1H), 8.62 (m, 1H), 7.57 (m, 2H); MS (FD) m/e 125 (M+);
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 2.5 h; Stage #2: at -78℃; for 1.5 h; Stage #3: With water; ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene at -30℃;
Into a stirred solution of 3-fluoropyridine (14 G, 144.2 MMOL) in anhydrous THF (150 mL), cooled TO-78°C and under argon, 79.2 mL (158. 6 MMOL) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ETHYLBENZENE, were slowly dropped in about 1H. After stirring for 2.5h a cooled solution (ca. 0°C) of acetaldehyde (8.9 ML, 158.5 MMOL) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred AT-78°C for 1.5 h. The solution was warmed to-30°C and a solution of ammonium chloride (150g) in 700 mL of water was added. The mixture was extracted with ETHYLACETATE (3 x 400 mL) and the organic layers were washed with brine (4 x 200 mL) and dried over sodium sulfate. After concentration the oil was crystallized with n-hexane (40 mL) and 15.6 G (76percent yield) of 1- (3- fluoropyridin-4-yl) ethanol were obtained.
76%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 3.5 h; Stage #2: at -78℃; for 1.5 h; Stage #3: With water; ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene at -30℃;
EXAMPLE 15 Preparation of 2-bromo-1-(3-fluoropyridin-4-yl)ethanone hydrobromide Into a stirred solution of 3-fluoropyridine (14 g, 144.2 mmol) in anhydrous THF (150 mL), cooled to -78° C. and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1 h. After stirring for 2.5 h a cooled solution (ca. 0° C.) of acetaldehyde (8.9 mL, 158.5 mmol) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at -78° C. for 1.5 h. The solution was warmed to -30° C. and a solution of ammonium chloride (150 g) in 700 mL of water was added. The mixture was extracted with ethylacetate (3*400 mL) and the organic layers were washed with brine (4*200 mL) and dried over sodium sulfate. After concentration the oil was crystallized with n-hexane (40 mL) and 15.6 g (76percent yield) of 1-(3-fluoropyridin-4-yl)ethanol were obtained.
76%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 3.5 h; Stage #2: at -78 - -30℃; for 1.5 h; Stage #3: With water; ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene at -30℃;
Example 2; 2-Bromo-1 -(3"fluoropyridin-4-yl)ethanone hydrobromide; Into a stirred solution of 3-fluoropyridine (14 g, 144.2 rnmol) in anhydrous THF (150 mL), cooled to -780C and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamsde (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1h. After stirring for 2.5h a cooled solution (ca. 0DC) of acetaldehyde (8.9 mL, 158.5 mmot) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at -78°C for <n="33"/>1.5 h. The solution was warmed to -30°C and a solution of ammonium chloride (15Og) in 700 mL of water was added. The mixture was extracted with ethylacetate (3 x 400 ml_) and the organic layers were washed with brine (4 x 200 mL) and dried over sodium sulfate. After concentration, the oil was crystallized with n-hexane (40 mL) and 15.6 g (76percent yield) of 1-{3- fiuoropyridin-4-yl)ethanol were obtained. A mixture of 1-(3-fiuoropyridin-4-y.)ethanoi (10 g, 70.3 mrnol) and commercial activated MnO2 (8 g, 92.1 mmol) in toluene (100 mL) were refluxed until disappearance of starting material. After cooling, the mixture was filtered on a bed of celite, the cake washed with toluene and the organic phases concentrated to give 3- f.uoro-4-acetyi pyridine (6.9 g, 70percent) that was used directly in the next step. To a stirred solution of 3-fluσro-4-acetyipyridine (5.3 g, 38.1 mmol} in glacial acetic acid (14 mL) and 48percent hydrobromic acid (5.3 mL), bromine (2 mL, 38 mmol) in glacial acetic acid (5.3 mL) was added slowly and dropwise. After addition, the solution was stirred at 60DC for 2.5 hour. This solution was cooled down and ethylacetate (70 mL) was added. After 30 minutes of stirring, the mixture was filtered and the solid was washed thoroughly with ethylacetate and dried. The title compound was obtained in 82percent yield (9.4 g).1H NMR (DMSOd6 /400 MHz) δ ppm 4.88 (s, 2 H) 7.83 (dd, 1 H) 8.62 (dd, 1 H) 8.81 (d, 1 H).
With triethylsilane; [Rh(μ-H)(1,3-bis(diisopropylphosphanyl)propane)]2 In benzene-d6 at 50℃; for 48 h; Inert atmosphere
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube α,α,α-trifluorotoluene (1–2 μL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(μ-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
Reference：
[1] Journal of Fluorine Chemistry, 2013, vol. 155, p. 132 - 142
39
[ 372-47-4 ]
[ 78191-00-1 ]
[ 194278-45-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 679 - 683
40
[ 2875-18-5 ]
[ 372-47-4 ]
[ 3512-18-3 ]
[ 76469-41-5 ]
[ 71902-33-5 ]
Yield
Reaction Conditions
Operation in experiment
24 %Spectr.
With triethylsilane; [Rh(μ-H)(1,3-bis(diisopropylphosphanyl)propane)]2 In benzene-d6 at 50℃; for 48 h; Inert atmosphere
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube α,α,α-trifluorotoluene (1–2 μL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(μ-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
Reference：
[1] Journal of Fluorine Chemistry, 2013, vol. 155, p. 132 - 142
41
[ 700-16-3 ]
[ 372-47-4 ]
[ 2875-18-5 ]
[ 71902-33-5 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 10, p. 1705 - 1713
42
[ 372-47-4 ]
[ 124-38-9 ]
[ 152126-31-3 ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane; n-butyllithium In diethyl ether; hexane at -78 - -60℃; for 1 h; Stage #2: at -78 - -10℃; for 0.333333 h;
To a solution of 1 ,4-diazabicyclo[2.2.2]octane (1.15 g, 10.3 mmol) in diethylether (50 ml) is added n- butyllithium (2.6M in hexane) (3.95 ml, 10.3 mmol) at -78 °C. The reaction mixture is stirred at -20 °C for 1 h followed by the addition of a solution of 3-fluoro-pyridine (1.00 g, 10.29 mmol) in diethylether (30 ml) at -78 °C. The yellow suspension is stirred at -60 °C for 1 h and then cooled to -78 °C followed by the addition of excess dry ice. The resulting solution allowed to warm to to -10 °C over 20 min. The precipitate is filtered and the residue is washed with ether which yields pure 3-fluoro-pyridine-2-carboxylic acid (1.20 g, 8.51 mmol, 83percent).
Reference：
[1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123
47
[ 372-47-4 ]
[ 860296-24-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123
48
[ 372-47-4 ]
[ 68-12-2 ]
[ 870063-60-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -65 - -60℃; Inert atmosphere Stage #2: at -60℃; for 1 h; Stage #3: at 0℃; for 1 h;
[0122] A mechanically stirred solution of 3-fluoropyridine (600 g, 6.18 mol) in dry THE (6 L) was cooled to -65°C under N2 atmosphere. Lithium diisopropylamine solution in THE (3.4 L, 6.5 mol) was added over 2 hours while keeping the temperature below -60°C, and the reaction mixture was allowed to stir an additional hour below -60°C. Neat DME (804 mL, 10.4 mol) was then added over a one hour period at a rate as to maintain the temperature below -60°C. The reaction mixture was monitored by TLC for the complete consumption of 3-fluoropyridine starting material. Upon completion, the reaction mixture was then warmed to -10°C, and H20 (1.1 Kg, 62 mol) was added. Sodium borohyd ride (234 g, 6.18 mol) was then added in two portions over several minutes at 0°C with stirring. Then 6 M HCI (5.6 L) was added over 1 h while maintaining the reaction quenching temperature between 0-25°C. The reaction mixture was then heated to 40°C and stirred at this temperature overnight. To the mixture 6 M NaOH was then slowly added at 0-15°C to adjust the pH to 12. The aqueous layer was extracted with isopropylacetate (500 mL x 1, 1 Lx 3). The combined organic layers were washed with brine, dried over Na2504 and concentrated in vacuo. To the crude product was added heptane-isopropylacetate (1.2 L, v/v = 5/1), and the mixture was stirred at 0 °C for 30 mm. The product crystallized as a pale-yellow solid during stirring. The mixture was filtered, the filter cake was extracted with cooled heptane (250 mL x 1), collected and dried under vacuum to give the title compound as a pale-yellow solid (688 g, 88percent). 1H NMR (400 MHz, CDCI3) 6 8.42 (d, i = 4.8 Hz, 1H), 8.40 (d, i = 1.6 Hz, 1H), 7.49 (t, i = 4.8 Hz, 1H), 4.85 (s, 2H), 2.35 (br s, 1H).
88%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -65 - -60℃; for 3 h; Inert atmosphere Stage #2: at -60℃; for 1 h; Inert atmosphere Stage #3: With sodium tetrahydroborate; water In tetrahydrofuran at -10 - 0℃; Inert atmosphere
Step 1. (3-fluoropyridin-4-yl)methanol [0171] A mechanically stirred solution of 3-fluoropyridine (600 g, 6.18 mol) in dry THF (6 L) was cooled to -65 °C under N2 atmosphere. Lithium diisopropylamine solution in THF (3.4 L, 6.5 mol) was added over 2 hours while keeping the temperature below -60 °C, and the reaction mixture was allowed to stir an additional hour below -60 °C. Neat DMF (804 mL, 10.4 mol) was then added over a one hour period at a rate as to maintain the temperature below -60 °C. The reaction mixture was monitored by TLC for the complete consumption of 3-fluoropyridine starting material. Upon completion, the reaction mixture was then warmed to -10 °C, and H20 (1.1 Kg, 62 mol) was added. Sodium borohydride (234 g, 6.18 mol) was then added in two portions over several minutes at 0 °C with stirring. Then 6 M HCI (5.6 L) was added over 1 h while maintaining the reaction quenching temperature between 0-25 °C. The reaction mixture was then heated to 40 °C and stirred at this temperature overnight. To the mixture 6 M NaOH was then slowly added at 0-15 °C to adjust the pH to 12. The aqueous layer was extracted with isopropylacetate (500 m L x 1, 1 L x 3). The combined organic layers were washed with brine, dried over Na2S04 and concentrated in vacuo. To the crude product was added heptane-isopropylacetate (1.2 L, v/v = 5/1), and the mixture was stirred at 0 °C for 30 min. The product crystallized as a pale-yellow solid during stirring. The mixture was filtered, the filter cake was extracted with cooled heptane (250 m L x 1), collected and dried under vacuum to give the title compound as a pale-yellow solid (688 g, 88percent). 1H N M R (400 M Hz, CDCI3) δ 8.42 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.49 (t, J = 4.8 Hz, 1H), 4.85 (s, 2H), 2.35 (br s, 1H).
Into a stirred solution of 3-fluoropyridine (14 G, 144.2 MMOL) in anhydrous THF (150 mL), cooled TO-78C and under argon, 79.2 mL (158. 6 MMOL) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ETHYLBENZENE, were slowly dropped in about 1H. After stirring for 2.5h a cooled solution (ca. 0C) of acetaldehyde (8.9 ML, 158.5 MMOL) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred AT-78C for 1.5 h. The solution was warmed to-30C and a solution of ammonium chloride (150g) in 700 mL of water was added. The mixture was extracted with ETHYLACETATE (3 x 400 mL) and the organic layers were washed with brine (4 x 200 mL) and dried over sodium sulfate. After concentration the oil was crystallized with n-hexane (40 mL) and 15.6 G (76% yield) of 1- (3- fluoropyridin-4-yl) ethanol were obtained.
76%
EXAMPLE 15 Preparation of 2-bromo-1-(3-fluoropyridin-4-yl)ethanone hydrobromide Into a stirred solution of 3-fluoropyridine (14 g, 144.2 mmol) in anhydrous THF (150 mL), cooled to -78 C. and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1 h. After stirring for 2.5 h a cooled solution (ca. 0 C.) of acetaldehyde (8.9 mL, 158.5 mmol) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at -78 C. for 1.5 h. The solution was warmed to -30 C. and a solution of ammonium chloride (150 g) in 700 mL of water was added. The mixture was extracted with ethylacetate (3*400 mL) and the organic layers were washed with brine (4*200 mL) and dried over sodium sulfate. After concentration the oil was crystallized with n-hexane (40 mL) and 15.6 g (76% yield) of 1-(3-fluoropyridin-4-yl)ethanol were obtained.
76%
Example 2; 2-Bromo-1 -(3«fluoropyridin-4-yl)ethanone hydrobromide; Into a stirred solution of 3-fluoropyridine (14 g, 144.2 rnmol) in anhydrous THF (150 mL), cooled to -780C and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamsde (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1h. After stirring for 2.5h a cooled solution (ca. 0DC) of acetaldehyde (8.9 mL, 158.5 mmot) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at -78C for <n="33"/>1.5 h. The solution was warmed to -30C and a solution of ammonium chloride (15Og) in 700 mL of water was added. The mixture was extracted with ethylacetate (3 x 400 ml_) and the organic layers were washed with brine (4 x 200 mL) and dried over sodium sulfate. After concentration, the oil was crystallized with n-hexane (40 mL) and 15.6 g (76% yield) of 1-{3- fiuoropyridin-4-yl)ethanol were obtained. A mixture of 1-(3-fiuoropyridin-4-y.)ethanoi (10 g, 70.3 mrnol) and commercial activated MnO2 (8 g, 92.1 mmol) in toluene (100 mL) were refluxed until disappearance of starting material. After cooling, the mixture was filtered on a bed of celite, the cake washed with toluene and the organic phases concentrated to give 3- f.uoro-4-acetyi pyridine (6.9 g, 70%) that was used directly in the next step. To a stirred solution of 3-flu?ro-4-acetyipyridine (5.3 g, 38.1 mmol} in glacial acetic acid (14 mL) and 48% hydrobromic acid (5.3 mL), bromine (2 mL, 38 mmol) in glacial acetic acid (5.3 mL) was added slowly and dropwise. After addition, the solution was stirred at 60DC for 2.5 hour. This solution was cooled down and ethylacetate (70 mL) was added. After 30 minutes of stirring, the mixture was filtered and the solid was washed thoroughly with ethylacetate and dried. The title compound was obtained in 82% yield (9.4 g).1H NMR (DMSOd6 /400 MHz) delta ppm 4.88 (s, 2 H) 7.83 (dd, 1 H) 8.62 (dd, 1 H) 8.81 (d, 1 H).
With iodine; lithium diisopropyl amide; In tetrahydrofuran; diethyl ether; n-heptane; water;
The starting material was prepared as follows: A solution of 3-fluoropyridine (19.4 g) in dry tetrahydrofuran (20 ml) was added dropwise over 30 minutes, under an atmosphere of argon, to a stirred solution of 2M lithium diisopropylamide/tetrahydrofutran/heptane (100 ml) in dry tetrahydrofuran (700 ml) at -70° C. The mixture was stirred at -70° C. for 4 hours. A solution of iodine (50.7 g) in dry tetrahydrofuran (160 ml) was added dropwise to this stirred suspension at -70° C. over 45 minutes and stirring was continued for a further 45 minutes. A mixture of tetrahydrofuran (160 ml)/water (40 ml) was added to the resulting solution at -70° C. The solution was allowed to warm to 0° C. Water (200 ml) was added and diethyl ether (400 ml). The mixture was allowed to stand at ambient temperature for 16 hours. The ether layer was separated. The aqueous layer was extracted with ether (2*100 ml). The ether layers were all combined, washed with aqueous sodium thiosulphate solution (2*250 ml) and saturated brine (2*100 ml), dried (Na2O4) and evaporated to low bulk. The residue was dissolved in dry diethyl ether and the solution was cooled to -50° C. The solid, which had separated, was filtered off and washed with pentane at -50° C. to give 3-fluoro-4-iodopyridine (22.8 g) as a white solid: NMR (CDCl3): 7.75 (t, 1H), 8.05 (d, 1H), 8.3 5 (s, 1H); m/z 223 M.
To a solution of 1 ,4-diazabicyclo[2.2.2]octane (1.15 g, 10.3 mmol) in diethylether (50 ml) is added n- butyllithium (2.6M in hexane) (3.95 ml, 10.3 mmol) at -78 C. The reaction mixture is stirred at -20 C for 1 h followed by the addition of a solution of 3-fluoro-pyridine (1.00 g, 10.29 mmol) in diethylether (30 ml) at -78 C. The yellow suspension is stirred at -60 C for 1 h and then cooled to -78 C followed by the addition of excess dry ice. The resulting solution allowed to warm to to -10 C over 20 min. The precipitate is filtered and the residue is washed with ether which yields pure 3-fluoro-pyridine-2-carboxylic acid (1.20 g, 8.51 mmol, 83%).
n-Butyllithium (2.5 M in hexanes; 230 ml, 0.57 mol) was added to a solution of 1, [4-DIAZABICYCLO] [[2.] 2. [2]] octane (pre-dried by azeotropic removal of water with toluene) (63. 8 g, 0.57 mol) in [ET20] (2. [5 1)] holding the temperature between-20 [AND-30C.] After stirring for 1 h, the temperature was adjusted to-65C and a solution of [3-FLUOROPYRIDINE] (50.0 g, 0.52 mol) in [ET20] (250 ml) was added dropwise over 10 min and the mixture stirred for a further 1 h. A solution of hexachloroethane (136.5 g, 0.58 mol) in [ET20] (350 ml) was then added dropwise over 15 min, holding the temperature [BELOW-60C] and the mixture was stirred for 2 h, allowing the temperature to rise [TO-40C.] The reaction was quenched by addition of saturated aqueous [NH4C1] solution (250 ml), warmed to ambient temperature and separated. The aqueous phase was extracted with [ET20] (2 x 250 ml) and the combined organics washed with further saturated aq. [NH4C1] (250 [ML),] dried over anhydrous [MGS04] and concentrated in vacuo. The residue was diluted with isohexane (150 ml) and washed with 2 N hydrochloric acid (3 x 100 ml), followed by 37% hydrochloric acid (3 x 50 ml). The acid washings were then extracted with isohexane (3 x 100 ml), basified to pH 14 by careful addition of 4 N aqueous [NAOH] solution (500 ml) and re-extracted with [CH2CL2] (3 x 150 ml). The organic fractions were dried over anhydrous [MGS04] and concentrated in vacuo. The residue was purified by distillation (bp [74-82C,] 1 atm) to afford 2-chloro-3- fluoropyridine as a straw-coloured oil (42.6 g, 63%): [8H] (400 MHz, CDC13) 7.25-7. 30 [(1H,] m), 7.47-7. 51 [(1H,] m), 8.24 [(1H,] dd, [J 0.] 8 and 4.7) ; m/z (ES+) 132 (100%, [[MH] +).] A mixture of 2-chloro-3-fluoropyridine (21.0 g, 0.16 mol), benzophenone imine (32.3 g, 0.18 mol), [CS2CO3] (73.0 g, 0.23 mol), BINAP (5.96 g, 9.6 mmol), palladium (II) acetate (1.45 g, 6.4 mmol) and toluene (370 ml) were heated to [95C] for 42 h, then cooled, filtered and the residue extracted with further toluene (2 x 210 ml). The filtrate was washed with 0.5 N hydrochloric acid (200 ml) and saturated aqueous [NAHCO3] (200 ml), dried over anhydrous [MGS04] and concentrated in vacuo, affording crude benzhydrylidene [(3-FLUOROPYRIDIN-2-YL) AMINE] as a brown oil (49.4 g) which was used directly without further purification: [N7c/Z] (ES+) 277 (100%, [[MH] +).] A mixture of crude [BENZHYDRYLIDENE] (3-fluoropyridin-2-yl) amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48% hydrobromic acid (20 ml) and water (20 ml) were heated to [90C] for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), NaHCOs [(68] g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 [ML)] and the combined organics were stirred and heated to [50C] for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2 x 440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear [(11).] The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous NaHCO3 solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2 x 220 ml). The combined organic extracts were dried over anhydrous [MGS04] and concentrated in vacuo affording crude [8-FLUOROIMIDAZO [1, 2-APYRIDINE.] Purification was achieved by dissolving the crude material in EtOAc (1 l) and extracting with 2 N hydrochloric acid (5 x 50 [ML).] The acid washings were back-extracted with EtOAc (3 x 100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5 x 100 [ML).] The combined organic fractions were washed with brine, dried over anhydrous [MGS04] and concentrated [17] vacua to afford 8- [FLUOROIMIDAZO] [[L,] 2-a] pyridine (11.4 [G, 76%] from 2-chloro-3-fluoropyridine): [No.H ] [(400] MHz, CDCl3) 6.69-6. 74 [(1H,] m), 6.84-6. 87 [(1H,] m), 7.65-7. 66 (2H, m), 7.97 [(1H,] dd, J 1.0 and 6.8) [; M/Z (ES+)] 137 (100%, [[MH]] +). A solution of bromine in [MEOH,] saturated with [KBR] (0. 86 M, 1.0 ml, 0.86 mmol) was added to a cooled, stirred solution of 8-fluoroimidazo[1, 2- pyridine (118 mg, 0. 86 mmol) and NaOAc (85 mg, 1.04 mmol) in methanol saturated with [KBR] (1.6 ml). After 2 min, the solution was poured into water (50 [ML)] and the resulting yellow solution extracted with [CH2CL2] (3 x 50 ml). The combined organic fractions were dried over anhydrous [NA2SO4] and concentrated in vacuo, yielding 3-bromo-8- [FLUOROIMIDAZO] [1, 2-a] pyridine as a yellow solid (155 mg, 83%), used without further purification: [5H] (400 MHz, [CD13)] 6. [86-6.] 91 [(1H,] m), 6.95-6. 99 (1H, m), 7.65 [(1H,] s), 7.98 [(1H,] dd, [J 0.] 8 and 6.7) ; [M/Z] (ES+) 217 [(100%,] [[MH] +),] 215 (100). [3-BROMO-8-FLUOROIMIDAZO] [1, [2-A] PYRIDINE,] 3- [[3- (5,] 5-dimethyl- ...
63%
n-Butyllithium (2.5 M in hexanes; 230 ml, 0.57 mol) was added to a solution of [1,] 4-diazabicyclo [2.2. [2]] octane (pre-dried by azeotropic removal of water with toluene) (63. [8] g, 0. [57] mol) in Et20 (2. [5 1)] holding the temperature between-20 [AND-30C.] After stirring for 1 h, the temperature was adjusted to-65C and a solution of 3-fluoropyridine (50.0 g, 0.52 mol) in [ET20] (250 [ML)] was added dropwise over 10 min and the mixture stirred for a further 1 h. A solution of hexachloroethane (136.5 g, 0. 58 mol) in [ET20] (350 [ML)] was then added dropwise over [15 MIN,] holding the temperature [BELOW-60C] and the mixture was stirred for 2 h, allowing the temperature to rise [TO-40C.] The reaction was quenched by addition of saturated aqueous [NH4CL] solution (250 ml), warmed to ambient temperature and separated. The aqueous phase was extracted with [ET20] (2 x 250 [ML)] and the combined organics washed with further saturated aq. NH4Cl (250 ml), dried over anhydrous [MGS04] and concentrated in uacuo. The residue was diluted with isohexane (150 ml) and washed with 2 N hydrochloric acid (3 x 100 ml), followed by 37% hydrochloric acid (3 x 50 ml). The acid washings were then extracted with isohexane (3 x 100 ml), basified to pH 14 by careful addition of 4 N aqueous [NAOH] solution (500 ml) and re-extracted with [CH2CL2] (3 x 150 ml). The organic fractions were dried over anhydrous [MGS04] and concentrated in vacuo. The residue was purified by distillation (bp 74-82C, 1 atm) to afford 2-chloro-3- fluoropyridine as a straw-coloured oil (42.6 g, 63%): 8H (400 MHz, [CDCL3)] 7. [25-7. 30 (1H, M), 7.] 47-7.51 [(1H,] m), 8. 24 [(1H,] dd, J 0. 8 and 4.7) ; m/z (ES+) 132 (100%, [MH] +). A mixture of 2-chloro-3-fluoropyridine (21.0 g, 0.16 mol), benzophenone imine (32.3 g, 0. 18 mol), Cs2CO3 (73.0 g, 0. [23 MOL), BINAP] (5.96 g, 9.6 mmol), palladium (II) acetate (1.45 g, 6.4 mmol) and toluene (370 ml) were heated to [95C] for 42 h, then cooled, filtered and the residue extracted with further toluene (2 x 210 ml). The filtrate was washed with 0.5 N hydrochloric acid (200 ml) and saturated aqueous [NAHCO3] [(200] ml), dried over anhydrous [MGS04] and concentrated [IN VACUO, AFFORDING] crude benzhydrylidene [(3-FLUOROPYRIDIN-2-YL)] amine as a brown oil (49.4 g) which was used directly without further purification : [M/Z] [(ES+)] 277 (100%, [ [MH] NU+)-] A mixture of crude benzhydrylidene (3-fluoropyridin-2-yl) amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48% hydrobromic acid (20 ml) and water (20 [ML)] were heated to [90C] for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), [NAHCO3] [(68] g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 ml) and the combined organics were stirred and heated to [50C] for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2 x 440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear [(11).] The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous [NAHCO3] solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2 x 220 ml). The combined organic extracts were dried over anhydrous MgS04 and concentrated in vacuo affording crude [8-FLUOROIMIDAZO [1, 2-A]] pyridine. Purification was achieved by dissolving the crude material in EtOAc [(11)] and extracting with 2 N hydrochloric acid (5 x 50 ml). The acid washings were back-extracted with EtOAc (3 x 100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5 x 100 ml). The combined organic fractions were washed with brine, dried over anhydrous [MGS04] and concentrated in vacuo to afford 8- [FLUOROIMIDAZO] [1, 2-a] pyridine (11.4 g, 76% from 2-chloro-3-fluoropyridine): 8H (400 MHz, CDCl3) 6.69-6. 74 [(1H,] m), 6. [84-6. 87 (1H,] m), 7.65-7. 66 (2H, m), 7.97 [(1H,] dd, J 1.0 and 6.8) [; M/Z] (ES+) 137 [(100%,] [[MHJ+).] 8-Fluoroimidazo [1, 2-a] pyridine (68 mg, 0.50 mmol), 2-chloro-6- [TRIFLUOROMETHYLPYRIDINE] (182 mg, 1.0 [MMOL),] [CS2CO3] (326 mg, 1.0 mmol), tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.05 mmol) and 1,4- dioxane (3 ml) were heated to [150C] for 800 s in a Smith Personal [SYNTHESISERTM] using microwave irradiation. On cooling, the mixture was partitioned between [CH2CL2] (2 ml) and water (2 ml), and the phases separated using a [WHATMAN 5, UM] teflon filter tube. The organics were concentrated in vacuo and purified by column chromatography (silica; 90% EtOAc/isohexane), yielding the title imidazopyridine as a white amorphous solid [(85] mg, 60%): 8H (400 MHz; DMSO) 7.19-7. 24 [(1H, M),] 7.38-7. 43 [(1H,] m), 7.83 [(1H,] d, [J 7.] 4), 8. 20 [(1H,] t, J 8. 2), 8.38 [(1H,] s), 8.64 [(1H,] s), 9.64 [(1H,] dd, J 1.2 and...
3-Fluoro-4-methylpyridine To a cooled (-780C) solution of Lambda/,Lambda/-diisopropylamine (15.92mL, 113.4mmol) in THF (14OmL) a solution of BuLi 2.5M in hexane (45.4ml, 113.4 mmol) was added dropwise over 30 minutes under an atmosphere of Argon. The mixture was stirred for 30 min. at - 780C and a solution of 3-fluoropyridine (1 Og1 103.1 mmol) in THF (5ml) was added. After 1h at -780C, the mixture was treated with MeI (7 ml, 113.4mmol) and then was allowed to reach 250C. A solution of NaHCO3 saturated (30ml) was added and the aqueous phase was extracted with diethyl ether. The organic layer was dried (MgSO4) and upon distillation the product was collected as a colourless liquid, bp 1300C, yield 5.3 g (47percent) delta 1 H-NMR (CDCI3): 8.25 (s, 1 H), 8.18 (m, 1 H), 7.02 (m, 1 H). ESI/MS m/e: 112 ([M+H]+, C6H6FN)
With diisopropylamine;
3-Fluoro-4-methylpyridine (5-1) To a stirred solution of LDA (5.5 mmol) at -78° C., was added 3-fluoropyridine (486 mg, 5.0 mmol) dropwise. After stirring for 4h at -78° C., methyl iodide was added dropwise (0.343 mL, 5.5 mmol). The reaction was quenched after stirring at -78° C. for 2 h, by the addition of 20 mL of sat. aq. NH4Cl. This mixture was extracted with EtOAc (3*25 mL), the combined organics dried and concentrated to afford the product as a yellow solid 5-1: 1H NMR (CDCl3) delta 8.36 (br s, 1H), 8.27 (d, 1H, 4.8 Hz), 7.15 (br dd, 1H, 5.7, 5.7 Hz), 2.32 (s, 3H).
To a solution of diisopropylamine in THF (200 mL) was added a 2.44 M H-BuLi in THF (116 mL) at 0 0C and the mixture was stirred at 0 0C for 20 min. The mixture was cooled to -60 0C and a solution of 3-fluoropyridine (25.0 g) in THF (100 mL) was added. The mixture was stirred at -60 0C for 3 h and a solution of iodomethane (17.6 mL) in THF (100 mL) was added. The mixture was stirred at -60 0C for 30 min and the reaction was quenched with saturated aqueous NH4CI (100 mL). The aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure to give a colorless oil (14.6 g). To a solution of the above oil (14.6 g) in CHCl3 (145 mL) was added a suspension of m-chloroperbenzoic acid (34.8 g) in CHCl3 (145 mL) at 0 0C and the mixture was stirred at ambient temperature for 3 h. To the mixture was added saturated aqueous Na2S2psi3 and the organic layer was separated. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was washed with IM aqueous NaOH and saturated aqueous NaCl, dried over MgSO4, filtered, concentrated under reduced pressure EPO <DP n="102"/>and purified by medium-pressure liquid chromatography (silica gel, 2percent to 4percent MeOH in CHCl3) to give the title compound (3.47 g).1HNMR (SOO MHz, CDCl3, delta): 2.28-2.32 (m, 3H), 7.06-7.13 (m, IH), 7.96-8.00 (m, IH), 8.11 (dd,J= 4.9, 1.8 Hz, IH); ESI MS m/z 150 (M++23, 100percent).
With n-butyllithium; In tetrahydrofuran; diethyl ether; water;
Example 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78 C. The reaction mixture was warmed to -20 C. for 1 hour and then recooled to -78 C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78 C., the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78 C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0 C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10% ethyl acetate/hexanes) to afford 3.5 g (52% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) delta7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium; In tetrahydrofuran; diethyl ether; water;
Example 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78 C. The reaction mixture was warmed to -20 C. for 1 hour and then recooled to -78 C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78 C, the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78 C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0 C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10% ethyl acetate/hexanes) to afford 3.5 g (52% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) delta 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium; In tetrahydrofuran; diethyl ether; water;
EXAMPLE 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78 C. The reaction mixture was warmed to -20 C. for 1 hour and then recooled to -78 C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78 C., the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78 C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0 C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10% ethyl acetate/hexanes) to afford 3.5 g (52% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) delta7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium; In tetrahydrofuran; diethyl ether; water;
EXAMPLE 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78 C. The reaction mixture was warmed to -20 C. for 1 hour and then recooled to -78 C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78C, the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78 C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0 C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10% ethyl acetate/hexanes) to afford 3.5 g (52% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) delta 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
52%
With n-butyllithium; In tetrahydrofuran; diethyl ether; water;
Example 28A 2-chloro-3-fluoropyridine 1,4-Diazabicyclo[2.2.2]octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was treated dropwise with n-butyllithium (32.2 mL, 51.5 mmol, 1.6M solution in hexanes) at -78 C. The reaction mixture was warmed to -20 C. for 1 hour and then recooled to -78 C. The recooled mixture was treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL) dropwise. After stirring for 2 hours at -78 C., the mixture was treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring for one hour at -78 C., the reaction mixture was treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture was warmed to 0 C. and, after 30 minutes, additional water and diethyl ether were added to the mixture. The layers were separated and the aqueous phase extracted with diethyl ether (2*). The combined ethereal layers were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (10% ethyl acetate/hexanes) to afford 3.5 g (52% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) delta 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.
a) synthesis of l-(3-Fluoro-pyridin-2-yl)-ethanone (2a)[0205] A solution of BuLi (39.5 ml, 98.7 mmol, 2.5 M in hexane) in 100 ml THF was added to a solution of 3-fluoropyridine (1) (8g, 82.3 mmol) in 20 ml THF of at - 78 C. The reaction mixture was stirred at -78 C for 30 min. Then, N-methyl-N- methoxyacetamide 10.9 ml (106.9 mmol) was added at - 78 C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hour. The reaction was quenched with ice-cold saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (Ethyl acetate: n-Hexane = 1 : 6) and a 1 : 1 mixture of (2a) and (2b) was obtained 4.78 g (yield: 42%).
Diisopropylamine (1.50 ml, 10.8 mmol) was dissolved in THF (30 mL) and cooled to -78 C under nitrogen. nBuLi (4.32 mL, 2.5 M in hexanes, 10.8 mmol) was added drop-wise and the resulting solution was stirred at -78 C for 10 min, at 0 C for 30 min and then re- cooled to -78 C. 3-Fluoro-pyridine (0.93 mL, 10.8 mmol) was added drop-wise over 5 min and the reaction mixture was stirred for 2 h. A solution of Intermediate 24 (1.87 g, 10.8 mmol) in THF (15 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAC (10 mL) and diluted with EtOAc (200 mL). The organic fraction was washed with water (2 x 50 mL), dried (MgS04) and concentrated in vacuo to give the crude title compound as an orange oil (1.45 g, 64%). LCMS (ES+): 210.1 (M+H)+.
1.45 g
Diisopropyl amine (1.50 ml, 10.8 mmol) was dissolved in THF (30 mL) and cooled to -78 C under nitrogen. nBuLi (4.32 mL, 2.5 M in hexanes, 10.8 mmol) was added drop-wise and the resulting solution was stirred at -78 C for 10 min, at 0 C for 30 min and then re-cooled to -78 C. 3-Fluoro-pyridine (0.93 mL, 10.8 mmol) was added drop-wise over 5 min and the reaction mixture was stirred for 2 h. A solution of Intermediate 37 (1.87 g, 10.8 mmol) in THF (15 mL) was added and the reaction mixture was allowed to warm to RT and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAC (10 mL) and diluted with EtOAc (200 mL). The organic fraction was washed with water (2 x 50 mL), dried (MgSC^) and concentrated in vacuo to give the crude title compound as an orange oil (1.45 g, 64%). LCMS (ES+): 210.1 [MH]+.
Diisopropylamine (1.50 ml, 10.8 mmol) was dissolved in THF (30 mL) and cooled to -78 C. under nitrogen. nBuLi (4.32 mL, 2.5 M in hexanes, 10.8 mmol) was added drop-wise and the resulting solution was stirred at -78 C. for 10 min, at 0 C. for 30 min and then re-cooled to -78 C. 3-Fluoro-pyridine (0.93 mL, 10.8 mmol) was added drop-wise over 5 min and the reaction mixture was stirred for 2 h. A solution of Intermediate 24 (1.87 g, 10.8 mmol) in THF (15 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAc (10 mL) and diluted with EtOAc (200 mL). The organic fraction was washed with water (2*50 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as an orange oil (1.45 g, 64%). LCMS (ES+): 210.1 (M+H)+.
Diisopropylamine (1.50 ml, 10.8 mmol) was dissolved in THF (30 mL) and cooled to -78 C. under nitrogen. nBuLi (4.32 mL, 2.5 M in hexanes, 10.8 mmol) was added drop-wise and the resulting solution was stirred at -78 C. for 10 min, at 0 C. for 30 min and then re-cooled to -78 C. 3-Fluoro-pyridine (0.93 mL, 10.8 mmol) was added drop-wise over 5 min and the reaction mixture was stirred for 2 h. A solution of Intermediate 37 (1.87 g, 10.8 mmol) in THF (15 mL) was added and the reaction mixture was allowed to warm to RT and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAc (10 mL) and diluted with EtOAc (200 mL). The organic fraction was washed with water (2*50 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as an orange oil (1.45 g, 64%). LCMS (ES+): 210.1 [MH]+.
Stage #1: 3-Methylpyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h;
Stage #2: 3-Fluoropyridine at 100℃;
18
Example 18Preparation of 3-(3-methyl-1H-pyrazol-1-yl)pyridine and 3-(5-methyl-1H-pyrazol-1-yl)pyridine To a solution of 3-methyl-1H-pyrazole (10.99 g, 134 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added sodium hydride (3.71 g, 154 mmol, 60% dispersion). The reaction was stirred at 0° C. for 2 hours. 3-Fluoropyridine (10.0 g, 103 mmol) was added, and the reaction was stirred at 100° C. overnight. The reaction was cooled to room temperature and water was added slowly. The mixture was extracted with dichloromethane and the combined organic phases were washed with brine, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to afford 3-(3-methyl-1H-pyrazol-1-yl)pyridine (8.4 g, 52.77 mmol, 51.2%) and 3-(5-methyl-1H-pyrazol-1-yl)pyridine (1.0 g, 6%). Analytical data of both products is consistent with that reported under Example 6, Step 1.3-(3-Bromo-1H-pyrazol-1-yl)pyridine was prepared from 3-fluoropyridine and 3-bromopyrazole, which was made as in WO2008130021, as described Example 18: mp 89.5-92.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.4 Hz, 1H), 8.62-8.49 (m, 1H), 8.03 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.42 (dd, J=8.2, 4.7 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H); ESIMS m/z 224 ([M]+).
1: 51.2%
2: 6%
Stage #1: 3-Methylpyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h;
Stage #2: 3-Fluoropyridine In N,N-dimethyl-formamide; mineral oil at 100℃;
18 Example 18 Preparation of 3-(3-methyl-1H-pyrazol-1-yl)pyridine and 3-(5-methyl-1H-pyrazol-1-yl)pyridine
To a solution of 3-methyl-1H-pyrazole (10.99 g, 134 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added sodium hydride (3.71 g, 154 mmol, 60% dispersion). The reaction was stirred at 0° C. for 2 hours. 3-Fluoropyridine (10.0 g, 103 mmol) was added, and the reaction was stirred at 100° C. overnight. The reaction was cooled to room temperature and water was added slowly. The mixture was extracted with dichloromethane and the combined organic phases were washed with brine, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to afford 3-(3-methyl-1H-pyrazol-1-yl)pyridine (8.4 g, 52.77 mmol, 51.2%) and 3-(5-methyl-1H-pyrazol-1-yl)pyridine (1.0 g, 6%). Analytical data of both products is consistent with that reported under Example 6, Step 1.
1: 51.2%
2: 6%
Stage #1: 3-Methylpyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h;
Stage #2: 3-Fluoropyridine In N,N-dimethyl-formamide; mineral oil at 100℃;
18 Example 18 Preparation of 3-(3-methyl-1H-pyrazol-1-yl)pyridine and 3-(5-methyl-1H-pyrazol-1-yl)pyridine
Example 18 Preparation of 3-(3-methyl-1H-pyrazol-1-yl)pyridine and 3-(5-methyl-1H-pyrazol-1-yl)pyridine [0296] [0297] To a solution of 3-methyl-1H-pyrazole (10.99 g, 134 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added sodium hydride (3.71 g, 154 mmol, 60% dispersion). The reaction was stirred at 0° C. for 2 hours. 3-Fluoropyridine (10.0 g, 103 mmol) was added, and the reaction was stirred at 100° C. overnight. The reaction was cooled to room temperature and water was added slowly. The mixture was extracted with dichloromethane and the combined organic phases were washed with brine, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to afford 3-(3-methyl-1H-pyrazol-1-yl)pyridine (8.4 g, 52.77 mmol, 51.2%) and 3-(5-methyl-1H-pyrazol-1-yl)pyridine (1.0 g, 6%). Analytical data of both products is consistent with that reported under Example 6, Step 1. [0298] 3-(3-Bromo-1H-pyrazol-1-yl)pyridine was prepared from 3-fluoropyridine and 3-bromopyrazole, which was made as in WO2008130021, as described Example 18: mp 89.5-92.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.4 Hz, 1H), 8.62-8.49 (m, 1H), 8.03 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.42 (dd, J=8.2, 4.7 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H); ESIMS m/z 224 ([M]+).
1: 51.2%
2: 6%
Stage #1: 3-Methylpyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h;
Stage #2: 3-Fluoropyridine In N,N-dimethyl-formamide; mineral oil at 100℃;
18 Example 18Preparation of 3-(3-methyl-1 H-pyrazol-1 -yl)pyridine and 3-(5-methyl-1 H-pyrazol-1 -yl)pyridine
10298] To a solution of 3-methyl-1H-pyrazole (10.99 g, 134 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added sodium hydride (3.71 g, 154 mmol, 60% dispersion). The reaction was stirred at 0°C. for2 hours. 3-Fluoropyridine (10.0 g, 103 mmol) was added, and the reaction was stirred at 100° C. overnight. The reaction was cooled to room temperature and water was added slowly. The mixture was extracted with dichloromethane and the combined organic phases were washed with brine, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to afford 3-(3-methyl-1H- pyrazol-1-yl)pyridine (8.4 g, 52.77 mmol, 5 1.2%) and 3-(5- methyl-i H-pyrazol- 1 -yl)pyridine (1.0 g, 6%). Analytical data of both products is consistent with that reported under Example 6, Step 1.
Stage #1: 3-Fluoropyridine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: N-Methoxy-N-methylacetamide In tetrahydrofuran; hexane at -78 - 20℃; for 1h;
Stage #3: Methyl thioglycolate With sodium hydride In tetrahydrofuran at 0℃; for 10h; Reflux;
2.b
b) synthesis of 3-Methyl-thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (3)[0207] 4.78 g (34.3 mmol) of 2a and2b, (1 : 1 mixture) was dissolved in 30 ml THF and 3.75 ml of methyl thioglycolate (41.1 mmol) was added and cooled to 0 °C in an ice bath. 2.74 g (68.6 mmol) of NaH was added in several steps. The reaction mixture was heated to reflux. After 10 hours at this temperature, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (Ethyl acetate: n-Hexane = 1 : 6) and the target compound (3) was obtained 1.29 g (yield: 18%). 1H NMR (300MHz, CDC13): d 8.78 (dd, J= 1.2 Hz, 4.5 Hz, 1H), 8.17 (dd, J= 1.2 Hz, 8.1 Hz, 1H), 7.37 (dd, 4.5 Hz, 8.1 Hz, 1H), 3.97 (s, 3H), 2.87 (s, 3H), MS: m/z 208 [M+l]
Stage #1: 3-Methylpyrazole With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;
Stage #2: 3-Fluoropyridine In dimethyl sulfoxide; mineral oil at 100℃; for 3h; Inert atmosphere;
6 Example 6 Preparation of 3-(3-methyl-1H-pyrazol-1-yl)pyridine
To a solution of 60% sodium hydride in mineral oil (0.494 g, 12.36 mmol) in dry DMSO (20.60 mL) was added 3-methyl-1H-pyrazole (1.015 g, 12.36 mmol) slowly under a N2. This was stirred at ambient temp until no bubbling was observed (1 hr). To this mixture was added 3-fluoropyridine (1.0 g, 10.30 mmol), and then the reaction mixture was heated at 100° C. for 3 hr. The reaction mixture was allowed to cool to ambient temperature and then, it was diluted with H2O and extracted with DCM. The organic phase was dried with MgSO4, filtered and then the solvent was removed in vacuo. The residual oil was purified by normal phase chromatography eluting with 0-60% acetone in hexanes to afford 3-(3-methyl-1H-pyrazol-1-yl)pyridine as a white solid (828 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 8.97-8.91 (m, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.01 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.37 (ddd, J=8.3, 4.7, 0.7 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H), 2.39 (s, 3H); ESIMS m/z 159 ([M+H]+).
Stage #1: 3-Fluoropyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; cyclohexane at -78℃; for 0.833333h;
Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; cyclohexane at -78 - 20℃;
40 tert-butyl 4-[(3-fluoropyridin-4-yl)hydroxymethyl]piperidine-1-carboxylate
Diisopropyl amine (0.66 ml, 4.69 mmol) was dissolved in THF (30 ml) and cooled to -78 °C. nBuLi (2.13 ml, 2.20 M in cyclohexane, 4.69 mmol) was added drop-wise and the reaction mixture was stirred at -78 °C for 10 min, at 0 °C for 30 min, and re -cooled to -78 °C. 3-Fluoro- pyridine (0.40 ml, 4.69 mmol) was added drop-wise over 5 min, and the reaction mixture was stirred for 45 min. A solution of N-Boc-4-piperidinecarboxaldehyde (1.00 g, 4.69 mmol) in THF (10 ml) was added and the reaction mixture was warmed to RT and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAC (10 mL), diluted with EtOAc (100 mL), washed with water (2 x 50 mL), dried (MgSO^.) and concentrated in vacuo to give the title compound as an orange oil (1.42 g, 98%). LCMS (ES+): 255.0 [MH-t-Bu]+.
98%
Stage #1: 3-Fluoropyridine With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; cyclohexane at -78℃; for 0.833333h;
Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; cyclohexane at 20℃; for 0.25h;
tert-Butyl 4-[(3-fluoropyridin-4-yl)(hydroxy)methyl]piperidine-1-carboxylate
Diisopropylamine (0.66 ml, 4.69 mmol) was dissolved in THF (30 ml) and cooled to -78° C. nBuLi (2.13 ml, 2.20 M in cyclohexane, 4.69 mmol) was added drop-wise and the reaction mixture was stirred at -78° C. for 10 min, at 0° C. for 30 min, and re-cooled to -78° C. 3-Fluoro-pyridine (0.40 ml, 4.69 mmol) was added drop-wise over 5 min, and the reaction mixture was stirred for 45 min. A solution of N-Boc-4-piperidinecarboxaldehyde (1.00 g, 4.69 mmol) in THF (10 ml) was added and the reaction mixture was warmed to RT and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAc (10 mL), diluted with EtOAc (100 mL), washed with water (2*50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as an orange oil (1.42 g, 98%). LCMS (ES+): 255.0 [MH-t-Bu]+.
With triethylsilane; [Rh(mu-H)(1,3-bis(diisopropylphosphanyl)propane)]2; In benzene-d6; at 50℃; for 48h;Inert atmosphere;
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube alpha,alpha,alpha-trifluorotoluene (1?2 muL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(mu-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
INTERMEDIATE 14 3-(3-Iodo-lH-pyrazol-l-yl)pyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (1.00 g, 5.16 mmol) in DMSO (15.1 mL) was added sodium hydride (60% in oil, 0.247 g, 6.19 mmol), and stirred for 0.5 h before 3- fluoropyridine (0.443 mL, 5.16 mmol) was added. The reaction mixture was stirred at 90 C overnight. This was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 40 g, 0-50 % EtOAc in hexanes) to give 3-(3- iodo-lH-pyrazol-l-yl)pyridine, as a white solid. LCMS calc. = 271.96; found = 271.85 (M+H)+. 1H NMR (500 MHz, CDC13): delta 8.93 (d, J= 2.5 Hz, 1 H); 8.57 (dd, J= 4.7, 1.1 Hz, 1 H); 8.04 (d, J= 8.4 Hz, 1 H); 7.79 (d, J= 2.5 Hz, 1 H); 7.41 (dd, J = 8.3, 4.8 Hz, 1 H); 6.68 (d, J= 2.4 Hz, 1 H).
[0122] A mechanically stirred solution of 3-fluoropyridine (600 g, 6.18 mol) in dry THE (6 L) was cooled to -65C under N2 atmosphere. Lithium diisopropylamine solution in THE (3.4 L, 6.5 mol) was added over 2 hours while keeping the temperature below -60C, and the reaction mixture was allowed to stir an additional hour below -60C. Neat DME (804 mL, 10.4 mol) was then added over a one hour period at a rate as to maintain the temperature below -60C. The reaction mixture was monitored by TLC for the complete consumption of 3-fluoropyridine starting material. Upon completion, the reaction mixture was then warmed to -10C, and H20 (1.1 Kg, 62 mol) was added. Sodium borohyd ride (234 g, 6.18 mol) was then added in two portions over several minutes at 0C with stirring. Then 6 M HCI (5.6 L) was added over 1 h while maintaining the reaction quenching temperature between 0-25C. The reaction mixture was then heated to 40C and stirred at this temperature overnight. To the mixture 6 M NaOH was then slowly added at 0-15C to adjust the pH to 12. The aqueous layer was extracted with isopropylacetate (500 mL x 1, 1 Lx 3). The combined organic layers were washed with brine, dried over Na2504 and concentrated in vacuo. To the crude product was added heptane-isopropylacetate (1.2 L, v/v = 5/1), and the mixture was stirred at 0 C for 30 mm. The product crystallized as a pale-yellow solid during stirring. The mixture was filtered, the filter cake was extracted with cooled heptane (250 mL x 1), collected and dried under vacuum to give the title compound as a pale-yellow solid (688 g, 88%). 1H NMR (400 MHz, CDCI3) 6 8.42 (d, i = 4.8 Hz, 1H), 8.40 (d, i = 1.6 Hz, 1H), 7.49 (t, i = 4.8 Hz, 1H), 4.85 (s, 2H), 2.35 (br s, 1H).
88%
Step 1. (3-fluoropyridin-4-yl)methanol [0171] A mechanically stirred solution of 3-fluoropyridine (600 g, 6.18 mol) in dry THF (6 L) was cooled to -65 C under N2 atmosphere. Lithium diisopropylamine solution in THF (3.4 L, 6.5 mol) was added over 2 hours while keeping the temperature below -60 C, and the reaction mixture was allowed to stir an additional hour below -60 C. Neat DMF (804 mL, 10.4 mol) was then added over a one hour period at a rate as to maintain the temperature below -60 C. The reaction mixture was monitored by TLC for the complete consumption of 3-fluoropyridine starting material. Upon completion, the reaction mixture was then warmed to -10 C, and H20 (1.1 Kg, 62 mol) was added. Sodium borohydride (234 g, 6.18 mol) was then added in two portions over several minutes at 0 C with stirring. Then 6 M HCI (5.6 L) was added over 1 h while maintaining the reaction quenching temperature between 0-25 C. The reaction mixture was then heated to 40 C and stirred at this temperature overnight. To the mixture 6 M NaOH was then slowly added at 0-15 C to adjust the pH to 12. The aqueous layer was extracted with isopropylacetate (500 m L x 1, 1 L x 3). The combined organic layers were washed with brine, dried over Na2S04 and concentrated in vacuo. To the crude product was added heptane-isopropylacetate (1.2 L, v/v = 5/1), and the mixture was stirred at 0 C for 30 min. The product crystallized as a pale-yellow solid during stirring. The mixture was filtered, the filter cake was extracted with cooled heptane (250 m L x 1), collected and dried under vacuum to give the title compound as a pale-yellow solid (688 g, 88%). 1H N M R (400 M Hz, CDCI3) delta 8.42 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.49 (t, J = 4.8 Hz, 1H), 4.85 (s, 2H), 2.35 (br s, 1H).
Stage #1: 3-Fluoropyridine With (hydroxylamino)sulfonic acid In water at 90℃; for 1h;
Stage #2: ethyl pent-2-ynoate With potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃; Cooling with ice;
8.A Example 8: Synthesis of (3,5-Dibromo-4-hydroxyphenyl){2-ethyl-6-(ethylthio)pyrazolo[l,5-a]pyridin-3-yl}methanone
Hydroxylaminesulfonic acid (7.91 g, 69.9 mmol) was dissolved in water (35 mL), 3-methylpyridine (19.5 g, 209 mmol) was added, and the resulting mixture was stirred at 90 °C for 1 hour. The liquid was distilled off under reduced pressure at 65° C., and then the water was removed under reduced pressure with toluene (50 mL×3). The reaction mixture was dissolved in DMF (100 mL), potassium carbonate (40.0 g, 290 mmol) was added in portions under ice-water bath, then ethyl 2-pentynoate (8.8 g, 69.8 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours and warmed to 50°C and stirred overnight. Water (500 mL) was added, extracted with ethyl acetate (200 mL of X 3), and the combined organic phases were sequentially washed with water (100 mL×2) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:100) to give 2-ethyl-4-methylpyrazo[1,5-a Ethyl pyridine-3-carboxylate (17) (2.06 g). The yield was 12.7%. For the experimental procedure of Step A, see Step A in Example 7, wherein 3-picoline in Example 7, Step A is replaced with 3-fluoropyridine
tert-butyl 3-(3-fluoroisonicotinoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.91 g
To freshly prepared LDA solution in THF (30.0 mmol, 60 mL) at -78 oC under N2 atmosphere was added 3-fluoropyridine (2.43 g, 25 mmol) dropwise and stirred for 30 min at -78 oC. Then a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate (5.99 g, 22.0 mmol) in dry THF (40 mL) was added. The resulting mixture was allowed to warm to RT slowly overnight before quenching with aq NH4Cl solution. It was extracted with EA, washed with H2O, brine successively, and dried over anhydrous Na2SO4, and filtered, and evaporated to dry. The residue was purified by flash chromatography to afford 4.91 g of tert-butyl 3-(3-fluoroisonicotinoyl)piperidine-1- carboxylate. LCMS method D: tR: 1.45 min; (M+H)+ = 309.1
(3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
3-Fluoropyridine (1.94 g, 20 mmol) was dissolved in dry tetrahydrofuran (40 mL), and cooled to -78C under the protection of nitrogen. A 2.4 mol/L n-hexane solution of n-BuLi (10 mL, 24 mmol) was added dropwise slowly. The reaction mixture was stirred at -78C for additional 30 min, and then a tetrahydrofuran (10 mL) solution of N-methoxy-N-methyltetrahydro-2H-pyran-4- carboxamide (4.16 g, 24 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature, and stirred overnight. An ammonium chloride aqueous solution was added to quench the reaction. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated saline solution, and dried. The solvent was removed under vacuum to obtain a crude product. The crude product was purified by column chromatography to obtain the product (1.5 g, 36%). 1H NMR (400 MHz, CDCl3): delta 8.61 (d, J=2.0 Hz, 1H), 8.55-8.57 (m, 1H), 7.56-7.59 (m, 1H), 4.00-4.04 (m, 2H), 3.48-3.54 (m, 2H), 3.27-3.34 (m, 1H), 1.73-1.86 (m, 4H).
2-chloro-1-(3-fluoropyridin-4-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
n-Butyllithium (2.5 M in hexane, 2.58 mL, 6.44 mmol) was added dropwise to a mixture of diisopropylamine (0.87 mL, 6.18 mmol) in Et20 (30 mL) at -10 °C. After 30 min the mixture was cooled to -60 °C and a solution of 3-fluoropyridine (0.44 mL, 5.15 mmol) in Et20 (10 mL) was added dropwise at -60 °C. After 45 min a solution of 2-chloro-/V-methoxy-/\/- methylacetamide (708.49 mg, 5.15 mmol)l in Et20 (10 mL) was added dropwise at -60 °C and the mixture was stirred at -60 °C for 1 h. The cooling bath was removed and NH4CI (aq, 10 percent, 20 mL) was carefully added. The organic phase was collected, diluted with EtOAc, washed with NH4CI (aq, 10 percent), brine, dried (Na2S04), filtered through silica gel and concentrated. The residue was partitioned between H2O and CH2CI2 and the aq phase was washed with CH2CI2. The combined organic phases were dried (Na2S04) and concentrated to give the sub-title compound (750 mg, 4.32 mmol, 84 percent).
With 2-Iodothiophene; 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran at 25℃; for 20h; Inert atmosphere; Glovebox; Sealed tube; regioselective reaction;
With bis(1,5-cyclooctadiene)nickel (0); triisobutylaluminum; 3-(2-hydroxyethyl)-1-(4-methoxy-2,6-dimethylphenyl)-4,5-dimethyl-1H-imidazol-3-ium bromide; sodium t-butanolate In toluene at 100℃; for 12h; Inert atmosphere;
A typical procedure for Ni-catalysed C3-alkenylation:
General procedure: to a 15 ml oven-dried tube were added ligand L10 (14.5 mg, 10 mol%), Ni(cod) 2 (11.0 mg, 10 mol%) and t BuONa (4.6 mg, 12.5 mol%) and dry degassed toluene (1.0 ml) under a N 2 atmosphere. The mixture solution was stirred at 80 °C in a dry block heater for 30 min and then cooled down to room temperature. The pyridine derivative (0.4 mmol, 1 equiv.), Al i Bu 3 (1.1 M in 36.3 μl of toluene, 10 mol%) and alkyne (1.2 mmol, 3 equiv.) were added, and the tube was sealed and stirred at 100 °C in a dry block heater for 12 h. After that, the mixture was cooled to room temperature, quenched with 2 ml of 5% ethylenediamine tetraacetic acid disodium salt solution, filtered through a short plug of silica gel (EtOAc as the eluent) and concentrated in vacuo to afford a crude product. Further purification by flash column chromatography on silica gel (eluting with EtOAc/hexanes) gave the pure product.
Stage #1: 3-Fluoropyridine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3h; Inert atmosphere;
Stage #2: ethyl acetate In water monomer Inert atmosphere;
Step-1: 5-Chloro-3-fluoro-2-methylisonicotinic acid (LI)
General procedure: To a stirred solution of commercially available 5-chloro-3-fluoro-2-methylpyridine (L) (1.0 g, 6.87 mmol) in dry THF (10 mL) was added n-BuLi (4.12 mL, 8.24 mmol, 2M solution in hexane) dropwise at -78 oC and stirring was continued for a further 2 h. The reaction mixture was quenched by the addition of excess dry ice pellets and stirred thoroughly for a further 1 h. The reaction mixture was concentrated under reduced pressure to a semi-solid mass, which was dissolved in water (10 mL) and washed with Ethyl acetate (25 mL). The aqueous layer was acidified with 1N HCl to maintain the pH ~1 and then extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulphate and evaporated under reduced pressure to give the titled compound (LI) (1.06 g, 81% yield and qualitative HPLC purity: >96% by area normalization) as a yellowish solid which was used in the next step without any further purification.
Stage #1: 3-Fluoropyridine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3h; Inert atmosphere;
Stage #2: ethyl acetate In water monomer Inert atmosphere;
Step-1: 5-Chloro-3-fluoro-2-methylisonicotinic acid (LI)
General procedure: To a stirred solution of commercially available 5-chloro-3-fluoro-2-methylpyridine (L) (1.0 g, 6.87 mmol) in dry THF (10 mL) was added n-BuLi (4.12 mL, 8.24 mmol, 2M solution in hexane) dropwise at -78 oC and stirring was continued for a further 2 h. The reaction mixture was quenched by the addition of excess dry ice pellets and stirred thoroughly for a further 1 h. The reaction mixture was concentrated under reduced pressure to a semi-solid mass, which was dissolved in water (10 mL) and washed with Ethyl acetate (25 mL). The aqueous layer was acidified with 1N HCl to maintain the pH ~1 and then extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulphate and evaporated under reduced pressure to give the titled compound (LI) (1.06 g, 81% yield and qualitative HPLC purity: >96% by area normalization) as a yellowish solid which was used in the next step without any further purification.
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