* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 12, p. 2740 - 2744
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567
3
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[ 113975-22-7 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 4 h; Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 1 h;
(a) 222 mL of n-butyllithium (1.57 mol/L hexane solution) was dropwise added at -20°C to a solution having 34.2 g (340 mmol) of diisopropylamine dissolved in 400 mL of tetrahydrofuran, followed by stirring for 1 hour. The solution was cooled to -78°C, a solution having 32.0 g (330 mmol) of 2-fluoropyridine dissolved in 50 mL of tetrahydrofuran was added thereto, followed by stirring for 4 hours, and a solution having 87.1 g (341 mmol) of iodine dissolved in 150 mL of tetrahydrofuran was added thereto, followed by stirring for 1 hour. 200 mL of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl ether was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure, to obtain 67.4 g (crude yield 92percent) of a crude product of 2-fluoro-3-iodopyridine.1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 6.91-6.88(m,1H), 8.08-8.12(m,2H)
83.6%
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 3 h;
[0188] To a solution of 2-fluoropyridine (5.0 g, 51.5 mmol) in dry THF (50 mL) was added LDA (25.8 mL of a 2M solution in THF, 51.5 mmol) dropwise at -78 °C. The mixture was then stirred at -78 °C for 1 hour. A solution of I2 (13.07 g, 51.5 mmol) in THF (30 mL) was added dropwise at -78 °C to the mixture. After stirring for 3 hours at -78°C, the reaction was quenched by addition of H20 (10 mL) and slowly warmed to room temperature. A solution of Na2S03 (50 mL, 2M in H20) was added. The organic layer was separated, washed with brine, dried over anhydrous Na2S04 and then concentrated to give crude product, which was purified via column chromatography to give 2-fluoro-3-iodopyridine (9.6 g, yield 83.6percent) as a white solid. LC/MS: m/z (M++H) = 224.
78%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 0℃; for 2.58 h; Stage #2: With iodine In tetrahydrofuran at -20℃; Stage #3: With water In tetrahydrofuran at 0℃;
To a solution of diisopropylamine (260 g, 2.57 mol) in anhydrous THF (6.5 L) at -30 to -40° C. under a blanket of N2 was added n-BuLi (156 g, 2.45 mol) dropwise via cannula. The resulting solution was allowed to warm to 0° C. and stirred at this temperature for 35 min. The solution was then cooled to -78° C. and 2-fluoropyridine (250 g, 2.57 mol, Alfa) was added dropwise. The reaction mixture was stirred at -78° C. for 2 h. This mixture was then added via cannula to a solution of iodine (654 g, 2.57 mol) in anhydrous THF (1.96 L) at -20° C. under N2. After the reaction was complete, the mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with sodium thiosulfate followed by water and brine. The organics were then dried (Na2SO4) and concentrated in vacuo to give 2-fluoro-3-iodopyridine (450 g, 78percent) as a solid, which was sufficiently pure to use in the subsequent step.
71%
Stage #1: With n-butyllithium; diethylamine In tetrahydrofuran at -78 - 0℃; for 2 h; Stage #2: With iodine In tetrahydrofuran
A-40 oC solution of diethylamine (12.4g, 125 mmol) in THF (100 mL) was treated dropwise with 1.6 M N-BUTYLLITHIUMI in hexane (79 mL, 125 mmol), stirred at 0 C briefly, cooled TO-78 C, treated with a solution of 2-fluororpyridine (9. 71g, 100 mmol) in THF (80 mL), stirred at-78 oC for 2 hours, treated with a solution of iodine (34.48g, 120 mmol) in THF (100 mL), and stirred overnight while gradually warming to room temperature. The reaction mixture was poured into water (1 L) and extracted with diethyl ether several times. The combined extracts were washed with water, NA2S203, and brine, dried (MGS04), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 25: 1 hexanes/ethyl acetate to provide 15. 9g (71percent) of the desired product.
61%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -70℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran; hexane at -20℃; Inert atmosphere
To a solution of diisopropylamine (104 g, 1 .03 mol) in dry THF (2.6 L) was added dropwise 2.5 M solution of π-BuLi in hexane (392 mL, 0.98 mol) at -30 to -40°C under N2. The resulting mixture was stirred at 0°C for 35 min. The mixture was cooled to -70°C and a solution of 2-fluoropyridine (I-25) (100 g, 1 .03 mol) in dry THF (800 mL) was added. After stirring at -70°C for 2 hr, the mixture was added to a solution of l2 (261 .6 g, 1 .03 mol) in dry THF (800 mL) at -20°C under N2. After the reaction was complete, the mixture was quenched with ice water (4 L). The mixture was diluted with EtOAc (4 L) and washed with aq. Na2S203 (500 mL) and brine (500 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by distillation in vacuum to afford 2-fluoro-3-iodopyridine (I-26) (140 g, 61 percent) as a yellow solid.
60.6%
With iodine; lithium diisopropyl amide In tetrahydrofuran
Synthesis of 2-fluoro-3-iodopyridine A 1 L 2-necked flask was charged with 100 mL of a 2 N solution of lithium diisopropylamide and 400 mL of tetrahydrofuran. This was cooled to -72° C. and 2-fluoropyridine (19.42 g, 200 mmol) dissolved in 100 mL of tetrahydrofuran was added dropwise. This was stirred at -70° C. for 4 h before dropwise addition of 51 g (200 mmol) of iodine dissolved in 150 mL of tetrahydrofuran. This was stirred for 1 h before being quenched with water. The mixture was diluted with ethyl acetate and aqueous sodium bisulfite. The organic layer was evaporated in vacuo and the product was distilled on a Kugelrohr yielding 2-fluoro-3-iodopyridine (27.0 g, 60.6percent yield).
60.6%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -72 - -70℃; for 4 h; Stage #2: With iodine In tetrahydrofuran for 1 h;
A I L 2-necked flask was charged with 100 mL of a 2 N solution of lithium diisopropylamide and 400 mL of tetrahydrofuran. This was cooled to "72 °C and 2-fluoropyridine (19.42 g, 200 mmol) dissolved in 100 mL of tetrahydrofuran was added dropwise. This was stirred at "70 °C for 4 h before dropwise addition of 51 g (200 mmol) of iodine dissolved in 150 mL of tetrahydrofuran. This was stirred for 1 h before being quenched with water. The mixture was diluted with ethyl acetate and aqueous sodium bisulfite. The organic layer was evaporated in vacuo and the product was distilled on a Kugelrohr yielding 2- fluoro-3-iodopyridine (27.0 g, 60.6percent yield).
59.4%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at -78℃; for 4.5 h; Stage #2: With iodine In tetrahydrofuran; hexanes at -78℃; for 0.5 h;
To a solution of n-butyllithium in hexanes (40.14 mL, 1.6 M) under argon at-78 °C was added diisopropylamine (6.5 g, 64.2 mmol, 1.0 eq). After stirring for 30 min at-78 °C, a solution OF 2-FLUOROPYRIDINE (6.23 g, 64.2 MMOL, 1.0 eq) in anhydrous THF (50 mL) was added. The reaction mixture was stirred at-78 °C for 4 h. Iodine (16.3 g, 64.2 MMOL, 1.0 eq) was then added, and the reaction mixture was stirred at-78 °C for another 30 min. The reaction was HYDROLYZED with 10percent water-THF, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure, and the crude product was purified on a MPLC (Biotage) eluted with 20/8020 v/v ethyl acetate-hexane to give 2-fluoro-3-iodo- pyridine as a yellow oil (8.50 g, 59. 4percent). H-NMR (ACETONE-D6) 8 8.14 (m, 2H), 6.94 (m, 1H) ; GC-MS (M+ = 223, RT = 9.50 min); Rf = 0.70 (30percent ethyl acetate-hexane).
59.4%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78℃; for 4 h; Stage #3: With iodine In tetrahydrofuran at -78℃; for 0.5 h;
Example 14; Method H-7; Preparation of 2-fluoro-3-iodo-pyridine; To a solution of n-butyllithium in hexanes (40.14 mL, 1.6 M) under argon at-78 °C was added diisopropylamine (6.5 g, 64.2 mmol, 1.0 eq). After stirring for 30 min at-78 °C, a solution of 2-fluoropyridine (6.23 g, 64.2 mmol, 1.0 eq) in anhydrous THF (50 mL) was added. The reaction mixture was stirred at-78 °C for 4 h. Iodine (16.3 g, 64.2 mmol, 1.0 eq) was then added, and the reaction mixture was stirred at-78 °C for another 30 min. The reaction was hydrolyzed with 10percent water-THF, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure, and the crude product was purified on a MPLC (Biotage) eluted with 20/8020 v/v ethyl acetate-hexane to give 2-fluoro-3-iodo- pyridine as a yellow oil (8.50 g, 59. 4percent). 1H-NMR (Acetone -d6) No. 8.14 (m, 2H), 6.94 (m, 1 H) ; GC-MS (M+ = 223, RT = 9.50 min); Rf = 0.70 (30percent ethyl acetate-hexane).
59.4%
Stage #1: With n-butyllithium; diisopropylamine In hexane at -78℃; for 0.5 h; Stage #2: at -78℃; for 4 h;
Preparation of 2-fluoro-3-iodo-pyridine. To a solution of n-butyllithium in hexanes (40.14 mL, 1.6 M) under argon at -78 0C was added diisopropylamine (6.5 g, 64.2 mmol, 1.0 eq). After stirring for 30 min at -78 0C, a solution of 2- fluoropyridine (6.23 g, 64.2 mmol, 1.0 eq) in anhydrous THF (50 mL) was added. The reaction mixture was stirred at -78 0C for 4 h. Iodine (16.3 g, 64.2 mmol, 1.0 eq) was then added, and the reaction mixture was stirred at -78 0C for another 30 min. The reaction was hydrolyzed with 10percent water - THF, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure, and the crude product was purified on a MPLC (Biotage) eluted with 20/8020 v/v ethyl acetate - hexane to give 2-fluoro-3- iodo-pyridine as a yellow oil (8.50 g, 59.4percent). 1H-NMR (Acetone -d6) 8.14 (m, 2H), 6.94 (m, IH); GC-MS (M+ = 223, RT = 9.50 min); Rf = 0.70 (30percent ethyl acetate - hexane).
37%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran at -78℃; for 3 h; Stage #2: With iodine In tetrahydrofuran for 1 h;
Example 85 Synthesis of 2-(4-((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile, I-85 Synthesis of Compound 85.2. To a solution of LDA (2.1 g, 21.0 mmol, 1.05 eq) in THF (15.0 mL) was added n-BuLi (8.6 mL, 21.0 mmol, 1.05 eq) at -20° C. The reaction was stirred at same temperature for 1 hour. Compound 85.1 (2.0 g, 20.0 mmol, 1.0 eq) was added at -78° C. and the reaction was stirred for 3 hours. Then a solution of I2 (5.3 g, 21.0 mmol, 1.05 eq) in THF (15.0 mL) was added dropwise to the reaction mixture and the reaction was stirred for 1 hour. After completion of the reaction, mixture was poured into water and product was extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain pure 85.2 (1.7 g, 37.0percent). MS(ES): m/z 222.99 [M+H]+.
26.5 g
With n-butyllithium; iodine; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 3.5 h; Inert atmosphere
A) 2-fluoro-3-iodopyridine [0390] To a solution of diisopropylamine (21.5 mL) in THF (300 mL) was added 1.6M n-butyllithium hexane solution (97 mL) under argon atmosphere at -20°C, and the mixture was stirred under argon atmosphere at 0°C for 30 min. To the reaction mixture was added a solution of 2-fluoropyridine (15.0 g) in THF (20 mL) at -78°C, and the mixture was stirred under argon atmosphere at -78C for 3 hr. To the reaction mixture was added a solution of iodine (39.2 g) in THF (80 mL) at -78°C, and the mixture was stirred under argon atmosphere at -78°C for 30 min. To the reaction mixture was added water, and then saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogencarbonate solution were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (26.5 g). 1H NMR (300 MHz, CDCl3) δ 6.92-7.01 (1H, m), 8.11-8.23 (2H, m).
With cesium fluoride In dimethyl sulfoxide at 130℃; for 4 h;
General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 °C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 percent) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.
Reference：
[1] Tetrahedron, 2016, vol. 72, # 17, p. 2196 - 2205
[2] Chemistry - A European Journal, 2010, vol. 16, # 27, p. 8191 - 8201
8
[ 372-48-5 ]
[ 113975-22-7 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 37, p. 10405 - 10416
9
[ 36178-05-9 ]
[ 113975-22-7 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
10
[ 124-41-4 ]
[ 113975-22-7 ]
[ 112197-15-6 ]
Yield
Reaction Conditions
Operation in experiment
85.4%
for 1 h; Heating / reflux
To a solution of sodium methoxide (8.0 mL, 35.9 mmol, 4.0 eq, 25percent in methanol) in methanol (60 mL) was added 2-fluoro-3-iodo-pyridine (2.0 g, 8.97 MMOL). The reaction mixture was REFLUXED under argon for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure to give 1.8 G (85.4percent) of crude product as a YELLOW OIL. H-NMR (ACETONE-D6) S 8.16 (m, 2H), 6.78 (m, 1H), 3.93 (s, 3H); LC-MS (ES MH+ = 236.2) ; Rf = 0.75 (30percent ethyl acetate-hexane).
85.4%
for 1 h; Heating / reflux
Example 15; Method H-8; Preparation of 3-iodo-2-methoxy-pvridine; To a solution of sodium methoxide (8.0 mL, 35.9 mmol, 4.0 eq, 25percent in methanol) in methanol (60 mL) was added 2-fluoro-3-iodo-pyridine (2.0 g, 8.97 mmol). The reaction mixture was refluxed under argon for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure to give 1.8 g (85.4percent) of crude product as a yellow oil.'H-NMR (Acetone-d6) 8 8.16 (m, 2H), 6. 78 (m, 1H), 3.93 (s, 3H); LC-MS (ES MH+ = 236.2) ; Rf = 0.75 (30percent ethyl acetate-hexane).
85.4%
for 1 h; Heating / reflux
Preparation of 3-iodo-2-methoxv-pvridine. To a solution of sodium methoxide (8.0 mL, 35.9 mmol, 4.0 eq, 25percent in methanol) in methanol (60 mL) was added 2-fluoro-3-iodo-pyridine (2.0 g, 8.97 mmol). The reaction mixture was refluxed under argon for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure to give 1.8 g (85.4percent) of crude product as a yellow oil. 1H-NMR (Acetone -d6) 08.16 (m, 2H), 6.78 (m, IH), 3.93 (s, 3H); LC-MS (ES MH+ = 236.2); Rf = 0.75 (30percent ethyl acetate - hexane).
With n-butyllithium; diethylamine In tetrahydrofuran at -78 - 0℃; for 2 h;
A-40 oC solution of diethylamine (5. 51G, 55.5 mmol) in THF (80 mL) was treated dropwise with 2.5 M n-butyllithium in hexane (22.2 mL, 55.5 mmol), stirred at 0 C briefly, cooled TO-78 C, treated with a solution of Example 68A (9.9g, 44.4 mmol) in THF (80 mL), stirred at-78 oC for 2 hours, treated with water (3.6g, 200 mmol), stirred for 5 minutes, then poured into water (500 mL), and extracted with diethyl ether several times. The combined extracts were washed water and brine, dried (MGS04), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 25: 1 hexanes/ethyl acetate to provide 9.5g (96percent) of the desired product.
89%
With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1 h;
(b) 189 mL of n-butyllithium (1.57 mol/L hexane solution) was dropwise added at -20°C to a solution having 30.2 g (302 mmol) of diisopropylamine dissolved in 380 mL of tetrahydrofuran, followed by stirring for 1 hour. The solution was cooled to -78°C, a solution having 67.4 g (302 mmol) of the crude product of 2-fluoro-3-iodopyridine obtained in step (a) dissolved in 100 mL of tetrahydrofuran was added thereto, followed by stirring for 1 hour. 300 mL of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl ether was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure, to obtain 59.3 g (crude yield 89percent) of a crude product of 2-fluoro-4-iodopyridine.1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 7.33(d,1H, J = 2.8 Hz), 7.51(d,1H, J = 5.2 Hz), 7.88(dd,1H, J=5.2 Hz, 2.8 Hz)
87.5%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 4 h; Stage #2: With water In tetrahydrofuran at -78 - 20℃;
[0189] To a solution of 2-fluoro-3-iodopyridine (4.0 g, 17.9 mmol) in dry THF (50 mL), was added LDA (8.96 mL of a 2M solution in THF, 17.9 mmol) dropwise at -78 °C. After stirring for 4 hours at -78 °C, H20 (0.5 mL) in THF (1 mL) was added. The mixture was slowly warmed to room temperature, followed by addition of brine (30 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2S04 and then concentrated to give crude product, which was purified by column chromatography to give 2-fluoro-4- iodopyridine (3.5 g, yield : 87.5percent) as a white solid. LC/MS: m/z (M++H) = 224.
Reference：
[1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 10, p. 1927 - 1948
[2] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[3] Patent: WO2004/76424, 2004, A1, . Location in patent: Page 85
[4] Patent: EP1559320, 2005, A1, . Location in patent: Page/Page column 6
[5] Patent: WO2013/6792, 2013, A1, . Location in patent: Paragraph 0189
[6] Tetrahedron, 2004, vol. 60, # 29, p. 6113 - 6120
[7] Organic Letters, 2010, vol. 12, # 9, p. 2136 - 2139
[8] Patent: WO2011/109254, 2011, A1, . Location in patent: Page/Page column 130
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 0.5 h; Inert atmosphere
2-Fluoro-4-iodo-3-methylpyridine (0412) To a solution of LDA (68 mL, 135 mmol) at −78° C. was added a solution of 2-fluoro-3-iodopyridine (30 g, 135 mmol) in THF (100 mL), and the mixture is stirred for 1 hour at −78° C. under nitrogen. MeI (25 mL, 405 mmol) was then added, and the mixture was stirred for 30 min at −78° C. The mixture was quenched with sat. aq. NaHCO3 solution at −78° C. and then extracted with ether. The combined ether extracts were dried with MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to give the title compound as a brown solid (22 g, 69percent). (0413) MS (ES+) C6H5FIN requires: 237, found: 238 [M+H]+.
72%
With n-butyllithium; diisopropylamine In tetrahydrofuran
EXAMPLE 4 2-Fluoro-4-iodo-3-methylpyridine (6) To a solution of LDA, freshly prepared from diisopropylamine (0.126 mL, 0.899 mmol) and n-BuLi (0.899 mmol), in THF (2 mL) at -78° C. is cannulated a solution of 2-fluoro-3-iodopyridine (200 mg, 0.897 mmol) in 0.4 mL of THF, and the mixture is stirred for 1 hour at -78° C. under nitrogen. Iodomethane (0.17 mL, 2.73 mmol) is added neat and the mixture is stirred for 30 min. at -78° C. The mixture is quenched with saturated sodium bicarbonate solution at -78° C. and then extracted with ether. Combined ether extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes) to give 154 mg (72percent) of product as an off-white solid having amp of 90-91 ° C.
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[2] Tetrahedron, 2004, vol. 60, # 29, p. 6113 - 6120
[3] Tetrahedron Letters, 1995, vol. 36, # 44, p. 7995 - 7998
[4] Patent: US2017/342078, 2017, A1, . Location in patent: Paragraph 0412; 0413
[5] Patent: US5496952, 1996, A,
14
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[ 109-94-4 ]
[ 153034-82-3 ]
Yield
Reaction Conditions
Operation in experiment
46%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -70℃; for 2 h; Stage #2: at -70 - 20℃;
To a solution of diisopropylamine (174.4g, 1 .73 mol) in dry THF (3 L) was added dropwise 2.5 M solution of n-BuLi in hexane (685 mL, 1 .71 mol) at -10°C. The resulting mixture was stirred at 0°C for 35 min. The mixture was cooled to -70°C and a solution of 2-fluoro-3-iodopyridine (I-26) (350 g, 1 .57 mol) in dry THF (1 L) was added. The mixture was stirred at -70°C for 2 hr. HCOOEt (128 g, 1 .73 mol) was added dropwise at -70°C. After the addition, the mixture was allowed to warm to room temperature and quenched with ice water (4 L). The mixture was diluted with EtOAc (4 L) and washed with brine (500 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with petroleum:EtOAc = 10:1 to afford 2-fluoro-4-iodonicotinaldehyde (I-27) (180 g, 46percent) as a yellow solid.1H NMR (400 MHz, CDCI3) δ ppm 10.08 (s, 1 H), 7.91 (d, 1 H), 7.81 (d, 1 H).
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[2] Patent: WO2016/97918, 2016, A1, . Location in patent: Page/Page column 58
15
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[ 113975-22-7 ]
[ 109-94-4 ]
[ 158669-26-2 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; n-heptane at -75 - -20℃; for 2 h; Stage #2: at -75℃; for 0.166667 h; Stage #3: at -75 - 20℃;
A mixture of DIPA (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 °C and nBuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 mm, the r.m. was cooled to -75 °C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 °C. The r.m. was cooled to -75 °C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 mill sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25percent purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), Et20 (100 mL) and the layers were separated. The aq. layer was extracted with Et20 (100 mL) and the combined organic layers weretreated with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94percent), which was used as such in the next reaction step.
64%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - -8℃; for 2.5 h; Stage #2: at -78 - 20℃; Stage #3: With water In tetrahydrofuran; methanol at 0℃;
To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrous THF (5 L) at -8 to -10° C. under a blanket of N2 was added n-BuLi (880 mL, 158 g, 2.46 mol) dropwise via cannula. The mixture was stirred at -10° C. for 30 min, cooled to -78° C. and treated with a solution of 2-fluoro-3-iodopyridine (500 g, 2.24 mol) in dry THF (2 L) dropwise. After the addition, the reaction mixture was warmed to -60° C. and this temperature was maintained for 2 h. The mixture was then cooled to -78° C., treated with ethyl formate (183 g, 2.47 mol) dropwise, followed by sodium methoxide (149 g, 2.75 mol) in MeOH (1.5 L) and warmed to ambient temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The layers were separated and the organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-iodo-2-methoxynicotinaldehyde (380 g, 64percent) as a solid.
44 g
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -66 - -10℃; for 2 h; Inert atmosphere Stage #2: at -66℃; Inert atmosphere
Under the stream of nitrogen, a THF (500 mL) solution of diisopropylamine (25 g) was added into a 2L-fourneckedflask. The solution was cooled to -25°C, and n-butyl lithium - hexane solution (1.57 mol/L) (157 mL) was droppedto the solution for 20 minutes (-25°C → -15°C), and the solution was stirred at -10°C for 30 minutes. The resulting solutionwas cooled to -66°C, and a THF (200 mL) solution of 2-fluoro-3-iodopyridine (CAS registration No.: 113975-22-7) (50g) was dropped thereto for 25 minutes, and stirred at -60°C for two hours. The resulting solution was cooled to -66°C,and ethyl formate (18.3 g) was dropped thereto for 10 minutes. Then, 28percent solution of sodium methoxide methanolsolution (53.2 g) in methanol (100 mL) was dropped, and lifted up from dry ice bath. The resulting product was naturallycooled to room temperature, and ice water (100 mL) was dropped thereto. A saturated saline solution (1 L) was addedthereto. The resulting solution was extracted with ethyl acetate (1 L), and washed with water (700 mL) and a saturatedsaline solution (700 mL). The water layer was combined and extracted with ethyl acetate (500 mL 3 2), and washedwith water (500 mL) and a saturated saline solution (500 mL). The organic layer was combined and dried over anhydroussodium sulfate, and the solvent was removed by evaporation under reduced pressure. The obtained residue was purifiedby column chromatography on silica gel (hexane : ethyl acetate = 9:1 → 6:1 → 5:1 → 4:1 → 3:1) to obtain the titlecompound (44 g) having the following physical property values
With n-butyllithium; sodium borohydrid; diisopropylamine In tetrahydrofuran; ethyl acetate
EXAMPLE 1 2-Fluoro-4-iodo-3-(hydroxymethyl)pyridine To a solution of LDA, freshly prepared from diisopropylamine (0.63 mL, 4.49 mmol) and n-BuLi (4.49 mmol) in THF (10 mL) at -78° C., is cannulated a solution of 2-fluoro-3-iodopyridine (1 g, 4.48 mmol) in 2 mL of THF, and the mixture is stirred for 1 hour at -78° C. under nitrogen. Ethyl formate (1.1 mL, 13.6 mmol) is added to the reaction mixture at -78° C. and stirring is continued for 30 min. The reaction is quenched with saturated sodium bicarbonate solution at -78° C. and allowed to warm to room temperature. Sodium borohydride (0.34 g, 8.99 mmol) is slowly added to the reaction mixture and then stirred for 30 min. The mixture is extracted with ethyl acetate. The combined ethyl acetate extracts are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes, 10percent EtOAc/hexanes, 20percent EtOAc/hexanes) to afford 708 mg (62 percent) of the product as a white solid having a mp of 69°-70° C. Elemental Analysis for C6 H5 FINO: theory: C 28.48, H 1.99, N 5.54; found: C 28.55, H 1.94, N 5.48. IR (KBr): cm1 3336, 1584, 1541, 1446, 1401, 1264, 1218, 1003, 870, 833,803,761,577. 1 H NMR (CDCl3): δ7.79-7.82 (d, 1H,J=5 Hz), 7.66-7.68 (d, 1H, J=5 Hz), 4.82-4.86 (d, 2H, J=7 Hz), 1.99-2.04 (t, 1H, J=14 Hz). 13 C NMR (CDCl3): δ 162.29, 159.05, 147.30, 147.09, 132.79, 132.73,126.14, 125.73, 114.21, 62.24.
Reference：
[1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 10, p. 1927 - 1948
19
[ 1065010-87-8 ]
[ 113975-22-7 ]
[ 1227177-68-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 130℃; for 2 h; Inert atmosphere; Microwave irradiation
2-Fluoro-3-iodopyridine (300 mg, 1 .34 mmol), potassium cyclopropyltrifluoroborate (498 mg, 3.36 mmol), palladium (II) acetate (30 mg, 0.135 mmol) are dissolved in toluene (4 mL) under a nitrogen flow. Tricyclohexylphosphine (75 mg, 0.27 mmol), tn-potassium phosphate (1.1 g, 5.38 mmol) and water (0.4 mL) are added and the reaction mixture is heated under microwave irradation (1 30°C) for 2h. At rt, water is added and the aqueous layer is extracted with DCM. Then the organic layer is washed with water and brine, separated and dried to furnish 3-cyclopropyl-2-fluoro- pyridine (200 mg, 97percent).U PLC-MS (Method 2): R = 0.94 mmMS (ESI pos): mlz = 138 (M+H)
97%
With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 130℃; for 2 h; Inert atmosphere; Microwave irradiation
10449] 2-Fluoro-3-iodopyridine (300 mg, 1.34 mmol), potassium cyclopropyltrifluoroborate (498 mg, 3.36 mmol), palladium (II) acetate (30 mg, 0.135 mmol) are dissolvedtoluene (4 mE) under a nitrogen flow. Tricyclohexylphosphine (75 mg, 0.27 mmol), tri-potassium phosphate (1.15.38 mmol) and water (0.4 mE) are added and the reaction mixture is heated under microwave irradation (130° C.) forh. At it, water is added and the aqueous layer is extracted with DCM. Then the organic layer is washed with water and brine, separated and dried to thmish 3-cyclopropyl-2-fluoro-pyri- dine (200 mg, 97percent).10450] UPEC-MS (Method 2): R=0.94 mm10451] MS (ESI pos): mlz=138 (M+H)
(a) 222 mL of n-butyllithium (1.57 mol/L hexane solution) was dropwise added at -20C to a solution having 34.2 g (340 mmol) of diisopropylamine dissolved in 400 mL of tetrahydrofuran, followed by stirring for 1 hour. The solution was cooled to -78C, a solution having 32.0 g (330 mmol) of 2-fluoropyridine dissolved in 50 mL of tetrahydrofuran was added thereto, followed by stirring for 4 hours, and a solution having 87.1 g (341 mmol) of iodine dissolved in 150 mL of tetrahydrofuran was added thereto, followed by stirring for 1 hour. 200 mL of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl ether was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure, to obtain 67.4 g (crude yield 92%) of a crude product of 2-fluoro-3-iodopyridine.1H-NMR(CDCl3, 400 MHz) : delta (ppm) = 6.91-6.88(m,1H), 8.08-8.12(m,2H)
83.6%
With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 3h;
[0188] To a solution of 2-fluoropyridine (5.0 g, 51.5 mmol) in dry THF (50 mL) was added LDA (25.8 mL of a 2M solution in THF, 51.5 mmol) dropwise at -78 C. The mixture was then stirred at -78 C for 1 hour. A solution of I2 (13.07 g, 51.5 mmol) in THF (30 mL) was added dropwise at -78 C to the mixture. After stirring for 3 hours at -78C, the reaction was quenched by addition of H20 (10 mL) and slowly warmed to room temperature. A solution of Na2S03 (50 mL, 2M in H20) was added. The organic layer was separated, washed with brine, dried over anhydrous Na2S04 and then concentrated to give crude product, which was purified via column chromatography to give 2-fluoro-3-iodopyridine (9.6 g, yield 83.6%) as a white solid. LC/MS: m/z (M++H) = 224.
78%
To a solution of diisopropylamine (260 g, 2.57 mol) in anhydrous THF (6.5 L) at -30 to -40 C. under a blanket of N2 was added n-BuLi (156 g, 2.45 mol) dropwise via cannula. The resulting solution was allowed to warm to 0 C. and stirred at this temperature for 35 min. The solution was then cooled to -78 C. and 2-fluoropyridine (250 g, 2.57 mol, Alfa) was added dropwise. The reaction mixture was stirred at -78 C. for 2 h. This mixture was then added via cannula to a solution of iodine (654 g, 2.57 mol) in anhydrous THF (1.96 L) at -20 C. under N2. After the reaction was complete, the mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with sodium thiosulfate followed by water and brine. The organics were then dried (Na2SO4) and concentrated in vacuo to give 2-fluoro-3-iodopyridine (450 g, 78%) as a solid, which was sufficiently pure to use in the subsequent step.
71%
A-40 oC solution of diethylamine (12.4g, 125 mmol) in THF (100 mL) was treated dropwise with 1.6 M N-BUTYLLITHIUMI in hexane (79 mL, 125 mmol), stirred at 0 C briefly, cooled TO-78 C, treated with a solution of 2-fluororpyridine (9. 71g, 100 mmol) in THF (80 mL), stirred at-78 oC for 2 hours, treated with a solution of iodine (34.48g, 120 mmol) in THF (100 mL), and stirred overnight while gradually warming to room temperature. The reaction mixture was poured into water (1 L) and extracted with diethyl ether several times. The combined extracts were washed with water, NA2S203, and brine, dried (MGS04), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 25: 1 hexanes/ethyl acetate to provide 15. 9g (71%) of the desired product.
61%
To a solution of diisopropylamine (104 g, 1 .03 mol) in dry THF (2.6 L) was added dropwise 2.5 M solution of pi-BuLi in hexane (392 mL, 0.98 mol) at -30 to -40C under N2. The resulting mixture was stirred at 0C for 35 min. The mixture was cooled to -70C and a solution of 2-fluoropyridine (I-25) (100 g, 1 .03 mol) in dry THF (800 mL) was added. After stirring at -70C for 2 hr, the mixture was added to a solution of l2 (261 .6 g, 1 .03 mol) in dry THF (800 mL) at -20C under N2. After the reaction was complete, the mixture was quenched with ice water (4 L). The mixture was diluted with EtOAc (4 L) and washed with aq. Na2S203 (500 mL) and brine (500 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by distillation in vacuum to afford 2-fluoro-3-iodopyridine (I-26) (140 g, 61 %) as a yellow solid.
60.6%
With iodine; lithium diisopropyl amide; In tetrahydrofuran;
Synthesis of 2-fluoro-3-iodopyridine A 1 L 2-necked flask was charged with 100 mL of a 2 N solution of lithium diisopropylamide and 400 mL of tetrahydrofuran. This was cooled to -72 C. and 2-fluoropyridine (19.42 g, 200 mmol) dissolved in 100 mL of tetrahydrofuran was added dropwise. This was stirred at -70 C. for 4 h before dropwise addition of 51 g (200 mmol) of iodine dissolved in 150 mL of tetrahydrofuran. This was stirred for 1 h before being quenched with water. The mixture was diluted with ethyl acetate and aqueous sodium bisulfite. The organic layer was evaporated in vacuo and the product was distilled on a Kugelrohr yielding 2-fluoro-3-iodopyridine (27.0 g, 60.6% yield).
60.6%
A I L 2-necked flask was charged with 100 mL of a 2 N solution of lithium diisopropylamide and 400 mL of tetrahydrofuran. This was cooled to "72 C and 2-fluoropyridine (19.42 g, 200 mmol) dissolved in 100 mL of tetrahydrofuran was added dropwise. This was stirred at "70 C for 4 h before dropwise addition of 51 g (200 mmol) of iodine dissolved in 150 mL of tetrahydrofuran. This was stirred for 1 h before being quenched with water. The mixture was diluted with ethyl acetate and aqueous sodium bisulfite. The organic layer was evaporated in vacuo and the product was distilled on a Kugelrohr yielding 2- fluoro-3-iodopyridine (27.0 g, 60.6% yield).
59.4%
To a solution of n-butyllithium in hexanes (40.14 mL, 1.6 M) under argon at-78 C was added diisopropylamine (6.5 g, 64.2 mmol, 1.0 eq). After stirring for 30 min at-78 C, a solution OF 2-FLUOROPYRIDINE (6.23 g, 64.2 MMOL, 1.0 eq) in anhydrous THF (50 mL) was added. The reaction mixture was stirred at-78 C for 4 h. Iodine (16.3 g, 64.2 MMOL, 1.0 eq) was then added, and the reaction mixture was stirred at-78 C for another 30 min. The reaction was HYDROLYZED with 10% water-THF, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure, and the crude product was purified on a MPLC (Biotage) eluted with 20/8020 v/v ethyl acetate-hexane to give 2-fluoro-3-iodo- pyridine as a yellow oil (8.50 g, 59. 4%). H-NMR (ACETONE-D6) 8 8.14 (m, 2H), 6.94 (m, 1H) ; GC-MS (M+ = 223, RT = 9.50 min); Rf = 0.70 (30% ethyl acetate-hexane).
59.4%
Example 14; Method H-7; Preparation of 2-fluoro-3-iodo-pyridine; To a solution of n-butyllithium in hexanes (40.14 mL, 1.6 M) under argon at-78 C was added diisopropylamine (6.5 g, 64.2 mmol, 1.0 eq). After stirring for 30 min at-78 C, a solution of 2-fluoropyridine (6.23 g, 64.2 mmol, 1.0 eq) in anhydrous THF (50 mL) was added. The reaction mixture was stirred at-78 C for 4 h. Iodine (16.3 g, 64.2 mmol, 1.0 eq) was then added, and the reaction mixture was stirred at-78 C for another 30 min. The reaction was hydrolyzed with 10% water-THF, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure, and the crude product was purified on a MPLC (Biotage) eluted with 20/8020 v/v ethyl acetate-hexane to give 2-fluoro-3-iodo- pyridine as a yellow oil (8.50 g, 59. 4%). 1H-NMR (Acetone -d6) No. 8.14 (m, 2H), 6.94 (m, 1 H) ; GC-MS (M+ = 223, RT = 9.50 min); Rf = 0.70 (30% ethyl acetate-hexane).
59.4%
Preparation of 2-fluoro-3-iodo-pyridine. To a solution of n-butyllithium in hexanes (40.14 mL, 1.6 M) under argon at -78 0C was added diisopropylamine (6.5 g, 64.2 mmol, 1.0 eq). After stirring for 30 min at -78 0C, a solution of 2- fluoropyridine (6.23 g, 64.2 mmol, 1.0 eq) in anhydrous THF (50 mL) was added. The reaction mixture was stirred at -78 0C for 4 h. Iodine (16.3 g, 64.2 mmol, 1.0 eq) was then added, and the reaction mixture was stirred at -78 0C for another 30 min. The reaction was hydrolyzed with 10% water - THF, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure, and the crude product was purified on a MPLC (Biotage) eluted with 20/8020 v/v ethyl acetate - hexane to give 2-fluoro-3- iodo-pyridine as a yellow oil (8.50 g, 59.4%). 1H-NMR (Acetone -d6) 8.14 (m, 2H), 6.94 (m, IH); GC-MS (M+ = 223, RT = 9.50 min); Rf = 0.70 (30% ethyl acetate - hexane).
37.0%
Example 85 Synthesis of 2-(4-((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)amino)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-3-fluorobenzonitrile, I-85 Synthesis of Compound 85.2. To a solution of LDA (2.1 g, 21.0 mmol, 1.05 eq) in THF (15.0 mL) was added n-BuLi (8.6 mL, 21.0 mmol, 1.05 eq) at -20 C. The reaction was stirred at same temperature for 1 hour. Compound 85.1 (2.0 g, 20.0 mmol, 1.0 eq) was added at -78 C. and the reaction was stirred for 3 hours. Then a solution of I2 (5.3 g, 21.0 mmol, 1.05 eq) in THF (15.0 mL) was added dropwise to the reaction mixture and the reaction was stirred for 1 hour. After completion of the reaction, mixture was poured into water and product was extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain pure 85.2 (1.7 g, 37.0%). MS(ES): m/z 222.99 [M+H]+.
A solution of lithium diisopropylamide (2M, 8 mL, 16 mmol) in tetrahydrofuran (40 mL) was cooled to - 78C and 2-fluoropyridine (1.4 mL, 16 mmol) added. The reaction was stirred at -78C for 4 hours. Iodine (4.1 g, 16 mmol) in tetrahydrofuran (12 mL) was added and the reaction stirred for 1 hour then quenched with water/tetrahydrofuran (1:1, 2 mL) at -78C. The mixture was warmed to 00C and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and evaporated to give 2-fluoro-3-iodopyridine. This was treated according to the method of Example 7 Step 4 at 1100C to give the title compound, m/z (ES+) 358 [MH+].
To a 1 neck-round flask N,N-diisopropylamine (20 mL, 0.14 mol) was dissolved in tetrahydrofuran (50 mL) and was cooled to -78 0C. To the resulting mixture, 1.6 M of n- butyllithium in hexanes (86 mL, 0.14 mol) was added and the reaction was stirred at -78 0C for 10 minutes and then warmed to 0 0C and stirred for 15 minutes. 2-fluoropyridine (10 mL, 0.1 mol) was dissolved in 50 mL anhydrous tetrahydrofuran and the resulting mixture was cooled at -78 0C. The LDA solution from the first flask was then added. The reaction was stirred at -78 0C for 1.5 hours and then iodine (32 g, 0.13 mol) was added. The mixture was stirred at -78 0C for and additional 1 hour and was then quenched with NH4Cl (aq). The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (10 % EtOAc 90 % hexanes) to give 16.3 g of the desired product. 1H NMR (400 MHz, CDCl3): delta 8.15-8.20 (m, 2H), 6.95-6.99 (m, IH). MS [M+H]=223.8
EXAMPLE 2; 3,4-Dichloro-N-(1-{3-ethyl-2-[3-(4-methyl-piperazin-1-yl)-phenoxy]-pyridin-4-yl}-ethyl)-benzenesulfonamide (Compound 3) [Show Image] 2-Fluoro-3-iodo-pyridine [Show Image] (1) Under a nitrogen atmosphere, to a solution prepared by adding lithium diisopropylamide (54.1 ml, 2 M in heptane/THF/ethylbenzene) to THF (100 ml), a solution of 2-fluoropyridine (10.503 g) in THF (10 ml) was added dropwise at -78C and stirred at the same temperature for 4 hours. To the reaction mixture, a solution of iodine (13.728 g) in THF (10 ml) was added dropwise and stirred at the same temperature for 2 hours. After addition of water (5 ml), the reaction mixture was warmed to room temperature, diluted with brine and then extracted with ether. The organic layer was dried over Na2SO4, filtered and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH-type SiO2, AcOEt/hexane = 9%) to give the titled compound (8.94 g, light-yellow oil). 1H NMR (200 MHz, CDCl3) delta ppm: 6.93-7.00 (m, 1 H), 8.13-8.22 (m, 2 H)
2-fluoro-3-iodopyridine To a solution of 0.103 mol of LDA in 200 mL of THF at -75 C. are added 10 g of 2-fluoropyridine in 50 mL of THF. The yellow solution is stirred for 3 hours at -75 C., followed by addition of 26.2 g of iodine in 80 mL of THF. The reaction mixture is stirred for 1.5 hours at -75 C., followed by addition of 50 mL of water at this temperature. The temperature is allowed to rise, and a further 100 mL of water are added at 0 C. The suspension is decolourized by adding sodium thiosulfate. The mixture is extracted with diethyl ether. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The oily residue is purified on silica Si60 (40-63 mum) (95/5 cyclohexane/diethyl ether). The product obtained is taken up in diethyl ether and an insoluble beige-coloured material is removed by filtration by suction. After drying under vacuum, 10.21 g of a white powder of 2-fluoro-3-iodopyridine are obtained. MS spectrum (ES+): m/z=224 [MH+]
2-Fluoropyridine (48.5 g, 0.5 mol) in THF (200 mL) was slowly added to -78 C solution of LDA (0.50 mol) in dry THF (800 mL). The resulting mixture was stirred for 4 h at -78 C, before addition of iodine (127 g, 0.50 mol) in THF (40 mL). Stirring was continued for 2 h at -78 C before the reaction was quenched by the addition of water (20 mL). After warming to 0 C, additional water (150 mL) was added and the mixture was subjected to a reductive workup with solid sodium thiosulfate. The mixture was extracted with Et20, dried over MgS04i concentrated under reduced pressure, and purified by silica gel chromatography to give 2-fiuoro-3- iodopyridine. 1H-NMR (CDC13, 400 MHz) delta 8.10(m, 2H)} 6.90 (m, IH). MS (M+H)+ 223,9.
26.5 g
With n-butyllithium; iodine; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; hexane; at -78 - 0℃; for 3.5h;Inert atmosphere;
A) 2-fluoro-3-iodopyridine [0390] To a solution of diisopropylamine (21.5 mL) in THF (300 mL) was added 1.6M n-butyllithium hexane solution (97 mL) under argon atmosphere at -20C, and the mixture was stirred under argon atmosphere at 0C for 30 min. To the reaction mixture was added a solution of 2-fluoropyridine (15.0 g) in THF (20 mL) at -78C, and the mixture was stirred under argon atmosphere at -78C for 3 hr. To the reaction mixture was added a solution of iodine (39.2 g) in THF (80 mL) at -78C, and the mixture was stirred under argon atmosphere at -78C for 30 min. To the reaction mixture was added water, and then saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogencarbonate solution were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (26.5 g). 1H NMR (300 MHz, CDCl3) delta 6.92-7.01 (1H, m), 8.11-8.23 (2H, m).
To a solution of sodium methoxide (8.0 mL, 35.9 mmol, 4.0 eq, 25% in methanol) in methanol (60 mL) was added 2-fluoro-3-iodo-pyridine (2.0 g, 8.97 MMOL). The reaction mixture was REFLUXED under argon for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure to give 1.8 G (85.4%) of crude product as a YELLOW OIL. H-NMR (ACETONE-D6) S 8.16 (m, 2H), 6.78 (m, 1H), 3.93 (s, 3H); LC-MS (ES MH+ = 236.2) ; Rf = 0.75 (30% ethyl acetate-hexane).
85.4%
In methanol; for 1h;Heating / reflux;
Example 15; Method H-8; Preparation of 3-iodo-2-methoxy-pvridine; To a solution of sodium methoxide (8.0 mL, 35.9 mmol, 4.0 eq, 25% in methanol) in methanol (60 mL) was added 2-fluoro-3-iodo-pyridine (2.0 g, 8.97 mmol). The reaction mixture was refluxed under argon for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure to give 1.8 g (85.4%) of crude product as a yellow oil.'H-NMR (Acetone-d6) 8 8.16 (m, 2H), 6. 78 (m, 1H), 3.93 (s, 3H); LC-MS (ES MH+ = 236.2) ; Rf = 0.75 (30% ethyl acetate-hexane).
85.4%
In methanol; for 1h;Heating / reflux;
Preparation of 3-iodo-2-methoxv-pvridine. To a solution of sodium methoxide (8.0 mL, 35.9 mmol, 4.0 eq, 25% in methanol) in methanol (60 mL) was added 2-fluoro-3-iodo-pyridine (2.0 g, 8.97 mmol). The reaction mixture was refluxed under argon for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure to give 1.8 g (85.4%) of crude product as a yellow oil. 1H-NMR (Acetone -d6) 08.16 (m, 2H), 6.78 (m, IH), 3.93 (s, 3H); LC-MS (ES MH+ = 236.2); Rf = 0.75 (30% ethyl acetate - hexane).
With acetamidine hydrochloride; sodium hydroxide; In water; dimethyl sulfoxide; at 130℃; for 24h;
2-Fluoro-3-iodopyridine (1 mmol, 223.0 mg), acetamidine hydrochloride (1.2 mmol, 113.4 mg), NaOH (2.5 mmol, 100 mg), H2O (0.5 mL) and Dimethyl sulfoxide (2.5 mL). The reaction was carried out at 130 C for a reaction time of 24 hours. After the reaction was completed, it was cooled to room temperature.The reaction was quenched by adding 10 mL of ethyl acetate, and washed with 6 mL of saturated brine.The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (6 mL of ethyl acetate each time). The organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, including organic solvent and inorganic solvent. Organic solvent,The title product 3-iodopyridin-2-amine was isolated by column chromatography to give a yield of 95%.
With n-butyllithium; diethylamine; In tetrahydrofuran; at -78 - 0℃; for 2h;
A-40 oC solution of diethylamine (5. 51G, 55.5 mmol) in THF (80 mL) was treated dropwise with 2.5 M n-butyllithium in hexane (22.2 mL, 55.5 mmol), stirred at 0 C briefly, cooled TO-78 C, treated with a solution of Example 68A (9.9g, 44.4 mmol) in THF (80 mL), stirred at-78 oC for 2 hours, treated with water (3.6g, 200 mmol), stirred for 5 minutes, then poured into water (500 mL), and extracted with diethyl ether several times. The combined extracts were washed water and brine, dried (MGS04), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 25: 1 hexanes/ethyl acetate to provide 9.5g (96%) of the desired product.
89%
With n-butyllithium; diisopropylamine; In tetrahydrofuran; at -78℃; for 1h;
(b) 189 mL of n-butyllithium (1.57 mol/L hexane solution) was dropwise added at -20C to a solution having 30.2 g (302 mmol) of diisopropylamine dissolved in 380 mL of tetrahydrofuran, followed by stirring for 1 hour. The solution was cooled to -78C, a solution having 67.4 g (302 mmol) of the crude product of <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> obtained in step (a) dissolved in 100 mL of tetrahydrofuran was added thereto, followed by stirring for 1 hour. 300 mL of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl ether was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure, to obtain 59.3 g (crude yield 89%) of a crude product of 2-fluoro-4-iodopyridine.1H-NMR(CDCl3, 400 MHz) : delta (ppm) = 7.33(d,1H, J = 2.8 Hz), 7.51(d,1H, J = 5.2 Hz), 7.88(dd,1H, J=5.2 Hz, 2.8 Hz)
87.5%
[0189] To a solution of <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (4.0 g, 17.9 mmol) in dry THF (50 mL), was added LDA (8.96 mL of a 2M solution in THF, 17.9 mmol) dropwise at -78 C. After stirring for 4 hours at -78 C, H20 (0.5 mL) in THF (1 mL) was added. The mixture was slowly warmed to room temperature, followed by addition of brine (30 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2S04 and then concentrated to give crude product, which was purified by column chromatography to give 2-fluoro-4- iodopyridine (3.5 g, yield : 87.5%) as a white solid. LC/MS: m/z (M++H) = 224.
With n-butyllithium; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -78℃;
n-BuLi (122 mL, 305 mmol) was added to a solution of diisopropylamine (30.81 g, 305 mmol) in 600 mL of dry THF at -78 C under an nitrogen atmosphere. After stirring for 30 min, a solution of <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (68.02 g, 305 mmol) in THF (150 mL) was added dropwise. The resulting mixture was stirred for 1 h at -78 C. Water was added (50 mL) to quench the reaction at -78 C and after warming to room temperature an additional 100 mL of water was added. The mixture was extracted with Et20 (2x), and the combined organic layers were dried over Na2S04, concentrated, and purified by silica gel chromatography to give of 2-fluoro-4-iodopyridine. - NMR (CDC13, 400 MHz) 3 7.91 (d, J=1.2 Hz, 1H), 7.53 (m, 1H), 7.35 (m, 1H). MS (M+H)+ 223.9.
A I L round bottom flask was charged with <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (27.0 g, 121 mmol) and 500 mL of 40%> aqueous solution of methylamine. This was stirred at reflux for 4 h before being cooled to ambient temperature. The product was extracted with dichloromethane. Evaporation of the dichloromethane gave 3- iodo-N-methylpyridin-2-amine (26.8 g, 95 %> yield).
81.0%
In water; for 4h;Heating / reflux;
To a solution of 40% METHYLAMINE in water (60 mL) was added 2-fluoro-3-iodo- pyridine (2.0 g, 8.97 MMOL), and the reaction mixture was refluxed under argon for 4 h. The cooled reaction was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure to give 1.70 g (81.0%) of crude PRODUCT. H-NMR (ACETONE-D6) 8 8.06 (dd, J = 4.8, 1. 5 Hz, 1H), 7.89 (dd, J = 7. 2, 1. 8 Hz, 1H), 6.34 (m, 1 H), 5.60 (broad, s, 1H), 2.94 (d, J = 4.5 Hz, 3H); Rf = 0.68 (30% ethyl acetate-hexane).
81.0%
In water; for 4h;Heating / reflux;
Example 16; Method H-9; Preparation of (3-iodo-pyridin-2-vl)-methvlamine; To a solution of 40% methylamine in water (60 mL) was added 2-fluoro-3-iodo- pyridine (2.0 g, 8.97 mmol), and the reaction mixture was refluxed under argon for 4 h. The cooled reaction was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure to give 1.70 g (81. 0%) of crude product.'H-NMR (Acetone-d6) 8 8.06 (dd, J = 4.8, 1.5 Hz, 1 H), 7.89 (dd, J = 7.2, 1.8 Hz, 1 H), 6.34 (m, 1 H), 5.60 (broad, s, 1 H), 2.94 (d, J = 4.5 Hz, 3H); Rf = 0.68 (30% ethyl acetate-hexane).
81.0%
In water; for 4h;Heating / reflux;
Preparation of (3-iodo-pyridin-2-yl)-methylamine. To a solution of 40% methylamine in water (60 mL) was added <strong>[113975-22-7]2-fluoro-3-iodo-pyridine</strong> (2.0 g, 8.97 mmol), and the reaction mixture was refluxed under argon for 4 h. The cooled reaction was diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dried. The solvent was evaporated under reduced pressure to give 1.70 g (81.0%) of crude product. 1H- NMR (Acetone -d6) 8.06 (dd, J = 4.8, 1.5 Hz, IH), 7.89 (dd, J = 7.2, 1.8 Hz, IH), 6.34 (m, 1 H), 5.60 (broad, s, IH), 2.94 (d, J = 4.5 Hz, 3H); Rf = 0.68 (30% ethyl acetate - hexane).
To a solution of diisopropylamine (174.4g, 1 .73 mol) in dry THF (3 L) was added dropwise 2.5 M solution of n-BuLi in hexane (685 mL, 1 .71 mol) at -10C. The resulting mixture was stirred at 0C for 35 min. The mixture was cooled to -70C and a solution of 2-fluoro-3-iodopyridine (I-26) (350 g, 1 .57 mol) in dry THF (1 L) was added. The mixture was stirred at -70C for 2 hr. HCOOEt (128 g, 1 .73 mol) was added dropwise at -70C. After the addition, the mixture was allowed to warm to room temperature and quenched with ice water (4 L). The mixture was diluted with EtOAc (4 L) and washed with brine (500 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with petroleum:EtOAc = 10:1 to afford 2-fluoro-4-iodonicotinaldehyde (I-27) (180 g, 46%) as a yellow solid.1H NMR (400 MHz, CDCI3) delta ppm 10.08 (s, 1 H), 7.91 (d, 1 H), 7.81 (d, 1 H).
2-Fluoro-4-iodo-3-methylpyridine (0412) To a solution of LDA (68 mL, 135 mmol) at -78 C. was added a solution of 2-fluoro-3-iodopyridine (30 g, 135 mmol) in THF (100 mL), and the mixture is stirred for 1 hour at -78 C. under nitrogen. MeI (25 mL, 405 mmol) was then added, and the mixture was stirred for 30 min at -78 C. The mixture was quenched with sat. aq. NaHCO3 solution at -78 C. and then extracted with ether. The combined ether extracts were dried with MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to give the title compound as a brown solid (22 g, 69%). (0413) MS (ES+) C6H5FIN requires: 237, found: 238 [M+H]+.
154 mg (72%)
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
EXAMPLE 4 2-Fluoro-4-iodo-3-methylpyridine (6) To a solution of LDA, freshly prepared from diisopropylamine (0.126 mL, 0.899 mmol) and n-BuLi (0.899 mmol), in THF (2 mL) at -78 C. is cannulated a solution of 2-fluoro-3-iodopyridine (200 mg, 0.897 mmol) in 0.4 mL of THF, and the mixture is stirred for 1 hour at -78 C. under nitrogen. Iodomethane (0.17 mL, 2.73 mmol) is added neat and the mixture is stirred for 30 min. at -78 C. The mixture is quenched with saturated sodium bicarbonate solution at -78 C. and then extracted with ether. Combined ether extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes) to give 154 mg (72%) of product as an off-white solid having amp of 90-91 C.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 25℃; for 16h;
Into a 1-neck round-bottom flask was added <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (1.0 g, 0.0045 mol), trimethylsilylacetylene (0.95 mL, 6.7 mmol), bis(triphenylphosphine)palladium(II) chloride (0.2 g, 0.2 mmol), copper(I) iodide (0.07 g, 0.4 mmol), and triethylamine (0.94 mL, 6.7 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred at 25 0C for 16 hours. EPO <DP n="85"/>The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by column chromatography on silica gel (10% ethyl acetate 90% hexanes) to give 0.747 g of the desired product. 1H NMR (400 MHz, CDC13): 67.86-7.89 (m, IH), 7.55-7.61 (m, IH), 6.86-6.90 (m, IH). MS [M+H]=194.0
Di-i-propylamine (1.623 g, 2.267 mL, 16.04 mmol) was dissolved in dryTHF (12 mL) and cooled to -700C. n-BuLi (6.140 mL of 2.5 M, 15.35 mmol) was added slowly dropwise, keeping the temperature below -600C, and the resultant mixture was stirred at 00C for ~2 minutes and recooled to -700C. A solution of 2-Fluoro-3-iodopyridine (3.11 g, 13.95 mmol) in dry THF (9 mL) was added slowly dropwise. This solution was stirred at -700C for ~lhr 45mins, and Acetaldehyde (3.073 g, 3.915 mL, 69.75 mmol) was added slowly dropwise over ~20 minutes. The resultant mixture was stirred at -700C for ~1 hour. The reaction was quenched by addition of water (~12mL) at -700C. The resulting mixture was partitioned with EtOAc and the aqueous layer was extracted with EtOAc (3 x 5OmL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give an orange/brown oil. The resulting mixture was purified by column chromatography (30% EtOAc in hexanes, ~300mL silica) to give a light yellow viscous gum (3.3412g, 90% Yield).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 12h;Heating / reflux;
(1) Production of 2-fluoro-3-(4-phenoxyphenyl)pyridine: Tetrakis(triphenylphosphine)palladium (492 mg, 0.45 mmol) and aqueous 2 N sodium carbonate solution (10 mL) were added to an ethylene glycol dimethyl ether (hereinafter referred to as 'DME') (66 mL) solution of <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (2.00 g, 8.97 mmol) and 4-(phenoxyphenyl)boronic acid (2.50 g, 11.66 g), and heated under reflux for 12 hours. Water was added to the reaction liquid, and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, then dried with anhydrous sodium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 to 17:3) to obtain the entitled compound (2.06 g, 87 %). Mass Spectrum (ESI): 266.1 (M+H).
Lithium diisopropylamide in THF (2.0 M; 12 mL, 24 mmol) was added to a mixture of 2-fluoro-3-iodopyridine (Alfa Aesar, 5.0 g, 22 mmol) in THF (50 mL) at ?78° C. The solution was stirred at ?78° C. for 1 h, then a solution of 1-chloro-3-iodo-propane, (5.0 g, 24 mmol) in 15 mL THF was added dropwise. The reaction mixture was stirred at ?78° C. for 30 min., then allowed to warm to room temperature. The reaction mixture was quenched with aq.NH4Cl and extracted with EtOAc. The combined organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 0 to 50percent EtOAc/hexanes, to give the sub-title compound (6.2 g, 92percent). LCMS calc. for C8H9ClFIN (M+H)+: m/z=299.9. Found: 300.1.
70%
a) Freshly prepared LDA (8.97 mmol) was added to a solution of 2-fluoro-3- iodopyridine (2.00 g, 8.97 mmol) in THF (15 mL) cooled at -78 °C. After 1 h, 1 - chloro-3-iodopropane (0.96 mL, 8.97 mmol) was added to the anion solution, allowing to reach room temperature (overnight). The reaction volume was reduced to ca. 10 mL and the mixture was poured over EtAcO (60 mL) and washed with water (2 x 20 mL); the organic layer was dried over anhydrous Na2S04 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (2>4percent EtAcO/hexanes), affording 1 .88 g of 3-(3-chloropropyl)-2-fluoro-4- iodopyridine [Rf= 0.70 (5percent EtAcO/hexanes), colorless oil, 70percent yield].LC-MS ESI+ m/z: 300 (M+1 , 98percent) (Method 5).1 H-NMR (CDCI3, 250 MHz, ?): 7.70 (d, J= 5.2 Hz, 1 H, ArH); 7.61 (d, J= 5.2 Hz, 1 H, ArH); 3.62 (t, J= 6.5 Hz, 2H); 2.99-2.90 (m, 2H); 2.10-1 .97 (m, 2H
3-(4-chlorobutyl)-2-fluoro-4-iodopyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
Stage #1: 2-fluoro-3-iodopyridine With lithium diisopropyl amide In tetrahydrofuran; n-heptane at -78℃; for 1h;
Stage #2: 1-chloro 4-iodobutane In tetrahydrofuran; n-heptane at -78 - 20℃; Further stages.;
With n-butyllithium; sodium borohydrid; diisopropylamine; In tetrahydrofuran; ethyl acetate;
EXAMPLE 1 2-Fluoro-4-iodo-3-(hydroxymethyl)pyridine To a solution of LDA, freshly prepared from diisopropylamine (0.63 mL, 4.49 mmol) and n-BuLi (4.49 mmol) in THF (10 mL) at -78 C., is cannulated a solution of 2-fluoro-3-iodopyridine (1 g, 4.48 mmol) in 2 mL of THF, and the mixture is stirred for 1 hour at -78 C. under nitrogen. Ethyl formate (1.1 mL, 13.6 mmol) is added to the reaction mixture at -78 C. and stirring is continued for 30 min. The reaction is quenched with saturated sodium bicarbonate solution at -78 C. and allowed to warm to room temperature. Sodium borohydride (0.34 g, 8.99 mmol) is slowly added to the reaction mixture and then stirred for 30 min. The mixture is extracted with ethyl acetate. The combined ethyl acetate extracts are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes, 10% EtOAc/hexanes, 20% EtOAc/hexanes) to afford 708 mg (62 %) of the product as a white solid having a mp of 69-70 C. Elemental Analysis for C6 H5 FINO: theory: C 28.48, H 1.99, N 5.54; found: C 28.55, H 1.94, N 5.48. IR (KBr): cm1 3336, 1584, 1541, 1446, 1401, 1264, 1218, 1003, 870, 833,803,761,577. 1 H NMR (CDCl3): delta7.79-7.82 (d, 1H,J=5 Hz), 7.66-7.68 (d, 1H, J=5 Hz), 4.82-4.86 (d, 2H, J=7 Hz), 1.99-2.04 (t, 1H, J=14 Hz). 13 C NMR (CDCl3): delta 162.29, 159.05, 147.30, 147.09, 132.79, 132.73,126.14, 125.73, 114.21, 62.24.
A mixture of DIPA (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 C and nBuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 mm, the r.m. was cooled to -75 C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 C. The r.m. was cooled to -75 C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 mill sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25% purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), Et20 (100 mL) and the layers were separated. The aq. layer was extracted with Et20 (100 mL) and the combined organic layers weretreated with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94%), which was used as such in the next reaction step.
64%
To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrous THF (5 L) at -8 to -10 C. under a blanket of N2 was added n-BuLi (880 mL, 158 g, 2.46 mol) dropwise via cannula. The mixture was stirred at -10 C. for 30 min, cooled to -78 C. and treated with a solution of 2-fluoro-3-iodopyridine (500 g, 2.24 mol) in dry THF (2 L) dropwise. After the addition, the reaction mixture was warmed to -60 C. and this temperature was maintained for 2 h. The mixture was then cooled to -78 C., treated with ethyl formate (183 g, 2.47 mol) dropwise, followed by sodium methoxide (149 g, 2.75 mol) in MeOH (1.5 L) and warmed to ambient temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The layers were separated and the organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-iodo-2-methoxynicotinaldehyde (380 g, 64%) as a solid.
44 g
Under the stream of nitrogen, a THF (500 mL) solution of diisopropylamine (25 g) was added into a 2L-fourneckedflask. The solution was cooled to -25C, and n-butyl lithium - hexane solution (1.57 mol/L) (157 mL) was droppedto the solution for 20 minutes (-25C ? -15C), and the solution was stirred at -10C for 30 minutes. The resulting solutionwas cooled to -66C, and a THF (200 mL) solution of 2-fluoro-3-iodopyridine (CAS registration No.: 113975-22-7) (50g) was dropped thereto for 25 minutes, and stirred at -60C for two hours. The resulting solution was cooled to -66C,and ethyl formate (18.3 g) was dropped thereto for 10 minutes. Then, 28% solution of sodium methoxide methanolsolution (53.2 g) in methanol (100 mL) was dropped, and lifted up from dry ice bath. The resulting product was naturallycooled to room temperature, and ice water (100 mL) was dropped thereto. A saturated saline solution (1 L) was addedthereto. The resulting solution was extracted with ethyl acetate (1 L), and washed with water (700 mL) and a saturatedsaline solution (700 mL). The water layer was combined and extracted with ethyl acetate (500 mL 3 2), and washedwith water (500 mL) and a saturated saline solution (500 mL). The organic layer was combined and dried over anhydroussodium sulfate, and the solvent was removed by evaporation under reduced pressure. The obtained residue was purifiedby column chromatography on silica gel (hexane : ethyl acetate = 9:1 ? 6:1 ? 5:1 ? 4:1 ? 3:1) to obtain the titlecompound (44 g) having the following physical property values
Di-i-propylamine (260.9 mg, 364.4 muL, 2.578 mmol) was dissolved in dryTHF (1.900 mL) and cooled to -700C. n-BuLi (986.4 muL of 2.5 M, 2.466 mmol) was added <n="153"/>slowly dropwise, and the resultant mixture was stirred at 00C for -2 minutes and recooled to -700C. A solution of <strong>[113975-22-7]2-fluoro-3-iodo-pyridine</strong> (500 mg, 2.242 mmol) in dry THF (1.400 mL) was added slowly dropwise and the resultant was stirred at -700C for -2.5 hours. 2,2,2-trifluoroacetaldehyde was added via cannula (bp. is - 200C) and the resultant mixture was stirred at -700C for ~1.5 hours. The reaction was quenched at -700C by the rapid addition of water (~2mL) and the resulting mixture was partitioned with EtOAc. The aqueous phase was extracted with EtOAc (3 x 2OmL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a mobile light brown oil (581.7mg). The resulting mixture was purified by column chromatography (5% EtOAc in DCM, -10OmL silica, loaded in DCM) to give a slightly yellow gum that solidified under high-vacuum to give a light yellow solid (225.2mg, 31% Yield).
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 80℃; for 0.166667h;Microwave irradiation;
Example 1-30 (Trans)-3-(2-fluoro-3-pyridinyl)-8-([5-(2-pyrimidinyl)-2-pyridinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one.dihydrochloride To a solution of (trans)-8-([5-(2-pyrimidinyl)-2-pyridinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 82, 40 mg, 0.118 mmol) and <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (31.5 mg, 0.141 mmol) in 1,4-dioxane (2 ml) were added copper(I) iodide (22.45 mg, 0.118 mmol), (+/-)-trans-1,2-diaminocyclohexane (0.028 ml, 0.236 mmol) and K3PO4 (125 mg, 0.589 mmol) in a sealed microwave tube and the mixture was irradiated at 80 C. for 10 min (four cycles). The solvent was evaporated. DCM (5 ml) was added to the resulting residue and this was filtered washing with more DCM (2*1 ml). The organic solution was concentrated to give a residue which was purified by KP-NH flash chromatography (via Biotage SP1, 12M NH column) eluding in gradient with 30%-100% EtOAc/cyclohexane to give 16.4 mg of desired compound contaminated by 5-(2-pyrimidinyl)-2-pyridinamine. This residue was dissolved in DCM and washed with a pH 3 citrate buffer solution (3 ml) to afford clean (trans)-3-(2-fluoro-3-pyridinyl)-8-([5-(2-pyrimidinyl)-2-pyridinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (13.4 mg, 0.031 mmol, 26%). 1H NMR (400 MHz, CDCl3): delta 1.69-1.84 (m, 3H), 1.84-1.94 (m, 2H), 2.02-2.10 (m, 4H), 3.26-3.39 (m, 2H), 3.85-3.96 (m, 2H), 4.95 (s, 1H), 6.44-6.52 (m, 1H), 7.06-7.16 (m, 1H), 7.21-7.33 (m, 2H), 8.08 (dt, 1H), 8.16-8.21 (m, 1H), 8.40-8.50 (m, 1H), 8.70-8.80 (m, 1H), 9.15-9.22 (m, 1H); UPLC-MS: 0.47 min, 435 [M+H]+.
With hydrazine hydrate; In ethanol; water; at 20 - 35℃;
Hydrazine hydrate (12.50 mL, 256 mmol) was added dropwise to a solution of <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (preparation 26a, 5.72 g, 25.7 mmol) in ethanol (43 mL) and the resulting mixture was stirred at room temperature for 24 hours and then at 35 C for a further 24 hours. The solvent was then evaporated in vacuo and water was added. The white solid that formed was filtered, washed with water and dried to yield the title compound (2.78 g, 46%) as a white solid which was used without further purification. LRMS (m/z): 236 (M+1)+.
Example 5 - 2,2'-Difluoro-4,4'-diiodo-3,3'-bipyridine (5a) 2-Fluoro-3-iodopyridine (7.80 mmol, 1.74 g) was dissolved in 40 ml of anhydrous THF under nitrogen atmosphere and the solution was cooled in acetone/C02 bath. LDA (1.1 eq., 1.2 M in hexanes-THF, 8.58 mmol, 7.15 ml) was added dropwise. The reaction mixture became yellowish and after stirring for 0.5h it was analyzed by GC/MS. A clean BCHD reaction was confirmed, the mixture was stirred for additional 0.5h and CuCl2 (1.1 eq., 8.58 mmol, 1.15 g) was added in one portion. The yellow reaction mixture became dark blue, then brown red (within 1-2 h) and then light greenish after warm up to room temperature. The reaction mixture was treated with hexanes and water, the organic phase was removed, and the aqueous phase was extracted with hexanes (2 x -20 ml). The combined organic phases were dried over MgS04 and the solvent was removed by rotary evaporation to give greenish- brownish oil which partially solidified on standing. This crude product was purified by column chromatography (200 ml of silica gel, hexanes :CH2C12 mixtures (2: 1, 1 : 1 : and then 1 :2) as eluants). The solvents were removed from combined fractions and the product was obtained as off-white solid (1.04 g, 60.1%). UV-vis (CH2C12) max, nm226, 244, 268. HRMS (EI) calculated for Ci0H4F2I2N2 443.8432; found 443.8417. 1H NMR (CDC13, 400 MHz): delta 8.01 (d, J= 5.2 Hz, 2H), 7.82 (d, J= 5.2 Hz, 2H); 13C{1H} NMR (CDCI3, 100 MHz): delta 159.28 (d, J (C-F) = 242.8 Hz, quaternary C), 148.5 (d, J(C-F) = 15.62 Hz, CH), 132.1 (d, J(C-F) = 4.6 Hz, CH), 125.0 (dd, J (C-F) = 33.4 Hz, 4.1 Hz), 114.5 (d, J(C-F) = 1.7 Hz). Anal. Calc. for Ci0H4F2I2N2: C, 27.05; H, 0.91; N, 6.31. Found: C, 27.52; H, 0.84;
60.1%
Example 5 - 2,2'-Difluoro-4,4'-diiodo-3,3'-bipyridine (5a) 2-Fluoro-3-iodopyridine (7.80 mmol, 1.74 g) was dissolved in 40 ml of anhydrous THF under nitrogen atmosphere and the solution was cooled in acetone/C02 bath. LDA (1.1 eq., 1.2 M in hexanes-THF, 8.58 mmol, 7.15 ml) was added dropwise. The reaction mixture became yellowish and after stirring for 0.5h it was analyzed by GC/MS. A clean BCHD reaction was confirmed, the mixture was stirred for additional 0.5h and CuCl2 (1.1 eq., 8.58 mmol, 1.15 g) was added in one portion. The yellow reaction mixture became dark blue, then brown red (within 1-2 h) and then light greenish after warm up to room temperature. The reaction mixture was treated with hexanes and water, the organic phase was removed, and the aqueous phase was extracted with hexanes (2 x -20 ml). The combined organic phases were dried over MgS04 and the solvent was removed by rotary evaporation to give greenish- brownish oil which partially solidified on standing. This crude product was purified by column chromatography (200 ml of silica gel, hexanes :CH2C12 mixtures (2: 1, 1 : 1 : and then 1 :2) as eluants). The solvents were removed from combined fractions and the product was obtained as off-white solid (1.04 g, 60.1%). UV-vis (CH2C12) max, nm226, 244, 268. HRMS (EI) calculated for Ci0H4F2I2N2 443.8432; found 443.8417. 1H NMR (CDC13, 400 MHz): delta 8.01 (d, J= 5.2 Hz, 2H), 7.82 (d, J= 5.2 Hz, 2H); 13C{1H} NMR (CDCI3, 100 MHz): delta 159.28 (d, J (C-F) = 242.8 Hz, quaternary C), 148.5 (d, J(C-F) = 15.62 Hz, CH), 132.1 (d, J(C-F) = 4.6 Hz, CH), 125.0 (dd, J (C-F) = 33.4 Hz, 4.1 Hz), 114.5 (d, J(C-F) = 1.7 Hz). Anal. Calc. for Ci0H4F2I2N2: C, 27.05; H, 0.91; N, 6.31. Found: C, 27.52; H, 0.84;
60.1%
With lithium diisopropyl amide; In tetrahydrofuran; hexane; for 1h;Inert atmosphere;
Example 5 - 2,2'-Difluoro-4,4'-diiodo-3,3'-bipyridine (5a) 2-Fluoro-3-iodopyridine (7.80 mmol, 1.74 g) was dissolved in 40 ml of anhydrous THF under nitrogen atmosphere and the solution was cooled in acetone/C02 bath. LDA (1.1 eq., 1.2 M in hexanes-THF, 8.58 mmol, 7.15 ml) was added dropwise. The reaction mixture became yellowish and after stirring for 0.5h it was analyzed by GC/MS. A clean BCHD reaction was confirmed, the mixture was stirred for additional 0.5h and CuCl2 (1.1 eq., 8.58 mmol, 1.15 g) was added in one portion. The yellow reaction mixture became dark blue, then brown red (within 1-2 h) and then light greenish after warm up to room temperature. The reaction mixture was treated with hexanes and water, the organic phase was removed, and the aqueous phase was extracted with hexanes (2 x -20 ml). The combined organic phases were dried over MgS04 and the solvent was removed by rotary evaporation to give greenish- brownish oil which partially solidified on standing. This crude product was purified by column chromatography (200 ml of silica gel, hexanes :CH2C12 mixtures (2: 1, 1 : 1 : and then 1 :2) as eluants). The solvents were removed from combined fractions and the product was obtained as off-white solid (1.04 g, 60.1%). UV-vis (CH2C12) max, nm226, 244, 268. HRMS (EI) calculated for Ci0H4F2I2N2 443.8432; found 443.8417. 1H NMR (CDC13, 400 MHz): delta 8.01 (d, J= 5.2 Hz, 2H), 7.82 (d, J= 5.2 Hz, 2H); 13C{1H} NMR (CDCI3, 100 MHz): delta 159.28 (d, J (C-F) = 242.8 Hz, quaternary C), 148.5 (d, J(C-F) = 15.62 Hz, CH), 132.1 (d, J(C-F) = 4.6 Hz, CH), 125.0 (dd, J (C-F) = 33.4 Hz, 4.1 Hz), 114.5 (d, J(C-F) = 1.7 Hz). Anal. Calc. for Ci0H4F2I2N2: C, 27.05; H, 0.91; N, 6.31. Found: C, 27.52; H, 0.84;
With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 120℃; for 4h;Inert atmosphere;
General procedure: 1.0 equiv of 3, 2.0 equiv of the halo-component, 2.0 equiv of KOAc, and 0.01 equiv of Pd(OAc)2 were charged into the reaction vessel in that same order. Dimethylacetamide was added and the reaction vial was evacuated and purged with argon three times. The reaction mixture was then stirred at 120 C until the reaction was complete. The solution was diluted with ethyl acetate, silica gel was added, and this mixture was concentrated in vacuo, followed by MPLC purification.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); at 150℃; for 0.333333h;microwave reaction vessel;
NaO'Bu, 150C [00209] A microwave reaction vessel was charged with <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong>(purchased from Maybridge) (0.565 g, 2.53 mmol), morpholine (purchased from Aldrich) (0.221 ml, 2.53 mmol), Pd2(dba)3(purchased from Strem) (0.154 g, 0.152 mmol), 2- dicyclohexylphosphino-2',6'-dimethoxy-l, -biphenyl (purchased from Strem) (0.135 g, 0.304 mmol), and sodium t-butoxide (0.8 g, 7.6 mmol). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, NC) at 150C for 20 min (125 watts, Powermax feature on, ramp time 5 min). Solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column, eluting with a gradient of 1% to 5% MeOH in CH2CI2, to provide 4-(2-fhioropyridin-3- yl)morpholine (0.311 g, 67.5% yield).
To a 2L 3 necked round bottomed flask fitted with a mechanical stirrer, under nitrogen atmosphere was placed Zinc dust, which was preactivated according to abovePreparation 2, (51.2 g, 0.78 mol, 1.94 eq) and dimethyl acetamide (162 mL). To the above suspension, 1, 2-dibromoethane (12.14 g, 0.0646 mol, 0.16 eq) was added dropwise at RT(exotherm and bubbling were observed), followed by dropwise addition of TMSC1 (6.99 g,0.0646 mol, 0.16 eq). A vigorous reaction (exotherm to 55 C) was observed. To this, a solution of N-Boc-3-iodoazetidine (2) (182.88 g, 0.646 mol, 1.6 eq) in dimethyl acetamide (378 mL) was added dropwise using an addition funnel (exotherm to 50 C was observed). The suspension was stirred for 1.5 h at RT and was then degassed with nitrogen for 15 min. Stirring was stopped and suspension was allowed to stand under nitrogen. To a 5L 3 necked round bottomed flask, fitted with mechanical stirrer, flushed with nitrogen were placed <strong>[113975-22-7]3-iodo-2-fluoropyridine</strong> (24) (90 g,0.404 mol, 1.0 eq), PdCl2dppf.CH2Cl2 (9.88 g, 0.012 mol, 0.03 eq), Cul (4.76 g, 0.025 mol, 0.062 eq ) and dimethyl acetamide (396 mL). The red colored suspension was degassed with nitrogen for 15 min.[00244] The Zinc reagent solution in 2L flask was cannulated into 5L round bottomed flask. The resulting reaction mixture was degassed again with nitrogen for 15 min with stirring and heated to 80C for overnight under nitrogen. LCMS indicates completion of reaction. The reaction was cooled to RT and quenched by addition of brine solution (1 L). To this EtOAc (1 L) and water (1 L) were added and layers were separated. The aqueous layer was extracted with EtOAc (2 x 2 L). The combined EtOAc layers were washed with water (2 L), brine (1 L), dried (Na2S04), filtered, and evaporated. The crude was purified by column chromatography to give 52 g of tert-butyl 3-(2-fluoropyridin-3-yl)azetidine-l-carboxylate (25) (yield: 51%) as an oil, which solidified on standing.1H NMR (300 MHz CDC13) : 8.13 (doublet, J = 4.8 Hz, 1H), 7.83-7.76 (dt, 1H), 7.28-7.20 (dt, 1H), 4.35 (t, J = 8.7 Hz, 2H), 4.05-3.88 (m, 3H), 1.46 (s, 9H). LC-MS: 253 (M+l); calcd for
a) Freshly prepared LDA (1 .44 mmol) was added to a solution of 2-fluoro-3- iodopyridine (0.32 g, 1 .44 mmol) in THF (12 mL) cooled at -78 C. After 1 .5 h, a solution of 3-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1 ,2,3-oxathiazolidine 2,2-dioxide (0.70 g, 1 .72 mmol) in 8 mL of THF was transferred via canula to the anion solution, allowing to reach room temperature (overnight). TLC showed an intense polar spot corresponding to the sulfamic acid intermediate. The solvent was evaporated and the resulting residue was dissolved in 1 ,4-dioxane (6 mL) and treated with 1 .0 mL of HCI (4 M in 1 ,4-dioxane), stirring at room temperature. After 16 h, the reaction was cooled to 0 C and slowly basified with NaOH (aqueous solution 10%, 5 mL). The mixture was poured over EtAcO (40 mL) and washed with brine (2 x 20 mL); the organic layer was dried over anhydrous Na2S04 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10D30% EtAcO/hexanes), affording 0.51 g of N-{5-chloro-2-[(4-chloro-2- fluorobenzyl)oxy]benzyl}-N-[2-(2-fluoro-4-iodopyridin-3-yl)ethyl]amine [Rf= 0.70 (10% MeOH/DCM), colorless oil, 64% yield].LC-MS ESI+ m/z: 549 (M+1 , 90%) (Method 5).1 H-NMR (CDCI3, 250 MHz, ?): 7.68 (d, J= 5.1 Hz, 1 H, ArH); 7.58 (d, J= 5.1 Hz, 1 H, ArH); 7.43-7.1 1 (m, 5H, ArH); 6.83 (d, J= 8.8 Hz, 1 H, ArH); 5.07 (s, 2H); 3.82 (s, 2H); 3.01 -2.74 (m, 4H).
With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 0.75h;Inert atmosphere;
1) tert-Butyl 3-cyano-3-(3-iodopyridin-2-yl)azetidine-1-carboxylate The cyanoazetidine (70 mg, 0.4 mmol) and 2-fluoro-3-iodopyridine (93 mg, 0.4 mmol) is dissolved in dry THF (18 ml) under nitrogen. LiHMDS (lithium hexamethyldisilazide) in THF (0.7 ml, 0.7 mmol) is added to the solution at RT and stirred for a further 45 min. The batch is then added to saturated aqueous ammonium chloride solution and extracted to exhaustion with ethyl acetate. Drying of the organic phase over sodium sulfate and chromatography of the organic residue on silica gel (petroleum ether/ethyl acetate=8:2) gives the product with a yield of 76% (110 mg); 1H NMR (DMSO-d6) delta [ppm] J [Hz]: ppm 8.65 (dd, 1H) 8.44 (dd, 1H) 7.27 (dd, 1H) 4.63 (d, 2H) 4.49 (d, 2H) 1.39 (s, 9H).
To a solution of 2-fluoro-3-iodopyridine (Ark Pharm, 2.989 g, 13.40 mmol) in THF (50 mL) at -78 C., a solution of lithium diisopropylanide in heptane/THF/ethylbenzene (2.0 M; 8.10 mL, 16.2 mmol) was added. The mixture was stirred at -78 C. for 90 min. A solution of 1,3,2-dioxathiolane 2,2-dioxide (2.206 g, 17.77 mmol) in THF (30 mL) was then added slowly to the mixture at -78 C., over a period of 20 min. After stirring at -78 C. for 20 min., the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then cooled to 0 C., and 12.0 M HCl in water (5.0 mL, 60 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 3 h. Saturated aq. NaHCO3 (250 mL) was added. The mixture was extracted with EtOAc (3*150 mL). The combined extracts were washed with brine (250 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a white solid (3.13 g, 87%). LCMS calc. for C7H8FINO (M+H)+: m/z=268.0. found 268.0
87%
A solution of 2.0 M lithium diisopropylamide in heptane/THF/ethylbenzene (8.10 mL, 16.2 mmol) was added to a solution of 2-fluoro-3-iodopyridine (Ark Pharm, 2.989 g, 13.40 mmol) in THF (50 mL) at -78 C., then the mixture was stirred at -78 C. for 90 min. With the temperature maintained at -78 C., a solution of 1,3,2-dioxathiolane 2,2-dioxide (2.206 g, 17.77 mmol) in THF (30 mL) was added slowly over a period of 20 min., the solution was stirred at -78 C. for a further 20 min., then allowed to warm to room temperature and stirred for 2 h. The mixture was then cooled to 0 C., and 12.0 M aq. HCl (5.0 mL, 60. mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Saturated aq. NaHCO3 (250 mL) was added, then the mixture was extracted with EtOAc (3×150 mL). The combined extracts were washed with brine (250 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a white solid (3.13 g, 87%). LCMS calc. for C7H8FINO (M+H)+: m/z=268.0. found 268.0.
N1,N2-bis(3-iodopyridin-2-yl)-N1,N2-dimethylethane-1,2-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With iron(III) chloride; potassium phosphate; 1,1-dimethylethyl-1-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; In toluene; at 135℃; for 48h;Inert atmosphere; Sealed tube;
General procedure: 1-(Indol-3-yl)-N-Boc-THIQ 4a (100 mg, 0.287 mmol, 1.0 equiv.), iron(III)-chloride (4.7 mg, 28.7 mumol, 0.1 equiv.), and K3PO4 (122 mg, 0.574 mmol, 2.0 equiv.) were placed in a 2 mL glass vial, and aryliodide (0.431 mmol, 1.5 equiv.) and DMEDA (5.6 muL, 57.4 mumol, 0.20 equiv.) were added followed by dry toluene (300 muL). The reaction mixture was purged with argon for 30 seconds, the vial sealed and heated to 135 C and stirred at this temperature for 24 hours. The black slurry was cooled down to rt, diluted with DCM and filtered through a plug of celite. The solvent of the filtrate was evaporated and the crude product directly subjected to column chromatography using gradient elution with PE:EtOAc=100:0 0:40 (50 minutes) to afford the desired products 7a-e,g.
With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 130.0℃; for 2.0h;Inert atmosphere; Microwave irradiation;
2-Fluoro-3-iodopyridine (300 mg, 1 .34 mmol), potassium cyclopropyltrifluoroborate (498 mg, 3.36 mmol), palladium (II) acetate (30 mg, 0.135 mmol) are dissolved in toluene (4 mL) under a nitrogen flow. Tricyclohexylphosphine (75 mg, 0.27 mmol), tn-potassium phosphate (1.1 g, 5.38 mmol) and water (0.4 mL) are added and the reaction mixture is heated under microwave irradation (1 30C) for 2h. At rt, water is added and the aqueous layer is extracted with DCM. Then the organic layer is washed with water and brine, separated and dried to furnish 3-cyclopropyl-2-fluoro- pyridine (200 mg, 97%).U PLC-MS (Method 2): R = 0.94 mmMS (ESI pos): mlz = 138 (M+H)
97%
With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 130.0℃; for 2.0h;Inert atmosphere; Microwave irradiation;
10449] 2-Fluoro-3-iodopyridine (300 mg, 1.34 mmol), potassium cyclopropyltrifluoroborate (498 mg, 3.36 mmol), palladium (II) acetate (30 mg, 0.135 mmol) are dissolvedtoluene (4 mE) under a nitrogen flow. Tricyclohexylphosphine (75 mg, 0.27 mmol), tri-potassium phosphate (1.15.38 mmol) and water (0.4 mE) are added and the reaction mixture is heated under microwave irradation (130 C.) forh. At it, water is added and the aqueous layer is extracted with DCM. Then the organic layer is washed with water and brine, separated and dried to thmish 3-cyclopropyl-2-fluoro-pyri- dine (200 mg, 97%).10450] UPEC-MS (Method 2): R=0.94 mm10451] MS (ESI pos): mlz=138 (M+H)
With cesium fluoride; In dimethyl sulfoxide; at 130℃; for 4h;
General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 %) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;
2-Fluoro-3-iodopyridine (0.065 g, 0.29 mmol), Cs2CO3 (0.19 g, 0.58 mmol) and cyclopentylthiol (0.03 g, 0.291mmol) were dissolved in 2 mL of DMF, and the mixture was stirred at 80C for 2 hours. NaCl aqueous solution wasadded to the reaction solution, and the mixture was extracted with EtOAc to separate an organic layer. The organic layerwas dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to obtain the title compound(0.053 g, 65 %).1H-NMR (CDCl3) delta 8.38(1H, m), 7.89(1H, m), 6.68(1H, m), 4.00(1H, m), 2.22(2H, m), 1.80(2H, m), 1.66(4H, m)
Cyclopropyl-methanol (0.089 g, 1.23 mmol) was dissolved in anhydrous DMF (2 mL), and NaH (60 %)(0.054g,1.35 mmol) was slowly added dropwise thereto at 0C. The mixture was stirred for 30 minutes. The mixture was slowlyadded to a flask containing <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (0.137 g, 0.617 mmol) and stirred at room temperature for 1 hour.NH4Cl aqueous solution was added to the reaction solution, and the reaction solution was extracted with EtOAc toseparate an organic layer. The organic layer was dried with MgSO4 and purified by column chromatography (eluent,EtOAc/Hex = 1/5) to obtain the title compound (0.141 g, 83 %).1H-NMR (CDCl3) delta 8.07(1H, m), 8.00(1H, m), 6.61(1H, m), 4.20(2H, d), 1.32(1H, m), 0.60(2H, m), 0.39(2H, m)
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;
Cyclobutane thiol (0.069 g, 0.782 mmol) obtained in Step A and <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> (0.1 g, 0.43 mmol)were dissolved in DMF (3 mL). Cs2CO3 (0.26 g, 0.86 mmol) was added thereto, and the mixture was heated to 80Cand stirred. NaCl aqueous solution was added to the reaction solution, and the mixture was extracted with EtOAc. Theorganic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to obtain thetitle compound (0.115 g, 91 %).1H-NMR (CDCl3) delta 8.36(1H, m), 7.90(1H, m), 6.69(1H, m), 4.33(1H, m), 2.54(2H, m), 2.14(2H, m), 2.05(2H, m)
(4-Methoxyphenyl)-methanol (0.34 g, 2.46 mmol) was dissolved in DMF (7.5 mL). NaH (60%)(0.107 g, 2.69mmol) was added thereto at 0C, and the mixture was stirred. 2-Fluoro-3-iodopyridine (0.5 g, 2.24 mmol) was addedthereto, and the mixture was stirred for 16 hours. After termination of the reaction, the reaction solution was diluted withwater and extracted with Et2O. The organic layer was dried with anhydrous magnesium sulfate and purified by columnchromatography (eluent, EtOAc/Hex = 1/10) to obtain the title compound (0.726 g, 95 %).NMR: 1H-NMR (CDCl3) delta 8.12(1H, d), 8.03(1H, d), 7.44(2H, d), 6.91(2H,d), 6.65(1H, m), 5.37(2H, s), 3.82(3H, s)
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 9h;
Azetidin-3-ol hydrochloride 1.22 g (11.1 mmol) and DIPEA 4.64 mL (26.6 mmol) were added to a DMSO (10 mL) solution of <strong>[113975-22-7]2-fluoro-3-iodopyridine</strong> 1.98 g (8.88 mmol), and the mixture was stirred at 100C for 9 hours. After the completion of the reaction, water was added to the reaction mixture, and followed by extraction with toluene. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (eluting solvent: hexane:ethyl acetate) to give the title compound 1.66 g (6.01 mmol, yield 68%) as a white solid. Mass spectrum (CI, m/z):277[M+1]+. 1H-NMR spectrum (400MHz, DMSO-d6) delta:8.12 (dd, J = 1.6,4.7 Hz, 1H), 8.00 (dd, J = 1.6, 7.5 Hz, 1H), 6.52 (dd, J = 4.7, 7.5 Hz, 1H), 5.56 (s, 1H), 4.46 - 4.36 (m, 3H), 3.87 - 3.81 (m, 2H).
(6R*,6aR*,9R*,9aS*)-6,6a,7,8,9,9a-hexahydro-5H-6,9-methanocyclopenta[c][1,8]naphthyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With 2-chloro-6-hydroxybenzaldehyde; palladium diacetate; silver trifluoroacetate; acetic acid; 2-hydroxy-5-(trifluoromethyl)pyridine In water at 120℃; for 48h;
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