* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With ammonium hydroxide In dimethyl sulfoxide at 100℃; for 40 h;
A mixture of 2-fluoro-4-iodopyridine (10.00g, 43.50mmol), ammonium hydroxide (10mL) in DMSO (20mL) was stirred at 100 °C for 40 hours. H2O (100mL) was added to the reaction mixture and the precipitate was filtered to afford the compound 10a as a brown solid (8.62g, 90percent). MS: 221 (M+H) +.
60%
With ammonia In water at 150℃; for 3 h; Sealed tube
Reference Example 2; 4-iodopyridin-2-amine2-Fluoro-4-iodopyridine (11.2 g, 50 mmol) obtained in Reference Example 1 and 28percent aqueous ammonia solution (100 ml) were stirred at 150° C. for 3 hr in a sealed tube. The mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (6.6 g, yield 60percent). melting point 167-168° C.1H-NMR (CDCl3) δ: 4.34 (2H, brs), 6.92 (1H, d, J=1.4 Hz), 6.99 (1H, dd, J=5.5, 1.4 Hz), 7.73 (1H, d, J=5.5 Hz).
37%
With acetamide; potassium carbonate In ethyl acetate at 180℃; for 7 h;
Example 75A 2-Amino-4-iodopyridine A mixture of 2-floro-4-iodopyridine (3.0 g, 13.5 mmol), acetylamide (15.8 g, 269 mmol) and potassium carbonate (9.2 g, 67 mmol) was stirred at 180° C. for 7 hours, poured into ice (100 g), extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50percent ethyl acetate/hexane to provide the title compound (1.1 g, 37percent). MS (DCI/NH3) m/e 221 (M+H).
Example 75A 2-Amino-4-iodopyridine A mixture of 2-floro-4-iodopyridine (3.0 g, 13.5 mmol), acetylamide (15.8 g, 269 mmol) and potassium carbonate (9.2 g, 67 mmol) was stirred at 180° C. for 7 hours, poured into ice (100 g), extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50percent ethyl acetate/hexane to provide the title compound (1.1 g, 37percent). MS (DCI/NH3) m/e 221 (M+H).
Reference：
[1] Patent: US2003/187026, 2003, A1,
3
[ 124-41-4 ]
[ 22282-70-8 ]
[ 98197-72-9 ]
Yield
Reaction Conditions
Operation in experiment
91%
for 3 h; Heating / reflux
(c) 59.4 g (253 mmol) of the crude product of 2-fluoro-4-iodopyridine obtained in step (b) was added to 500 mL of methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by refluxing by heating for 3 hours. 300 mL of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. Extraction with ethyl ether was carried out, then, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield 91percent) of a crude product of 4-iodo-2-methoxypyridine.1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 3.86(s,3H), 7.12-7.16(m,2H), 7.79(d,1H, J = 5.6 Hz)
(c); 500 ml of methanol was added to 59.4 g (253 mmol) of crude 2-fluoro-4-iodopyridine obtained in Step (b) so that it was dissolved in methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by reflux with heating for 3 hours. 300 ml of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield: 91percent) of crude 4-iodo-2-methoxypyridine. 1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 3.86(s,3H), 7.12-7.16(m,2H), 7.79(d,1H, J = 5.6 Hz)
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
8
[ 372-48-5 ]
[ 22282-70-8 ]
Yield
Reaction Conditions
Operation in experiment
28%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 5 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran; hexane for 1 h; Inert atmosphere
Reference Example 1; 2-fluoro-4-iodopyridineA 1.6 M n-butyllithium-hexane solution (19 ml, 30.5 mmol) was added dropwise to a solution (95 ml) of diisopropylamine (9.84 ml, 70 mmol) in tetrahydrofuran at -78° C., and the mixture was stirred for 30 min under an argon atmosphere. 2-Fluoropyridine (6.8 g, 30.5 mmol) was added dropwise to the mixture, and the mixture was stirred for 4 hr at -78° C. A solution (60 ml) of iodine (8.9 g, 30.5 mmol) in tetrahydrofuran was added, and the mixture was stirred for 1 hr. Water was added to the mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. A 1.6 M n-butyllithium-hexane solution (19 ml, 30.5 mmol) was added dropwise to a solution (95 ml) of diisopropylamine (9.84 ml, 70 mmol) in tetrahydrofuran at -78° C., and the mixture was stirred for 30 min under an argon atmosphere. A solution (15 ml) of the obtained residue in tetrahydrofuran was added dropwise to the mixture, and the mixture was stirred at -78° C. for 1 hr under an argon atmosphere. Water was added to the mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (3.4 g, yield 28percent) as a solid.1H-NMR (CDCl3) δ: 7.37 (1H, d, J=1.7 Hz), 7.54 (1H, d, J=5.2 Hz), 7.92 (1H, dd, J=5.2, 1.7 Hz).
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
12
[ 22282-70-8 ]
[ 74-88-4 ]
[ 153034-80-1 ]
Yield
Reaction Conditions
Operation in experiment
17.2 g
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 2 h; Inert atmosphere
n-Butyl lithium (1.6M hexane solution, 53.8 mL) was added to a solution of diisopropylamine (8.71 g) in THF (200 mL) at -10 C. After being stirred at the same temperature under nitrogen atmosphere for 1 hour, a solution of 2-fluoro-3-iodopyridine (18.3 g) in THF (70 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 1 hour. A solution of iodomethane (12.8 g) in THF (30 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was quenched with aqueous saturated ammonium chloride solution at 0 C and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through NH-silica and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.2 g). 1H NMR (300 MHz, CDCl3) delta 2.39 (3H, d, J=1.5 Hz), 7.57-7.63 (1H, m), 7.65-7.70 (1H, m).
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; n-heptane at -75 - -65℃; for 2 h; Stage #2: at -75 - 20℃;
A mixture of DIP A (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 °C and n- BuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 min, 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 min 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 were treated with brine (50 mL), dried over MgSC^, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94percent), which was used as such in the next reaction step.
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.
Example 216A 2-Fluoro-4-vinylpyridine A mixture of 2-fluoro-4-iodopyridine (2.23 g, 10.0 mmol), tributyl vinyl tin (3.8 g, 12 mmol), and Pd2Cl2 (PPh3)2 (703 mg, 1.0 mmol) in dioxane (20 mL) was heated under nitrogen at 80 C. overnight. After cooled, ethyl acetate (40 ml) and saturated KF aqueous solution were added to the reaction mixture. The mixture was stirred for 30 min. The organic layer was separated and washed with water, dried (MgSO4), and concentrated. The resulting residue was purified by flash column chromatography eluding with hexane/ethyl acetate (20:1) to provide the title compound (463 mg, 38%). 1H-NMR (500 MHz, CDCl3) delta ppm 5.55 (d, J=10.92 Hz, 1H) 5.99 (d, J=17.47 Hz, 1H) 6.67 (dd, J=17.47, 10.61 Hz, 1H) 6.88 (m, 1H) 7.17 (dt, J=5.30, 1.56 Hz, 1H) 8.16 (d, J=5.30 Hz, 1H).
Stage #1: 2-fluoropyridine With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: With iodine In tetrahydrofuran for 0.5h;
61%
Stage #1: 2-fluoropyridine With lithium dipropan-2-ylazanide In tetrahydrofuran
Stage #2: With iodine In tetrahydrofuran
28%
Stage #1: 2-fluoropyridine With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 5h; Inert atmosphere;
Stage #2: With iodine In tetrahydrofuran; hexane for 1h; Inert atmosphere;
1
Reference Example 1; 2-fluoro-4-iodopyridineA 1.6 M n-butyllithium-hexane solution (19 ml, 30.5 mmol) was added dropwise to a solution (95 ml) of diisopropylamine (9.84 ml, 70 mmol) in tetrahydrofuran at -78° C., and the mixture was stirred for 30 min under an argon atmosphere. 2-Fluoropyridine (6.8 g, 30.5 mmol) was added dropwise to the mixture, and the mixture was stirred for 4 hr at -78° C. A solution (60 ml) of iodine (8.9 g, 30.5 mmol) in tetrahydrofuran was added, and the mixture was stirred for 1 hr. Water was added to the mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. A 1.6 M n-butyllithium-hexane solution (19 ml, 30.5 mmol) was added dropwise to a solution (95 ml) of diisopropylamine (9.84 ml, 70 mmol) in tetrahydrofuran at -78° C., and the mixture was stirred for 30 min under an argon atmosphere. A solution (15 ml) of the obtained residue in tetrahydrofuran was added dropwise to the mixture, and the mixture was stirred at -78° C. for 1 hr under an argon atmosphere. Water was added to the mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (3.4 g, yield 28%) as a solid.1H-NMR (CDCl3) δ: 7.37 (1H, d, J=1.7 Hz), 7.54 (1H, d, J=5.2 Hz), 7.92 (1H, dd, J=5.2, 1.7 Hz).
Multi-step reaction with 2 steps
1.1: LDA / tetrahydrofuran / 4 h / -78 °C
1.2: 72 percent / I2 / tetrahydrofuran / 1 h / -78 °C
2.1: LDA / tetrahydrofuran / 4 h / -78 °C
2.2: 98 percent / H2O / tetrahydrofuran / 1 h / -78 °C
Multi-step reaction with 2 steps
1.1: LDA
1.2: 78 percent / I2
2.1: 80 percent / n-BuLi; diisopropylamine / tetrahydrofuran; hexane / 1 h / -78 °C
Multi-step reaction with 2 steps
1.1: lithium dipropan-2-ylazanide / tetrahydrofuran / 4 h / -78 °C
1.2: 2 h / -78 °C
2.1: N-ethyl-N,N-diisopropylamine; n-butyllithium / tetrahydrofuran / -78 °C
Multi-step reaction with 2 steps
1.1: lithium dipropan-2-ylazanide / tetrahydrofuran / 3 h / -78 °C
2.1: lithium dipropan-2-ylazanide / tetrahydrofuran / 4 h / -78 °C
2.2: -78 - 20 °C
Stage #1: 2-fluoropyridine With lithium dipropan-2-ylazanide In tetrahydrofuran at -70℃; for 1h; Inert atmosphere;
Stage #2: With iodine In tetrahydrofuran at -70℃; for 1h; Inert atmosphere;
12.1
A solution of 2-fluoropyridine (CAS No. 372-48-5, 19.42 g, 0.2 mol) in 100 mL of dry THF was cooled to -70 °Cunder N2 atmosphere. The above LDA solution was added dropwise to the solution while the temperature was keptbelow -70 °C. Then the solution was stirred at -70 °C for 1hour. To the reaction mixture was added a solution of I2 (61g, 0.24 mol) in 50 mL of dry THF dropwise and then the reaction was stirred at -75 °C for 1 hour. The reaction wasquenched with sat. NH4Cl and stirred at 25 °C for 30 minutes. THF was removed by evaporation. The residue wasextracted with EtOAc (500 mL2). The combined EtOAc solution was washed with water and brine, dried over Na2SO4.Filtered and concentrated to dry to give crude product 401-A (2-fluoro-4-iodopyridine, 30 g, yield: 67%).1H NMR (300MHz, DMSO-d6): δ 8.37-8.43 (m, 1H), 8.21-8.22 (m, 1H), 7.13-7.18 (m, 1H).
Multi-step reaction with 5 steps
1: n-butyllithium; di-i-propyl amine / tetrahydrofuran; hexane / 5 h / -78 - -20 °C
2: iodine / tetrahydrofuran; hexane / 1 h
3: n-butyllithium; di-i-propyl amine / tetrahydrofuran; hexane / -78 - -20 °C
4: tetrahydrofuran; hexane / 1 h
5: water monomer / tetrahydrofuran; hexane
With sodium carbonate;palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; water; at 100℃;
Example 77 Synthesis of 2-Chloro-2'-fluoro-[3,4']bipyridinyl; To 2-fluoro-4-iodopyridine (9.45 g, 42.4 mmol), 2- chloropyridine-3-boronic acid (1Q.0 g, 63.5 mmol), NazC03 (13.5 g, 127 mmol), Pd(OAc)z (480 mg, 2.12 mmol) and P (tBu)3No.HBF4 (1.23 g, 4.24 mmol) was added dioxane (125 mL) and water (45 mL). The mixture was heated overnight at 100 C in a sealed tube. The resulting mixture was diluted with EtOAc and extracted with water and brine. The organic layer was dried over Na2S04, filtered and concentrated. The resulting solid was triturated with n-Hexanes and dried to yield 2-chloro-2'-fluoro-[3,4']bipyridinyl. MS m/z = 209 [M+1]+. Calc'd for C10H6ClFN2: 208.62.
Example 5 (a) 2-(Benzyloxy)-4-iodopyridine. To a stirred suspension of sodium hydride (0.316 g, 60% in mineral oil, 13.2 mmol, Aldrich) in 10 mL of DMF in a 250-mL round-bottomed flask, phenylmethanol (0.93 ml, 9.0 mmol, Aldrich) was added slowly. The suspention was stirred at room temperature for 15 min. 2-Fluoro-4-iodopyridine (2.01 g, 9.00 mmol, Asymchem) in a total of 5 mL of DMF was added slowly at 0 C. The mixture was stirred at 0 C. for 30 min. The reaction mixture was poured into 150 mL of saturated aqueous NH4Cl. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×200 mL) and saturated aqueous NaCl (1×200 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.82 g of pale yellow oil. The crude product was purified by flush column chromatography (eluent: EtOAc in hexanes 0%-5%) to afford a clear oil. This material was further purified by flush column chromatography (eluent: CH3Cl/hexanes, 30%-70%) to afford 1.71 g of 2-(benzyloxy)-4-iodopyridine as a clear oil [MS (ESI, pos.ion) m/z: 312 (M+1)].
(c) 59.4 g (253 mmol) of the crude product of 2-fluoro-4-iodopyridine obtained in step (b) was added to 500 mL of methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by refluxing by heating for 3 hours. 300 mL of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. Extraction with ethyl ether was carried out, then, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield 91%) of a crude product of 4-iodo-2-methoxypyridine.1H-NMR(CDCl3, 400 MHz) : delta (ppm) = 3.86(s,3H), 7.12-7.16(m,2H), 7.79(d,1H, J = 5.6 Hz)
With caesium carbonate; In tetrahydrofuran; at 50℃; for 24h;
Step 1. Preparation of 4-iodo-2-methoxypyridine; To 2-fluoro-4-iodopyridine (500 mg, 2.2 mmol) and cesium carbonate (730 mg, 2.2 mmol) was added THF (5 mL) and MeOH (0.091 mL, 2.2 mmol). The resulting mixture was heated to 50 C for 24 hours in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to yield the title compound. MS m/z = 236 [M+1]+. Calc'd for C6H6INO: 235.03.
(c); 500 ml of methanol was added to 59.4 g (253 mmol) of crude 2-fluoro-4-iodopyridine obtained in Step (b) so that it was dissolved in methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by reflux with heating for 3 hours. 300 ml of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield: 91%) of crude 4-iodo-2-methoxypyridine. 1H-NMR(CDCl3, 400 MHz) : delta (ppm) = 3.86(s,3H), 7.12-7.16(m,2H), 7.79(d,1H, J = 5.6 Hz)
Example 75A 2-Amino-4-iodopyridine A mixture of 2-floro-4-iodopyridine (3.0 g, 13.5 mmol), acetylamide (15.8 g, 269 mmol) and potassium carbonate (9.2 g, 67 mmol) was stirred at 180 C. for 7 hours, poured into ice (100 g), extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexane to provide the title compound (1.1 g, 37%). MS (DCI/NH3) m/e 221 (M+H).
With ammonium hydroxide; In dimethyl sulfoxide; at 100℃; for 40h;
A mixture of 2-fluoro-4-iodopyridine (10.00g, 43.50mmol), ammonium hydroxide (10mL) in DMSO (20mL) was stirred at 100 C for 40 hours. H2O (100mL) was added to the reaction mixture and the precipitate was filtered to afford the compound 10a as a brown solid (8.62g, 90%). MS: 221 (M+H) +.
90%
With ammonium hydroxide; In dimethyl sulfoxide; at 100℃; for 40h;
A solution of 2-fluoro-4-iodopyridine (10.00 g, 43.50 mmol) and ammonia (10 mL) in DMSO (20 mL) was stirred at 100 C for 40 h.Water (100 mL) was added to the reaction solution, and a solid was precipitated. The brown solid compound 10a (8.62 g, 90%) was obtained by filtration
60%
With ammonia; In water; at 150℃; for 3h;Sealed tube;
Reference Example 2; 4-iodopyridin-2-amine2-Fluoro-4-iodopyridine (11.2 g, 50 mmol) obtained in Reference Example 1 and 28% aqueous ammonia solution (100 ml) were stirred at 150 C. for 3 hr in a sealed tube. The mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium hydrogensulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (6.6 g, yield 60%). melting point 167-168 C.1H-NMR (CDCl3) delta: 4.34 (2H, brs), 6.92 (1H, d, J=1.4 Hz), 6.99 (1H, dd, J=5.5, 1.4 Hz), 7.73 (1H, d, J=5.5 Hz).
37%
With acetamide; potassium carbonate; In ethyl acetate; at 180℃; for 7h;
Example 75A 2-Amino-4-iodopyridine A mixture of 2-floro-4-iodopyridine (3.0 g, 13.5 mmol), acetylamide (15.8 g, 269 mmol) and potassium carbonate (9.2 g, 67 mmol) was stirred at 180 C. for 7 hours, poured into ice (100 g), extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexane to provide the title compound (1.1 g, 37%). MS (DCI/NH3) m/e 221 (M+H).
2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
A-78 oC solution of Example 68B (3.35g, 15 mmol) diethyl ether (100 mL) was treated dropwise with 2.5 M n-butyllithium (7.2 mL, 18 mmol), stirred for 2 hours AT-78 C, TREATED with tributyl borate (4.14g, 18 mmol), stirred at-78 oC for one hour and warmed to room temperature over 2 hours. The solution was treated with pinacol (2.30g, 19.5 mmol) and acetic acid (0.9g, 15 mmol), stirred overnight, and filtered through diatomaceous earth (ELITE). The pad was washed with diethyl ether several times and the filtrate was concentrated to a volume of 50 ML. The mixture was diluted with ethyl acetate, washed with 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 2.34g (70%) of the desired product. MS (DCI) M/E 224 (M+H) + ; LH NMR (300 MHz, CDCl3,) 8 8.24 (d, J = 5.1 Hz, 1H), 7.50 (dd, J = 4.8, 2.7 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 1.36 (s, 12H).
With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 180℃; for 0.5h; Microwave irradiation; regioselective reaction;
48%
With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 180℃; for 0.5h; Inert atmosphere; Microwave irradiation; Sealed vial;
4.2. General procedure A
General procedure: Dihalopyridine (1 equiv), amine (1.2 equiv), K2CO3 (3.5 equiv), Pd(OAc)2 (2 mol %), and BINAP (2 mol %) were charged into a microwave vial and dry toluene was added. The vial was then sealed, evacuated, and flushed with argon. Then the reaction mixture was irradiated at 180 °C in a CEM Explorer microwave unit for 30 min (in few cases 45 min) with stirring. After cooling to rt, the solid material was removed by filtration and washed with 10 mL of EtOAc or CH2Cl2. The organic phases were combined and the solvent was evaporated. The resulting crude product was purified by flash column chromatography.
With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 180℃; for 0.5h; Microwave irradiation; regioselective reaction;
75%
With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 180℃; for 0.5h; Inert atmosphere; Microwave irradiation; Sealed vial;
4.2. General procedure A
General procedure: Dihalopyridine (1 equiv), amine (1.2 equiv), K2CO3 (3.5 equiv), Pd(OAc)2 (2 mol %), and BINAP (2 mol %) were charged into a microwave vial and dry toluene was added. The vial was then sealed, evacuated, and flushed with argon. Then the reaction mixture was irradiated at 180 °C in a CEM Explorer microwave unit for 30 min (in few cases 45 min) with stirring. After cooling to rt, the solid material was removed by filtration and washed with 10 mL of EtOAc or CH2Cl2. The organic phases were combined and the solvent was evaporated. The resulting crude product was purified by flash column chromatography.
75%
With potassium carbonate In toluene at 180℃; for 0.5h; Inert atmosphere; Microwave irradiation; Sealed vial;
41.41a
Example 1 2-(4-(4-Phenoxyphenylamino)pyridin-2-ylamino)ethan-l-ol -Fluoro-N-(4-phenoxyphenyl)pyridin-4-amine 100 mg of 2-fluoro-4-iodopyridine, 100 mg of 4-phenoxyaniline, 218 mg of 2CO3, 2 mg of Pd(OAc)2 and 6 mg of BINAP were charged into a microwave vial and 2 n L of dry toluene were added. The vial was sealed, evacuated and flushed with Argon. The mixture in the vial was irradiated at 180°C in a CEM Explorer microwave unit for 30 minutes with stirring. The mixture obtained was cooled to r.t.. From the mixture obtained solid material was filtered off and washed with 10 mL of CH2C12 and solvent from the combined filtrate and washing solvent was evaporated off. The evaporation residue obtained was subjected to flash column chromatography. 2-Fluoro-N-(4-phenoxyphenyl)pyridin-4-amine was obtained in the form of brown crystals. Yield: 75% of theory. M.p.: 149°C. NMR (CDCI3, 200MHz): 13C NMR (CDCb, 50MHz): δ = 92.0 (q, JC-F = 39.5 Hz), 107.8 (q, JQ-F - 3.2 Hz), 1 18.9 (d), 1 19.9 (d), 123.5 (d), 125.0 (d), 129.9 (d), 133.9 (s), 147.9 (q, Jc-F = 22.9 Hz), 154.8 (s), 155.8 (d, JC-F = 1 1.9 Hz) 157.0 (s), 165.6 (d, JC-F = 233.0Hz).
75%
With potassium carbonate In toluene at 180℃; for 0.5h; Inert atmosphere; Sealed vial; Microwave irradiation;
41.41a
41a. 2-Fluoro-N-(4-phenoxyphenyl)pyridin-4-amine 100 mg of 2-fluoro-4-iodopyridine, 100 mg of 4-phenoxyaniline, 218 mg of K2CO3, 2 mg of Pd(OAc)2 and 6 mg of BINAP were charged into a microwave vial and 2 mL of dry toluene were added. The vial was sealed, evacuated and flushed with Argon. The mixture in the vial was irradiated at 180° C. in a CEM Explorer microwave unit for 30 minutes with stirring. The mixture obtained was cooled to r.t. From the mixture obtained solid material was filtered off and washed with 10 mL of CH2Cl2 and solvent from the combined filtrate and washing solvent was evaporated off. The evaporation residue obtained was subjected to flash column chromatography. 2-Fluoro-N-(4-phenoxyphenyl)pyridin-4-amine was obtained in the form of brown crystals. Yield: 75% of theory. M.p.: 149° C. 1H NMR (CDCl3, 200 MHz): δ=6.51 (d, J=1.9 Hz, 1H) 6.61 (s, 1H) 6.81 (d, J=5.8 Hz, 1H) 7.23 (d, J=2.1 Hz, 2H) 7.37 (m, 3H) 7.48 (s, 1H) 7.57 (t, J=7.9 Hz, 3H) 8.80 (d, J=5.8 Hz, 1H) 13C NMR (CDCl3, 50 MHz): δ=92.0 (q, JC-F=39.5 Hz), 107.8 (q, JC-F=3.2 Hz), 118.9 (d), 119.9 (d), 123.5 (d), 125.0 (d), 129.9 (d), 133.9 (s), 147.9 (q, JC-F=22.9 Hz), 154.8 (s), 155.8 (d, JC-F=11.9 Hz) 157.0 (s), 165.6 (d, JC-F=233.0 Hz).
With sodium hydride In paraffin oil (nujol); N,N-dimethyl-formamide at 0 - 20℃; for 16h;
17
Reference Example 17; 2-(2-(3,4-Dimethoxyphenyl)ethoxy)-4-iodopyridine; Sodium hydride (60% liquid paraffin dispersion, 358 mg, 8.96 mmol) was added at 0°C to a DMF (3 mL) solution of 2-fluoro-4-iodopyridine (1.0 g, 4.48 mmol) and 2-(3,4-dimethoxyphenyl)ethanol (0.9 g, 5.0 mmol), and the mixture was stirred for 16 hours at room temperature. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated at reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 1:1) to give 0.88 g of the titled compound (yield: 51 %). Oily substance. 1H-NMR (CDCl3 ) δ : 3.00 (2H, t, J = 6.9 Hz), 3.86 (3H, s), 3.87 (3H, s), 4.46 (2H, t, J = 6.9 Hz), 6.77 - 6.80 (3H, m), 7.13 - 7.21 (2H, m), 7.79 (1H, d, J = 5.4 Hz).
2-fluoro-4-iodopyridine (2.21 kg, 9.91 mol) was suspended in a mixture of acetic acid (7 L) and H20 (3.5 L) with mechanical stirring. The mixture was heated at reflux overnight. After cooling to room temperature the solid was filtered off and concentrated in vacuo. The residue was stirred in Et20 (3 L), the title compound (1.72 kg, 7.78 mol) was collected by filtration as a pale yellow solid. 1H-NMR: (DMSO-d6, 300 MHz): delta 6.50 (d, 1 H), 6.85 (s, 1 H), 7.15 (d, 1 H), 1 1.80 (s, 1 H)
1.72 kg
With water; acetic acid;Reflux; Large scale;
2-fluoro-4-iodopyridine (2.21 kg, 9.91 mol) was suspended in a mixture of acetic acid (7 L) and H2O (3.5 L) with mechanical stirring. The mixture was heated at reflux overnight. After cooling to room temperature the solid was filtered off and concentrated in vacuo. The residue was stirred in Et20 (3 L), the title compound (1 .72 kg, 7.78 mol) was collected by filtration as a pale yellow solid. 1H NMR (DMSO-d6, 300 MHz) 5 ppm 6.50 (d, 1 H), 6.85 (s, 1 H), 7.15 (d, 1 H), 1 1.80 (s, 1 H).
Example IX.1 5-(4-Iodo-pyridin-2-yloxy)-pyrimidine To 259 mg (26.9 mmol) <strong>[26456-59-7]pyrimidin-5-ol</strong> (J. Chem. Soc. 1956, 2033) in 200 mL DMF are added 108 mg (26.9 mmol) sodium hydride (60% dispersion in mineral oil). The mixture is stirred for 20 min at rt. After that time, 500 mg (22.4 mmol) 2-fluoro-4-iodopyridine are added and the mixture is stirred for 12 h at 80 C. Subsequently the mixture is poured into water and extracted with ethyl acetate (3*). The combined organic layers are washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; heptane/ethyl acetate, gradient 0-60%) to yield the desired product. C9H61N3O (M=299.1 g/mol), ESI-MS: 300 [M+H]+
To 259 mg (26.9 mmol) <strong>[26456-59-7]pyrimidin-5-ol</strong> (J. Chem. Soc. 1956, 2033) in 200 mL DMF are added 108 mg (26.9 mmol) sodium hydride (60% dispersion in mineral oil). The mixture is stirred for 20 mm at r.t.. After that time, 500 mg (22.4 mmol) 2-fluoro-4-iodopyridine are added and the mixture is stirred for 12 h at 80 C. Subsequently the mixture is poured into water and extracted with ethyl acetate (3x). The combined organic layers are washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; heptane/EtOAc, 100/0 - 40/60).C9H6IN3O (M = 299.1 g/mol)ESI-MS: 300 [M+H]+ Rt(HPLC) : 2.87 mm (method C)
Example XXVIII.1 (General Route) 5-(4-Iodo-pyridin-2-yloxy)-pyrimidine To 259 mg (26.9 mmol) <strong>[26456-59-7]pyrimidin-5-ol</strong> (J. Chem. Soc. 1956, 2033) in 200 mL DMF are added 108 mg (26.9 mmol) sodium hydride (60% dispersion in mineral oil). The mixture is stirred for 20 min at r.t. After that time, 500 mg (22.4 mmol) 2-fluoro-4-iodopyridine are added and the mixture is stirred for 12 h at 80 0. Subsequently the mixture is poured into water and extracted with ethyl acetate (3*). The combined organic layers are washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; heptane/EtOAc, 100/0?40/60). C9H6IN3O (M=299.1 g/mol) ESI-MS: 300 [M+H]+Rt (HPLC): 2.87 min (method C)
Stage #1: 2-fluoro-4-iodopyridine; 3-amino-N-(dimethylethyl)benzenesulfonamide With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 1.5h; microwave irradiation;
Stage #2: 4-fluoro-2-methoxyphenylboronic acid In N,N-dimethyl-formamide at 140℃; for 1.5h; Inert atmosphere; microwave irradiation;
5
A mixture of 2-fluoro-4-iodopyridine (100 mg, 0.45 mmol), 3-amino-N-(tert- butyl)benzenesulfonamide (153 mg, 0.67 mmol), and CS2CO3 (291 mg, 0.89 mmol) in dry DMF (3 ml_) was heated at 150°C for 1 .5 h in a microwave oven. After addition of (4- fluoro-2-methoxyphenyl)boronic acid (152 mg, 0.89 mmol) the mixture was degassed with a stream of nitrogen for 5 minutes. Pd(dppf)Cl2 (73 mg, 0.09 mmol) was added and the reaction mixture was heated to 140°C for 90 minutes in a microwave oven. The mixture was diluted with EtOAc and washed twice with sat. aq. NaHC03-solution and once with brine. The organic layer was dried over MgS04 and concentrated under reduced pressure, and the residue was purified by preparative HPLC (water/ACN 95:5 to 0: 100) to yield the desired product D2 as a yellow solid (9 mg, 5%). 1 H NMR (400MHz, de-DMSO, 300K) 5 1 .12 (s, 9H), 3.82 (s, 3H), 6.89 (m, 2H), 6.97 (s, 1 H), 7.06 (dd, J = 1 1 .5 Hz, J = 2.4 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.39 (m, 2H), 7.44 (s, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 8.24 (m, 1 H), 9.39 (s, 1 H). MS (ES) C22H24FN3O3S requires: 429, found: 430 (M+H)+.
With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 6h;
Example 25A 2-(tricyclo[3.3.1.13,7]dec-1-ylmethoxy)-4-iodo-pyridine <strong>[770-71-8]1-Adamantanemethanol</strong> (0.820 g) and 2-fluoro-4-iodopyridine (0.22 g) in tetrahydrofuran (5 mL) was treated with sodium hydride (60% in mineral oil) (0.057) at room temperature for 6 hours. The reaction was quenched with ice-water and extracted with ethyl acetate (3*10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC, eluting with petroleum ether/ethyl acetate (20/1) to provide the title compound.
1-(4-iodo-2-pyridyl)indazole-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 2-fluoro-4-iodopyridine; 1,2-diazabicyclo[3,3,04,8]octa-3,8-diene-3-carboxylic acid ethyl ester With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;
Stage #2: With water; lithium hydroxide at 50℃; for 1h;
Synthesis of 1- (4-iodo-2-pyridyl)-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxylic acid
General procedure: Similar to as described in General Procedure A, ethyl1,4,5 ,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate was reacted with 2-fluoro-4-iodo-pyridine to give the title compound, as well as some remaining ester. Lithium hydroxide (1.0 eq.) in water(1.0 M) was added and the reaction was stirred at 50 °C for lh to afford complete conversion to the desired acid. The crude material was used directly in subsequent reactions.;To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N,N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). The reaction was heated to 100 °C and stirred at this temperature for 2 hours. The reaction was then cooled to roomtemperature and acidified to pH = 1 with 10 % aqueous HC1 solution if product contains a carboxylic acid, or diluted with water if neutral. The solution was extracted with twice with dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was either used directly in subsequent reactions or purified by flash chromatography.
1-(4-iodopyridin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2.0h;
General procedure: Similar to General Procedure A, to a solution of <strong>[6076-13-7]4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid</strong> (50 mg, 0.30 mmol) and cesium carbonate (3.0 equiv., 294 mg, 0.902 mmol) in N,N-dimethylformamide (0.60 mL) was added 2-fluoro-4-iodo-pyridine (1.1 equiv., 73.8 mg,0.33 1 mmol). The reaction was heated to 100 C and stirred at this temperature for 2 hours. The reaction was then cooled to room temperature and acidified to pH = 1 with 10 % aqueous HC1 solution. The solution was extracted with twice with dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was used directly in subsequent reactions; To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N,N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). The reaction was heated to 100 C and stirred at this temperature for 2 hours. The reaction was then cooled to roomtemperature and acidified to pH = 1 with 10 % aqueous HC1 solution if product contains a carboxylic acid, or diluted with water if neutral. The solution was extracted with twice with dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was either used directly in subsequent reactions or purified by flash chromatography.
n-Butyl lithium (1.6M hexane solution, 53.8 mL) was added to a solution of diisopropylamine (8.71 g) in THF (200 mL) at -10 C. After being stirred at the same temperature under nitrogen atmosphere for 1 hour, a solution of 2-fluoro-3-iodopyridine (18.3 g) in THF (70 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 1 hour. A solution of iodomethane (12.8 g) in THF (30 mL) was added to the reaction mixture at -78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was quenched with aqueous saturated ammonium chloride solution at 0 C and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through NH-silica and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.2 g). 1H NMR (300 MHz, CDCl3) delta 2.39 (3H, d, J=1.5 Hz), 7.57-7.63 (1H, m), 7.65-7.70 (1H, m).
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-4-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 at that temperature. The mixture was then cooled to 0 C, and 12.0 M aqueous HC1 (5.0 mL, 60. mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred at that temperature for 3 h. Saturated aqueous NaHCC (250 mL) was added, then the reaction mixture was extracted with EtOAc (3 x 150 mL). The combined extracts were washed with brine (250 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient elution with 0-100% EtOAc in hexanes) to give the sub-title compound as a white solid (3.13 g, 87%). LCMS calc. for CvHsFINO (M+H)+: m/z = 268.0; found 268.0.
1950 mg
A solution of LDA, 2M in n-heptane / THF / ethylbenzene (5.3 mL; 10.6 mmol) was added to a solution of 2-fluoro-4-iodopyridine (2000 mg; 8.79 mmol) in THF (40 mL) at -78 C. The reaction mixture was stirred at -78 C for 1.5 h. With the temperature maintained at -78 C, a solution of 1,3,2-dioxathiolane 2,2-dioxide (1450 mg; 11.4 mmol) in THF (20 mL) was added slowly over a period of 20 min. The solution was further stirred at -78 C for 20 min, then allowed to warm to rt and stirred for additional 2 h. The mixture was then cooled to 0 C, and 12 M aqueous HC1 (3.3 mL) was added. The reaction mixture was allowed to warm to rt and stirred for 3 h. Saturated aqueous solution of NaHCC>3 (200 mL) was added and the product was extracted with EA (3 x 150 mL). The combined extracts were washed with brine (250 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; n-Hex : EA; 1 :0 to 0: 1 ; v/v) to afford 2-(2-fluoro-4-iodo- 3-pyridyl)ethanol (1950 mg) as a white solid. (0758) MS m/z (+ESI): 268.0 [M+H]+. (0759) 'H-NMR (400 MHz, DMSO-/ + D20) delta ppm: 7.77 (d, J= 5.2 Hz, 1H), 7.72 (d, J= 5.2 Hz, 1H), 3.52 (t, J= 7.2 Hz, 2H), 2.88 (t, J= 7.2 Hz, 2H).
N-(2,3-dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With hydrogenchloride; In 1,4-dioxane; water; at 100℃; for 15h;Sealed tube;
To a suspension of <strong>[42933-43-7]2,3-dihydrobenzofuran-5-amine</strong> (1 g, 7.4 mmol) in 1:1 dioxane: water (200 mL) was added 2-fluoro-4-iodopyridine (1.982 g, 8.8 mmol) and aqueous HCl (2 mL, 35percent). The mixture was stirred for 15 h at 100° C. in a sealed glass tube. Reaction mixture was cooled and basified by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated to give crude product residue, which was purified by gradient column chromatography using ethyl acetate in n-hexane as eluent to afford N-(2,3-dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine as yellow solid, (600 mg, 24percent). 1HNMR (400 MHz, CDCl3): delta 7.76 (d, J=4.8 Hz, 1H), 7.13 (s, 1H), 7.00-6.97 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.48 (s, 1H), 4.60 (t, J=8.8 Hz, 2H), 3.23 (t, J=8.8 Hz, 2H). LC-MS calcd exact mass 337.99, found m/z 339.0 [M+H]+.
Stage #1: 2-fluoro-4-iodopyridine With TurboGrignard In tetrahydrofuran at -30 - -10℃; for 1.5h; Inert atmosphere; Large scale;
Stage #2: 4-Chloro-2-methylthiopyrimidine With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride In tetrahydrofuran at 50 - 62℃; Inert atmosphere; Large scale;
2.1
Step 1: A 1000 L reactor was charged with 2-fluoro-4-iodopyridine (82.2 kg) and dry THF (205 kg). The reactor was evacuated and backfilled with N2 three times then cooled to between -30 and -20° C. To the solution was added dropwise i-PrMgCl.LiCl (319 kg, 1.3M in THF). The reaction was warmed to between -20 and -10° C. and stirred for 1.5 h to complete the transmetallation. A 2000 L reactor was charged with 4-chloro-2-methylthiopyrimidine (45.6 kg), dry THF (205 kg) and [1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium(II) dichloride (PEPPSI-IPr, 1.850 kg). The 2000 L reactor was evacuated and backfilled with N2 three times and heated to between 55 and 57° C. To the reactor was added over 0.5 to 1 h, the solution of (2-fluoropyridin-4-yl)magnesium chloride while maintaining the temperature between 50 and 62° C. The resulting reaction mixture was stirred at between 50 and 62° C. for a further 2 h. The reaction mixture was cooled to between 5 and 25° C. while the reaction was quenched with water (273 kg). The pH of the mixture was adjusted to 8 to 9 by adding solid citric acid monohydrate (7.3 kg). The organic layer was separated, washed with 12.5% aqNaCl (228 kg) and concentrated in vacuo below 50° C. to afford 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (38.3 kg, 61% yield) as product in THF.
Stage #1: 2-fluoro-4-iodopyridine With TurboGrignard In tetrahydrofuran at -10 - -5℃; Inert atmosphere; Flow reactor;
Stage #2: 4-Chloro-2-methylthiopyrimidine With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl) palladium(II) dichloride In tetrahydrofuran at 60 - 65℃; Inert atmosphere; Flow reactor;
4-(2-(4-(benzyloxy)phenyl)benzofuran-3-yl)-2-fluoropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
General procedure: 2-Iodophenol (1.14mmol, 250mg) and Pd(Ph3P)2Cl (5mol%, 40mg) were placed in a 20mL microwave vial, and purged with N2. Dry THF (0.8mL) was added and the mixture was stirred until the iodophenol was completely dissolved. Then dry triethylamine (2mL) and a solution of CuI (3mol%, 5.4mg) in triethylamine (1mL) were added and the mixture was stirred for 10min. 4-Ethynylanisole (1.2 equiv., 180.3mg) in THF (0.5mL) was then added under N2, and the mixture was stirred in the microwave reactor for 30minat 40C. The corresponding 3-iodopyridine (1.2 equiv., 279.6mg) in dry CH3CN (3.7mL) was added under N2, and the reaction mixture was heated in the microwave reactor at 100C for 30min. The reaction was monitored with TLC and LC-MS. After cooling, the solvents were evaporated and the product was purified on silica followed by preparative HPLC (25?100% B over 25min).
4-(3-(2-fluoropyridin-4-yl)benzofuran-2-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: 2-Iodophenol; 4-ethynylphenol With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine In tetrahydrofuran at 40℃; for 0.5h; Microwave irradiation; Inert atmosphere;
Stage #2: 2-fluoro-4-iodopyridine In acetonitrile at 100℃; for 0.5h; Inert atmosphere; Microwave irradiation;
3-(2-(4-methoxyphenyl)benzofuran-3-yl)pyridine, 1
General procedure: 2-Iodophenol (1.14mmol, 250mg) and Pd(Ph3P)2Cl (5mol%, 40mg) were placed in a 20mL microwave vial, and purged with N2. Dry THF (0.8mL) was added and the mixture was stirred until the iodophenol was completely dissolved. Then dry triethylamine (2mL) and a solution of CuI (3mol%, 5.4mg) in triethylamine (1mL) were added and the mixture was stirred for 10min. 4-Ethynylanisole (1.2 equiv., 180.3mg) in THF (0.5mL) was then added under N2, and the mixture was stirred in the microwave reactor for 30minat 40°C. The corresponding 3-iodopyridine (1.2 equiv., 279.6mg) in dry CH3CN (3.7mL) was added under N2, and the reaction mixture was heated in the microwave reactor at 100°C for 30min. The reaction was monitored with TLC and LC-MS. After cooling, the solvents were evaporated and the product was purified on silica followed by preparative HPLC (25→100% B over 25min).
2-fluoro-4-(6-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of the 2-Iodo-5-methoxyphenol (1mmol, 252mg) and the 4-Ethynylanisole (1.2 equiv., 166mg) in dry THF (1.6mL, 0.6M of the Iodophenol), at 0C under N2, was added CH3MgBr (THF solution, 2.3M, 2 equiv., 0.792mL) dropwise. The mixture was allowed to warm to room temperature, and Pd(Ph3P)2Cl (3mol%, 21.3mg) was added before the mixture was heated to 65C for 2h under N2. The reaction mixture was then cooled to room temperature and the THF was removed under reduced pressure. DMSO (2mL) was added to the residue followed by addition of 2-Fluoro-4-iodopyridine (1.2 equiv., 269.7mg) and the mixture was heated to 80C for 4h under N2. The mixture was cooled to room temperature and diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SO4, concentrated and purified on silica followed by preparative HPLC (25?100% B over 25min).
2-fluoro-4-(5-fluoro-2-(4-methoxyphenyl)benzofuran-3-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: To a solution of the 2-Iodo-5-methoxyphenol (1mmol, 252mg) and the 4-Ethynylanisole (1.2 equiv., 166mg) in dry THF (1.6mL, 0.6M of the Iodophenol), at 0C under N2, was added CH3MgBr (THF solution, 2.3M, 2 equiv., 0.792mL) dropwise. The mixture was allowed to warm to room temperature, and Pd(Ph3P)2Cl (3mol%, 21.3mg) was added before the mixture was heated to 65C for 2h under N2. The reaction mixture was then cooled to room temperature and the THF was removed under reduced pressure. DMSO (2mL) was added to the residue followed by addition of 2-Fluoro-4-iodopyridine (1.2 equiv., 269.7mg) and the mixture was heated to 80C for 4h under N2. The mixture was cooled to room temperature and diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SO4, concentrated and purified on silica followed by preparative HPLC (25?100% B over 25min).
4-(5-fluoro-3-(2-fluoropyridin-4-yl)benzofuran-2-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: To a solution of the 2-Iodo-5-methoxyphenol (1mmol, 252mg) and the 4-Ethynylanisole (1.2 equiv., 166mg) in dry THF (1.6mL, 0.6M of the Iodophenol), at 0C under N2, was added CH3MgBr (THF solution, 2.3M, 2 equiv., 0.792mL) dropwise. The mixture was allowed to warm to room temperature, and Pd(Ph3P)2Cl (3mol%, 21.3mg) was added before the mixture was heated to 65C for 2h under N2. The reaction mixture was then cooled to room temperature and the THF was removed under reduced pressure. DMSO (2mL) was added to the residue followed by addition of 2-Fluoro-4-iodopyridine (1.2 equiv., 269.7mg) and the mixture was heated to 80C for 4h under N2. The mixture was cooled to room temperature and diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SO4, concentrated and purified on silica followed by preparative HPLC (25?100% B over 25min).
3-(2-fluoropyridin-4-yl)-2-(4-hydroxyphenyl)benzofuran-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: 4-ethynylphenol; 4-iodobenzene-1,3-diol With trans-bis(triphenylphosphine)palladium dichloride In tetrahydrofuran at 0 - 65℃; for 2h; Inert atmosphere;
Stage #2: 2-fluoro-4-iodopyridine In dimethyl sulfoxide at 80℃; for 4h; Inert atmosphere;
2-fluoro-4-(6-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)pyridine, 12
General procedure: To a solution of the 2-Iodo-5-methoxyphenol (1mmol, 252mg) and the 4-Ethynylanisole (1.2 equiv., 166mg) in dry THF (1.6mL, 0.6M of the Iodophenol), at 0°C under N2, was added CH3MgBr (THF solution, 2.3M, 2 equiv., 0.792mL) dropwise. The mixture was allowed to warm to room temperature, and Pd(Ph3P)2Cl (3mol%, 21.3mg) was added before the mixture was heated to 65°C for 2h under N2. The reaction mixture was then cooled to room temperature and the THF was removed under reduced pressure. DMSO (2mL) was added to the residue followed by addition of 2-Fluoro-4-iodopyridine (1.2 equiv., 269.7mg) and the mixture was heated to 80°C for 4h under N2. The mixture was cooled to room temperature and diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SO4, concentrated and purified on silica followed by preparative HPLC (25→100% B over 25min).
A mixture of DIP A (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 C and n- BuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 min, 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 min 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 were treated with brine (50 mL), dried over MgSC^, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94%), which was used as such in the next reaction step.
2-(3-fluoro-4-methylphenoxy)-4-iodopyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
Cesium carbonate (1.17 g, 3.59 mmol) was added dropwise to a stirred solution of 3- fluoro-4-methylphenol (250 mg, 1.97 mmol) in DMF (10 mL) at 0C under nitrogen. The resulting solution was stirred 0C for 30 min before 2-fluoro-4-iodopyridine (400 mg, 1.80 mmol) was added. The ice bath was removed, and the mixture was left to stir at room temperature for 18 h. The mixture was hydrolyzed with water, extracted with Et20, the organics were washed with brine, dried over MgSCU and concentrated in vacuo to afford, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate - 100:0 to 70:30 the title compound as a white foam (420 mg, 72% yield). ESIMS m/z [M+H]+ 330.18.
4-iodo-2-(4-methyl-1H-imidazol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 4h; Inert atmosphere;
1 Step 1: preparation of 4-iodo-2-(4-methyl-1H-imidazol-1-yl)pyridine
2-fluoro-4-iodopyridine (2.0 g, 8.97 mmol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (3.7 g, 26.9 mmol) and 4-methyl-1H-imidazole (0.81 g, 9.86 mmol) were added at room temperature. The reaction solution was stirred at 80° C. for 4 hrs, then poured into water (50 mL), and then extracted twice with ethyl acetate (30 mL*2). The organic phases were combined and washed once with a brine (40 mL), dried over sodium sulfate, filtered and concentrated to obtain a crude product of 4-iodo-2-(4-methyl-1H-imidazol-1-yl)pyridine (2.2 g, yield 86%). MS m/z (ESI): 286 [M+H]30 .
A solution of 401-A (21.6 g, 96.9 mmol) in 100 mL of dry THF was cooled to -70 C. The above LDA solutionwas added dropwise to the solution while the temperature was kept below -70 C. Then the solution was stirred at -70C for 1 hour. Ethyl formate (10 mL, 121 mmol) was added dropwise to the solution and slowly warmed to -50 C during1 hour. The reaction mixture was quenched with sat. NH4Cl and stirred at 25 C for 30 minute. THF was removed byevaporation and the reaction solution was extracted with EtOAc (300 mL2). The combined organic phase was washedwith water and brine, dried over Na2SO4. Na2SO4 was filtered and the organic phase was concentrated to dry and theresidue was purified by column chromatography on silica gel (PE/EtOAc: 50:1 to 10:1) to give the product 401-B (2-fluoro-4-iodonicotinaldehyde, 13.0 g, yield: 53%).1H NMR (300 MHz, DMSO-d6): delta 10.15 (s, 1H), 7.97 (d, J = 5.1 Hz, 1H), 7.87 (d, J = 5.1 Hz, 1H).
To a solution of 2-fluoro-4-iodo-pyridine (7.70 g, 34.53 mmol, 1.00 eq) in tetrahydrofuran (80 mL) was added lithium diisopropylamide (2 M, 20.72 mL, 1.20 eq) at -78 C for 1.5 h. Then the mixture was added a solution of 1-chloro-3-iodo-propane (14.12 g, 69.06 mmol, 7.43 mL, 2.00 eq) in tetrahydrofuran (10 mL) at -78C and stirred for 0.5 h. Then the mixture was warmed to 15 C and stirred for 1 h. The mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1) to give 3-(3-chloropropyl)-2-fluoro-4-iodo-pyridine (9.00 g, 30.05 mmol, 87% yield) as a light yellow oil.1H-NMR (400MHz, CDCl3) d 7.69 (d, J=5.6 Hz, 1H), 7.61 (d, J=5.2 Hz, 1H), 3.61 (t, J=6.4 Hz, 2H), 2.90 - 2.97 (m, 2H), 2.04 - 2.08 (m, 1H), 1.99 - 2.03 (m, 1H).
3-(4-iodo-2-pyridyl)-6-oxa-3-azabicyclo[3.1.1]heptane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
Stage #1: 6-oxa-3-azabicyclo[3.1.1]heptane With triethylamine In 1,4-dioxane at 20℃; for 0.5h;
Stage #2: 2-fluoro-4-iodopyridine In 1,4-dioxane at 110℃; for 37.5h;
262.1 Step 1: 3-(4-Iodo-2-pyridyl)-6-oxa-3-azabicyclo[3. 1. 1 ]heptane
To a solution of 6-oxa-3-azabicyclo[3.1.1]heptane (200.66 mg, 1.48 mmol) in dioxane (2 mL) was added EtsN (1.36 g, 13.45 mmol) at 20 °C. The mixture was stirred at 20 °C for 0.5 hr and then 2-fluoro-4-iodopyridine (300 mg, 1.35 mmol) was added to the mixture and stirring was continued at 110 °C for 37.5 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-21% EtOAc/petr oleum ether gradient eluent to afford the title compound (130 mg, 31%) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 7.89 (d, J=5.25 Hz, 1 H), 7.01 (br d, J=5.00 Hz, 1 H), 6.96 (br s, 1 H), 4.77 (br d, J=6.50 Hz, 2 H), 3.66 - 3.78 (m, 4 H), 3.26 - 3.34 (m, 1 H), 1.97 (d, J=8.88 Hz, 1 H). MS-ESI (m/z) calc’d for C10H12IN2O [M+H]+: 302.9. Found 303.1.
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