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[ CAS No. 153034-78-7 ]

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CAS No. :153034-78-7 MDL No. :MFCD03095303
Formula : C6H5FIN Boiling Point : 252.5°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :237.01 g/mol Pubchem ID :10243220
Synonyms :

Safety of [ 153034-78-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
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Application In Synthesis of [ 153034-78-7 ]

  • Upstream synthesis route of [ 153034-78-7 ]
  • Downstream synthetic route of [ 153034-78-7 ]

[ 153034-78-7 ] Synthesis Path-Upstream   1~4

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  • [ 2369-19-9 ]
  • [ 153034-78-7 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 2 h;
Stage #2: With iodine In tetrahydrofuran at -78℃; for 1 h;
Diisopropylamine (910.7 mg, 1.261 mL, 9.000 mmol) was dissolved in dry TηF(20mL) and cooled to -78 0C, n-Buli (3.600 mL of 2.5 M, 9.000 mmol) was added slowly dropwise and the resultant mixture was then allowed to warm to -20 0C over 40min before being cooled back down to -78 0C.[ 00363 ] A solution of 2-fluoro-5-methyl-pyridine (1.0 g, 9.000 mmol) in dry THF(1OmL) was added dropwise and the solution was stirred at this temp for 2 hours. A solution of iodine (2.284 g, 463.3 μL, 9.000 mmol) in THF (1OmL) was then added and the resultant mixture stirred for a further 1 hour at this temp before being quenched with water. The resulting mixture was partitioned between sodium thiosulfate solution and Et2ψ, organics separated and washed further with saturated NaCl. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a colourless oil. The resulting mixture was purified by column chromatography (30percent EtOAc in hexanes, ~200mL silica) to give a colourless foam (1.409g, 66percent Yield). 1 H NMR (400.0 MHz, DMSO) d 1 .42 (s, 1 H) and 7.07 - 7.12 (s, 2H) ppm
65%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -20℃; for 4.16667 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere
To a solution of diisopropylamine (252 mL, 1.80 mmol) in anhydrous tetrahydrofuran (5 mL) was added under argon at 20 °C, a 2.5 M solution of n-butyllithium in hexanes (719 mL, 1.80 mmol). After stirring at 20 °C for 30 min, the reaction was cooled to 78 °C, then a solution of 2-fluoro-5-methylpyridine (14) [27] (200 mg, 1.80 mmol) in anhydrous tetrahydrofuran (1 mL) was added over 10 min. The reaction was stirred at 78 °C for 3.5 h, then a solution of iodine (457 mg, 1.80 mmol) in anhydrous tetrahydrofuran (1 mL) was added. The mixture was stirred at 78 °C for additional 1 h, before quenching with a solution of water (2 mL) and tetrahydrofuran (10 mL). After warming to 0 °C, the mixture was diluted with water (50 mL) and sodium bisulfite was added until a colorless solution was obtained. After extraction with dichloromethane (3 x 30 mL), the combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/cyclohexane, 5/5, v/v) to give 2-fluoro-3-iodo-5-methylpyridine (15) (275 mg, 1.16 mmol) as a colorless solid. Yield 65percent; Rf (SiO2, dichloromethane/cyclohexane, 5/5, v/v) 0.21; mp 40-45 °C; IR (KBr) ν 1049, 1379, 1446, 2930 cm-1; 1H NMR (200 MHz, CDCl3) δ 2.28 (s, 3H, CH3), 7.95 (m, 2H, H-4, H-6); 13C NMR (50 MHz, CDCl3) δ 17.0 (CH3), 75.4 (d, 2JC-F = 44 Hz, C-3), 132.7 (d, 4JC-F = 5 Hz, C-5), 146.8 (d, 3JC-F = 13 Hz, C-6), 150.4 (C-4), 160.4 (d, 1JC-F = 232 Hz, C-2); 19F NMR (470 Mz, CDCl3) 61.7; ESI-MS m/z 237.89 [M+H]+.
33%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane for 4 h;
Stage #2: With iodine In tetrahydrofuran; hexane for 2 h;
(a) 26.5 mL of n-butyllithium (1.57 mol/L hexane solution) was dropwise added at -78°C to a solution having 4.02 g (39.8 mmol) of diisopropylamine dissolved in 70 mL of tetrahydrofuran, followed by stirring for 30 minutes. To this solution, a solution having 4.42 g (39.8 mmol) of 2-fluoro-5-methylpyridine dissolved in 18 mL of tetrahydrofuran was added, followed by stirring for 4 hours. Then, a solution having 10.1 g (39.8 mmol) of iodine dissolved in 27 mL of tetrahydrofuran was added, followed by stirring for 2 hours. 16 mL of water and 120 mL of an aqueous sodium thiosulfate solution were added, and extraction with ethyl ether was carried out. Then, the organic layer was dried over magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 3.15 g (yield: 33percent) of 2-fluoro-3-iodo-5-methylpyridine.1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 2.27(s, 3H), 7.95(m, 2H)
61% With n-butyllithium; iodine In tetrahydrofuran EXAMPLE 38A
2-fluoro-4-iodo-5-methylpyridine
A solution of dilsopropylamine (7.0 mL, 50.0 mmol) in THF (100 mL) at -78° C. was treated with 2.5M n-butyllithium in hexanes (20 mL, 50.0 mmol), stirred for 15 minutes, treated dropwise with a solution of 2-fluoro-5-methylpyridine (5.55 g, 50.0 mmol) in THF (20.0 mL), stirred for 4 hours, treated slowly with a solution of iodine (12.7 g. 50.0 mmol) in THF (50 mL), quenched with water, and extracted with diethyl ether.
The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated.
The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/diethyl ether to provide 7.24 g (61percent) of 2-fluoro-3-iodo-5-methylpyridine.
61% With n-butyllithium; iodine; diisopropylamine In tetrahydrofuran Example 38A
2-fluoro-4-iodo-5-methylpyridine
A solution of diisopropylamine (7.0 mL, 50.0 mmol) in THF (100 mL) at -78° C. was treated with 2.5M n-butyllithium in hexanes (20 mL, 50.0 mmol), stirred for 15 minutes, treated dropwise with a solution of 2-fluoro-5-methylpyridine (5.55 g, 50.0 mmol) in THF (20.0 mL), stirred for 4 hours, treated slowly with a solution of iodine (12.7 g. 50.0 mmol) in THF (50 mL), quenched with water, and extracted with diethyl ether.
The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated.
The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/diethyl ether to provide 7.24 g (61percent) of 2-fluoro-3-iodo-5-methylpyridine.
109.69 g
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -75℃; for 3.5 h;
Stage #2: With iodine In tetrahydrofuran; hexane at -75℃; for 1.91667 h;
(1)
Synthesis of 2-fluoro-3-iodo-5-methylpyridine
Diisopropylamine (92 mL) was added to THF (1.2 L), and the mixture was cooled to -18° C. in a nitrogen atmosphere.
A 2.69 M solution of n-butyllithium in hexane (224 mL) was added dropwise to the solution.
After completion of the dropwise addition, the mixture was warmed to -5° C. with stirring over 20 minutes.
The reaction mixture was cooled to -73° C. A solution of 2-fluoro-5-methylpyridine (61 g) in THF (240 mL) was added dropwise to the reaction mixture.
The reaction mixture was stirred at -75° C. for 3.5 hours.
A solution of iodine (139 g) in THF (24 mL) was added dropwise to the reaction mixture.
The reaction mixture was stirred at -75° C. for one hour and 55 minutes.
After completion of the reaction, water (220 mL) was added to the reaction mixture at the same temperature.
The mixture was stirred at the same temperature for five minutes.
The reaction mixture was returned to room temperature, and water (1.2 L) was then added.
A solution of sodium thiosulfate pentahydrate (136 g) in water (300 mL), and water (300 mL) were added to the mixture, followed by stirring for 10 minutes.
The mixture was extracted with MTBE (1.2 L).
The organic layer was washed with brine (500 mL).
The combined aqueous layers were extracted with MTBE (1 L).
The combined organic layers were dried over anhydrous magnesium sulfate.
The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
n-heptane was added to the residue, followed by cooling.
The precipitated solid was collected by filtration.
The residue was washed with n-heptane.
The filtrate was cooled, and the precipitated solid was collected by filtration.
This operation was repeated five times to give the title compound (109.69 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.29-2.31 (m, 3H), 7.93-8.14 (m, 214).
ESI-MS m/z 238 [M+H]+
109.69 g
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75 - -73℃; for 3.5 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; hexane at -75℃; for 1.91667 h;
(1)
Synthesis of 2-fluoro-3-iodo-5-methylpyridine
A 2.69 M n-butyllithium hexane solution (224 mL) was added dropwise to a mixture of diisopropylamine (92 mL) and THF (1.2 L) at -18°C under a nitrogen atmosphere.
Upon completion of the dropwise addition, the mixture was stirred while raising the temperature to -5°C over a period of 20 minutes.
The reaction mixture was cooled to -73°C, and then a solution of 2-fluoro-5-methylpyridine (61 g) in THF (240 mL) was added dropwise thereto.
The reaction mixture was stirred at -75°C for 3.5 hours.
A solution of iodine (139 g) in THF (24 mL) was added dropwise to the reaction mixture.
The reaction mixture was stirred at -75°C for 1 hour and 55 minutes.
Upon completion of the reaction, water (220 mL) was added to the reaction mixture at the same temperature.
The mixture was stirred for 5 minutes at the same temperature.
The reaction mixture was warmed to room temperature, and then water (1.2 L) was added.
An aqueous sodium thiosulfate pentahydrate (136 g) solution (300 mL) and water (300 mL) were added to the mixture, and the resultant was stirred for 10 minutes.
The mixture was extracted with MTBE (1.2 L).
The organic layer was washed with brine (500 mL).
The combined aqueous layer was extracted with MTBE (1 L).
The combined organic layer was dried over anhydrous magnesium sulfate.
The desiccant was filtered out, and the filtrate was concentrated under reduced pressure.
After adding n-heptane to the residue, the mixture was cooled.
The precipitated solid was filtered out, and then was rinsed with n-heptane.
The filtrate was cooled and the precipitated solid was filtered out.
This procedure was repeated 5 times to obtain the title compound (109.69 g).
1H-NMR (400 MHz, CDCl3) δ (ppm):2.29-2.31 (m, 3H), 7.93-8.14 (m, 2H).
ESI-MS m/z 238 [M+H]+

Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 18, p. 4603 - 4606
[3] Patent: WO2009/73300, 2009, A1, . Location in patent: Page/Page column 169
[4] European Journal of Medicinal Chemistry, 2015, vol. 92, p. 818 - 838
[5] Patent: EP1559320, 2005, A1, . Location in patent: Page/Page column 7
[6] Patent: US2003/87940, 2003, A1,
[7] Patent: US2002/115640, 2002, A1,
[8] Patent: US2013/143907, 2013, A1, . Location in patent: Paragraph 0426; 0427; 0428
[9] Patent: EP2982674, 2016, A1, . Location in patent: Paragraph 0061; 0062
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Reference: [1] Patent: EP1679003, 2006, A1, . Location in patent: Page/Page column 13-14
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  • [ 153034-78-7 ]
Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 92, p. 818 - 838
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YieldReaction ConditionsOperation in experiment
87% With n-butyllithium; diisopropylamine In tetrahydrofuran A solution of diisopropylamine (4.3 mL, 30.5 mmol) in THF (50 mL) at -78° C. was treated with 2.5M n-butyllithium in hexanes (12.2 mL, 30.5 mmol), stirred for 30 minutes, treated dropwise with a solution of 2-fluoro-3-iodo-5-methylpyridine (7.24 g, 30.5 mmol) in THF (30 mL), stirred for 4 hours, quenched with water, and extracted with diethyl ether.
The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated to provide 6.3 g (87percent) of the desired product. MS (DCI/NH3) m/z 238 (M+H)+; 1H NMR (CDCl3) δ7.99 (s, 1H), 7.43 (d, 1H), 2.38 (m, 3H).
87% With n-butyllithium; diisopropylamine In tetrahydrofuran A solution of diisopropylamine (4.3 mL, 30.5 mmol) in THF (50 mL) at -78° C. was treated with 2.5M n-butyllithium in hexanes (12.2 mL, 30.5 mmol), stirred for 30 minutes, treated dropwise with a solution of 2-fluoro-3-iodo-5-methylpyridine (7.24 g, 30.5 mmol) in THF (30 mL), stirred for 4 hours, quenched with water, and extracted with diethyl ether.
The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated to provide 6.3 g (87percent) of the desired product. MS (DCI/NH3) m/z 238 (M+H)+; 1H NMR (CDCl3) δ 7.99 (s, 1H), 7.43 (d, 1H), 2.38 (m, 3H).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 18, p. 4603 - 4606
[2] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[3] Patent: US2003/87940, 2003, A1,
[4] Patent: US2002/115640, 2002, A1,
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