* 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, 2002, vol. 67, # 7, p. 2345 - 2347
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 10, p. 5086 - 5098
[3] Patent: US2011/263541, 2011, A1,
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9531 - 9540
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4009 - 4022
5
[ 5470-18-8 ]
[ 124-41-4 ]
[ 20265-38-7 ]
Yield
Reaction Conditions
Operation in experiment
3.91 g
Stage #1: at 0 - 20℃; for 3.5 h; Inert atmosphere Stage #2: With palladium 10% on activated carbon; hydrogen In tetrahydrofuran; methanol
Step Four: To a suspension of 2-chloro-3-nitropyridine (5.00 g, 31.5 mmol) in anhydrous methanol (20 mL) at 0° C. under nitrogen, a solution of sodium methoxide in methanol (25percent, 14.4 mL, 63.1 mmol) was added dropwise over 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 3 hours then was poured into saturated aqueous ammonium chloride. The resulting mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (7 mL) and methanol (7 mL), and palladium on carbon (10percent, catalytic amount) was added. The mixture was placed under a hydrogen atmosphere (toggle between vacuum and hydrogen gas from a balloon several times) and stirred overnight. The reaction was not complete, so the reaction mixture was filtered through Celite® and the filtrate was treated with fresh palladium on carbon and placed under hydrogen as before. The mixture was stirred for 7 hours, then filtered through Celite® and concentrated to give 2-methoxypyridin-3-amine (2-4, 3.91 g).
Reference：
[1] Chemische Berichte, 1935, vol. 68, p. 315,321
[2] Tetrahedron, 1997, vol. 53, # 37, p. 12505 - 12524
[3] Chemische Berichte, 1936, vol. 69, p. 2593,2604
7
[ 5470-18-8 ]
[ 18699-87-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With sodium t-butanolate In 1-methyl-pyrrolidin-2-one at 16 - 35℃; for 2 h; Stage #2: at 29 - 50℃; for 1.16667 h; Stage #3: With sulfuric acid In water at 50 - 100℃; for 0.75 h;
Add NMP (2.0 L) to a 12-L, 3-neck flask fitted with a stirrer, a temperature probe and a reflux condenser fitted with a gas adapter for N2 and cool to 16° C.. Add sodium tert-butoxide (0.675 kg, 6.81 mol, 2.2 equiv., corrected for 97percent purity) in one portion whereupon one observes an immediate exotherm to 29° C. Stir the mixture for 30 min to partially dissolve the NaOt-Bu and then add diethyl malonate (0.943 L, 6.19 mol, 2.0 equiv.) at 20° C. to 35° C. over 70 min with continual cooling whereupon a homogeneous solution forms. Stir for 20 min and add a solution of 2-chloro-3-nitropyridine (1a-1, 0.491 kg, 3.09 mol, 1.0 equiv.) and NMP (1.0 L) to the reaction mixture at 29° C. to 44° C. over 70 min. Heat the reaction mixture to 50° C. Monitor the progress of the reaction HPLC (Agilent series 1100; Waters Symmetry C8 (5μ) column (3.9.x.150 mm), flow rate at 1.0 mL/min. Isocratic: CH3CN/0.1percent aq. TFA, 50/50; λ=220 nm. RT: diethyl malonate=2.6 min, 2-chloro-3-nitropyridine=2.7 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester =3.9 min). Typically >99percent conversion occurs within 1-2 h. Discontinue heating and add 6M H2SO4 (2.17 L) at 50° C. to 59° C. over 45 min. A thick solid precipitate forms during the addition. Heat the mixture to 100° C. The evolution of gas occurs. Monitor the progress of the reaction by HPLC as previously described (RT: 2-methyl-3-nitropyridine 2a-1=2.0 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester=3.9 min). Typically one observes >99percent conversion within 12 h. Allow the mixture to cool to 40° C. and pour into ice water (20 kg, pH 1.5). Add 25percent aq. NaOH (2.65 L) at -11° C. to -6° C. over 20 min to pH 11. Add toluene (4.0 L) and stir the mixture for 10 min. Filter the mixture through Celite.(R). to remove inorganic solids and wash the filtercake with toluene (6.0 L). Separate the phases and extract the aqueous phase twice with toluene (6.0 L and 4.0 L). Filter the combined toluene phases through Celite.(R). and wash the filter cake with toluene (1.0 L). Combine the toluene filtrates and wash with water (2.x.3.0 L). Dry (MgSO4) the toluene phase, filter and concentrate to give 2-methyl-3-nitropyridine 2a-1 (0.34 kg, 80percent yield, correct for residual NMP and toluene) as an oil. HPLC analysis shows the material to be 96percent pure. 1H NMR (CDCl3) δ 2.87 (s, 3H), 7.35 (dd, 1H, J=4.8, 8.1 Hz), 8.27 (dd, 1H, J=1.4, 8.1 Hz), δ 8.72 (dd, 1H, J=1.4, 4.8 Hz).
Reference：
[1] Patent: US2005/131012, 2005, A1, . Location in patent: Page/Page column 13-14
[2] Organic and Biomolecular Chemistry, 2005, vol. 3, # 20, p. 3701 - 3706
[3] Synthetic Communications, 1990, vol. 20, # 19, p. 2965 - 2970
[4] Patent: WO2011/73092, 2011, A1,
[5] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1040 - 1045
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 339 - 342
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9531 - 9540
8
[ 5470-18-8 ]
[ 13061-96-6 ]
[ 18699-87-1 ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate In 1,4-dioxane for 24 h; Heating / reflux
A mixture of 2-chloro-3-nitropyridine (1.6g, 10.09mmol), Pallac tetrakis(triphenylphosphine) (1170mg, 1.01 mmol), methylboronic acid (665mg, mmol ) and potassium carbonate (4180mg, 30.3 mmol) was refluxed in dioxane 1 days. The reaction was cooled to room temperature, and then filtered. The filtrate concentrated and the residue was purified by flash column chromatography (? EtOAc/Hexanes) to afford 760mg (55percent) of 2-methyl-3-nitropyridine. 1H NMR (CDC 8.71 (tetra, 1.7Hz, 5.0Hz, 1H), 8.26 (tetra, 1.7Hz, 8.3Hz, 1H)1 7.34 (dd, 5.( 8.3Hz, 1 H), 2.85 (s, 3H). MS m/z 139.1(M+H)+.
Method 1 Into a flask containing diethyl malonate (20 g, 0.125 mol) was added sodium (2.0 g, 0.087 mol). The reaction mixture was stirred for 1 h at room temperature and then allowed to warm to 120° C. (oil bath temperature) for 50 min. To this yellow suspension of the solid mass was added toluene (120 mL) followed by addition of a solution of 2-chloro-3-nitropyridine 1 (12.8 g, 0.08 mol) in 40 mL of toluene. The reaction mixture was refluxed for 8 h, and then stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 30percent H2 SO4 (60 mL). This reaction mixture was heated to 125° C. (oil bath) for 7 h, cooled and poured into ice (200 g). The reaction mixture was neutralized with saturated NaHCO3 solution, filtered through Celite, extracted several times with ether. The combined extracts were dried over anhydrous Na2 SO4. The solvent was evaporated and the residue was distilled under reduced pressure to provide 6.65 g (60percent) of the desired product 3.
Reference：
[1] Organic Letters, 2009, vol. 11, # 6, p. 1357 - 1360
[2] Patent: US5869676, 1999, A,
With potassium carbonate In 1,4-dioxane for 24 - 48 h; Heating / reflux
Example 77; N-Methyl-3-(2-(2-oxoindolin-5-ylamino)-5-(trifluoromethvπpyridin-4-ylamino)picolinamide; 2-Methyl-3-nitropyridine; Reference: Gray, M.; Andrews, I.P.; Hook, D. F.; Kitteringham, J.; Voyle, M.; Tetrahedron Lett.; 2000, 41, 6237 - 6240.The mixture of 2-chloro-3-nitropyridine (50 g, 0.315mol, 1.0 eq), TMB (50 mL, 1.1 eq), (PPh3)4Pd (0) (36.4 g, 0.1 eq), K2CO3 (130.6 g, 3.0 eq) and dioxane (1500 mL) was refluxed under argon for 2 days. The mixture was cooled to room temperature and filtered through a celite pad to remove K2CO3 and catalyst. The celite pad was washed with EtOAc. The organic solutions were combined and concentrated to get the crude which was purified by silica gel chromatography (0percent~40percent EtO Ac/Hex) to obtain the desired product 2-methyl-3-nitropyridine (30.5g, isolated yield 70percent) (Note: isolated yield 42percent was obtained when the reaction was refluxed for 24 h).
3-Nitropyridin-2-amine (1): 2-chloro-3-nitropyridine (4 g, 25.23 mmol) was taken in a sealed tube and aqueous NH3 (8.57 g, 504.6 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mass was then cooled to 0 °C and filtered to obtain 1 (3.4 g, 97percent) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 6.74 (m, 1H), 7.87 (s, 2H), 8.38 (m, 2H). MS m/z (M+H): 140.3
Reference：
[1] Patent: WO2014/149164, 2014, A1, . Location in patent: Paragraph 001189
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1696 - 1701
16
[ 5470-18-8 ]
[ 77287-34-4 ]
[ 4214-75-9 ]
Reference：
[1] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 8, p. 1439 - 1445
17
[ 5470-18-8 ]
[ 6332-56-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 12, p. 3973 - 3977
18
[ 5470-18-8 ]
[ 1480-87-1 ]
Yield
Reaction Conditions
Operation in experiment
77%
With cesium fluoride In dimethyl sulfoxide at 90℃; 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] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 2, p. 330 - 339
[2] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6043 - 6046
[3] Heterocycles, 1986, vol. 24, # 11, p. 3213 - 3221
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2004, vol. 47, # 6, p. 373 - 383
[5] Tetrahedron, 2001, vol. 57, # 4, p. 739 - 750
[6] Journal of the American Chemical Society, 1959, vol. 81, p. 2674
[7] Heterocycles, 1992, vol. 34, # 8, p. 1507 - 1510
With tert-butylhypochlorite; sodium carbonate; sodium chloride In dichloromethane at 25℃; for 20 h; Schlenk technique
Weighing 3-nitropyridine-2-carboxylic acid (50.4 mg, 0.3 mmol),Sodium carbonate (64.0 mg, 0.6 mmol), NaCl (17.6 mg, 0.3 mmol), tert-butyl hypochlorite (32 μL, 0.3 mmol) into a 25 mL of Schlenk reaction bottle, Then CH2Cl2 (3 mL) was added and placed in a 25 °C oil bath for 20 h. After completion of the reaction, the solvent was removed under reduced pressure and eluted with petroleum ether / ethyl acetate.The solvent was separated on a silica gel column, The yield of 2-chloro-3-nitropyridine was 58percent.
Reference：
[1] Patent: CN108586334, 2018, A, . Location in patent: Paragraph 0060-0062
21
[ 6332-56-5 ]
[ 5470-18-8 ]
Reference：
[1] Yakugaku Zasshi, 1944, vol. 64, # 4, p. 201[2] Chem.Abstr., 1951, p. 4717
[3] Journal of the Chemical Society, 1952, p. 2042,2044
[4] Journal of the Chemical Society, 1954, p. 4516,4520
[5] Gazzetta Chimica Italiana, 1963, vol. 93, p. 65,66,67,70
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
22
[ 31594-44-2 ]
[ 5470-18-8 ]
Reference：
[1] Journal of Chemical Research - Part S, 1996, # 4, p. 194 - 195
23
[ 20265-35-4 ]
[ 5470-18-8 ]
Reference：
[1] Journal of Chemical Research - Part S, 1996, # 4, p. 194 - 195
24
[ 111301-96-3 ]
[ 5470-18-8 ]
Reference：
[1] Journal of Chemical Research - Part S, 1996, # 4, p. 194 - 195
25
[ 6332-56-5 ]
[ 5470-18-8 ]
Reference：
[1] Russian Journal of General Chemistry, 2001, vol. 71, # 7, p. 1076 - 1087
26
[ 2403-01-2 ]
[ 4548-45-2 ]
[ 5470-18-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
27
[ 142-08-5 ]
[ 5470-18-8 ]
Reference：
[1] Russian Journal of General Chemistry, 2001, vol. 71, # 7, p. 1076 - 1087
28
[ 142-08-5 ]
[ 5470-18-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
29
[ 4214-75-9 ]
[ 5470-18-8 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 476[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1020
30
[ 7647-01-0 ]
[ 4214-75-9 ]
[ 5470-18-8 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 476[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1020
31
[ 5470-18-8 ]
[ 51315-07-2 ]
Yield
Reaction Conditions
Operation in experiment
58.8 g
at 120℃; for 16 h; Inert atmosphere
under nitrogen atmosphere, in a three-necked flask of 2-chloro-3-nitropyridine 192.7Mg, dimethyl sulfoxide 1.0mL and copper cyanide 129.4mg was added.The resulting mixture was stirred at 120 ° C. for 16 hours.Saturated ammonium chloride aqueous solution and ethyl acetate were added to the resulting reaction mixture, and extraction was performed to obtain an organic layer and an aqueous layer.The obtained aqueous layer was extracted with ethyl acetate.The obtained organic layer and the obtained ethyl acetate layer were mixed and dried to obtain a solution containing 58.8 mg of 2-cyano-3-nitropyridine
Reference：
[1] Patent: JP2015/209389, 2015, A, . Location in patent: Paragraph 0072
32
[ 5470-18-8 ]
[ 124-41-4 ]
[ 20265-35-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0℃; for 4 h;
A suspension of sodium methoxide (40.5 g, 0.750 mol) in 200 mL of methanol was slowly added to a solution of 2-chloro-3- nitro-pyridine (79.3 g, 0.500 mol) in 800 mL of methanol at 0 °C. The reaction mixture was stirred for 4 hours and then poured into 1000 g of ice. The resulting precipitate was filtered, washed with water, and dried to give 2-methoxy-3-nitro-pyridine (70. g, 0.45 mmol, 90 percent) as a white solid.
Reference：
[1] Patent: WO2005/26137, 2005, A2, . Location in patent: Page/Page column 233
[2] Journal of the Chemical Society, 1954, p. 4516,4520
[3] Canadian Journal of Chemistry, 1953, vol. 31, p. 1181,1183,1186
[4] Magnetic Resonance in Chemistry, 1986, vol. 24, p. 507 - 511
[5] Tetrahedron, 1997, vol. 53, # 37, p. 12505 - 12524
33
[ 5470-18-8 ]
[ 20265-35-4 ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium methylate In methanol
EXAMPLE 12 Synthesis of 2-methoxy-3-nitropyridine STR27 2-Chloro-3-nitropyridine (25 g, 0.157 mol) was suspended in methanol (300 ml) and sodium methoxide (17 g, 0.315 mol) was added. The mixture was refluxed for 2 hr and part of the solvent removed under reduced pressure. The reaction mixture was diluted with water (1 litre) and the precipitate collected by filtration. The white solid obtained was washed with more water and dried under vacuum to give the title compound (18.2 g, 75percent). 1 H NMR (CDCl3): 8.42 (dd, J=5, 2 Hz, 1H); 8.28 (dd, J=8, 2 Hz, 1H); 7.06 (dd, J=8, 5 Hz, 1H); 4.13 (s, 3H)
To a solution of 3-nitro-2-chloropyridine (4.0 g, 25.2 mmol) in 15 mL 2-methoxyethanol was added methylamine (2.0 M in THF, 32 mL). The reactionwas stirred for 8 hr at 80 °C in a sealed tube. After cooling to rt, the reaction mixture was evaporated to afford 15 quantitatively (3.6 g, 23.2 mmol). 1H NMR (500 MHz, CDCl3) δ 8.47 – 8.37 (m, 2H), 8.20 (s, 1H), 6.64 (dd, J = 8.3, 4.4 Hz, 1H), 3.17 (d, J = 4.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 156.0, 153.5, 135.4, 111.7, 28.4. HRMS (ESI+) m/z calcd for C6H8N3O2+ 154.0617, found 154.0610.
98.5%
at 0 - 20℃; for 3 h;
Methylamine (33percent in EtOH) (1 10 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0 °C using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0 °C and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3 x 150 mL. Combine organic layer was dried over Na2SC"4, filtered and concentrated to give a bright orangish yellow solid(19 g , 98.5percent).
95.76%
With triethylamine In dichloromethane at 20℃; for 5 h;
24 mL of methylamine, 39.5 mL of triethylamine was added to 240 mL of dichloromethane, and 30 g(0.18 mol) of 2-chloro-3-nitropyridine, and the reaction was completed at room temperature for 5 h. After completion of the reaction, the reaction solution was washed three times with waterInto anhydrous sodium sulfate in addition to water, suction filtration, steaming, yellow crystalline solid product 44.8g (yield 95.76percent).
86%
With sodium acetate In water; acetonitrile at 20℃; Heating / reflux
2-chloro-3-nitropyridine 70.0 g, 0.44 mol) was dissolved in recently distilled acetonitrile (400 mL) under stirring. Sodium acetate (55.2 g, 0.67 mol) and 30percent aqueous solution of methylamine (111 mL) were added under vigorous stirring. The obtained suspension was stirred at room temperature for 30 min, refluxed for 1 h, and kept overnight at room temperature. The yellow reaction mixture was concentrated under reduced pressure to remove approximately 300 mL of the solvent. The residue was diluted with 20percent aqueous solution of K2CO3 (1 L) under stirring. The yellow precipitate was filtered off, washed with water (3° * 200 mL), and dried to afford W-Methyl-3-nitropyridin-2-amine in 86percent (58.14 g, 0.38 mol) yield as bright yellow crystals.
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6097 - 6099
[2] Patent: WO2012/121936, 2012, A2, . Location in patent: Page/Page column 93
[3] Patent: CN106831776, 2017, A, . Location in patent: Paragraph 0097; 0098; 0099
[4] European Journal of Organic Chemistry, 2009, # 22, p. 3753 - 3764
[5] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
[6] Patent: WO2008/12622, 2008, A2, . Location in patent: Page/Page column 57
[7] Open Medicinal Chemistry Journal, 2018, vol. 12, # 1, p. 74 - 83
[8] Chemistry - A European Journal, 2017, vol. 23, # 57, p. 14173 - 14176
[9] Patent: US4520196, 1985, A,
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1696 - 1701
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5493 - 5496
36
[ 5470-18-8 ]
[ 4093-88-3 ]
Yield
Reaction Conditions
Operation in experiment
98.5%
With methylamine In ethanol; water
Synthesis of N-methyl-3-nitropyridin-2-amine Methylamine (33percent in EtOH) (110 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0° C. using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0° C. and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3*150 mL. Combine organic layer was dried over Na2SO4, filtered and concentrated to give a bright orangish yellow solid (19 g, 98.5percent).
Reference：
[1] Patent: US2012/228583, 2012, A1,
37
[ 5470-18-8 ]
[ 4093-88-3 ]
[ 33742-70-0 ]
Reference：
[1] Patent: US5624935, 1997, A,
38
[ 123-39-7 ]
[ 5470-18-8 ]
[ 4093-88-3 ]
Reference：
[1] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 8, p. 1439 - 1445
39
[ 79-16-3 ]
[ 5470-18-8 ]
[ 4093-88-3 ]
Reference：
[1] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 8, p. 1439 - 1445
40
[ 5470-18-8 ]
[ 25391-59-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 12, p. 3973 - 3977
41
[ 5470-18-8 ]
[ 2789-25-5 ]
Reference：
[1] Chemical Communications, 1998, # 15, p. 1519 - 1520
[2] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11622 - 11628
42
[ 5470-18-8 ]
[ 2789-25-5 ]
[ 84487-03-6 ]
Reference：
[1] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
[2] Chemical Communications, 1998, # 15, p. 1519 - 1520
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 11, p. 1406 - 1411
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1145 - 1151
[3] Patent: US9226970, 2016, B2,
55
[ 5470-18-8 ]
[ 98-80-6 ]
[ 134896-35-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: for 0.75 h; Stage #2: With sodium carbonate In 1,2-dimethoxyethane; ethanol; water for 1.5 h; Heating / reflux
A 5 L round bottom flask fitted with a condenser, mechanical stirrer and a nitrogen inlet was charged with 152.3 g (0.96 mol) of 2-chloro-3-nitropyridine and 1.65 L of 1,2-dimethoxyethane. The solution was degassed by bubbling nitrgen through the solution for 10 min and 56.7 g (0.49 mol, 0.05 equiv) of tetrakis (tliphenylphosphine)-palladium (0) was added. The mixture was degassed for an additional 45 min during which time the catalyst dissolved leaving a clear dark red solution. A degassed solution of 180.3 g (1.48 mol, 1.54 equiv) of phenylboronic acid in 800 [ML] of absolute ethanol was added followed by 1.65 L of degassed 2M aqueous sodium carbonate solution. The cloudy mixture was heated to reflux, and refluxed for 1.5 h. While at reflux a yellow suspension formed. The suspension was cooled to ambient temperature, diluted with 1 L of ethyl acetate, and filtered through [CELITE THE] cake was washed with 2 L of ethyl acetate and the filtrate washed with water (2 x 3 L), saturated sodium bicarbonate solution [(1 X 3] L), and saturated sodium chloride solution (1 x 3 L). The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated. The residue was dissolved in 1.5 L of ether, washed with 2.5N [NAOH] (2 x 500 mL) and brine (500 mL). The solution was dried with magnesium sulfate, filtered through 400 g of silica and the cake washed with additional ethyl acetate. The filtrate was concentrated to an oil which was chromatographed [5 kg Silica Gel 60,70-230 mesh, hexanes/ethyl acetate 80: 20 (12 L), 75: 25 (8 L), 70: 30 (11 L) and 60: 40 (7 L) ]. The product fractions were concentrated yielding 188.0 g (97percent yield) of the title compound 2-phenyl-3-nitropyridine, as a pale yellow oil: [IH] NMR [(CDCL3)] 8 7.39-7. 49 (m, [4H),] 753-7.95 (m, 2H), 8.12 (m, 1H) 8.84 (m, [1H).] MS [(EI)] [M/Z] 200. Anal. Calcd for [CLLH8N204] : C, 66.00 ; H, 4.03 ; N, 13.99. Found: C, 66.19 ; H, 4.09 ; N, 13.98.
95.45%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene for 12 h; Reflux
2-chloro-3-nitro pyridine 25 g (157.6 mmol), phenylboronic acid 24.9 g (204.9 mmol), Pd (PPh3) 4 5.4 g (4.73 mmol), K2CO3 54.48 g (394.2 mmol), 150 mL of distilled water, toluene 300 mL, into a 100 mL ethanol was stirred under reflux. After 12 hours cooled to ambient temperature and add deionized water. Extracted with MC, and dried over anhydrous MgSO4. Reduced pressure to separate after the distillation column. Compound 4-1 30 g (149.85 mmol, 95.45percent) was obtained.
93%
With palladium diacetate; potassium carbonate; triphenylphosphine In 1,4-dioxane; water for 24 h; Inert atmosphere; Reflux
5 g of 2-chloro-3-nitropyridine,4.7 g of benzene boronic acid,8.7 grams of potassium carbonate,0.1 g of palladium acetate,0.4 g of triphenylphosphine,60 ml of 1,4-dioxane / distilled water (3: 1) was added to a three-necked flask,Under nitrogen protection,Reflux stirring 24hAfter completion of the reaction,Add distilled water to the system,Until the solution becomes clear,And extracted with ethyl acetate,Saturated brine washing,Dried, concentrated, and chromatographed to give 6.0 g of a solid, 93percent yield.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 9, p. 1015 - 1020
[2] Patent: WO2004/29024, 2004, A2, . Location in patent: Page 13-14
[3] Synthesis, 2012, vol. 2012, # 2, p. 290 - 296
[4] Patent: KR2015/141179, 2015, A, . Location in patent: Paragraph 0113-0115
[5] Journal of Organic Chemistry, 2003, vol. 68, # 24, p. 9412 - 9415
[6] Patent: CN106916170, 2017, A, . Location in patent: Paragraph 0067; 0068; 0069
[7] Applied Organometallic Chemistry, 2014, vol. 29, # 4, p. 244 - 246
[8] Tetrahedron Letters, 1991, vol. 32, # 20, p. 2273 - 2276
[9] Tetrahedron, 1992, vol. 48, # 37, p. 8117 - 8126
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[12] Patent: WO2015/148344, 2015, A2, . Location in patent: Page/Page column 57; 58
[13] Patent: WO2008/101682, 2008, A2, . Location in patent: Page/Page column 85-86
Stage #1: at -78 - -20℃; Inert atmosphere Stage #2: With water; ammonium chloride In tetrahydrofuran
2-Chloro-3-nitropyridine (10.0 g, 63.07 mmol) was dissolved in 500 mL anydrous THF and magnetically stirred at -78 °C. Excess vinylmagnesium bromide (1 M in THF, 200 mL, 200.0 mmol) was added dropwise, after the addition was complete, the solution was allowed to warm to -20 °C. After 16 h, an aqueous solution of saturated ammonium chloride (300 g/L, 150 mL, 841.25 mmol) was added dropwise under vigorous stirring. The resulting suspension was filtered over Hyflo Super Cel medium (calcined) and extracted with EtOAc ( .x. 3). The combined organic fractions were concentrated and automated flash chromatography (CH2Cl2/MeOH, 97:3 and then CH2Cl2/MeOH/NH4OH, 980:18.75:1.25) was used to obtain pure 43 (3.87 g, 38percent yield). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.04 (d, J = 5.5 Hz, 1H), 7.53-7.46 (m, 1H), 7.43 (dd, J = 6.2, 3.4 Hz, 1H), 6.64 (dd, J = 3.1, 2.1 Hz, 1H).
37%
at -78 - -20℃;
EXAMPLE 19: 4-(4-(7-Chloro-l-ethyl-l//-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-ylamino)phenol (Compound70); A solution of 2-chloro-3-nitropyridine (31.5 mmol) in dry THF (200 mL) was cooled to -78°C. Vinylmagnisium bromide (1.0 M in THF, 10OmL) was added dropwise under N2. The mixture was stirred at -78°C for lhr, followed by -200C for further 8 hrs. The mixture was quenched with 150 mL NH4Cl (20percent in H2O) and extracted with EtOAc (3xl50mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to elute 7- chloro-l/f-pyrrolo[2,3-c]pyridine as white solid (1.77 g, yield 37percent). 1H-NMR (DMSO-J6) δ: 6.63 (d, IH, J= 3.2 Hz, Ar-H), 7.58 (d, IH, J= 5.6 Hz, Ar-H), 7.66 (d, IH, J= 2.8 Hz, Ar-H), 7.90 (d, IH, J= 5.2 Hz, Ar-H). MS (ESI+) m/z 153.0260 (M+H)+.
37%
Stage #1: at -78 - -20℃; for 9 h; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuran; water
Example 19; 4-(4-(7-Chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-ylamino)phenol (Compound 70) A solution of 2-chloro-3-nitropyridine (31.5 mmol) in dry THF (200 mL) was cooled to -78° C. Vinylmagnisium bromide (1.0 M in THF, 100 mL) was added dropwise under N2. The mixture was stirred at -78° C. for 1 hr, followed by -20° C. for further 8 hrs. The mixture was quenched with 150 mL NH4Cl (20percent in H2O) and extracted with EtOAc (3.x.150 mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to elute 7-chloro-1H-pyrrolo[2,3-c]pyridine as white solid (1.77 g, yield 37percent). 1H-NMR (DMSO-d6) δ: 6.63 (d, 1H, J=3.2 Hz, Ar-H), 7.58 (d, 1H, J=5.6 Hz, Ar-H), 7.66 (d, 1H, J=2.8 Hz, Ar-H), 7.90 (d, 1H, J=5.2 Hz, Ar-H). MS (ESI+) m/z 153.0260 (M+H)+.
37%
at -78 - 25℃; for 14 h;
To a solution of 2-chloro-3-nitropyridine (50 g, 315 mmol, 1.0 eq) in THF (1.5 L) was added dropwise vinylmagnesium bromide (1 M in THF, 946.14 mL, 3.00 eq) at -78 °C. After the addition was complete, the mixture was allowed to warm to 25 °C and stirred for 14 h. TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.25) showed that the reaction was complete. The reaction was quenched with saturated NH4Cl (400 mL) and extracted with EtOAc (500 mL x 3). The combined organic layer was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1) to give 7-chloropyrrolo[2,3-c]pyridine (18 g, 118 mmol, 37percent yield) as a yellow solid. 1H NMR (400 MHz CDCl3) = 8.72 (br s, 1H), 8.07 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.46 - 7.44 (m, 1H), 6.66 (t, J = 2.8 Hz, 1H). ESI-MS( m/z): 153.1(M+H)+
36.45%
Stage #1: at -78 - -20℃; for 10 h; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuran; water
A solution of 2-chloro-3-nitropyridine (1 g, 6.3 mmol) in dry tetrahydrofuran (100 mL) was treated with vinyl magnesium bromide (60 mL, 60 mmol) at -78 °C in a drop-wise manner under inert atmosphere. The resulting reaction mixture was stirred at the same temperature for 2 hours followed by stirring at -20 °C for 8 hours. The reaction was quenched slowly with aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (3 x 50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using ethyl acetate and hexane gradient elution to afford 7-chloro-1 H-pyrrolo[2,3-c]pyridine (0.350 g, 36.45percent).1H NMR (400 MHz, CHCI3-cf): δ 8.04 (d, J=5.46 Hz, 1 H), 7.50 (dd, J=5.46, 0.75 Hz, 1 H) 7.43 (dd, J=3.1 1 , 2.54 Hz, 1 H), 6.64 (dd, J=3.14, 2.07 Hz, 1 H). MS: 152.98 (M+).
36.45%
at -78 - -20℃; for 10 h; Inert atmosphere
A solution of 2-chloro-3-nitropyridine (1 g, 6.3 mmol) in dry tetrahydrofuran (100 mL) was treated with vinyl magnesium bromide (60 mL, 60 mmol) at -78° C. in a drop-wise manner under inert atmosphere. The resulting reaction mixture was stirred at the same temperature for 2 hours followed by stirring at -20° C. for 8 hours. The reaction was quenched slowly with aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (3*50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using ethyl acetate and hexane gradient elution to afford 7-chloro-1H-pyrrolo[2,3-c]pyridine (0.350 g, 36.45percent). 1H NMR (400 MHz, CHCl3-d): δ 8.04 (d, J=5.46 Hz, 1H), 7.50 (dd, J=5.46, 0.75 Hz, 1H) 7.43 (dd, J=3.11, 2.54 Hz, 1H), 6.64 (dd, J=3.14, 2.07 Hz, 1H). MS: 152.98 (M+).
31%
at -78 - -20℃; for 13 h;
Typical procedure for preparing azaindole from nitropyridine: Preparation of 7-chloro-6-azaindole, Precursor 2a, is an example of Step A of Scheme 1. 2-chloro-3-nitropyridine (5.0 g, 31.5 mmol) was dissolved in dry THF (200 mL). After the solution was cooled to -78° C., vinyl magnesium bromide (1.0M in THF, 100 mL) was added dropwise. The reaction temperature was maintained at -78° C. for 1 h, and then at -20° C. for another 12 h before it was quenched by addition of 20percent NH4Cl aqueous solution (150 mL). The aqueous phase was extracted with EtOAc (3.x.150 mL). The combined organic layer was dried over MgSO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (EtOAc/Hexane, 1/10) to afford 1.5 g (31percent) of 7-chloro-6-azaindole, Precursor 2a. 1H NMR (500 MHz, CD3OD) δ7.84 (d, 1H, J=10.7 Hz), 7.55 (dd, 1H, J=10.9, 5.45 Hz), 6.62 (d, 1H, J=5.54 Hz), 4.89 (s, 1H). MS m/z: (M+H)+ calcd for C7H6ClN2: 153.02; found 152.93. HPLC retention time: 0.43 minutes (column A).
31%
Stage #1: at -20℃; for 8 h; Stage #2: With water; ammonium chloride In tetrahydrofuran
Preparation of azaindole, Method A: Preparation of 7-Chloro-6-azaindole 1e: 2-Chloro-3-nitropyridine 22e (5.0 g) was dissolved in dry THF (200 ml). After the solution was cooled down to -78° C., an excess of vinyl magnesium bromide (1.0 M in THF, 100 ml) was added. Then, the reaction was left at -20° C. for eight hours before being quenched with 20percent NH4Cl (150 ml). The aqueous phase was extracted with EtOAc (3.x.150 ml). The combined organic layer was dried over MgSO4. After filtration and concentration, the crude product was purified by silica gel column chromatography to afford 1.5 g of 7-chloro-6-azaindole 1e in 31percent yield.
28%
Stage #1: at 0℃; for 1.33333 h; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuran; water
To a 1L three-necked flask under nitrogen is added commercially available vinylmagnesium bromide solution (1 M in THF, 500 mL, 500 mmol). At 0 °C a solution of of 2-chloro-3-nitro- pyridine (25 g, 160 mmol) in THF (100 mL) is added dropwise via addition funnel over 40 minutes. After stirring an additional 40 minutes at 0 °C the reaction is quenched with aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers are dried over MgS04, filtered and concentrated in vacuo. The crude material is passed through a plug of silica gel with CH2Cl2/heptanes (33percent) as eluant to give a solid that is recrystallized from CH2Cl2/heptanes to deliver 6.9 g (28percent) of the titled product as a beige solid mp 182- 185 0 C. 1H NMR (CDCI3) δ 8.60 (br s, 1H), 8.05 (m, 1H), 7.50 (m, 1H), 7.42 (m, 1H), 6.64 (m, 1H). LCMS m/z: 153 (M+H).
26%
Stage #1: at -78 - -20℃; for 8 h; Stage #2: With water; ammonium chloride In tetrahydrofuran
To a solution of 2-chloro-3-nitropyridine (5g, 31 .Smmol)) in THF (200mL) at -78°C, was added vinylmagnesium bromide (lOOmL, l.OM in THF) The reaction mixturewas stirred at -20°C for 8 hours, quenched with NHUC1 solution (20percent, 150mL), extractedwith EtOAc, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by\\flash chromatography, eluent EtOAc/hexane (1:5), to afford the title compound 259 (1.23g,26percent yield) as a white solid FZ. Zhang, et al.. J. Ore. Chem., 2002. 67. 2345-23471. MS(m/z): 153.1(M+H) (found).
353 mg
at -78 - -30℃; for 0.5 h;
To a solution of 2-chloro-3-nitropyridine (1 g) in THF (30mL) cooled at -78°C was slowly added vinylmagnesium bromide (1 M in THF, 20.2ml_). The reaction mixture was warmed up to -30°C and was stirred at -30°C for 30min. Sat. NH4CI was added and the mixture was extracted with EA twice. The combined org. layers were dried (Na2S04) and evaporated in vacuo. CC (Biotage, SNAP 50g cartridge, solvent A: Hept; solvent B: EA; gradient in percentB: 8 for 4CV, 8 to 66 over 10CV, 66 for 2CV) afforded 353mg of rosa solid. LC-MS (B): tR = 0.47 min; [M+H]+: 153.22.
353 mg
at -78 - -30℃; for 0.5 h;
To a solution of 2-chloro-3-nitropyridine (1 g) in THF (30 mL) cooled at −78° C. was slowly added vinylmagnesium bromide (1 M in THF, 20.2 mL). The reaction mixture was warmed up to −30° C. and was stirred at −30° C. for 30 min. Sat. NH4Cl was added and the mixture was extracted with EA twice. The combined org. layers were dried (Na2SO4) and evaporated in vacuo. CC (Biotage, SNAP 50 g cartridge, solvent A: Hept; solvent B: EA; gradient in percent B: 8 for 4CV, 8 to 66 over 10CV, 66 for 2CV) afforded 353 mg of rosa solid. LC-MS (B): tR=0.47 min; [M+H]+: 153.22.
Reference：
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With cesium fluoride; In dimethyl sulfoxide; at 90℃; 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 potassium hydroxide; thiourea; In ethanol; water;
Example 98A 3-nitropyridine-2-thiol 2-mercapto-3-nitropyridine was prepared by treating 3-nitro-2-chloro-pyridine (50 g, 0.0317 mol) with thiourea (24 g, 0.0317 mol) in 200 mL of ethanol at reflux for several hours. After the reaction mixture was allowed to cool, 7.19 mL solution of KOH (42.8 g in 115 mL of water) was added and the resulting mixture was heated at reflux for 3 hours. The crude reaction mixture was cooled to room temperature and then concentrated to 50% of its volume in vacuo.
2-mercapto-3-nitropyridine was prepared by treating 3-nitro-2-chloro-pyridine (50 g, 0.0317 mol) with thiourea (24 g, 0.0317 mol) in 200 ML of ethanol at reflux for several hours.After the reaction mixture was allowed to cool, 7.19 ML solution of KOH (42.8 g in 115 ML of water) was added and the resulting mixture was heated at reflux for 3 hours.The crude reaction mixture was cooled to room temperature and then concentrated to 50% of its volume in vacuo.After diluting with 300 ML of water, the product was isolated by vacuum filtration as an orange solid that was used without further purification. MS (DCI/NH3) m/z 157 (M+H)+. 1H NMR (300 MHz, DMSO-d6) delta 5.76 (m, 1H), 7.67 (dd, J=8.46, 4.78 Hz, 1H), 8.63 (dd, J=8.46, 1.47 Hz, 1H), 8.73 (dd, J=4.60, 1.65 Hz, 1H).
3-nitropyridine-2-thiol 2-mercapto-3-nitropyridine was prepared by treating 3-nitro-2-chloro-pyridine (50 g, 0.0317 mol) with thiourea (24 g, 0.0317 mol) in 200 ML of ethanol at reflux for several hours.After the reaction mixture was allowed to cool, 7.19 ML solution of KOH (42.8 g in 115 ML of water) was added and the resulting mixture was heated at reflux for 3 hours.The crude reaction mixture was cooled to room temperature and then concentrated to 50% of its volume in vacuo.After diluting with 300 ML of water, the product was isolated by vacuum filtration as an orange solid that was used without further purification. MS (DCI/NH3) m/z 157 (M+H)+. 1H NMR (300 MHz, DMSO-d6) delta 5.76 (m, 1H), 7.67 (dd, J=8.46, 4.78 Hz, 1H), 8.63 (dd, J=8.46, 1.47 Hz, 1H), 8.73 (dd, J=4.60, 1.65 Hz, 1H).
In 2-methoxy-ethanol; at 80℃; for 8.0h;Sealed tube;
To a solution of 3-nitro-2-chloropyridine (4.0 g, 25.2 mmol) in 15 mL 2-methoxyethanol was added methylamine (2.0 M in THF, 32 mL). The reactionwas stirred for 8 hr at 80 C in a sealed tube. After cooling to rt, the reaction mixture was evaporated to afford 15 quantitatively (3.6 g, 23.2 mmol). 1H NMR (500 MHz, CDCl3) delta 8.47 - 8.37 (m, 2H), 8.20 (s, 1H), 6.64 (dd, J = 8.3, 4.4 Hz, 1H), 3.17 (d, J = 4.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) delta 156.0, 153.5, 135.4, 111.7, 28.4. HRMS (ESI+) m/z calcd for C6H8N3O2+ 154.0617, found 154.0610.
98.5%
In ethanol; at 0 - 20℃; for 3.0h;
Methylamine (33% in EtOH) (1 10 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0 C using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0 C and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3 x 150 mL. Combine organic layer was dried over Na2SC"4, filtered and concentrated to give a bright orangish yellow solid(19 g , 98.5%).
95.76%
With triethylamine; In dichloromethane; at 20℃; for 5.0h;
24 mL of methylamine, 39.5 mL of triethylamine was added to 240 mL of dichloromethane, and 30 g(0.18 mol) of 2-chloro-3-nitropyridine, and the reaction was completed at room temperature for 5 h. After completion of the reaction, the reaction solution was washed three times with waterInto anhydrous sodium sulfate in addition to water, suction filtration, steaming, yellow crystalline solid product 44.8g (yield 95.76%).
86%
With sodium acetate; In water; acetonitrile; at 20℃;Heating / reflux;
2-chloro-3-nitropyridine 70.0 g, 0.44 mol) was dissolved in recently distilled acetonitrile (400 mL) under stirring. Sodium acetate (55.2 g, 0.67 mol) and 30% aqueous solution of methylamine (111 mL) were added under vigorous stirring. The obtained suspension was stirred at room temperature for 30 min, refluxed for 1 h, and kept overnight at room temperature. The yellow reaction mixture was concentrated under reduced pressure to remove approximately 300 mL of the solvent. The residue was diluted with 20% aqueous solution of K2CO3 (1 L) under stirring. The yellow precipitate was filtered off, washed with water (3 * 200 mL), and dried to afford W-Methyl-3-nitropyridin-2-amine in 86% (58.14 g, 0.38 mol) yield as bright yellow crystals.
80%
In N-methyl-acetamide;
A. 2-Methylamino-3-nitropyridine 25 g (0.16M) of 2-chloro-3-nitropyridine is dissolved in 200 ml dimethylformamide. For three hours monomethylamine is bubbled into the solution. The mixture is heated to reflux overnight. After the solvent is removed the oily residue is triturated with water and the solid is collected and air dried. The crude material is recrystallized from hexane to give 19.5 g (80% yield) of title compound, melting point 62-3 C. Analysis for: C6 H7 N3 O2: Calculated: C, 47.05; H, 4.61; N, 27.44. Found: C, 46.92; H, 4.73; N, 27.13.
A 5 L round bottom flask fitted with a condenser, mechanical stirrer and a nitrogen inlet was charged with 152.3 g (0.96 mol) of 2-chloro-3-nitropyridine and 1.65 L of 1,2-dimethoxyethane. The solution was degassed by bubbling nitrgen through the solution for 10 min and 56.7 g (0.49 mol, 0.05 equiv) of tetrakis (tliphenylphosphine)-palladium (0) was added. The mixture was degassed for an additional 45 min during which time the catalyst dissolved leaving a clear dark red solution. A degassed solution of 180.3 g (1.48 mol, 1.54 equiv) of phenylboronic acid in 800 [ML] of absolute ethanol was added followed by 1.65 L of degassed 2M aqueous sodium carbonate solution. The cloudy mixture was heated to reflux, and refluxed for 1.5 h. While at reflux a yellow suspension formed. The suspension was cooled to ambient temperature, diluted with 1 L of ethyl acetate, and filtered through [CELITE THE] cake was washed with 2 L of ethyl acetate and the filtrate washed with water (2 x 3 L), saturated sodium bicarbonate solution [(1 X 3] L), and saturated sodium chloride solution (1 x 3 L). The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated. The residue was dissolved in 1.5 L of ether, washed with 2.5N [NAOH] (2 x 500 mL) and brine (500 mL). The solution was dried with magnesium sulfate, filtered through 400 g of silica and the cake washed with additional ethyl acetate. The filtrate was concentrated to an oil which was chromatographed [5 kg Silica Gel 60,70-230 mesh, hexanes/ethyl acetate 80: 20 (12 L), 75: 25 (8 L), 70: 30 (11 L) and 60: 40 (7 L) ]. The product fractions were concentrated yielding 188.0 g (97% yield) of the title compound 2-phenyl-3-nitropyridine, as a pale yellow oil: [IH] NMR [(CDCL3)] 8 7.39-7. 49 (m, [4H),] 753-7.95 (m, 2H), 8.12 (m, 1H) 8.84 (m, [1H).] MS [(EI)] [M/Z] 200. Anal. Calcd for [CLLH8N204] : C, 66.00 ; H, 4.03 ; N, 13.99. Found: C, 66.19 ; H, 4.09 ; N, 13.98.
95.45%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 12h;Reflux;
2-chloro-3-nitro pyridine 25 g (157.6 mmol), phenylboronic acid 24.9 g (204.9 mmol), Pd (PPh3) 4 5.4 g (4.73 mmol), K2CO3 54.48 g (394.2 mmol), 150 mL of distilled water, toluene 300 mL, into a 100 mL ethanol was stirred under reflux. After 12 hours cooled to ambient temperature and add deionized water. Extracted with MC, and dried over anhydrous MgSO4. Reduced pressure to separate after the distillation column. Compound 4-1 30 g (149.85 mmol, 95.45%) was obtained.
93%
With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,4-dioxane; water; for 24h;Inert atmosphere; Reflux;
5 g of 2-chloro-3-nitropyridine,4.7 g of benzene boronic acid,8.7 grams of potassium carbonate,0.1 g of palladium acetate,0.4 g of triphenylphosphine,60 ml of 1,4-dioxane / distilled water (3: 1) was added to a three-necked flask,Under nitrogen protection,Reflux stirring 24hAfter completion of the reaction,Add distilled water to the system,Until the solution becomes clear,And extracted with ethyl acetate,Saturated brine washing,Dried, concentrated, and chromatographed to give 6.0 g of a solid, 93% yield.
79.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 16h;Inert atmosphere; Reflux;
To a 3-liter flask, 2-chloro-3-nitropyridine (45 g, 284 mmol), phenylboronic acid (41.5 g, 341 mmol), sodium carbonate (60.2 g, 568 mmol), Pd(Ph3P)4 (13.12 g, 11.35 mmol),1,2-dimethoxyethane (811 ml), and water (324 ml) were added. The flask was evacuated and backfilled with nitrogen. Evacuation and back-fill procedure was repeated twice. The reaction mixture was then refluxed overnight (approx. 16 hours). After completion, the reaction mixture was extracted with dichloromethane and concentrated. Resulting residue was purified by column chromatography (DCM/heptane) to afford 45.1 g (79.2% yield) of 3-nitro-2-phenylpyridine.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;
Step A: 3-Nitro-2-phenylpyridineTo a deoxygenated mixture of 2-chloro-3-nitropyridine (10.0 g, 63.1 mmol) in dioxane (150 mL) and water (75 mL) was added PdC dppf) (2.31 g, 3.15 mmol), phenylboronic acid (11.5 g, 95.0 mmol), K2CO3 (17.4 g, 126 mmol). The resulting mixture was heated at 90 C for 16 h, then cooled, filtered and concentrated. The residue was partitioned with water (50 mL) and ethyl acetate (50 mL x 2). The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by flash silica gel chromatography (ISCO, 120 g SepaFlash Silica Flash Column, ethyl acetate in petroleum ether: 0-20%, dry loaded) to give the title compound. NMR (400 MHz, CDC13) delta 8.92-8.82 (m, 1H), 8.19-8.11 (m, 1H), 7.61- 7.54 (m, 2H), 7.52-7.42 (m, 4H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 20.25h;Heating / reflux;
Example P33: Preparation of 3-Nitro-2-phenyl-pyridine:Error. Objects cannot be created from editing field codes.In a 250 mL single-necked round-bottomed flask equipped with a condensor, 10.0 g of 2- chloro-3-nitro-pyridine (CA registry number 5470-18-8) is dissolved in 75.0 ml of toluene and 9.3 ml of ethanol under argon. Then, 19.18 g of potassium carbonate in 12.0 ml of water is <n="87"/>added, followed by 7.69 g of phenyl boronic acid. After stirring for 15 minutes under a flow of argon, 2.19 g of tetrakis(triphenylphosphine)palladium is added. The mixture is then stirred for 20 hours under heating to reflux. The dark brown mixture is then cooled down to ambient temperature, followed by the addition of 100 ml of saturated aqeous NH4CI solution. This mixture is extracted with AcOEt (2x100ml). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to give 15.26 g of a dark brown oil. After purification by flash chromatography [silica gel cartridge (20 g, 60 ml) of a solid deposition with hexane/ethyl acetate 3:2 (v:v), 12.23 g of the title compound is obtained as a brown oil. title compound is obtained as a brown oil.1H NMR (400MHz, CDCI3): delta 7.46 (m, 4H), 7.56 (m, 2H)1 8.13 (dd, 1 H), 8.85 (dd, 1 H). LC: UV Detection: 220 nm; R, = 1.54 min.TLC: Plates: Merck DC-Plates, silica gel F2S4, saturated atmosphere in developing tank, UV detection, eluent: heptane/ ethyl acetate 1 :1 (v:v); Rf of title compound = 0.44, Rf of starting material = 0.44.
Example 121 1-Benzyl-4-[N-methyl-N-(3-nitro-2-pyridinyl)amino]piperidine A mixture of 1-benzyl-4-methylaminopiperidine (EXAMPLE 9, 10.8 g), 2-chloro-3-nitropyridine (6.7 g) and anhydrous potassium carbonate (14.6 g) in dry acetonitrile (211 ml) is stirred under nitrogen at 20-25 for 5 days. The mixture is then concentrated under reduced pressure, diluted with methylene chloride (200 ml) and water (50 ml), and the phases are separated. The organic phase is washed with saline (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed (silica gel, 70-230 mesh, 100 g; eluding with ethyl acetate/hexane (50/50) to give the title compound, mp=92-95.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 24h;Heating / reflux;
A mixture of 2-chloro-3-nitropyridine (1.6g, 10.09mmol), Pallac tetrakis(triphenylphosphine) (1170mg, 1.01 mmol), methylboronic acid (665mg, mmol ) and potassium carbonate (4180mg, 30.3 mmol) was refluxed in dioxane 1 days. The reaction was cooled to room temperature, and then filtered. The filtrate concentrated and the residue was purified by flash column chromatography (? EtOAc/Hexanes) to afford 760mg (55%) of 2-methyl-3-nitropyridine. 1H NMR (CDC 8.71 (tetra, 1.7Hz, 5.0Hz, 1H), 8.26 (tetra, 1.7Hz, 8.3Hz, 1H)1 7.34 (dd, 5.( 8.3Hz, 1 H), 2.85 (s, 3H). MS m/z 139.1(M+H)+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 16h;Product distribution / selectivity;
Heat a mixture of 2-chloro-3-nitro-pyridine (1a-1, 7.9 g, 49.8 mmol), methylboronic acid (1.10 equiv. 54.8 mmol, 3.30 g), K2CO3 (3.0 equiv, 150 mmol, 20.7 g) and Pd(PPh3)4 (1.2 g, 1.2 mmol) to 110 C. in dioxane (250 mL) for 16 h. Allow the reaction to cool to rt, concentrate to a dark oil and flash chromatograph on SiO2 (heptane/Et2O 3:1, dilute the oil with limited quantities of CH2Cl2 to apply to the column) to give compound 2a-1 (Niu, C.; Li, J.; Doyle, T. W.; Chen, S-H. Tetrahedron, 1998, 6311-6318).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 48h;Heating / reflux;
Preparation 1.; 2-(4-fluorophenoxymethyl)-3-nitropyridine; Step 1: 2-methyl-3-nitropyridine; A solution of 2-chloro-3-nitropyridine (20 g, 0.126 mol), methyl boronic acid (8.3g, 0.139 mol), tetrakis(triphenylphosphine)palladium (0) (14.58 g, 0.013 mol) andpotassium carbonate (52.3 g, 0.378 mol) in anhydrous 1,4-dioxane (100 ml) wasrefluxed for 2 days. The reaction mixture was cooled to room temperature, filtered, andconcentrated under reduced pressure. The resulting residue was purified with silica gelcolumn chromatography (ethyl acetate/n-hexane=l/3, v/v) to give 14 g of the titledcompound as brown oil.lH-NMR(400MHz, CDC1) 5 8.74(d, 1H), 8.27(d, 1H), 7.34(t, 1H), 2.88(s, 3H)
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 48h;Heating / reflux;
Preparation 1. (4-fluorophenyl)-(3-nitropyridin-2-ylmethyl)carbamic acid tert-butylester; Step 1: 2-methyl-3-nitropyridine; A solution of 2-chloro-3-nitropyridine (20 g, 0.126 mol), methylboronic acid (8.3g, 0.139 mol), tetrakis(triphenylphosphine)palladium (0) (14.58 g, 0.013 mol), andpotassium carbonate (52.3 g, 0.378 mol) in 1,4-dioxane (100 ml) was refluxed for 2days. The reaction mixture was cooled to room temperature and then filtered. Thefiltrate was concentrated under reduced pressure. The resulting residue was purifiedwith silica gel column chromatography (ethyl acetate/n-hexane=l/3, v/v) to give 14 gof the titled compound as brown oil.lH-NMR(400MHz, CDCy 5 8.74(d, 1H), 8.27(d, 1H), 7.34(t, 1H), 2.88(s, 3H)
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 48h;Inert atmosphere;
2-Methyl-3-nitropyridine; 2-Chloro-3-nitropyridine (20 g, 126.18 mmol), methane boronic acid (9.8 g, 164 mmol), tetrakis(triphenylphosphine)palladium (11.66 g, 10 mmol) and potassium carbonate (51.48 g, 378.6 mmol) were all mixed in 1-4 dioxane (500 mL), degasified and heated to 100 C. for 48 h under N2. Work up was carried out by allowing the reaction mass to cool to ambient temperature and quenched with water and extracted with ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a solid. The solid was further purified by silica gel column chromatography using 6% of ethyl acetate in hexane as eluent to give 2-methyl-3-nitropyridine as an off white solid: 1H-NMR (CDCl3) delta: 2.9 (s, 3H), 7.4 (m, 1H), 8.3 (d, 1H), 8.7 (d, 1H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 24 - 48h;Heating / reflux;Product distribution / selectivity;
Example 77; N-Methyl-3-(2-(2-oxoindolin-5-ylamino)-5-(trifluoromethv?pyridin-4-ylamino)picolinamide; 2-Methyl-3-nitropyridine; Reference: Gray, M.; Andrews, I.P.; Hook, D. F.; Kitteringham, J.; Voyle, M.; Tetrahedron Lett.; 2000, 41, 6237 - 6240.The mixture of 2-chloro-3-nitropyridine (50 g, 0.315mol, 1.0 eq), TMB (50 mL, 1.1 eq), (PPh3)4Pd (0) (36.4 g, 0.1 eq), K2CO3 (130.6 g, 3.0 eq) and dioxane (1500 mL) was refluxed under argon for 2 days. The mixture was cooled to room temperature and filtered through a celite pad to remove K2CO3 and catalyst. The celite pad was washed with EtOAc. The organic solutions were combined and concentrated to get the crude which was purified by silica gel chromatography (0%~40% EtO Ac/Hex) to obtain the desired product 2-methyl-3-nitropyridine (30.5g, isolated yield 70%) (Note: isolated yield 42% was obtained when the reaction was refluxed for 24 h).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 110℃; for 22h;
A mixture OF 2-CHLORO-3-NITROPYRIDINE (L. OOG, 6. 30mmol), potassium carbonate (2.62g, 18.90mmol), tetrakis (triphenylphosphine) palladium (0.73g, 0. 63MMOL) and trimethyl boroxine (0.88mL, 6. 30MMOL) in 1,4-dioxane (2mL) and water (8mL) was heated to 110C (oil bath temperature) for 6h and then stirred for 16h at rt. The mixture was then filtered through a celite pad, washing through with THF. The filtrate was adsorbed onto silica gel in vacuo and purified via flash column chromatography eluting with ethyl acetate/hexanes (3: 7) to give the title compound as a yellow solid. 8H (CDCl3): 2.86 (3H, s), 7.34 (1H, dd), 8. 26 (1H, dd), 8. 71 (1H, dd).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 24h;Heating / reflux;
2-Chloro-3-nitropyridine (4.37 g, 27.6 mmol), phenethylboronic acid (4.6 g, 30.4 mmol), tetrakis(triphenylphosphine)palladium (0) (3.19 g, 2.76 mmol), and potassium carbonate (11.4 g, 82.8 mmol) were added to 1,4-dioxane (60 ml). The reaction mixture was refluxed for 24 hours and then cooled to room temperature. The reaction mixture was filtered with a Celite pad and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=l/10, v/v) and then crystallized with ethyl ether to give the titled compound (4.1 g, 55 percent) as a white solid. The product was used in the subsequent step without further purification.[595] 1H-NMR (400MHz, CDCl ) delta 8.78 (d,lH), 8.21 (d,lH), 7.35(m,lH), 7.29 (m,4H),7.22 (m,lH), 3.42 (m,2H), 3.11 (m,2H)
2-Chloro-3-nitropyridine (10.0 g, 63.07 mmol) was dissolved in 500 mL anydrous THF and magnetically stirred at -78 C. Excess vinylmagnesium bromide (1 M in THF, 200 mL, 200.0 mmol) was added dropwise, after the addition was complete, the solution was allowed to warm to -20 C. After 16 h, an aqueous solution of saturated ammonium chloride (300 g/L, 150 mL, 841.25 mmol) was added dropwise under vigorous stirring. The resulting suspension was filtered over Hyflo Super Cel medium (calcined) and extracted with EtOAc ( × 3). The combined organic fractions were concentrated and automated flash chromatography (CH2Cl2/MeOH, 97:3 and then CH2Cl2/MeOH/NH4OH, 980:18.75:1.25) was used to obtain pure 43 (3.87 g, 38% yield). 1H NMR (400 MHz, CDCl3) delta 8.73 (s, 1H), 8.04 (d, J = 5.5 Hz, 1H), 7.53-7.46 (m, 1H), 7.43 (dd, J = 6.2, 3.4 Hz, 1H), 6.64 (dd, J = 3.1, 2.1 Hz, 1H).
37%
In tetrahydrofuran; at -78 - -20℃;
EXAMPLE 19: 4-(4-(7-Chloro-l-ethyl-l//-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-ylamino)phenol (Compound70); A solution of 2-chloro-3-nitropyridine (31.5 mmol) in dry THF (200 mL) was cooled to -78C. Vinylmagnisium bromide (1.0 M in THF, 10OmL) was added dropwise under N2. The mixture was stirred at -78C for lhr, followed by -200C for further 8 hrs. The mixture was quenched with 150 mL NH4Cl (20% in H2O) and extracted with EtOAc (3xl50mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to elute 7- chloro-l/f-pyrrolo[2,3-c]pyridine as white solid (1.77 g, yield 37%). 1H-NMR (DMSO-J6) delta: 6.63 (d, IH, J= 3.2 Hz, Ar-H), 7.58 (d, IH, J= 5.6 Hz, Ar-H), 7.66 (d, IH, J= 2.8 Hz, Ar-H), 7.90 (d, IH, J= 5.2 Hz, Ar-H). MS (ESI+) m/z 153.0260 (M+H)+.
37%
Example 19; 4-(4-(7-Chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-ylamino)phenol (Compound 70) A solution of 2-chloro-3-nitropyridine (31.5 mmol) in dry THF (200 mL) was cooled to -78 C. Vinylmagnisium bromide (1.0 M in THF, 100 mL) was added dropwise under N2. The mixture was stirred at -78 C. for 1 hr, followed by -20 C. for further 8 hrs. The mixture was quenched with 150 mL NH4Cl (20% in H2O) and extracted with EtOAc (3×150 mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to elute 7-chloro-1H-pyrrolo[2,3-c]pyridine as white solid (1.77 g, yield 37%). 1H-NMR (DMSO-d6) delta: 6.63 (d, 1H, J=3.2 Hz, Ar-H), 7.58 (d, 1H, J=5.6 Hz, Ar-H), 7.66 (d, 1H, J=2.8 Hz, Ar-H), 7.90 (d, 1H, J=5.2 Hz, Ar-H). MS (ESI+) m/z 153.0260 (M+H)+.
37%
In tetrahydrofuran; at -78 - 25℃; for 14h;
To a solution of 2-chloro-3-nitropyridine (50 g, 315 mmol, 1.0 eq) in THF (1.5 L) was added dropwise vinylmagnesium bromide (1 M in THF, 946.14 mL, 3.00 eq) at -78 C. After the addition was complete, the mixture was allowed to warm to 25 C and stirred for 14 h. TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.25) showed that the reaction was complete. The reaction was quenched with saturated NH4Cl (400 mL) and extracted with EtOAc (500 mL x 3). The combined organic layer was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1) to give 7-chloropyrrolo[2,3-c]pyridine (18 g, 118 mmol, 37% yield) as a yellow solid. 1H NMR (400 MHz CDCl3) = 8.72 (br s, 1H), 8.07 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.46 - 7.44 (m, 1H), 6.66 (t, J = 2.8 Hz, 1H). ESI-MS( m/z): 153.1(M+H)+
36.45%
A solution of 2-chloro-3-nitropyridine (1 g, 6.3 mmol) in dry tetrahydrofuran (100 mL) was treated with vinyl magnesium bromide (60 mL, 60 mmol) at -78 C in a drop-wise manner under inert atmosphere. The resulting reaction mixture was stirred at the same temperature for 2 hours followed by stirring at -20 C for 8 hours. The reaction was quenched slowly with aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (3 x 50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using ethyl acetate and hexane gradient elution to afford 7-chloro-1 H-pyrrolo[2,3-c]pyridine (0.350 g, 36.45%).1H NMR (400 MHz, CHCI3-cf): delta 8.04 (d, J=5.46 Hz, 1 H), 7.50 (dd, J=5.46, 0.75 Hz, 1 H) 7.43 (dd, J=3.1 1 , 2.54 Hz, 1 H), 6.64 (dd, J=3.14, 2.07 Hz, 1 H). MS: 152.98 (M+).
36.45%
In tetrahydrofuran; at -78 - -20℃; for 10h;Inert atmosphere;
A solution of 2-chloro-3-nitropyridine (1 g, 6.3 mmol) in dry tetrahydrofuran (100 mL) was treated with vinyl magnesium bromide (60 mL, 60 mmol) at -78 C. in a drop-wise manner under inert atmosphere. The resulting reaction mixture was stirred at the same temperature for 2 hours followed by stirring at -20 C. for 8 hours. The reaction was quenched slowly with aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (3*50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using ethyl acetate and hexane gradient elution to afford 7-chloro-1H-pyrrolo[2,3-c]pyridine (0.350 g, 36.45%). 1H NMR (400 MHz, CHCl3-d): delta 8.04 (d, J=5.46 Hz, 1H), 7.50 (dd, J=5.46, 0.75 Hz, 1H) 7.43 (dd, J=3.11, 2.54 Hz, 1H), 6.64 (dd, J=3.14, 2.07 Hz, 1H). MS: 152.98 (M+).
31%
In tetrahydrofuran; at -78 - -20℃; for 13h;
Typical procedure for preparing azaindole from nitropyridine: Preparation of 7-chloro-6-azaindole, Precursor 2a, is an example of Step A of Scheme 1. 2-chloro-3-nitropyridine (5.0 g, 31.5 mmol) was dissolved in dry THF (200 mL). After the solution was cooled to -78 C., vinyl magnesium bromide (1.0M in THF, 100 mL) was added dropwise. The reaction temperature was maintained at -78 C. for 1 h, and then at -20 C. for another 12 h before it was quenched by addition of 20% NH4Cl aqueous solution (150 mL). The aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layer was dried over MgSO4, filtered and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (EtOAc/Hexane, 1/10) to afford 1.5 g (31%) of 7-chloro-6-azaindole, Precursor 2a. 1H NMR (500 MHz, CD3OD) delta7.84 (d, 1H, J=10.7 Hz), 7.55 (dd, 1H, J=10.9, 5.45 Hz), 6.62 (d, 1H, J=5.54 Hz), 4.89 (s, 1H). MS m/z: (M+H)+ calcd for C7H6ClN2: 153.02; found 152.93. HPLC retention time: 0.43 minutes (column A).
31%
Preparation of azaindole, Method A: Preparation of 7-Chloro-6-azaindole 1e: 2-Chloro-3-nitropyridine 22e (5.0 g) was dissolved in dry THF (200 ml). After the solution was cooled down to -78 C., an excess of vinyl magnesium bromide (1.0 M in THF, 100 ml) was added. Then, the reaction was left at -20 C. for eight hours before being quenched with 20% NH4Cl (150 ml). The aqueous phase was extracted with EtOAc (3×150 ml). The combined organic layer was dried over MgSO4. After filtration and concentration, the crude product was purified by silica gel column chromatography to afford 1.5 g of 7-chloro-6-azaindole 1e in 31% yield.
28%
To a 1L three-necked flask under nitrogen is added commercially available vinylmagnesium bromide solution (1 M in THF, 500 mL, 500 mmol). At 0 C a solution of of 2-chloro-3-nitro- pyridine (25 g, 160 mmol) in THF (100 mL) is added dropwise via addition funnel over 40 minutes. After stirring an additional 40 minutes at 0 C the reaction is quenched with aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers are dried over MgS04, filtered and concentrated in vacuo. The crude material is passed through a plug of silica gel with CH2Cl2/heptanes (33%) as eluant to give a solid that is recrystallized from CH2Cl2/heptanes to deliver 6.9 g (28%) of the titled product as a beige solid mp 182- 185 0 C. 1H NMR (CDCI3) delta 8.60 (br s, 1H), 8.05 (m, 1H), 7.50 (m, 1H), 7.42 (m, 1H), 6.64 (m, 1H). LCMS m/z: 153 (M+H).
26%
To a solution of 2-chloro-3-nitropyridine (5g, 31 .Smmol)) in THF (200mL) at -78C, was added vinylmagnesium bromide (lOOmL, l.OM in THF) The reaction mixturewas stirred at -20C for 8 hours, quenched with NHUC1 solution (20%, 150mL), extractedwith EtOAc, dried over anhydrous Na2SC>4 and concentrated. The residue was purified byflash chromatography, eluent EtOAc/hexane (1:5), to afford the title compound 259 (1.23g,26% yield) as a white solid FZ. Zhang, et al.. J. Ore. Chem., 2002. 67. 2345-23471. MS(m/z): 153.1(M+H) (found).
With ammonium chloride; In tetrahydrofuran;
Preparation of 7-chloro-6-azaindole, Precursor 2a, is an example of Step A of Scheme 1. 2-chloro-3-nitropyridine (5.0 g, 31.5 mmol) was dissolved in dry THF (200 mL). After the solution was cooled to -78 C., vinyl magnesium bromide (1.0M in THF, 100 mL) was added dropwise. The reaction temperature was maintained at -78 C. for 1 h, and then at -20 C. for another 12 h before it was quenched by addition of 20% NH4Cl aqueous solution (150 mL). The aqueous phase was extracted with EtOAc (3*150 mL).
To a solution of 2-chloro-3-nitropyridine E-I (20 g, 126 mmol, 1 eq.) in anhydrous TEtaF (800 mL) cooled to -78 0C was added a solution of vinyl magnesium bromide (400 mL of a 1.0 M solution in TEtaF, 400 mmol, 3.2 eq.) by cannula. The mixture was stirred for 6 hours while allowing the mixture to slowly warm to -15 0C. After this period, a solution of saturated aqueous NH4Cl was added, followed by the addition of H2O, and the mixture was extracted with ethyl acetate three times. The combined organic phases were concentrated onto Celite (trade name) and the material was subjected to silica gel chromatography ({CHCI3 (90%), CH3OH (10%), concentrated aqueous NH4OH (1%)} : CHCl3) to provide Compound E-2: LCMS m/e 153 (M+H); 1H NMR (400 MHz, Methanol-d4)deltappm 6.64 (d, J=3.O3 Hz, 1 H), 7.56 (d, J=5.56 Hz, 1 H), 7.58 (d, J=3.07 Hz, 1 H), 7.86 (d, J=5.56 Hz, 1 H).
353 mg
In tetrahydrofuran; at -78 - -30℃; for 0.5h;
To a solution of 2-chloro-3-nitropyridine (1 g) in THF (30mL) cooled at -78C was slowly added vinylmagnesium bromide (1 M in THF, 20.2ml_). The reaction mixture was warmed up to -30C and was stirred at -30C for 30min. Sat. NH4CI was added and the mixture was extracted with EA twice. The combined org. layers were dried (Na2S04) and evaporated in vacuo. CC (Biotage, SNAP 50g cartridge, solvent A: Hept; solvent B: EA; gradient in %B: 8 for 4CV, 8 to 66 over 10CV, 66 for 2CV) afforded 353mg of rosa solid. LC-MS (B): tR = 0.47 min; [M+H]+: 153.22.
353 mg
In tetrahydrofuran; at -78 - -30℃; for 0.5h;
To a solution of 2-chloro-3-nitropyridine (1 g) in THF (30 mL) cooled at -78 C. was slowly added vinylmagnesium bromide (1 M in THF, 20.2 mL). The reaction mixture was warmed up to -30 C. and was stirred at -30 C. for 30 min. Sat. NH4Cl was added and the mixture was extracted with EA twice. The combined org. layers were dried (Na2SO4) and evaporated in vacuo. CC (Biotage, SNAP 50 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 8 for 4CV, 8 to 66 over 10CV, 66 for 2CV) afforded 353 mg of rosa solid. LC-MS (B): tR=0.47 min; [M+H]+: 153.22.
In tetrahydrofuran; at -40 - 20℃; for 16.5h;
To a solution of 2-chloro-3-nitropyridine in anhydrous THF, a 1 mol/L solution of vinylmagnesium bromide tetrahydrofuran was added dropwise at -40 C for about 30 minutes, and the reaction was allowed to gradually rise to room temperature for 16 hours. After completion of the reaction, the mixture was cooled, and a saturated aqueous solution of ammonium chloride was added, and the mixture was combined with ethyl acetate. The ethyl acetate phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate Elution with ethyl acetate / petroleum ether gradient 10-30% to give 7-chloro-1H-pyrrolo[2,3-c]pyridine;
Add NMP (2.0 L) to a 12-L, 3-neck flask fitted with a stirrer, a temperature probe and a reflux condenser fitted with a gas adapter for N2 and cool to 16 C.. Add sodium tert-butoxide (0.675 kg, 6.81 mol, 2.2 equiv., corrected for 97% purity) in one portion whereupon one observes an immediate exotherm to 29 C. Stir the mixture for 30 min to partially dissolve the NaOt-Bu and then add diethyl malonate (0.943 L, 6.19 mol, 2.0 equiv.) at 20 C. to 35 C. over 70 min with continual cooling whereupon a homogeneous solution forms. Stir for 20 min and add a solution of 2-chloro-3-nitropyridine (1a-1, 0.491 kg, 3.09 mol, 1.0 equiv.) and NMP (1.0 L) to the reaction mixture at 29 C. to 44 C. over 70 min. Heat the reaction mixture to 50 C. Monitor the progress of the reaction HPLC (Agilent series 1100; Waters Symmetry C8 (5mu) column (3.9×150 mm), flow rate at 1.0 mL/min. Isocratic: CH3CN/0.1% aq. TFA, 50/50; lambda=220 nm. RT: diethyl malonate=2.6 min, 2-chloro-3-nitropyridine=2.7 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester =3.9 min). Typically >99% conversion occurs within 1-2 h. Discontinue heating and add 6M H2SO4 (2.17 L) at 50 C. to 59 C. over 45 min. A thick solid precipitate forms during the addition. Heat the mixture to 100 C. The evolution of gas occurs. Monitor the progress of the reaction by HPLC as previously described (RT: 2-methyl-3-nitropyridine 2a-1=2.0 min, 2-(3-nitro-pyridin-2-yl)-malonic acid diethyl ester=3.9 min). Typically one observes >99% conversion within 12 h. Allow the mixture to cool to 40 C. and pour into ice water (20 kg, pH 1.5). Add 25% aq. NaOH (2.65 L) at -11 C. to -6 C. over 20 min to pH 11. Add toluene (4.0 L) and stir the mixture for 10 min. Filter the mixture through Celite to remove inorganic solids and wash the filtercake with toluene (6.0 L). Separate the phases and extract the aqueous phase twice with toluene (6.0 L and 4.0 L). Filter the combined toluene phases through Celite and wash the filter cake with toluene (1.0 L). Combine the toluene filtrates and wash with water (2×3.0 L). Dry (MgSO4) the toluene phase, filter and concentrate to give 2-methyl-3-nitropyridine 2a-1 (0.34 kg, 80% yield, correct for residual NMP and toluene) as an oil. HPLC analysis shows the material to be 96% pure. 1H NMR (CDCl3) delta 2.87 (s, 3H), 7.35 (dd, 1H, J=4.8, 8.1 Hz), 8.27 (dd, 1H, J=1.4, 8.1 Hz), delta 8.72 (dd, 1H, J=1.4, 4.8 Hz).
With N-ethyl-N,N-diisopropylamine; In ethanol; at 65℃; for 1h;
To a single neck flask equipped with a condenser and under nitrogen atmosphere was charged 2-CHLORO-3-NITROPYRIDINE (25g, 0. 158 MOLE), Aminomethylbenzimidazole hydrochloride (36. 5g, 0.166 mole) and 200 ml of Ethanol. To this slurry was charged diisopropylethyl amine (137 ml, 0.790 mole) and heated to 65 degrees celcius for 1 hour. Tlc in 5% methanol/ Methylene Chloride (product Rf; 0.5). The reaction was concentrated under vacuo to 100 ml and then cool in an ice bath. Filtered solid and washed cake with minimal amount of Methyl ethyl Ketone to give (LH-BENZOIMIDAZOL-2-YLMETHYL)- (3-NITRO-PYRIDIN-2-YL)-AMINE, a canary Yellow solid (wt= 15.76 g)
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃; for 2h;
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70C for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate =3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methyl pyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate :methanol =100:3), to afford 74 g of the title compound as colorless crystals.1H-NMR (400 MHz, CDCl3) delta2.25 (3H, s), 2.53 (3H, s), 7.00 (1H, bs), 7.18 (1H, dd, J = 4.6, 8.0 Hz), 8.23 (1H, d, J = 8.0 Hz), 8.30 (1H, d, J = 4.6 Hz).
Example 39 GENERAL PROCEDURE: NUCLEOPHILIC DISPLACEMENT WITH 2-CHLORO-3- NITRO-PYRIDINE; Piperazine (2-5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol) were dissolved in DMF or acetonitrile (2-3 mL) and stirred for 5 min at room temperature. A slight exothermic was observed shortly after addition of the solvent. When TLC analysis showed that the reaction was complete, the mixture was diluted with dichloromethane, and washed with water. The organic layer was dried, filtered and concentrated, then chromatographed in 10% methanol in dichloromethane to yield the desired product.
92%
In N,N-dimethyl-formamide; at 20℃; for 0.0833333h;
EXAMPLE 6 General Procedure: Nucleophilic Displacement with 2-Chloro-3-NitroPyridine Piperazine (2-5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol) were dissolved in DMF or acetonitrile (2-3 mL) and stirred for 5 min at room temperature. A slight exotherm was observed shortly after addition of the solvent. When TLC analysis showed that the reaction was complete, the mixture was diluted with dichloromethane, and washed with water. The organic layer was dried, filtered and concentrated, then chromatographed in 10% methanol in dichloromethane to yield the desired product.; In this manner the following compounds were synthesized: Example Structure Name Yield 6.1 (3S)-3-methyl-1-(3-nitropyridin-2-yl) piperazine 92%1H 1.11(d, J=6.3 Hz, 3H); 2.74(dd, J=12.8, 10.4 Hz, 1H); 2.99(m, 4H); 3.72(m, 2H); NMR 6.74(dd, J=8.1, 4.5 Hz, 1H); 8.14(dd, J=8.1, 1.8 Hz, 1H); 8.34(dd, J=4.5, 1.8 Hz, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h;
EXAMPLES Example 1 3-ETHYL-5-(3-NITRO-PYRIDIN-2-YL)-2-(2-THIAZOL-2-YL-IMIDAZOL-1-YLMETHYL)-4,5,6,7-TETRAHYDRO-3H-IMIDAZO [4,5-c] PYRIDINE (Compound 1) [0187] [CHEMMOL-00013] [0188] Step 1: A mixture of <strong>[62002-31-7]4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride</strong> (2.0 g, 12.5 mmol; prepared essentially as described by Habermehl, E., Heterocycles 5:127,133 (1976)), 2-chloro-3-nitropyridine (1.7 g, 11.25 mmol) and K2CO3 (5.2 g, 37.5 mmol) in 25 mL of DMF is heated at 50 C. for 4 hours and then allowed to cool to room temperature. The mixture is then partitioned between ethyl acetate and water and the layers are separated. The aqueous layer is then further extracted with ethyl acetate and the combined organic extracts are dried over Na2SO4, filtered and the solvents removed under reduced pressure. Column chromatography of the residue on silica gel (5% MeOH in CH2Cl2 as eluent) gives 5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro1H-imidazo[4,5-c]pyridine as a yellow solid (1.5 g). 1H NMR delta (CDCl3): 8.34 (d, 1H), 8.16 (dd, 1H), 7.53(s, 1H), 6.74 (q, 1H), 4.31 (s, 2H), 3.94(t, 2H) and 2.91(t, 2H) . MS: 246.3 (m+1).
1) Preparation of Azaindole 1 Preparation of azaindole, Method A: Preparation of 7-Chloro-6-azaindole 1e: 2-Chloro-3-nitropyridine 22e (5.0 g) was dissolved in dry THF (200 ml). After the solution was cooled down to -78 C., an excess of vinyl magnesium bromide (1.0 M in THF, 100 ml) was added. Then, the reaction was left at -200C for eight hours before quenched with 20% NH4Cl (150 ml). The aqueous phase was extracted with EtOAc (3*150 ml).
In tetrahydrofuran;
1) Preparation of Azaindole 1 Preparation of azaindole, Method A: Preparation of 7-Chloro-6-azaindole 1e: 2-Chloro-3-nitropyridine 22e (5.0 g) was dissolved in dry THF (200 ml). After the solution was cooled down to -78 C., an excess of vinyl magnesium bromide (1.0 M in THF, 100 ml) was added. Then, the reaction was left at -20 C. for eight hours before quenched with 20% NH4Cl (150 ml). The aqueous phase was extracted with EtOAc (3*150 ml).
Method 1 Into a flask containing diethyl malonate (20 g, 0.125 mol) was added sodium (2.0 g, 0.087 mol). The reaction mixture was stirred for 1 h at room temperature and then allowed to warm to 120 C. (oil bath temperature) for 50 min. To this yellow suspension of the solid mass was added toluene (120 mL) followed by addition of a solution of 2-chloro-3-nitropyridine 1 (12.8 g, 0.08 mol) in 40 mL of toluene. The reaction mixture was refluxed for 8 h, and then stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 30% H2 SO4 (60 mL). This reaction mixture was heated to 125 C. (oil bath) for 7 h, cooled and poured into ice (200 g). The reaction mixture was neutralized with saturated NaHCO3 solution, filtered through Celite, extracted several times with ether. The combined extracts were dried over anhydrous Na2 SO4. The solvent was evaporated and the residue was distilled under reduced pressure to provide 6.65 g (60%) of the desired product 3.
Method 2 A mixture of 2-chloro-3-nitropyridine 1 (793 mg, 5.0 mmol), methylboronic acid (329 mg, 5.5 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol) and K2 CO3 (2.073 g, 15.0 mmol) in dioxane (25 mL) was refluxed for 2 days. It was then cooled to room temperature and filtered. The solvent was removed and the residue was isolated by flash chromatography (50% ethyl acetate in hexanes) to provide 623 mg (90%) of 2-methyl-3-nitropyridine 3. 1 H NMR (CDCI3) delta 2.88 (s, 3H), 7.36 (dd, 1H, J=4.8 & 8.4 Hz), 8.28 (dd, 1H, J=1.2 & 8.1 Hz), 8.73 (dd, 1H, J=1.2 & 4.8 Hz).
2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In dimethyl sulfoxide;
15.1 Synthesis of 2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine (Intermediate IIa) (Process 1). A mixture of <strong>[84478-72-8]5-amino-2-chloro-4-fluorophenol</strong> (0.64 g), powdered potassium hydroxide (0.24 g), and 2-chloro-3-nitropyridine (0.76 g) in dimethylsulfoxide (15 ml) was heated at 110 C. with stirring for 2 hours. The solution was processed and the resulting oil chromatographed on silica gel eluding with methanol:methylene chloride, 3:97, to yield 2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine (Intermediate IIa) as a yellow semi-solid (0.45 g).
With potassium tert-butylate; In tetrahydrofuran; N-methyl-acetamide;
EXAMPLE I STR27 To a solution containing <strong>[2221-13-8]3-Phenyl-imidazoline-2,4-dione</strong> (1.76 g) in dimethylformamide (200 mL) at 0 C. was added 1M potassium tert-butoxide (10 mL) in tetrahydrofuran. After 5 min Copper (I) Iodide (1.9 gm) was added and the solution was allowed to stir at room temperature for 15 min. 2-Chloro-3-nitropyridine (2.21 g) was then added and the mixture was heated under nitrogen at 150 C. for 5 h. The mixture was cooled to room temperature and then partitioned between saturated ammonium chloride (250 mL) and ethyl acetate (200 mL) The organic layer was washed successively with saturated ammonium chloride (2x), water (2x) and then dried with sodium sulfate. The solvent was removed at reduced pressure and purified by column chromatography to yield 1-(3-Nitropyridyl)-3-phenyl-imidazoline-2,4(1H,3H)-dione as a white solid.
PREPARATION 104 2-Methylamino-3-nitropyridine A procedure similar to that described in Preparation 66 was repeated, except that 24.9 g of 2-chloro-3-nitropyridine, 41.7 g of sodium carbonate, 22.7 ml of a 30 % ethanolic solution of methylamine were reacted in 250 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was crystallized by trituration with isopropanol, to give 24.0 g of the title compound, melting at 52-53 C.
EXAMPLE 12 Synthesis of 2-methoxy-3-nitropyridine STR27 2-Chloro-3-nitropyridine (25 g, 0.157 mol) was suspended in methanol (300 ml) and sodium methoxide (17 g, 0.315 mol) was added. The mixture was refluxed for 2 hr and part of the solvent removed under reduced pressure. The reaction mixture was diluted with water (1 litre) and the precipitate collected by filtration. The white solid obtained was washed with more water and dried under vacuum to give the title compound (18.2 g, 75percent). 1 H NMR (CDCl3): 8.42 (dd, J=5, 2 Hz, 1H); 8.28 (dd, J=8, 2 Hz, 1H); 7.06 (dd, J=8, 5 Hz, 1H); 4.13 (s, 3H)
benzyl (R)-2-(tert.butoxycarbonylamino)-8-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylate[ No CAS ]
[ 70384-51-9 ]
benzyl (R)-2-tert.butoxycarbonylamino-8-(3-nitro-2-pyridoxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane;
EXAMPLE 4.2.1.a 52 mg (1.2 mmol) of sodium hydride dispersion (55percent) were added at 0° and under argon to a solution of 374 mg (0.98 mmol) of benzyl (R)-2-tert.butoxycarbonylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate in 3 ml of dioxan, whereupon the mixture was stirred for 30 minutes. Thereafter, 63 mg (20 mol percent) of tris-[2-(2-methoxyethoxy)-ethyl]amine (TDA I) and 311 mg (1.96 mmol) of 2-chloro-3-nitropyridine were added, whereupon the mixture was stirred at 120° for 1 hour. The reaction mixture was poured into saturated ammonium chloride solution and ethyl acetate. The organic phase was washed with saturated NaCl solution, dried with Na2 SO4 and concentrated. The residue was chromatographed or 50 g of silica gel with chloroform, whereupon after drying 328 mg (65percent) of benzyl (R)-2-tert.butoxycarbonylamino-8-(3-nitro-2-pyridoxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylate were obtained as a beige solid. M.p. 64°-66°. MS: 463 (M-=<, 1), 402 (24), 293 (21), 284 (36), 250 (21), 145 (17), 91 (100), 57 (85).
With sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;
Step 3. 3'-nitro-3-phenyl-3,4,5,6-tetrahydro-27/-[l,2']bipyridinyl; 2-Chloro-3-nitropyridine (3.0 g, 18.92 mmol), <strong>[3973-62-4]3-phenylpiperidine</strong> (3.1 g, 18.92mmol), and sodium carbonate (3.1 g, 28.62 mmol) were added to N,N- dimethyl-formamide (30 ml). The reaction mixture was stirred for 1 hour at 100C, cooled toroom temperature, diluted with ethyl acetate, washed with water three times, and thenwashed with a saturated sodium hydroxide solution. The organic layer was dried onanhydrous magnesium sulfate and then concentrated under reduced pressure to give 5.3g of the titled compound as yellow oil (Yield: 98 %).1H-NMR (400MHz,CDCy 5 8.33(d, 1H), 8.12(d, 1H), 7.33-7.24(m, 5H), 6.70(m,1H), 3.95-3.85(m, 2H), 3.07-3.01(m, 2H), 2.94(m, 1H), 1.87(m, 1H), 1.83-1.75(m, 3H)
N-(1H-imidazol-2-ylmethyl)-3-nitro-2-pyridine[ No CAS ]
2-(4-chlorophenyl)-3-(1H-imidazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In ethanol;
EXAMPLE 8 2-(4-Chlorophenyl)-3-(1H-imidazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine A suspension of 2-chloro-3-nitropyridine (7.74 g, 0.0490 mol) and 2-aminomethyl imidazole dihydrochloride (10.0 g, 0.0588 mol) in absolute ethanol (250 mL) was stirred at room temperature and triethylamine (11.88 g, 0.118 mol) was added. The mixture was heated at reflux for 4 hours, additional triethylamine (5.9 g, 0.0588 mol) was added, and refluxing was continued for 2 additional hours. The solvents were removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The insoluble solid was collected by filtration and was combined with the product that was obtained by separating the layers of the filtrate followed by washing the ethyl acetate with saturated sodium chloride solution. The product was recrystallized from ethyl acetate/isopropyl ether/light petroleum ether to give 3.10 g of crude N-(1H-imidazol-2-ylmethyl)-3-nitro-2-pyridine. An additional recrystallization of 0.5 g of the solid from ethyl acetate/light petroleum ether gave 0.33 g, mp 144-146 C. Anal. for C9 H9 N5 O2: Calcd: C, 49.31; H, 4.14; N, 31.95. Found: C, 49.36; H, 4.05; N, 31.88.
tert-butyl [2-[3-(3-nitro-pyridin-2-yloxy)phenyl]ethyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92.5%
With potassium carbonate; In N,N-dimethyl-formamide;
(2) A mixture of 2-chloro-3-nitropyridine (4.76 g, 30 mmols), <strong>[129150-68-1]N-tert-butoxycarbonyl-3-hydroxyphenethylamine</strong> (7.11 g, 30 mmols), potassium carbonate (4.14 g, 30 mmols) and N,N-dimethylformamide (50 ml) was stirred at 100C for 12 hours. The reaction mixture was cooled, then poured into water, and then extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an yellow oil of tert-butyl [2-[3-(3-nitro-2-pyridyloxy)phenyl]ethyl]carbamate (10.1 g, 92.5 %). Elemental Analysis for C18H21N3O5: Calcd.: C, 60.16; H, 5.89; N, 11.69 Found: C, 60.11; H, 5.98; N, 11.58 1H-NMR (CDCl3) delta: 1.43(9H,s), 2.83(2H,t,J=6.6Hz),
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 4h;
To a mixture of 2-chloro-3-nitropyridine (6.3 g, 40 mmol) in toluene (100 mL) was added compound 79 (11.6 g, 40 mmol), followed by solid K2CO3 (11 g, 80 mmol), and the resulting reaction was heated to 110 C. and allowed to stir at this temperature for 16 h. BINAP (500 mg, 2% mol) and Pd(OAc)2 (180 mg, 2% mol) were then added to the reaction mixture and the reaction was allowed to stir for an additional 4 h at 110 C. The reaction mixture was cooled to room temperature, then EtOAc (250 mL) and water (200 mL) were added, and the resulting solution was filtered through Celite to remove any insoluble material. The filtrate was separated and the aqueous phase was extracted with EtOAc (200 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel, eluting with EtOAc-Hexane (1:1) to provide compound 80 as a red solid (24.1 g).
With potassium carbonate; sodium iodide; In toluene; for 48h;Heating / reflux;
A stirred mixture of compound 10 (HCl salt) (4.28 g, 13 mmol), anhydrous potassium carbonate (3.87 g, 28 mmol), 2-chloro-3-nitropyridine (2.06 g, 13 mmol) and NaI (0.1 g) in toluene (80 mL) was heated under reflux for 48 h. After being cooled to room temperature, the mixture was treated with water and extracted with ether. Ether extracts were washed with water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated to a solid which was triturated with ether-hexane (1:2) and filtered to give 5 g of compound 11.
With N-ethyl-N,N-diisopropylamine; In ethanol; at 85℃; for 18h;
Example 1Ethyl N-(tert-butoxycarbonyl)-4-[(3-nitropyridin-2-yl)amino]-L-phenylalaninate (Intermediate 1)To a stirred solution of <strong>[67630-01-7]N-(tert-butyloxycarbonyl)-4-amino-L-phenylalanine ethyl ester</strong> (2Og) (CAS No. 67630-01-7) and DIPEA (13ml) in EtOH (200ml) is added 2-Chloro- 3-nitropyridine (11.85g) (CAS No. 34515-82-7). The reaction is heated at 85C for 18 hours. The reaction is allowed to cool and the majority of the EtOH removed in vacuo. The residue is partitioned between EtOAc (100ml) and water (50ml). The aqueous layer is extracted with EtOAc (50ml) and the combined organic layers are washed with brine (20ml), dried (MgSO4) and concentrated in vacuo. The residue is purified in two batches by chromatography on silica, eluting with EtOAc-heptane to afford the title compound as an orange solid (13.17g, 46%). LCMS (Method A) 429 [M-H]-, RT 4.17 mins. 1 H NMR 300 MHz (CDCI3) 51.25 (t, 3H), 1.40 (s, 9H), 3.1 (m, 2H), 4.2 (q, 2H), 4.6 (dd, 1 H), 5.00 (d,1 H), 6.8 (dd, 1 H), 7.15 (d, 2H), 7.6 (d, 2H), 8.45-8.55 (m, 2H).
46%
With N-ethyl-N,N-diisopropylamine; In ethanol; at 85℃; for 18h;
Example 1Ethyl N-(tert-butoxycarbonyl)-4-[(3-nitropyridin-2-yl)amino]-L-phenylalaninate(Intermediate 1)To a stirred solution of <strong>[67630-01-7]N-(tert-butyloxycarbonyl)-4-amino-L-phenylalanine ethyl ester</strong> (2Og) (CAS No. 67630-01-7) and DIPEA (13mL) in EtOH (20OmL) is added 2-Chloro- 3-nitropyridine (11.85g) (CAS No. 34515-82-7). The reaction is heated at 85C for 18 hours. The reaction is allowed to cool and the majority of the EtOH removed in vacuo. The residue is partitioned between EtOAc (10OmL) and water (5OmL). The aqueous phase is extracted with EtOAc (5OmL) and the combined organic extracts washed with brine (2OmL), dried (MgSO4) and concentrated in vacuo. The residue is purified in two batches by chromatography on silica, eluting with EtOAc-heptane to afford the title compound as an orange solid (13.17g, 46%). LCMS (Method A) 429 [M-H]-, RT 4.17 mins. 1H NMR 300 MHz (CDCI3) .51.25 (t, 3H), 1.40 (s, 9H), 3.1 (m, 2H), 4.2 (q, 2H), 4.6 (dd, 1 H), 5.00 (d, 1 H), 6.8 (dd, 1 H), 7.15 (d, 2H), 7.6 (d, 2H), 8.45-8.55 (m, 2H).
With 18-crown-6 ether; potassium hydroxide; In toluene;
General procedure: To a solution of 2-chloro-3-nitropyridine (200 mg, 0.63 mmol) in toluene (10 mL) was added different phenylmethanol (1.89 mmol, including phenylmethanol, (2-chlorophenyl) methanol, (3-chlorophenyl) methanol, (4-chlorophenyl) methanol, (2-fluorophenyl) methanol, (4-fluorophenyl) methanol, 1,1'-biphenyl-4-ylmethanol, pyridin-2-ylmethanol, (1-(4-chlorophenyl)-1H-pyrazol-3-yl) methanol and (5-(2,5-dichlorophenyl)furan-2-yl) methanol). Then 18-crown-6 (33 mg, 0.13 mmol) and KOH (142 mg, 2.52 mmol) were added. The reaction was stirred until the consumption of 2-chloro-3-nitropyridine was complete. The reaction mixture was partitioned between EtOAc (100 mL) and brine (40 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel provided the desired compounds. The physical data in detail can be found in the Supporting Information.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; for 0.25h;Inert atmosphere; Microwave irradiation;
General procedure: A 30-mL screw-cap culture tube was charged with 2-chloro-3-nitropyridine (3.16 mmol), phenyl boronic acid (3.80 mmol, 1.2 equiv), and DMF (10 mL). Pd(PPh3)4 (5% eq) and K2CO3 (0.3 mL of 2 M aqueous solution, 0.60 mmol, 2 equiv) were added to the tube sparged with N2 for 5 min. The reaction mixture was stirred and then irradiated for 15 min at 50 W. The resulting mixture was diluted with ethyl acetate and washed with water and brine, and then was dried over anhydrous Na2SO4. The residue was concentrated with an evaporator, and purified by flash chromatography on silica gel using petroleum ether/ethyl acetate as the eluent, yielded the desired product.
Synthesis of N-methyl-3-nitropyridin-2-amine Methylamine (33% in EtOH) (110 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0 C. using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0 C. and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3*150 mL. Combine organic layer was dried over Na2SO4, filtered and concentrated to give a bright orangish yellow solid (19 g, 98.5%).
With triethylamine; In butan-1-ol;Reflux; Inert atmosphere;
2-chloro-3- nitropyridine (4.39 g, 27.7 mmol), dibenzo[¾,<i]furan-4-amine (5.58 g, 30.5 mmol), triethylamine (4.3 mL, 30.9 mmol), and butanol (90 mL) were mixed in a 250 mL round bottom flask. The reaction mixture was refluxed overnight under nitrogen. The solvent was evaporated, leaving an orange solid which was dried under vacuum. The solid was taken up in ethyl acetate, water was added and the layers were separated. The organic layer with washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified on by column chromatography eluting with 10% ethyl acetate/hexanes followed by ethyl acetate (4.6 g, 54%).
With triethylamine; In butan-1-ol;
Synthesis of N-(dibenzo[b,d]furan-4-yl)-3-nitropyridin-2-amine 2-chloro-3-nitropyridine (4.39 g, 27.7 mmol), <strong>[50548-43-1]dibenzo[b,d]furan-4-amine</strong> (5.58 g, 30.5 mmol), triethylamine (4.3 mL, 30.9 mmol), and butanol (90 mL) were mixed in a 250 mL round bottom flask. The reaction mixture was refluxed overnight under nitrogen. The solvent was evaporated, leaving an orange solid which was dried under vacuum. The solid was taken up in ethyl acetate, water was added and the layers were separated. The organic layer with washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified on by column chromatography eluting with 10% ethyl acetate/hexanes followed by ethyl acetate (4.6 g, 54%).
With N-ethyl-N,N-diisopropylamine; In toluene; at 120℃; for 16h;Sealed tube;
General procedure: A mixture of 6 (1.55 mmol), 2 (0.77 mmol), and i-Pr2NEt(1.55 mmol) in toluene (unless otherwise stated) (0.77 ml) was stirred at 120 C in a sealed tube for 16 h. The mixture was allowed to cool to room temperature. Purification method A: the mixture was concentrated and the residue was purified by reverse phase automatedpreparative HPLC. Purification method B: the mixture was concentrated and the residue was purified by flash column chromatography (SiO2). Purification method C: the mixture was diluted(DCM), washed (satd Na2CO3), dried (filtered through a Biotage phase separator), and concentrated. The residue was purified by reverse phase automated preparative HPLC.
With triethylamine; In dimethyl sulfoxide; at 100℃; for 5h;
A solution of 2-chloro-3-nitropyridine (31.5 mmol), 1 ,1 -dimethylethyl (35 -3- (amino methyl)- 1 -pyrrolidinecarboxylate (34.7 mmol), and triethylamine (47.3 mmol) in dimethylsulfoxide (50 mL) was heated at 100 C for 5 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude title product.
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 2h;
Tert-butyl(trans-3-aminocyclobutyl)carbamate (1.38 g, 7.41 mmol), 2-chloro-3-nitropyridine (1.25 g, 7.88 mmol) and potassium carbonate (0.655 ml, 10.85 mmol) were combined in dry dimethylsulfoxide (20 mL) and heated at 110 C. After 2 hours the reaction was cooled and partitioned between ethyl acetate (300 mL) and water (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired tert-butyl(trans-3-((3-nitropyridin-2-yl)amino)cyclobutyl)carbamate (1.45 g, 4.70 mmol, 63.5% yield).
With triethylamine; In acetonitrile; for 2h;Reflux;
3 mmol of <strong>[142-64-3]piperazine dihydrochloride</strong> hydrate was added of 10 mL of CH3CN, TEA (6 mmol) and 2-chloro-3-nitropyridine (1 mmol). After 2 h, at reflux, the mixture was evaporated under reduced pressure and the residue was treated with H2O (5mL) and ethylacetate (5 mL). The aqueous phase was separated and extracted twice with ethylacetate (2×5 mL). The combined organic phases were dried on Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography, using dichloromethane/methanol (9:1) as eluent. Yield 62%, as yellow solid. 1H NMR (DMSO-d6): 8.44 (dd, 1H, J=4.5 Hz, J=1.6 Hz), 8.29 (dd, 1H, J=8.1 Hz, J=1.6 Hz), 6.94 (dd, 1H, J=8.1 Hz, J=4.5 Hz), 3.56 (m, 4H), 2.80 (m, 4H).
With (+/-)-7-(2,3-diacetoxypropyl)theophylline; palladium diacetate; lithium carbonate; In water; at 120℃; for 0.166667h;Microwave irradiation; Green chemistry;
General procedure: Suzuki-Miyaura couplings were performed in glass tubes suitable for microwave. Halopyridines (0.44 mmol), phenyl boronic acid (65.17 mg, 0.53 mmol), Li2CO3 (63.7 mg, 0.89 mmol), 1 mol % of Pd(OAc)2 (1 mg, 4.45 ? 10-3 mol), and 2 mol % of the corresponding ligand in 3 mL of distilled water. The mixtures were stirred and heated at 120 C under microwave radiation during 10 min with a ramp of 1 min in a CEM Discover reactor coupled to a CEM Explorer robotic system. The resulting reaction mixture was cooled to room temperature and the mixture extracted with CH2Cl2 (3 ? 2 mL), the organic phase was treated with anhydrous Na2SO4 after filter over celite and analyzed by Gas Chromatography (GC-MS) on an Agilent 6890N GC with a 30.0 m DB-1MS capillary column coupled to an Agilent 5973 Inert Mass Selective detector. Additional experiments of catalysis were carried out under the same reaction conditions using different bases Na2CO3, K2CO3, Li2CO3, Cs2CO3, Rb2CO3, NaOH, KOH, Et3N, and DIPEA.
General procedure: Solution of NH-heterocycle (10 mmol) in dry DMF (12 mL) was cooled to 0 C, followed by the portionwise addition of NaH (2.9 mg, 12 mmol) under stirring. The mixture was stirred for 15 min at 0C, and corresponding chloronitropyridine (1.59 g,10 mmol) was portionwise added to the mixture. After 30 min of stirring, the mixture was brought to room temperature, treated with water (100 mL), and the formed precipitate of hetaryl-3(5)-nitropyridine was filtered off.
With tetrakis(triphenylphosphine) palladium(0); sodium hydroxide; In tetrahydrofuran; water; at 80.0℃; for 12.0h;Inert atmosphere;
Under a nitrogen stream, 2-chloro-3-nitropyridine (10.95,69.07mmol), said obtained in 6-4,4,5,5- tetramethyl-1,3,2 dioxaborolan-2-yl) -1H- indole (20.15g, 82.88mmol), NaOH (8.29g, 207.21mmo), and was mixed with THF / H2 (300ml / 150ml), Pd at 40 ( PPh3) put 4 (3.99g, 5mol%), and the mixture was stirred for 12 hours at 80 .After completion of the reaction, and extracted with methylene chloride, put MgSO4, and filtered. The resulting solvent was removed from the organic layer, column chromatography (hexane: EA = 1: 1 (v / v)) was purified by by 6- (3-nitro-pyridin-2-yl)-lH-indole (11 .90g, 72% yield).
(3-nitro-pyridin-2-yl)-(4-trifluoromethoxy-benzyl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With caesium carbonate; In 1,4-dioxane; for 3h;Reflux;
A solution of 2-chloro-3-nitropyridine (5g, 31.54mmol) in dioxane (100mL) was treated with cesiumcarbonate (13.36g, 41mmol) and <strong>[93919-56-3]4-(trifluoromethoxy)benzylamine</strong> (7.32g, 38.3mmol) and heated toreflux for 3 hours. The yellow suspension was cooled, diluted with water (50 mL) and evaporated toremove most of the dioxane. The mixture was diluted with ethyl acetate (200 mL), washed with water(x2) and saturated sodium citrate (x2), dried and evaporated. The oily product was crystallised inmethanol and evaporated to provide the title compound as a yellow solid (9.88g, 100%)
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