* 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 the Chemical Society, 1952, p. 2042,2044
[2] Journal of the Chemical Society, 1952, p. 2042,2044
[3] Journal of the Chemical Society, 1952, p. 2042,2044
2
[ 15862-34-7 ]
[ 98786-86-8 ]
Yield
Reaction Conditions
Operation in experiment
53%
With tin(ll) chloride In ethyl acetate at 50℃; for 20 h;
A mixture of 5-bromo-3-nitropyridin-2-ol (1.26 g, 4.6 mmol) and tin chloride dihydrate (3.91 g, 17.3 mmol) in ethyl acetate (19.3 mL) was heated at 50° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with brine. The aqueous layer was separated and extracted with ethyl acetate (5*50 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo to give a black solid 580 mg (53percent), which was used without further purification.
Reference：
[1] Patent: US2005/256137, 2005, A1, . Location in patent: Page/Page column 10
[2] Yakugaku Zasshi, 1951, vol. 71, p. 169,172[3] Chem.Abstr., <1952> 8108,
[4] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 720,724
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 9, p. 1036 - 1040
[6] Patent: CN108570001, 2018, A, . Location in patent: Paragraph 0012-0014; 0018; 0022
[7] Patent: EP1219622, 2002, A2, . Location in patent: Page 20
3
[ 15862-34-7 ]
[ 588729-99-1 ]
Reference：
[1] Patent: US2012/238587, 2012, A1,
4
[ 15862-34-7 ]
[ 588729-99-1 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 2042,2044
[2] Journal of the Chemical Society, 1952, p. 2042,2044
[3] Journal of the Chemical Society, 1952, p. 2042,2044
5
[ 15862-34-7 ]
[ 90902-84-4 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 2042,2044
[2] Patent: WO2007/107758, 2007, A1,
6
[ 15862-34-7 ]
[ 90902-84-4 ]
Reference：
[1] Patent: WO2008/128961, 2008, A1,
7
[ 15862-34-7 ]
[ 573675-27-1 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 2042,2044
8
[ 15862-34-7 ]
[ 669066-89-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3608 - 3612
9
[ 15862-34-7 ]
[ 67443-38-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: for 3 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In diethyl ether
Step B. 5-Bromo-2-chloro-3-nitropyridine A mixture of 5-bromo-3-nitropyridin-2(1H)-one (Step A, 2.5 g, 10.4 mmol), phosphoryl chloride (25 mL) and N,N-dimethylformamide (2.5 mL) was stirred under reflux for 3 h. After removal of solvent, the residue was dissolved in water (20 mL) and diethylether (20 mL) at 0° C. and the solution was separated. The organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated to afford the title compound (2.5 g, 89percent) as a pale yellow solid. 1H-NMR (CDCl3) δ: 8.70 (d, J=1.7 Hz, 1H), 8.37 (d, J=1.7 Hz, 1H).
89%
With trichlorophosphate In N,N-dimethyl-formamide for 2 h; Heating / reflux
Step B. 5-Bromo-2-chloro-3-nitropyridineA mixture of 5-bromo-3-nitropyridin-2(1 H)-one (Step A, 7.2 g, 32.9 mmol), phosphoryl chloride(72 mL) and λ/,λ/-dimethylformamide (7.2 mL) was stirred under reflux for 2 h. After removal of solvent, the residue was dissolved in water (100 mL) and ethyl acetate(30 mL) and the solution was separated.The organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated to afford the title compound (6.97 g, 89percent) as a pale yellow solid.1H-NMR (CDCI3) δ: 8.70 (d, J= 1.7 Hz, 1 H), 8.37 (d, J= 1.7 Hz, 1 H).
85%
With trichlorophosphate In N,N-dimethyl-formamide for 2 h; Reflux
To a solution of 5-bromo-3-nitropyridin-2(1H)-one (4.62 g, 21.10 mmol) in POCl3 (46.2 ml) was added DMF (4.62 ml, 59.7 mmol) at room temperature. The mixture was refluxed for 2 hours, and then cooled to room temperature and concentrated in vacuo. The residue was treated with saturated aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give 5-bromo-2-chloro-3-nitropyridine (4.24 g, 85percent) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 8.37 (1H, d, J=2.4 Hz), 8.70 (1H, d, J=2.0 Hz).
With thionyl chloride In N,N-dimethyl-formamide for 1 h; Reflux
N,N'-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux. After 1 hour, the solution was cooled and the solvent was evaporated. The mixture was co-evaporated with toluene to give a dark solid. Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82percent) as a yellow solid. 1H-NMR δ (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.70 (d, J=3.0 Hz, 1H).
82%
With thionyl chloride In N,N-dimethyl-formamide for 1 h; Reflux
N,N'-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux. After 1 hour, the solution was cooled and the solvent was evaporated. The mixture was co-evaporated with toluene to give a dark solid. Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82percent) as a yellow solid. 1H-NMR δ (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.70 (d, J=3.0 Hz, 1H).
81%
With trichlorophosphate In N,N-dimethyl-formamide for 3 h; Reflux
A mixture of 5-bromo-2-hydroxy-3-nitropyridine (14) (28.8 g, 131.5 mmol), POCl3 (288 mL) and anhydrous DMF (30 mL) was stirred and heated at reflux for 3 h. After removal of POCl3, the residue was poured into ice water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (4:1 hexanes/EtOAc) to afford 15 (25.4 g, 81percent) as a pale yellow solid, mp 66-67 °C (lit32 68 °C). 1H NMR (CDCl3) δ 8.70 (d, J = 2.0 Hz, 1H, Ar-H), 8.37 (d, J = 2.5 Hz, 1H, Ar-H).
81%
With trichlorophosphate In N,N-dimethyl-formamide for 12 h; Inert atmosphere; Reflux
General procedure: 2-Hydroxy-3-nitropyridine 5 (0.015 mol) was suspended in POCl3 (15 mL). Anhydrous DMF (2 mL) was added and the resulting mixture was heated at reflux for 12 h. The excess of POCl3 was removed by distillation, the residue was taken up in a mixture of DCM with ice and the mixture was stirred for 30 min. The organic layer was separated, washed with water (3 x), dried over anhydrous Na2SO4, filtered and concentrated to yield analytically pure product.
Reference：
[1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
[2] Patent: EP2108641, 2009, A1, . Location in patent: Page/Page column 46
[3] Patent: EP2113503, 2009, A1, . Location in patent: Page/Page column 29
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[5] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
[6] Yakugaku Zasshi, 1951, vol. 71, p. 169,171[7] Chem.Abstr., 1952, p. 8108
[8] Journal of the Chemical Society, 1952, p. 2042,2044
[9] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1980, vol. 16, # 12, p. 1234 - 1238[10] Khimiya Geterotsiklicheskikh Soedinenii, 1980, vol. 16, # 12, p. 1632 - 1636
[11] Patent: US2003/162968, 2003, A1,
[12] Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4547 - 4553
[13] Patent: US2004/63744, 2004, A1, . Location in patent: Page/Page column 31; 32
[14] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 117
[15] Patent: WO2005/121140, 2005, A1, . Location in patent: Page/Page column 28-29
[16] Patent: WO2005/121140, 2005, A1, . Location in patent: Page/Page column 45
[17] Patent: WO2006/101456, 2006, A1, . Location in patent: Page/Page column 56
Reference：
[1] Patent: US4665078, 1987, A,
[2] Patent: US4532252, 1985, A,
[3] Patent: US4537890, 1985, A,
[4] Patent: US4537891, 1985, A,
13
[ 15862-34-7 ]
[ 15862-37-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With phosphorus(V) oxybromide In N,N-dimethyl-formamide; toluene at 90℃; for 16 h;
Intermediate 12; N-[(R)-1-(5-Bromo-3-fluoro-pyridin-2-yl)-ethyl]-acetamide Step A: 2,5-Dibromo-3-nitro-pyridine To a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90° C. (the reaction mixture was protected from light). A solution of POBr3 (31.41 g, 109.51 mmol) in toluene (40 ml) was added dropwise at 90° C. and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous 1N NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2SO4 and evaporated obtain the title compound as yellow solid (25.2 g, 97percent).
97%
Stage #1: With phosphorus(V) oxybromide In N,N-dimethyl-formamide; toluene at 90℃; for 16 h; Darkness Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide; toluene
Step A: 2,5-Dibromo-3-nitro-pyridineTo a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90°C (the reaction mixture was protected from light). A solution of POBr3 (31.41 g,109.51 mmol) in toluene (40 ml) was added dropwise at 90°C and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous IN NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2S04 and evaporated obtain the title compound as yellow solid (25.2 g, 97percent).
80.03%
With phosphorus tribromide In N,N-dimethyl-formamide at 120℃; for 0.333333 h;
To a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF was added PBr3 (6.60 ml, 68.49 mmol) and the reaction mixture was heated at 12O0C for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3 x 200 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (10.30 g, 80.03percent).
Reference：
[1] Patent: US2012/165338, 2012, A1, . Location in patent: Page/Page column 2
[2] Patent: WO2012/89601, 2012, A1, . Location in patent: Page/Page column 53
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 3927 - 3936
[4] Patent: WO2007/107758, 2007, A1, . Location in patent: Page/Page column 124
[5] Journal of the Chemical Society, 1952, p. 2042,2044
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 6053
[7] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3608 - 3612
[8] Patent: WO2005/63690, 2005, A1, . Location in patent: Page/Page column 28
[9] Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4547 - 4553
[10] Patent: WO2006/52514, 2006, A1, . Location in patent: Page/Page column 7
[11] Patent: WO2006/132837, 2006, A1, . Location in patent: Page/Page column 19
14
[ 15862-34-7 ]
[ 15862-37-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With pyridine; phosphorus(V) oxybromide In toluene at 90℃; for 15.5 h;
Example 15; 4-{7- [(2,3-dihydro [1 ,4] dioxino [2,3-c] pyridin-7-ylmethyl)amino] -5- methyl-6-oxo-5,6,7,8-tetrahydro-l,5-naphthyridin-3-yl}-6-(methyloxy)pyrido[2,3- b]pyrazin-3(4H)-one; <n="74"/>(a) 2,5-Dibromo-3-nitropyridine; 5-Bromo-3-nitro-2(lH)-pyridinone (5g, 22.83 mmol) was suspended in toluene (50 ml). DMF (0.177 ml, 2.283 mmol) was added and the mixture was protected from light. A solution of phoshorous oxybromide (7.85 g, 27.4 mmol) in toluene (50 ml) was added to the pyridine mixture over 1.5h at 90 0C. The reaction mixture was heated at 90 0C for 14h, cooled down and extracted with water. The organic layer was washed with IN NaOH and brine and dried over MgSOφ The solvent was removed to give title compound (6.45 g, 22.88 mmol, 100 percent yield) as yellow solid. MS (ES+) m/z 282(MH+).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3608 - 3612
[2] Journal of the Chemical Society, 1952, p. 2042,2044
[3] Patent: US2012/165338, 2012, A1,
[4] Patent: WO2012/89601, 2012, A1,
[5] Patent: WO2006/132837, 2006, A1,
17
[ 6945-68-2 ]
[ 15862-34-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sulfuric acid; sodium nitrite In water at 0 - 20℃; Inert atmosphere
General procedure: 2-Amino-3-nitropyridine 8 (0.015 mol) was dissolved, on cooling with ice, in 70percent sulfuric acid and treated with a solution of NaNO2 (1.24 g) in water (8 mL), which was added dropwise so as to maintain the reaction temperature in 0-5 °C range. The reaction was allowed to warm up to rt and stirred at that temperature for 3 h. The precipitate formed was isolated by filtration, washed with water and dried at 60 °C overnight.
Reference：
[1] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
[2] Journal of the Chemical Society, 1952, p. 2042,2044
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 9, p. 1036 - 1040
18
[ 1072-97-5 ]
[ 15862-34-7 ]
Reference：
[1] Yakugaku Zasshi, 1959, vol. 79, p. 1129,1132[2] Chem.Abstr., 1960, p. 3418
[3] Patent: US5445763, 1995, A,
[4] Patent: US4665078, 1987, A,
[5] Patent: US4532252, 1985, A,
[6] Patent: US4537890, 1985, A,
[7] Patent: US4537891, 1985, A,
[8] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
[9] Patent: US2018/44335, 2018, A1, . Location in patent: Paragraph 0441
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 6053
21
[ 1072-97-5 ]
[ 7664-93-9 ]
[ 7697-37-2 ]
[ 15862-34-7 ]
Reference：
[1] Yakugaku Zasshi, 1959, vol. 79, p. 1129,1132[2] Chem.Abstr., 1960, p. 3418
22
[ 15862-34-7 ]
[ 74-88-4 ]
[ 152684-30-5 ]
Yield
Reaction Conditions
Operation in experiment
45%
With silver carbonate In chloroform at 20℃; for 48 h;
Example 4N-(2-Methyl-3-(5-(5-(4-methylpiperazin-l-yl)pyridine-2-ylamino)-6-oxo-l,6- dihydropyridin-3-yl)phenyl)-4,5,6,7-tetrahydrobenzo[Z>]thiophene-2- carboxamide (19); 5-Bromo-2-methoxy-3-nitropyridine (15)[00197] In a 1 L, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-3-nitropyridin-2-ol (50.0 g, 0.23 mol) in CHCl3 (500 mL) under nitrogen in the dark (wrapped in aluminum foil.) To this solution was added Ag2CO3 (75.5 g, 0.28 mol) and MeI (142.0 mL, 2.3 mol). After the mixture was stirred for 48 h at room temperature, it was filtered through a pad of Celite, washed with CH2Cl2, and concentrated. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:4) to give 24.0 g (45percent) of 5-bromo-2- methoxy-3-nitropyridine (15) as a solid.
34%
With silver carbonate In methylene chloride at 20℃; for 48 h; Inert atmosphere; Darkness
Method B: to a suspension of 14 (5.0 g, 22.8 mmol) in anhydrous CH3Cl (50 mL) under N2 in the dark (wrapped in aluminum foil) was added Ag2CO3 (7.55 g, 28.0 mmol), followed by CH3I (14.2 mL, 230.0 mmol). After stirring at rt for 48 h, the reaction mixture was filtered through a pad of Celite, washed with abundant CH2Cl2, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10:1 hexanes/EtOAc) to afford 16 (1.86 g, 34percent) as a pale yellow solid. The analytical data were same as aforementioned.
Reference：
[1] Patent: WO2008/33854, 2008, A1, . Location in patent: Page/Page column 74
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
23
[ 15862-34-7 ]
[ 152684-30-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
24
[ 15862-34-7 ]
[ 425380-38-7 ]
Reference：
[1] Patent: WO2005/121140, 2005, A1,
25
[ 15862-34-7 ]
[ 669066-91-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3608 - 3612
26
[ 15862-34-7 ]
[ 669066-93-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3608 - 3612
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 228 - 238
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 3021 - 3029
29
[ 15862-34-7 ]
[ 910543-72-5 ]
Reference：
[1] Patent: US2018/44335, 2018, A1,
30
[ 15862-34-7 ]
[ 884495-39-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
31
[ 15862-34-7 ]
[ 1086062-66-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
With silver carbonate; In chloroform; at 20℃; for 48h;
Example 4N-(2-Methyl-3-(5-(5-(4-methylpiperazin-l-yl)pyridine-2-ylamino)-6-oxo-l,6- dihydropyridin-3-yl)phenyl)-4,5,6,7-tetrahydrobenzo[Z>]thiophene-2- carboxamide (19); 5-Bromo-2-methoxy-3-nitropyridine (15)[00197] In a 1 L, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-3-nitropyridin-2-ol (50.0 g, 0.23 mol) in CHCl3 (500 mL) under nitrogen in the dark (wrapped in aluminum foil.) To this solution was added Ag2CO3 (75.5 g, 0.28 mol) and MeI (142.0 mL, 2.3 mol). After the mixture was stirred for 48 h at room temperature, it was filtered through a pad of Celite, washed with CH2Cl2, and concentrated. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:4) to give 24.0 g (45%) of 5-bromo-2- methoxy-3-nitropyridine (15) as a solid.
34%
With silver carbonate; In methylene chloride; at 20℃; for 48h;Inert atmosphere; Darkness;
Method B: to a suspension of 14 (5.0 g, 22.8 mmol) in anhydrous CH3Cl (50 mL) under N2 in the dark (wrapped in aluminum foil) was added Ag2CO3 (7.55 g, 28.0 mmol), followed by CH3I (14.2 mL, 230.0 mmol). After stirring at rt for 48 h, the reaction mixture was filtered through a pad of Celite, washed with abundant CH2Cl2, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10:1 hexanes/EtOAc) to afford 16 (1.86 g, 34%) as a pale yellow solid. The analytical data were same as aforementioned.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃;
A solution of 5-bromo-3-nitro-pyridin-2-ol (5.0 g, 22.8 mmol) and K2CO3 (9.5 g, 3 equiv. , 69 mmol) in DMF (25 mL) was treated with benzyl bromide (4.3 g, 1.1 equiv. , 25 mmol) and heated to 50 C. After stirring overnight, the solution was poured into water (150 mL) and extracted with ethyl acetate (2 X 150 mL). The combined organic layers were washed with sat'd aq NACL, dried over anhydrous MGSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (30-40% ethyl acetate in heptane) afforded 1-benzyl-5-bromo-3-nitro- LH-PYRIDIN-2-ONE as a yellow solid (5.56 g, 79%).
79%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;
A solution of 5-bromo-3-nitro-pyridin-2-ol (5.0 g, 22.8 mmol) and K2CO3 (9.5 g, 3 equiv., 69 mmol) in DMF (25 mL) was treated with benzyl bromide (4.3 g, 1.1 equiv., 25 mmol) and heated to 50 C. After stirring overnight, the solution was poured into water (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (30-40% ethyl acetate in heptane) afforded 1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one as a yellow solid (5.56 g, 79%).
With cesium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 60℃; for 7h;
Cesium carbonate (14.88 g, 45.66 mmol) was added to a solution of 5-bromo-3- nitropyridin-2-ol (10.0 g, 45.7 mmol) and 2-BROMOETHYL methyl ether (4.29 mL, 45.66 mmol) in N, N-dimethylformamide (400 mL). After 3 h, additional 2-BROMOETHYL METHYL ether (4.29 mL, 45.7 mmol) was added, and the reaction was heated to 60 oC. After 4 h, water was added. The mixture was extracted with ethyl acetate (3x), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes) 40% ethyl acetate/hexanes) gave the title compound (7.39 g). MS 277 (M).
With dmap; triethylamine; In dichloromethane; at 20℃; for 16h;
5-Bromo-3-nitropyridin-2-ol (30. 00G, 0. 137MMOL) andp-toluenesulfonyl chloride (30.03g, 0. 158MMOL) were suspended in CH2C12 under N2 and treated dropwise with triethylamine (38. 2mL, 0.274mmol) prior to the addition of DMAP (3.35g, 0.027mmol). After stirring at rt forl6h the mixture was diluted with CH2C12 (500mL) then washed with 1M HCl (aq) (2 x 500 mL) and brine (500ML). The aqueous layer was back-extracted with CH2C12 (200ML) and the combined organic layers dried over NA2S04, and concentrated IRA vacuo. The crude material thus isolated was chromatographed over silica gel eluting with 50% EtOAc/hexane to give, on evaporation, a solid which was crystallized from 50% EtOAc/hexane to afford 5-bromo- 3-NITROPYRIDIN-2-YL 4-METHYLBENZENESULFONATE. 1H NMR (400MHZ, CDCL3) No. 2.51 (s, 3H), 7.43 (dd, 2H, J= 8. 4,0. 4 Hz), 7.99 (dt, 2H, J= 6. 8, 2.0 Hz), 8. 52 (d, 1H, J= 2.4 Hz), 8. 60 (d, LH, J=2. 4HZ).
With dmap; triethylamine; In dichloromethane; at 20℃; for 16h;
a) 5-Bromo-3-nitropyridin-2-ol (30.00 g, 0.137 mmol) and p-toluenesulfonyl chloride (30.03 g, 0.158 mmol) were suspended in CH2Cl2 under N2 and treated dropwise with triethylamine (38.2 mL, 0.274 mmol) prior to the addition of DMAP (3.35 g, 0.027 mmol). After stirring at rt for 16 h the mixture was diluted with CH2Cl2 (500 mL) then washed with 1M HCl(aq) (2*500 mL) and brine (500 mL). The aqueous layer was back-extracted with CH2Cl2 (200 mL) and the combined organic layers dried over Na2SO4, and concentrated in vacuo. The crude material thus isolated was chromatographed over silica gel eluding with 50% EtOAc/hexane to give, on evaporation, a solid which was crystallized from 50% EtOAc/hexane to afford 5-bromo-3-nitropyridin-2-yl 4-methylbenzenesulfonate. 1H NMR (400 MHz, CDCl3) delta 2.51 (s, 3H), 7.43 (dd, 2H, J=8.4, 0.4 Hz), 7.99 (dt, 2H, J=6.8, 2.0 Hz), 8.52 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz).
16.1a. 5-(4-chlorophenyl)-3-nitropyridin-2-ol Under an argon atmosphere a mixture of 22.10 g (100.91 mmol) of 5-bromo-3-nitropyridin-2-ol, 23.46 g (150.00 mmol) of 4-chlorophenylboric acid, 0.73 g (1.00 mmol) of bis(diphenylphosphine)ferrocene]palladium (II) chloride, and 200 mL of 2N aqueous sodium carbonate solution in 400 mL of acetone was stirred for 16 hours at 60 C. and then evaporated down in vacuo. The aqueous phase was neutralized with 160 mL of 1M citric acid solution and exhaustively extracted with EtOAc and a little MeOH. The combined organic phases were dried over magnesium sulfate and evaporated down in vacuo. The residue was triturated with a little EtOAc, the precipitate was filtered off and dried. Yield: 9.70 g (22% of theoretical); C11H7ClN2O3 (M=250.638); calc.: molpeak (M-H)-: 249/251 (Cl); found: molpeak (M-H)-: 249/251 (Cl); HPLC-MS: 6.83 minutes (method A).
EXAMPLE 23 4-(6-BROMO-OXAZOLO[5,4-b]PYRIDIN-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE The title compound was prepared from 6-bromo-2-methylsulfanyl-oxazolo[5,4-b]pyridine (prepared from 5-bromo-2-hydroxy-3-nitropyridine by the methods described in Examples 4, 5 and 7) by the procedure described in Example 9 in 64% yield: 1H NMR (CDCl3, 400 MHz) delta 7.90 (d, 1H, J=2.1 Hz), 7.59 (d, 1H, J=2.1 Hz), 4.50-4.49 (m, 1H), 3.91 (t, 2H, J=5.8 Hz), 3.18-3.11 (m, 4H), 3.03-2.96 (m, 2H), 2.16-2.08 (m, 2H), 1.85-1.76 (m, 2H); 13C NMR (CDCl3, 100 MHz) delta 161.4, 138.8, 125.3, 121.4, 116.7, 116.2, 57.0, 50.6, 46.4, 44.3, 26.8; MS (Cl) m/z 323.0 (M+1); HPLC retention time=3.08 min. The hydrochloride salt was prepared by diluting in ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate: mp>300 C.
EXAMPLE 2 5-Bromo-2-hydroxy-3-nitropyridine (9) (5.736 g, 0.0262 mol) and 15 mL thionyl chloride were added under argon. N,N dimethylformamide (1 mL) was then added and the solution was heated to reflux for 1 hr. By the end of the reaction, the bromohydroxynitropyridine was completely dissolved in solution. After cooling to ambient temperature, 5 mL of toluene was added, and the solution was concentrated under vacuum. The product, 5-bromo-2-chloro-3-nitropyridine, was a yellow crystalline solid.
With thionyl chloride; In toluene;
EXAMPLE 2 STR13 5-Bromo-2-hydroxy-3-nitropyridine (9) (5.736 g, 0.0262 mol) and 15 mL thionyl chloride were added under argon. N,N dimethylformamide (1 mL) was then added and the solution was heated to reflux for 1 hr. By the end of the reaction, the bromohydroxynitropyridine was completely dissolved in solution. After cooling to ambient temperature, 5 mL of toluene was added, and the solution was concentrated under vacuum. The product, 5-bromo-2-chloro-3-nitropyridine, was a yellow crystalline solid.
5-Bromo-1-methyl-3-nitropyridin-2-one (41); A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-bromo-3-nitro-2-hydroxypyridine (24.0 g, 0.11 mol), anhydrous DMF (280 mL) and powdered potassium carbonate (-350 mesh, 33.4 g, 0.24 mol), and the suspension stirred for 15 min at ambient temperature. After this time methyl iodide (17.1 g, 0.124 mol) was added, and the mixture stirred at room temperature for 18 h. The reaction mixture was then diluted with water (750 mL) and extracted with ethyl acetate (3×1.0 L). The organic extracts were combined, washed with brine (500 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by flash chromatography on silica to afford an 85% yield (21.7 g) of 41 as a yellow solid: mp 122-123 C.; 1H NMR (300 MHz, CDCl3) delta 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).
With caesium carbonate; In N,N-dimethyl-formamide; for 18h;
Cesium carbonate (44.6 g, 137 mmol) was added to a solution of 5-bromo-2-hydroxy-3- nitropyridine (20.0 g, 91.3 mmol) and iodomethane (19.4 g, 137 mmol) in NN-dimethylformamide (500 mL). After 18 h, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (3x), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 233.1 (M).
5-Bromo-1-methyl-3-nitro-1H-pyridin-2-one H A 1-L round-bottomed flask equipped with a magnetic stirrer is purged with nitrogen, then charged with 5-bromo-3-nitro-pyridin-2-ol G (20.0 g; 0.09 mol), DMF (200 mL) and K2CO3 (25.2 g; 0.18 mol). The suspension is stirred for 15 min at RT, MeI (14.3 g; 0.10 mol) is added and the mixture is stirred at RT for 18 h. The reaction mixture is diluted with water and extracted with EtOAc (3*200.0 mL). The combined extracts are washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography. HPLC-MS: (M+H)+=233/235; tRet=0.828 min; method M7
(b) A solution of 2-hydroxy-3-nitro-5-bromopyridine (23.4 g) in phosphoryl chloride (16 ml) was heated under reflux for 2.5 hr. The reaction mixture was poured into ice/water and a brown solid was produced which was removed by filtration. The solid was dissolved in chloroform, dried (MgSO4) and decolourised by heating with charcoal for 30 min. The solvent was evaporated from the decolourised solution to yield a yellow solid (24.0 g) which was recrystallized from ether/petroleum ether (40-60 C.) to yield 2-chloro-3-nitro-5-bromopyridine (19.4 g) m.p. 66-68 C.
In chloroform; trichlorophosphate;
(b) A solution of 2-hydroxy-3-nitro-5-bromopyridine (23.4 g) in phosphoryl chloride (16 ml) was heated under reflux for 2.5 hr. The reaction mixture was poured into ice/water and a brown solid was produced which was removed by filtration. The solid was dissolved in chloroform, dried (MgSO4) and decolourised by heating with charcoal for 30 min. The solvent was evaporated from the decolourised solution to yield a yellow solid (24.0 g) which was recrystallized from ether/petroleum ether (40-60 C.) to yield 2-chloro-3-nitro-5-bromopyridine (19.4 g) m.p. 66-68 C.
In chloroform; trichlorophosphate;
(b) A solution of 2-hydroxy-3-nitro-5-bromopyridine (23.4 g) in phosphoryl chloride (16 ml) was heated under reflux for 2.5 hr. The reaction mixture was poured into ice/water and a brown solid was produced which was removed by filtration. The solid was dissolved in chloroform, dried (MgSO4) and decolourised by heating with charcoal for 30 min. The solvent was evaporated from the decolourised solution to yield a yellow solid (24.0 g) which was recrystallized from ether/petroleum ether (40-60 C.) to yield 2-chloro-3-nitro-5-bromopyridine (19.4 g) m.p. 66-68 C.
In chloroform; trichlorophosphate;
(b) A solution of 2-hydroxy-3-nitro-5-bromopyridine (23.4 g) in phosphoryl chloride (16 ml) was heated under reflux for 2.5 hr. The reaction mixture was poured into ice/water and a brown solid was produced which was removed by filtration. The solid was dissolved in chloroform, dried (MgSO4) and decolourised by heating with charcoal for 30 min. The solvent was evaporated from the decolourised solution to yield a yellow solid (24.0 g) which was recrystallized from ether/petroleum ether (40-60 C.) to yield 2-chloro-3-nitro-5-bromopyridine (19.4 g) m.p. 66-68 C.
With sodium carbonate;Pd(dppf)Cl2; In water; acetone;
3.65b 5-(4-chloro-phenyl)-3-nitro-pyridin-2-ol 23.5 g (150 mmol) 4-chlorophenyl-boric acid are added under argon to a solution of 22.1 g (101 mmol) 5-bromo-3-nitro-pyridin-2-ol, 200 mL (400 mmol) of a 2 M Na2CO3 solution and 731 mg (1.00 mmol) Pd(dppf)Cl2 in 400 mL acetone and 80 mL water. The reaction mixture is stirred for 18 h at 60 C. Acetone is eliminated i.vac. and the residue is adjusted to pH 7 with 160 mL 1 M citric acid. The aqueous phase is extracted three times with EtOAc and once with MeOH. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The residue is triturated with EtOAc. Yield: 9.70 g (22.0% of theory). C11H7ClN2O3 (M=250.643).
With sulfuric acid; nitric acid; at 20℃;Cooling with ice;
A mixture of 5-bromopyridin-2-ol (I-99, Aldrich, Wis.; 53 g, 0.30 mol) in concentrated.H2SO4 (250 mL) was stirred with ice bath cooling and concentrated HNO3 (105 mL) was added slowly to the mixture. The reaction mixture was stirred for 4 hours at room temperature and then poured onto ice and stirred for additional 30 minutes. A yellow precipitate was filtered off used in the following step without further purification (45 g, 68%). MS (ESI): m/z 220 (M+1)+.
A mixture of 5-bromo-3-nitro-2-pyridinol (2.00 g, 9.13 mmol), and silver carbonate 50% by weight on Celite (6.30 g, 1 1.42 mmol) in toluene (60 mL) was stirred as 2-iodopropane (1 .83 mL, 18.27 mmol) was added. The resulting mixture was allowed to stir at roomtemperature overnight. The organic layer was diluted with EtOAc and filtered through Celite. The filtrate was washed with NaHC03 then brine before being dried with Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography. The column was eluted with 0-40% EtOAc in hexanes. Fractions containing the product were combined and concentrated to yield 5-bromo-2-[(1 -methylethyl)oxy]-3-nitropyridine (1 .72 g, 72%) as a dark oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.67 - 8.65 (d, J=2.4 Hz, 1 H) 8.64 (d, J=2.4 Hz, 1 H) 5.42 - 5.36 (m, 1 H) 1 .33 (d, J=6.2 Hz, 6 H).
To a solution of 5-bromo-2-hydroxy-3-nitropyridine (14g, 63.9 mmol) in THF (200mL) at room temperature was added tBuOK (7.5g, 67.1 mmol), and stirred for 0.5 hour.(Bromomethyl)cyclopropane (8.7 mL, 92 mmol) and DMF (200mL) were added to the suspension and the resulting mixture was warmed to 85 C. The mixture was stirred overnight at 85 C. Water (600 mL) was added, and extracted with ethyl acetate (500mL*3). The organic phase was washed with water, brine, dried over Na2SO4, filtered, and evaporated in vacuum to give the crude Compound. The crude (18g) intermediate was purified by column chromatography over silica gel (eluent: Petrol ether Ethyl acetate=23). The desired fractions were evaporated in vacuum to give the product as a brown solid: 13.0 g of intermediate 75i, yield 74.5%.
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