* 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, 1957, p. 560,562
7
[ 7732-18-5 ]
[ 57-50-1 ]
[ 1121-78-4 ]
[ 4664-12-4 ]
[ 40222-77-3 ]
[ 123-76-2 ]
Reference：
[1] Nippon Nogei Kagaku Kaishi, 1940, vol. 16, p. 249,253, 264[2] Chem.Abstr., 1940, p. 6278,6940
[3] Bulletin of the Agricultural Chemical Society of Japan, 1939, vol. 15, p. 107
[4] Nippon Nogei Kagaku Kaishi, 1939, vol. 15, p. 629[5] Nippon Nogei Kagaku Kaishi, 1940, vol. 16, p. 253[6] Chem.Abstr., 1940, p. 432 6940
8
[ 7732-18-5 ]
[ 1113-38-8 ]
[ 57-50-1 ]
[ 1121-78-4 ]
[ 4664-12-4 ]
[ 40222-77-3 ]
[ 123-76-2 ]
Reference：
[1] Nippon Nogei Kagaku Kaishi, 1940, vol. 16, p. 249,253, 264[2] Chem.Abstr., 1940, p. 6278,6940
[3] Bulletin of the Agricultural Chemical Society of Japan, 1939, vol. 15, p. 107
[4] Nippon Nogei Kagaku Kaishi, 1939, vol. 15, p. 629[5] Nippon Nogei Kagaku Kaishi, 1940, vol. 16, p. 253[6] Chem.Abstr., 1940, p. 432 6940
Reference：
[1] Patent: US2008/138656, 2008, A1,
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
[3] Patent: US4038396, 1977, A,
11
[ 1121-78-4 ]
[ 15128-90-2 ]
Yield
Reaction Conditions
Operation in experiment
36.3%
With nitric acid In conc. H2 SO4; ethyl acetate
117a. 3-Hydroxy-6-methyl-2-nitropyridine 5-Hydroxy-2-methylpyridine (23.6 g, 216 mmole)was dissolved in conc. H2 SO4 (50 mL) and cooled to 0° C. Fuming HNO3 (50 mL) was added over one hour. The solution was stirred at room temperature for one hour, poured onto ice (400 g), and filtered. The solids were dissolved in EtOAc washed with brine (100 mL). The organic extracts were dried (MgSO4), and the solvent was evaporated to yield 12.1 g (36.3percent) of the title compound. mp 102-105° C. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.44 (s, 3H), 7.52 (d, J=8.5 Hz, 1H), 7.58 (d J=8.5 Hz, 1H). MS (ESI -Q1MS) m/e 153(M-H)+. Anal. calcd. for C6 H6 N2 O3 C, 46.76 H, 3.92; N, 18.18 Found: C, 46.65 H, 3.98; N, 18.10.
Reference：
[1] Heterocycles, 1994, vol. 38, # 3, p. 529 - 540
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
[3] Patent: US6133253, 2000, A,
[4] Patent: US5155116, 1992, A,
[5] Patent: US5084456, 1992, A,
[6] Patent: US4038396, 1977, A,
12
[ 1121-78-4 ]
[ 23003-30-7 ]
Yield
Reaction Conditions
Operation in experiment
50%
With iodine; sodium hydroxide In water at 20℃; for 16 h;
Step A: 6-Methylpyridin-3-ol (0.5 g, 4.58 mmol) was dissolved in aqueous NaOH (4.5 mL, 1 M, 4.5 mmol). To the solution was added iodine (1.28 g, 5.2 mmol) and the mixture was stirred at room temperature overnight. The mixture was neutralized with aqueous HCl (2 M) to pH ˜7. A white precipitate formed and was collected by filtration. The solid was washed with water and dried to give 2-iodo-6-methylpyridin-3-ol (0.8 g, 50percent). MS m/z 236.0 [M+H]+.
43.9%
Stage #1: With sodium carbonate In water at 20℃; Stage #2: With iodine; potassium iodide In water for 0.583333 h;
Sodium carbonate (68.0 g) and water (810 mL) were added to 5-hydroxy-2-methylpyridine (1-014-01) (36.11 g), and the reaction mixture was stirred at room temperature, dissolved. To the reaction mixture was added dropwise a solution of iodine (117 g) and potassium iodide (117 g) in water (810 mL) for 35 min. The resulting pink-yellow crystal was filtered and dried under reduced pressure to give 2-iodo-3-hydroxy-6-methylpyridine (2-014-01) (34.1 g, 43.9percent, m.p. 187-190 °C)1H-NMR (300MHz, CDCl3+CD3OD): δ 2.45 (s,3H), 6.45 (d, J = 6.9 Hz, 1H), 7.02 (dd, J = 6.6, 1.5 Hz, 1H)
43.9%
With iodine; sodium carbonate; potassium iodide In water at 20℃; for 0.583333 h;
Sodium carbonate (68.0 g) and water (810 mL) were added to 5-hydroxy-2-methylpyridine (1-014-01) (36.11 g), and the reaction mixture was stirred at room temperature, dissolved. To the reaction mixture was added dropwise a solution of iodine (117 g) and potassium iodide (117 g) in water (810 mL) for 35 min. The resulting pink-yellow crystal was filtered and dried under reduced pressure to give 2-iodo-3-hydroxy-6-methylpyridine (2-014-01) (34.1 g, 43.9percent, m.p. 187-190 DEG C)<1>H-NMR (300MHz, CDCl3+CD3OD): delta 2.45 (s,3H), 6.45 (d, J= 6.9 Hz, 1H), 7.02 (dd, J= 6.6, 1.5 Hz, 1H)
8.19 g
With iodine; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 72 h;
To tetrahydrofuran / water (50 / 50mL) was added a mixed solution of pyridine-5 (6.458g, 60mmol), stirMix was added to the reaction flask followed by dissolution of iodine (16.8g, 66mmol), sodium bicarbonate (5.281g, 66mmol), at room temperature for 3 days, the reaction solution was dark purple solid separated, was added 10percent sodium thiosulfate solution purple to disappear, there are a lot of white solid precipitated was suction-white solid 8.19g, was verified by NMRThe product 6.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 16, p. 2117 - 2122
[2] Patent: US9617268, 2017, B2, . Location in patent: Page/Page column 400; 401
[3] Patent: EP1477186, 2004, A1, . Location in patent: Page/Page column 35; 36
[4] Patent: EP1357111, 2003, A1, . Location in patent: Page/Page column 54
[5] Tetrahedron, 2007, vol. 63, # 13, p. 2787 - 2797
[6] Patent: US2011/230461, 2011, A1, . Location in patent: Page/Page column 32
[7] Patent: CN105693737, 2016, A, . Location in patent: Paragraph 0047; 0048
a. 2-Bromo-3-hydroxy-6-methyl-pyridine. To a solution of 5-hydroxy-2-methylpyridine (8.80 g, 80.6 mmol) in 125 mL of pyridine was added a solution of bromine (14.18 g, 88.7 mmol) in 50 mL pyridine dropwise. The temperature of the reaction mixture rose to 40° C. upon completion of addition. After 1 hour the pyridine was removed under vacuum and the resulting solid was suspended into water (200 mL) and stirred overnight. The solid was collected and dried to give the desire product as a brownish solid (8.05 g, 53.1percent yield). 1H NMR (500 MHz, CDCl3): δ2.21 (s, 3 H), 6.73 (d, J=8.1 Hz, 1 H), 6.94 (d, J=8.1 Hz, 1 H), 9.36 (brs, 1 H).
53.1%
With bromine In pyridine; water
a. 2-Bromo-3-hydroxy-6-methyl-pyridine To a solution of 5-hydroxy-2-methylpyridine (8.80 g, 80.6 mmol) in 125 mL of pyridine was added a solution of bromine (14.18 g, 88.7 mmol) in 50 mL pyridine dropwise. The temperature of the reaction mixture rose to 40° C. upon completion of addition. After 1 hour the pyridine was removed under vacuum and the resulting solid was suspended into water (200 mL) and stirred overnight. The solid was collected and dried to give the desire product as a brownish solid (8.05 g, 53.1percent yield). 1H NMR (500 MHz, CDCl3): δ2.21 (s, 3H), 6.73 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 9.36 (brs, 1H).
37%
at 20℃; cooling with ice
2-methyl-5-hydroxypyridine (4.4 g, 40.3 mmol) was suspended in pyridine (85 mL) and cooled at ice-water. The bromine (7.1 g, 44.3 mmol) was slowly dropped into above cooled suspension. The ice-water bath was removed after finished bromine addition and the mixture was stirred overnight at room temperature. The pyridine was removed in vacuo. The residue was treated with water (100 mL) and stirred for 1 h. The solid product 48 (2.8 g, 37percent) was collected by filtration.
31.3%
With bromine In pyridine; water
(1) Synthesis of 6-bromo-5-hydroxy-2-methylpyridine [R4=Br in Compound (XIV)] To a solution obtained by dissolving 5-hydroxypicoline (10 g, 0.0916 mol) in pyridine (30 ml) was added dropwise bromine (15.4 g, 0.0916*1.05 mol), followed by stirring at room temperature for 4 hours. Pyridine was then distilled off by an evaporator. To the residue was added water and the precipitate was filtered out, washed with water to obtain a white solid. Yield: 5.38 g, percent yield: 31.3percent, m.p.: 185-187° C. IR KBr cm-1: 2776, 1563, 1296, 1221, 1083, 831. 1H-NMR (60 MHz, d6-DMSO, δ): 2.26 (3H, s, CH3), 6.93 (1H, d, J=8 Hz, pyridine ring H), 7.1 (1H, d, J=8 Hz, pyridine ring H), 10.2 (1H, s OH).
Reference：
[1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[6] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[7] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
Stage A: 2-Nitro-3-Hydroxy-6-Methylpyridine 5.45 g (50 mmol) of 5-hydroxy-2-methylpyridine are added to 20 ml of concentrated sulfuric acid while cooling in an ice bath. The temperature is maintained at +6 C. and 2.35 ml of fuming nitric acid are added with stirring. The mixture is left overnight at room temperature. 100 g of ice are added with stirring. The product is filtered off, rinsed with water and dried.
With sulfuric acid; nitric acid;
Stage A: 2-NITRO-3-HYDROXY-6-METHYLPYRIDINE 5.45 g (50 mmol) of 5-hydroxy-2-methylpyridine are added to 20 ml of concentrated sulfuric acid, cooling in an ice bath. The temperature is maintained at 30 6 C. and 2.35 ml of fuming nitric acid are added with stirring. The mixture is left overnight at room temperature. 100 g of ice are added with stirring. The product is filtered off, rinsed with water and dried.
With sulfuric acid; nitric acid;
Step A Preparation of 3-hydroxy-6-methyl-2-nitropyridine To 40 ml. of ice cold concentrated sulfuric acid was added 10.9 g. of 3-hydroxy-6-methylpyridine. Maintaining the temperature at 6 C., 4.7 ml. of fuming nitric acid was added dropwise with stirring. The mixture was allowed to warm to room temperature overnight. Ice (200 g.) was added with stirring. After the ice had melted, the precipitate was collected, washed with water and dried to give 3-hydroxy-6-methyl-2-nitropyridine, m.p. 103-105 C.
12.1 g (36.3%)
With nitric acid; In conc. H2 SO4; ethyl acetate;
117a. 3-Hydroxy-6-methyl-2-nitropyridine 5-Hydroxy-2-methylpyridine (23.6 g, 216 mmole)was dissolved in conc. H2 SO4 (50 mL) and cooled to 0 C. Fuming HNO3 (50 mL) was added over one hour. The solution was stirred at room temperature for one hour, poured onto ice (400 g), and filtered. The solids were dissolved in EtOAc washed with brine (100 mL). The organic extracts were dried (MgSO4), and the solvent was evaporated to yield 12.1 g (36.3%) of the title compound. mp 102-105 C. 1 H NMR (DMSO-d6, 300 MHz) delta: 2.44 (s, 3H), 7.52 (d, J=8.5 Hz, 1H), 7.58 (d J=8.5 Hz, 1H). MS (ESI -Q1MS) m/e 153(M-H)+. Anal. calcd. for C6 H6 N2 O3 C, 46.76 H, 3.92; N, 18.18 Found: C, 46.65 H, 3.98; N, 18.10.
Stage #1: 5-Hydroxy-2-methylpyridine With tetrabutylammomium bromide; potassium hydroxide In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: benzyl bromide In tetrahydrofuran at 20℃; for 48h;
96%
With sodium hydroxide In water; acetone for 16h; Heating;
94%
With NaH In ammonium chloride; dimethyl sulfoxide
1 Step A-Preparation of 5-Benzyloxy-2-methyl-pyridine.
Step A-Preparation of 5-Benzyloxy-2-methyl-pyridine. A suspension of NaH 60% (1.210 g) in anhydrous DMSO (40 ml) was stirred at 100° C. for 20 minutes (gas liberation), cooled to room temperature 6-methyl-pyridin-3-ol (3.000 g) was added in one portion. The resulting mixture was stirred at room temperature for 20 minutes and benzyl bromide (3.60 ml) was added. The mixture was stirred for 78 hours, dropped in NH4Cl sat. and extracted with ether (3*). The combined organic layers were washed with water, brine and dried (MgSO4). Flash chromatography (ether) of the crude gave 5.131 g (94% yield) of pure desired product as a colorless oil.
91%
With sodium hydride In N,N-dimethyl-formamide at 0℃;
86%
With sodium hydroxide In water; acetone
c.53 5-Benzyloxy-2-methyl-pyridine
Preparation c-53 5-Benzyloxy-2-methyl-pyridine To a solution of 5-hydroxy-2-methylpyridine (20 g, 183.2677 mmol) and sodium hydroxide (8.0638 g, 201.5944 mmol) in acetone (400 mL) and water (120 mL) was added benzyl bromide (24 mL, 201.5944 mmol). The resulting mixture was refluxed for 16 hours and allowed to cool to ambient temperature. The acetone was removed in vacuo and the mixture extracted with ethyl acetate (3*150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (200 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the pure product (31.35 g, 86%) as an orange oil. LRMS(m/z): 200 (M+H)+. 1H NMR (CDCl3, 300 MHz): 8.25 (1H, d, J=2.8 Hz), 7.43-7.31 (5H, m), 7.15 (1H, dd, J=8.5, 2.8Hz), 7.04 (1H, d, J=8.5 Hz), 5.06 (2H, s), 2.47 (3H, s).
86%
With sodium hydroxide In water; acetone for 16h; Heating / reflux;
c-53 Preparation c-53; 5-BENZVLOXV-2-METHVL-PVRIDINE
To a solution of 5-hydroxy-2-methylpyridine (20 g, 183. 2677 MMOL) and sodium hydroxide (8. 0638 G, 201. 5944 MMOL) in acetone (400 mL) and water (120 mL) was added benzyl bromide (24 mL, 201. 5944 MMOL). The resulting mixture was REFLUXED for 16 hours and allowed to cool to ambient temperature. The acetone was removed in vacuo and the mixture extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (200 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the pure product (31. 35 g, 86%) as an orange oil LRMS (M/Z) : 200 (M+H) +. H NMR (CDCl3, 300 MHz) : 8. 25 (1 H, d, J= 2. 8 Hz), 7. 43-7. 31 (5H, m), 7. 15 (1 H, dd, J = 8. 5, 2. 8 Hz), 7. 04 (1 H, d, J = 8. 5 HZ), 5. 06 (2H, s), 2. 47 (3H, s).
82%
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;
81%
With sodium hydroxide In water; acetone at 85℃; for 8h;
66.a
(a) 5-Benzyloxypyridin-2-carbaldehyde; 5-Hydroxy-2-methylpyridine (10.20 g, 91.60 mmol) was dissolved in a mixture of acetone (160 mL) and water (60 mL). Sodium hydroxide (4.20 g, 100.76 mmol) and benzyl bromide (11.97 mL, 100.76 mmol) were added to the solution, and the obtained mixture was then stirred at 85°C for 8 hours. Thereafter, the reaction solution was concentrated, and methylene chloride and water were added to the residue and the two layers were separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain a benzyl compound (14.80 g, yield: 81%) in the form of a yellow oily substance. The obtained benzyl compound (14.80 g, 74.28 mmol) was dissolved in chloroform (150 mL), and 3-chloroperbenzoic acid (19.23 g, 111.42 mmol) was then added thereto under ice cooling. The reaction solution was stirred at room temperature for 2 hours. Thereafter, a 20% sodium sulfite aqueous solution (60 mL) was added to the reaction solution, and the obtained mixture was further stirred at room temperature for 20 minutes. The reaction solution was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away. The obtained residue was purified by NH column chromatography (methylene chloride/methanol). The obtained oxidized compound was dissolved in methylene chloride (200 mL), and trifluoroacetic anhydride (42 mL, 297.12 mmol) was then added to the solution under ice cooling. The obtained mixture was stirred at room temperature for 16 hours. Thereafter, methanol (100 mL) was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 20 minutes, followed by concentration. Methylene chloride and a 5 N sodium hydroxide aqueous solution were added to the residue and the two layers were separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away. The obtained residue was purified by NH column chromatography (methylene chloride/methanol), so as to obtain an alcohol compound (10.80 g, yield in two steps: 68%) in the form of a pale brown solid. The obtained alcohol compound (4.86 g, 22.58 mmol) was dissolved in chloroform (100 mL), and manganese dioxide (24 g) was then added to the solution. The obtained mixture was stirred at room temperature for 23 hours. Thereafter, the reaction solution was filtered with celite, and the solvent was then distilled away. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the title compound (3.83 g, yield: 80%) in the form of a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ (ppm) = 10.0 (1H, s), 8.52 (1H, d, J = 2.7 Hz), 7.97 (1H, d, J = 8.6 Hz), 7.46-7.36 (6H, m), 5.22 (2H, s).
71%
Stage #1: 5-Hydroxy-2-methylpyridine With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h;
Stage #2: benzyl bromide In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 16h;
I 5-(benzyloxy)-2-methylpyridine
[00257] To a suspension of sodium hydride (60% in mineral oil, 6.82 g, 170.45 mmol) in tetrahydrofuran (300 mL) at 0 °C was added a solution of 6-methylpyridin-3- ol (15.5 g, 142.2 mmol) in DMF (150 mL), and the mixture was stirred for 30 min. Benzyl bromide (26.72 g, 156.24 mmol) was then added and the mixture was warmed to room temperature and stirred for 16 h. To the resulting solution was added saturated aq. sodium bicarbonate (300 mL) and the solution was extracted with ethyl acetate (3 x 200 mL). The combined the organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography eluting with ethyl acetate/petroleum ether (1 : 20) to give the title compound (20.1 g, 71%). MS (ESI): m/z 200 [M + H]+.
35%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
23%
With potassium carbonate In acetonitrile at 20℃; for 12h;
43.1
1) 5-Benzyloxy-2-methylpyridine Benzyl bromide (10.9 mL) was added to a solution of 5-hydroxy-2-methylpyridine (10.0 g) and potassium carbonate (38.0 g) in acetonitrile (200 mL) at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate - hexane), to thereby give 5-benzyloxy-2-methylpyridine as an oil (4.14 g, 23%). 1H-NMR(400MHz,CDCl3)δ:2.48(3H,s), 5.08(2H,s), 7.05(1H,d,J=8.5Hz), 7.16(1H,dd,J=8.5,2.9Hz), 7.31-7.43(5H,m), 8.26 (1H, d, J=2.9Hz). MS(EI)m/z:199(M+).
23%
With potassium carbonate In acetonitrile at 20℃; for 12h;
14.1
[Referential Example 14] 5-(5-Benzyloxy-2-pyridyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-c arboxylic acid; [Show Image] 1) 5-Benzyloxy-2-methylpyridine; Benzyl bromide (10.9 ml) was added to a solution of 3-hydroxy-6-methylpyridine (10.0 g) and potassium carbonate (38.0) inacetonitrile (200ml) at room temperature, and the mixture was stirred for 12 hours. Water and ethyl acetate were added to the reaction liquid, then the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate-hexane) to give 5-benzyloxy-2-methylpyridine (4.14 g, 23%) as an oily product. 1H-NMR (400 MHz, CDCl3)δ: 2.48 (3H, s), 5.08 (2H, s), 7.05 (1H, d, J = 8.5 Hz), 7.16 (1H, dd, J = 8.5, 2.9 Hz), 7.31-7.43 (5H, m), 8.26 (1H, d, J = 2.9 Hz). EI-MS m/z: 199 (M+).
23%
With potassium carbonate In acetonitrile at 20℃; for 12h;
37.1
1) 5-Benzyloxy-2-methylpyridine Benzyl bromide (10.9 mL) was added to a solution of 5-hydroxy-2-methylpyridine (10.0 g) and potassium carbonate (38.0 g) in acetonitrile (200 mL) at room temperature, and the resultant mixture was stirred for 12 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 5-benzyloxy-2-methylpyridine (4.14 g, 23%) as an oily product. 1H-NMR(400MHz, CDCl3)δ: 2.48(3H, s), 5.08(2H, s), 7.05(1H, d, J=8.5Hz), 7.16(1H, dd, J=8.5, 2.9Hz), 7.31-7.43(5H, m), 8.26(1H, d, J=2.9Hz). EI-MSm/z: 199(M+).
23%
With potassium carbonate In acetonitrile at 20℃; for 12h;
2.1; 20.1
1) 5-Benzyloxy-2-methylpyridine Benzyl bromide (10.9 mL) was added to a suspension of 5-hydroxy-2-methylpyridine (10.0 g) and potassium carbonate (38.0 g) in acetonitrile (200 mL) at room temperature, and the mixture was stirred for 12 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 5-benzyloxy-2-methylpyridine (4.14 g, 23%) as an oily product. 1H-NMR (400MHz, CDCl3) δ: 2.48 (3H, s), 5.08 (2H, s), 7.05 (1H, d, J=8.5Hz), 7.16 (1H, dd, J=8.5, 2.9Hz), 7.31-7.43 (5H, m), 8.26 (1H, d, J=2.9Hz). EI-MS m/z: 199 (M+). 1) 5-Benzyloxy-2-methylpyridine Benzyl bromide (10.9 ml) was added to a solution of 3-hydroxy-6-methylpyridine (10.0 g) and potassium carbonate (38.0) in acetonitrile (200 ml) at room temperature, and the resultant mixture was stirred for 12 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 5-benzyloxy-2-methylpyridine (4.14 g, 23%) as an oily product. 1H-NMR (400MHz, CDCl3) δ: 2.48 (3H, s), 5.08 (2H, s), 7.05 (1H, d, J=8.5Hz), 7.16 (1H, dd, J=8.5, 2.9Hz), 7.31-7.43 (5H, m), 8.26 (1H, d, J=2.9Hz). EI-MS m/z: 199 (M+).
With sodium In methanol; water; dimethyl sulfoxide
4 Preparation of 5-benzyloxypyridine-2-aldehyde-1'-phthalazinylhydrazone (PH 22-6)
EXAMPLE 4 Preparation of 5-benzyloxypyridine-2-aldehyde-1'-phthalazinylhydrazone (PH 22-6) 3.3 g of sodium were dissolved in 60 ml of methanol and stirred with 15 g of 5-hydroxy-2-methylpyridine in 230 ml of DMSO for 1 hour at a temperature of 80° to 90° C. The methanol was spun or rotated out after cooling the mixture. 23.5 g of benzylbromide were then added, followed by stirring for 20 hours at room temperature. The reaction mixture was then acidified with 2N HCL and mixed with 1500 ml of water. The mixture was then extracted with diethyl ether and the ether phase was discarded. The pH-value of the aqueous phase was then adjusted to approximately 8 and the solution was extracted with ether. The organic phase was evaporated. 24.1 g of 5-benzyloxy-2-methylpyridine were obtained.
With ammonium chloride; calcium carbonate In N,N-dimethyl-formamide
2.a.n.d.3 Example 2 and 3
Example 2 and 3 To a solution of 5-hydroxy-2-methylpyridine (2.18 g, 20 mmol) in DMF (15 ml) were added under ice-cooling benzylbromide (4.00 g, 24 mmol) and calcium carbonate (3.30 g, 24 mmol). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous solution of ammonium chloride. The mixture was extracted with diethyl ether, washed with water, dried and concentrated. The obtained residue was chromatographed on silica gel (n-hexane-ethyl acetate) to give 5-benzyloxy-2-methylpyridine (2.04g).
With pyridine; bromine; at 0 - 30℃;Inert atmosphere;
Compound 144 6-methylpyridin-3-ol 16a (10.9 g, 100 mmol) was dissolved in 145 pyridine (400 mL). The solution was cooled to 0 C. and added slowly with 146 bromine (16 g, 100 mmol). The obtained mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was added with a solution of 118 sodium bicarbonate (200 mL) and extracted with ethyl acetate (200 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The residue was washed with petroleum ether/ethyl acetate (3/1, 50 mL) and filtered. The filter cake was dried in air. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=6/1 to 2/1). The obtained product was combined with the above filter cake to give the target 147 compound 2-bromo-6-methylpyridin-3-ol 16b (12.2 g, light yellow solid). Yield: 65%1H NMR (400 MHz, DMSO-d6) delta 10.42 (brs, 1H), 7.18 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 2.34 (s, 3H).
53.1%
With bromine; In pyridine; water;
a. 2-Bromo-3-hydroxy-6-methyl-pyridine. To a solution of 5-hydroxy-2-methylpyridine (8.80 g, 80.6 mmol) in 125 mL of pyridine was added a solution of bromine (14.18 g, 88.7 mmol) in 50 mL pyridine dropwise. The temperature of the reaction mixture rose to 40 C. upon completion of addition. After 1 hour the pyridine was removed under vacuum and the resulting solid was suspended into water (200 mL) and stirred overnight. The solid was collected and dried to give the desire product as a brownish solid (8.05 g, 53.1% yield). 1H NMR (500 MHz, CDCl3): delta2.21 (s, 3 H), 6.73 (d, J=8.1 Hz, 1 H), 6.94 (d, J=8.1 Hz, 1 H), 9.36 (brs, 1 H).
53.1%
With bromine; In pyridine; water;
a. 2-Bromo-3-hydroxy-6-methyl-pyridine To a solution of 5-hydroxy-2-methylpyridine (8.80 g, 80.6 mmol) in 125 mL of pyridine was added a solution of bromine (14.18 g, 88.7 mmol) in 50 mL pyridine dropwise. The temperature of the reaction mixture rose to 40 C. upon completion of addition. After 1 hour the pyridine was removed under vacuum and the resulting solid was suspended into water (200 mL) and stirred overnight. The solid was collected and dried to give the desire product as a brownish solid (8.05 g, 53.1% yield). 1H NMR (500 MHz, CDCl3): delta2.21 (s, 3H), 6.73 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 9.36 (brs, 1H).
37%
With pyridine; bromine; at 20℃;cooling with ice;
2-methyl-5-hydroxypyridine (4.4 g, 40.3 mmol) was suspended in pyridine (85 mL) and cooled at ice-water. The bromine (7.1 g, 44.3 mmol) was slowly dropped into above cooled suspension. The ice-water bath was removed after finished bromine addition and the mixture was stirred overnight at room temperature. The pyridine was removed in vacuo. The residue was treated with water (100 mL) and stirred for 1 h. The solid product 48 (2.8 g, 37%) was collected by filtration.
31.3%
With bromine; In pyridine; water;
(1) Synthesis of 6-bromo-5-hydroxy-2-methylpyridine [R4=Br in Compound (XIV)] To a solution obtained by dissolving 5-hydroxypicoline (10 g, 0.0916 mol) in pyridine (30 ml) was added dropwise bromine (15.4 g, 0.0916*1.05 mol), followed by stirring at room temperature for 4 hours. Pyridine was then distilled off by an evaporator. To the residue was added water and the precipitate was filtered out, washed with water to obtain a white solid. Yield: 5.38 g, percent yield: 31.3%, m.p.: 185-187 C. IR KBr cm-1: 2776, 1563, 1296, 1221, 1083, 831. 1H-NMR (60 MHz, d6-DMSO, delta): 2.26 (3H, s, CH3), 6.93 (1H, d, J=8 Hz, pyridine ring H), 7.1 (1H, d, J=8 Hz, pyridine ring H), 10.2 (1H, s OH).
With bromine; In pyridine; water;
Step 1 Preparation of 2-bromo-6-methyl-pyridin-3-ol (124A) To a solution of 5-hydroxy-2-methyl pyridine (20 g, 183.2 mmol) in dry pyridine (350 mL) was added a solution of bromine (10.3 mL, 201.5 mmol) in dry pyridine (100 mL) dropwise. After 1.5 h, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with water (160 mL) and filtered. The resultant pale solid was washed with water (300 mL) and air dried. The crude product was recrystallized in EtOH (200 mL) to give the title compound as a solid.
With nitrogen; bromine; In water; hydrogen bromide; acetic acid;
a 2-Bromo-3-hydroxy-6-methylpyridine 16.0 g (0.14 mol) of 3-hydroxy-6-methylpyridine are dissolved in 122 ml of 30% strength HBr in glacial acetic acid, and the solution is heated to 70 C. 70.4 [lacuna] (24.3 ml, 0.47 mol) of bromine are added dropwise at this temperature over a period of 1 hour. The reaction solution is stirred at this temperature for another 5 hours. After the reaction is complete, nitrogen is passed through the reaction solution for 2 hours (to drive off bromine). The reaction solution is then concentrated to 50 ml in vacuo. In this manner, an orange-red paste of the hydrobromide of the desired compound is obtained. The hydrobromide is boiled in 400 ml of water and then brought to a PH of 8 with a 1N bicarbonate solution. The dirty brown crude product obtained is recrystallized from water/methanol (2:3), giving colorless crystals of the pure product. Yield 14.2 g (54.1%)--melting point 193-194 C. (ref12) 191192 C.).--1 H-NMR ((D6)DMSO/TMS): 2.33 (s, 3H, CH3), 7.03 (d. J4.5 =8.0 Hz 1H, 4-H), 7.18 (d, J5.4 =8.0 Hz, 1H, 5-H).
With N-Bromosuccinimide; In pyridine; at 0 - 50℃;
With cooling with ice, N-bromosuccinimide (18 g) was added to a pyridine (75 ml) solution of 6-methylpyridin-3-ol (10 g), and stirred at room temperature for 4 hours. After further stirred overnight at 50C, the solvent was evaporated away under reduced pressure. The residue was dissolved in ethyl acetate, and washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water. After dried, the solvent was evaporated away, and the residue was crystallized with chloroform to obtain the entitled compound as a white solid
With pyridine; bromine; at 20℃; for 2.0h;
Intermediate 18, 2-bromo-6-methyl-3-pyridinol To a solution of 5-hydroxy-2-methlypyridine (Commercial, Aldrich, 44.5g) in pyridine (400ml) is added dropwise over 30 min at room temperature a solution of bromine (71 .64g) in pyridine (550ml). The reaction mixture was stirred for an additional 1 .5h. The reaction mixture was poured into water (4 litres), stirred for a few minutes and extracted with diethyl ether (4 X 300ml). The combined organics were dried over sodium sulphate and concentrated in vacuo to give a brown solid that was purified through silica using a 0-30% ethyl acetate in hexane system, to give the title compound as a beige solid, 37g.NMR 1 H NMR (400 MHz, DMSO-d6) delta ppm 10.43 (1 H, s, OH), 7.16 ppm (1 H, d, CH), 7.06 (1 H, d, CH), 2.31 (3H, s, CH3)
With bromine; In pyridine; at 20℃; for 2.0h;
Intermediate 18, 2-bromo-6-methyl-3-pyridinol To a solution of 5-hydroxy-2-methylpyridine (Commercial, Aldrich, 44.5 g) in pyridine (400 ml) is added dropwise over 30 min at room temperature a solution of bromine (71.64 g) in pyridine (550 ml). The reaction mixture was stirred for an additional 1.5 h. The reaction mixture was poured into water (4 litres), stirred for a few minutes and extracted with diethyl ether (4*300 ml). The combined organics were dried over sodium sulphate and concentrated in vacuo to give a brown solid that was purified through silica using a 0-30% ethyl acetate in hexane system, to give the title compound as a beige solid, 37 g. NMR 1H NMR (400 MHz, DMSO-d6) delta ppm 10.43 (1H, s, OH), 7.16 ppm (1H, d, CH), 7.06 (1H, d, CH), 2.31 (3H, s, CH3)
With pyridine; bromine; at 15 - 25℃; for 19.8333h;Industrial scale;
To a solution of 3-hydroxy-6-methylpyridine (2a) (3000 g, 27.5 mol) in pyridine (24 L) cooled to 15 C was added a solution of bromine (4.83 kg, 1.55 L, 30.2 mol) in pyridine (3 L) over a period of 50 min maintaining the internal temperature between 20 to 25 DC. After stirring for 19 h at room temperature the solvent was removed under vacuum and the residue was triturated with water. The solid separated was collected by filtration, washed with water and dried under vacuum to give 2-bromo-3-hydroxy-6-methylpyridine (2b) (3502 g, 67.7 %) as a light brown solid which was used as such without further purification; 1H NMR (300 MHz, DMSO-d6) delta 10.43 (s, 1H), 7.18 (d, J = 8.0 Hz, 1 H), 7.08 (d, J MS (ES+) 188.35, 186.36 (M+1).
With pyridine; bromine; at 0 - 20℃; for 16.0h;
[0123] 5-Hydroxy-2-methylpyridine (XXXXIII) (1.0 g, 9.16 mmol) was dissolved in 30 ml of pyridine. To the resulting solution was slowly added bromine (879 mg, 5.50 mmol) at 0 C and the solution was stirred at room temperature for 16 hrs. After pyridine was removed, the solution was extracted with 60 ml of ethylacetate (EA) and 60 ml of water. The organic layer was treated with magnesium sulfate (MgSO4), filtered, and concentrated for a next reaction.
4.8 g
With pyridine; bromine; at 20℃;Inert atmosphere;
To a solution of 6-methylpy din-3-ol (5, 45.8mmol) in Pyridine (15 ml) was added dropwise bromine (3.66g, 22.9). The mixture was strried overnight at rt under a nitrogen atmosphere. To the reaction mixture was added water (200 ml) and the mixture was extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (3x50 ml), dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 2-bromo-6-methylpyridin-3-ol (4.8g) as a light yellow solids 1 H NMR (400 MHz, CDCI3) delta 7.17 (d, J = 8Hz, 1 H), 7.09 (d, J = 8Hz, 2H), 2.40 (s, 3H)ppm
With iodine; sodium hydroxide; In water; at 20℃; for 16h;
Step A: 6-Methylpyridin-3-ol (0.5 g, 4.58 mmol) was dissolved in aqueous NaOH (4.5 mL, 1 M, 4.5 mmol). To the solution was added iodine (1.28 g, 5.2 mmol) and the mixture was stirred at room temperature overnight. The mixture was neutralized with aqueous HCl (2 M) to pH ?7. A white precipitate formed and was collected by filtration. The solid was washed with water and dried to give 2-iodo-6-methylpyridin-3-ol (0.8 g, 50%). MS m/z 236.0 [M+H]+.
43.9%
Sodium carbonate (68.0 g) and water (810 mL) were added to 5-hydroxy-2-methylpyridine (1-014-01) (36.11 g), and the reaction mixture was stirred at room temperature, dissolved. To the reaction mixture was added dropwise a solution of iodine (117 g) and potassium iodide (117 g) in water (810 mL) for 35 min. The resulting pink-yellow crystal was filtered and dried under reduced pressure to give 2-iodo-3-hydroxy-6-methylpyridine (2-014-01) (34.1 g, 43.9%, m.p. 187-190 C)1H-NMR (300MHz, CDCl3+CD3OD): delta 2.45 (s,3H), 6.45 (d, J = 6.9 Hz, 1H), 7.02 (dd, J = 6.6, 1.5 Hz, 1H)
43.9%
With iodine; sodium carbonate; potassium iodide; In water; at 20℃; for 0.583333h;
Sodium carbonate (68.0 g) and water (810 mL) were added to 5-hydroxy-2-methylpyridine (1-014-01) (36.11 g), and the reaction mixture was stirred at room temperature, dissolved. To the reaction mixture was added dropwise a solution of iodine (117 g) and potassium iodide (117 g) in water (810 mL) for 35 min. The resulting pink-yellow crystal was filtered and dried under reduced pressure to give 2-iodo-3-hydroxy-6-methylpyridine (2-014-01) (34.1 g, 43.9%, m.p. 187-190 DEG C)<1>H-NMR (300MHz, CDCl3+CD3OD): delta 2.45 (s,3H), 6.45 (d, J= 6.9 Hz, 1H), 7.02 (dd, J= 6.6, 1.5 Hz, 1H)
To a mixture of 6-methylpyridin-3-ol (235 g, 2.75 mol) and water (5.28 L) at 0 C. was added Na2CO3 (440 g, 5.5 mol) and the mixture was stirred at room temperature for 30 minutes. A solution of I2 (760 g, 3.85 mol) and KI (760 g, 5.83 mol) in water (5.28 L) was added dropwise to the reaction over a period of 1 hour. The mixture was stirred at room temperature for 3 hours and the resulting precipitate was collected by filtration to afford 2-iodo-6-methylpyridin-3-ol (390 g, 77.0%) as a yellow solid which was used without further purification.
8.19 g
With iodine; sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 72h;
To tetrahydrofuran / water (50 / 50mL) was added a mixed solution of pyridine-5 (6.458g, 60mmol), stirMix was added to the reaction flask followed by dissolution of iodine (16.8g, 66mmol), sodium bicarbonate (5.281g, 66mmol), at room temperature for 3 days, the reaction solution was dark purple solid separated, was added 10% sodium thiosulfate solution purple to disappear, there are a lot of white solid precipitated was suction-white solid 8.19g, was verified by NMRThe product 6.
With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 8h; Inert atmosphere;
77%
Stage #1: With potassium hydroxide In dimethyl sulfoxide for 1h;
Stage #2: 5-Hydroxy-2-methylpyridine; methyl iodide In dimethyl sulfoxide for 1h;
75%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 4h;
54%
Stage #1: 5-Hydroxy-2-methylpyridine With potassium hydroxide In dimethyl sulfoxide at 20℃; for 1h;
Stage #2: methyl iodide In dimethyl sulfoxide for 16h;
C.1
1) 5-Methoxy-2-methyl-pyridine 5-Hydroxy-2-methylpyridine (16.4 g, 150.3 mmol) was added to a suspension of KOH (34.6 g, 616 mmol) in DMSO (250 ml) and stirred for 1 h at r.t. followed by the dropwise addition of methyl iodide (10.3 ml, 165 mmol). The reaction mixture was stirred for a further 16 h, poored onto ice-cold water (500 ml) and extracted with diethyl ether (4*350 ml). The combined ether extracts were washed with water (50 ml), brine (50 ml) and dried (MgSO4). Filtration and concentration of the filtrate under reduced pressure gave a crude oil which was purified over silica gel (ethyl acetate/n-heptane 1:2 to 1:1): light brown oil 10.5 g (54%); 1H NMR (CDCl3) δ 2.49 (s, 3H), 3.82 (s, 3H),7.04-7.10 (m, 2H), 8.20 (d, 2H); MS: m/e=123.0 (M), 108.0 (M-CH3).
53%
Stage #1: 5-Hydroxy-2-methylpyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere;
Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere;
1 5.1.1 2-Methyl-5-methoxypyridine (10)
To a stirred suspension of NaH (60% dispersed in oil) (1.47 g, 36.8 mmol) in DMF (50 mL) at 0 °C under argon a solution of 5-hydroxy-2-methylpyridine (4.00 g, 36.7 mmol) in DMF (20 mL) was added slowly, then the reaction mixture was allowed to warm at room temperature. Methyl iodide (5.21 g, 36.7 mmol) was added to the reaction mixture which was stirred for 1 h. The reaction mixture was quenched by addition of isopropanol (20 mL), followed by H2O (20 mL) under argon. The reaction mixture was taken up in AcOEt and washed with aqueous NaHCO3, dried (Na2SO4) and concentrated in vacuo to give compound 10 as a pure liquid (2.40 g, 53% yield). 1H NMR (CDCl3): δ 2.49 (s, 3H), 3.83 (s, 3H), 7.05-7.16 (m, 2H), 8.19 (d, 1H, J = 2.8 Hz); GC/MS m/z 124 (M++1, 9) 123 (M+, 100), 108 (71), 80 (43).
36.8%
Stage #1: 5-Hydroxy-2-methylpyridine With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: methyl iodide In tetrahydrofuran at 0 - 20℃;
92 Example 92: Synthesis of compound 161
Potassium /-butoxide (43.19 g, 384.869 mmol) was added to 6-methylpyridin- 3-ol (40.00 g, 366.542 mmol) in THF (1.6 L) at 0 °C. The mixture was stirred at rt for 30 min. CH3I (54.63 g, 384.869 mmol) was added dropwise at 0 °C, and stirring was continued at rt for overnight. Water (500 mL) was added and the mixture was evaporated to half its volume and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA/PE (1/3) to give 5-methoxy-2-methylpyridine (17.5 g, 36.8%). 1H NMR (300 MHz, Methanol- cU) d 8.09 (d, J = 3.0 Hz, 1H), 7.33 (dd, J = 8.6, 3.0 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 2.46 (s, 3H). LCMS (ESI, m/z): 124 [M+H]+.
29%
Stage #1: 5-Hydroxy-2-methylpyridine With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: methyl iodide In tetrahydrofuran at 0 - 20℃;
5.1.44. 5-methoxy-2-methylpyridine (22)
To a suspension of 6-methylpyridin-3-ol (25.0 g, 229 mmol) inTHF (500 mL) was added potassium tert-butoxide (28.2 g,252 mmol) portionwise at 0 °C. After 30 min, iodomethane(15.7 mL, 252 mmol) was added and the mixture was stirred overnight. To the mixture was added water and the solvent was removed in vacuo. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silicagel, eluted with 50% EtOAc in hexane) to give 8.20 g (29%) of 22 as pale orange oil. 1H NMR (300 MHz, CDCl3) d 2.49 (3H, s), 3.83 (3H,s), 7.02-7.15 (2H, m), 8.20 (1H, d, J = 2.6 Hz).
With potassium hydroxide In dimethyl sulfoxide
With potassium hydroxide In methanol; dichloromethane; dimethyl sulfoxide
A.f (f)
(f) 5-Methoxy-2-methylpyridine 150 ml of 3-hydroxy-6-methylpyridine are metered into a solution of 84 g of potassium hydroxide in 400 ml of methanol and 500 ml of dimethyl sulphoxide in the course of one hour. After removal of the methanol on a rotary evaporator, 213 g of methyl iodide, dissolved in 100 ml of dimethyl sulphoxide, are added dropwise, while cooling with ice, and the reaction mixture is stirred at 20° C. for 15 hours and subjected to steam distillation. The distillate is extracted continuously in the extractor with methylene chloride and the extract is concentrated. 85 g (56% of theory) of 5-methoxy-2-methylpyridine are obtained as a colourless oil.
With potassium hydroxide In methanol; dichloromethane; dimethyl sulfoxide
f (f)
(f) 5-Methoxy-2-methylpyridine 150 ml of 3-hydroxy-6-methylpyridine are metered into a solution of 84 g of potassium hydroxide in 400 ml of methanol and 500 ml of dimethyl sulfoxide in the course of one hour. After removal of the methanol on a rotary evaporator, 213 g of methyl iodide, dissolved in 100 ml of dimethyl sulfoxide, are added dropwise, while cooling with ice, and the reaction mixture is stirred at 20° C. for 15 hours and subjected to steam distillation. The distillate is extracted continuously in the extractor with methylene chloride and the extract is concentrated. 85 g (56% of theory) of 5-methoxy-2-methylpyridine are obtained as a colorless oil.
With sodium hydroxide; NaH In <i>N</i>-methyl-acetamide; hexane; chloroform; N,N-dimethyl-formamide
9 EXAMPLE 9
EXAMPLE 9 To sodium hydride (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3X, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3X). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5-methoxy-2 -methylpyridine.
With sodium hydroxide; NaH In <i>N</i>-methyl-acetamide; hexane; chloroform; N,N-dimethyl-formamide
9 EXAMPLE 9
EXAMPLE 9 To sodium hydroxide (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3*, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3*). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5 -methoxy-2-methylpyridine.
Stage #1: 5-Hydroxy-2-methylpyridine With sodium hydride In dimethyl sulfoxide at 0℃; for 0.916667h;
Stage #2: methyl iodide In dimethyl sulfoxide at 20℃; for 2.25h;
9.1
1) 5-Methoxypyridine-2-carboxylic acid N-methoxy-N-methylamide Under an argon atmosphere, a solution of 5-hydroxy-2-methylpyridine (30.0 g) in dimethylsulfoxide (200 mL) cooled to 0°C was added dropwise to a suspension of sodium hydride (55% in oil, 12.6 g) in dimethylsulfoxide (100 mL) over 20 minutes, and then the resultant mixture was stirred for 35 minutes. At the same temperature, methyl iodide (18.0 mL) was added dropwise to the reaction solution over 15 minutes, and the mixture was stirred for 2 hours at room temperature. Water and diethyl ether were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and 5-methoxy-2-methylpyridine (18.7 g) was obtained. To a solution of this crude product (18.7 g) in pyridine (187 mL), selenium dioxide (33.7 g) was added, and the mixture was heated to reflux for 62 hours. After air cooling, water and chloroform were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and 5-methoxypyridine-2-carboxylic acid (19.1 g) was obtained. To a suspension of the crude product thus obtained (19.1 g), N, O-dimethylhydroxyamine hydrochloride (16.3 g), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (32.1 g) and 1-hydroxybenzotriazole (22.6 g) in dichloromethane (250 mL), triethylamine (46.6 mL) was added at 0°C, and the mixture was stirred for 30 minutes, and then stirred for 14 hours at room temperature. Water and chloroform were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform), to obtain 5-methoxypyridine-2-carboxylic acid N-methoxy-N-methylamide (15.3 g, 51%) as an oily product. 1H-NMR(400MHz, CDCl3)δ: 3.44 (3H, s), 3.79-3.84 (3H, m), 3.91(3H, s), 7.24-7.28(1H, m), 7.75(1H, d, J=8.5Hz), 8.30(1H, d, J=2.9Hz). FAB-MSm/z: 197(M+H)+.
With potassium hydroxide In dimethyl sulfoxide for 1h;
7
EXAMPLE 7 ; 2-ϖ.r-biphenyl-4-ylVN-[ϖR)-l-(5-methoxypyridin-2-yl)ethvnacetainide; 5-methoxy-2-methylpyridine:; To a suspension of potassium hydroxide (113g, 2mol) in DMSO(800ml) was added 53.9g, (0.49mol) 5-hydroxy-2-methylpyridine and the mixture stirred for Ih. To this was added CH3I (34ml, 0.55mol) and the reaction mixture was stirred for one hour, then poured into water (2400ml) and extracted with ether (1000ml X 5). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to provide 5- methoxy-2-methylpyridine as a yellow oil. 1H NMR: (400MHz5 CDCl3) δ 8.19 (d. J=2.8Hz, IH)5 7.14 (dd5 J=8.8, 3.8Hz, IH)5 7.08 (d, J=8.4Hz, IH)5 3.83 (s, 3H)5 2.65 (s, 3H).
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
(Reference Example 7) Synthesis of 2-((6-methylpyridin-3-yl)oxy)ethylamine dihydrochloride To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (49.9 g, 310 mmol) and 4-dimethylaminopyridine (42 g, 340 mmol) in dichloromethane (500 mL) was slowly added tosyl chloride (59 g, 310 mmol) under ice-cooling. The mixture was allowed to cool to room temperature, stirred for 15 hr, washed with water and saturated brine, and concentrated to give 2-((tert-butoxycarbonyl)amino)ethyl 4-methyl benzenesulfonate (98 g). 66 g (209 mmol) of these was dissolved in DMF (500 mL), 5-hydroxy-2-methylpyridine (22.8 g, 209 mmol) and cesium carbonate (102 g, 314 mmol) were added, and the mixture was stirred at 100C for 2 hr. The reaction mixture was allowed to cool to room temperature, poured into cool water, and extracted with ethyl acetate three times. The organic layer was washed with saturated brine, and concentrated to give crystals (35 g). The crystals were washed with tert-butyl-methyl ether to give tert-butyl (2-((6-methylpyridin-3-yl)oxy)ethyl)carbamate (24.5 g) as white crystals. The crystals were treated with 2N-HCl/Dioxane solution (140 ml) at room temperature, and the obtained insoluble substance was collected by filtration to give the object compound of 2-((6-methylpyridin-3-yl)oxy)ethylamine dihydrochloride (17.6 g). 1H-NMR(300MHz, DMSO-d6)δ(ppm) : 8.49(d,1H), 8.42(br-s,2H), 8.05(dd,1H), 7.78(d,1H), 4.40(t,2H)3.23-3.13(m,2H)
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃;
Example A33 <strong>[4110-35-4]3,5-dinitro-benzonitrile</strong> (3 g, 16 mmol), 6-methylpyridin-3-ol (1.7 g, 16 mmol), and K2CO3 (4.3 g, 31 mmol) were dissolved in DMF and heated to 110 C. overnight. The reaction mixture was poured into water and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to provide 3-(6-methylpyridin-3-yloxy)-5-nitrobenzonitrile (3 g, 76% yield). 1H NMR (400 MHz, DMSO) delta 8.50 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.59-7.56 (d, J=10 Hz, 1H), 7.38-7.36 (d, J=8.4 Hz, 1H), 1.98 (s, 3H); MS (ESI) m/z; 256.3 [M+H]+.
76%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃;
<strong>[4110-35-4]3,5-dinitro-benzonitrile</strong> (3 g, 16 mmol), 6-methylpyridin-3-ol (1.7 g, 16 mmol), and K2CO3 (4.3 g, 31 mmol) were dissolved in DMF and heated to 1 10 C overnight. The reaction mixture was poured into water and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried (Na2S04), concentrated in vacuo and purified by silica gel chromatography to provide 3-(6- methylpyridin-3-yloxy)-5-nitrobenzonitrile (3 g, 76% yield ). FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO) delta 8.50 (s, 1 H), 8.38 (s, 1 H), 8.08 (s, 1 H), 8.01 (s, 1 H), 7.59-7.56 (d, J = 10 Hz, 1 H), 7.38-7.36 (d, J = 8.4 Hz, 1 H), 1.98 (s, 3 H); MS (ESI) m/z: 256.3 [M+H]+.
Multi-step reaction with 2 steps
1.1: 91 percent / NaH / dimethylformamide; various solvent(s) / 0 °C
2.1: m-chloroperbenzoic acid / CHCl3 / 0 - 20 °C
2.2: 55 percent / 0.67 h / 120 °C
Multi-step reaction with 3 steps
1: 82 percent / NaH / tetrahydrofuran; dimethylformamide / 20 °C
2: 96 percent / meta-chloroperoxybenzoic acid / CHCl3 / 1 h / cooling
3: 77 percent / 0.5 h / 130 °C
Multi-step reaction with 3 steps
1.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C
1.2: 16 h / 0 - 20 °C
2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2.5 h / 0 °C
3.1: 0.5 h / 130 °C
Multi-step reaction with 3 steps
1.1: tetrabutylammomium bromide; potassium hydroxide / tetrahydrofuran / 0.17 h / 20 °C
1.2: 48 h / 20 °C
2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 16 h / 20 °C
3.1: Reflux
Synthesis Example 3 Synthesis of Exemplified Compound No. 2 6-methyl-2-amino-pyridin-3-ol [8] was obtained from 6-methyl-pyridin-3-ol [6] in a total yield of 26% by a known method described in a document.
Stage #1: 5-Hydroxy-2-methylpyridine With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 0.5h;
Stage #2: With methyl iodide In tetrahydrofuran at 0 - 20℃; for 8h;
4; 4
Potassium tert-butoxide (5.4 g, 48 mmol) was added to 3-methyl-pyridin-3-ol (5 g, 45.87 mmol) in THF (200 mL) at 0° C. The mixture was stirred at room temperature for 30 min. MeI (3.2 mL, 48 mmol) was added dropwise at 0° C. and stirring was continued at room temperature for 8 h. Water was added and the mixture was evaporated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography to give 5-methoxy-2-methyl-pyridine (4.8 g, 85%).
With sodium methylate In <i>N</i>-methyl-acetamide; hexane
43.b b
b 3-Methoxy-6-methylpyridine A solution of 3-hydroxy-6-methylpyridine (2.5 g), sodium methoxide (1.36 g) and phenyltrimethylammonium chloride (4.33 g) in dry dimethylformamide (25 ml) was heated at reflux under argon for 2.5 h. The mixture was allowed to cool then stirred at room temperature overnight. Insoluble material was removed by filtration and washed with ethanol. The filtrate was acidified with 6M hydrochloric acid and the solvent was removed in vacuo. The residue was then diluted with water, basified with 2M sodium hydroxide and extracted with ether. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The crude product was purified by column chromatography on silica gel eluding with 3% ethyl acetate in hexane (1.55 g, 55%). MS (ES) 124 (M+H)+. 1H NMR (CDCl3) 8.19 (1H, d), 7.10 (1H, dd), 7.05 (1H, d), 3.83 (3H, s), 2.48 (3H, s).
7.1 Step 1
Step 1 5-Methoxy-2-picoline Sodium hydride (3.6 g, 150 mmol) was added portionwise to 5-hydroxy-2-picoline (15.0 g, 137 mmol) in DMF (120 mL). After 30 min., CH3 I (10.2 mL, 156 mmol) was added and the mixture stirred 2 hours at r.t. Water was added and the compound was extracted with Et2 O (3*). The organic extracts were washed with brine (2*), dried over Na2 SO4 and concentrated in vacuo to give 6.7 g of the title compound.
With potassium carbonate at 180℃; for 0.05h; Microwave;
MW = 460.48 ; MS(+1) = 461.1, MS(-l) = 459.0, MS(+Na) = 483.1 was prepared by replacing trifluoromethanesulfonic acid 2,2,2-trifluoro-1-(R»S)-phenylethyl ester with trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-(3 -hydroxy-6-methyl-pyridin-2-yl)-ethyl ester prepared as described below.[0218] 6-Methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyridin-3-ol was prepared by a modification of a procedure detailed in J. Heterocyclic Chetn., 38, 25 (2001), p 25 by replacing traditional heating with microwave heating as follows. EPO Step l[0219] A mixture of commercially available 6-methylpyridin-3-ol (500 mg), trifluoroacetaldehyde methylhemiacetal (715 mg) and potassium carbonate (69 mg) was heated in a microwave reactor at 180 °C for 3 min. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using 1 : 1 hexane: ethyl acetate and recrystallized from ethyl acetate and hexane to give 627 mg of 6-methyl-2-(2,2,2- trifluoro-1-hydroxyethyl)pyridin-3-ol.
Stage #1: 5-Hydroxy-2-methylpyridine With sodium hydride In N,N-dimethyl-formamide for 0.5h; Cooling with ice;
Stage #2: benzyl chloride In N,N-dimethyl-formamide at 20℃; for 12h;
11.1
Sodium hydride (4.76 g, 119 mmol) was added to a dimethylformamide solution (100 ml) of 6-methylpyridin-3-ol (10.0 g, 91.6 mmol) under ice cooling, and this mixture was stirred for 30 minutes, follwed by adding benzyl chloride (12.7 ml, 110 mmol) to the mixture and stirring it for 12 hours at room temperature. Water and a saturated saline solution (1 :1) and ethyl acetate were added to this reaction solution, and the solution was extracted. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:l to 1 :2) to obtain 5-(benzyloxy)- 2-methylpyridine (16.4 g, yield: 90%) as an orange-colored product.
In <i>N</i>-methyl-acetamide; mineral oil
1 EXAMPLE 1
Other starting materials may be prepared as follows: The solution of 32.7 g of 2-methyl-5-hydroxy-pyridine in 300 ml of dimethylformamide is added to a suspension of 12.8 g of sodium hydride (57% mineral oil dispersion) in 150 ml of dimethylformamide, with stirring. Then the mixture is heated to 100° and maintained at 100° for 18 hours. After that, the mixture is cooled to room temperature and to the cooled mixture is added a solution of 49.8 g of benzyl chloride in 100 ml of dimethylformamide over a period of 30 minutes. The mixture is then refluxed for 7 hours, cooled and then evaporated to a residue. The residue is partitioned between water and ether, the layers are separated and the water layer extracted with ether. The ether layer is combined with ether extract, dried over sodium sulfate, filtered and the ethereal filtrate is distilled off. The residue is distilled to yield 5-benzyloxy-2-methyl-pyridine, boiling at 100°-102°/0.02 mm/Hg.
With potassium carbonate In N,N-dimethyl acetamide at 90℃; for 5h;
1
The 2-[5-(6,7-dimethoxyquinazolin-4-yloxy)pyridin-2-yl]acetic acid used as a starting material was prepared as follows :-A mixture of 5-hydroxy-2-methylpyridine (100 g), benzyl chloride (116 ml), potassium carbonate (177.2 g) and DMA (1.5 litres) was stirred and heated to 900C for 5 hours. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica using an increasingly polar solvent gradient of mixtures of petroleum ether and ethyl acetate (95:5 up to 1:1) as eluent. There was thus obtained 5-benzyloxy-2-methylpyridine (135.6 g); 1H NMR: (CDCl3) 2.5 (s, 3H), 5.1 (s, 2H), 7.05 (d, IH), 7.15 (m, IH), 7.4 (m, 5H), 8.25 (d, IH).
With potassium carbonate In ISOPROPYLAMIDE at 90℃; for 5h;
1 N-(1-ethylpyrazol-4-yl)-2-[5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl]acetamide
A mixture of 5-hydroxy-2-methylpyridine (100 g), benzyl chloride (116 ml), potassium carbonate (177.2 g) and DMA (1.5 litres) was stirred and heated to 90° C. for 5 hours. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica using an increasingly polar solvent gradient of mixtures of petroleum ether and ethyl acetate (95:5 up to 1:1) as eluent. There was thus obtained 5-benzyloxy-2-methylpyridine (135.6 g); 1H NMR: (CDCl3) 2.5 (s, 3H), 5.1 (s, 2H), 7.05 (d, 1H), 7.15 (m, 1H), 7.4 (m, 5H), 8.25 (d, 1H).
In N,N-dimethyl-formamide at 0 - 20℃;
8.1
Reference Example 8: Production of 6-(methoxymethyl)pyridin-3-ol: (Step 1) Production of 5-benzyloxy-2-methylpyridine: 3-Hydroxy-6-methylpyridine (140 g) was dissolved in dimethylformamide (1.4 L), and with cooling with ice, benzyl chloride (178 ml) was added to it, and stirred overnight at room temperature. The reaction liquid was poured into water with ice, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate = 40/1 to 2/1) to obtain the entitled compound as an orange oil.
Compound c-8
Group C compound Compound c-8 A solution of 5-hydroxy-2-methylpyridine (2.18 g, 20 mmol) in DMF (15 ml) was combined with benzylbromide (4.00 g, 24 mmol) and calcium carbonate (3.30 g, 24 mmol) under ice-cooling and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was combined with an aqueous ammonium chloride, extracted with diethyl ether,washed with water, and dried. The solvent was evaporated, and the residue was subjected to a column chromatography on a silica gel, and the fraction eluted with n-hexane-ethyl acetate was concentrated to obtain a 5-benzyloxy-2-methylpyridine (2.04 g).
4-(3-chlorpyridyl-5-oxy)-2,5-dimethylnitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate; In N,N-dimethyl-formamide; for 2h;Heating / reflux;
4-(3-chlorpyridyl-5-oxy)-2,5-dimethylnitrobenzene - compound of formula (IV); 2.00 g (10.78 mmol) of <strong>[34633-69-7]4-chloro-2,5-dimethylnitrobenzene</strong>, 1.29 g (11.86 mmol) of 3- hydroxy-6-methylpyridine and 1.93 g (14.01 mmol) of potassium carbonate were suspended in 10 ml of DMF. The reaction mixture was refluxed for 2h, cooled down to room temperature, treated with 100 ml of water and 50 ml of a 2N solution of sodium hydroxide in water and extracted with dichloromethane (2x 100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with cyclohexane/ethyl acetate to yield the title compound in94% yield (2.9, 95% purity); log P (pH 2.3) = 3.61.1H NMR delta(ppm) 2.30 (s, 3H, CH3), 2.42 (s, 3H, CH3), 2.58 (s, 3H, CH3), 6.79 (m, 1 H, aryl- H), 7.32 (m, 1 H, aryl-H), 7.43 (m, 1 H, aryl-H), 8.04 (m, 1 H, aryl-H), 8.29 (m, 1 H, aryl-H),
With potassium carbonate In N,N-dimethyl-formamide at 90 - 140℃; for 22h;
16
Reference Example 16; 2-methyl-5- (3-nitrophenoxy) pyridine; A mixture of 6-methylpyridin-3-ol (17.6 g, 161 mmol) , 1- fluoro-3-nitrobenzene (25.0 g, 177 mmol), potassium carbonate(66.8 g, 483 mmol) and N,N-dimethylformamide (200 mL) was stirred at 9O0C for 13 hr, 1200C for 5 hr and 1400C for 4 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (x3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (28.6 g, 77%) as a yellow oil. 1H-NMR (DMSO-de, 300 MHz) δ 2.50 (3H, s) , 7.35 (IH, d, J = 8.4 Hz), 7.48 - 7.55 (2H, m) , 7.65 - 7.72 (2H, m) , 7.97 - 8.01 (IH, m) , 8.35 (IH, d, J = 3.0 Hz) .
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h;
21
EXAMPLE 21 Preparation of 1H-indole-3-carboxylic acid[6-(6-methyl-pyridine-3-yloxy)-pyridine-3-yl]-amide 6-methylpyridine-3-ol (1.0 g, 9.16 mmol) was dissolved in is DMF (20 ml), and the solution was stirred with NaH (230 mg, 9.6 mmol) and 2-chloro-5-nitro pyridine (1.45 g, 9.16 mmol) at room temperature for 1 hour. Subsequently, the product was filtered, washed, and dried under reduced pressures to yield a solid product (2.08 g, 98%). The solid product (1.0 g, 4.32 mmol) was added to a mixed solution of ethanol (80 ml) and conc. hydrochloric-acid (20 ml), SnCl2 (2.9 g, 15.12 mmol) was added to the mixture, and the resulting solution was stirred at 50° C. for 1 hour. And then the product was filtered, washed, and dried to prepare 6-(6-methylpyridine-3-yloxy)-pyridine-3-amine (0.73 g, 84%).
98%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h;
21
6-methylpyridine-3-ol (1.0 g, 9.16 mmol) was dissolved in DMF (20 m), and the solution was stirred with NaH (230 mg, 9.6 mmol) and 2-chloro-5-nitro pyridine (1.45 g, 9.16 mmol) at room temperature for 1 hour. Subsequently, the product was filtered, washed, and dried under reduced pressures to yield a solid product (2.08 g, 98 %).
98%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h;
21
6-methylpyridine-3-ol (1.0 g, 9.16 mmol) was dissolved in DMF (20 ), and the solution was stirred with NaH (230 , 9.6 mmol) and 2-chloro-5-nitro pyridine (1.45 g, 9.16 mmol) at room temperature for 1 hour. Subsequently, the product was filtered, washed, and dried under reduced pressures to yield a solid product (2.08 g, 98 %).
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;
With potassium carbonate; In acetone; at 20℃; for 20h;
K2CO3 (113 mg, 0.82 mmol) was added to a solution of 2-bromo-l-(2,4,6-trimethyl- phenyl)-ethanone (100 mg, 0.41 mmol) and 5-hydroxy-2-methylpyridine (45 mg, 0.41 mmol) in acetone (5 mL) at room temperature. The reaction was stirred for 2Oh at room temperature then was quenched by addition of water. The extraction was conducted with EtOAc (x2) then the organic phase was washed with brine and dried over MgSO4. The crude residue was the purified by flash chromatography (DCM/MeOH 0-5% gradient) to give the expected compound (62.7 mg, 57%) as yellow oil. TLC single spot at R/ 0.46 (DCM/MeOH 9:1); 1H NMR (270 MHz, CDCl3): delta 2.22 (6H, s), 2.27 (3H, s), 2.46 (3H, s), 4.86 (2H, s), 6.84 (2H, s), 7.02 (IH, d, J = 8.3 Hz), 7.11 (IH, dd, J = 2.8, 8.5 Hz), 8.16 (IH, d, J = 2.8 Hz); LC/MS (APCI) m/z 270 (M+ +H); HPLC tr = 1.84 min (100%) in 10% water-acetonitrile.
Sodium hydride (25.6 g, 60percent dispersion in oil, 0.64 mol) was added portionwise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40°C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and <strong>[455-88-9]2-fluoro-5-nitrotoluene</strong> (91.3 g, 0. 59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80°C for 3 hours and then cooled. The solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and then dried over MGS04. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 30percent ethyl acetate in petroleum ether) to give 2-methyl-5- (2-methyl-4-nitrophenoxy) pyridine (141 g, 98percent) as an oil; NMR spectrum (CDC13) ; 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 8.32 (s, 1H).
98%
Example 51; 2-1[4-(13-Methyl-4-[(6-methylpyridin-3-yl)oxyjphenyllamino)quinazolin-5- yl] oxy} acetamide; A mixture of 1[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} amino)quinazolin-5-yl]oxy} acetic acid (120 mg, 0.27 mmol), diisopropylethylamine (72 mul, 0.4 mmol) and HATU (155 mg, 0.41 mmol) was stirred at 50 °C for 18 hours. After cooling, gaseous ammonia was bubbled through the mixture for 15 minutes. After evaporation of the solvents in vacuo, the residue was triturated with water. The pH of the solution was adjusted to 8 by addition of 5percent aqueous sodium bicarbonate solution. The resultant beige precipitate was filtered, washed with water and ether and dried over P205 under high vacuum. The precipitate was stirred in ethyl acetate for 1 hour, filtered and dried under high vacuum at 50 °C to give the title compound as a beige solid (140 mg, 78percent); NMR spectrum: (400 MHz; DMSO-d6 + CF3C02D) 2.29 (s, 3H), 2.71 (s, 3H), 5.01 (s, 2H), 7.24 (d, 1H), 7.30 (d, 1H), 7.48 (d, 1H), 7.86 (m, 1H), 7.93 (m, 2H), 8.09 (m, 2H), 8.74 (s, 1H), 8.96 (s, 1H); Mass spectrum: MH+ 416; The [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5- yl] oxy}acetic acid used as starting material was obtained as follows: Sodium hydride (25.6 g, 60percent dispersion in oil, 0.64 mol) was added portionwise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40 °C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and <strong>[455-88-9]2-fluoro-5-nitrotoluene</strong> (91.3 g, 0.59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80 °C for 3 hours, then cooled. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over MgS04. After evaporation of the solvents, the residue was purified by chromatography on silica gel eluting with 30percent ethyl acetate in petroleum ether to give 2-methyl-5-(2-methyl-4- nitrophenoxy) pyridine as an oil (141 g, 98percent) ; NMR spectrum: (400 MHz; CDC13) 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 8.32 (s, 1H); A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10percent palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. The mixture was then purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline as a white solid (120.6 g, 98percent) ; Mass spectrum: MH+ 215. 3-Methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5- fluoroquinazoline (obtained as described in Example 1, preparation of starting materials, 5 g, 27.5 mmol) in acetonitrile (100 ml). The mixture was stirred at 80 °C for 2 hours. After cooling, the precipitate was washed with acetonitrile. This precipitate was partitioned between DCM and 5percent aqueous sodium bicarbonate solution and the pH was adjusted to 8. The organic layer was washed with brine and dried over MgS04. Evaporation of the solvents gave 5-fluoro-N {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl] quinazolin-4- amine as a dark gum (9.3 g, 94percent) which crystallised on standing; NMR spectrum: (400 MHz; CDCl3) 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H), 8.37 (d, 1H), 8.71 (s, 1H); A mixture of 5-fluoro-N- {3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (10.8 g, 30 mmol) and sodium methoxide (4.86 g, 90 mmol) in methanol (250 ml) was heated at reflux for 16 hours. After cooling and evaporation of the solvents, the residue was dissolved in dichloromethane. This solution was washed with water and brine and dried over MgS04. Evaporation of the solvents gave 5-methoxy-N- {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine as a white solid (10.7 g, 96percent) ; NMR spectrum: (400 MHz; CDC13) 2.29 (s, 3H), 2.53 (s, 3H), 4.12 (s, 3H), 6.92 (m, 2H), 7.12 (m, 2H), 7.48 (d, 1H), 7.55 (d, 1H), 7.63 (m, 2H), 8.27 (s, 1H), 8.64 (s, 1H), 9.78 (bs, 1H); A mixture of 5-methoxy-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (10.04 g, 27 mmol) and pyridine hydrochloride (12.42 g, 108 mmol) in pyridine (100 ml) was heated at reflux for 2 hours. After cooling and evaporation of the solvents, the residue was triturated in 5percent aqueous sodium bicarbonate and the resulting mixture was stirred for 30 minutes. The yellowish precipitate was filtered, washed with water and ether, and dried over P205 under high vacuum to give 5- hydroxy-N- {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (9.3 g, 96percent) ; NMR spectrum: (400 MHz) 2.20 (s, 3H), 2.44 (s, 3H), 6.71 (m, ...
98%
Sodium hydride (25.6 g, 60percent dispersion in oil, 0.64 mol) was added portion-wise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40°C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and <strong>[455-88-9]2-fluoro-5-nitrotoluene</strong> (91.3 g, 0.59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80°C for 3 hours and then cooled. The solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 30percent ethyl acetate in petroleum ether) to give 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine as an oil (141 g, 98percent); NMR spectrum (CDCl3): 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, IH), 7.21 (d, IH), 7.27 (d, IH), 8.00 (d, IH), 8.17 (s, IH), 8.32 (s, IH).
94%
To a DMF suspension (60 mL) of sodium hydride (1.39 g, 60percent in mineral oil) was slowly added a DMF solution (40 mL) of 5-HYDROXY-2-METHYLPYRIDINE (3.80 g, 34.8 MMOL) dropwise, keeping the temp < 5 °C. The ice bath was removed, and the contents allowed to warm with stirring for 60 min. To the light yellow colored contents was added a DMF SOLUTION OF 2-FLUORO-5-NITROTOLUENE (4.50 g, 29.0 MMOL) dropwise, and the contents heated to 95°C, overnight. The dark brown contents were removed from heating, and allowed to cool to rt with stirring. The mixture was quenched with water (5 mL), and concentrated in vacuo. The residue was diluted with water (100 mL) and EtOAc (75 mL). The layers were separated, and the aq. layer extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine (2X50 mL), dried over MGS04, filtered and concentrated in vacuo to collect the 2-Methyl-5- (2-methyl-4-nitro-phenoxy)-pyridine as a yellow oil (7.0 g, 94percent). The solution of 2-Methyl-5- (2-methyl-4-nitro-phenoxy)-pyridine (6.4 g, 26.2 MMOL), 10WTpercent Pd/C (0.50 g) in ethanol (100 mL) was stirred under 1 atm hydrogen at rt for 24 h. Then the Pd/C catalyst was removed by filtration through a layer of celite. Removal of the solvent gave the desired product as an off-white solid (5.55g, 99percent).'H-NMR (DMSO-d6) 8 8. 04 (d, J = 2. 7 HZ, 1 H), 7.13 (d, J = 5. 4 HZ, 1 H), 7.02 (dd, J = 8.7, 3.1 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1 H), 6.49 (d, J = 2.6 Hz, 1 H), 6.42 (DD, J = 8.4, 2.8 Hz, 1 H), 4.96 (br, 2H), 2.39 (s, 3H), 1.97 (s, 3H). LCMS RT = 1.04 min; [M+H] + = 215.2.
80%
With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 4h;
A mixture of <strong>[455-88-9]1-fluoro-2-methyl-4-nitrobenzene</strong> (1 g, 6.4 mmol), 6-methylpyridin-3-ol (0.77 g, 7.09 mmol), CS2CO3 (2.5 g, 7.7 mmol) and N-N-dimethylformamide (10 mL) was heated to 110° C. for 4 hours. The reaction mixture was cooled to room temperature and then quenched with water, extracted with ethyl acetate (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and dried under vacuum to give 1.2 g (80percent). 1H NMR 400 MHz (DMSO-d6): delta 8.33 (d, J=3.2 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.06 (m, 1H), 7.52 (m, 1H), 7.33 (m, 1H), 6.86 (d, J=9.2 Hz, 1H) 2.50 (s, 3H), 2.39 (s, 3H); MS (ES) m/e 245 [M+1]+.
The 5- (1, 3-dioxolan-2-ylmethoxy)-2-methylpyridine used as starting material was prepared as follows:- To a stirred solution of 2-methyl-5-hydroxypyridine (16.0 g, 0.147 mole) in dry DMF (100 mL) at 25C was added portionwise sodium hydride (60% dispersion in oil, 6.0 g, 0.15 mole) during 10 minutes. To the mixture was added 2-bromomethyl-1, 3-dioxolane (16. 0 mL, 0.154 mole) and the resulting mixture heated at 100C for 12 hours, cooled to 25C and diluted with ice/water (400 g). The product was extracted into diethyl ether (400 mL), dried over anhydrous magnesium sulphate, and the solvent evaporated at reduced pressure to give the title compound as an oil (25 g, 87%) ; NMR Spectrum: (CDCl3) 2.50 (s, 3H), 3.94-4. 04 (m, 6H), 5.27 (t, 1H), 7.05 (d, 1H), 7.15 (dd, 1H), 8.22 (d, 1H) ; Mass Spectrum : M+H+ 196.
With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 4h;
Step A: 5-(2-methyl-4-nitrophenoxy)-2-methylpyridine (compound 12.1) [0139] The mixture of l-chloro-2-methyl-4-nitrobenzene (17.2 g), 6-methylpyridin-3-ol (12 g) and Cs2CO3 (39 g) in DMF (150 mL) was heated at 110 0C for 4h. The solid was filtered and water (100 mL) and EtOAc (200 mL) were added. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained yellow solid was used for the next step directly.
methyl 3-bromo-5-fluoro-4-((6-methylpyridin-3-yl)oxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5 g
With potassium carbonate at 85℃; for 18h;
Intermediate 19: Methyl 3-bromo-5-fluoro-4- 6-methylpyridin-3-yl)oxy)benzoate
Intermediate 19: Methyl 3-bromo-5-fluoro-4- 6-methylpyridin-3-yl)oxy)benzoate To a stirred solution of methyl 3-bromo-4,5-difluorobenzoate (4.5 g) in DMF (30 mL), was added 6-methylpyridin-3-ol (2.15 g, 19.7 mmol, Alfa) and K2C03 (2.48 g, 17.9 mmol) and the mixture heated at 85 °C for 18 h The reaction mixture was quenched with ice water (10ml), and extracted with ethyl acetate (2 x 100 ml), washed with brine solution (2 x 100ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the title compound (5.0 g) as a colorless liquid. (0294) LCMS Method B: m/z [M+H]+ 340, tR 0.98 min.
methyl 3-bromo-5-fluoro-4-((5-methylpyrazin-2-yl)oxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 g
With potassium carbonate In acetonitrile at 20℃; for 18h;
Intermediate 47: methyl 3-bromo-5-fluoro-4-((5-methylpyrazin-2-yl) oxy)benzoate
Intermediate 47: methyl 3-bromo-5-fluoro-4-((5-methylpyrazin-2-yl) oxy)benzoate To a stirred solution of methyl 3-bromo-4,5-difluorobenzoate (3.0 g, 12.0 mmol) in acetonitrile (50 mL), was added 6-methylpyridin-3-ol (1.45 g, 17.9 mmol, IS Pharma) and K2C03 (2.478 g, 17.93 mmol) and the mixture stirred at RT for 18 h .The reaction mixture was treated with water (100 ml), and extracted with ethyl acetate (3 x 100ml). The organic layers were washed with brine solution (150 ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the crude title compound (4 g). The crude compound was purified by column chromatography using silica gel 100-200 mesh, eluting with 15% EtOAc/hexane. The product containing fractions were combined and concentrated under reduced pressure to give the title compound (1.0 g) as a white solid. (0430) ^ NMR (400 MHz, DMSO d6) δ: 8.67 (1H, s), 8.10 (1H, d), 8.06 (1H, s,), 7.96-7.93 (1H, m), 3.90 (3H, s), 2.47 (3H, s)
With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.5h;
General procedure: To a vigorously stirred solution of 2-chloro-6-hydroxypyridine(0.13 g, 1.0 mmol) in acetonitrile (2 mL) at room temperature was added a 6 M aqueous solution of potassium hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwiseto the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water(20 mL) and extracted with diethyl ether (2 ×10 mL) and ethyl acetate(3 ×10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethylether (100:0 to 70:30) as eluent to afford the pure title compound
With caesium carbonate; In dimethyl sulfoxide; at 130℃; for 17h;
Compound (III-1) (5.46 g, 28.4 mmol) and compound (II-2) (3.25 g, 29.8 mmol) were dissolved in DMSO (20mL), cesium carbonate (13.9 g, 42.5 mmol) was added and the mixture was stirred at 130C for 17 hr. The reactionmixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethylacetate = 90:10 ?40:60) to give compound (IV-6) (yield 7.30 g, 97%) as a yellow oil
97%
With caesium carbonate; In dimethyl sulfoxide; at 130℃; for 17h;
Compound (III-1) (5.46 g, 28.4 mmol) and compound (II-2) (3.25 g, 29.8 mmol) were dissolved in DMSO (20 mL)Cesium carbonate (13.9 g, 42.5 mmol) was added,Followed by stirring at 130 C. for 17 hours. The reaction solution was cooled,Water was added and extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine,After drying with anhydrous sodium sulfate, filtration was carried out.After distilling off the solvent under reduced pressure,The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 ? 40: 60),Compound (IV-6)(Yield 7.30 g, Yield 97%)As a yellow oil.
Multi-step reaction with 2 steps
1: hydrogenchloride; chlorine / water / 68 - 74 °C
2: methanol; sodium methylate / 72 h / 150 °C
Multi-step reaction with 2 steps
1: [bis(acetoxy)iodo]benzene / 0.25 h / 20 °C / Inert atmosphere
2: palladium on activated carbon; hydrogen / methanol / 20 h / 20 °C
4,5-bis(4′-methylpyridin-3′-yloxy)phthalonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;
4,5-Dichlorophthalonitrile (1.0g, 5.3mmol) and 13 5-hydroxy-2-methylpyridine (1.4g, 12.4mmol) were dissolved in 15mL of dry 14 N,N-dimethylformamide at 80C under N2. 15 Potassium carbonate (4.5g, 32.6mmol) was added to the reaction solution in 5 portions every 5min. The reaction mixture was heated for 3h at 80C, then cooled to room temperature, and poured into 100mL of 16 ice-water. The title compound was extracted for the reaction liquid using 50mL of 17 CHCl3 at 3 times. After filtration under vacuum, the 18 title compound was obtained as a white powder. Yield, 1.8g (97% (based on 4,5-Dichlorophthalonitrile)). Anal. Calc. for C20H14N4O2: C; 70.17, H; 4.12, N; 16.37. Found: C; 69.93, H; 4.21, N; 16.08%. HR-MS (ESI-TOF): Found 343.1190m/z. [M+H]+ (calcd. for C20H14N4O2 343.1191). 1H NMR (CD2Cl2): delta=8.31 (s, 2H, Ar-H), 7.34 (d, 2H, J=8.4Hz, Ar-H), 7.26 (d, 2H, J=8.4Hz, Ar-H), 7.23 (s, 2H, Ar-H), and 2.57ppm (s, 6H, CH3).
With L-Selectride In tetrahydrofuran for 24h; Reflux; Inert atmosphere; chemoselective reaction;
Demethylation of Methoxypyridines; General Procedure:
General procedure: Toa solution of 1 (1.00 mmol) in THF (7.0 mL) was added L-selectride(1 M in THF, 3.0 mL, 3.00 mmol, 3 equiv) under an argonatmosphere. After being refluxed and monitored by TLC, thereaction mixture was quenched with MeOH and evaporated invacuo. The residue was purified by silica gel column chromatographyto give the desired compound 2.
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 120℃; for 0.333333h;Microwave irradiation;
Di-/er/-butyl azodicarboxylate (CAS: 870-50-8; 240.6 mg, 1.05 mmol) was added to a mixture of (2V,4//)-/<2/7-butyl 4-hydroxy-2-methylpiperi dine- 1-carboxylate (CAS: 790667-91-3; 150 mg, 0.70 mmol), 5-hydroxy-2-methylpyridine (CAS: 1121-78-4; 76 mg, 0.70 mmol) and triphenylphosphine (274.1 mg, 1.05 mmol) in THF (1.5 mL) at 0 C, and the resulting reaction mixture was stirred in a microwave oven at 120 C for 20 min. Then, the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiC , EtOAc in heptane 0/100 to 70/30). The desired fractions were collected and concentrated in vacuo to yield intermediate 4, contaminated with triphenylphosphine oxide, as a colorless oil, which was used in next step without further purification.
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