* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium carbonate In methanol at 20℃; for 2 h;
2-Chloro-5-acetoxypyridine (21.66 g, 126 mmol) was dissolved in 300 mL of methanol and K2CO3(8.70 g, 63 mmol) was added. The reaction was stirred at room temperature for approx. 2 h, then concentrated in vacuo. The residue was diluted with diethyl ether and water, and the aqueous layer was adjusted to neutral pH by the addition of 1N aqueous HCl. Following extraction with diethyl ether, the organics were combined, washed with a solution of saturated aqueous NaCl, dried with MgSO4, and concentrated in vacuo. The resulting yellow solid (15.58 g, 96percent) was used without further purification.
96%
With hydrogenchloride; potassium carbonate In methanol
11b. 2-chloro-5-hydroxypyridine 5-Acetoxy-2-chloropyridine (11.1 g, 64.7 mmol) from step 11a was dissolved in MeOH at ambient temperature and solid potassium carbonate (4.47 g, 32.4 mmol) was added. After stirring for 2 h, the volatiles were removed in vacuo and the residue was diluted with Et2 O and H2 O. The aqueous phase was neutralized to pH 7 by the addition of 1 N aqueous HCl. The layers were separated and the aqueous phase was extracted twice with Et2 O. The combined organic extracts were dried (MgSO4) and concentrated to provide the title compound as a white solid (8.03 g, 96percent): mp 155° C.; 1 H NMR (CD3 OD, 300 MHz) δ 7.20-7.28 (m, 2H), 7.88 (m, 1H); MS (CI/NH3) m/z: 130,132 (M+H)+; 147,149 (M+NH4)+.
91%
at 20℃; for 20 h;
3) 2-Chloro-5-hydroxypyridine; Potassium carbonate (400 mg) was added to a solution of the 5-acetoxy-2-chloropyridine (10 g) in methanol (200 ml), and the mixture was stirred at room temperature for 20 hours. The reaction solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (ethyl acetate) to give 2-chloro-5-hydroxypyridine (6.86 g, 91percent) as a solid. 1H-NMR (400 MHz, DMSO-d6)δ: 7.24 (1H, dd, J = 8.8, 2.9 Hz), 7.29 (1H, d, J = 8.8 Hz), 7.91 (1H, d, J = 2.9 Hz), 10.22 (1H, br). LC-MSm/z: 130 (M+H)+.
82%
With potassium carbonate In methanol at 20℃; for 2 h;
To a solution of acetic acid 6-chloro-pyridin-3-yl ester (1.67 g, 9.8 MMOL) in methanol (10 mL) was added potassium carbonate (676 mg, 4.9 MMOL), and the resulting reaction stirred at ambient temperature for 2 hours. The reaction was concentrated to an oily solid which was partitioned between water and diethyl ether. The water layer was neutralized with 3N HCI (3.7 mL), and extracted with diethyl ether (1X). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the above named compound as a tan solid (1.04 g, 82percent).
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 5, p. 876 - 880
12
[ 462-34-0 ]
[ 41288-96-4 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 5, p. 876 - 880
13
[ 41288-96-4 ]
[ 74-88-4 ]
[ 139585-48-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium methylate In methanol; N,N-dimethyl-formamide at 20℃; for 1.5 h;
4) 2-Chloro-5-methoxypyridine; To a solution of the 2-chloro-5-hydroxypyridine (1.30 g) and methyl iodide (1.25 ml) in N,N-dimethylformamide (26 ml) was added dropwise 28percent solution of sodium methoxide in methanol (2.0 ml), and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction liquid, then the phases were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (hexane-ethyl acetate) to give 2-chloro-5-methoxypyridine (1.40 g, 98percent) as a solid. 1H-NMR (400 MHz, CDCl3)δ: 3.85 (3H, s), 7.17-7.25 (2H, m), 8.05 (1H, d, J = 2.9 Hz). LC-MSm/z: 144 (M+H)+.
84%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere
Example 7; Synthesis of 1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one (compound No. 430); Step 1; 2-chloro-5-methoxy-pyridine; Under a nitrogen atmosphere, potassium carbonate (5.52 g) was added to a mixture of 2-chloro-5-hydroxy-pyridine (2.591 g), methyl iodide (1.50 ml) and dimethylformamide (26 ml), and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added ethyl acetate and the mixture was placed in a separatory funnel. The organic layer was washed 4 times with aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.403 g, 84percent).1H-NMR (CDCl3) δ: 8.07 (1H, d, J=3.0 Hz), 7.24 (1H, dd, J=8.8, 0.7 Hz), 7.20 (1H, dd, J=8.6, 3.0 Hz), 3.87 (3H, s).
Reference：
[1] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 24
[2] Patent: US2010/240634, 2010, A1, . Location in patent: Page/Page column 74
[3] European Journal of Inorganic Chemistry, 2015, vol. 2015, # 28, p. 4666 - 4677
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2462 - 2471
[5] Chemische Berichte, 1992, vol. 125, # 5, p. 1131 - 1140
14
[ 41288-96-4 ]
[ 89809-63-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2462 - 2471
15
[ 41288-96-4 ]
[ 188057-26-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
With iodine; sodium carbonate In water at 20℃; for 48 h;
A solution of the above material (15.48 g, 119 mmol) and Na2CO3 (26.56 g, 251 mmol) in water (300 mL) was charged with iodine (30.3 g, 119 mmol). The reaction mixture was stirred at room temperature until the iodine color disappeared, approx. 48 h. The solution was adjusted to pH =5 with 1 N aqueous HCl, and extracted with ethyl acetate. The organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting white solid was recrystallized from methanol to provide 17.8 g (95percent) of the title compound. MS(m/e): 256 (M+); Calculated for C5H3ClINO: Theory: C, 23.51; H, 1.18; N, 5.48; Found: C, 23.72; H, 1.19; N, 5.45.
94%
With iodine; sodium carbonate In water at 25℃; for 2 h; Inert atmosphere
To a stirred solution of 2-chloro-5-hydroxypyridine (6.0 g, 46.3 mmol) in H20 (80 mL) were added Na2C03 (10.3 g, 97.3 mmol) and I2 (11.8 g, 46.3 mmol). The resulting mixture was stirred at 25 °C under N2 for 2 h. Then it was neutralized by HC1 (1M, aprox. 50 mL) to pH=7 and extracted with EtOAc (3x110 mL). The organic extracts were washed with brine (150 mL), dried over Na2S04, filtered, and the solvent was evaporated. The product was obtained as a pale yellow solid (11.1 g, 94 percent). 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H); 7.30 (d, J = 8.40 Hz, 1H); 7.18 (d, J = 8.40 Hz, 1H). I3C NMR (126 MHz, DMSO-d6) S 153.9, 138.1, 124.0, 123.9, 107.7. HRMS (APCI): calcd. for C5H4C1IN0 [M+H]+ = 255.9021; found [M+H]+ = 255.9018
75%
With iodine; sodium carbonate In tetrahydrofuran; water at 20℃; for 4 h;
Step 1: 6-chloro-2-iodopyridin-3-ol To solution of 6-chloro-pyridin-3-ol (112 g, 868 mmol) in THF (800 mL)/Water (800 mL) was added sodium carbonate (92.0 g, 1.736 mol;) and iodine (244.2 g, 1.04 mol;). The reaction mixture was stirred rt 4 h. The aqueous layer containing product was separated and washed with hexane (400 mL.x.2). The aqueous layer was neutralized to pH=7 with HCl and then extracted EtOAc (500 mL.x.4). The combined organic layers were dried over Na2SO4, and filtered. The filtrate was concentrated to the crude product, which was washed with EtOAc to afford 163 g of 6-chloro-2-iodopyridin-3-ol, yield: 75percent. 1H NMR (DMSO, 400 MHz): δ11.13 (s, 1H, OH), 7.31 (dd, J=8.4, 12.8 Hz, 2H).
70.9%
With iodine; sodium carbonate In water at 20℃; for 2 h; Inert atmosphere
6-chloropyridin-3-ol (5.0 g, 38.60 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.37 mmol) was added followed by iodine (9.8 g, 38.81 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into 1 M Na25203 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2504 and concentrated to give the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9percent). ‘H-NMR (CDC13, 400 MHz) 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J 8.4 Hz, 1H). MS (M+H): 256 /258.
70.9%
With iodine; sodium carbonate In water at 20℃; for 2 h; Inert atmosphere
Step 12-Synthesis of 6-chloro-2-iodopyridin-3-ol 6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to provide the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9percent). 1H-NMR (CDCl3, 400 MHz) δ 7.17 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H). MS (M+H)+: 256/258.
70.9%
With iodine; sodium carbonate In water at 25℃; for 2 h; Inert atmosphere
6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2C03 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol) The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S203 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04 and concentrated to give the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9percent). 1H- MR (CDC13, 400 MHz) δ 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H). MS (M+H)+: 256 / 258.
70.9%
With iodine; sodium carbonate In water at 20℃; for 2 h; Inert atmosphere
6-chloropyridin-3-ol (5.0 g, 38.60 mmol) was dissolved in water (50 mL) andplaced under an N2 atmosphere. Na2C03 (8.2 g, 77.37 mmol) was added followed by iodine (9.8g, 38.81 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture waspoured into 1 M Na2S20 3 and extracted with EtOAc. The combined organic phases were washedwith brine, dried over Na2S04 and concentrated to give the product of 6-chloro-2-iodopyridin-3-20 ol (7.0 g, yield: 70.9percent). 1H-NMR (CDCh, 400 MHz) 8 7.17 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4Hz, 1H). MS (M+Ht: 256 /258.
70.9%
With iodine; sodium carbonate In water at 20℃; for 2 h; Inert atmosphere
Compound 1 (5.0 g, 38.60 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.37 mmol) was added followed by iodine (9.8 g, 38.81 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into 1M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the product of Compound 2 (7.0 g, yield: 70.9percent). 1H-NMR (CDCl3, 400 MHz) d 7.17 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H).
2.04 g
With iodine; sodium carbonate In tetrahydrofuran; water at 20℃; for 1.5 h;
Reference Example 15 [Step a] To a mixed solution of compound 1 (1.00 g, 7.71 mmol) and sodium carbonate (1.71 g, 16.2 mmol) in tetrahydrofuran (5.00 mL) and water (5.00 mL) was added iodine (2.94 g, 16.2 mmol) in 3 portions at room temperature, and the mixture was stirred for 1.5 hr. The reaction solution was neutralized with 1 M-hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2 (2.04 g). MS(ESI)m/z: 256 (M+1)+
Reference：
[1] Tetrahedron Letters, 2003, vol. 44, # 4, p. 725 - 728
[2] Patent: US6696439, 2004, B1, . Location in patent: Page column 20
[3] Patent: WO2015/165428, 2015, A1, . Location in patent: Page/Page column 18
[4] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1227 - 1238
[5] Patent: US2011/76291, 2011, A1, . Location in patent: Page/Page column 148
[6] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
[7] Patent: WO2014/123793, 2014, A1, . Location in patent: Page/Page column 37
[8] Patent: US2014/213571, 2014, A1, . Location in patent: Paragraph 0802
[9] Patent: WO2014/121418, 2014, A1, . Location in patent: Page/Page column 36
[10] Patent: WO2014/121416, 2014, A1, . Location in patent: Page/Page column 37
[11] Tetrahedron Letters, 2017, vol. 58, # 14, p. 1373 - 1375
[12] Patent: EP3135667, 2017, A1, . Location in patent: Paragraph 0434-0435
[13] Patent: WO2004/39753, 2004, A2, . Location in patent: Page 85
16
[ 41288-96-4 ]
[ 497-19-8 ]
[ 188057-26-3 ]
Reference：
[1] Patent: US6001849, 1999, A,
17
[ 41288-96-4 ]
[ 100-39-0 ]
[ 84611-43-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 18 h;
6-chloropyridin-3-ol (1.0 g),Benzyl bromide (1.5 g) and potassium carbonate (2.4 g)Was dissolved in DMF (40 mL) and stirred at 60 ° C. for 18 hours.After filtering the reaction solution,The solvent of the obtained filtrate was distilled off under reduced pressure to obtain a residue,Purification by silica gel column chromatography (hexane-ethyl acetate)5- (benzyloxy) -2-chloropyridine1.3 g (yield quant.) Was obtained.
79%
With caesium carbonate In N,N-dimethyl-formamide
Example 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79percent). mp <50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6 H), 5.19 (s, 2H).
79%
With caesium carbonate In N,N-dimethyl-formamide
Example 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79percent). mp<50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
79%
With caesium carbonate In N,N-dimethyl-formamide
EXAMPLE 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79percent). mp <50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
79%
With caesium carbonate In N,N-dimethyl-formamide
EXAMPLE 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79percent). mp <50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
79%
With caesium carbonate In N,N-dimethyl-formamide
Example 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79percent). mp<50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6 H), 5.19 (s, 2H).
8000 mg
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h;
To a mixture of A-36 (5 g, 38.6 mmol) and K2C03 (10.65 g, 77.2 mmol) in DMF (40 mL) was added bromomethylbenzene (5.04 mL, 42.46 mmol). The reaction mixture was heated to 60 °C and stirred for 16 hours. After cooling, the mixture was diluted with H20 (150 mL), and the mixture was extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (80 mL), dried over Na2SC>4, filtered and concentrated to afford A-37 (8000 mg, 36.42 mmol), which was used directly in next step. 1H NMR (CDC13, 400MHz) δH = 8.14 (d, 1H), 7.44 - 7.34 (m, 5H), 7.26 - 7.21 (m, 2H), 5.11 (s, 2H).
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 25, p. 7450 - 7465
20
[ 41288-96-4 ]
[ 1206972-45-3 ]
Reference：
[1] Patent: US2015/307465, 2015, A1,
21
[ 41288-96-4 ]
[ 75-03-6 ]
[ 856851-48-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 40℃; for 2 h;
To a stirred solution of 6-chloropyridin-3-ol (3.0 g, 23.2 mmol) in N,N-dimethylformamide (30 mL) was added iodoethane (4.33 g, 27.8 mmol, 2.22 mL), and potassium carbonate (9.60 g, 69.6 mmol) at 0°C. The reaction was warmed and stirred at 40 00 for 2 h. The reaction mixture was quenched by addition of water (30 mL) then the mixture was extracted with ethyl acetate (60 mL x 3). The combined organicphases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine (3.30 g, 20.9 mmol, 90 percent) as a yellow solid. 1H NMR (400 MHz, ODd3) O 7.97(d, J2.9 Hz, 1H), 7.17- 7.07(m, 2H), 3.99 (q, J7.0 Hz, 2H), 1 .36 (t, J7.0 Hz, 3H).
Reference：
[1] Patent: WO2013/127268, 2013, A1,
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 18, p. 8345 - 8368
23
[ 41288-96-4 ]
[ 1885-46-7 ]
[ 1206980-28-0 ]
Yield
Reaction Conditions
Operation in experiment
74%
With potassium hydroxide In water; acetonitrile at 20℃; for 0.5 h;
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
Reference：
[1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165
24
[ 41288-96-4 ]
[ 75-46-7 ]
[ 1206980-28-0 ]
Yield
Reaction Conditions
Operation in experiment
48%
Stage #1: With potassium hydroxide In water for 0.5 h; Stage #2: at 20℃; for 3 h;
General procedure: Using an apparatus previously described for method B [21] , potassium hydroxide (2.52 g, 45 mmol, 15 equiv) and water (2.52 g) were added to the reaction vessel and the mixture was allowed to stir until the potassium hydroxide was almost completely dissolved. Then, 2-bromo-3-pyridinol (0.354 g, 3 mmol) was added and the mixture stirred for 30 min, after which acetonitrile (10 mL) was added via syringe and the mixture stirred at room temperature. Fluoroform was then bubbled slowly into the mixture for 2 h, after which the resulting mixture was stirred for one additional hour. After being quenched with water and extracted with ethyl acetate, the ethyl acetate layer was washed with a saturated solution on sodium hydroxide, separated and concentrated. Additional impurities were removed via column chromatography on silica gel using an 80:20 mixture of hexanes/methylene chloride to give a 53percent yield of the liquid product, 2-bromo-3-difluoromethoxypyridine (3d):
Reference：
[1] Journal of Fluorine Chemistry, 2014, vol. 168, p. 34 - 39
25
[ 41288-96-4 ]
[ 1206980-28-0 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 6, p. 2075 - 2084
With sodium methylate; In methanol; N,N-dimethyl-formamide; at 20℃; for 1.5h;
4) 2-Chloro-5-methoxypyridine; To a solution of the <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (1.30 g) and methyl iodide (1.25 ml) in N,N-dimethylformamide (26 ml) was added dropwise 28% solution of sodium methoxide in methanol (2.0 ml), and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction liquid, then the phases were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (hexane-ethyl acetate) to give 2-chloro-5-methoxypyridine (1.40 g, 98%) as a solid. 1H-NMR (400 MHz, CDCl3)delta: 3.85 (3H, s), 7.17-7.25 (2H, m), 8.05 (1H, d, J = 2.9 Hz). LC-MSm/z: 144 (M+H)+.
84%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;
Example 7; Synthesis of 1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one (compound No. 430); Step 1; 2-chloro-5-methoxy-pyridine; Under a nitrogen atmosphere, potassium carbonate (5.52 g) was added to a mixture of <strong>[41288-96-4]2-chloro-5-hydroxy-pyridine</strong> (2.591 g), methyl iodide (1.50 ml) and dimethylformamide (26 ml), and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added ethyl acetate and the mixture was placed in a separatory funnel. The organic layer was washed 4 times with aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.403 g, 84%).1H-NMR (CDCl3) delta: 8.07 (1H, d, J=3.0 Hz), 7.24 (1H, dd, J=8.8, 0.7 Hz), 7.20 (1H, dd, J=8.6, 3.0 Hz), 3.87 (3H, s).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 4h;
First Step Synthesis of 2-Chloro-5-((1-(tert-butoxycarbonyl))-2-(R)-azetidinylmethoxy)pyridine To a solution (2.5 mL) of diisopropyl azodicarboxylate (0.19 mL, 1.0 mmol) in tetrahydrofuran, triphenylphosphine (0.26 g, 1.0 mmol) was added at 0 C., and the resulting mixture was kept at 0 C. and stirred. Half an hour later, 1-(tert-butoxycarbonyl)-2-(R)-azetidinylmethanol (0.19 g, 1.0 mmol) and 6-chloropyridin-3-ol (0.13 g, 1.0 mmol) were added thereto, and the resultant was stirred at room temperature. Four hours later, the reaction solution was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 70/30) to obtain the title compound (0.27 g; 90%) as a yellow liquid. 1H-NMR (400 MHz, CDCl3) delta: 1.41 (9H, s), 2.23-2.40 (2H, m), 3.87-3.91 (2H, m), 4.09-4.14 (1H, m), 4.28-4.37 (1H, m), 4.47-4.54 (1H, m), 7.21-7.28 (2H, m), 8.10 (1H, d, J=3.6 Hz).MS (ESI) [M+H]+ [0047] 299
With potassium carbonate; In methanol; at 20℃; for 2h;
2-Chloro-5-acetoxypyridine (21.66 g, 126 mmol) was dissolved in 300 mL of methanol and K2CO3(8.70 g, 63 mmol) was added. The reaction was stirred at room temperature for approx. 2 h, then concentrated in vacuo. The residue was diluted with diethyl ether and water, and the aqueous layer was adjusted to neutral pH by the addition of 1N aqueous HCl. Following extraction with diethyl ether, the organics were combined, washed with a solution of saturated aqueous NaCl, dried with MgSO4, and concentrated in vacuo. The resulting yellow solid (15.58 g, 96%) was used without further purification.
96%
With hydrogenchloride; potassium carbonate; In methanol;
11b. 2-chloro-5-hydroxypyridine 5-Acetoxy-2-chloropyridine (11.1 g, 64.7 mmol) from step 11a was dissolved in MeOH at ambient temperature and solid potassium carbonate (4.47 g, 32.4 mmol) was added. After stirring for 2 h, the volatiles were removed in vacuo and the residue was diluted with Et2 O and H2 O. The aqueous phase was neutralized to pH 7 by the addition of 1 N aqueous HCl. The layers were separated and the aqueous phase was extracted twice with Et2 O. The combined organic extracts were dried (MgSO4) and concentrated to provide the title compound as a white solid (8.03 g, 96%): mp 155 C.; 1 H NMR (CD3 OD, 300 MHz) delta 7.20-7.28 (m, 2H), 7.88 (m, 1H); MS (CI/NH3) m/z: 130,132 (M+H)+; 147,149 (M+NH4)+.
91%
With methanol; potassium carbonate; at 20℃; for 20h;
3) 2-Chloro-5-hydroxypyridine; Potassium carbonate (400 mg) was added to a solution of the 5-acetoxy-2-chloropyridine (10 g) in methanol (200 ml), and the mixture was stirred at room temperature for 20 hours. The reaction solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (ethyl acetate) to give 2-chloro-5-hydroxypyridine (6.86 g, 91%) as a solid. 1H-NMR (400 MHz, DMSO-d6)delta: 7.24 (1H, dd, J = 8.8, 2.9 Hz), 7.29 (1H, d, J = 8.8 Hz), 7.91 (1H, d, J = 2.9 Hz), 10.22 (1H, br). LC-MSm/z: 130 (M+H)+.
82%
With potassium carbonate; In methanol; at 20℃; for 2h;
To a solution of acetic acid 6-chloro-pyridin-3-yl ester (1.67 g, 9.8 MMOL) in methanol (10 mL) was added potassium carbonate (676 mg, 4.9 MMOL), and the resulting reaction stirred at ambient temperature for 2 hours. The reaction was concentrated to an oily solid which was partitioned between water and diethyl ether. The water layer was neutralized with 3N HCI (3.7 mL), and extracted with diethyl ether (1X). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the above named compound as a tan solid (1.04 g, 82%).
With acetic acid; In aqueous KOH;
2-chloro-5-hydroxypyridine Scale: 16.5 g, 96.2 mmol Method: 2-chloro-5-acetoxypyridine (16.5 g, 96.2 mmol) was dissolved in 2M aqueous KOH solution (125 ml) with ice-bath cooling. The resulting solution was stirred at 4 C. for 3 hours after which time the reaction was judged complete by tlc. The reaction mixture was neutralised by the addition of acetic acid (approx. 10 ml) whereupon a white solid appeared. The product was collected on a Buchner funnel and dried under high vacuum at 40 C. Yield=11.9 g (96%) Rf=0.21 (10% Et2O/CH2Cl2) 1H-NMR (300 MHz, d6-DMSO): d=7.2 (m, 2H), 7.87 (d, 1H). MS (ESP+): m/e 130/2 (M+H)+. Found: C, 46.3; H, 3.1; N, 10.7; C5H4ClNO requires: C, 46.4; H, 3.11; N, 10.8%.
With iodine; sodium carbonate; In water; at 20℃; for 48h;
A solution of the above material (15.48 g, 119 mmol) and Na2CO3 (26.56 g, 251 mmol) in water (300 mL) was charged with iodine (30.3 g, 119 mmol). The reaction mixture was stirred at room temperature until the iodine color disappeared, approx. 48 h. The solution was adjusted to pH =5 with 1 N aqueous HCl, and extracted with ethyl acetate. The organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting white solid was recrystallized from methanol to provide 17.8 g (95%) of the title compound. MS(m/e): 256 (M+); Calculated for C5H3ClINO: Theory: C, 23.51; H, 1.18; N, 5.48; Found: C, 23.72; H, 1.19; N, 5.45.
94%
With iodine; sodium carbonate; In water; at 25℃; for 2h;Inert atmosphere;
To a stirred solution of <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (6.0 g, 46.3 mmol) in H20 (80 mL) were added Na2C03 (10.3 g, 97.3 mmol) and I2 (11.8 g, 46.3 mmol). The resulting mixture was stirred at 25 C under N2 for 2 h. Then it was neutralized by HC1 (1M, aprox. 50 mL) to pH=7 and extracted with EtOAc (3x110 mL). The organic extracts were washed with brine (150 mL), dried over Na2S04, filtered, and the solvent was evaporated. The product was obtained as a pale yellow solid (11.1 g, 94 %). 1H NMR (500 MHz, DMSO-d6) delta 11.10 (s, 1H); 7.30 (d, J = 8.40 Hz, 1H); 7.18 (d, J = 8.40 Hz, 1H). I3C NMR (126 MHz, DMSO-d6) S 153.9, 138.1, 124.0, 123.9, 107.7. HRMS (APCI): calcd. for C5H4C1IN0 [M+H]+ = 255.9021; found [M+H]+ = 255.9018
75%
With iodine; sodium carbonate; In tetrahydrofuran; water; at 20℃; for 4h;
Step 1: 6-chloro-2-iodopyridin-3-ol To solution of 6-chloro-pyridin-3-ol (112 g, 868 mmol) in THF (800 mL)/Water (800 mL) was added sodium carbonate (92.0 g, 1.736 mol;) and iodine (244.2 g, 1.04 mol;). The reaction mixture was stirred rt 4 h. The aqueous layer containing product was separated and washed with hexane (400 mL×2). The aqueous layer was neutralized to pH=7 with HCl and then extracted EtOAc (500 mL×4). The combined organic layers were dried over Na2SO4, and filtered. The filtrate was concentrated to the crude product, which was washed with EtOAc to afford 163 g of 6-chloro-2-iodopyridin-3-ol, yield: 75%. 1H NMR (DMSO, 400 MHz): delta11.13 (s, 1H, OH), 7.31 (dd, J=8.4, 12.8 Hz, 2H).
70.9%
With iodine; sodium carbonate; In water; at 20℃; for 2h;Inert atmosphere;
6-chloropyridin-3-ol (5.0 g, 38.60 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.37 mmol) was added followed by iodine (9.8 g, 38.81 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into 1 M Na25203 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2504 and concentrated to give the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9%). ?H-NMR (CDC13, 400 MHz) 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J 8.4 Hz, 1H). MS (M+H): 256 /258.
70.9%
With iodine; sodium carbonate; In water; at 20℃; for 2h;Inert atmosphere;
Step 12-Synthesis of 6-chloro-2-iodopyridin-3-ol 6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to provide the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H-NMR (CDCl3, 400 MHz) delta 7.17 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H). MS (M+H)+: 256/258.
70.9%
With iodine; sodium carbonate; In water; at 25℃; for 2h;Inert atmosphere;
6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2C03 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol) The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S203 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04 and concentrated to give the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H- MR (CDC13, 400 MHz) delta 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H). MS (M+H)+: 256 / 258.
70.9%
With iodine; sodium carbonate; In water; at 20℃; for 2h;Inert atmosphere;
6-chloropyridin-3-ol (5.0 g, 38.60 mmol) was dissolved in water (50 mL) andplaced under an N2 atmosphere. Na2C03 (8.2 g, 77.37 mmol) was added followed by iodine (9.8g, 38.81 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture waspoured into 1 M Na2S20 3 and extracted with EtOAc. The combined organic phases were washedwith brine, dried over Na2S04 and concentrated to give the product of 6-chloro-2-iodopyridin-3-20 ol (7.0 g, yield: 70.9%). 1H-NMR (CDCh, 400 MHz) 8 7.17 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4Hz, 1H). MS (M+Ht: 256 /258.
70.9%
With iodine; sodium carbonate; In water; at 20℃; for 2h;Inert atmosphere;
Compound 1 (5.0 g, 38.60 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.37 mmol) was added followed by iodine (9.8 g, 38.81 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into 1M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the product of Compound 2 (7.0 g, yield: 70.9%). 1H-NMR (CDCl3, 400 MHz) d 7.17 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H).
2.04 g
With iodine; sodium carbonate; In tetrahydrofuran; water; at 20℃; for 1.5h;
Reference Example 15 [Step a] To a mixed solution of compound 1 (1.00 g, 7.71 mmol) and sodium carbonate (1.71 g, 16.2 mmol) in tetrahydrofuran (5.00 mL) and water (5.00 mL) was added iodine (2.94 g, 16.2 mmol) in 3 portions at room temperature, and the mixture was stirred for 1.5 hr. The reaction solution was neutralized with 1 M-hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2 (2.04 g). MS(ESI)m/z: 256 (M+1)+
With iodine; sodium carbonate; In water; at 20℃; for 72h;
6-CHLORO-3-PYRIDINOL (2. 0g, 15. 44MMOL) was stirred in water (40MOI) containing sodium carbonate (3.43g, 32. 36MMOL) and iodine (3.92g, 15. 44MMOL) was added. The mixture was stirred at room temperature for 72 hours. The pH was adjusted to pH8 with 1 M hydrochloric acid solution and the mixture extracted with ethyl acetate (*2). The combined organic extracts were washed with brine and DRIED (MGSO4). The aqueous layer was acidified to pH5 with 1 M hydrochloric acid solution and extracted with ethyl acetate, which was washed with brine, dried (MGS04) and the combined solutions evaporated to leave the title compound as a buff solid (3.70g). 1H NMR (CDCl3) delta: 7.18 (1H, d, J=2.5Hz), 7.31 (1H, d, J=2.5Hz), 9.53 (1H, brs).
Preparation 9; 2-Chloro-5-methoxymethoxy -pyridine; Suspend sodium hydride (3.7 g, 93 mmol) in DMF (50 mL) and add a solution of <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (10 g, 77 mmol) in DMF (20 mL) dropwise over 45 min. Stir the resulting solution at room temperature for 1.5 hours. Add chloromethylmethyl ether (6.6 mL, 86 mmol) dropwise over 45 min. Stir the resulting mixture at room temperature for 12 hours. Dilute the mixture with ethyl acetate, water, and saturated aqueous sodium chloride. Isolate the organic solution and wash with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 330 g of silica gel eluting with a gradient from hexane to 30 % ethyl acetate in hexane over 20 min and then hold at 30 % ethyl acetate in hexane for 30 min to give the title compound (10.8 g, 81 %) as a clear oil. MS (ES) m/z 174.0 [MH-I]+.
81%
Preparation 582-Chloro-5-methoxymethoxy -pyridineSuspend sodium hydride (3.7 g, 93 mmol) in DMF (50 mL) and add a solution of <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (10 g, 77 mmol) in DMF (20 mL) dropwise over 45 min. Stir the resulting solution at RT for 1.5 h. Add chloromethylmethyl ether (6.6 mL, 86 mmol) dropwise over 45 min. Stir the resulting mixture at RT for 12 h. Dilute the mixture with ethyl acetate, water, and saturated aqueous sodium chloride. Isolate the organic solution and wash with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 330 g of silica gel eluting with a gradient from hexane to 30 % ethyl acetate in hexane over 20 min and then hold at 30 % ethyl acetate in hexane for 30 min to give the title compound 10.8 g (81 %) as a clear oil. MS (ES) m/z 174.0 [M+lf.
80%
N,N-Dimethylformamide (25 mL) was added to suspend 503 sodium hydride (60% in oil, 1.8 g, 45mmol), and a solution of 504 <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (5.0 g, 39 mmol) in 107 N,Ndimethylformamide(10 mL) was slowly added dropwise over 45 min. The reaction mixture was stirred atroom temperature for 1.5 hr, 505 chloromethylmethylether (3.3 mL, 43 mmol) was added dropwise over10 min, and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added 57ethyl acetate and the mixture was washed successively with water and saturated brine. The organic layer wasdried over sodium sulfate, and the desiccant was filtered off. The solvent was evaporated and the obtainedresidue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the 506title compound ( 5.4 g , 31 mmol, 80%). MS (ESI) m/z 174 (M+H)+ 1H NMR (400 MHz, CDCl3) delta 8.17 (d, J=2.8 Hz, 1H), 7.36 (dd, J=2.8, 9.2 Hz, 1H), 7.24 (d, J=9.2 Hz,1H), 5.18 (s, 2H), 3.46 (s, 3H) .
With potassium carbonate; In acetone; at 20℃; for 3h;
Add chloro-methoxy-methane (3.3 mL, 44 mmol) to a suspension of 2-chloro-5 -hydroxy- pyridine (4.75 g, 36.7 mmol) and K2CO3 (10.0 g, 73.4 mmol) in acetone at room temperature dropwise and stir the mixture at room temperature for 3 hours. Concentrate and partition the mixture between EtOAc and water. Dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 15% EtOAc/hexanes to give the title compound.
Sodium hydride, 60% dispension in mineral oil (3:2, Sodium hydride:Mineral Oil, 2.32 g) was added portion wise to a solution of 6-Chloro-pyridin-3-ol (5.00 g, 38.6 mmol) in a mixture of Tetrahydrofuran (10.0 mL, 123 mmol) and N,N-Dimethylformamide (20.0 mL, 258 mmol). The mixture formed was stirred for 15 min and Chloromethyl Methyl Ether (3.66 mL, 48.2 mmol) was added dropwise. The above mixture was stirred for 6 hours (monitored by LCMS), poured into water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum. Purified on 40 g silica column eluting with 10-40% ethyl acetate in heptane to give 6.33 g of 2-chloro-5-(methoxymethoxy)pyridine.
3 g
2-Chloro-5-hydroxy-pyridine (3 g, 30.9 mmol) in DMF (5 ml.) was added to a cold (0C) solution of NaH (1.5 g, 37.1 mmol) in DMF (20 ml_). The mixture was stirred at 0C for 1 h. Chloromethyl methyl ether (4.95 g, 60.8 mmol) was added. The reaction mixture was allowed to warm to rt, stirred overnight, cooled to 0C, quenched by addition of water, and extracted with EtOAc. The organic layer was dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, 98:2) to afford 3 g of the title compound. tR: 0.56 min (LC-MS 2); ESI-MS: 174.0 [M+H]+(LC-MS 2); Rf= 0.67 (hexane/ethyl acetate, 1 :1 ).
2.8 g
To a solution of 6-chloropyridin-3-ol (2 g, 15.439 mmol) in DMF (10 mL) was added NaH (0.960 g, 23.200 mmol) under nitrogen atmosphere at 0 C. The reaction mixture was stirred at 0 C for 30 min. Then, to this reaction mixture was added a solution of chloro(methoxy)methane (1.62 g, 20.121 mmol) in DMF (2 mL) dropwise. This reaction mixture was stirred at 0 C for 30 min. The progress of reaction was monitored by TLC. After completion reaction, the mixture was quenched with ice- cold water (20 mL), extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (2x75 mL) and brine (75 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-chloro-5- (methoxymethoxy)pyridine (2.8 g) as a brown liquid
4.16 g
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
To a solution of 6-chloropyridin-3-ol (5.0 g, 38.5 mmol) and N,N-diisopropylethylamine (9.92 g, 76.9 mmcl) in anhydrous DCM (120 mL) at 0 C under an atmosphere of nitrogen wasadded methyl chloromethyl ether (6.15 g, 76.9 mmol) dropwise. The resulting mmxture was allowed to warm to room temperature overnight. The reaction mixture was extracted with DCM and washed with sat NaHCO3 several times. The organic phase was combined, washed with brine, dried over Na2SO4 and concentrated in vacuum to give the crude product which was purified by column eluting with PE/EtOAc (10:1 to 7:1) to give the title compound (4.16 g, 63%) as yellow oil.1H NMR (300 MHz, CDCI3): 8.15 (d, J 2.7 Hz, 1H), 7.34 (dd, J = 8.4, 3.0 Hz 1H) 7.21 (d, J= 9.0 Hz, 1H), 5.16 (s, 2H), 3.47 (s, 3H).LC-MS: (mobile phase: from 90% water (0.02% NH4Ac) and 10% CH3CN to 5% water (0.02%NH4Ac) and 95% CH3CN in 6.5 mm, purity is >95%, Rt = 3.642 mm; MS Calcd.:173, MSFound: 174 [M+H].
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;
6-chloropyridin-3-ol (1.0 g),Benzyl bromide (1.5 g) and potassium carbonate (2.4 g)Was dissolved in DMF (40 mL) and stirred at 60 C. for 18 hours.After filtering the reaction solution,The solvent of the obtained filtrate was distilled off under reduced pressure to obtain a residue,Purification by silica gel column chromatography (hexane-ethyl acetate)5- (benzyloxy) -2-chloropyridine1.3 g (yield quant.) Was obtained.
82%
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 25h;
2-Chloro-5-hydroxypyridine 23a (2.0 g, 15 mmol) was dissolved in N,N-dimethylformamide (10 mL).Potassium carbonate (3.2 g, 23 mmol) and benzyl bromide (1.9 mL, 16 mmol) were added, and the mixture was reacted at 40 C for 25 hours.After cooling to room temperature, water (10 mL) was added to the reaction mixture to quench.Extracted with ethyl acetate (20 mL).The combined organic phases were washed with a saturated sodium chloride solution (10 mL).Dry over anhydrous sodium sulfate, concentrate by suction filtration, and the residue obtained was purified by silica gel column chromatographyPurification of the title compound 28a (2.78 g,yield: 82%)
79%
With caesium carbonate; In N,N-dimethyl-formamide;
Example 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23 C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp <50 C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) delta8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6 H), 5.19 (s, 2H).
79%
With caesium carbonate; In N,N-dimethyl-formamide;
Example 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23 C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp<50 C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) delta 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
79%
With caesium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23 C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp <50 C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) delta8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
79%
With caesium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23 C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp <50 C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) delta 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
79%
With caesium carbonate; In N,N-dimethyl-formamide;
Example 29A 5-(benzyloxy)-2-chloropyridine 2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23 C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluding with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp<50 C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) delta 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6 H), 5.19 (s, 2H).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 40℃; for 18h;
[1867] 6-Chloropyridin-3-ol (6 g, 46 mmol) in N,N-dimethylformamide (50 mL) was treated with benzylbromide (5.5 mL, 46 mmol) and potassium carbonate (12.8 mmol) and the reaction mixture heated to 40 C. for 18 hours. The reaction was cooled to room temperature, poured into brine (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (3×100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-benzyloxy-2-chloropyridine. This crude product was dissolved in propionitrile (50 mL) and treated with trimethylsilylbromide (12.36 mL, 92 mmol) and the reaction mixture was heated at 100 C. for 113 hours. The reaction mixture was cooled to room temperature and poured into 2.0 M sodium hydroxide solution to which 50 g of ice had been added. The aqueous phase was extracted with diethyl ether, (3×75 mL). The organic layers were combined and washed with water (2×100 mL) and brine (75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue (light brown oil) was purified by flash column chromatography on silica gel using 8% ethyl acetate:hexanes as eluent to give 4.72 g of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) delta5.19 (s, 2H), 7.42 (m, 6H), 7.57 (d, J=6 Hz, 1H), 8.19 (d, J=3 Hz, 1H), MS (DCI/NH3) m/e 365 (M+H)+.
With potassium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 273A 5-(benzyloxy)-2-bromopyridine 6-Chloropyridin-3-ol (6 g, 46 mmol) in N,N-dimethylformamide (50 mL) was treated with benzylbromide (5.5 mL, 46 mmol) and potassium carbonate (12.8 mmol) and the reaction mixture heated to 40 C. for 18 hours. The reaction was cooled to room temperature, poured into brine (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (3*100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-benzyloxy-2-chloropyridine.
8000 mg
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;
To a mixture of A-36 (5 g, 38.6 mmol) and K2C03 (10.65 g, 77.2 mmol) in DMF (40 mL) was added bromomethylbenzene (5.04 mL, 42.46 mmol). The reaction mixture was heated to 60 C and stirred for 16 hours. After cooling, the mixture was diluted with H20 (150 mL), and the mixture was extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (80 mL), dried over Na2SC>4, filtered and concentrated to afford A-37 (8000 mg, 36.42 mmol), which was used directly in next step. 1H NMR (CDC13, 400MHz) deltaH = 8.14 (d, 1H), 7.44 - 7.34 (m, 5H), 7.26 - 7.21 (m, 2H), 5.11 (s, 2H).
Example 35: 2-(6-Chloro-pyridin-3-yloxy)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acetamide [Show Image] Step 1: (6-Chloro-pyridin-3-yloxy)-acetic acid ethyl ester To a suspension of 6-Chloro-pyridin-3-ol (1000 mg, 7.72 mmol) and Bromoethyl acetate (1933 mg, 11.57 mmol) in CH3CN was added Cs2CO3 (3772 mg, 11.57 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc, then washed three times with H2O and brine, and then dried. MgSO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield the (6-Chloro-pyridin-3-yloxy)-acetic acid ethyl ester (1.5 g, 90%). 1H-NMR (300MHz, CDCl3): delta 8.07 (dd, 1H, J = 2.7, 0.9 Hz), 7.27 - 7.23 (m, 2H), 4.65 (s, 2H), 4.28 (q, 2H, J = 7.2 Hz), 1.30 (t, 3H, J = 7.2 Hz).
With potassium carbonate;copper; In DMF (N,N-dimethyl-formamide); at 120℃; for 6h;
A mixture of 6-chloro-pyridin-3-ol (418 mg, 3.2 MMOL), 2-FLUOROBENZALDEHYDE (522 mg, 4.21 MMOL), potassium carbonate (442 mg, 3.2 MMOL) and copper powder (201 mg, 3.2 MMOL) was heated in DMF (6.4 mL) at 120 C for 6 hours. The reaction was then cooled, and concentrated to an oil. The residue was purified by flash chromatography (eluting with 20% ethyl acetate/hexane) to give the title compound as a brown solid (700 mg, 93%).
With dmap; In 1,2-dichloro-benzene; at 140℃; for 2h;
Compound 206: 4-(6-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline; 2-Chloro-5-hydroxypyridine (100 mg), 4-chloro-6,7-dimethoxyquinoline (861 mg), and 4-dimethylaminopyridine (283 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140C for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (164 mg, yield 67%). 1H-NMR (CDCl3, 400 MHz): delta 4.00 (s, 3H), 4.02 (s, 3H), 6.45 (d, J = 5.2 Hz, 1H), 7.31 - 7.49 (m, 4H), 8.31 (d, J = 3.2 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 317 (M+1)+
64.8%
<strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (310 mg, 2.3 mmol) and TEA (5 mL, 28.7 mmol) were added sequentially to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (354 mg, 1.58 mmol) in chlorobenzene (3 mL). The resulting solution was heated to 140 C for 12 h. The reaction mixture was quenched with H20 (100 mL), and EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eluting with 0No.10% CH30H in EtOAc) to give 4-[(6-chloropyridin-3- yl) oxy]-6,7-dimethoxyquinoline as a light brown yellow oil (324.2 mg; 1.02 mmol; 64.8% yield) ; MS (APCI) (M+H)(at) 317. 'H NMR (400 MHz, CDCls) 6 ppm 4.00 (s, 3 H) 4.01 (s, 3 H) 6.45 (d, .1=5.3 Hz, 1 H) 7.44 (m, 4 H) 8.32 (d, J=2.5 Hz, 1 H) 8.51 (d, J=5.1 Hz, 1 H).
1.16g
With triethylamine; In chlorobenzene; at 140℃; for 120h;Inert atmosphere;
In the nitrogen flow, the 4-chloro -6,7-dimethoxy-quinoline (1.00g) (CAS Denn segni: 35654-56-9) in chlorobenzene (9 ml) of the solution in the, 6-chloro-pyridine-3-ol (0.65g) and triethylamine (11.3 ml) in 100 ml flask in four necks, and the mixture is in the bath temperature (140 C) stirring five days. The cup the obtained solution to room temperature, adding water and ethyl acetate, and the solution separation. The aqueous layer is extracted once again with ethyl acetate, the combined organic layer with saturated aqueous salt solution washing, drying with anhydrous sodium sulfate. The solvent is distilled under reduced pressure. The resulting residue with silica gel column chromatography (hexane: ethyl acetate = 1:8) purification, to obtain the title compound (1.16g), which has the following physical property value.
28 g
With dmap; In chlorobenzene; at 140℃; for 42h;Inert atmosphere;
Example 1 4-[(6-chloro-3-pyridinyl)oxy]-6,7-dimethoxy quinoline Under a stream of nitrogen, a solution of 4-chloro-6,7-dimethoxy quinoline (39 g) (CAS registration No.: 35654-56-9) in chlorobenzene (400 mL), <strong>[41288-96-4]6-chloropyridine-3-ol</strong> (25 g), and 4-dimethylaminopyridine (DMAP) (64 g) were placed into a 2-L four-necked flask, and the mixture was stirred at a bath temperature (140C) for 42 hours. The resulting solution was allowed to cool to room temperature, water (700 mL) and ethyl acetate (1 L) were added thereto, and the solution was separated. The water layer was extracted again with ethyl acetate (1 L). The combined organic layer was washed with a saturated saline solution (500 mL), and dried over anhydrous sodium sulfate, and a solvent was removed by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1:8) to obtain the title compound (28 g) having the following physical property values. TLC: Rf 0.22 (hexane : ethyl acetate = 1:3); 1H-NMR (DMSO-d6): delta 8.52, 8.48, 7.87 - 7.85, 7.66, 7.49, 7.43, 6.65, 3.95, 3.93.
With triethylamine; In tetrahydrofuran; at 20℃; for 2h;
Example 59 4-Isopropyl-benzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester 59.1 4-Isopropyl-benzenesulfonic acid 6-chloro-pyridin-3-yl ester A reaction flask containing 500 mg of 6-chloropyridin-3-ol (3.86 mmol) and 844 mg of 4-isopropyl-benzenesulfonylchloride (0.20 mmol) in dry tetrahydrofurane (10 ml) was flushed with N2. 1.6 ml of triethylamine were added and the reaction mixture was stirred at room temperature for 2 h. Thereby 4-isopropyl-benzenesulfonic acid 6-chloro-pyridin-3-yl ester ester was obtained in 98% yield. MS [m+1]: 312 1H-NMR (400 MHz, DMSO-d6): delta [ppm] 8.1 (d, 1H); 7.8 (d, 2H); 7.6 (m, 4H); 3.0 (m,1H); 1.2 (d, 6H).
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 16h;
Potassium nitrate (14g, 138.4mmol) was added in several portions to a mixture of 2- chloropyridin-5-ol (lOg, 77.2mmol) in concentrated sulphuric acid (50ml) at 0C and further stirred at room temperature for 16h. After the completion of reaction, reaction mixture was poured over crushed ice and the solid was filtered and dried to get the tittle compound (10.5g, 78%). LCMS: m/z = 173.3 (M+1) +.
57%
With nitric acid; acetic acid; at 20℃;
At 5-10C, fuming nitric acid (99 mL, 2.21 mol) was added dropwise to a solution of 6-chloropyridin-3-ol (220 g, 1.70 mol) in acetic acid (2 L) under water/ice-bath cooling within 45 minutes. After the addition was complete, the reaction mixture was maintained at r.t. overnight. The reaction mixture was purged with nitrogen, then concentrated in vacuo. The residue was triturated from water (150 mL), filtered and washed with diisopropyl ether (150 mL), then dried by air current on the filter, to afford the title compound (HQ). % g, 57%). LCMS [M+H]+ 175/177, RT 1.35 minutes
With nitric acid; acetic acid; In water; at 0 - 25℃; for 4h;
EXAMPLESEXAMPLE 1 4-(5-Ethyl-oxazolo[4.5-biPyridin-2-yl)-1.4-diaza-bicvclof3.2.21nonaneIntermediate 1 6-Chloro-2-nitro-pyridin-3-ol To a stirred mixture of 6-chloro-pyridin-3-ol (30.0 g, 233 mmol) and acetic acid (300 mL) at O0C was added fuming nitric acid (14.8 mL, 350 mmol) dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 4 h. The mixture was then cooled to O0C and the pH of the mixture was adjusted to -7 with 50%wt NaOH aqueous solution. The mixture was extracted with EtOAc (3x1000 mL). The organic layers were combined, washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the resulted solid was dissolved in methylene chloride (600 mL) and stirred with excess NaHCO3 solid (100g) for 3 h. The mixture was then filtered and the filtrate was concentrated to give 29 g of 6-chloro-2-nitro-pyridin-3-ol. GC-MS for C5H3CIN2O3: retention time 1.77 min, m/z 174 (M)+.
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In N,N-dimethyl-formamide; at 50℃; under 760.051 Torr;
Production Example 4-1: Ethyl 5-hydroxypyridine-2-carboxylate: Palladium acetate (267 mg), 1,1'-bis(diphenylphosphino)ferrocene (1.3 g) and triethylamine (3.2 mL) were added to an ethanol-DMF mixed solvent (1/1, 20 mL) of 6-chloropyridin-3-ol (1.5 g), and stirred overnight in a carbon monoxide atmosphere (1 atmospheric pressure) at 50C. Ethanol was evaporated off under reduced pressure from the reaction solution, water was added to the resulting residue, and extracted with chloroform/methanol (10/1). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate = 2/3) to obtain the entitled compound (500 mg).
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 2h;
A mixture of 6-bromo-pyridine-3-carbaldehyde (0.930 g, 5.00 rnmol), 6- chloropyridin-3-ol (0.650 g, 5.00 mmol) and K2CO3 (0.690 g, 5.00 mmol) in DMF (10 mL) EPO <DP n="128"/>was stirred at 130 0C for 2 h. The mixture was cooled to room temperature, DMF was removed and water (30 mL) was added. The mixture was extracted with CH2Cl2 (3 X 30 mL) and the combined extract was dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on silica gel (Et2OZCH2Cl2, 1 :20 v/v) to afford 6-(6-chloro-pyridin-3-yloxy)-pyridine-3-carbaldehyde as a white solid (1.15 g, 98%). 1H NMR (CDCl3) delta 7.14 (d, IH, J= 8.7 Hz), 7.41 (d, IH, J= 8.7 Hz), 7.55 (dd IH, J = 8.7, 3.0 Hz), 8.24 (dd, IH, J= 8.7, 2.1 Hz), 8.31 (d, IH, J= 3.0 Hz), 8.58 (d, IH, J= 2.1 Hz).
With potassium carbonate; In acetone; at 60℃; for 4h;
To <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (61A) in acetone (80 mL) was added K2CO3 (8.96 g, 65 mmol) and methylchloroacetate (2.54 mL, 29 mmol). The mixture was heated at 60 C. for 4 h. After cooling to RT, the mixture was filtered, and the solids were washed with acetone (50 mL). The filtrate was concentrated in vacuo to give 4.3 g intermediate (92% yield). The intermediate (4.3 g, 21.3 mmol) was dissolved in CHCl3 (75 mL) and treated with m-chloroperbenzoic acid (4.78 g, 27.7 mmol). The resulting solution was heated at 50 C. for 4 h, then stirred at RT overnight. The mixture was treated with sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (5%-10% MeOH in DCM) provided 61B (3.46 g, 75%).
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 20℃; for 13h;
34
Preparation 34; 2-Aminomethyl-5-cycloheptyloxy-pyridine; 6-Chloro-S-cycloheptyloxy-pyridine; Add 6-chloro-pyridin-3-ol (2 g, 15.4 mmol), cycloheptanol (1.93 g, 17 mmol), tri-n-butylphosphine (4.67 mL, 19.3 mmol), and ADDP (4.87 g, 19.3 mmol) to THF (60 mL) at 0°C under a nitrogen atmosphere. Stir the mixture at 0°C for 1 h and at room temperature for 12 h. Dilute with EtOAc (50 mL), add water (50 mL) and separate the layers. Extract the aqueous layer with EtOAc (4x30 mL). Wash the combined organic extracts with water (30 mL) and brine (20 mL). Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (2.36 g, 68%). MS (APCI+) m/z: 226 (M H)+.
With potassium hydroxide; In N,N-dimethyl-formamide; at 60℃;
6-Chloro-3-(3<3-dimethylcvclohexyloxy')-pyridine; Under a nitrogen atmosphere, add 3,3-dimethylcyclohexyl 4-methylbenzenesulfonate (1.2 g, 4.25 mmol), 6-chloro-pyridin- 3-ol (0.5 g, 3.86 mmol) and potassium hydroxide (238 mg, 4.25 mmol) to DMF (10 mL). Heat the mixture to 60C and stir overnight. Add water (20 mL) and diethyl ether (20 mL) and separate the layers. Extract the aqueous layer with diethyl ether (3x20 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 over 60 min, 80 mL/min) to obtain the desired intermediate as a white solid (728 mg, 79%). MS (APCI+) m/v. 240 (M+H)+.
With caesium carbonate In N,N-dimethyl-formamide at 20 - 135℃; for 22.8333h;
131.A
Example 131; Preparation of 4-(7-(6-chloropyridin-3-yloxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide; Step A: Preparation of 7-(6-chloropyridin-3-yloxy)-2-iodothieno[3,2-b]pyridine; Related methodology was described in WO 2005/121125. A stirred mixture of 7-chloro-2-iodothieno[3,2-b]pyridine (1.48 g, 5.00 mmol, prepared according to Ragan, J. A. Org. Proc. Res. 2003, 7, 676), cesium carbonate (2.44 g, 7.50 mmol), and DMF (50 mL) was heated to 135° C. under nitrogen with an attached reflux condenser. Next a solution of 6-chloropyridin-3-ol (0.972 g, 7.50 mmol) in DMF (20 mL) was added dropwise by syringe (2 mL approx every 5 min over a period of 50 minutes). The reaction was heated for 4 hours more after addition was complete. The reaction was left stirring at room temperature for 18 hours for convenience. The dark mixture was partitioned between EtOAc (100 mL) and water (100 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (50 mL). The combined organic phases were washed with water (3×200 mL), brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by Biotage Flash 40M, eluting with 20% EtOAc/hexanes (1 L) followed by 1:1 EtOAc/hexanes (1 L). The product was obtained as a beige solid (628 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 7.80 (s, 1H), 7.48 (m, 1H), 7.43 (d, J=9 Hz, 1H), 6.54 (d, J=6 Hz, 1H).
A mixture of 4-chloro-6,7-dimethoxyquinazoline (0.63 g, 2.80 mmol), 6- chloropyridin-3-oi (0.37 g, 2.84 mol), and DMAP (0.35 g, 2.84 mmol) in DMSO (3 mL) was stirred at 80 C for 3 h. The reaction mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and dried over sodium sulfate. The diying agent was filtered off, and the filtrate concentrated under reduced pressure to give a residue, which was purified by chromatography (ethyl acetate/hexanes = 6/4) to provide 4-((6-chloropyridin-3-yl)oxy)-6,7-dimethoxyquinazoline as a white solid (0.8 g,90%). fH NMR (DMSO-de, 300 MHz) 8 57 (s, 1H), 8.50 (d, ./= 3.0 Hz, 1H), 7.95 (dd, J= 8.7, 3.0 Hz, 1H), 7 67 (d, ,/ = 8.7 Hz, 1 1 1). 7 57 (s, 1 1 1). 7.40 (s, 1 1 1). 3.98 (s, 3H), 3.97 (s, 3H) ppm; MS m/e 318.1 (M i l)
83%
Potassium t-butoxide (1 mL, 1 mmol, 1 M in THF) was added to <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (198 mg, 1.5 mmol) under inert atmosphere. The reaction mixture was stirred at room temperature for 15 min, then a solution of 6,7-dimethoxy-4-chloroquinozoline (225 mg, 1 mmol) in DMSO (1 mL) was added. The resulting solution was heated to 75 C for 2 h. The reaction mixture was quenched with H20 (50 mL) and EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eluting with 60-(at)70% EtOAc in hexanes) to give 4-[(6-chloropyridin-3-yl)oxy]-6,7-dimethoxyquinazoline (264 mg; 0.83 mmol; 83% yield) ; MS (APCI) (M+H)+ 318. ¹H NMR (400 MHz, CHLOROFORM-D) 6 ppm 4.04 (s, 3 H) 4.05 (s, 3 H) 7.42 (d, (at)8.6 Az, 1 H) 7.48 (s, 1 H) 7.63 (dd, J=8.6, 3.0 Hz, 1 H) 8.38 (d, JL2.8 Hz, 1 H) 8.57 (s, 1 H).
9.1g
With dmap; In dimethyl sulfoxide; at 20 - 80℃; for 2h;Inert atmosphere;
Under the argon, the DMAP (4.4g) added to the 4-chloro -6,7-dimethoxyquinazoline (8.0g) and 6-chloro-pyridine-3-ol (4.6g) of suspension in DMSO (20 ml), the bath temperature (80 C) heating and stirring 2 hours, at room temperature and to a cup. Later, the reaction solution is diluted with ethyl acetate, and washing water and saturated sodium bicarbonate aqueous solution. The organic layer is dried with anhydrous sodium sulfate and concentrated. The resulting residue with hexane-ethyl acetate (3:1) washing, to obtain the title compound (9.1g), which has the following physical property value.
9.1 g
With dmap; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
Example 7 4-[(6-chloro-3-pyridinyl)oxy]-6,7-dimethoxy quinazoline Under an argon atmosphere, DMAP (4.4 g) was added to a DMSO suspension (20 mL) of 4-chloro-6,7 dimethoxy quinazoline (CAS registration No: 13790-39-1) (8.0 g) and <strong>[41288-96-4]6-chloropyridine-3-ol</strong> (4.6 g), and the mixture was heated and stirred at a bath temperature (80C) for two hours. The mixture was allowed to cool to room temperature. The reaction solution was diluted with ethyl acetate, and washed with water and a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was washed with hexane-ethyl acetate (3:1) to obtain the title compound (9.1 g) having the following physical property values. TLC: Rf 0.16 (hexane: ethyl acetate =1:1); 1H-NMR (DMSO-d6): delta 3.97, 3.99, 7.41, 7.58, 7.69, 7.97, 8.50, 8.57.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
To a solution of 15 (50.0g, 386mmol) and potassium carbonate (80.0g, 580mmol) in DMF (300mL) was added p-methoxybenzyl chloride (66.5g, 425mmol), and the mixture was stirred at 80C for 4h. EtOAc and water were added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with methanol to give 16 (61.3g, 64%) as a white solid. 1H NMR (DMSO-d6) delta 3.76 (3H, s), 5.10 (2H, s), 6.82-7.06 (2H, m), 7.34-7.46 (3H, m), 7.50-7.59 (1H, m), 8.17 (1H, d, J=2.6Hz).
64%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
To a solution of <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (50 g, 0.386 mol) and potassium carbonate (80 g, 0.579 mol) in N, N- dimethylformamide (300 mL) was added p-methoxybenzyl chloride(66.5 g, 0.425 mol), and the mixture was stirred at 8O0C for 4 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and <n="189"/>filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with methanol to give the title compound (61.3 g, 64%) as a white solid.1H-NMR (DMSO-d6, 300 MHz) delta 3.76 (3H, s), 5.10 (2H, s), 6.82 - 7.06 (2H, m) , 7.34 - 7.46 (3H, m) , 7.50 - 7.59 (IH, m) , 8.17 (IH, d, J = 2.6 Hz) .
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;
1 a. 2-Chloro-5-cyclopentyloxypyridine Cyclopentyl bromide (690.3 mg, 4.63 mmol), <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (500 mg, 3.86 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were stirred in 30 ml of DMF at room temperature for 3 h. The reactants had not yet completely reacted. 50% of each of cyclopentyl bromide and cesium carbonate were added, and stirring was continued for 2 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate and water. The organic phase was separated off and concentrated. Yield: 737 mg (97%), M+H+: 198.08.
With caesium carbonate; In diethylene glycol dimethyl ether; at 160℃; for 4h;microwave irradiation;
5.2 g (40.0 mmol) of 6-chloropyridin-3-ol, 11.9 g (60.0 mmol) of 1-iodo-2,2-dimethylpropane, 19.6 g (60.0 mmol) of cesium carbonate and 120 ml of diethylene glycol dimethyl ether are divided into five portions of equal size and reacted portion-wise in a single-mode microwave oven (CEM Explorer) at 160 C. for 4 h. The five reaction mixtures obtained are then combined, the solid is filtered off and washed with diethylene glycol dimethyl ether and filtrate and wash solutions are combined. Most of the solvent is removed, and 300 ml of water are added to the concentrated (about 50 ml) solution. The mixture is stirred for 30 min, and the solid obtained is filtered off, washed once with water and dried under high vacuum. Yield: 7.0 g (88% of theory) LC-MS (Method 6): Rt=2.47 min; MS (ESIpos): m/z=200 [M+H]+; 1H-NMR (400 MHz, CDCl3): delta=8.05 (d, 1H), 7.25-7.15 (m, 2H), 3.61 (s, 2H), 1.03 (s, 9H).
88%
With caesium carbonate; In diethylene glycol dimethyl ether; at 160℃; for 4h;Microwave irradiation;
5.2 g (40.0 mmol) 6-chloropyridin-3-ol, 11.9 g (60.0 mmol) 1-iodo-2,2-dimethylpropane, 19.6 g (60.0 mmol) cesium carbonate and 120 ml diethylene glycol dimethyl ether are divided into five portions of equal size and are reacted in portions at 160 C. for 4 h in a single mode microwave (CEM Explorer). Thereafter, the five reaction mixtures obtained are combined, the solid is filtered off and rinsed with diethylene glycol dimethyl ether and the filtrate and wash solutions are combined. The majority of the solvent is removed and 300 ml water are added to the concentrated solution (approx. 50 ml). The mixture is stirred for 30 min and the solid obtained is filtered off, washed once with water and dried under a high vacuum.Yield: 7.0 g (88% of th.)LC-MS (Method 8): Rt=2.47 min; MS (ESIpos): m/z=200 [M+H]+;1H-NMR (400 MHz, CDCl3): delta=8.05 (d, 1H), 7.25-7.15 (m, 2H), 3.61 (s, 2H), 1.03 (s, 9H).
With triethylamine;copper diacetate; In dichloromethane; for 72h;Molecular sieve; under air;
A mixture of 2-chloro-5-hydroxypyridine (3.0 gm, 0.023 mol), 3-(N,N-dimethylamino)-phenylboronic acid (5.73 gm, 0.034 mol), copper(II)acetate (4.62 gm, 0.023 mmol), triethylamine (16.0 mL, 0.115 mol) and powdered 4 A molecular sieves in dichloromethane (80 mL) was stirred under air for 3 days. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluding with ethyl acetate: hexane 3:7 to afford [3-(6-chloropyridin-3-yloxy)phenyl]-dimethylamine as a colourless oil (1.7 g, 29%). ES+ 249 (M+H)+ deltaH (d6-DMSO) 2.90 (3H, s), 6.30 (1H, dd), 6.44 (1H, dd), 6.57 (1H, dd), 7.21 (1H, t), 7.46 (1H, dd), 7.50 (1H, d) and 8.18 (1H, d)
With triethylamine In dichloromethane for 72h; Molecular sieve; under air;
19 Intermediate 19: 4-{2-[3-(6-chloropyridin-3-yloxy)phenoxy]ethyl}morpholine
A mixture of 2-chloro-5-hydroxypyridine (0.68 g, 0.0052 mol), 3-(2-morpholino-ethoxy)phenylboronic acid (1.3 g, 0.0052 mol), copper(II)acetate (1.04 g, 0.0052 mol), triethylamine (3.7 mL, 0.262 mol) and powdered 4 molecular sieves in dichloromethane (60 mL) was stirred under air for 3 days. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluting with dichloromethane:methanol (19:1) to afford 4-{2-[3-(6-chloropyridin-3-yloxy)phenoxy]ethyl}morpholine as a colourless oil (1.14 g, 65%).ES+ 335 (M+H)+
With triethylamine;copper diacetate; In dichloromethane; for 72.0h;Molecular sieve; under air;
A mixture of 2-chloro-5-hydroxypyridine (294 mg, 5.257 mol), <strong>[659731-18-7]3-(1-pyrrolidinyl)phenyl boronic acid</strong> (500 mg, 5.257 mol), copper(II)acetate (453 mg, 5.257 mol), triethylamine (5.3 mL, 26.285 mol) and powdered 4 A molecular sieves in dichloromethane (20 mL) was stirred under air for 3 days. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluding with ethyl acetate:hexane (3:7) to afford 2-chloro-5-(3-pyrrolidin-1-ylphenoxy)pyridine as a colourless oil (340 mg, 24%). ES+ 275 (M+H)+ deltaH (d6-DMSO) 1.92 (4H, m) 3.20 (41-1, m) 6.20 (1H, s) 6.21 (1H, d) 6.36 (1H, d) 7.15 (1H, t) 7.43 (2H, m) 8.15 (1H, d).
Step 1 : A mixture of 2, 5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2- chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105 C and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2 ~ 3 with 6N HC1. The aqueous layer was extracted with EtOAc (3 X 5 L). The combined organic layers were dried over Na2S04, filtered and concentrated to give 1.28 Kg of 5-bromo-2- (6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.
Step 1 : A RBF was charged with 2, 5-dibromobenzoic acid (1244 g, 4.44 mol), 5- hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol). The resulting mixture was stirred for 20 minutes under nitrogen atmosphere at which time copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL) were added in sequence. The resulting suspension was heated to 105 C for 2 h and cooled to RT. The toluene was decanted and water (8 L) and EtOAc (8 L) were added to the residue. The mixture was stirred until the solids were completely dissolved. The organic layer was separated and the pH of the aqueous layer was adjusted to pH 2 ~ 3 with 6N HC1. This mixture was then extracted with EtOAc (3 X 5 L). The combined organic layers were dried over Na2S04, filtered and concentrated to give 1.28 kg of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid, which was used in next step without further purification.
Step 1 : A mixture of 2,5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2- chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105 C and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2 ~ 3 with 6N HCl. The aqueous layer was extracted with EtOAc (3 X 5 L). The combined organic layers were dried over Na2S04, filtered and concentrated to give 1.28 Kg of 5-bromo-2- (6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.
With copper diacetate; triethylamine; In dichloromethane;
Intermediate 10: 4-[3-(6-Chloro ridin-3-yloxy)phenyl]morpholineA mixture of 2-chloro-5-hydroxypyridine (2g, 0.0154mol), 3-morpholin-4- ylphenylboronic acid (3.2g, 0.0154mol), copper (II) acetate (2.8g, 0.0154mol), triethylamine (10.8mL, 0.077mol) and powdered 4A molecular sieves in dichloromethane (90mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The reaction mixture was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate :hexane 1: 1) to afford 4-[3-(6-chloropyridin-3-yloxy)phenyl] morpholine (l.Og, 22percent) as colourless oil.Mass: (ES+) 291 (M+H)+
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18h;
A solution of 2-chloro-5-hydroxy pyridine (5.00 g, 38.60 mmol), 1-Boc-4-hydroxypiperidine (9.32 g, 46.31 mmol) and triphenyl phosphine (15.19 g, 57.90 mmol) in THF (200 mL) at 0 C. was treated dropwise with diisopropylazodicarboxylate (11.14 mL, 57.90 mmol). The mixture was stirred at room temperature for 18 hours, diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (25-40% EtOAc in petrol (40-60 C.)) gave 4-(6-chloro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.70 g, 47%) as a pale yellow residue. 1H NMR (300 MHz, CDCl3) delta 8.06 (d, J=2.8 Hz, 1H), 7.23-7.16 (m, 2H), 4.51-4.41 (m, 1H), 3.75-3.64 (m, 2H), 3.40-3.29 (m, 2H), 1.99-1.86 (m, 2H), 1.83-1.67 (m, 2H), 1.47 (s, 9H). LCMS (m/z, Method A) ES+ 311.1 [M+1]+.
47%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18h;
A solution of 2-chloro-5-hydroxy pyridine (5.00 g, 38.60 mmol), 1-Boc-4-hydroxypiperidine(9.32 g, 46.31 mmol) and triphenyl phosphine (15.19 g, 57.90 mmol) in THF (200 mL) at 0was treated dropwise with diisopropylazodicarboxylate (11.14 mL, 57.90 mmol). Themixture was stirred at room temperature for 18 hours, diluted with EtOAc, washed with water and brine, dried over Na2504 and concentrated under vacuum. Purification by silica gel column chromatography (25-40% EtOAc in petrol (40-60 C)) gave 4-(6-chloro-pyridin-3- yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.70 g, 47%) as a pale yellow residue.?H NMR (300 MHz, CDC13) oe 8.06 (d, J= 2.8 Hz, 1H), 7.23-7.16 (m, 2H), 4.5 1-4.41 (m, 1H), 3.75-3.64 (m, 2H), 3.40-3.29 (m, 2H), 1.99-1.86 (m, 2H), 1.83-1.67 (m, 2H), 1.47 (s, 9H). LCMS (mz, Method A) ES 311.1 [M+1j.
45%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃; for 18h;
Intermediate-6: rt-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine- 1 -carboxylate.To a mixture of 4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (15.5 g, 77 mmol), 2- Chloro-5-hydroxy-pyridine (9.9g, 77mmol) and triphenylphosphine (24.24 g, 92.4 mmol) in THF, diisopropylazodicarboxylate (18.6 g, 92.4 mmol) was added at 0C and stirred for 18 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo, resulting residue was purified by flash column chromatography to give tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-l -carboxylate (1 lg, 45%); MS: 335.2 (M+23).
Multi-step reaction with 3 steps
1.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C
1.2: 20 °C
2.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C
2.2: 1 h / -78 °C
3.1: hydrogenchloride / water; methanol / 4 h / Reflux
Multi-step reaction with 3 steps
1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere
1.2: 0.5 h / 0 °C
2.1: n-butyllithium / hexane; tetrahydrofuran / 1 h / -78 °C / Inert atmosphere
2.2: 0.25 h / -78 °C
3.1: hydrogenchloride; water / tetrahydrofuran / 2 h / 60 °C
Multi-step reaction with 3 steps
1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.17 h / 0 - 20 °C / Inert atmosphere
1.2: 2 h / 20 °C
2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere
2.2: 2 h / -78 °C
3.1: hydrogenchloride / tetrahydrofuran / 2 h / 60 °C
Multi-step reaction with 3 steps
1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C
2.1: n-butyllithium / tetrahydrofuran / 1.5 h / -78 °C
2.2: 16 h / 20 °C
3.1: hydrogenchloride / water; methanol / 4 h / Reflux
Multi-step reaction with 3 steps
1.1: sodium hydride / N,N-dimethyl-formamide / 2.25 h / 20 °C
1.2: 12.75 h / 20 °C
2.1: tert.-butyl lithium / tetrahydrofuran; pentane / 0.67 h / -70 °C
2.2: 1.5 h / -70 - 20 °C
3.1: hydrogenchloride / tetrahydrofuran / 3 h / 60 °C
3.2: 20 °C / pH 7
Multi-step reaction with 3 steps
1.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 5 °C / Inert atmosphere
1.2: 20 °C
2.1: n-butyllithium / tetrahydrofuran; acetone / 1 h / -70 - -65 °C / Inert atmosphere
2.2: -60 - 20 °C
3.1: hydrogenchloride / methanol; water / 50 °C
60% NaH (29.2 g, 0.73 mol) was added to 400 ml of dry DMF, and 100 ml of 6-chloropyridin-3-ol (64 g, 0.5 mol) in DMF was added dropwise under N2.The temperature control does not exceed 5 C. After stirring for 1 h, bromomethyl methyl ether (122 g, 0.97 mol) was added dropwise, and the mixture was slowly warmed to room temperature overnight. The reaction solution was poured into 1 L of water, extracted with EA (200 ml*2), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and dried over the column (RhoEpsilon: EpsilonAlpha = 20:1)A colorless oil of 2-chloro-5-(methoxymethoxy)pyridinium (85 g, yield: 99%) was obtained.
87%
[01234] Sodium hydride (2.8 g, 60% in mineral oil, 1.26 equiv) was added in portions into a solution of 6-chloropyridin-3-ol (12 g, 92.63 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL) at 0C under nitrogen. The mixture was stirred for 10 minutes at room temperature. To the above was added bromo(methoxy)methane (15 g, 120.03 mmol, 1.29 equiv) dropwise and the reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with petroleum ether ethyl acetate (101) to afford the title compound (14 g, 87%) as colorless oil. LCMS [M+H] 174.
75%
To a solution of 6-chloropyridin-3-ol ( 10 g, 77. 19 mmol, 1.00 equiv) in DMF ( 120 mL) maintained under nitrogen at 0C was added NaH (3.8 g , 60%) in small portions. The resulting solution was stirred at rt for 1 h. 1 -Bromo-2-methoxyethane (1 3 g, 93.53 mmol, 1 .21 equiv) was then added dropwise with stirring to the reaction mixture while maintaining the reaction temperature at < 10C. The resulting solution was stirred at rt for another 2 h. Water (200 mL) was added to quench the reaction. The resulting solution was extracted with 2x200 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether to give 10 g (75%) of 2-chloro-5-(methoxymethoxy)pyridine as a colorless oil. TLC: petroleum ether: ethyl acetate = 5: 1 , Rf = 0.5.
With caesium carbonate In acetonitrile for 3h; Reflux;
56.1 t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin-1-carboxylate
t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin-1-carboxylate: t-Butyl 4-((methylsulfonyloxy)methyl)piperidin-1-carboxylate (the product of synthesis step 2 of compound 431; 2.0 g, 6.82 mmol) was dissolved in ACN 10 mL. 6-chloropyridine-3-ol (1.06 g, 8.18 mmol), Cs2CO3 (3.33 g, 10.23 mmol) was added thereto, and refluxed with heating for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgSO4, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAcHexane) to yield the title compound as white solid (1.6 g, 72%)
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 4h;
Intermediate BA10: 4-{2-[(6-chloropyridin-3-yl)oxy]ethyl}morpholine To a stirred solution of PPh3 (4.22 g, 16.1 mmol) in THF (55 mL) cooled at 0 C., DEAD 97% (3 mL, 16.1 mmol) was added and the mixture was stirred for 15 min. Then a solution of 4-(2-hydroxyethyl)morpholine (1.96 mL, 16.1 mmol) in THF (16 mL) was added followed by <strong>[41288-96-4]2-chloro-5-hydroxypyridine</strong> (1.5 g, 11.5 mmol). The mixture was allowed to warm to room temperature and stirred for 4 h. The solvent was removed and the residue was purified by flash chromatography on Biotage silica-NH SNAP cartridge (cyclohexane to cyclohexane:EtOAc=70:30) to afford a title compound a pink oil (2.722 g, 11.2 mmol, 97% yield). MS/ESI+ 243.3 [MH]+, Rt=0.71 min (Method J).
Potassium carbonate (1.7g, 6.201mmol) was added to a solution of 6-chloropyridin-3-ol (0.8g, 6.201 mmol) in DMF (15mL) under argon atmosphere. The resulting reaction mixture was stirred for 30 min. l-(bromomethyl)-3,5-dimethoxybenzene (1.6g, 6.821 mmol) was then added to the reaction mixture and heated at 60C for 2h. The resultant reaction mixture was cooled to RT, quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3x30mL). The organic phase was washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (1.4g, yield: 78%) as a solid. MS (ESI): 280.0 [M+H]+.
3-(bromomethyl)-2,4-difluoro-1,5-dimethoxybenzene[ No CAS ]
2-chloro-5-((2,6-difluoro-3,5-dimethoxybenzyl)oxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
To a solution of 2-chloro-5-hydroxy pyridine (0.8g, 6 mmol) in DMF (lOmL) added potassium carbonate (1.71g, 12mmol) and stirred the reaction mass for lOmin. Added 3-(bromomethyl)- 2,4-difluoro-l,5-dimethoxybenzene (1.65g, 6.6 mmol) and heated the reaction mass for 4hr at 80 C. Reaction mass was quenched with ice cold water and extracted with ethyl acetate (3x25mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by 60-120 silica gel column chromatography to afford the title compound (2g, yield: 100%). MS (ESI): 315.9 [M+H]?.
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 N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere;
2-Chloro-5-hydroxypyridine (0.300 g 2.316 mmol) and 2-fluoroethyl-4- methylbenzenesulfonate (0.505 g, 2.316 mmol, CAS 383-50-6) were dissolved in DMF (7 mL). CS2CO3 (1.132 g, 3.474 mmol) was added under nitrogen atmosphere. The mixture was heated to 85 C for 5 h. After cooling to ambient temperature, the dark brown suspension was diluted with water and extracted with EtOAc. The org layers were washed with brine, dried over MgS04, filtered and concentrated. The product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 35/65). The desired fractions were collected and concentrated in vacuo providing intermediate 15 (0.374 g, 92%).
With caesium carbonate; In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere;
2-Chloro-5-hydroxypyridine (0.300 g, 2.316 mmol) and 3-fluoropropyl (0184) 4-methylbenzenesulfonate (0.538 g, 2.316 mmol, CAS 312-68-5) were dissolved in DMF (7 mL). CS2CO3 (1.132 g, 3.474 mmol) was added under nitrogen atmosphere. The mixture was heated to 85 C for 5 h. After cooling to ambient temperature, the dark brown suspension was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The product was purified by flash column chromatography (silica; EtOAc in heptane, 0/100 to 30/70). The desired fractions were collected and concentrated in vacuo providing intermediate 16 (0.408 g, 93%).
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 40℃; for 2h;
To a stirred solution of 6-chloropyridin-3-ol (3.0 g, 23.2 mmol) in N,N-dimethylformamide (30 mL) was added iodoethane (4.33 g, 27.8 mmol, 2.22 mL), and potassium carbonate (9.60 g, 69.6 mmol) at 0C. The reaction was warmed and stirred at 40 00 for 2 h. The reaction mixture was quenched by addition of water (30 mL) then the mixture was extracted with ethyl acetate (60 mL x 3). The combined organicphases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine (3.30 g, 20.9 mmol, 90 %) as a yellow solid. 1H NMR (400 MHz, ODd3) O 7.97(d, J2.9 Hz, 1H), 7.17- 7.07(m, 2H), 3.99 (q, J7.0 Hz, 2H), 1 .36 (t, J7.0 Hz, 3H).
6-chloro-N-methoxy-N-methyl-4-(trifluoromethyl)pyridine-3-carboxamide[ No CAS ]
6-[(6-chloro-3-pyridyl)oxy]-N-methoxy-N-methyl-4-(trifluoromethyl)pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; potassium carbonate; In dimethylsulfoxide-d6; at 100℃; for 2h;
A mixture of 6-chloro-A^-methoxy-A^-methyl-4-(trifluoromethyl)pyridine-3-carboxamide (12.0 g, 44.6 mmol), 6- chloropyridine-3-ol (5.78 g, 44.6 mmol), potassium carbonate (15.4 g, 111 mmol), copper(I) iodide (851 mg, 4.46 mmol), and TMEDA (1.3 mL, 8.93 mmol) in DMSO (100 mL) was heated for 2 h at 100 C. The reaction mixture was then cooled to rt, water added, extracted with ethyl acetate, dried (over Na2SO t), concentrated and purified via flash column chromatography (gradient, up to heptane/ethyl acetate=50/50, 254 nm) to give 14.7 g (89% yield, 98% pure) of the target compound. MS (ESI): 362.04 ([M+H]+)
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane;
(36-1) Tetrakis(triphenylphosphine)palladium (0) (220 mg, 0.193 mmol) and a 2N aqueous sodium carbonate solution (4.63 ml) were added to a solution of <strong>[454185-98-9]methyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate</strong> (1.07 g, 3.86 mmol) obtained in Example (12-1) and 2-chloro-5-hydroxypyridine (500 mg, 3.86 mmol) in dimethoxyethane (20 ml), and the mixture was stirred under heating with reflux overnight. The reaction mixture was diluted with ethyl acetate and water, and the insolubles were removed by filtration through Celite. After the obtained filtrate was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluding solvent: n-hexane/ethyl acetate=2/1-1/1) to give methyl [4-(5-hydroxy-2-pyridinyl)phenyl]acetate (230 mg, yield: 24%). 1H-NMR (500MHz, CDCl3): delta 8.30 (1H, s), 7.85 (2H, d, J = 8.3 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.36 (2H, d, J = 8.3 Hz), 7.21 (1H, d, J = 8.3 Hz), 3.71 (3H, s), 3.67 (2H, s).
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3h;
3.1 tert-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin-1-carboxylate
The product was dissolved in DMF 10 mL. K2CO3 (1.13 g, 3.48 mmol) and 2-chloro-5-hydroxypyridine (0.3 g, 2.32 mmol) were added thereto slowly. After increasing the temperature, the mixture was stirred with heating at 100 °C for 3 hours. After the completion of the reaction, the reaction mixture was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-30 % EtOAc/hexane) to yield the title compound as white solid (0.45 g, 59%).
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 16℃;Inert atmosphere;
6-Chloropyridine-3-hydroxy 23a (1.0 g, 7.7 mmol) and 4-fluorophenylboronic acid (1.6 g, 11.43 mmol) were dissolved in a mixed solution of dioxane (50 mL) and water (10 mL).Then, bistriphenylphosphinepalladium dichloride (0.77 g, 1.09 mmol) and cesium carbonate (5.00 g, 15.4 mmol) were added, and the mixture was replaced with nitrogen three times, and the reaction was stirred at 90 C for 16 hours.Concentrated under reduced pressure, and the residue obtained was applied to silica gel column chromatography[ethyl acetate / petroleum ether (v / v) = 1 / 5] purified,The title compound 23b (1.2 g, yield 86%) was obtained as white solid.
6-((6-chloropyridin-3-yl)oxy)-1-isopropyl-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃; for 18h;
Intermediate 2 (4.45 g, 19.6 mmol) and 126 6-chloropyridin-3-ol (3.31 g, 25.5 mmol, 1.3 eq.) were combined in 12 DMF (89 ml) and treated with 127 DIEA (8.6 mL, 49 mmol, 2.50 eq.). The mixture was heated to 85 C. for 18 h. It was cooled, concentrated under vacuum and purified by flash LC (elution with 0-70% ethyl acetate in hexanes) to afford 6.04 g (96%) of the title compound as a beige solid. 1H NMR (400 MHz, CDCl3) delta 8.42 (d, J=2.81 Hz, 1H) 8.02 (s, 1H) 7.61 (dd, J=8.68, 2.93 Hz, 1H) 7.40-7.54 (m, 1H) 4.61 (spt, J=6.72 Hz, 1H) 3.66 (s, 3H) 1.41 (d, J=6.85 Hz, 6H). [M+H]=320.1.
4-(3-((4-((6-chloropyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)propyl)-morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With dmap In toluene at 125℃; for 24h;
1.2
A solution of 4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine (10 0 g, 29.7 mmol), 6-chloropyridin-3-ol (5 g, 38.6 mmol) and DMAP (4.35 g, 35.6 mmol) in toluene (50 mL) was allowed to stir at 125 °C for 24 h. LC/'MS traces indicated starting material was still present and hence heating was continued for another 24 h. The reaction mixture was cooled down to room temperature, diluted with DCM (400 mL) and water (400 mL) and the layers were separated. The resulting aqueous layer was extracted with DCM (5X100 mL) add the resulting combined organic layer was dried (MgSCL), filtered and concentrated under reduced pressure to give 9.8 g (77%) of 4-(3-((4-((6-chloropyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)propyl)- morphoime (4) as an off-white solid. NMR (DMSO-tfe, 300 MHz) 6 8.51 (d, J = 5.3 Hz, 1H), 8.47 (d, ,1= 2.9 Hz, 1H), 7.86 (dd, J= 8.8, 2.9 Hz, 1H), 7.66 (d, J= 8.5 Hz, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 6.64 (d, J = 5.3 Hz, 1H), 4.20 (t, J= 6.4 Hz, 2H), 3.93 (s, 3H), 3.59 (dd. ./ 4.7. 4.4 Hz, 4H), 2.47 (t, J= 7.3 Hz, 2H), 2.39 (t, J= 4.4 Hz, 4H), 1.98 (p, J= 6.7 Hz, 2H). MS m/e 430 (1 · i )
2-((6-chloropyridin-3-yl)oxy)-5-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; caesium carbonate; In toluene; at 110℃;
Dissolve <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (100g, 0.54mol) in toluene (500mL),Add 2-chloro-5-hydroxy-pyridine (69.7g, 0.54mol) at room temperature,Cuprous iodide (30.4g, 0.16mol) and cesium carbonate (351.0g, 1.08mol),The reaction was carried out at 110 C overnight.After the reaction was completed, it was desolvated under reduced pressure.Add water and ethyl acetate, extract three times, combine organic phases, wash with saturated sodium chloride, and dry over anhydrous sodium sulfateDesolvation under reduced pressure to give the title compound
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
