* 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 sulfuric acid In toluene at 95℃; for 72 h; Heating / reflux
To 3-hydroxypyridine-2-carboxylic acid (25 g, 179.5 mmol) in a 1 L dried flask was added 400 mL ethanol and 100 mL toluene followed by the addition of 10 mL sulfuric acid. The mixture was heated at reflux (95° C.) for 3 days. After cooling to rt, the mixture was concentrated to 1/4 of its volume, and diluted with 600 mL ethyl acetate and 200 mL water. The aqueous layer was extracted with 200 mL ethyl acetate, and the combined organic layers were washed with sat NaHCO3 (3.x.200 mL), brine, and dried over Na2SO4. The solid was filtered off and the solvent was concentrated under reduced pressure to give 21.9 g of ethyl 3-hydroxypyridine-2-carboxylate (73percent), which was used in the next step without purification. This ester (21.9 g, 131 mmol) was dissolved in pyridine and cooled to -40° C., followed by addition of trifluoromethanesulfonic anhydride (48 g, 170 mmol). The reaction mixture was then warmed to 0° C. for 30 min, and then warmed to rt for another 30 min. Water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3.x.200 mL), and the combined organic layers were washed with sat sodium bicarbonate (200 mL), water (200 mL), brine (200 mL), and dried over sodium sulfate. The solid was filtered off, and the solvent was removed under reduced pressure to give 39 g (99percent) of desired product, which was used in the next step without further purification. 1H NMR (300 MHz, CD2Cl2) δ 8.73 (dd, 1H), 7.72 (dd, 1H), 7.62 (dd, 1H), 4.46 (q, 2H), 1.42 (t, 3H).
70%
With sulfuric acid In toluene at 78℃; for 60 h; Dean-Stark
A solution of 3-hydroxypicolinic acid (2.50 g, 18.0 mmol) in EtCH (60 mL) and toluene (20 mL) was treated with conc. H2S04 (1 mL) and stirred under reflux for 60 h withazeotropic removal of water via Dean-Stark trap. The solvent was evaporated, the residue was dissolved in water (50 mL) and carefully basified with a sat. NaHCO3 solution, upon which a white precipitate appeared. The mixture was diluted with EtOAc (30 mL) and the aqueous layer was extracted three times with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Mg504, filtered and evaporated to giveethyl 3-hydroxypicolinate (2.10 g, 70percent) as a colorless liquid.1H NMR (400 MHz, Chloroform-o) 6 = 10.78 (s, 1H, OH), 8.30 (dd, J= 4.2, 1.5 Hz, 1H,H-Ar), 7.47 — 7.34 (m, 2H, H-Ar), 4.54 (q, J= 7.1 Hz, 2H, O-CH2CH3), 1.49 (t, J= 7.1Hz, 3H, O-CH2CH3) ppm.MS (ESl+, H20/MeCN) mlz(percent): 168.0 (100, [M + H]j.
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 665 - 668
[2] Patent: US2005/192294, 2005, A1, . Location in patent: Page/Page column 20-21
[3] Patent: WO2018/229193, 2018, A1, . Location in patent: Page/Page column 138
[4] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4702 - 4713
[5] Patent: WO2005/42538, 2005, A1, . Location in patent: Page/Page column 15; 16
[6] MedChemComm, 2015, vol. 6, # 10, p. 1767 - 1772
2
[ 874-24-8 ]
[ 73406-50-5 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 4466,4468
[2] Patent: US6316464, 2001, B1,
3
[ 874-24-8 ]
[ 16478-52-7 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 1051 - 1063
4
[ 874-24-8 ]
[ 676-58-4 ]
[ 13210-29-2 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With triethylamine In tetrahydrofuran at 60 - 65℃; for 5 h; Stage #2: With Methyl formate In tetrahydrofuran at 5 - 20℃; Stage #3: With hydrogenchloride; water In tetrahydrofuran at 10℃;
Example 2; 3-methyl-N4[(1S)-3-methyl-1-([(4S,7R)-7-methyl-3-oxo-1-(2-pyridinylsulfonyl) hexahydro-1H-azepin-4-yl]amino}carbonyl)butyl]furo[3,2-b]pyridine-2-carboxamide; Preparation of 3-methylfuro[3,2-b]pyridine-2-carboxylic acid (6-1); Under nitrogen, charge the flask with 3 M methyl magnesium chloride in THF (600 mL, 1.80 mol, 5.0 equiv) and THF (500 mL). Heat the solution to 60-65° C. and add a solution of 3-hydroxypicolinic acid (1) (50 g, 0.36 mole), triethylamine (50 mL, 0.36 mole) in THF (250 mL) to the reaction mixture over approximately 3 h. Continue heating at reflux for 2 h. Cool the reaction to 5-10° C. and add methyl formate (44 mL) keeping the reaction temperature less than 20° C. At 10° C., add 10percent aqueous HCl to a pH 34. Transfer to separatory funnel and allow the layers to separate. Remove the top organic phase and extract the aqueous phase with THF (250 mL). Combine the organic phases combined and concentrate to 13-15 volumes and add water (170 mL). Continue with the vacuum distillation until all the THF has been removed. Cool the solution to 10° C., stir 0.5 h, filter and dry 1-(3-hydroxypyridin2-yl)ethanone (2) as the tan solid (38.1 g, 77percent yield).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
