2-Pyridinecarboxylic acid, 5-hydroxy-, methyl ester

Yellow solid

Methanol (70 mL) was added to 5-hydroxypyridine-2-carboxylic acid (Combi-Blocks, 5.01 g, 36.0 mmol). Then sulfuric acid (5.8 mL, 110 mmol) was carefully added to the reaction mixture. Reaction mixture was stirred at 75 °C overnight. After this time the solvent was evaporated and the product was dissolved in EtOAc. To the resultant solution was added saturated aq. NaHCC to pH 3. Formed precipitate was collected by filtration and dried under vacuum. The rest of the product was extracted with EtOAc. Collected organic fractions were washed with brine, dried over Na2S04 and the solvent was evaporated under reduced pressure. Obtained solid product (5.3 g, 96percent) was used in the next step without further purification. LCMS calc. for CvHsNOs (M+H)(a) Preparation of 5-Hydroxy-pyridine-2-carboxylic acid methyl ester 2:To a 100 mL round bottle flask with 5-Hydroxy-pyridine-2-carboxylic acid 1 (1.0 g, 7.2 mmol) in methanol (50 mL) was added dropwise thionyl chloride (3.0 mL) at ambient temperature. After addition the reaction mixture was heated to reflux for 3 h. Methanol was removed to give 5-Hydroxy-pyridine-2-carboxylic acid methyl ester 2 as a white solid which was used for the next step without further purification. Yield: 0.957 g, 86.9percent.To a solution of 5-hydroxypieolinic acid (4.0 g, 28.77 mmol) in methanol (75 mL), cone. HTo a solution of 5-hydroxypicolinic acid (4.0 g, 28.77 mmol) in MeOH (75 mL), cone. HTo a suspension of 5-hydroxypyridine-2-carboxylic acid (19.0 g, 137 mmol, 1 eq.) in methanol (200 mL) was added thionyl chloride (49 mL, 683 mmol, 5 eq.) at 0-5 °C. The reaction mixture was heated to reflux for 24 h. After completion, the reaction mixture was quenched with saturated solution sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get methyl 5-hydroxypyridine-2-carboxylate (9.0 g, 43percent) as off white solid.5-Hydroxy-2-pyridinecarboxylic Acid Methyl Ester (Compound No. 1): Gaseous hydrogen chloride was passed through a solution of 5 g of dry 5-hydroxy-2-pyridinecarboxylic acid in 100 ml methanol for 5 hours at 70 C. The mixture was kept for 2 days at room temperature and the solvent removed in vacuo. The residue was taken up in a minimum amount of water and neutralized with ammonium hydroxide. The precipitate was removed by filtration and the ester was separated in 70% yield from the acid by recrystallizing from isopropyl alcohol; m.p. 188-190. Calc. for C7 H7 NO3: C, 55.0; H, 4.6; N, 9.2. Found: C, 56.3; H, 5.3; N, 9.6.A solution of compound Int-4 (741 mg, 3.27 mmol, 1.0 eq), Triphenylphosphine (1.17 g, 4.45 mmol) was added to a stirred mixture of methyl 5- hydroxypyridine-2-carboxylate (CAS: 30766-12-2; 500 mg, 3.27 mmol) and l-Boc-4- hydroxypiperidine (CAS: 109384-19-2; 597 mg, 2.97 mmol) in anhydrous THF (30 mL) under N2 atmosphere. The reaction mixture was stirred at room temperature for 15 min, and DIAD (CAS: 2446-83-5; 0.88 mL, 4.45 mmol) was added dropwise at 0 C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 30:70). The desired fractions were collected and concentrated in vacuo to afford intermediate 189 (750 mg, 74%) as a colorless oil.Compound 25A (100 mg, 0.65 mmol), (3, 5-Dichloro-2-(ethoxymethoxy)benzyl)methanol (212 mg, 0.85 mmol), And triphenylphosphine (205 mg, 0.78 mmol) was dissolved in dry tetrahydrofuran.DIAD (263 mg, 1.3 mmol) was added dropwise at 0 C and stirred at room temperature for 1 hour.Spin dry, the crude product was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate = 3:1.Compound 25B (230 mg, 92% yield) was obtained.

Molecular Weight:153.14
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:153.042593085
Monoisotopic Mass:153.042593085
Topological Polar Surface Area:59.4
Heavy Atom Count:11
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes