2-CHLOROPYRIDINE-5-ACETIC ACID

S1: taking 8.72 mmol of 2-chloro-5-chloromethylpyridine catalyst and solvent DMF into the reaction kettle;S2: Carbon dioxide was introduced to make the pressure in the autoclave 3 MPa, and the reaction was adjusted at 40 ° C for 15 hours.S3: acidification was carried out by adding dilute hydrochloric acid to the reaction vessel, ethyl acetate was extracted, the organic phase was combined, and the liquid was removed by rotary evaporation.Further drying in vacuo to give 6-chloro-3-pyridine acetic acidThe catalyst comprises zinc powder and lithium chloride, a chloromethyl heterocyclic compound and zinc powder, and a molar ratio of lithium chloride to the reaction vessel is 1:3:3.2.8 to 2.9 ml of solvent DMF was added per mmol of 2-chloro-5-chloromethylpyridine.A 4.45 g (29.3 MMOL) portion of Preparatory Compound E was treated with 5 mL of concentrated hydrochloric acid. The mixture was stirred and heated at 80 °C for 24 hours. The solution was poured in to ice and the resulting precipitate filtered. Residual water was removed from the sample by treatment with toluene and removal of the azeotrope under reduced pressure. This procedure yielded 3.93 g (78percent) of Preparatory Compound F, (6-chloro-3-pyridinyl) acetic acid, as a fine yellow powder: mp 170-171 °C ;'H NMR (CDCI3) 8 8.34 (d, J = 3. 0 Hz, 1H), 7.66 (dd, J = 3.0 and 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 3.70 (s, 2H) ppm. MS: (ES+) m/z 172 (M+). Anal. CALCD for C7H6CINO2 : C, 49.0 ; H, 3.52 ; N, 8.16. Found: C, 49.3 ; H, 3.53 ; N, 8.11.Synthesis of compound 169.1. To a solution of 169.1 (5.0g, 29.23mmol, l .Oeq) in MeOH (50 mL), Sulfuric acid (1.9ml) were added at room temperature. Reaction was stirred at room temperature for 1 hour. After completion of the reaction, mixture was poured into NaHC03 solution and extracted using EtOAC. Organic layer was dried over sodium sulfate and concentrate under reduced pressure. Crude was purified by column chromatography to afford 169.2 (5.0 g, 92.4 %). MS (ES): m/z 185.4 [M+H] +Acetyl chloride (15.1 g, 192.3 mmol, 3.3 eq) was added slowly to MeOH (100 mL) at room temperature. The reaction stirred at room temperature for 15 minutes. Compound 55.1 (10 g, 58.3 mmol, 1.0 eq) was added slowly and the reaction mixture was allowed to stir at room temperature for 16 hours. After completion of the reaction, solvent was evaporated under reduced pressure. Satd. NaHCO3 solution was added to reaction mixture and product was extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain pure 55.2 (10.0 g, 92.4%). MS(ES): m/z 185.61 [M+H]+.Compound B4a (5.0 g, 29 mmol) is dissolved in MeOH (50 mL) and sulfuric acid (1 .9 mL) is added. The reaction is stirred at RT for 45 min and then is concentrated. The residue is partitioned between EtOAc and saturated NaHC03. The organic layer is washed with water and brine, dried over MgS04, filtered and concentrated to give B4bStep A: methyl 2-(6-chloropyridin-3-yl)acetate To a solution of Step A: methyl 2-(6-chloropyridin-3-yl)acetate To a solution of Step A: methyl 2-(6-chloropyridin-3-yl)acetate ci N ' To a solution of Step 1. Synthesis of methyl 2-(6-chloropyridin-3-yl)acetate To a stirred solution of MeOH (25 mL) was added slowly acetyl chloride (3.5 mL). After 30 min, Intermediate M-1 was synthesized through the esterification of the carboxylic acid moiety of A 4.45 g (29.3 MMOL) portion of Preparatory Compound E was treated with 5 mL of concentrated hydrochloric acid. The mixture was stirred and heated at 80 C for 24 hours. The solution was poured in to ice and the resulting precipitate filtered. Residual water was removed from the sample by treatment with toluene and removal of the azeotrope under reduced pressure. This procedure yielded 3.93 g (78%) of Preparatory Compound F, (6-chloro-3-pyridinyl) acetic acid, as a fine yellow powder: mp 170-171 C ;'H NMR (CDCI3) 8 8.34 (d, J = 3. 0 Hz, 1H), 7.66 (dd, J = 3.0 and 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 3.70 (s, 2H) ppm. MS: (ES+) m/z 172 (M+). Anal. CALCD for C7H6CINO2 : C, 49.0 ; H, 3.52 ; N, 8.16. Found: C, 49.3 ; H, 3.53 ; N, 8.11. (4 g, 24 mmol) in THF (30 mL) was added to a solution of 1M KHMDS (55 mL, 55 mmol) in THF at -78 C. over a period of 10 min. Reaction mass was stirred for 1 h at the same temperature, followed by drop wise addition of isopropyl iodide (5.17 g, 30 mmol) over a period of 5 min. Reaction mixture was warm to room temperature and stirred overnight. Reaction mass was quenched with 2N HCl and organic layer was separated from aqueous layer. Aqueous layer was further extracted with ethyl acetate and combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound. Crude was further purified with silica column chromatography by eluting with ethylacetate:hexane (30:70) mixture as mobile phase to afford pure title compound (3.7 g, 74%). LCMS: m/z=214 (M+H)+ (200 mg, 1.17 mmol), 4-fluoroaniline (130 mg, 1.17 mmol), HATU (445mg, 1.17mmol)After stirring with TEA (236 mg, 2.34 mmol) in DMF (10 mL) at room temperature for 2 h, Water (50 mL) was poured and extracted with ethyl acetate (2×50 mL).The organic phase was separated and washed with saturated aqueous NaCl (2×).The organic phase was separated and dried over anhydrous Na2SO4, filtered and concentrated.The residue was purified by silica gel column chromatography.Elution with ethyl acetate/petroleum ether (1:3) gave the desired compound 19 (250 mg, 81%).

Molecular Weight:171.58
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:171.0087061
Monoisotopic Mass:171.0087061
Topological Polar Surface Area:50.2
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes