3-ACETYL-2-CHLOROPYRIDINE

Step 2: l-(2-Chloropyridin-3-yl)ethanone.A solution of l-(2-chloropyridin-3-yl)ethanone (1O g, 0.0635 mol) in dry acetone (200 mL) was introduced under argon into a 1 L flask. The mixture was cooled to -30 Step 2[00176] To a solution of l-(2-chloropyridin-3-yl)ethanol (II) in dry acetone at - 30°C under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30°C and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated NaHC0To a solution of 1-(2-chloropyridin-3-yl)ethanol (XII) in dry acetone at −30° C. under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at −30° C. and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCOStep 2 To a solution of 1-(2-chloropyridin-3-yl)ethanol (X) in dry acetone at -30°C under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30°C and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCCb solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1 -(2-chloropyridin-3 -yl)ethanone (XI) as a brown liquid (0.72 g, 4.63 mmol, 77percent yield). 1H NMR (CDCl3) δ ppm 2.71 (s, 3H), 7.35 (dd, J=7.63Hz, J=4.80Hz, 1H), 7.91 (dd, J=7.54Hz, J=1.88Hz, 1H), 8.55 (dd, J=4.71Hz, J=1.88Hz, 1H).A solution of 2-chloro-N-methoxy-N-methyl-nicotinamide (23.6 g, 118 mmol) in tetrahydrofuran (350 mL, 0.34M) at 0° C. was treated dropwise via an addition funnel with methyl magnesium chloride (3.0M solution in tetrahydrofuran, 100 mL, 300 mmol).General procedure: Methylmagnesium chloride (0.5 M in THF, 8.0 mL, 4.0 mmol) was added to a solution of 2-pyridyl 2-chloropyridine-3-carboxylate (2c, 939 mg, 4.0 mmol) in THF (12 mL) at 0 °C under argon atmosphere. After stirring for 0.5 h, the mixture was quenched with saturated NHTo a solution of 2 (473 mg, 3.0 mmol) in THF (8 mL) was added phenylethynyllithium, generated from phenylacetylene (306 mg, 3.0 mmol) and methyllithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) for 0.5 h at 0 C, or methyllithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) at 0 C. After being stirred for 0.5 h, the mixture was quenched with 0.5 N HCl (5 mL) and THF was evaporated in vacuo. The mixture was poured into 0.1 N HCl (30 mL) and extracted with dichloromethane(3 × 20 mL). The condensed residue was purified by silicagel column chromatography using 30percent EtOAc/n-hexane or vacuum distillation using a Kugelrohr apparatus to give 3a (616 mg, 85percent) and 6 (420 mg, 90percent), respectively.Phenylacetylene (306 mg, 3.0 mmol) and methyl lithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) were reacted at 0 C for 0.5 hour Was added to a solution of compound 2 (473 mg, 3.0 mmol) in THF (8 mL). For 0.5 hours After mixing, the reaction was quenched by the addition of 0.5 N HCl (5 mL) and THF to the mixture and evaporated in vacuo. evaporation The resulting mixture was taken up in 0.1 N HCl (30 mL) and extracted with dichloromethane (3 x 20 mL). The concentrated residue was dissolved in 30percent The residue was purified by silica gel column chromatography using EtOAc / n-hexane as an extraction solvent to obtain Compound 3a (616 mg, 85percent) Respectively. Also, methyllithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) was added to a solution of compound 2 (473 mg, 3.0 mmol). After mixing for 0.5 h, the reaction was stopped by adding 0.5 N HCl (5 mL) to the mixture THF was evaporated in vacuo. The evaporated mixture was poured into 0.1 N HCl (30 mL) and added with dichloromethane (3 x 20 mL) . The concentrated residue was vacuum distilled using a Kugelrohr distillation column to yield compound 6 (420 mg, 90percent).After diluting the product in step b) with the appropriate amount of dry toluene, Slowly added to the stirred solution of step a) at room temperature.After stirring for 40 min, the solution was concentrated with concentrated HCl (261 g, 2.32 mol).The toluene layer was evaporated and cooled to give a pale yellow solid.To this solid was added DMSO (650 ml) and water (29 ml).The mixture was heated and maintained at 155 ° C for 3 hours and then heated until the reaction solution was cooled and poured into 2.5 L of cold water, A large amount of off-white solid precipitated, filtered and dried.To give 96 g of product 2-chloro-3-acetylpyridine in 72percent yield.Water (1.3 mL) was added to a solution of diethyl 2-(2-chloronicotinoyl)malonate (31.7 mmol) in dimethylsulfoxide (50 mL). A solution of diethyl 2-(2-chloronicotinoyl)malonate (267 mmol) in dimethylsulfoxide (100 ml) was added dropwise over 1.5 h to a 130° C. solution of water (10 mL) in dimethylsulfoxide (260 mL).

Molecular Weight:155.58
XLogP3:1.5
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:155.0137915
Monoisotopic Mass:155.0137915
Topological Polar Surface Area:30
Heavy Atom Count:10
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes