CHEMPACIFIC 38158

Manufacturing Example 52-1-2 2-Chloro-6chloromethyl-pyridine; To a mixture of (6-chloro-pyridine-2-yl)-methanol (200 mg, 1.39 mmol) described in Manufacturing Example 52-1-1 and toluene (3 mL) was added thionyl chloride (152 μL, 2.09 mmol) on an ice bath, which was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (163.2 mg, 73percent).To a mixture of (6-chloro-pyridine-2-yl)-methanol (200 mg, 1.39 mmol) described in Manufacturing Example 52-1-1 and toluene (3 mL) was added thionyl chloride (152 μL, 2.09 mmol) on an ice bath, which was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (163.2 mg, 73percent). 2. tert-Butyl (5S)-2-[(6-chloropyridin-2-yl)methyl]-3-oxo-2, 3, 5, 6, 7, 8-hexahydro[1, 2, 4]triazolo[4, 3-a]pyridine-5-carboxylate tert-Butyl (5S)-3-oxo-2, 3, 5, 6, 7, 8-hexahydro[1, 2, 4]triazolo[4, 3-a]pyridine-5-carboxylate (266 mg, 1.11 mmol) was initially charged in acetonitrile (10 ml). Caesium carbonate (904 mg, 2.77 mmol) and To a stirred solution of 1H-indole-3-carboxaldehyde (145.2mg, lrnmol) and 2- chloro-6-(chloromethyl)pyridine (178.2mg, 1.lmmol) in 5.0 mL of MeCN was added Cs2CO3(980mg, 3mmol) at room temperature. The mixture was then heated to 80C and kept stirring for 3h. When 1H-indole-3-carboxaldehyde was consumed monitored by TLC, MeCN was evaporated. The residue was partitioned in 15 mL of water and 15 rnL of ethyl acetate. The aqueous layer was extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried, and concentrated. The crude product was purified by silica gel column chromatography to give 1 -((6-chloropyridin-2- yl)methyl)- 1 H-indole-3 -carbaldehyde(232. 8mg, 86% yield).ESI-MS m/z 271.7 [M+H].

Molecular Weight:162.01
XLogP3:2.2
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:160.9799046
Monoisotopic Mass:160.9799046
Topological Polar Surface Area:12.9
Heavy Atom Count:9
Complexity:87.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes