6-CHLORO-2-PICOLINICACIDMETHYLESTER

Add thionyl chloride (3.7 ml, 50.8 mmol) to a solution of 6-chloropicolinic acid (4.0 g, 25.4 mmol) in methanol (85 ml) at 0 C. Stir the resultant solution for 15 minutes at 0 C, 0.5 hours at room temperature, and 6 hours at 50 C. Concentrate the reaction in vacuo and dilute with CHCl3 (150ml). Wash the organic solution with saturated aqueous sodium bicarbonate (3 x 100 ml), and brine (1 x 100 ml) and dry with sodium sulfate. Filtration and concentration afford methyl 6-chloropicolinate 4.38 g (100 percent) as a white solid. 1H NMR (CDCl3): δ 8.05 (m, 1H), 7.73 (m, 1H), 7.42 (m, 1H), 3.95 (s, 3H)PREPARATION 1: Preparation of β-chloropyridine-^-carboxylic acid methyl ester6.5 g (41.2 mmol) of -chloropyridine^-carboxylic acid was dissolved in 100 ml of methanol, and 5 ml of 2 N hydrochloric acid solution in methanol was added thereto, then stirred under reflux for 15 hours. After completion of the reaction, the reaction solution was concentrated, and 100 ml of water was added thereto, then neutralized using 1 N aqueous sodium hydroxide solution. The resulting solution was extracted twice with 70 ml of ethyl acetate, and concentrated to obtanin 6.69 g (39.1 mmol, yield of 95percent) of the title compound.(a) Methyl -chloro-pyridine^-carboxylate; The following may be mentioned as preferred compounds of the general formula (I) which can be prepared by the process according to the invention: ... 2, 4-dichloropyridine 2, 6-dichloropyridine 2-chloro-3-cyano-pyridine 2-chloro-6-cyano-pyridine methyl 6-chloro-pyridine-2-carboxylate ethyl 6-chloro-pyridine-2-carboxylate N, N-dimethyl-6-chloro-pyridine-2-carboxamide N, N-diethyl-6-chloro-pyridine-2-carboxamide ...The following may be mentioned as compounds of the general formula (I) which can preferably be prepared using the process according to the invention: ... 2, 4-Dichloropyridine 2, 6-Dichloropyridine 2-Chloro-3-cyano-pyridine 2-Chloro-6-cyano-pyridine Methyl 6-chloro-pyridine-2-carboxylate Ethyl 6-chloro-pyridine-2-carboxylate N, N-Dimethyl-6-chloro-pyridine-2-carboxamide N, N-Diethyl-6-chloro-pyridine-2-carboxamide ...A solution of compound Int-45 (1.5 g, 7.24 mmol, 1.0 eq), Methyl 6-[1-(tert-butoxycarbonyl)hydrazino]pyridine-2-carboxylate Methyl 6-chloropyridine-2-carboxylate (32.5 g, 189 mmol), tert-butyl hydrazinecarboxylate (25.0 g, 189 mmol) and caesium carbonate (61.6 g, 189 mmol) in toluene (325 ml) were degassed with argon, before [1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.9 g, 10 mmol) was added. The reaction mixture was stirred at 100 C. overnight. The reaction mixture was diluted with dichloromethane and filtered through kieselguhr. The filtrate was concentrated under reduced pressure and the residue was purified via column chromatography (silica gel, eluent: methanol/dichloromethane 4/96). The product-containing fractions were concentrated under reduced pressure and stirred with methyl tert-butyl ether. 28.8 g (57% of theory) of the title compound were obtained. LC-MS (Method 5): Rt=3.45 min; MS (ESIpos): m/z=268 [M+H]+General procedure: An oven-dried Schlenk flask was evacuated and back-filled with argon three times. (Hetero)aryl (di)halide (1 equiv), base (1.5 equiv per halogen) and a solution of SPO (1.2 equiv per halogen) in anhydrous solvent (5 mL/mmol per halogen) were added to the flask. The solution was bubbled with argon for 10 min and Pd(OAc)2 (1 mol% per halogen) and ferrocene-based bidentate phosphine ligand (2 mol% per halogen) were added to the flask simultaneously [2.5 mol% Pd(OAc)2 per halogen and 5 mol% dppf per halogen for compounds 2j, 2l, 2r, 2t, 2w]. The resulting mixture was heated at the indicated temperature for the given time. Workup procedures are described below for two different conditions. Final purification of crude products was achieved by column chromatography on silica gel (40-60 mum) using CH2Cl2-MeOH as eluent. Reaction scale and yields are shown in Table 1 (2a-w), Scheme 1 (3a-h) and Scheme 2 (4a-g). Notice that all compounds with two phosphine oxide groups are beige-to-brown solids or slowly solidifying viscous brown oils. Conditions I: ligand: dppf, solvent: DMF, base: Cs2CO3 (2d-n, 2q, 2r, 2t-w, 4a-g) or K2CO3 (3a-h), temperature: 120 C, time: 7 h (20 h for 2j, 2l, 2r, 2w). Workup: after cooling, the reaction mixture was poured into a fourfold excess of brine. The mixture was extracted three times with CH2Cl2 (40 mL/mmol each). The combined organic layers were washed with brine to remove traces of DMF, dried over Na2SO4 and then evaporated to dryness. Conditions II: ligand: dippf, solvent: toluene, base: t-BuOK, temperature: 110 C, time: 7 h. Workup: after cooling, the reaction mixture was evaporated to dryness. Then, the mixture was diluted with CH2Cl2 (40 mL/mmol) and washed with water and brine (40 mL/mmol). The organic layer was dried over Na2SO4 and the CH2Cl2 was removed under reduced pressure.A solution of

Molecular Weight:171.58
XLogP3:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:171.0087061
Monoisotopic Mass:171.0087061
Topological Polar Surface Area:39.2
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes