4-CHLOROPICOLINALDEHYDE

To a solution of the above methyl ester (2.5 g, 14.6 mmol) in 100 mL of dry THF at -78° C. was added diisobutylaluminum hydride dropwise (1.0 M in THF, 29.1 mmol) and the reaction mixture was stirred at that temperature under Ar2 for 2 h. The reaction was quenched with MeOH at -78° C. and then sodium potassium tartrate solution (1.0 M, 180 mL) was added and the mixture was stirred and warmed up to room temperature over 1 h. The slurry was diluted with EtOAc (60 mL) and the organic layer was separated and washed with brine and dried with sodium sulfate. The solvent was removed under mild vacuum at room temperature (volatile compound) to give the desired aldehyde (1.87 g, 91percent) which solidified as a light yellow crystal by standing at room temperature.Methyl 4-chloropyridine-2-carboxylate (3.42 g, 20.0 mmol) was dissolved in THF (100 ml) and DIBAL (1.5M toluene solution, 20.0 ml, 30.0 mmol) was dropwise added to the solution in a nitrogen flow at -70°C (dry ice - acetone). A suspension of 25 (2.0 g, 13.9 mmol) and MnOManganese dioxide (3.03 g) was added to a solution of (4-chloropyridin-2-yl)methanol (1.00 g) obtained in Reference Example 21-7 (1) in ethyl acetate (20 mL), followed by refluxing for 3.5 hours. The reaction mixture was cooled to room temperature, the insoluble materials were filtered off, and the solvent was distilled off under reduced pressure. The obtained residues were purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1), whereby 4-chloropicolinic aldehyde (425 mg) was obtainedGeneral procedure: Under the protection of nitrogen, Add 3L DCM to the 5L three-neck bottle to cool down.240g of oxalyl chloride was added dropwise during cooling;At -60 C, 295.6 g of Dimethyl sulfoxide (DMSO) was added dropwise to the reaction solution.Keep warm for 30min;At -60 C, 237.5 g of Cpd 3 was added dropwise to the reaction solution.The reaction was carried out at -65 C for 1 hour;At this temperature, 3.5 eq of triethylamine (TEA) was added dropwise.After the solution was allowed to stand, the plate was measured.Through the column, the product 4-bromopyridine-2-carbaldehyde is obtained.(Cpd 4) 177.2g, The yield was 75%.Preparation of 4-chloropicolinaldehyde A suspension of MnO2 (7.3 g, 84 mmol) and (4-chloro-pyrindin-2-yl)methanol (1 g, 7 mmol) in CHCl3 was heated to refulx for 90 minutes. The mixture was filtered though a layer of Celite and concentrated in vacuo to afford 520 mg of 4-chloropicolinaldehyde as a white solid. HPLC 1.8 minutes and MS 142 as M=1 peak.Acetic acid (0.086 mL, 1.51 mmol) and sodium cyanoborohydride (47 mg, 0.76 mmol) was added to a stirred solution of intermediate 3 (0.21 g, 0.76 mmol), 4-chloropyridine- 2-carbaldehyde (CAS 63071-13-6, 0.12 g, 0.83 mmol) and sodium acetate anhydrous (0.24 g, 2.95 mmol) in EtOH (5 mL) at rt. The reaction mixture was stirred at rt for 6 h.

Molecular Weight:141.55
XLogP3:1.3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:140.9981414
Monoisotopic Mass:140.9981414
Topological Polar Surface Area:30
Heavy Atom Count:9
Complexity:107
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes