4-Iodo-2-methoxypyridine-3-carboxaldehyde

A mixture of DIPA (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 °C and nBuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 mm, the r.m. was cooled to -75 °C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 °C. The r.m. was cooled to -75 °C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 mill sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25percent purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), Et20 (100 mL) and the layers were separated. The aq. layer was extracted with Et20 (100 mL) and the combined organic layers weretreated with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford intermediate 1 (6.15 g, 94percent), which was used as such in the next reaction step.To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrous THF (5 L) at -8 to -10° C. under a blanket of NUnder the stream of nitrogen, a THF (500 mL) solution of diisopropylamine (25 g) was added into a 2L-fourneckedflask. The solution was cooled to -25°C, and n-butyl lithium - hexane solution (1.57 mol/L) (157 mL) was droppedto the solution for 20 minutes (-25°C → -15°C), and the solution was stirred at -10°C for 30 minutes. The resulting solutionwas cooled to -66°C, and a THF (200 mL) solution of 2-fluoro-3-iodopyridine (CAS registration No.: 113975-22-7) (50g) was dropped thereto for 25 minutes, and stirred at -60°C for two hours. The resulting solution was cooled to -66°C, and ethyl formate (18.3 g) was dropped thereto for 10 minutes. Then, 28percent solution of sodium methoxide methanolsolution (53.2 g) in methanol (100 mL) was dropped, and lifted up from dry ice bath. The resulting product was naturallycooled to room temperature, and ice water (100 mL) was dropped thereto. A saturated saline solution (1 L) was addedthereto. The resulting solution was extracted with ethyl acetate (1 L), and washed with water (700 mL) and a saturatedsaline solution (700 mL). The water layer was combined and extracted with ethyl acetate (500 mL 3 2), and washedwith water (500 mL) and a saturated saline solution (500 mL). The organic layer was combined and dried over anhydroussodium sulfate, and the solvent was removed by evaporation under reduced pressure. The obtained residue was purifiedby column chromatography on silica gel (hexane : ethyl acetate = 9:1 → 6:1 → 5:1 → 4:1 → 3:1) to obtain the titlecompound (44 g) having the following physical property valuesSynthesis of Difluoro Compound General Scheme; [00632] 4-Iodo-2-methoxynicotinic aldehyde: To a solution of t-BuLi (1.7 M, 7.36 niL, 12.51 mmol) in 20 niL THF at -78 °C was added dropwise 2-bromomesitylene (0.91 niL, 5.95 mmol). After stirred for 1 h, 2-methoxypyridine (0.48 mL, 4.58 mmol) was added dropwise, and the mixture was warmed to 0 °C and stirred for 2 h. The solution was cooled to -78 °C and JV-formyl-iV, iV, 7V-trimethylethylenediamine (0.7 mL, 5.06 mmol) was added. The mixture was stirred at -78 °C for 30 min and then warmed to -23 °C. A hexane solution of W-BuLi (2.5 M, 2.75 mL, 6.87 mmol) was added dropwise, and the resulting yellow mixture was stirred for 3 h. The mixture was cooled to -78 °C and transferred via a double- tipped needle to a solution of iodine (2.17 g, 8.23 mmol) in 30 mL of THF at -78 °C. After stirred at -78 °C for 30 min, the cooling bath was removed and the reaction mixture was allowed to warm to the room temperature. After the reaction mixture was cooled to -5 °C, aqueous solution OfNHA mixture of DIP A (3.5 mL, 25 mmol) in THF (100 mL) was cooled to -20 °C and n- BuLi (2.7 M in heptane, 9.2 mL, 25 mmol) was added dropwise. After stirring 10 min, the r.m. was cooled to -75 °C and 2-fluoro-3-iodopyridine (5.55 g, 25 mmol) in THF (50 mL) was added dropwise. Stirring was continued for 2 h at -65 °C. The r.m. was cooled to -75 °C and ethyl formate (2.3 mL, 28 mmol) in THF (25 mL) was added dropwise. After 10 min sodium methoxide (5.8 mL, 0.95 g/mL, 25 mmol, 25percent purity) was added dropwise. The cooling bath was removed and the r.m. was allowed to come to r.t. and treated with brine (50 mL), EtSynthesis of 4-iodo-2-methoxypyridine-3-carbaldehyde (DeTMS-PM) A solution of 2-methoxypyridine (2.18 g, 20 mmol) in 100 ml THF is cooled to -78 Example A5: A -78°C solution of 2-methoxypyridine (40 g, 0.37 mol) in THF (1 L) was treated with t-BuLi (163 mL, 0.41 mol), stirred at -78°C for 0.5 h, treated with N-(2-dimethylaminoethyl)-N-methylformamidine (52.9 g, 0.41 mol) over 10 mm, stirred at -78°C for another 0.5 h, then warmed to -20°C for 45 minutes. The mixture was cooled to -40°C, treated with n-BuLi (289 mL, 0.46 mol), stirred at -40°C for 1.5 h, then cooled to -78°C. The cold mixture was added via syringe to a solution of 12 (187.8 g, 0.74 mol) in THF at -78°C, stirred at -78°C for 0.5 h, then warmed to 0°C. The mixture was quenched with satd. NaS2O3, the organic layer washed with brine, dried over Na2SO4, concentrated under reduce pressure, and purified by chromatography. The resulting solid was washed with pet ether to afford 4-iodo-2-methoxynicotinaldehyde (22 g, 23percent). ‘H NMR (400 MHz, CDC13): 5 10.20 (s, 1 H), 7.84 (d, J = 5.6 Hz, 1 H), 7.53 (d, J = 5.2 Hz, 1 H), 3.99 (s, 3 H).EXAMPLE 10 (4-Iodo-2-methoxy-pyridin-3-yl)methanol (2b) Following the procedure in Example 1, the reaction was carried out with 1b (1.88 g, 7.1 mmol) and NaBH4 (0.135 g, 3.56 mmol) in EtOH (40 mL) to afford 2b as a pale yellow oil (1.83 g, 97%).

This compound is used in the synthesis of insulin-like growth factor 1-receptor inhibitors that display anti-tumor activity.

Molecular Weight:263.03
XLogP3:1.3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:262.94433
Monoisotopic Mass:262.94433
Topological Polar Surface Area:39.2
Heavy Atom Count:11
Complexity:142
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes