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With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;
To a solution under nitrogen gas of methyl 2-methoxy-4-chlorobenzoate (10.0 g, 50 mmol) in THF (100 mL) was added at 0C a 1.0 M LiAlH4 solution in THF (75 mL, 75 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. Then, the solvent was removed under vacuum and the residue was stirred in a 5% aqueous acetic acid solution (pH 6) for 15 minutes. The aqueous layer was extracted with EtOAc, then the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product as a tan oil. The crude product was purified by flash chromatography (gradient petroleum ether/EtOAc 100/5) to give 7.5 g (yield = 87 %) of white solid corresponding to 2-methoxy-4-chlorobenzyl alcohol (14-1). 1H NMR (400 MHz, CDCl3)
With lithium borohydride; In tetrahydrofuran; at 60℃; for 16h;Inert atmosphere;
General procedure: To a solution of methyl 4-bromo-2-methoxybenzoate (7.14g, 29mmol) in THF (35mL) was added a 2M solution of LiBH4 in THF (35mL, 70mmol, 2.4equiv). The solution was heated at 60C for 16h. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The residue was stirred in a 5% aqueous acetic acid solution (pH 6) for 15min. The aqueous layer was extracted with EtOAc (2×50mL), then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to yield the crude product as a tan oil. The oil was purified by flash chromatography using 5% EtOAc in hexanes to provide 5.96g (94%) of the product as a white solid.
With methanol; sodium tetrahydroborate; at 60℃; for 4h;
Step 2; To the solution of meihyl 4-chioro-2-methoxybenzoate in 5 mL of MeOH was added aBH4 (304 mg, 8.04 mmol). The reaction was stirred at 60 C for 4h. The completion of the reaction was monitored by HPLC. Upon completion, solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHC03, brine and dried over Na2'04. Filtration and removal of the solvent provided 49 mg (35% overall yield) of the title compound as a colorless oil, which was used without further purification; . 1H N (400 MHz, CDC ) ~ 7.22 (d, J - 7.9 Hz, 1 H), 6.94 (dd, J = 2,0, 7.9 Hz, 1 H), 6.88 (d, J ~ 2.0 Hz, 1 H), 4.65 (s, 2 H), 3.87 (s, 3 H).
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; iodine; sodium hydrogencarbonate; In water; toluene; at 20℃; for 72h;
INTERMEDIATE 6(4-Chloro-2-methoxybenzylidene)malononitrile EPO <DP n="45"/>Step A: 4-Chloro-2-methoxybenzaldehydeFollowing the general method of R. A. Miller and R. S. Hoerrner, Org. Lett, 5, 285 (2003), a solution of 2.5 g (14.1 mmol based on 97% purity) of 4-chloro-2-methoxybenzyl alcohol in 35 mL of toluene was treated with 35 mL of water and 3.54 g (42.3 mmol) of sodium bicarbonate. The resulting two-phase mixture was stirred at ambient temperature as 7.2 g (28.2 mmol) of iodine was added, followed by 0.223 g (1.41 mmol) of 2,2,6,6-tetramethyl-l-piperidinyloxy, free radical (TEMPO). After 3 days, the dark mixture was cooled to 5 0C and quenched by addition of a solution of 1.8 g of sodium sulfite in 18 mL of water. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic phase was then dried over anhydrous sodium sulfate. The supernatant was concentrated to a volume of approximately 5 mL and kept at 5 0C for 1 h. The solid that separated was collected on a filter, washed twice with small volumes of cold toluene, and dried in vacuo to yield the title compound as a white solid. LC-MS 171 (M + 1).
A solution of anhydrous DMSO (5.1mL, 73mmol, 3.0equiv) in anhydrous dichloromethane (50mL) was cooled to -78C in a dry ice/i-PrOH bath. Oxalyl chloride (6.4mL, 73mmol, 3.0equiv) was added dropwise over 45min. The mixture was stirred for 15min and a solution of 4-bromo-2-methoxybenzyl alcohol (30b; 5.30g, 24mmol) in dichloromethane (10mL) was added dropwise. The resulting mixture was stirred for 30min at -78C. Triethylamine (12.4g, 120mmol, 5.0equiv) was then added, and the mixture was allowed to warm to rt over 16h. The mixture was quenched with water (100mL) and extracted with chloroform (3×200mL). The combined organic extracts were washed with water (1×150mL), brine (1×150mL), dried (MgSO4), filtered, and evaporated to yield the crude product as dark residue. The residue was purified by flash chromatography using chloroform to obtain an off-white solid that was recrystallized from hexanes to yield 3.73g (71%) of the product as a white solid.
With 4-methyl-morpholine;molecular sieve; In dichloromethane;
[Referential Example 296] 4-Chloro-1-formyl-2-methoxybenzene In methylene chloride (80 ml) was dissolved (4-chloro-2-methoxyphenyl)methanol (3.69 g). Under ice cooling, molecular sieve 4A (4.57 g), N-methylmorpholine (2.81 g) and tetra-n-propylammonium perruthenate (420 mg) were addedto the resulting solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was distilled under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane: ethyl acetate = 9:1), whereby the title compound (3.07 g) was obtained as pale yellow oil. 1H-NMR (CDCl3) delta: 3.94(3H,s), 6.99(1H,d,J=2.0Hz), 7.00-7.05(1H,m), 7.77(1H,d,J=8.3Hz), 10.39(1H,s).
(137-2) Under nitrogen atmosphere, a solution of the compound of Example 137-1 (4.50 g) in THF (75 mL) was cooled to 0C, and thereto was added LiAlH4 (984 mg) in portions. The mixture was stirred at room temperature for 2 hours, and cooled to 0C. Water (1.0 mL), a 2N aqueous NaOH solution (2.0 mL) and water (1.0 mL) were added successively to the mixture, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, and washed with ethyl acetate. The filtrate and the washing were combined, washed with a saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure to give (4-chloro-2-methoxyphenyl)methanol (3.88 g, 100 %). 1H NMR (CDCl3, 400MHz) δ 7.21(d, 1H, J=8.0 Hz), 6.93 (dd, 1H, J=1.9, 8.0 Hz), 6.87 (d, 1H, J=1.9Hz), 4.64 (s, 2H), 3.86 (s, 3H).