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With sodium hydroxide; nitric acid; acetic anhydride;
Step 1 Methyl 2-(3-Nitro4-methoxyphenyl)acetate An oven-dried 2-L, 3-neck round bottom flask, equipped with a mechanical stir motor, a low-temperature thermometer and an equalizing dropping funnel, was charged with acetic anhydride (631 mL) and subsequently cooled to -78 C. Fuming nitric acid (Baker, 90%, 27 mL) was added dropwise via the dropping funnel protected with a drying tube filled with CaCl2. After addition was completed, the reaction temperature was allowed to warm to 20 C. over 1 h. The reaction mixture was cooled to -78 C. again and added 4-methoxyphenylacetic acid (50 g, 0.28 mol) dropwise via the dropping funnel. After stirring at -50 C. for 1 h., the reaction mixture was allowed to warm to -30 C. over 20 min. and then cooled to -50 C. again. The reaction mixture was quenched with H2O (500 mL) at -50 C. and warmed up to room temperature and stirred for 0.5 h. The reaction mixture was partitioned between CH2Cl2 (500 mL) and H2O. The aqueous layer was extracted with CH2Cl2 (3*500 mL). The combined CH2Cl2 extracts were concentrated in vacuo to give a yellow oil. This was added slowly to a 2 M solution of NaOH (2 L) cooled at 0 C. and stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 (500 mL) and H2O. The aqueous layer was extracted with CH2Cl2 (3*500 mL). The combined CH2Cl2 extracts were stirred with 2 M NaOH solution (1 L) for 1 h. The layers were separated and the organic layer was washed with H2O (500 mL), brine (500 mL), dried over Na2SO4 and filtered. The solvents were removed in vacuo to afford crude product as a light yellow solid (56 g). Purification by recrystallization from MeOH (600 mL) gave product. Yield 48 g (77%).
EXAMPLE 20 7-Chloro-3-(4-hydroxyphenyl)-2(1H)-quinolone 2-Amino-4-chlorobenzyl alcohol (4 g, 25.3 mol) and 4-methoxyphenyl acetic acid (14.0 g, 76.4 mmol) were reacted in a similar manner to that described in Example 19 to give 7-chloro-3-(4-methoxyphenyl)-2(1H)-quinolone; mp 256-257 C. (ethyl acetate).
DIISOPROPYLAMINE (7. 4ml, 52. [8MMOL)] was added to anhydrous THF under argon. The solution was stirred and cooled to-35C in a dry ice/acetone bath and N-butyl lithium (1.6M, 31. 2ml, 50.4mmol) was added via a syringe over 2-3 mins, controlling the exotherm to [BELOW-20C.] After the addition was complete the reaction was cooled to-70C and a solution of 4-methoxyphenylacetic acid (3.89g, [24MMOL)] in THF (48ml) was transferred to the reaction mixture via a cannula, adding the solution dropwise and keeping the temperature below-55C. The reaction was stirred for 10 mins [AT-70C] and then allowed to warm up to [- L5C.] A solution [OF N-METHYL-N-METHOXY-4-FLUOROPHENYLCARBAMOYL] (4. [38G,] 26. [4MMOL)] in THF (48ml) was added via a dropping funnel dropwise, while the reaction mixture exothermed to [0C.] After addition was complete, the reaction was allowed to warm up to room temperature and stirred for 1.5 hours. The reaction was added to a stirred solution of concentrated hydrochloric acid [(13ML)] in water [(250ML),] and was stirred for 10 mins before the addition of ether. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine and dried (MgS04). The solvent removed in vacuo to give a sticky solid. This was triturated with methanol, and the resultant solid was dried under high vacuum to give a white solid (2.2g). Mp [107-109C] ; NMR [(200MHZ)] 3.78 (3H, s), 4.17 (2H, s), 6.87 (2H, d), 7.13 (4H, m), 8.03 (2H, dd).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; at 0 - 70℃;
Step I: To a stirred solution of 6-bromo-3,4-dihydro-2H-benzo(1,4Joxazine (1.5 g, 7.0 mmol) in dichloromethane - dimethylforrnamide (1:1 mixture. 40 ml) was added 4- methoxyphenyl acetic acid (1.8 g, 10.5 mmol), HOBt (2.4 g, 17.5 mmol), diisopropyiethylamine (4.8 ml, 28 mmol ). EDCI.HCI (3.4 g . 17.5 mmol) at 0 C After 15 rnin, reaction mixture was heated to 70 C for 15 h. quenched by the addition of water. After usual work up, the compound was purified by silica gel column chromatography (10% ethyl acetate in hexane) to furnish 1-(6-bromo-2,3-dihydro-benzo[1.4]oxazin-4-yl)- 2-(4-methoxy-phenyl)-ethanone (1.8 g).1H NMR (400 MHz, CDCI3): delta 3.79 (s, 3H), 3.86 (bs, 4H), 4.14 (bs. 2H): 6.76 (ds J * 8.4 Hz, 1H), 6.86 (d. J « 8.8 Hz. 2H)1 7,16 (d, J * 8.4 Hz: 4H). MS (ES) iWz 364.0 (M+2).
16A) 1-(2-Chloro-4-fluorophenyl)-2-(4-methoxyphenyl)ethanone 230 ml of a 2M solution of NaHMDS in THF are introduced into 250 ml of THF under nitrogen. The solution is cooled to -60 C. and then 30.5 g of (4-methoxyphenyl)acetic acid in 120 ml of THF are added at this temperature. After 1 h 30 min at -60 C., 33 g of <strong>[85953-29-3]methyl 2-chloro-4-fluorobenzoate</strong> are added and the mixture is stirred at -60 C. for 45 min and then allowed to return to 0 C. The reaction medium is poured onto 500 ml of ice-cold 2N HCl and extracted with ether and the extract is washed with water and then with a saturated aqueous sodium chloride solution. After drying, concentrating to dryness and then crystallizing from pentane, 27.4 g of the expected compound are obtained.
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