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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.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 5.33333h;Inert atmosphere;
a) Preparation of N-(p-methoxylphenylacetyl)-D-leucine benzyl ester[0196] P- methoxyl phenylacetic acid (1.29g) , D- leucine benzyl ester hydrochloride (2g) and DIEA (2.2g) were dissolvedin anhydrous dichloromethane (60ml) , cooled down to 0C under the protection of nitrogen, and then HOBt (1.1g)and EDCI (1.8g) were added. The resulting mixture was stirred at 0C for 20min and allowed to warm up naturally toroom temperature to react for 5 hours. The organic layer was washed in turn with 5% potassium hydrosulphate solution,saturated sodium hydrogencarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressue to give 4.1g crude product, which was purified with column chromatographyto give a colourless oil (3.06g, yield: 100%) . The content was 99% (HPLC, mobile phase 1, method 1) .Rf = 0.2Developer: petroleum ether: ethyl acetate = 4: 1Color development: ultraviolet, iodine and 1% ninhydrin solutionMS: 370 (M+H)
With benzotriazol-1-ol;
a) Preparation of N-(p-methoxylphenylacetyl)-D-leucine benzyl ester P-methoxyl phenylacetic acid (1.29 g), <strong>[68838-94-8]D-leucine benzyl ester hydrochloride</strong> (2 g) and DIEA (2.2 g) were dissolved in anhydrous dichloromethane (60 ml), cooled down to 0 C. under the protection of nitrogen, and then HOBt (1.1 g) and EDCI (1.8 g) were added. The resulting mixture was stirred at 0 C. for 20 min and allowed to warm up naturally to room temperature to react for 5 hours. The organic layer was washed in turn with 5% potassium hydrosulphate solution, saturated sodium hydrogencarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4.1 g crude product, which was purified with column chromatography to give a colourless oil (3.06 g, yield: 100%). The content was 99% (HPLC, mobile phase 1, method 1).
3-(4-methoxyphenyl)-9-nitro-2-oxo-2,5-dihydropyrano[3,2-c]chromen-5-yl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium carbonate; at 70℃; for 2h;
General procedure: A mixture of 1.74 g (10.0 mmol, 1.00 mol eq) of 4-oxo-4H-chromone-3-carbaldehyde together with 1.50 g (11.0 mmol, 1.10 mol eq) 2-phenylacetic acid and 138 mg (1.00 mmol, 0.10 mol eq) of K2CO3 (abs) was stirred in15 mL of freshly distilled Ac2O at 70 C for 2 h. After cooling the reaction mixture to rt, the precipitated product 1a was filtered off, washed with H2O (3 × 10 mL), Et2O(3 × 10 mL) and dried under vacuum to yield 2.374 g (7.1 mmol, 71%) of 1a.
With potassium ethoxide; In 1,4-dioxane; at 100℃; for 24h;
To a 100 mL reaction flask equipped with a stir bar, add <strong>[475250-52-3]4-methoxybenzylboronic acid pinacol ester</strong> (0.3 mmol, 1 equivalent, 74.4 mg), potassium ethoxide (0.6 mmol, 50.5 mg), 5 mL dioxane ,Lyophilize the solvent in a liquid nitrogen bath and fill with carbon dioxide three times,The reaction bottle was closed and heated to 100 C to stir the reaction for 24 hours.After the reaction, the reaction mixture was freed from the solvent under reduced pressure,The mixture was transferred to a 125 mL separatory funnel via ethyl acetate, and 5 mL of dilute hydrochloric acid (1 mol / L) was added,Add 40mL ethyl acetate and 30mL water to extract three times,The organic phases were combined, the solvent was removed under reduced pressure, and purified by column chromatography to obtain the desired product 4-methoxyphenylacetic acid in 15% yield.
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