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Stage #1: With oxalyl dichloride In dichloromethane at 0℃; for 2 h; Stage #2: With aluminum (III) chloride In dichloromethane at 20℃; for 16 h;
8-Fluorochroman-4-one. Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluoroρhenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 °C for 2 hours, then aluminum chloride (7.39g, 55.42mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20percent EtOAc/Hex) to give of the title compound (8.2Og, 98percent).
98%
Stage #1: With oxalyl dichloride In dichloromethane Stage #2: With aluminum (III) chloride In dichloromethane
8-fluorochroman-4-one (37). Oxalyl chloride (8.79 mL) and one drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0° C. for two hours, aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at RT. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, dried, evaporated, and purified by column chromatography (eluding with 20percent EtOAc/Hex) to give 8-fluorochroman-4-one (37) (8.20 g, 98percent). 8-Fluorochroman-4-one. Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0° C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20percent EtOAc/Hex) to give of the title compound (8.20 g, 98percent).
53%
at 100℃; for 2 h;
A mixture of compound (174a) (3.7 g, 20.3 mmol) in polyphosphoric acid (59.5 g, 607.6 mmol) was stirred at 100° C for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated in diethyl ether and filtered. The filtrate was concentrated to provide compound (174b) (1.80 g, 10.8 mmol, 53percent) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.83-2.90 (m, 2H), 4.60-4.68 (m, 2H), 6.95 (td, J = 8.0/4.4 Hz, 1H), 7.30 (ddd, J = 1.4/8.0/10.6 Hz, 1H), 7.67 (td, J = 1.4/8.0 Hz, 1H). MS m/z ([M+H]+) 167.
8-Fluorochroman-4-one. Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluororhohenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 C for 2 hours, then aluminum chloride (7.39g, 55.42mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give of the title compound (8.2Og, 98%).
98%
8-fluorochroman-4-one (37). Oxalyl chloride (8.79 mL) and one drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 C. for two hours, aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at RT. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, dried, evaporated, and purified by column chromatography (eluding with 20% EtOAc/Hex) to give 8-fluorochroman-4-one (37) (8.20 g, 98%). 8-Fluorochroman-4-one. Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give of the title compound (8.20 g, 98%).
53%
With polyphosphoric acid; at 100℃; for 2h;
A mixture of compound (174a) (3.7 g, 20.3 mmol) in polyphosphoric acid (59.5 g, 607.6 mmol) was stirred at 100 C for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated in diethyl ether and filtered. The filtrate was concentrated to provide compound (174b) (1.80 g, 10.8 mmol, 53%) which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 2.83-2.90 (m, 2H), 4.60-4.68 (m, 2H), 6.95 (td, J = 8.0/4.4 Hz, 1H), 7.30 (ddd, J = 1.4/8.0/10.6 Hz, 1H), 7.67 (td, J = 1.4/8.0 Hz, 1H). MS m/z ([M+H]+) 167.
With polyphosphoric acid; at 100℃; for 3.5h;
Polyphosphoric acid (7.0 g) was added to the compound 1-2 (450 mg) , and the mixture was stirred at 100C for 3.5 hours. The heat source was turned off and the temperature was lowered to 75C. At that time, crushed ice was gradually added to the reaction mixture with vigorous stirring. When the temperature was returned to room temperature, the reaction solution was added to ice water. The aqueous layer was extracted with diethyl ether, and the organic layer was sequentially washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (273 mg) .IH NMR (400 MHz, CDCl3) (ppm) : 2.89 (t, J=6.4 Hz, 2H), 4.66 (t, J=6.4 HZ, 2H), 6.98 (td, J=4.4 , 8.0 Hz, IH), 7.29-7.34 (m, IH), 7.71 (dt, J=I.5, 8.0 Hz, IH)
3-(2-fluorophenoxy)propanoic acid chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 2h;
8-Fluorochroman-4-one.; Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of <strong>[2967-72-8]3-(2-fluorophenoxy)propanoic acid</strong> (9.27 g) in DCM (50 mL). The solution was stirred at 0 C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give of the title compound (8.20 g, 98%).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 2h;
Oxalyl chloride (8.79 mL) and one drop of DMF were added to an ice cold solution of <strong>[2967-72-8]3-(2-fluorophenoxy)propanoic acid</strong> (9.27 g) in DCM (50 mL). The solution was stirred at 0 0C for two hours, aluminum chloride (7.39g, 55.42mM) was added and the solution was stirred for 16 hours at RT. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, dried, evaporated, and purified by column <n="36"/>chromatography (eluting with 20% EtOAc/Hex) to give 8-fluorochroman-4-one (37) (8.2Og, 98%),
3-(2-Fluorophenoxy)propanoic acid.; A mixture of 2-fluorophenol (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5 g of less pure compound.
A solution of 2-fluorophenol (compound 1-1, 3.0 g) in N,N-dimethylformamide (7.0 ml) was added to a solution of 50% sodium hydride (3.22 g) in N,N- dimethylformamide (100 ml) in a nitrogen atmosphere with cooling in an ice bath. After stirring at the same temperature for 30 minutes, a solution of 3-bromo- propionic acid (4.91 g) in N, N-dimethylformamide (8.0 ml) was added. The mixture was returned to room temperature and stirred at the same temperature for 24 hours. The pH was adjusted to 1 to 2 with 1 N hydrochloric acid (100 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine . The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding a mixed solvent of 20% ethyl acetate-hexane to obtain the title compound (1.53 g) .; IH NMR (400 MHz, DMSO-d6) (ppm) : 2.73 (t, J=6.0 Hz,2H) , 4.24 (t, J=6.0 Hz, 2H) , 6.90-7.00 (m, IH) , 7.09-7.24 (m, 3H) , 12.41 (br. S., IH) .
3-(2-Fluorophenoxy)propanoic acid. A mixture of 2-fluorophenol (15 g), 3- bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 5OmL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a EPO <DP n="98"/>white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5g of less pure compound.
Example 15 Synthesis of 8-fluorochroman-4-amine 3-(2-fluorophenoxy)propanoic acid (36). A mixture of 2-fluorophenol (35) (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to RT and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted three times with EtOAc to yield 2.5 g of less pure compound (36). 3-(2-Fluorophenoxy)propanoic acid. A mixture of 2-fluorophenol (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5 g of less pure compound.
A mixture of 2-fluorophenol (35) (15 g), 3-bromoprorhoanoic acid (20 g) and NaOH (11 g) was refluxed in 5OmL of water. The solution was cooled to RT and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted three times with EtOAc to yield 2.5g of less pure compound (36).
With potassium tert-butylate; In tetrahydrofuran; at 0 - 50℃; for 3h;
To a suspension of 2-fluorophenol (3.0 g, 26.8 mmol) in THF (30 mL) at 0-5C was dropped a solution of potassium tert-butoxide (1N in THF, 28.1 mL, 28.1 mmol), followed by beta-propiolactone (1.85 mL, 29.4 mmol) in one portion. The mixture was warmed to room temperature for 1 hour and then heated at 50C for 2 hours. After cooling to room temperature, the mixture was quenched with a saturated solution of sodium hydrogenocarbonate and diluted with water. The aqueous layer was washed with ethyl acetate, acidified with 1 M hydrochloric acid until pH 2 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound (174a) (3.73 g, 20.3 mmol, 76%) which was used without further purification. MS m/z ([M-H]-) 183.
Potassium t-butoxide (2.42 g) was added to a solution of the compound 1-1 (2.20 g) in tetrahydrofuran (100 ml) at room temperature. After stirring for five minutes at the same temperature, beta-propiolactone (2.71 ml) was added. Because of heat generation, the mixture was moved to an ice bath and stirred at the same temperature for one hour. After further stirring at room temperature for four hours, the mixture was made acidic with 1 N hydrochloric acid to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding a mixed solvent of 20% ethyl acetate-hexane to obtain the title compound (1.44 g) . IH NMR (400 MHz, DMSO-d6) (ppm) : 2.73 (t, J=6.0 Hz,2H) , 4.24 (t, J=6.0 Hz, 2H) , 6.90-7.00 (m, IH) , 7.09-7.24 (m, 3H) , 12.41 (br. S., IH) .
To a stirred solution of <strong>[2967-72-8]3-(2-fluorophenoxy)propanoic acid</strong> (prepared according to the procedure reported in WO2010013794, 14.0 gm, 76.08 mmol) in methanol (140 ml) was added thionyl chloride (13.57 gm, 8.5 ml, 1 14.12 mmol) in a drop wise manner at 0C. The resulting mixture was stirred at room temperature for 2 hr. The completion of reaction was monitored by TLC. Reaction mixture was concentrated at reduced pressure and dissolved in Ethyl acetate (300 ml). Organic layer was washed with water (2x 50 ml), dried over anhydrous sodium sulphate, filtered and concentrated at reduced pressure to get a crude product; which was purified by column chromatography using 20% ethyl acetate in hexanes as an eluent to yield the title compound (12.9 gm, 85.66%).MS: m/z 221 (M+23), .HNMR (CDCla, 400 MHz): delta 6.88 - 7.09 (m, 4H), 4.32 (t, J=6.4 Hz, 2H), 3.72 (s, 3H), 2.84 (t, J=6.4 Hz, 2H).
3-(2-fluorophenoxy)propionic acid (4-acetylaminophenylcarbamoyl)methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;
General procedure: To a stirred solution of amide 8 (0.42 mmol) in MeOH (4 mL) was added K2CO3 (88 mg, 0.64mmol), and the resulting mixture was stirred at room temperature for 2 hr. The resulting mixture wasquenched with H2O and the aqueous mixture was extracted with AcOEt. The organic extracts werecombined, dried over Na2SO4, and concentrated in vacuo to afford the alcohol, which was used forthe next reaction without further purification. To a stirred solution alcohol, obtained above, inCH2Cl2 (5 mL) were added EDC (163 mg, 0.85 mmol), DMAP (5 mg, 0.04 mmol) and variouspropanoic acid (0.42 mmol), and the resulting mixture was stirred at room temperature for 18 hr. Theresulting mixture was diluted with CH2Cl2 and quenched 10 % HCl aq., and organic phase wasseparated, the aqueous mixture was extracted with CH2Cl2. The organic phase and extracts werecombined, dried over Na2SO4, and concentrated in vacuo.The residue was chromatographed on SiO2(CH2Cl2: MeOH = 70: 1) to give corresponding amide 9A-H.
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