* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: at 150℃; for 6 h; Stage #2: With hydrogenchloride In methanol; water at 100℃; for 2 h;
To a solution of compound S4 (37.4 g, 0.136 mol) in acetic acid (110 ml) was subsequently added acetic anhydride (380 ml, 10 v/m) and sodium acetate (74g, 2 m/m). The resulting suspension was heated at reflux for 6 h. Then acetic anhydride and acetic acid were removed by vacuum concentration. The residue was cooled and poured in to water, subsequently extracted with ethyl acetate. The organic extracts were concentrated. To the residue in methanol was added 1N HCl (150 ml). The resulting suspension was heated at 100 °C for 2 h and concentratedthe resulting red precipitate was recovered by filtration, and dried at infrared to give white solid S5 (yield: 93percent). 1H-NMR (300MHzCDCl3): δ ppm 4.88 (s, 2H), 7.28 (d, J = 8.76 Hz, 1H), 7.79 (d, J = 2.01 Hz, 1H), 7.84 (dd, J = 8.76, 2.01 Hz, 1H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4537 - 4543
2
[ 872191-29-2 ]
[ 54450-20-3 ]
Yield
Reaction Conditions
Operation in experiment
86.9%
With hydrogenchloride In methanol; water
Synthesis of 5-bromo-3(2H)-benzofuranone (Compound 4) A mixture of Compound 3, methanol (10 mL), purified water (5 mL), and 1 N HCl (2 mL) was heated to reflux for 3 h under stirring. After completion of the reaction, the reaction solution was cooled and purified water (100 ml) was added thereto. The crystals formed were collected by vacuum filtration to give Compound 4. Yield: 0.50 g (yield rate: 86.9 percent) 1H NMR (300 MHz, CDCl3) d 4.67 (s, 2H), 7.06 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 2.1, 2.1 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H).
Stage #1: With aluminum (III) chloride In dichloromethane at 25 - 40℃; for 78.75 h; Inert atmosphere Stage #2: With sodium acetate In ethanol for 2 h; Reflux; Inert atmosphere
General procedure: To a solution of 1-fluoro-4-methoxybenzene (48, 10.0 mmol) indichloromethane (30 mL) was added chloroacetyl chloride(11.0 mmol) at 0 °C. After stirring for 15 min, the reaction mixturewas added anhydrous aluminium chloride (11.0 mmol) over 30 min. After stirring for 6 h at 40 °C, the reaction mixture was cool to rt. After stirring for 72 h at rt, the reaction mixture was poured into ice water (50 mL) and extracted with dichloromethane(3 30 mL). The combined organic phases were washed with brine,dried over anhydrous Na2SO4, and evaporated under vacuum without further purification. To a solution of the residue in ethanol(30 mL) was added anhydrous sodium acetate (20.0 mmol). After refluxing for 2 h, the reaction mixture was cooled to rt and concentrated under vacuum. The residue was dissolved in water (50 mL) and extracted with dichloromethane (3 40 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude mixture was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 40/1) to afford the title compound. Bright yellow solid, yield 60percent;
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 195 - 208
4
[ 100959-21-5 ]
[ 54450-20-3 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 26, p. 8328 - 8332
[2] Patent: US2011/28414, 2011, A1, . Location in patent: Page/Page column 17
8b) A solution of 8.34 g (33.4 mmol) of 1-(5-bromo-2-hydroxyphenyl)-2-chloroethanone and 3.3 g (40.1 mmol) of anhydrous sodium acetate in 350 ml of methanol is heated at 65 C. for one hour, subsequently evaporated to dryness, the residue is taken up in 50 ml of water, and the aqueous mixture is extracted twice with 50 ml of methylene chloride each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (n-heptane/methylene chloride 7:3), giving 2.14 g of 5-bromobenzofuran-3-one as yellow solid; LC/MS: 214 (M+H).
Step 2 5-Bromobenzofuran-3-one To a solution of the foregoing ethanone (18 g, 72 mmol) in methanol (150 ml) was added sodium acetate (7 g, 85 mmol). The solution was heated at 65 C. for 1 hour, then the methanol was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous solution reextracted once with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give a gum which was purified by column chromatography on alumina using dichloromethane to afford a solid (5.6 g, 36%). mp 102-106 C. 1 H NMR (250 MHz, CDCl3) delta 4.67 (2H, s), 7.05 (1H, d, J=9 Hz), 7.69 (1H, dd, J=2 and 9 Hz), 7.79 (H, d, J=2 Hz).
36%
Step 2 5-Bromobenzofuran-3-one To a solution of the foregoing ethanone (18 g, 72 mmol) in methanol (150 ml) was added sodium acetate (7g, 85 mmol). The solution was heated at 65 C. for 1 hour, then the methanol was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous solution reextracted once with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give a gum which was purified by column chromatography on alumina using dichloromethane to afford a solid (5.6 g, 36%), mp 102-106 C. 1 H NMR (250 MHz, CDCl3) delta4.67 (2H, s), 7.04 (1H, d, J=9 Hz), 7.69 (1H, dd, J=2 and 9 Hz), 7.79 (H, d, J=2 Hz).
21
[ 867-13-0 ]
ammonium chloride[ No CAS ]
[ 54450-20-3 ]
[ 200204-85-9 ]
Yield
Reaction Conditions
Operation in experiment
With potassium hexamethylsilazane; In tetrahydrofuran; dichloromethane; ethyl acetate; toluene;
Step 3 5-Bromobenzofuran-3-ylacetic acid ethyl ester To a solution of triethyl phosphonoacetate (6 ml, 30.2 mmol) in dry tetrahydrofuran (200 ml) at -78 C. was added a solution of potassium bis(trimethylsilyl)amide in toluene (58 ml of a 0.5M solution). After stirring for 2 hours at -78 C., <strong>[54450-20-3]5-bromobenzofuran-3-one</strong> (5.5 g, 26 mmol) was added dropwise. The resulting solution was stirred 1 hour at -78 C. and overnight at room temperature. Saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated and evaporated to dryness to give the crude title compound which was purified by column chromatography on silica using dichloromethane, followed by column chromatography on alumina using dichloromethane. 5-Bromobenzofuran-3-ylacetic acid ethyl ester was obtained as a low melting solid (4.2 g, 57%). mp 38-40 C. 1 H NMR (250 MHz, CDCl3) delta 1.28 (3H, t, J=7 Hz), 3.65 (2H, d, J=1 Hz), 4.20 (2H, q, J=7 Hz), 7.36 (1H, s), 7.38 (1H, d, J=2 Hz), 7.63 (1H, s), 7.71 (1H, d, J=2 Hz).
Synthesis of 5-bromo-3(2H)-benzofuranone (Compound 4) A mixture of Compound 3, methanol (10 mL), purified water (5 mL), and 1 N HCl (2 mL) was heated to reflux for 3 h under stirring. After completion of the reaction, the reaction solution was cooled and purified water (100 ml) was added thereto. The crystals formed were collected by vacuum filtration to give Compound 4. Yield: 0.50 g (yield rate: 86.9 %) 1H NMR (300 MHz, CDCl3) d 4.67 (s, 2H), 7.06 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 2.1, 2.1 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H).
N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2'-oxo-1',2'-dihydro-3H-spiro[1-benzofuran-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide[ No CAS ]
With potassium carbonate; In acetone; for 18h;Reflux;
INTERMEDIATE 2 2'-Oxo-l 2'-dihvdro-3H-spirorbenzofuran-2,3'-pyrrolor2,3-/?1pyridine1-5-carboxylic acid Step A: Ethyl 5-bromo-3-oxo-2 -dihydro-l-benzofuran-2-carboxylate Potassium carbonate (1.66 g, 12 mmol) is added to a solution of 5-bromo-l- benzofuran-3(2H)-one (2.13 g, 10 mmol) in acetone (25 mL). The stirred mixture is treated dropwise with ethyl chloro formate (1.05 mL, 1 1 mmol). The mixture is then heated at reflux for 18 h. The solids are filtered off and the filtrate concentrated in vacuo. The residue is partitioned between EtOAc and saturated aqueous aHC03. The layers are separated and the organic layer washed with brine, dried (Na2S04), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes -EtOAc) to afford the title compound.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In toluene; at 80℃;Schlenk technique; Inert atmosphere; Sealed tube;
Step 1. 5-(3-Fluorophenyl)benzofuran-3(2H)-one Cesium carbonate (612 mg, 1.88 mmol) was added to a solution of <strong>[54450-20-3]5-bromobenzofuran-3(2H)-one</strong> (200 mg, 0.939 mmol), (3-fluorophenyl)boronic acid (263 mg, 1.88 mmol) and toluene (20 mL) in a 50 mL Schlenk tube. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3*), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.01 mmol) was added to the reaction. The flask was sealed and heated in a 80 C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes?100% ethyl acetate/hexanes, gradient), to afford 212 mg (99%) of 5-(3-fluorophenyl)benzofuran-3(2H)-one.
5-bromo-2-(2-hydroxypropan-2-yl)benzofuran-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With aluminum oxide; at 20℃;
General procedure: To a solution of benzofuran-3(2H)-one (134.0 mg, 1.0 mmol) in acetone (5.0 ml) was added activated basic alumina (1.02 g, 10 mmol) at room temperature. The reaction was monitored by TLC until complete consumption. The alumina was filtered and washed abundantly with acetone. The filtrate was then concentrated to afford crude product which was purified by column chromatography (petroleumether/EtOAc, 8:1) to give product 2-(2-hydroxypropan-2-yl) benzofuran-3(2H)-one (165.1 mg, 86.0%) as a light yellow solid.
General procedure: To a solution of 1-fluoro-4-methoxybenzene (48, 10.0 mmol) indichloromethane (30 mL) was added chloroacetyl chloride(11.0 mmol) at 0 C. After stirring for 15 min, the reaction mixturewas added anhydrous aluminium chloride (11.0 mmol) over 30 min. After stirring for 6 h at 40 C, the reaction mixture was cool to rt. After stirring for 72 h at rt, the reaction mixture was poured into ice water (50 mL) and extracted with dichloromethane(3 30 mL). The combined organic phases were washed with brine,dried over anhydrous Na2SO4, and evaporated under vacuum without further purification. To a solution of the residue in ethanol(30 mL) was added anhydrous sodium acetate (20.0 mmol). After refluxing for 2 h, the reaction mixture was cooled to rt and concentrated under vacuum. The residue was dissolved in water (50 mL) and extracted with dichloromethane (3 40 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude mixture was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 40/1) to afford the title compound. Bright yellow solid, yield 60%;
(Z)-5-bromo-2-(3-ethoxy-4-hydroxybenzylidene)benzofuran-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With aluminum oxide; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: To a solution of benzofuran-3(2H)-one (1.0 mmol) and benzaldehyde(1.0 mmol) in dichloromethane (6 mL) was addedaluminum oxide (30.0 mmol) at room temperature. After stirringfor 6 h, the reaction mixture was filtered off. The filtrate wasconcentrated under vacuum and the residue was purified by flash chromatography on silica gel to give the desired compound.
With para-xylene; N-ethyl-N,N-diisopropylamine; at 120℃; for 12h;Inert atmosphere;
<strong>[54450-20-3]5-bromobenzofuran-3(2H)-one</strong> 76a (5 g, 23.471 mmol, prepared by a method disclosed in the patent application ""), acetonyltriphenylphosphonium chloride (12.5 g, 35.206 mmol), and N,N-diisopropylehtylamine (9.1 g, 70.413 mmol) were dissolved in 60 mL of dimethylbenzene. The mixture was warmed up to 120C and stirred for 12 hours, then the reaction was stopped. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 1-(5-bromobenzofuran-3-yl)propan-2-one 76b (3.1 g, yield 53%) as a yellow oil.
(E)-methyl3-(4-((1R,3R/1S,3S)-6-bromo-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)-3,5-difluorophenyl)acrylate[ No CAS ]
(E)-methyl 3-(4-((1R,3R/1S,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)-3,5-difluorophenyl)acrylate[ No CAS ]
(E)-3-(4-((1R,3R/1S,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)-3,5-difluorophenyl)acrylic acid[ No CAS ]
(E)-3-(4-((1R,3R/1S,3S)-6-bromo-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)-3,5-difluorophenyl)acrylic acid[ No CAS ]
(E)-3-(4-((1R,3R)-6-(1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)-3,5-difluorophenyl)acrylic acid[ No CAS ]
(E)-3-(4-((1S,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)-3,5-difluorophenyl)acrylic acid[ No CAS ]
5-bromo-N-(4-nitrophenyl)benzofuran-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With toluene-4-sulfonic acid; In toluene; for 2h;Reflux;
To a solution of compound S5 (1.3 g6.1 mmol) in toluene was subsequently p-nitrotoluene (0.9 g, 6.l mmol). The resulting suspension was heated at reflux for 2 h with and concentrated, then the resulting yellow precipitate was recovered by filtration. (yield: 100%, 2.03 g). 1H-NMR (300MHzd6-DMSO): delta ppm 9.19 (s, 1H), 8.33 (s, 1H), 8.10 (d, J = 9.21 Hz, 2H), 7.89 (d, J = 1.95 Hz,1H), 7.58 (d, J = 8.73 Hz, 1H), 7.52 (dd, J = 1.95, 8.73 Hz, 1H), 7.04 (d, J = 9.21 Hz, 2H).
100%
With toluene-4-sulfonic acid; In toluene; for 2h;Reflux;
To a solution of compound S5 (1.3?g, 6.1?mmol) in toluene was subsequently paranitroaniline (0.9?g, 6.l?mmol). The resulting suspension was heated at reflux for 2?h with and concentrated, then the resulting yellow precipitate was recovered by filtration. (yield: 100%, 2.03?g). 1H NMR (300?MHz, d6-DMSO): delta ppm 9.19 (s, 1H), 8.33 (s, 1H), 8.10 (d, J?=?9.2?Hz, 2H), 7.89 (d, J?=?1.95?Hz,1H), 7.58 (d, J?=?8.7?Hz, 1H), 7.52 (dd, J?=?1.9, 8.7?Hz, 1H), 7.04 (d, J?=?9.2?Hz, 2H).
To a solution of compound S4 (37.4 g, 0.136 mol) in acetic acid (110 ml) was subsequently added acetic anhydride (380 ml, 10 v/m) and sodium acetate (74g, 2 m/m). The resulting suspension was heated at reflux for 6 h. Then acetic anhydride and acetic acid were removed by vacuum concentration. The residue was cooled and poured in to water, subsequently extracted with ethyl acetate. The organic extracts were concentrated. To the residue in methanol was added 1N HCl (150 ml). The resulting suspension was heated at 100 C for 2 h and concentratedthe resulting red precipitate was recovered by filtration, and dried at infrared to give white solid S5 (yield: 93%). 1H-NMR (300MHzCDCl3): delta ppm 4.88 (s, 2H), 7.28 (d, J = 8.76 Hz, 1H), 7.79 (d, J = 2.01 Hz, 1H), 7.84 (dd, J = 8.76, 2.01 Hz, 1H).
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