* 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.
With N-Bromosuccinimide; iodine In acetonitrile for 12 h; Darkness
General procedure: To a reaction tube charged with NBS (1.5 equiv, 0.3 mmol), catalyst (10 molpercent, 0.02 mmol) and CH3CN (1.0 mL),was added para-chloroanisole 1a (0.2 mmol). After being stirred at room temperature for 12 h in dark, the reaction was quenched by saturated aq. solution of Na2S2O3 (2 mL). The resulting mixture was extracted by ethyl acetate (3 5 mL). The combined organic extracts were washed by brine (10 mL), dried over Na2SO4 and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residuewas purified by flash chromatography on a silica gel column with petroleum ether/dichloromethane (5:1) as the eluent to give 4.3.1. 2-Bromo-4-chloroanisole (2a)
95%
With hydrogenchloride; N-Bromosuccinimide In water; acetone at 20℃; for 3 h;
Compound 41-2 (0492) To a solution of 41-1 (2.0 g, 13.32 mmol) in acetone (25 mL) was added NBS (2.37 g, 13.32 mmol) and 1M HCl aq. (0.13 mL, 0.13 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated to dryness under reduced pressure. The residue was dissolved with PE (40 mL) the resultant precipitate was filtered and dried in vacuum to afford 41-2 as a white solid (2.90 g, yield: 95percent).
Reference：
[1] Tetrahedron, 2017, vol. 73, # 50, p. 7105 - 7114
[2] Tetrahedron Letters, 2006, vol. 47, # 27, p. 4707 - 4710
[3] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 312-313
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1423 - 1428
[5] Synthesis (Germany), 2013, vol. 45, # 11, p. 1497 - 1504
2
[ 1450-75-5 ]
[ 74-88-4 ]
[ 16740-73-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate In acetone
1-(5-Bromo-2-methoxy-phenyl)-ethanone A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 47 mmol), methyl iodide (3.5 mL, 56 mmol), and potassium carbonate (10 g, 73 mmol) in acetone (80 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the resulting white solid filtered and washed thoroughly with ethyl acetate. The filtrate was washed with water, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide the title compound (10 g, 94percent) as a white solid.
91%
Stage #1: With potassium carbonate In [(2)H6]acetone at 20℃; for 1 h; Stage #2: at 20℃; for 20 h;
Potassium carbonate (9.6 g) was added to a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et2O and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91percent yield). LC-MS (Method 1): m/z [M+H]+=229.1 (MW calc.=229.07); Rt=3.30 min.
91%
Stage #1: With potassium carbonate In acetone at 20℃; for 1 h; Stage #2: at 20℃; for 20 h;
Intermediate 7a) Potassium carbonate (9.6 g) was added to a solution of 1 -(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et20 and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91 percent yield). LC-MS (Method 1): m/z [M+H]+ = 229.1 (MW calc. = 229.07); R, = 3.30 min.
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
A mixture of 5-Bromo-2-hydroxyacetophenone 2a (10g, 46.5mmol, 1 eq), potassium carbonate (9.62g, 69.75mmol, 1.5 eq) and iodomethane (5.8mL, 93mmol, 2 eq) in DMF (120mL) were stirred overnight in a sealed round bottom flask at room temperature. DMF was removed under reduced pression and the residue was partitioned between water and EtOAc. The combined EtOAc extracts were washed with brine, 0.5M NaOH and then three times with water. The organic layer was dried over MgSO4 and the solvent evaporated. The product was obtained as an off-white solid (9.5g, 89percent). m.p. 31–32°C. SM (ESI): m/z 251–253 [M+Na]+. 1H NMR (δ ppm): 2.54 (s, 3H, COCH3), 3.90 (s, 3H, OCH3), 7.18 (d, Jortho=8.9Hz, 1H, CHar), 7.66 (d, Jmeta=2.6Hz, 1H, CHar), 7.72 (dd, Jortho=8.9Hz, Jmeta=2.6Hz, 1H, CHar).
75%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 12 h; Inert atmosphere
To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethan- 1-one 1 (10 g, 46.51 mmol) in DMF (100 mL) were added K2C03 (9.63 g, 69.77 mmol) and Mel (5.8 mL, 93.02 mmol) at 0°C under Ar. The mixture was stirred at RT for 12 h then quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure to afford compound 2 (8.8 g, 75percent) as pale yellow liquid. ‘H NIVIR (500MHz, DMSO-d6): 7.70 (dd, J 9.0, 2.6 Hz, 1H), 7.64 (d, J= 2.6 Hz, 1H), 7.16 (d, J= 9.0 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H); LC-MS (ESI):m/z 228.8 (M + Hf).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2561 - 2563
[2] Tetrahedron, 2001, vol. 57, # 24, p. 5027 - 5038
[3] Chemistry - A European Journal, 2016, vol. 22, # 30, p. 10415 - 10419
[4] Patent: US2003/187007, 2003, A1,
[5] Patent: US2014/194443, 2014, A1, . Location in patent: Paragraph 0427-0429
[6] Patent: WO2014/108337, 2014, A1, . Location in patent: Page/Page column 56; 57
[7] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 774 - 796
[8] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 8, p. 1115 - 1123
[9] Patent: WO2017/15221, 2017, A1, . Location in patent: Paragraph 00255
[10] Organic and Biomolecular Chemistry, 2005, vol. 3, # 24, p. 4432 - 4443
[11] Advanced Synthesis and Catalysis, 2018, vol. 360, # 8, p. 1634 - 1638
With N-Bromosuccinimide; iodine; In acetonitrile; for 12h;Darkness;
General procedure: To a reaction tube charged with NBS (1.5 equiv, 0.3 mmol), catalyst (10 mol%, 0.02 mmol) and CH3CN (1.0 mL),was added para-chloroanisole 1a (0.2 mmol). After being stirred at room temperature for 12 h in dark, the reaction was quenched by saturated aq. solution of Na2S2O3 (2 mL). The resulting mixture was extracted by ethyl acetate (3 5 mL). The combined organic extracts were washed by brine (10 mL), dried over Na2SO4 and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residuewas purified by flash chromatography on a silica gel column with petroleum ether/dichloromethane (5:1) as the eluent to give 4.3.1. 2-Bromo-4-chloroanisole (2a)
95%
With hydrogenchloride; N-Bromosuccinimide; In water; acetone; at 20℃; for 3h;
Compound 41-2 (0492) To a solution of 41-1 (2.0 g, 13.32 mmol) in acetone (25 mL) was added NBS (2.37 g, 13.32 mmol) and 1M HCl aq. (0.13 mL, 0.13 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated to dryness under reduced pressure. The residue was dissolved with PE (40 mL) the resultant precipitate was filtered and dried in vacuum to afford 41-2 as a white solid (2.90 g, yield: 95%).
With copper(ll) bromide; In chloroform; ethyl acetate; at 100℃; for 5h;Inert atmosphere;
A mixture of copper(ll) bromide (19.50 g, 87 mmol) in Ethyl acetate (150 mL) was heated to 100 C and then a solution of 1 -(5-bromo-2-methoxyphenyl)ethanone (10 g, 43.7 mmol) in Chloroform (50 mL) was added dropwise under a nitrogen atmosphere. The mixture was stirred at 100 C for 5 h. The mixture was filtered through a pad of silica gel (100-200 mesh) and the filtrate was evaporated to afford the crude product. The crude product was triturated in a mixture of EtOAc/petroleum ether = 1/1 (30 mL) to afford pure 2-bromo-1 -(5-bromo-2- methoxyphenyl)ethanone (12 g, 15.59 mmol, 35.7 % yield) as a white solid, m/z: [M + H]+ Calcd for 306.9; Found 307
1-(5-Bromo-2-methoxy-phenyl)-ethanone A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 47 mmol), methyl iodide (3.5 mL, 56 mmol), and potassium carbonate (10 g, 73 mmol) in acetone (80 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the resulting white solid filtered and washed thoroughly with ethyl acetate. The filtrate was washed with water, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide the title compound (10 g, 94%) as a white solid.
91%
Potassium carbonate (9.6 g) was added to a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et2O and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91% yield). LC-MS (Method 1): m/z [M+H]+=229.1 (MW calc.=229.07); Rt=3.30 min.
91%
Intermediate 7a) Potassium carbonate (9.6 g) was added to a solution of 1 -(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et20 and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91 % yield). LC-MS (Method 1): m/z [M+H]+ = 229.1 (MW calc. = 229.07); R, = 3.30 min.
89%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
A mixture of 5-Bromo-2-hydroxyacetophenone 2a (10g, 46.5mmol, 1 eq), potassium carbonate (9.62g, 69.75mmol, 1.5 eq) and iodomethane (5.8mL, 93mmol, 2 eq) in DMF (120mL) were stirred overnight in a sealed round bottom flask at room temperature. DMF was removed under reduced pression and the residue was partitioned between water and EtOAc. The combined EtOAc extracts were washed with brine, 0.5M NaOH and then three times with water. The organic layer was dried over MgSO4 and the solvent evaporated. The product was obtained as an off-white solid (9.5g, 89%). m.p. 31-32C. SM (ESI): m/z 251-253 [M+Na]+. 1H NMR (delta ppm): 2.54 (s, 3H, COCH3), 3.90 (s, 3H, OCH3), 7.18 (d, Jortho=8.9Hz, 1H, CHar), 7.66 (d, Jmeta=2.6Hz, 1H, CHar), 7.72 (dd, Jortho=8.9Hz, Jmeta=2.6Hz, 1H, CHar).
75%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;
To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethan- 1-one 1 (10 g, 46.51 mmol) in DMF (100 mL) were added K2C03 (9.63 g, 69.77 mmol) and Mel (5.8 mL, 93.02 mmol) at 0C under Ar. The mixture was stirred at RT for 12 h then quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure to afford compound 2 (8.8 g, 75%) as pale yellow liquid. ?H NIVIR (500MHz, DMSO-d6): 7.70 (dd, J 9.0, 2.6 Hz, 1H), 7.64 (d, J= 2.6 Hz, 1H), 7.16 (d, J= 9.0 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H); LC-MS (ESI):m/z 228.8 (M + Hf).
An oven dried 500 mL flask, was charged under nitrogen with (S)-2-METHYL-CBS- OXAZABOROLIDINE 1M in toluene (2.18mL) and dissolved in CH2CI2 (100 mL). Me2-BH3 (13.10 mL, 26.20 mmol) was then added and cooled reaction to-30 C then stirred for 15 minutes. 5- Bromo-2-methoxyacetophenone (5 g, 21.83 mmol) was dissolved in CH2CI2 (10 mL) and slowly added via addition funnel to the previous solution. The resulting reaction was stirred at-30 C for 1 hour. The solution was carefully quenched with MeOH, the solvent was removed in vacuo and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide the desired product (5 g, 100%) as a clear OIL. 1H NMR (400MHZ, CDCI3) : 5 1.47 (d, J = 6.41 Hz, 3H), 2.44 (d, J = 5Hz, 1H), 3.84 (s, 3H), 5.03-5. 11 (m, 1H), 6.74 (d, J = 8.7Hz, 1H), 7.33 (dd, J = 8.7, 2.5 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H).
Example 57 3-(2-Amino-pyrimidin-4-yl)-biphenyl-4,4'-diol One equivalent of <strong>[16740-73-1]5'-bromo-2'-methoxy-acetophenone</strong> and 15 eq. of N,N-dimethylformamide diethyl acetal are combined and heated to 120 C. overnight. The reaction mixture is concentrated in vacuo and dissolved in butanol (0.1 M) with 3 equivalents of sodium ethoxide followed by 1.1 equivalents of guanidine hydrochloride. This mixture is heated to 120 C. overnight. The reaction mixture was extracted with dichloromethane, washed with water and then dried over sodium sulfate. The resulting 4-(2-methoxy-5-bromo-phenyl)-pyrimidin-2-ylamine was obtained after purification on a silica gel column. The Suzuki reaction is then performed followed General Procedure G with 4-methoxyphenylboronic acid to give 4-(4,4'-Dimethoxy-biphenyl-3-yl)-pyrimidin-2-ylamine in 90% yield.
3-(5-Bromo-2-methoxy-phenyl)-3-oxo-propionic Acid Methyl Ester A mixture of 1-(5-bromo-2-methoxy-phenyl)-ethanone (10 g, 44 mmol), and 60% sodium hydride (2.8 g, 70.0 mmol) in dimethyl carbonate (100 mL) was heated at reflux for 2 h. To the resulting brown suspension was added 0.5 M aq. citric acid until a clear solution was obtained. The clear solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude title compound was used in the next step without purification.
aluminium trichloride; In hexane; dichloromethane; ethyl acetate;
5-Bromo-2-methoxyacetophenone (Compound G) To a slurry of 8.55 g (64.2 mmol) of aluminum chloride in 75 mL of dichloromethane cooled to 0 C. (under a blanket of argon) was added dropwise a solution of 10.0 g (53.5 mmol) of 4-bromoanisole and 4.6 mL (64.2 mmol) of acetyl chloride in 25 mL of dichloromethane. After the addition was complete, the clear yellow solution was stirred at 0 C. for 15 minutes, poured into 200 mL of 10% HCl (aq.) solution, cooled to 0 C. in an ice bath and then extracted with dichloromethane (3*200-mL portions). The organic phases were combined and then washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow semi-solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a white solid. PMR (CDCl3): delta 2.60 (3H, s), 3.91 (3H, s), 6.86 (1H, d, J=8.9 Hz), 7.55 (1H, dd, J=2.7, 8.9 Hz), 7.84 (1H, d, J=2.7 Hz).
5-Bromo-2-methoxy-4'-methylbenzophenone (Compound H) Employing the same general procedure as for the preparation of 5-bromo-2-methoxyacetophenone (Compound G), 1.3 mL (1.7 g, 9.2 mmol) of 4-bromoanisole was converted into the title compound using 1.5 g (11.3 mmol) of aluminum chloride, 1.3 mL (1.6 g, 10.1 mmol) of p-toluoyl chloride and 20 mL of dichloromethane. Deviations from the general procedure involved continued overnight stirring (ambient temperature, 16.75 hours) following stirring at 0 C. for 35 minutes and using a 10% solution of c. H2 SO4 in crushed ice (v/v) instead of cold 10% HCl (aq.) solution during the subsequent workup procedure.
2-methoxy-5-trimethylsilanylethynyl acetophenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(I) iodide;bis(triphenylphosphine)palladium(II)-chloride; In hexane; chloroform; ethyl acetate; diethylamine;
2-Methoxy-5-trimethylsilanylethynyl acetophenone (Compound W) To a sparged solution (a stream of argon was bubbled vigorously into the solution for several minutes) of diethylamine (5 mL) in a pressure tube vessel was added a solution of 1.85 g (8.1 mmol) of <strong>[16740-73-1]5-bromo-2-methoxyacetophenone</strong> (Compound G) in 20 ml of diethylamine. After sparging with argon for 5 minutes, 0.4 g (2.0 mmol) of cuprous iodide was added to the solution and the resultant mixture was sparged with argon for 2 minutes. To this reaction mixture was then added 1.4 g (2.0 mmol) of bis(triphenylphosphine)palladium(II) chloride. After sparging with argon for 3 minutes, 4.3 mL (40.4 mmol) of trimethylsilyl acetylene was added to the reaction mixture. The pressure tube was then sealed and heated in an oil bath (55 C.) for 5 days. The reaction mixture was filtered through celite and washed with ethyl ether (400 mL). The filtrate was extracted with water (3*200 mL-portions) and brine, dried over MgSO4, filtered and concentrated in vacuo to give a dark brown residue. Purification by flash chromatography (preabsorbed onto silica with chloroform, 10% ethyl acetate in hexane) gave the title compound as a yellow solid. PMR (CDCl3): delta 0.24 (9H, s), 2.01 (2H, t, J=7.1 Hz), 2.59 (3H, s), 3.92 (3H, s), 6.90 (1H, d, J=8.6 Hz), 7.55 (1H, dd, J=2.2, 8.6 Hz), 7.84 (1H, d, J=2.2 Hz).
EXAMPLE 86 3-[3-[3-[3-[(aminoiminomethyl)amino]phenyl]-1-oxopropenyl]-4-methoxyphenyl]propenoic acid, trifluoroacetate salt STR265 The above compound was prepared as in Example 84, Steps A-E starting from <strong>[16740-73-1]5-bromo-2-methoxyacetophenone</strong> and 3-nitrobenzaldehyde. Anal. calcd for C20 H19 N3 O4 +1.0 TFA+0.75 H2 O: C, 53.61; H, 4.09; N, 8.52. Found: C, 53.60; H, 4.12; N, 8.47.
Example 86 3-[3-[3-[3-[(aminoiminomethyl)amino]phenyl]-1-oxopropenyl]-4-methoxyphenyl]propenoic acid, trifluoroacetate salt The above compound was prepared as in Example 84, Steps A-E starting from <strong>[16740-73-1]5-bromo-2-methoxyacetophenone</strong> and 3-nitrobenzaldehyde.
The mixture of l-(5-bromo-2-methoxyphenyl)ethanone (10 g, 43.6 mmol), phenylhydrazine (7.07 g, 65.5 mmol) was stirred in PPA (50 mL) at 110 C for 2 hours. The reaction mixture was added to water and basified to pH = 7, then extracted with ethyl acetate and washed with brine, dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography to provide the product of 2-(5-bromo-2-methoxyphenyl)-lH- indole (10 g, yield: 71%). 1H- MR (CDC13, 400 MHz) delta 9.57 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.34-7.42 (m, 2H), 7.09-7.21 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 4.00 (s, 3H). MS (M+H)+: 302 / 304.
71%
With PPA; In water; at 110℃; for 2h;
Step 1-Synthesis of 2-(5-bromo-2-methoxyphenyl)-1H-indole The mixture of <strong>[16740-73-1]1-(5-bromo-2-methoxyphenyl)ethanone</strong> (10 g, 43.6 mmol), phenylhydrazine (7.07 g, 65.5 mmol) was stirred in PPA (50 mL) at 110 C. for 2 hours. The reaction mixture was added to water and basified to pH=7, then extracted with ethyl acetate and washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography to provide the product of 2-(5-bromo-2-methoxyphenyl)-1H-indole (10 g, yield: 71%). 1H-NMR (CDCl3, 400 MHz) delta 9.57 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.34?7.42 (m, 2H), 7.09?7.21 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 4.00 (s, 3H). MS (M+H)+: 302/304.
With sodium; In diethyl ether; ethanol; at 20℃; for 20h;
Intermediate 7b) Sodium (533 mg) was dissolved in dry EtOH (20 mL) and subsequently solutions of diethyl oxalate (3.39 g) in dry Et20 (10 mL) and intermediate 7a (4.83 g) in Et20 (10 mL) were added. The reaction mixture was stirred at rt for 20 h followed by addition of 2N aqueous HCI (40 mL) and extraction with EtOAc. The combined organic layers were dried and the solvent removed under reduced pressure to yield crude material of the desired product (98% yield). LC-MS {Method 1): m/z [M+H]+ = 329.1 (MW calc. = 329.14); R, = 3.90 min.
With ethanol; sodium; In diethyl ether; at 20℃; for 20h;
Sodium (533 mg) was dissolved in dry EtOH (20 mL) and subsequently solutions of diethyl oxalate (3.39 g) in dry Et2O (10 mL) and intermediate 7a (4.83 g) in Et2O (10 mL) were added. The reaction mixture was stirred at rt for 20 h followed by addition of 2N aqueous HCl (40 mL) and extraction with EtOAc. The combined organic layers were dried and the solvent removed under reduced pressure to yield crude material of the desired product (98% yield). LC-MS (Method 1): m/z [M+H]+=329.1 (MW calc.=329.14); Rt=3.90 min.
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