* 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.
Reference：
[1] Asian Journal of Chemistry, 2011, vol. 23, # 4, p. 1829 - 1832
2
[ 936-08-3 ]
[ 57381-49-4 ]
Yield
Reaction Conditions
Operation in experiment
57%
at 150℃; for 1 h; Microwave irradiation
Example 1A2-Bromo-4-chlorobenzonitrile; 588 mg (2.5 mmol) of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in dichloromethane/methanol and concentrated onto 364 mg of alumina (neutral) on a rotary evaporator. The residue is microwaved at 150° C. for a total of 60 min. After cooling, the residue is stirred with ethyl acetate and water, filtered, and the aqueous phase is separated. The organic phase is washed with a sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated on a rotary evaporator and then dried under high vacuum. The product (383 mg, 80percent pure, 57percent of theory.) is reacted further without additional purification.1H NMR (300 MHz, CDCl3): δ=7.72 (d, 1H), 7.60 (d, 1H), 7.42 (dd, 1H).
Reference：
[1] Journal of the Chemical Society, 1904, vol. 85, p. 1269
[2] Journal of the Chemical Society, 1914, vol. 105, p. 1910
[3] Collection of Czechoslovak Chemical Communications, 1975, vol. 40, p. 3530 - 3544
6
[ 106-43-4 ]
[ 936-08-3 ]
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 1910
7
[ 95-46-5 ]
[ 936-08-3 ]
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 1910
8
[ 119-32-4 ]
[ 936-08-3 ]
Reference：
[1] Journal of the Chemical Society, 1904, vol. 85, p. 1269
9
[ 7745-87-1 ]
[ 936-08-3 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1975, vol. 40, p. 3530 - 3544
Stage #1: at 0 - 5℃; for 0.166667 h; Stage #2: for 12 h; Heating / reflux
Step 1: Synthesis of 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99percent), which was directly used in the following step.
99%
at 0℃; Reflux
Thionyl chloride (29.2 ml, 400 mmol) was added dropwise over 10 minutes at 0-5 ° C (ice-water bath) in a 500 ml 2-necked RB flask containing anhydrous methanol (300 ml).Remove the ice-water bath and add 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol).The mixture was heated to moderate reflux for 12 hours.Reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated.The crude product was dissolved in dichloromethane (DCM, 250 ml)Washed with water (50 ml), saturated aqueous NaHCO3 (50 ml), brine (50 ml)Dried over sodium sulfate,Concentration gave 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99percent) which was used directly in the next step.
98%
Cooling with ice; Heating; Reflux
Concentrated sulfuric acid (5 ml_) was added drop-wise to an ice-cold mixture of 2- bromo-4-chloro-benzoic acid (10.14 g, 0.0431 mol) and methanol (40 ml_). The resulting mixture was heated at reflux for 17 hours. After this time, the reaction mixture was cooled to room temperature, and then poured into ice-cold water (150 ml_), creating a white suspension. The suspension was extracted with ethyl acetate (150 ml_). The organic phase was washed with saturated aqueous NaHCO3 (I OO ml_), followed by saturated aqueous NaCI (100 ml_). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 98percent yield) as a clear oil.
Reference：
[1] Patent: US2008/153852, 2008, A1, . Location in patent: Page/Page column 19
[2] Patent: CN104045626, 2017, B, . Location in patent: Paragraph 0227
[3] Patent: WO2010/55005, 2010, A1, . Location in patent: Page/Page column 71
[4] Journal of the American Chemical Society, 2016, vol. 138, # 18, p. 5813 - 5816
12
[ 936-08-3 ]
[ 57381-62-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
With thionyl chloride In methanol; dichloromethane
Step 1: Synthesis of 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99percent), which was directly used in the following step.
Reference：
[1] Patent: US2009/29993, 2009, A1,
13
[ 936-08-3 ]
[ 77-78-1 ]
[ 57381-62-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7232 - 7246
Example 26 rel-7-Chloro-3-[4-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-ylcarbamoyl)-2-oxo-2H-pyridin-1-ylmethyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester A solution of <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (25.0 g, 106.0 mmol) in 2-ethoxy ethanol (40 mL) was treated with copper powder (0.74 g, 11.6 mmol), copper (I) oxide (0.76 g, 5.3 mmol) and potassium carbonate (15.8 g, 114.0 mmol) at 25 C. under nitrogen. The reaction was stirred at 25 C. for 5 min. At this time, the reaction was treated with aniline (11.2 mL, 124 mmol) and then was heated 135 C. for 48 h. At this time, the reaction was cooled to 25 C., diluted with water (30 mL) and was acidified with a 1N aqueous hydrochloric acid solution. The resulting mixture was stirred at 25 C. overnight. At this time, the resulting precipitate was collected by filtration through a sintered glass funnel. The solids were washed with an excess amount of water (2*100 mL) and then were dried under high vacuum to afford 4-chloro-2-phenylamino-benzoic acid (19 g, 72.3%) as a brown solid.
Step 1 : Preparation of 4-chloro-2-phenylamino-benzoic acid To a solution of <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (25.0 g, 106.0 mmol) in 2-ethoxyethanol (40 mL) was added copper powder (0.74 g, 11.6 mmol), copper (I) oxide (0.76 g, 5.3 mmol), potassium carbonate (15.8 g, 114.0 mmol) at room temperature under nitrogen. After stirring for 5 min., aniline (11.2 mL, 124 mmol) was added to the reaction mixture. The reaction mixture was heated at 135 C for 48 hr. Completion of the reaction was confirmed by silica TLC (mobile phase; hexane: ethyl acetate = 1 : 1; Rf = 0.6). The reaction mixture was cooled to room temperature, poured into water (30 mL) with continuous shaking and was acidified with aqueous IN HC1 to form a precipitate. The mixture was stirred overnight at room temperature. The mixture was filtered through a sintered glass funnel. The solids were washed with water (2 x 100 mL). The obtained solids were dried under high vacuum to yield 4-chloro-2-phenylamino-benzoic acid (19.0 g, 72.3% crude yield). The crude product was used in the next step without further purification. MS calcd. for C13H10ClNO2 [(M+H)+] 247, obsd. 248.
2-Bromo-4-chlorobenzoic acid (1.0 g, 4.25 mmol) was dissolved in 10 mL of MeOH. The mixture was cooled in an ice-bath and to it was added thionyl chloride (3.1 mL, 42.5 mmol) dropwise. The cooling bath was removed and the mixture was stirred at rt under N2 for 12 h. The solvent was removed and dried under vacuum to give 1.0 g of colorless oil. LC/MS: 251.1 (M+1)+.
(-)-trans-acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-1-methyl-pyrrolidin-2-ylmethyl ester[ No CAS ]
[ 936-08-3 ]
(+)-trans-2-bromo-4-chloro-benzoic acid 2-(2-acetoxymethyl-1-methylpyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;
Example 67: (+)-frans-2-Bromo-4-chlorobenzoic acid 2-(2-acetoxymethyl-1 -methylpyrrolidin- 3-yl)-6-acetyl-3,5-dimethoxyphenyl ester; A mixture of the compound of example (6)(1.12 g, 3.2 mmol), 2-bromo-4- chlorobenzoic acid (0.9 g, 3.8 mmol), DCC (1.32 g, 6.4 mmol) and DMAP (0.4 g, 3.2 mmol) were dissolved in dichloromethane (25 ml_) and stirred at room temperature for 12 hrs. The reaction mixture was cooled to 0 0C, the <n="77"/>precipitated dicyclohexylurea was filtered and the organic layer concentrated and the residue was purified by column chromatography with 1 percent methanol in chloroform and 0.1 percent ammonia as eluent to yield the title compound, {+)-trans- <strong>[936-08-3]2-bromo-4-chloro-benzoic acid</strong> 2-(2-acetoxymethyl-1 -methyl-pyrrolidin-3-yl)-6- acetyl-3,5-dimethoxy-phenyl ester . Yield: 0.6 g (33 percent); MS(ES+): 569 (M+1 ).
A. (2-bromo-4-chlorophenyl)methanol [00855] Added BH3 (1M in THF, 40 mL) to a solution of <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (3.14 g, 13.33 mmol) in THF (3 mL) drop wise at 0°C. The reaction mixture was stirred at room temperature overnight. Extracted with ethyl acetate twice, and washed the organic phase with brine and dried with anhydrous Na2S04, concentrated to give the title compound (2.5 g, 85percent). 1H NMR (300 MHz, CDC13): delta 4.72 (2H, s), 7.32 (1H, dd, J= 1.8 Hz, 8.1 Hz), 7.43 (1H, d, J= 8.1 Hz), 7.56 (1H, d, J= 2.1 Hz).
80%
Add borane-THF (1 M in THF, 3.2 mL) complex dropwise to an ice-cooled solution of <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (500 mg, 2.1 mmol) in THF (2 mL). Remove the cooling bath and stir overnight. Slowly add water (1 mL) and solid sodium carbonate. Stir 1 h. Filter and wash solids with THF. Chromatograph on silica gel, eluting with EPO <DP n="48"/>0:100 to 30:70 ethyl acetate:dichloromethane to give 2-bromo-4-chlorobenzyl alcohol as a white solid (378 mg5 80percent).
In tetrahydrofuran; at 20℃; for 18h;
INTERMEDIATE 13; fert-Butyl-4-[5-chloro-2-(difluoromethyl)phenyl]carbonyl}piperidine-l-carboxylate; Step 1 : (2-Bromo-4-chlorophenyl)methanol; Into a 500 mL round-bottom flask equipped with a magnetic stir bar was dissolved 2-bromo-4-chlorophenylbenzoic acid (10.0 g, 42.5 mmol) in THF (42.5 mL). It was stirred at rt for 18 h. The mixture was quenched with 10percent aqueous HCl and it was poured into a 1000 mL separatory funnel and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound.
4-chloro-2-(N-methylsulphonylamino)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4-chloro-2-(N-methylsulphonylamino)benzoic acid, m.p. 188-192° C. from <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong>, employing copper (I) bromide and methanesulphonamide and 3 equivalents of sodium hydride;
4-chloro-2-(N-methoxy-N-methylsulphonyl)aminobenzoic acid, m.p. 159-160° C. from <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> employing copper (I) bromide and N-methoxy-methanesulphonamide.
Step A: A mixture of <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (5 g), 2,6-diaminopyridine (6.95 g), K2CO3 (3.18 g), Cu powder (0.13 g) and Cu(I) oxide (0.15 g) in ethoxyethanol (10 mL) was heated at 130° C. for 2 h, until the reaction was complete (as confirmed by tlc). The mixture was cooled to RT, and water (70 mL) and activated carbon was added, and the mixture stirred for 3 h. The product was then filtered, and HCl (4 M) was added until pH 7 was reached. The resulting brown precipitate was filtered and dried in an oven (50° C., pressure=30 mbar) overnight to provide 2-(6-amino-pyridin-2-ylamino)-4-chlorobenzoic acid (2.4 g).
To a solution of <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (2.35 g, 10.0 mmol) in tetrahydrofuran (THF) (15 mL) was added, a 1.6 M solution in hexane, n-butyllithium (Parham, W. E; Egberg, D. C; Sayed, Y. A; Thraikill, R. W; Keyser, G. E; William, M. N; Montgomery, M. C; Jones, L. D., J. Org. Chem., 1976, 41, 2628-2633) (20 mL, 32.0 mmol) slowly at -78°C under nitrogen. After addition was complete the reaction mixture was stirred at -78°C for 3 hours (h). Then a solution of 1-benzylpiperidin-4-one (3.78 g, 20.0 mmol) in THF (10 mL) was added slowly to the reaction mixture at-78°C. After addition was complete the reaction temperature was raised to room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of water (H2O) (60 mL) and diethyl ether (60 mL), layers were separated. The aqueous layer was extracted with diethyl ether (2 x 20 mL). The aqueous layer was acidified with aq 6 M HCl to pH 2 and boiled for 1 h, cooled to 0°C, pH was adjusted to 10 by addition of aqueous sodium hydroxide (NaOH) (6M) and rapidly extracted with trichloromethane (CHCl3). The organic layer was washed with H2O, dried over sodium sulphate (Na2SO4), filtered and concentrated in vacuo to give sub-titled compound (1.22 g) and it was pure enough for the next step. 1H-NMR (CDCl3, 400 MHz): delta 7.84 (d, J = 8.2 Hz, 1H) ; 7.51 (dd, J = 1.7, 8.2 Hz, 1H) ; 7.45-7.25 (m, 6H); 3.67 (s, 2H); 3.00 (br. d; J= 9.4 Hz, 2H); 2.61 (br. t, J= 11.2 Hz, 2H); 2.32 (br, s, 2H); 1.74 (d, J= 12.2 Hz, 2H). APCI-MS: m/z 328 (MH+).
(-)-trans-acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-yl methyl ester[ No CAS ]
[ 936-08-3 ]
(+)-trans-2-bromo-4-chloro-benzoic acid 2-(2-acetoxymethyl-1-methylpyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;
Example 67 (+)-trans-2-Bromo-4-chlorobenzoic Acid 2-(2-acetoxymethyl-1-methylpyrrolidin-3-yl)-6-acetyl-3,5-dimethoxyphenyl Ester A mixture of the compound of example (6)(1.12 g, 3.2 mmol), <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (0.9 g, 3.8 mmol), DCC (1.32 g, 6.4 mmol) and DMAP (0.4 g, 3.2 mmol) were dissolved in dichloromethane (25 mL) and stirred at room temperature for 12 hrs. The reaction mixture was cooled to 0° C., the precipitated dicyclohexylurea was filtered and the organic layer concentrated and the residue was purified by column chromatography with 1percent methanol in chloroform and 0.1percent ammonia as eluent to yield the title compound, (+)-trans-<strong>[936-08-3]2-bromo-4-chloro-benzoic acid</strong> 2-(2-acetoxymethyl-1-methyl-pyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester. Yield: 0.6 g (33percent); MS (ES+): 569 (M+1).
General procedure: A suspension of 2-amino-3-methoxybenzoic acid (1.67 g, 10 mmol), 2-bromobenzoic acid derivative (11 mmol, 1.1 equiv), K2CO3 (2.77 g, 20 mmol, 2 equiv) and copper powder (0.125 g, 2 mmol, 0.2 equiv) was stirred in EtOH (20 mL) and heated to reflux for 1.5 h. The suspension was cooled to room temperature and H2O (20 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with H2O and the resulting solution was acidified with concentrated HCl to a pH of 2-3. The resulting suspension was stirred for 1 h at 10 °C, the solid was filtered and washed with H2O. The product was recrystallized in EtOH/H2O and dried under vacuum.
3-([2-(4-hydroxymethyl-piperidin-1-yl)-thiazole-5-carbonyl]amino}methyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide[ No CAS ]
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