* 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] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1976, vol. 283, p. 319 - 321
6
[ 99-92-3 ]
[ 14401-73-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 72, p. 146 - 159
7
[ 99-92-3 ]
[ 33720-71-7 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 11, p. 2883 - 2888
[2] Arzneimittel-Forschung/Drug Research, 1984, vol. 34, # 11 A, p. 1612 - 1624
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2016, vol. 59, # 13, p. 546 - 551
8
[ 7446-09-5 ]
[ 99-92-3 ]
[ 1788-10-9 ]
Yield
Reaction Conditions
Operation in experiment
55%
With hydrogenchloride; acetic acid; sodium nitrite In water
EXAMPLE 24 5-p-Dimethylaminosulphonylphenyl-2-(1-normon-2-yl)oxazole A The diazonium salt prepared from p-aminoacetophenone (27 g, 0.2 mmol), concentrated hydrochloric acid (140 ml), water (30 ml) and sodium nitrite (14 g, 0.2 mol) was added to a mixture of acetic acid (250 ml), sulphur dioxide (80 g), and cuprous chloride (3 g) at 20° C. After 40 min the mixture was cooled to 0° C. and water (1 l) added. Filtration, and drying of the residue followed by recrystallisation from carbon tetrachloride then gave p-acetylbenzenesulphonyl chloride as off-white needles (24 g, 55percent); m.p. 70°-72° C., lit mp=85° C.; δH (CDCl3) 8.1 (4H, S, aryl), 2.6 (3H, S, Me).
Reference：
[1] Patent: US4812470, 1989, A,
9
[ 99-92-3 ]
[ 1788-10-9 ]
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 26, p. 9103 - 9113
[2] Bollettino chimico farmaceutico, 1964, vol. 103, p. 48 - 64
10
[ 99-92-3 ]
[ 1788-10-9 ]
Reference：
[1] Patent: US5859036, 1999, A,
11
[ 99-92-3 ]
[ 124-63-0 ]
[ 5317-89-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 0 - 20℃; for 2 h;
A cooled solution of 4'-aminoacetophenon (10 mmol) in pyridine (10 mL) at 0 °C was treated with METHANESULFONYL chloride (15 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with HZ0 and extracted with EtOAc several times. The combined organic layers were washed with H20 and brine, dried over MGS04, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes to afford 4'- (Methylsulfonylamino) acetophenone (13-5, LJO-298). 95percent yield, mp = 161 °C 1H NMR (CDC13) 8 7.97 (dd, 2 H, J= 2,6. 8 Hz, ), 7.26 (dd, 2 H, J= 2, 6.8 Hz), 6. 87 (bs, 1 H), 3.10 (s, 3 H), 2.59 (s, 3 H)
66%
With pyridine In tetrahydrofuran at 20℃; for 12 h;
General procedure: To a solution of 4-aminoacetophenone (0.68g, 5mmol) and pyridine (1.6mL, 20mmol) in THF (10mL) was slowly added the substituted sulfonyl chloride (5mmol). The reaction mixture was stirred at room temperature for 12h. Water (50mL) was added and the mixture was extracted with ethyl acetate (10mL×3), the combined organic phase was washed with 1N hydrochloric acid (30mL×2) and water (30mL×2), dried over anhydrous Na2SO4 and concentrated under vacuum to afford the product.
Reference：
[1] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 6, p. 846 - 867
[2] Organic Process Research and Development, 1998, vol. 2, # 2, p. 71 - 77
[3] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 18, p. 6043 - 6053
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2685 - 2688
[5] Patent: WO2005/3084, 2005, A1, . Location in patent: Page 79
[6] Journal of Organic Chemistry, 1987, vol. 52, # 19, p. 4377 - 4379
[7] Journal of Organic Chemistry, 2001, vol. 66, # 25, p. 8293 - 8296
[8] Journal of the American Chemical Society, 2015, vol. 137, # 11, p. 3731 - 3734
[9] Arkivoc, 2016, vol. 2016, # 4, p. 227 - 245
[10] Asian Journal of Chemistry, 2012, vol. 24, # 3, p. 1316 - 1318
[11] Chemistry - A European Journal, 2016, vol. 22, # 47, p. 16998 - 17005
[12] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 48 - 65
[13] Journal of medicinal chemistry, 1966, vol. 9, # 1, p. 88 - 97
[14] Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy, 1982, vol. 38, # 7, p. 791 - 796
[15] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 2, p. 1056 - 1061
[16] Synthesis, 2012, vol. 44, # 9, p. 1329 - 1338
[17] Medicinal Chemistry Research, 2014, vol. 23, # 10, p. 4383 - 4394
[18] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2685 - 2688
12
[ 99-92-3 ]
[ 7143-01-3 ]
[ 5317-89-5 ]
Reference：
[1] Patent: US2003/153596, 2003, A1,
13
[ 937-31-5 ]
[ 14235-81-5 ]
[ 99-92-3 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 35, p. 4807 - 4810
14
[ 110-91-8 ]
[ 99-92-3 ]
[ 1197-55-3 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 2335,2338
[2] Journal of Organic Chemistry, 1946, vol. 11, p. 798,800
15
[ 99-92-3 ]
[ 14401-72-0 ]
Reference：
[1] Journal of Organic Chemistry, 1947, vol. 12, p. 617,680
16
[ 99-92-3 ]
[ 56759-32-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-Bromosuccinimide In acetonitrile at 20℃; for 20 h; Cooling with ice
Example 23 4-acetyl-2-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenylamino}benzonitrile (23a) 1-(4-amino-3-bromophenyl)ethanone 1-(4-Aminophenyl)ethanone (10.0 g, 74.0 mmol) was dissolved in acetonitrile (50 mL) and, under ice-cooling, a solution (30 mL) of N-bromosuccinimide (13.8 g, 77.7 mmol) in acetonitrile was added dropwise, and the mixture was stirred at room temperature for 20 hr. The solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title object compound as a yellow powder (15.8 g, yield 100percent). 1H-NMR (CDCl3, 400 MHz) δ: 2.49 (3H, s), 4.52-4.70 (2H, br), 6.73 (1H, d, J=8.5 Hz), 7.73 (1H, dd, J=8.5, 1.9 Hz), 8.05 (1H, d, J=1.9 Hz).
85%
With N-Bromosuccinimide In acetonitrile at 0 - 20℃;
To a solution of 4-aminoacetophenone (5.67 g, 0.0419 mol) in 30 mL of CH3CN at 0° C. was added N-bromosuccinimide (7.83 g, 0.0439 mol) in 20 mL of CH3CN dropwise. The reaction was allowed to warm to room temperature and concentrated in vacuo after stirring 16 h. The crude residue was dissolved in EtOAc (100 mL), washed with saturated aqueous NaHCO3 (1.x.100 mL), brine (1.x.100 mL) and dried (Na2SO4). The solvent was removed under vacuum to afford the title compound (7.62 g, 85percent) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C8H8BrNO, 213.9 (M+H), found 214.0.
71%
With N-Bromosuccinimide In toluene at 40℃; for 0.75 h;
j00122j Step 1. To a suspension of 1-(4-aminophenyl)-ethanone (14.7 g, 109 mmol) in toluene (150 mL) at 40 °C was added N-bromosuccinimide (19.4 g, 109 mmol) in several portions over 30 mm. After the addition was complete, the mixture was stirred at 40 °C for 15 mm. Water (30 mL) was added and the organic layer was separated, washed with water (3 x 30 mL), dried over magnesium sulfate and evaporated to give the title compound (16.5 g, 77 mmol, 71percent) as a brown crystalline solid. The crude product was used without further purification. LCMS: 97percent, Rt 1.188 mill, ESMS m/z 214 (M+H).
Reference：
[1] Patent: US2016/207883, 2016, A1, . Location in patent: Paragraph 0644-0646
[2] Synthetic Communications, 2009, vol. 39, # 2, p. 215 - 219
[3] Chemistry - A European Journal, 2017, vol. 23, # 69, p. 17463 - 17468
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2016, vol. 59, # 13, p. 552 - 556
[5] Agricultural and Biological Chemistry, 1984, vol. 48, # 11, p. 2883 - 2888
[6] Journal of Labelled Compounds and Radiopharmaceuticals, 2016, vol. 59, # 13, p. 546 - 551
[7] Patent: US2007/249649, 2007, A1, . Location in patent: Page/Page column 77-78
[8] Journal of Chemical Research, Synopses, 1995, # 11, p. 457
[9] Patent: WO2015/50471, 2015, A1, . Location in patent: Paragraph 00121; 00122
[10] Patent: US4404222, 1983, A,
[11] Patent: US4407819, 1983, A,
[12] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 8-9
[13] Chemistry - A European Journal, 2011, vol. 17, # 49, p. 13665 - 13669
[14] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7360 - 7377
[15] Patent: WO2015/20553, 2015, A1, . Location in patent: Paragraph 00128
[16] Patent: WO2015/50472, 2015, A1, . Location in patent: Paragraph 00125; 00126
[17] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
[18] Advanced Synthesis and Catalysis, 2017, vol. 359, # 7, p. 1144 - 1151
[19] Chinese Journal of Chemistry, 2018, vol. 36, # 9, p. 815 - 818
17
[ 99-92-3 ]
[ 107-21-1 ]
[ 56759-32-1 ]
Reference：
[1] Synthesis, 2007, # 10, p. 1471 - 1474
18
[ 99-92-3 ]
[ 90434-58-5 ]
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 15, p. 5265 - 5270
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 31, p. 7034 - 7038
19
[ 99-92-3 ]
[ 51529-96-5 ]
Reference：
[1] Journal of the Chemical Society, 1930, p. 252,255
20
[ 591-50-4 ]
[ 99-92-3 ]
[ 23600-83-1 ]
Yield
Reaction Conditions
Operation in experiment
53.4%
With copper; potassium carbonate In <i>N</i>-methyl-acetamide
368.1 1-(4-anilinophenyl)ethanone 4-amino-acetophenone (4.87 g; 36.0 mmol) is dissolved in dimethylformamide (75 ml). 15 g (0.108 mol) of potassium carbonate (previously dried at 170° C. under an argon atmosphere), 7.236 g (36.0 mmol) of iodobenzene, 0.4 g of copper in powder form and a catalytic quantity of copper iodide are added. The reaction mixture is taken to reflux for 12 hours. After leaving the reaction medium to return to ambient temperature, it is filtered on celite and poured into ice-cold water. After extraction with ethyl acetate, the organic phase is washed with water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The product obtained is purified by crystallization from heptane in order to produce a yellow solid with a yield of 53.4percent. Melting point: 105° C.
With potassium carbonate In <i>N</i>-methyl-acetamide
335.1 1-(4-anilinophenyl)ethanone 4-amino-acetophenone (4.87 g; 36.0 mmol) is dissolved in dimethylformamide (75 ml). 15 g (0.108 mol) of potassium carbonate (previously dried at 170° C. under an argon atmosphere), 7.236 g (36.0 mmol) of iodobenzene, 0.4 g of copper powder and a catalytic quantity of copper iodide are added. The reaction mixture is taken to reflux for 12 hours. After leaving the reaction medium to return to ambient temperature, the latter is filtered on celite and poured into ice-cooled water. After extraction with ethyl acetate, the organic phase is washed with water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The product obtained is purified by crystallization from heptane in order to produce a yellow solid with a yield of 53.4percent. Melting point: 105° C.
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 48, p. 14487 - 14491[2] Angew. Chem., 2015, vol. 127, # 48, p. 14695 - 14699,5
30
[ 99-92-3 ]
[ 23600-83-1 ]
Reference：
[1] Journal of the Chemical Society, 1955, p. 1278,1280
[2] Bollettino Scientifico della Facolta di Chimica Industriale di Bologna, 1959, vol. 17, p. 33,37,41
31
[ 99-92-3 ]
[ 37148-48-4 ]
Reference：
[1] Journal of Organic Chemistry, 1947, vol. 12, p. 617,680
32
[ 7782-50-5 ]
[ 99-92-3 ]
[ 64-19-7 ]
[ 37148-48-4 ]
[ 634-93-5 ]
Reference：
[1] Journal of Organic Chemistry, 1947, vol. 12, p. 617,680
33
[ 99-92-3 ]
[ 118727-34-7 ]
Reference：
[1] Green Chemistry, 2010, vol. 12, # 8, p. 1370 - 1372
[2] European Journal of Organic Chemistry, 2011, # 28, p. 5696 - 5703
34
[ 13675-18-8 ]
[ 99-92-3 ]
[ 149104-90-5 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
35
[ 99-92-3 ]
[ 149104-90-5 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
36
[ 99-92-3 ]
[ 157014-41-0 ]
Reference：
[1] Journal of the American Chemical Society, 1997, vol. 119, # 10, p. 2453 - 2463
[2] Patent: WO2011/12577, 2011, A1,
37
[ 887144-94-7 ]
[ 99-92-3 ]
[ 343564-14-7 ]
Yield
Reaction Conditions
Operation in experiment
61%
With tris[2-phenylpyridinato-C2,N]iridium(III) In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Irradiation
Under nitrogen or argon, 0.4 mmol, 0.2mmol, Ir(ppy) 3(2 mg) was added to the reaction and DMF1 ml flask, and irradiated with a blueLED strip (7W) at room temperature until complete conversion of trivalent iodine reagentcompletion of the reaction. Add 10 ml of saturated Na 2CO 3Aqueous solution, andextracted three times with ethyl acetate, the organic layer was washed with water andonce with saturated brine, dried over anhydrous Na 2SO 4The organic layer was dried.Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 15: 1-8: 1) to give the product in 61percent yield.
56%
With potassium carbonate; nickel(II) hydroxide In dimethyl sulfoxide at 35℃; for 2 h;
In the preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is p-aminoacetophenone, and other reactions and post- treatment processes are the same as in the embodiment 28. The preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is aniline, and the nickel compound is nickel hydroxide.The base is potassium carbonate, and the reaction process parameters are: 1-trifluoromethyl-1,2-phenyliodo-3(H)-one (0.5 mmol, 1.0 eq).Aromatic amine (1.5 mmol, 3.0 eq), nickel hydroxide 10 molpercent, potassium carbonate (1.5 mmol, 3.0 eq),DMSO (2 mL) was reacted at 35 ° C for 2 h, and the other reactions and workup procedures were the same as in Example 1.
Reference：
[1] Patent: CN103553857, 2016, B, . Location in patent: Paragraph 0025-0026
[2] Organic Letters, 2014, vol. 16, # 6, p. 1768 - 1771
[3] Organic Letters, 2018, vol. 20, # 13, p. 3732 - 3735
[4] Patent: CN108503552, 2018, A, . Location in patent: Paragraph 0150-0154
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 20h;Cooling with ice;
Example 23 4-acetyl-2-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenylamino}benzonitrile (23a) 1-(4-amino-3-bromophenyl)ethanone 1-(4-Aminophenyl)ethanone (10.0 g, 74.0 mmol) was dissolved in acetonitrile (50 mL) and, under ice-cooling, a solution (30 mL) of N-bromosuccinimide (13.8 g, 77.7 mmol) in acetonitrile was added dropwise, and the mixture was stirred at room temperature for 20 hr. The solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title object compound as a yellow powder (15.8 g, yield 100%). 1H-NMR (CDCl3, 400 MHz) delta: 2.49 (3H, s), 4.52-4.70 (2H, br), 6.73 (1H, d, J=8.5 Hz), 7.73 (1H, dd, J=8.5, 1.9 Hz), 8.05 (1H, d, J=1.9 Hz).
89%
With N-Bromosuccinimide; ammonium acetate; In acetonitrile; at 20℃; for 0.166667h;
To a solution of l-(4-aminophenyl)ethanone (118) (10g, 74mmol) in MeCN (lOOmL), ammonium acetate was added (0.548g, 7.4mmol) following by addition of N-bromosuccinimide (13.3g, 75mmol) portionwise at ambient temperature. The reaction mixture was stirred for 10 min at ambient temperature. The reaction was quenched with aq Na2SO3, MeCN was partially evaporated, the residue was diluted with water and extracted with EtOAc, the combined organic extracts were dried with Na2S04 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1-20% EtOAc in hexane to give l-(4-amino-3-bromophenyl)ethanone (119) (14.1 g, 89%), 1H-NMR (CDCI3, 400 MHz): 8.05 (d, J=1.8 Hz, 1H), 7.72 (dd, Ji=1.8Hz, J2=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.61(br.s, 2H), 2.50 (s, 3H).
85%
With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;
To a solution of 4-aminoacetophenone (5.67 g, 0.0419 mol) in 30 mL of CH3CN at 0 C. was added N-bromosuccinimide (7.83 g, 0.0439 mol) in 20 mL of CH3CN dropwise. The reaction was allowed to warm to room temperature and concentrated in vacuo after stirring 16 h. The crude residue was dissolved in EtOAc (100 mL), washed with saturated aqueous NaHCO3 (1×100 mL), brine (1×100 mL) and dried (Na2SO4). The solvent was removed under vacuum to afford the title compound (7.62 g, 85%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C8H8BrNO, 213.9 (M+H), found 214.0.
71%
With N-Bromosuccinimide; In toluene; at 40℃; for 0.75h;
j00122j Step 1. To a suspension of 1-(4-aminophenyl)-ethanone (14.7 g, 109 mmol) in toluene (150 mL) at 40 C was added N-bromosuccinimide (19.4 g, 109 mmol) in several portions over 30 mm. After the addition was complete, the mixture was stirred at 40 C for 15 mm. Water (30 mL) was added and the organic layer was separated, washed with water (3 x 30 mL), dried over magnesium sulfate and evaporated to give the title compound (16.5 g, 77 mmol, 71%) as a brown crystalline solid. The crude product was used without further purification. LCMS: 97%, Rt 1.188 mill, ESMS m/z 214 (M+H).
With N-Bromosuccinimide; In toluene;
EXAMPLE 34 5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide is added in portions over 0.5 hours at below 40 C. After 15 minutes, the mixture is washed with H2 O (4*100 ml). The solution is dried (MgSO4) and evaporated to dryness to afford 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62 C.
With N-Bromosuccinimide; In toluene;
EXAMPLE 36 5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide is added in portions over 0.5 hours at below 40 C. After 15 minutes, the mixture is washed with H2 O (4*100 ml). The solution is dried (MgSO4) and evaporated to dryness to afford 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62 C.
With N-Bromosuccinimide; In toluene; at 20℃; for 0.25h;
N-(4-acetyl-2-bromophenyl)-2,2,2-trifluoroacetamide (K5).; l-(4- aminophenyl)ethanone (2.50 g; 18.5 mmol) was dissolved in 100 mL toluene. NBS (3.30 g; <n="11"/>18.8 mmol) was added portionwise. After 15 min stirring at RT, the organic phase was washed with water twice, and dried over Na2SO4. The solvent was removed by rotavap to get oil, which was purified by silica gel chromatography, to afford 1.7 g of a white solid, l-(4- amino-3-bromophenyl)ethanone (1.7 g; 7.94 mmol).
With N-Bromosuccinimide; In toluene; at 40℃; for 0.75h;
Step 1. To a suspension of 1 -(4-aminophenyl)-ethanone (14.7 g, 109 mmol) in toluene (150 mL) at 40 C was added N-bromosuccinimide (19.4 g, 109 mmol) in several portions over 30 min. After the addition was complete, the mixture was stirred at 40 C for 15 min. Water (30 mL) was added and the organic layer was separated, washed with water (3 x 30 mL), dried over magnesium sulfate and evaporated to give the title compound (16.5 g, 77 mmol, 71%) as a brown crystalline solid. The crude product was used without further purification. LCMS: 97%, Rt 1.188 min, ESMS m/z 214 (M+H)+.
With N-Bromosuccinimide; In toluene; at 40℃; for 0.75h;
To a suspension of 1-(4-aminophenyl)-ethanone (14.7 g, 109 mmol) in toluene (150 mL) at 40 C was added N-bromosuccinimide (19.4 g, 109 mmol) in several portions over 30 mm. After the addition was complete, the mixture was stirred at 40 C for 15 mm. Water (30 mL) was added and the organic layer was separated, washed with water (3 x 30 mL), dried over magnesium sulfate and evaporated to give the title compound (16.5 g, 77 mmol, 71%) as a brown crystalline solid. The crude product was used without further purification. LCMS: 97%, Rt 1.188 mm, ESMS m/z 214 (M+H).
Step 1: N-[4-(2-Bromoacetyl)-phenyl]-4-trifluoromethoxybenzenesulfonamide 4-Trifluoromethoxybenzenesulfonyl chloride (3.18 g, 2.07 mL, 1.22 mmol) was added to a solution of 4'-aminoacetophenone (1.5 g, 1.11 mmol) and triethylamine (3.1 mL, 2.22 mmol) in anhydrous methylene chloride (50 mL). The reaction was stirred for 16 hours and then poured into water (50 mL), and extracted with diethyl ether (3*30 mL). The combined extract was washed with 0.5 N hydrochloric acid (2*10 mL), water and finally brine. The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product methyl ketone was used in the subsequent bromination step without further purification. Phenyltrimethylammonium tribromide (4.68 g, 1.22 mmol) was added to a solution of the methyl ketone (prepared in the previous step) in anhydrous dioxan (50 mL). The reaction eas stirred at room temperature for 3 hours and then poured into water (50 mL), and extracted with diethyl ether (3*30 mL). The combined extract was washed with 0water and brine. The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 20% ethyl acetate/heptane as eluent, afforded the title compound has a white solid (4.36 g, 89%);
With pyridine; In tetrahydrofuran; at 20℃; for 16h;
Example 9 Thioacetic acid S-{2-oxo-2-[4-(4-trifluoromethoxy-benzoylamino)-phenyI]-ethyl} ester:Step 1 yV-^-Acetyl-pheyl^-trifluoromethoxy-benzamide: To a solution of 4'-aminoacetophenone (2.0 g, 14.8 mmol) in anhydrous THF (20 mL) was added <strong>[36823-88-8]4-(trifluoromethoxy)benzoyl chloride</strong> (3.3 g, 14.8 mmol) and pyridine (3.5 g, 44.4 mmol). The reaction mixture was stirred for 16 h at room temperature. The solid was collected by filtration and triturated in EtOAc (40 mL) to afford the desired product (1.23 g, 26%) as a white solid. LC-MS (ES+): 324 [MH]+ m/e.
With CuCl2; sodium nitrite; In hydrogenchloride; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; acetic acid;
(A) p-Acetylbenzenesulfonamide A warmed solution of 54 g (0.4 mole) of p-aminoacetophenone in 280 ml of concentrated HCl and 40 ml of water is cooled to 0 C. and a solution of 28 g of NaNO2 in 160 ml of water is added over 0.5 hour. The reaction mixture is stirred at 0 C. for an additional 0.25 hour and then poured cautiously into a well-stirred mixture of 6.0 g of CuCl2 in 500 ml of acetic acid saturated with SO2 at 0 C. When the foaming ceases (approx. 1 hour) the mixture is poured into 2 liters of ice water. The resulting solid is filtered off, washed with water and warmed with excess (NH4)2 CO3 to give a solid. Crystallization from aqueous ethanol yields 44.3 g of the title compound, melting point 177-178 C.
PREPARATION 1 A mixture of p-aminoacetophenone (20 g), pyridine (11.7 g), and iodobenzene dichloride (40 g) in tetrahydrofuran (300 ml) was stirred for 5 hours at 0° C. The insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was crystallized from ethanol to give colorless crystals of 4'-amino-3'-chloroacetophenone (20.1 g). IR (Nujol): 3420, 3340, 3230, 1665, 1635, 1590 cm-1.
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-acetylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 108 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-acetylaniline 4-Acetylaniline (0.159 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 1:2) to obtain the titled compound (0.160 g, 0.326 mmol, 61percent).
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(pyridin-3-ylmethyloxy)benzoyl]-4-acetylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 129 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoyl]-4-acetylaniline 4-Acetylaniline (0.128 g, 0.946 mmol), triethylamine (0.096 g, 0.946 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.160 g, 0.946 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) and then recrystallized from ether to obtain the titled compound (0.080 g, 0.148 mmol, 31percent).
With pyridine; In tetrahydrofuran; at 20℃; for 12h;
General procedure: To a solution of 4-aminoacetophenone (0.68g, 5mmol) and pyridine (1.6mL, 20mmol) in THF (10mL) was slowly added the substituted sulfonyl chloride (5mmol). The reaction mixture was stirred at room temperature for 12h. Water (50mL) was added and the mixture was extracted with ethyl acetate (10mL×3), the combined organic phase was washed with 1N hydrochloric acid (30mL×2) and water (30mL×2), dried over anhydrous Na2SO4 and concentrated under vacuum to afford the product.
General procedure: Aryl amine (10 mmol) was dissolved in a mixture of 5 mL of distilled water and 3.4 mL of 50% hydrofluoroboric acid. After cooling the reaction mixture to 0 C using ice bath and the sodium nitrite (0.69 g in 2 mL distilled water), was added dropwise in 5 min interval of time. The resulting mixture was stirred for 1 h and the precipitate was collected by filtration and redissolved in minimum amount of acetone. Diethylether was added until precipitation of aryl diazonium tetrafluoroborate, which is filtered, washed several times with diethyl ether and dried under vacuum. Typical reaction procedure: General procedure: Diazonium tetrafluoroborate salts (0.5 mmol) and B2pin2 (1.5 mmol) were transferred into an oven-dried tube under air. Then acetone/H2O (2/1, 4 mL) were added into the tube via syringe. The sealed tube was keep at 20 C and stirred for 1-2 h. After the reaction was complete, dichloromethane was added to extract the product and the combined organic solution was dried by Na2SO4. The pure product was isolated after column chromatography on silica gel (petroleum ether/ethyl acetate).
60%
With tert.-butylnitrite; dibenzoyl peroxide; In acetonitrile; at 20℃; for 4h;
EXAMPLE 3 Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone B2pin2 (1 mmol, 254 mg), benzoyl peroxide (0.02 mmol, 5 mg), 1-(4-aminophenyl)ethanone (1 mmol, 135 mg) and acetonitrile (3 mL) were added to a 25 mL tube-type reactor, followed by the addition of tert-butyl nitrite (1.5 mmol, 154 mg). The reaction was conducted at room temperature for 4 h. The solution was concentrated after the reaction and the resultant was purified by column chromatography (eluted by petroleum ether:ethyl acetate=20:1, V:V) to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone having the following structure: This compound is pale yellow solid and obtained in 60% yield. Its NMR data are as follows: 1H NMR (400 MHz, CDCl3) delta 7.94~7.88 (m, 4H), 2.62 (s, 3H), 1.36 (s, 12H); 13C NMR (100 MHz, CDCl3) delta 198.4, 138.9, 134.8, 127.2, 105.3, 84.1, 26.7, 24.8.
60%
With tert.-butylnitrite; dibenzoyl peroxide; In acetonitrile; at 20℃; for 4h;
B2pin2 (1 mmol, 254 mg), benzoyl peroxide (0.02 mmol, 5 mg), 1-(4-aminophenyl)ethanone (1 mmol, 135 mg) and acetonitrile (3 mL) were added to a 25 mL tube-type reactor, followed by the addition of tert-butyl nitrite (1.5 mmol, 154 mg). The reaction was conducted at room temperature for 4 h. The solution was concentrated after the reaction and the resultant was purified by column chromatography (eluted by petroleum ether : ethyl acetate = 20:1, V:V) to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone having the following structure: This compound is pale yellow solid and obtained in 60% yield. Its NMR data are as follows: 1H NMR (400 MHz, CDCl3) delta 7.94~7.88 (m, 4H), 2.62 (s, 3H), 1.36 (s, 12H); 13C NMR (100 MHz, CDCl3) delta 198.4, 138.9, 134.8, 127.2, 105.3, 84.1, 26.7, 24.8.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;
Example 92 N-(4-acetylphenyl)-3-(piperidin-1-ylsulfonyl)benzamide 1-(4-aminophenyl)ethanone (151 mg), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (565 mg) and N,N-diisopropylethylamine (0.39 mL) were added in that order to a DMF (4.0 mL) solution of <strong>[7311-93-5]3-(piperidin-1-ylsulfonyl)benzoic acid</strong> (200 mg), and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction liquid, washed three times with water, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 80%, gradient) to give the entitled compound (117 mg, 41%) as a white crystal. 1H-NMR (CDCl3) delta: 1.38-1.47 (2H, m), 1.58-1.67 (4H, m), 2.61 (3H, s), 2.97-3.04 (4H, m), 7.68 (1H, t, J=7.8 Hz), 7.83 (2H, d, J=8.8 Hz), 7.89-7.93 (1H, m), 8.00 (2H, d, J=8.8 Hz), 8.15-8.19 (1H, m), 8.20-8.23 (1H, m), 8.43 (1H, s)
With 2,4,6-trimethyl-pyridine; HATU; In N,N-dimethyl-formamide; at 10℃; for 18h;
In a 250 ml flask equipped with a magnetic stirrer, 5.O g of N,N'-dibenzyloxycarbonyl-L- lysine (12.06 mmol, 1.0 eq), 9.17 g of HATU (24.13 mmol, 2.0 eq) and 2.19 g of 2,4,6- collidine (18.10 mmol, 1.5 eq) are dissolved in 70 ml of N,N-dimethylformamide, then 1.96 g of 4-aminoacetophenone (14.48 mmol, 1.2 eq) are added. The light yellow mixture is stirred at 1O0C for 18 h. The reaction mixture is diluted with 40 ml of saturated aqueous NH4Cl solution. The white precipitate is filtered and the filter cake is washed thoroughly with water and isopropyl ether to give the 5.3 g of the desired product as solid.MS (ESI+): 532.3 [M+H].1H-NMR (400 MHz, DMSO-d6) ppm: 10.34 (s, IH), 7.90 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 7.58 (m, IH), 7.33-7.30 (m, 10H), 7.20 (m, IH), 5.00 (s, 2H), 4.95 (s, 2H), 4.10 (m, IH), 2.96 (m, 2H), 2.50 (s, 3H), 1.71-1.27 (m, 6H).
General procedure: The mixtures of aniline derivatives (3 mmol), water (5 mL) and concentrated sulfuric acid (7.5-9 mmol) were heated with stirring until a clear solution was obtained. These solutions were cooled to 0-4 C and a solution of sodium nitrite (0.207 g, 3 mmol) in water was added drop wise while the temperature was maintained below 4 C. The resulting mixtures were stirred for 45-60 min in an ice bath. After diazotization was complete, the azo liquor was slowly added to a stirred solution of aromatic amines (3 mmol) dissolved in 10 mL of buffer solution of acetic acid-acetate sodium (pH = 5) and 2-5 mL ethanol. The resulting mixture was stirred at 0-4 C for 2 h in an ice bath. After this stage, the pH of the reaction mixture was maintained at 6.5-7.5 by addition of acetate sodium solution. Then the resulting dyes were filtered and washed with cold water. The crude dyes were purified using recrystallization method with EtOH and DMF/H2O. The physical and spectral data of the purified dyes are as follows.
General procedure: Preparation of the arenediazonium chloride To an ice-cooled degassed solution of aniline (5.00 mmol) in 3 N hydrochloric acid (5 mL) and water (5 mL) was dropwise added a degassed solution of sodium nitrite (5.00 mmol, 0.35 g) in water (2.5 mL) over a period of 10 min. After stirring for 20 more minutes at 0 C, the clear solution was used for the aryl-aryl coupling reactions (5 mmol/12.5 mL = 0.4 M). Biaryl synthesis A 5 mL aliquot of the 0.4 M arenediazonium chloride solution (2.00 mmol) was added dropwise by a syringe pump to a vigorously stirred solution of <strong>[60-19-5]tyramine hydrochloride</strong> (6.00 mmol, 1.04 g) in water (6 mL), acetonitrile (4 mL), and titanium(III)-chloride (4.00 mmol, 4.00 mL, ca. 1 M solution in 3 N hydrochloric acid) under nitrogen atmosphere over 10-15 min. After the addition was complete, the mixture was left to stir for 10 more minutes and a solution of sodium hydroxide (2 g) and sodium sulfite (2 g) in water (20 mL) was added. After extraction with diethylether (3 × 75 mL), the combined organic phases were washed with satd. aqueous sodium chloride and dried over sodium sulfate. The solvent was removed under reduced pressure. Prior to purification by HPLC, the crude product was dissolved in dichloromethane (10 mL) and TFA (1.5 equiv) was added. After concentration in vacuo, the trifluoroacetate salt was submitted to preparative HPLC (gradient: CH3CN/(H2O + 0.1% TFA) = 10:90?95:5 over 8 min, flow: 20 mL/min). Additional analytic data obtained from the characterization of the compounds can be found in the Supplementary data.
Step 1:<strong>[60230-36-6]2,6-difluorobenzene-1-sulfonyl chloride</strong> was added dropwise to a stirred solution of 1-(4-aminophenyl)ethanone and 1 mL of pyridine. The reaction was stirred at room temperature overnight. When complete as determined by HPLC using the protocol described above, as well as by LCMS, THF was evaporated, the evaporation residue was dissolved in 50 mL ethyl acetate, washed with 100 mL of 1M KHSO4, and then washed with brine and dried on Na2SO4. The solvent was evaporated and the residue was used for the next step without further purification (2.4 g, yield 46percent).
General procedure: The appropriate substituted phenylhydrazine (1a-g, 1.0 mmol) and substituted acetophenone (2a-f, 1.0 mmol) were mixed in ethanol (20 mL) and a few drops of glacial AcOH were added. The solution was heated under reflux at 80 C for 1-2 h. The solvents were evaporated in vacuo to give a solid that was added to polyphosphoric acid (PPA) (30 mL), and the mixture slowly heated to 120 C and kept at this temperature for a few hours until the reaction was complete (TLC monitoring). The mixture was allowed to cool and then poured into cold water (50 mL). The acidic solution was neutralised by the slow addition of 1 M NaOH (aq) and the solid precipitate of crude product was collected. Purification by column chromatography (hexane/ethyl acetate) gave the required product(s) (3a-q).
General procedure: The appropriate substituted phenylhydrazine (1a-g, 1.0 mmol) and substituted acetophenone (2a-f, 1.0 mmol) were mixed in ethanol (20 mL) and a few drops of glacial AcOH were added. The solution was heated under reflux at 80 C for 1-2 h. The solvents were evaporated in vacuo to give a solid that was added to polyphosphoric acid (PPA) (30 mL), and the mixture slowly heated to 120 C and kept at this temperature for a few hours until the reaction was complete (TLC monitoring). The mixture was allowed to cool and then poured into cold water (50 mL). The acidic solution was neutralised by the slow addition of 1 M NaOH (aq) and the solid precipitate of crude product was collected. Purification by column chromatography (hexane/ethyl acetate) gave the required product(s) (3a-q).
General procedure: To a stirred mixture of 4-hydroxy-2-quinolones 2 (4.0 mmol) and sodium acetate (3.8 g) in water (20 mL), a solution of aryl diazonium chloride [prepared from aniline (637 mg), conc.HCl (2 mL and sodium nitrite (345 mg) in water (2 mL)] was added dropwise at 0-5 C. After completion of addition, the reaction mass was stirred for 1h at the same temperature. The reaction mass was allowed to warm at ambient temperature and stirred for 30 min. The products were isolated by filtration and washed with cold isopropanol. Finally, it was purified by recrystallization in 95% ethanol, to afford pure products. The representative procedure was followed for the syntheses of compounds 4-82.
Dissolved 0.500 g <strong>[17823-69-7]2-cyano-3,3-bis(methylthio)acrylamide</strong> in 15 mL EtOH and added 4'-aminoacetophenone (1.0 eq.) . Stirred reaction at 75 degrees C until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75 C until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 3-((4-acetylphenyl)amino)-5-amino-lH-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. 3-((4-acetylphenyl)amino)-5-amino-lH-pyrazole-4-carboxamide
With potassium carbonate; In acetonitrile; at 75.0℃; for 6.0h;Schlenk technique; Inert atmosphere;
General procedure: Experimental Procedure: A dried 25 mL Schlenk tube equipped with a magnetic stir bar was charged with Togni?s Reagent 2 (0.25 mmol, 1.0 equiv), free anilines 1 (0.75 mmol, 3.0 equiv), K2CO3 (0.375 mmol, 1.5 equiv) and CH3CN (1.5 mL). The reaction mixture was then stirred at 75 C for 6 h under an argon atmosphere. The reaction progress was monitored by TLC. After cooling to room temperature, the mixture was washed with water and extracted with CH2Cl2 three times, then washed with saturated NaCl solution. The combined organic layer was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (Elutent: petroleum ether-EtOAc) to give the pure product. The products were characterized by 1H NMR, 13C NMR, 19F NMR, GC -MS.
61%
With tris[2-phenylpyridinato-C2,N]iridium(III); In N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere; Irradiation;
Under nitrogen or argon, 0.4 mmol, 0.2mmol, Ir(ppy) 3(2 mg) was added to the reaction and DMF1 ml flask, and irradiated with a blueLED strip (7W) at room temperature until complete conversion of trivalent iodine reagentcompletion of the reaction. Add 10 ml of saturated Na 2CO 3Aqueous solution, andextracted three times with ethyl acetate, the organic layer was washed with water andonce with saturated brine, dried over anhydrous Na 2SO 4The organic layer was dried.Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 15: 1-8: 1) to give the product in 61% yield.
56%
With potassium carbonate; nickel(II) hydroxide; In dimethyl sulfoxide; at 35.0℃; for 2.0h;
In the preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is p-aminoacetophenone, and other reactions and post- treatment processes are the same as in the embodiment 28. The preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is aniline, and the nickel compound is nickel hydroxide.The base is potassium carbonate, and the reaction process parameters are: 1-trifluoromethyl-1,2-phenyliodo-3(H)-one (0.5 mmol, 1.0 eq).Aromatic amine (1.5 mmol, 3.0 eq), nickel hydroxide 10 mol%, potassium carbonate (1.5 mmol, 3.0 eq),DMSO (2 mL) was reacted at 35 C for 2 h, and the other reactions and workup procedures were the same as in Example 1.
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; under 760.051 Torr; for 12h;Green chemistry;
General procedure: A reaction flask was charged with amine substrate, PTC, base, solvent, and DMC. The mixture was heated to 130C, and the reaction was monitored by thin-layer chromatography (TLC). After reaction completion, the mixture was extracted with EtOAc and washed with H2O. The combined organic extracts were dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, petroleum ether/EtOAc) to afford the desired compound.
With calcium hydride; 5%-palladium/activated carbon; In toluene; at 30℃; for 16h;Sealed tube;
General procedure: In a sealed tube was introduced an amine (1 equiv), paraformaldehyde (1 equiv) in toluene (0.5 M) followed by the addition at room temperature under of argon of palladium on carbon 5% (2 mol %) and then calcium hydride (60 mol %). The pressure tube was closed and introduced in a preheated oil bath at 30C where it was stirred for 16 h at 700 rpm.
N-(4-acetylphenyl)-5-methylisoxazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of <strong>[42831-50-5]5-methylisoxazole-4-carboxylic acid</strong> (0.5 g, 0.0039 mol) and 4-aminoacetophenone (0.58 g, 0.0043mol) and Et3N (few drops) in DMF (10 ml), HBTU or BOP (0.0039 mol) was added then the mixture was stirred at ambient temperature for 24 hours. Water was added and the mixture was extracted with EtOAC (3 x 40 ml) and dried (Na2SO4) and evaporated under reduced pressure giving our desired compound as white solid yield: 0.14 g (15 %).
With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 5h;
<strong>[25812-30-0]Gemfibrozil</strong>, 1. 07 g of dicyclohexylcarbodiimide, 0. 54 g of p-aminoacetophenone, 60 ml of dichloromethane, 60 ml of100ml single-mouth bottle, room temperature for 5 hours, evaporated to dryness solvent, column chromatography compound d1 1. 31g.
(2E)-1-(4-aminophenyl)-3-(quinoxalin-2-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
This procedure is based on our previous report27 and vogels procedure36. To a conical flask containing NaOH solution (1.5eq, 10 mL H2O) was added substituted acetophenones (1mmole) in ethanol (10 mL), and the reaction mixture was stirred for 10 minutes to allow enolate formation, to this was added quinoxaline-2- carbaldehyde 1 (1mmole) and the reaction mixture was stirred till completion. After completion of the reaction, as monitored by TLC the reaction mixture was poured in an ice bath and was acidified using conc. HCl. The solid obtained was then filtered, dried and recrystallized using Ethanol. The quinoxalinyl chalcone 2a-n were then characterized using IR, NMR (1H, 13C) and HR-MS spectroscopy. The purity was checked by HPLC measurements using mobile phase consisting methanol and water in the ratio 90:10.
N-(4-acetylphenyl)-5-chloro-2-methoxybenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With pyridine; In tetrahydrofuran; at 20℃; for 12h;
General procedure: To a solution of 4-aminoacetophenone (0.68g, 5mmol) and pyridine (1.6mL, 20mmol) in THF (10mL) was slowly added the substituted sulfonyl chloride (5mmol). The reaction mixture was stirred at room temperature for 12h. Water (50mL) was added and the mixture was extracted with ethyl acetate (10mL×3), the combined organic phase was washed with 1N hydrochloric acid (30mL×2) and water (30mL×2), dried over anhydrous Na2SO4 and concentrated under vacuum to afford the product.
2-(4-acetylphenyl)-5-(tert-butyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium acetate; acetic acid; for 12h;Reflux;
General procedure: A mixture of 4-aminoacetophenone (10.0 mmol), anhydrous sodiumacetate (1.38 g, 10.0 mmol) and an appropriate acid anhydride(10.0 mmol) in glacial acetic acid (50 mL) was heated under reflux for12 hr. After cooling of the reaction mixture, the precipitate obtainedwas filtered, washed with water, dried and re-crystallised from acetic acid.
General procedure: The synthesis of chalcone derivatives [I] was conductedaccording to the procedure reported in the reference byClaisen-Schmidt condensation reaction.10-12 Acetophenonederivative (2.5 mmol) and substituted benzaldehydes (2.5mmol) were dissolved in 30 ml methanol. To the solution,10 ml NaOH (20%) solution was added dropwise and thereaction mixture was stirred for 1-2 hour at room temperatureby a magnetic stirrer and kept for overnight. Subsequently,it was poured into ice water and neutralized.The solid precipitates were filtered off and recrystallizedfrom methanol or ethyl acetate.
1-(4-(2-chloro-6-phenylpyrimidin-4-yl-amino)-phenyl) ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; ethanol; for 12h;Reflux;
To a solution of 1mu mole of <strong>[26032-72-4]2,4-dichloro-6-phenylpyrimidine</strong>, 1mu mole of 4-aminoacetophenone,5muL of ethyl alcohol and 5muL dioxane: hydrochloride were heated under reflux for 12 hr. After completion of the reaction as indicated by TLC, the alcohol and dioxane was completely evaporated and the residue was poured into ice cold sodium carbonate solution to neutralize the reaction mixture. The precipitated solid was collected by filtration. The solid thus obtained was recrystallized from ethanol (Scheme-1).
With N-chloro-succinimide; In acetonitrile; at 20℃; for 3.5h;
Weigh 7.9 g (59.2 mmol) of NCS in a 250 ml three-necked flask.Add 60ml MeCN, stir to dissolve,4-Aminoacetophenone (4 g, 29.6 mmol) dissolved in 50 ml of acetonitrile was slowly dropped into the reaction apparatus using a constant pressure dropping funnel, and the addition was completed in half an hour.Stir at room temperature for 3 hours. Spin out most of the solvent,Add ethyl acetate and stir to dissolve.Each time, it was washed 3 times with 50 ml of pure water, and the organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the solvent is dried to give the main product acetophenone intermediate4-amino-3,5-dichloroacetophenone 4.8 g, yield 80%;At the same time, 0.9 g of by-product 4-amino-3-chloroacetophenone was obtained, and the yield was 18%.
45%; 20%
With N-chloro-succinimide; In acetonitrile; at 20℃; for 4.5h;
Weigh 5g (37mmol) of 4-aminoacetophenone in a 250ml round bottom flask.Add 60 ml of MeCN, stir to dissolve, and then weigh 5.4 g (40.4 mmol) of NCS dissolved in 50 ml of MeCN.Slowly drip it into the reaction device using a constant pressure dropping funnel.The addition was completed in half an hour and stirred at room temperature for 4 h. Most of the solvent was distilled off, and ethyl acetate was added to stir and dissolve.Each time, it was washed 3 times with 50 ml of pure water, and the organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to give 3 g of phenylethyl ketone intermediate product 4-amino-3-chloroacetophenone in a yield of 45%;At the same time, 1.5 g, by-product 4-amino-3,5-dichloroacetophenone, in a yield of 20%, was obtained.It can be used in Example 1 as a raw material for the synthesis of clenbuterol.
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 3.5h;
Weigh 11.6 g, 65.1 mmol of N-bromosuccinimide (NBS) in a 250 ml three-necked flask, and add 60 ml of MeCN.The mixture was stirred and dissolved, and 4 g of 29.6 mmol of 4-aminoacetophenone dissolved in 50 ml of acetonitrile was slowly dropped into the reaction apparatus through a constant pressure dropping funnel, and the addition was completed in half an hour, and the mixture was stirred at room temperature for 3 hours. Spin out most of the solvent,Add ethyl acetate and stir to dissolve.It was washed 3 times with 50 ml of pure water, and the organic phase was collected and dried over anhydrous sodium sulfate.After filtration, the solvent was dried to give 6.9 g of acetophenone intermediate.The main product 4-amino-3,5-dibromoacetophenone, the yield was 80%; at the same time, 1.2 g of by-product 4-amino-3-bromoacetophenone was obtained in a yield of 20%, which can be used in Example 3 And 4 as raw materials for the preparation of sibuterol and cimaterol.
14%; 71%
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 3.5h;
Weigh 4g (29.6mmol) of 4-aminoacetophenone in a 250ml three-necked flask.Add 40ml MeCN, stir to dissolve,5.8 g (32.6 mmol) of NBS dissolved in 50 ml of acetonitrile was slowly dropped into the reaction apparatus using a constant pressure dropping funnel.After half an hour, the addition was completed, and the mixture was stirred at room temperature for 3 hours.Most of the solvent was distilled off, and ethyl acetate was added to stir and dissolve.Wash the organic phase three times with 50 ml of pure water each time.Dry over anhydrous sodium sulfate.After filtration, the solvent is dried to give the main product of acetophenone intermediate.4-amino-3-bromoacetophenone 4.5 g, yield 71%;At the same time, 1.2 g of by-product 4-amino-3,5-dibromoacetophenone was obtained in a yield of 14%, which was used forExample 2 was used as a raw material for the synthesis of bromobuterol.
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