* 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] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 11, p. 4466 - 4477
2
[ 95-57-8 ]
[ 3964-56-5 ]
[ 2040-88-2 ]
[ 4526-56-1 ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-Bromosuccinimide; thiourea In acetonitrile at 20℃; for 2 h;
General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
Reference：
[1] Tetrahedron, 2017, vol. 73, # 46, p. 6564 - 6572
[2] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
[3] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[4] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[5] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
[6] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
[7] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
3
[ 95-57-8 ]
[ 3964-56-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sulfuric acid; C20H22Br2N2O5V; dihydrogen peroxide In methanol; water at 20℃; for 1.33333 h;
General procedure: In a 10-mL round-bottom flask equipped with a magnetic stirring bar, 1 mM of the 2-nitrophenol was reacted with different amounts of the oxidant, acid, bromide source, and the vanadyl Schiff base complex in 4 mL of solvent. The content was stirred at room temperature.The progress of the reaction was monitored by GLC.
69%
With potassium hydrogensulfate; potassium bromide; isoquinolinium chlorochromate In water at 20℃; Sonication
General procedure: The general method for ultrasonically assisted brominationreaction is almost similar to conventional reaction as mentionedabove. A centimolar (0.01 mol) organic substrate (phenols,anilines, or acetanilides), 0.001 mol potassium halide(KBr), about 50 mg of dilute KHSO4, and hypervalent Cr(VI) reagent (IQCC or IQDC) were suspended in about30 mL solvent (DCE or ACN) in a previously cleaned roundbottom(R.B) flask placed in a sonicator. The reaction mixtureis sonicated at room temperature about 30–40 min. Progressof the reaction was monitored by TLC technique. Workupprocedure after completion of the reaction mixture is similarto the one described previously.
Reference：
[1] Synthetic Communications, 2007, vol. 37, # 2, p. 323 - 328
[2] Journal of Coordination Chemistry, 2014, vol. 67, # 22, p. 3664 - 3677
[3] Journal of the Serbian Chemical Society, 2011, vol. 76, # 5, p. 685 - 692
[4] Synthetic Communications, 2005, vol. 35, # 14, p. 1947 - 1952
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 11, p. 2542 - 2545
[6] RSC Advances, 2014, vol. 4, # 49, p. 25898 - 25903
[7] Polyhedron, 2014, vol. 68, p. 144 - 150
[8] Egyptian Journal of Chemistry, 2011, vol. 54, # 2, p. 155 - 174
[9] Monatshefte fur Chemie, 2013, vol. 144, # 2, p. 179 - 181
[10] Russian Journal of Organic Chemistry, 2007, vol. 43, # 9, p. 1282 - 1284
[11] Chinese Chemical Letters, 2012, vol. 23, # 4, p. 387 - 390
[12] Journal of the Iranian Chemical Society, 2012, vol. 9, # 3, p. 321 - 326
[13] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
[14] Tetrahedron Letters, 2007, vol. 48, # 7, p. 1255 - 1259
[15] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2016, vol. 46, # 6, p. 832 - 837
[16] Synthetic Communications, 2010, vol. 40, # 6, p. 868 - 876
[17] Journal of the American Chemical Society, 1933, vol. 55, p. 2125,2129
[18] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[19] Canadian Journal of Chemistry, 1982, vol. 60, p. 2099 - 2103
[20] Tetrahedron Letters, 2008, vol. 49, # 1, p. 189 - 194
[21] Patent: US4223166, 1980, A,
[22] Patent: WO2013/91096, 2013, A1, . Location in patent: Page/Page column 38
[23] Heterocycles, 1999, vol. 50, # 1, p. 109 - 116
4
[ 95-57-8 ]
[ 3964-56-5 ]
[ 4526-56-1 ]
Yield
Reaction Conditions
Operation in experiment
13 %Chromat.
With N-Bromosuccinimide In acetonitrile at 20℃; for 2 h;
General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
Reference：
[1] ACS Catalysis, 2018, vol. 8, # 5, p. 4033 - 4043
[2] Asian Journal of Chemistry, 2018, vol. 30, # 1, p. 167 - 170
[3] Journal of the Indian Chemical Society, 1989, vol. 66, # 5, p. 301 - 303
[4] Journal of the Chemical Society, 1930, p. 1853,1860
[5] Journal of the Indian Chemical Society, 1989, vol. 66, # 5, p. 301 - 303
[6] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2001, vol. 40, # 11, p. 1196 - 1202
[7] Journal of the Indian Chemical Society, 2002, vol. 79, # 5, p. 420 - 425
Reference：
[1] Monatshefte fuer Chemie, 1927, vol. 48, p. 209
11
[ 50638-47-6 ]
[ 3964-56-5 ]
Reference：
[1] Monatshefte fuer Chemie, 1927, vol. 48, p. 209
12
[ 704892-51-3 ]
[ 3964-56-5 ]
Reference：
[1] Monatshefte fuer Chemie, 1936, vol. 67, p. 320,322
13
[ 2973-80-0 ]
[ 3964-56-5 ]
Reference：
[1] Monatshefte fuer Chemie, 1936, vol. 67, p. 320,322
14
[ 95-57-8 ]
[ 3964-56-5 ]
[ 2040-88-2 ]
[ 4526-56-1 ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-Bromosuccinimide; thiourea In acetonitrile at 20℃; for 2 h;
General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
Reference：
[1] Tetrahedron, 2017, vol. 73, # 46, p. 6564 - 6572
[2] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
[3] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[4] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[5] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
[6] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
[7] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
15
[ 95-57-8 ]
[ 3964-56-5 ]
[ 2040-88-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 15, p. 1877 - 1878
[2] Journal of Chemical Research - Part S, 2003, # 9, p. 597 - 598
[3] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
[4] Monatshefte fur Chemie, 2012, vol. 143, # 7, p. 1039 - 1044
Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: at 50℃;
(RS)-4-(3-Bromo-4-fluoro-phenyl)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine 4-Bromo-2-chloro-1-methoxy-benzene [50638-47-6] A mixture of 4-bromo-2-chlorophenol (7.0 g, 33.0 mmol, 1 eq), N,N-dimethylformamide (50 mL) and cesium carbonate (8.5 g, 42.0 mmol, 1.2 eq) was stirred at room temperature then iodomethane (2.5 mL, 1.2 eq) was added. The mixture was heated to 50° C. overnight, cooled to room temperature and treated with water (500 mL). The reaction was extracted with dichloromethane, dried (sodium sulfate) and concentrated in vacuo. The crude was purified by flash chromatography eluding with cyclohexane. 7.5 g of clean product in a quantitative yield. Mass (calculated) C7H6BrClO [221] MH+ not observed LC Rt=3.15 min (5 min method) 1H-NMR (CDCl3): 3.88 (s, 3H), 6.80 (d, 1H), 7.32 (m, 1H), 7.50 (m, 1H)
26.7 g
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2 h;
1) Synthesis of 4-bromo-2-chloro-1-methoxybenzene (compound 211-1) [0352] 4-Bromo-2-chlorophenol (25.0 g) was dissolved in N,N-dimethylformamide (150 ml), potassium carbonate (33.2 g) and methyl iodide (25.6 g) were added, and the mixture was stirred at 60°C for 2 hr. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound 211-1 (26.7 g) as a pale-yellow solid. 1H-NMR(CDCl3)δ(ppm):3.88(3H,s), 6.79(1H,d,J=9.4Hz), 7.32(1H,dd,J=8.6,2.4Hz), 7.49(1H,d,J=2.4Hz).
Reference：
[1] Patent: US2009/209529, 2009, A1, . Location in patent: Page/Page column 24
[2] Patent: US4623650, 1986, A,
[3] Angewandte Chemie - International Edition, 2014, vol. 53, # 25, p. 6443 - 6448[4] Angew. Chem., 2014, vol. 126, # 25, p. 6561 - 6566
[5] Angewandte Chemie - International Edition, 2013, vol. 52, # 35, p. 9144 - 9148[6] Angew. Chem., 2013, vol. 52, # 35, p. 9144 - 9148,5
[7] Patent: US2003/232717, 2003, A1,
[8] Patent: EP2842937, 2015, A1, . Location in patent: Paragraph 0352-0353
18
[ 3964-56-5 ]
[ 77-78-1 ]
[ 50638-47-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6224 - 6229
[2] Journal of Medicinal Chemistry, 1996, vol. 39, # 9, p. 1846 - 1856
[3] Journal of Heterocyclic Chemistry, 1968, vol. 5, p. 165 - 177
[4] Journal of Organic Chemistry, 1994, vol. 59, # 21, p. 6233 - 6244
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Stage #2: With Trimethyl borate In tetrahydrofuran at -78 - 20℃; for 19 h; Stage #3: With hydrogenchloride In tetrahydrofuran; water at 20℃;
3-chIoro-4-hydroxyphenylboronic acid 83. To a stirred solution of 4-bromo-2-chlorophenol (5 g5 24 mmol) in dry THF (75 mL)5 cooled to -780C5 was added slowly drop-wise n-BuLi (12 mL of a 2.44 M solution, 29 mmol) and the reaction was stirred at -78°C for 2 h. To this was then added trimethyl borate (3.3 mL, 29 mmol) and the reaction was allowed to warm slowly to r.t. with stirring for 19 h. The reaction was quenched with HCl (aq., 2 M) and the organics extracted into EtOAc (2 x 60 mL). These extracts were combined and concentrated under reduced pressure to give a white precipitate in an oily substance. To this was added hexane and the white powder was collected by filtration and washed with hexane. Yield 15percent: 1H NMR δ (270 MHz, DMSOd6) 6.49 (bs), 6.91 (IH5 d, J= 7.9 Hz)5 7.54 (IH, dd, J= 8.2, 1.5 Hz)5 7.72 (IH5 d, J= 1.5 Hz)5 8.02 (bs), 10.32 (IH, s); HPLC tr = 3.36 min (>91percent) 90percent MeCN in H2O; LC/MS (APCI) m/z 171.16 (M-H)-.
12%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.33333 h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -78℃; for 0.25 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water at 0℃; for 0.25 h;
3-ChIoro-4-hydroxyphenylboronic acid (TJA01187) C6H6BClO3 MW 172.37. A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g, 24.1 mmol) and purged with N2(g). Anhydrous THF (100 mL) added with stirring and the vessel cooled to -78 0C (dry ice/acetone bath). After 30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was added dropwise over 20 min. The reaction was left to stir for 1 h. Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with the reaction still at -78 0C. After 15 min of stirring at this temperature the dry ice/acetone bath was removed. At about 0 0C 2 M HCl(aq) (5 mL) was added and the reaction left to stir for a further 15 min. THF removed under vacuum and residues taken up in ethyl acetate (50 mL). Distilled H2O (50 mL) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic portions were combined and washed with sat. Na2CO3 (aq). The aqueous layer was separated and treated with 2M HCl (aq) until the pH was about 4. This was then extracted with ethyl acetate (50 mL x 2). The organic portions were then dried over MgSO4 and solvent removed. The resultant off white residues were taken up in a minimum of ethyl acetate (2-3 mL) and added to dropwise to hexane (50 mL) with stirring. The white ppt was filtered to give the title compound as an off white solid (0.490 g, 12 percent).1H NMR (600 MHz, DMSO-^6) δ 6.89-6.92 (IH5 d, J= 8.2 Hz, ArH), 7.52-7.56 (IH5 dd, J= 1.8 7.9 Hz, ArH)&5 7.72-7.73 (IH, d, J= 1.5 Hz5 ArH)5 7.98 (2H, s, ArB(OH)2) and 10.33 (IH5 s, ArOH); HPLC (70 percent CH3CN in H2O) tτ= 3.654 (97.92 percent); LCMS (APCI), m/z 173.11 (37ClM-- H5 15 percent)5 171.10 (35ClM"- H5 55), 129.05 ((37ClM" - H) - B(OH)2, 3O)5 127.04 ((35ClM- - H) - B(OH)2, 100).
Reference：
[1] Patent: WO2007/96647, 2007, A2, . Location in patent: Page/Page column 125-126
[2] Patent: WO2007/68905, 2007, A1, . Location in patent: Page/Page column 120-121; 148-149; 152-153; 154-155
[3] Journal of the American Chemical Society, 2007, vol. 129, # 7, p. 1894 - 1895
22
[ 3964-56-5 ]
[ 75-26-3 ]
[ 201849-21-0 ]
Yield
Reaction Conditions
Operation in experiment
56 g
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 16 h; Inert atmosphere
To a solution of 4-bromo-2-chlorophenol (50 g) in N,N-dimethylformamide (DMF) (250 mL) stirred under nitrogen at room temperature was added K2CO3 (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85° C. for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6*100 mL), the organic phase was dried over MgSO4 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D10) (56 g) as a yellow oil. δH (CDCl3, 400 MHz): 1.37 (6H, d), 4.52 (1H, m), 6.82 (1H, d), 7.29 (1H, m), 7.50 (1H, d).
With sulfuric acid; nitric acid; sodium nitrite In water; propionic acid at 30℃; for 3.166h;
49
To a solution of 4-bromo-2-chlorophenol (25.0 g, 120 mmol) in propionic acid (160 ml) were added 70% nitric acid (0.8 ml, 12.0 mmol), sulfuric acid (1.6 ml, 30 mmol) and an aqueous sodium nitrite solution (3.3 mg, 0.048 mmol in a 5 drops of water) at 300C. Additional 70% nitric acid (64 ml, 100 mmol) was added to the mixture over 10 min. After stirring for 3 hr at 300C, the reaction mixture was diluted with H2O. The orange precipitate was collected by filtration, washed with H2O and dried in vacuo to give the title compound (26.7 g, 88%). 1H-NMR (300 MHz, DMSCHd6) δ: 8.07 (IH, , J = 2.5 Hz), 8.10 (1 H, d, J = 2.5 Hz) .
84%
With nitric acid In acetic acid at 20℃;
109
To a solution of 4-bromo-2-chlorophenol (400 g, 1.93 mol) in acetic acid (2.0 1) at room temperature was added nitric acid (70%, 231 ml, 3.86 mol) slowly and the resulting solution was stirred at room temperature overnight. The reaction mixture was poured into water and the yellow precipitate was collected by filtration to afford the title compound (412 g, 84%) . LCMS (ESI"), M-H+: 252.
72%
With nitric acid; acetic acid at 20 - 30℃; for 4.25h;
20.1
In a three neck flask with dropping funnel, thermometer and nitrogen bubbler (no nitrogen input), 4-bromo-2- chlorophenol (5.0 g, 0.024 mol) was fully dissolved in acetic acid (25 mL) at room temperature. Nitric acid (70%, 2.9 mL, 0.048 mol) was added slowly dropwise over approx 15 minutes keeping the temperature at below 30oC. The reaction turned orange with an orange precipitate. The reaction was stirred for a further 4 hours at 20oC. After this time the reaction mixture was cautiously transferred via pipette onto approximately 50 mL ice. Once the ice had melted the yellow precipitate was filtered and washed with water (50 mL). The yellow solid was air dried under vacuum for 1 hour before being dissolved in DCM and dry loaded onto 5.5g silica. The compound was purified by flash column chromatography (elution; 100% heptane, to 20% DCM in heptane, to 40% DCM in heptane, to 50%> DCM in heptanes) to give the desired compound (4.38 g, 72% yield (at) 100% UV purity) as a yellow solid. Tr = 1.97min m/z (ES+) no ionisation.
70%
With sulfuric acid; nitric acid; acetic acid; sodium nitrite at 30℃; for 3h;
1 Synthesis of 4-bromo-2-chloro-6-nitrophenol (48)
[00392] Synthesis of 4-bromo-2-chloro-6-nitrophenol (48): 4-bromo-2-chlorophenol (47; 25.0 g, 121 mmol) was dissolved in acetic acid (120 mL). Nitric acid (0.8 mL, 12.0 mmol, 70%), sulfuric acid (1.6 ml, 30 mmol) and sodium nitrite (3 mg, 0.05 mmol) were added at 30 °C. Additional nitric acid (64 mL, 100 mmol, 70%) was added to the mixture over 10 min. After stirring for 3 h at 30 °C, the reaction mixture was diluted with H20. The yellow precipitate was collected by filtration, washed with H20 and dried in vacuo to give 21 g of 4-bromo-2-chloro-6-nitrophenol (48) (70% yield). LCMS: m/z 252.1 [M+H]+, tR = 1.72 min.
With nitric acid; acetic acid
durch Nitrierung;
24 g
With nitric acid; acetic acid In water at 20℃;
16.i 4-Bromo-2-chloro-6-nitrophenol
70% aqueous nitric acid (11.5 mL, 190 mol) was added slowly to a solution of 4-bromo-2-chlorophenol (20.0 g, 96.4 mmol) in acetic acid (100 mL) at rt. The resultant precipitate was collected by filtration to afford the subtitled compound as a yellow solid (24.0 g). Used without further purification in the next step.
24 g
With nitric acid; acetic acid In water at 20℃;
70% aqueous nitric acid (11.5 mL, 190 mol) was added slowly to a solution of 4-bromo-2-chlorophenol (20.0 g, 96.4 mmol) in acetic acid (100 mL) at rt. The resultant precipitate was collected by filtration to afford the subtitled compound as a yellow solid (24.0 g). Used without further purification in the next step.
With N-Bromosuccinimide; thiourea; In acetonitrile; at 20℃; for 2h;
General procedure: Reaction conditions: Thiourea (5.1 mol%, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10% aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10% Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5% CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;
039.1
Step 1 Preparation of Compound 61 (0648) Benzyl bromide (1.57 mL, 13.3 mmol) and potassium carbonate (2.17 g, 15.7 mmol) were added to DMF solution (25 mL) of Compound 60 (2.50 g, 12.1 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate. The solvent was condensed under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate-hexane) to afford Compound 61 (3.56 g, yield 99%). (0649) 1H-NMR (CDCl3) δ: 7.52 (d, J=2.0 Hz, 1H), 7.45-7.25 (m, 6H), 6.83 (d, J=8.6 Hz, 1H), 5.14 (s, 2H). (0650) [M+H]=298, Method Condition 2: retention time 2.79 min
93%
With potassium carbonate In acetone for 5h; Heating;
90%
With potassium carbonate In acetone for 2h; Heating;
83%
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;
19
A mixture of 4-bromo-2-chlorophenol (5.0 g, 24 mmol), cesium carbonate (15.7 g, 48 mmol), and benzyl bromide in DMF (50 mL) was stirred at room temperature for 30 min. Water was added and the resulting mixture was extracted with ether. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was triturated with hexanes to provide 1-benzyloxy-4-bromo-2- chlorobenzene (5.91 g, 83% yield) as a white solid. ¹H NMR (400 MHz, CDCl3) No. 7.52 (d, 1H), 7.45-7.27 (m, 6H), 6.84-6.82 (d, 1H), 5.14 (s, 2H).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #1: hexamethylenetetramine; 4-bromo-2-chlorophenol With trifluoroacetic acid at 90℃; for 20h;
Stage #2: With sulfuric acid at 20℃; for 2h;
Stage #1: hexamethylenetetramine; 4-bromo-2-chlorophenol With trifluoroacetic acid at 18 - 90℃; Inert atmosphere;
Stage #2: With sulfuric acid In water at 18 - 25℃; for 2h;
15.2 Step 2
To a solution of crude bromide 15b (116.5 g, 0.56 mol) in trifluoroacetic acid (400 mL) is added hexamethylenetetramine (157.6 g, 1.12 mol) in three portions over 20 min under N2. The mixture is stirred at RT for 20 min, and then at 90°C ovenight. After being cooled to RT, water (650 mL) and a 50% aqueous solution of sulfuric acid (303 mL) are sequentially added. The mixture is stirred at RT for 2 h. The precipitate is collected by filtration and air dried to give crude aldehyde 15c.
With trifluoroacetic acid at 90℃; for 20h;
24.1 Intermediate X (Method 24): 5-bromo-3-chloro-2-isobutoxybenzonitrile Step 1: 5-bromo-3-chloro-2-hydroxybenzaldehyde
To a mixture of 4-bromo-2-chlorophenol (Alfa) (10 g, 48 mmol) in 40 ml of trifluoroacetic acid was added hexamethylenetetramine (14 g, 97 mmol). The resulting mixture was stirred at 90° C. for 20 hrs. After cooling to ambient temperature, the reaction mixture was water and followed by an 50% sulfuric acid aqueous solution (28 ml). The mixture was stirred at ambient temperature for an additional 2 hrs. The precipitate was collected and dried to afford the title compound as yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.39 (1H, s), 9.84 (1H, s), 7.74 (1H, d), 7.62 (1H, d).
Stage #1: hexamethylenetetramine; 4-bromo-2-chlorophenol With trifluoroacetic acid at 90℃; for 20h;
Stage #2: With sulfuric acid; water at 20℃; for 2h;
1 Step 1 : 5-bromo-3-chloro-2-hvdroxybenzaldehvde:
Step 1 : 5-bromo-3-chloro-2-hvdroxybenzaldehvde: To a mixture of 4-bromo-2-chlorophenol (Alfa) (10 g, 48 mmol) in 40 ml of trifluoroacetic acid was added hexamethylenetetramine (14 g, 97 mmol). The resulting mixture was stirred at 90 °C for 20 hrs. After cooling to ambient temperature, the reaction mixture was water and followed by an 50% sulfuric acid aqueous solution (28 ml). The mixture was stirred at ambient temperature for an additional 2 hrs. The precipitate was collected and dried to afford the title compound as yellow solid. 1H NMR (400 MHz, CDCI3) δ 1 1.39 (1 H, s), 9.84 (1 H, s), 7.74 (1 H, d), 7.62 (1 H, d).
With trifluoroacetic acid at 0 - 90℃; for 20h;
1 5-bromo-3-chloro-2- hydroxybenzaldehyde 89
[00447] 4-Bromo-2-chlorophenol (13; 30 g, 145.6 mmol) was dissolved in TFA mL) and hexamethylenetetramine (40.8 g, 291 mmol) was added at 0 C (ice bath) in three portions over 20 min. The reaction mixture was allowed to warm to room temperature and heated at 90 °C for 20 h. After cooling down to room temperature, the reaction mixture was poured into water (168 mL) and 50% H2SO4 aqueous solution (84 mL) was added. The resulting mixture was stirred at room temperature for 2 h. The yellow precipitate was collected by filtration and dried in vacuum to afford 27.6 g of 5-bromo-3-chloro-2- hydroxybenzaldehyde 89, which was used in next step without further purification (81% yield). LCMS: m/z 249.5 [M+MeOH-OH]+, tR = 1.79 min.
1 Step 1, Method 8: 5-Bromo-3-chloro-2-hydroxybenzaldehyde
Step 1, Method 8: 5-Bromo-3-chloro-2-hydroxybenzaldehyde [00206] Powdered sodium hydroxide (23.14 g, 578 mmol) was added to a solution of 4-bromo-2-chlorophenol (20 g, 96 mmol) and water (1.8 mL, 96 mmol) in chloroform (200 mL) and the reaction mixture was stirred at reflux for 7.5 hours. Powdered sodium hydroxide (7.71 g, 193 mmol) was added and the reaction mixture was refluxed for an additional 19 hours, allowed to cool to room temperature, diluted with water (250 mL), acidified to pH=l with 2N HC1 and extracted with EtOAc (3x500 mL). The combined organic extracts were filtered to remove a small amount of insoluble off-white solid, washed with brine (2x500 mL), dried (MgS04), filtered and concentrated under reduced pressure to leave a dark brown oil (18.42 g). Purification by column chromatography (Biotage, 2-20% EtOAc in heptane, Rf=0.35 in 10% EtOAc in heptane) afforded the title compound as a pale yellow solid (3.42 g, 14%) yield), which was used without further purification. 5H NMR (500 MHz, DMSO-) 1 1.21 (s, 1H), 10.12 (s, 1H), 8.00 (d, J= 2.5 Hz, 1H), 7.84 (d, J= 2.5 Hz, 1H). Tr = 1.94 min, no mass ion.
3-chIoro-4-hydroxyphenylboronic acid 83. To a stirred solution of 4-bromo-2-chlorophenol (5 g5 24 mmol) in dry THF (75 mL)5 cooled to -780C5 was added slowly drop-wise n-BuLi (12 mL of a 2.44 M solution, 29 mmol) and the reaction was stirred at -78°C for 2 h. To this was then added trimethyl borate (3.3 mL, 29 mmol) and the reaction was allowed to warm slowly to r.t. with stirring for 19 h. The reaction was quenched with HCl (aq., 2 M) and the organics extracted into EtOAc (2 x 60 mL). These extracts were combined and concentrated under reduced pressure to give a white precipitate in an oily substance. To this was added hexane and the white powder was collected by filtration and washed with hexane. Yield 15percent: 1H NMR delta (270 MHz, DMSOd6) 6.49 (bs), 6.91 (IH5 d, J= 7.9 Hz)5 7.54 (IH, dd, J= 8.2, 1.5 Hz)5 7.72 (IH5 d, J= 1.5 Hz)5 8.02 (bs), 10.32 (IH, s); HPLC tr = 3.36 min (>91percent) 90percent MeCN in H2O; LC/MS (APCI) m/z 171.16 (M-H)-.
12 - 27%
3-ChIoro-4-hydroxyphenylboronic acid (TJA01187) C6H6BClO3 MW 172.37. A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g, 24.1 mmol) and purged with N2(g). Anhydrous THF (100 mL) added with stirring and the vessel cooled to -78 0C (dry ice/acetone bath). After 30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was added dropwise over 20 min. The reaction was left to stir for 1 h. Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with the reaction still at -78 0C. After 15 min of stirring at this temperature the dry ice/acetone bath was removed. At about 0 0C 2 M HCl(aq) (5 mL) was added and the reaction left to stir for a further 15 min. THF removed under vacuum and residues taken up in ethyl acetate (50 mL). Distilled H2O (50 mL) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic portions were combined and washed with sat. Na2CO3 (aq). The aqueous layer was separated and treated with 2M HCl (aq) until the pH was about 4. This was then extracted with ethyl acetate (50 mL x 2). The organic portions were then dried over MgSO4 and solvent removed. The resultant off white residues were taken up in a minimum of ethyl acetate (2-3 mL) and added to dropwise to hexane (50 mL) with stirring. The white ppt was filtered to give the title compound as an off white solid (0.490 g, 12 percent).1H NMR (600 MHz, DMSO-^6) delta 6.89-6.92 (IH5 d, J= 8.2 Hz, ArH), 7.52-7.56 (IH5 dd, J= 1.8 7.9 Hz, ArH)5 7.72-7.73 (IH, d, J= 1.5 Hz5 ArH)5 7.98 (2H, s, ArB(OH)2) and 10.33 (IH5 s, ArOH); HPLC (70 percent CH3CN in H2O) ttau= 3.654 (97.92 percent); LCMS (APCI), m/z 173.11 (37ClM-- H5 15 percent)5 171.10 (35ClM"- H5 55), 129.05 ((37ClM" - H) - B(OH)2, 3O)5 127.04 ((35ClM- - H) - B(OH)2, 100).
With 1,1'-bis(diphenylphosphanyl)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In 1,4-dioxane at 100℃; for 3h; Inert atmosphere;
1.1.2.11 1.1.2.11 Intermediate 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenol (12c in the synthesis process diagram )Synthesis
In a 250ml round-bottomed flask, add 4-bromo-2-chlorophenol (11c in the synthesis process diagram), dissolve it with 1,4-dioxane, add biboronic acid pinacol ester under stirring, Pd( dppf) Cl2·CH2Cl2, DPPF and AcOK, the addition was completed, nitrogen protection was carried out, and the reaction was carried out at 100° C. After 3 h, the completion of the reaction was monitored by TLC.The reaction solution was filtered with suction, 100 ml of water was added to the filtrate, extracted with ethyl acetate (100 ml × 4), the organic phases were combined, washed with saturated brine (100 ml × 3), and finally dried over anhydrous sodium sulfate, and spun under reduced pressure. The dry solvent yields a pale yellow oil, which is 12c in the synthesis process diagram.The molar ratio of 11c and biboronic acid pinacol ester, Pd(dppf)Cl2·CH2Cl2, DPPF and AcOK in the synthesis process diagram is 1:1.2:0.05:0.05:2.5, 11c and 1,4- The mass-volume ratio of dioxane is 1:40-60 (g/ml).2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenol (12c in the synthesis scheme): pale yellow oil material, the yield was 87.70%.
77%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In 1,4-dioxane for 3h; Inert atmosphere; Reflux;
3.A Step A: 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
4-Bromo-2-chlorophenol (2.0 g, 9.6 mmol), bis(pinacolato)diboron (2.81 g, 11 mmol), potassium acetate (3.78 g, 38.5 mmol) and DPPF (0.27 g, 0.49 mmol) were dissolved in 32 mL of 1,4-dioxane. The mixture was charged with N2 gas for 5 minutes. PdCl2(dppf)-DCM (0.4 g, 0.49 mmol) was added thereto, and the mixture was stirred for 3 hours under reflux. The mixture was filtered through Celite and purified by column chromatography to obtain the title compound (1.91 g, 77 %). 1H NMR (CDCl) δ 7.77 (1H, s), 7.62 (1H, dd), 7.00 (1H, d), 5.73 (1H, s), 1.36 (12H, s)
57%
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In tetrahydrofuran at 80℃; Inert atmosphere;
With anhydrous potassium acetate In methanol at 65℃; for 24h;
33
A solution of 4-bromo-2-chlorophenol (246mg, 1.18mmol), bis(pinacolato)diboron (332mg, 1.3mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladiumII) chloride (26mg, 0.035mmol) and potassium acetate [(222MG,] 2.26mmol) in dry methanol (4mL) was degassed and heated at 65QC for 24h. After cooling, the reaction mixture was diluted with ether and filtered through Celite. The solvent was removed under reduced pressure and the residue purified by chromatography using dichloromethane-hexane (90 : 10) as eluant. The boronate thus obtained (50mg) was reacted with 6-chloro-N-[(1S)-1- [PHENYLETHYL PYRAZIN-2-AMINE (50MG, 0. 2MMOL)] under conditions analogous to those of, example 2, to furnish the pure product after chromatography eluting with [DICHLOROMETHANE-ETHER] [(90] :10) (44mg, 68%). [1H-N.M.R. # # 1.59 (D, 3H, J = 6.0 HZ, CH3), 4.88 (M, 1H, CH), 5.08 (BR ] s, [1] NH), [5.] 69 [(BR S, 1H,] NH), 7. 07 [(D,] [IHJ==] J = 8. 5 Hz, ArH), 7.27-7.36 (m, 6H, Ar-H), 7. 48 (d, [1H,] J= 1.5Hz, ArH), 7.62 (s, 1H, pyraz-H), 7. 80 (s, IH, [PYRAZ-H).]
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 100℃; Inert atmosphere;
30 g
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); anhydrous potassium acetate In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere;
2.1
To a solution of 4-bromo-2-chlorophenol (30 g, 144.6 mmol, 1.0 eq) in DMF (250 mL) was added Bis(pinacolato)diboron (44 g, 173.5 mmol, 1.2 eq) and potassium acetate (49.6 g, 506.1 mmol, 3.5 eq). The reaction mixture was purged with nitrogen and dichlorobis(triphenylphosphino)palladium(II) (2 g, 2.85 mmol, 0.02 eq) was added. The reaction was heated at 80 °C for 24 hours, cooled to RT, filtered through celite and washed with ethyl acetate. The solid was dried over Na2S04, filtered, and concentrated. Purification by column chromatography on silica gel to give 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenol 30 g as a yellow oil.
3.48 g
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In 1,4-dioxane at 80℃; for 5h; Inert atmosphere;
2-53.1
(1) 4-bromo-2-chlorophenol (2 g),Bis (pinacolato) diboron (4.9g),Potassium acetate (1.89g)1,4-dioxane (40mL)After degassing the solution, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (780 mg)It was stirred for 5 hours at an external temperature of 80 in addition.The reaction mixture was evaporated under reduced pressure under solvent was allowed to cool to. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 90: 10) to obtain the 2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl) phenol (3.48 g) as a colorless solid
Step 1 Preparation of 4-bromo-2-chloroanisole Under nitrogen, 7.3 mL (77 mmol) of dimethylsulfate was added to a stirred suspension of 10 g (48 mmol) of 4-bromo-2-chlorophenol and 5.4 g (38 mmol) of powered K2 CO3 in 75 mL of fresh acetone. After 2 hours at reflux, the reaction was cooled to ambient temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate; the resulting solution was washed with water and dried over MgSO4. Concentration in vacuo gave 10.2 g (96%) of 4-bromo-2-chloroanisole as a colorless solid: mp 68.5-70.5 C.; NHR (CDCl3) delta 3.88 (s, 3H), 6.80 (d, J=9 Hz, 1H), 7.33 (dd, J=2, 9 Hz, 1H), 7.50 (d, J=2 Hz, 1H).
(RS)-4-(3-Bromo-4-fluoro-phenyl)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine 4-Bromo-2-chloro-1-methoxy-benzene [50638-47-6] A mixture of 4-bromo-2-chlorophenol (7.0 g, 33.0 mmol, 1 eq), N,N-dimethylformamide (50 mL) and cesium carbonate (8.5 g, 42.0 mmol, 1.2 eq) was stirred at room temperature then iodomethane (2.5 mL, 1.2 eq) was added. The mixture was heated to 50 C. overnight, cooled to room temperature and treated with water (500 mL). The reaction was extracted with dichloromethane, dried (sodium sulfate) and concentrated in vacuo. The crude was purified by flash chromatography eluding with cyclohexane. 7.5 g of clean product in a quantitative yield. Mass (calculated) C7H6BrClO [221] MH+ not observed LC Rt=3.15 min (5 min method) 1H-NMR (CDCl3): 3.88 (s, 3H), 6.80 (d, 1H), 7.32 (m, 1H), 7.50 (m, 1H)
98%
In tetrahydrofuran;
A. A solution of 4-bromo-2-chlorophenol (5.18 g) in 20 ml tetrahydrofuran was added dropwise to a stirred mixture of sodium hydride (0.72 g) in tetrahydrofuran (50 ml). After 30 minutes, iodomethane (4.26 g) was added and the mixture was stirred overnight at room temperature. A further 7.1 g of iodomethane was added and the mixture was heated at reflux overnight. The reaction mixture was then partitioned between water and chloroform. The combined organic extracts were dried and evaporated to yield the product after washing with hexanes as a white solid (5.4 g, 98% yield) of m.p. 63 C. Anal.: Calcd. for C7H6BrC10: C, 38.00; H, 2.71%. Found: C, 38.07; H, 2.80%.
With potassium carbonate; In acetone;
Ligand Precursor 2: Following Scheme 3, a mixture of 4-bromo-2-chlorophenol (4.66 g, 22.45 mmol), iodomethane (3.1 mL, 50 mmol), and powdered K2CO3 (13.8 g, 100 mmol) in acetone (20 mL) is stirred at 65 C. for 1 hour. After filtration and removal of the solvent, 4.3 g (19.4 mmol, 86%) of 4-bromo-2-chloroanisole are obtained as a white solid.
26.7 g
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;
1) Synthesis of 4-bromo-2-chloro-1-methoxybenzene (compound 211-1) [0352] 4-Bromo-2-chlorophenol (25.0 g) was dissolved in N,N-dimethylformamide (150 ml), potassium carbonate (33.2 g) and methyl iodide (25.6 g) were added, and the mixture was stirred at 60C for 2 hr. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound 211-1 (26.7 g) as a pale-yellow solid. 1H-NMR(CDCl3)delta(ppm):3.88(3H,s), 6.79(1H,d,J=9.4Hz), 7.32(1H,dd,J=8.6,2.4Hz), 7.49(1H,d,J=2.4Hz).
With sodium iodide; potassium carbonate In water; N,N-dimethyl-formamide
R.91 Reference Example 91
Reference Example 91 To a solution of 4-bromo-2-chlorophenol (10 g) in DMF (200 ml) were added at room temperature potassium carbonate (9.99 g), sodium iodide (7.95 g) and 2-chloroethylpropylether (6.7 ml), and the mixture was stirred at 90° C. for 24 hours. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with water, 1N sodium hydroxide solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give pale yellow oil of 4-bromo-2-chloro-1-(2-propoxyethoxy)benzene (14.91 g). 1H-NMR (200 MHz, CDCl3) δ 0.93 (3H, t, J=7.3 Hz), 1.54-1.70 (2H, m), 3.52 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 6.85 (1H, d, J=8.8 Hz), 7.31 (1H, dd, J=8.8, 2.4 Hz), 7.50 (1H, d, J=2.4 Hz). IR (neat) 1584, 1483, 1452, 1290, 1265, 1250, 1128, 1086, 1066, 800 cm-1.
With potassium carbonate; In water; N,N-dimethyl-formamide;
Reference Example 64 To a mixture of 4-bromo-2-chlorophenol (10.81 g) and potassium carbonate (8.65 g) in DMF (10 ml) was added at room temperature ethyl iodide (4.17 ml), and the mixture was stirred for 68 hours. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give pale yellow oil of 4-bromo-2-chloro-1-ethoxybenzene (12.28 g).
With potassium carbonate; In water; N,N-dimethyl-formamide; at 120℃;
EXAMPLE 95Preparation of: 2-Amino-5-[3-chloro-4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-hydroxyphenyl)-3- methyl-3,5-dihydro-4H-imidazol-4-oneStep 1: 4-Bromo-2-chloro-1-(difluoromethoxy)benzene; Into a 500 mL round-bottomed flask was charged 4-bromo-2-chlorophenol (10 g, 48.2 mmol), DMF (115 mL), and water (29 mL) were added to give a colorless solution. K2CO3 (40 g, 289.2 mmol) was added followed by <strong>[76-04-0]2-<strong>[76-04-0]chloro-2,2-difluoroacetic acid</strong></strong> (9.43 g, 72.3 mmol, 6.1 mL) and the reaction was heated at 120 0C overnight. The reaction was cooled and diluted with water and extracted with EtOAc. The organic was washed with 1 N NaOH (3 x 100 m L) to remove unreacted phenol. The organic was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to 16 g of an oil. This oil was absorbed onto 50 g Celite. Flash chromatography (SiO2, Hexanes to 5:95 EtOAc:Hexanes) provided 12.61 g, 67%, of the title compound as a colorless oil. 1H NMR 500 MHz (CDCI3) delta 6.49 (t, 1 H , J = 73.02 Hz); 7.1 (dd, 1 H, J = 8.69 Hz, 0.81 Hz); 7.37 (dd, 1 H, J = 8.69 Hz, 2.32 Hz); 7.58 (d, 1 H, J = 2.32 Hz)
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 4h;
26.3
Intermediate 26-3: (lr.,4r)-tert-Butyl 4-(4-bromo-2-chlorophenoxy)cvclohexane- carboxylateTo a solution of Intermediate 26-4 (5.3 g, 26.46 mmol, CAS 931110-79-1), 4-bromo-2- chlorophenol (6.59 g, 31.76 mmol) and triphenylphosphine (8.33 g, 31.76 mmol) in THF (200 mL) was added diisopropyl azodicarboxylate (5.73 mL, 29.11 mmol). The solution was stirred at room temperature for 4 h. The reaction mixture was evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (4.27 g, 41.4 %) as a colourless oil.1U NMR (400 MHz, DMSO) δ 1.37 - 1.53 (13H, m), 1.88 - 2.03 (4H, m), 2.23 - 2.28 (IH, m), 4.35 - 4.39 (IH, m), 7.19 (IH, d), 7.42 - 7.44 (IH, m), 7.63 (IH, d); HPLC tR= 3.65 min.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 85℃; for 16.0h;Inert atmosphere;
Description for D117 4-bromo-2-chloro-1-[(1-methylethyl)oxy]benzene (D117)To a solution of 4-bromo-2-chlorophenol (50 g) in Lambda/,Lambda/-dimethylformamide (DMF) (250 ml_) stirred under nitrogen at room temperature was added K2CCb (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85 0C for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6* 100 mL), the organic phase was dried over MgSO4 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D117) (56 g) as a yellow oil. deltaH (CDCI3, 400MHz): 1.37 (6H, d), 4.52 (1 H, m), 6.82 (1H, d), 7.29 (1H, m), 7.50 (1H, d).
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 16.0h;Inert atmosphere;
Description for D104-bromo-2-chloro-1 -[(1 -methylethyl)oxy]benzene (D10) To a solution of 4-bromo-2-chlorophenol (50 g) in N.N-dimethylformamide (DMF) (250 mL) stirred under nitrogen at room temperature was added K2C03 (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85 C for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6* 100 mL), the organic phase was dried over MgS04 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D10) (56 g) as a yellow oil. 5H (CDCI3, 400MHz): 1.37 (6H, d), 4.52 (1H, m), 6.82 (1H, d), 7.29 (1H, m), 7.50 (1H, d).
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 16.0h;Inert atmosphere;
DESCRIPTION FOR D684-bromo-2-chloro-1-[(1-methylethyl)oxy]benzene (D68)To a solution of 4-bromo-2-chlorophenol (50 g) in N,N-dimethylformamide (DMF) (250 mL) stirred under nitrogen at room temperature was added K2CO3 (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85 C. for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6*100 mL), the organic phase was dried over MgSO4 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D68) (56 g) as a yellow oil. deltaH (CDCl3, 400 MHz): 1.37 (6H, d), 4.52 (1H, m), 6.82 (1H, d), 7.29 (1H, m), 7.50 (1H, d).
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 16.0h;Inert atmosphere;
To a solution of 4-bromo-2-chlorophenol (50 g) in Nu,Nu-dimethylformamide (DMF) (250 mL) stirred under nitrogen at room temperature was added K2C03 (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85 C for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6* 100 mL), the organic phase was dried over MgS04 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D68) (56 g) as a yellow oil. deltaEta (CDCI3, 400MHz): 1.37 (6H, d), 4.52 (1 H, m), 6.82 (1 H, d), 7.29 (1 H, m), 7.50 (1 H, d).
56 g
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 16.0h;Inert atmosphere;
To a solution of 4-bromo-2-chlorophenol (50 g) in N,N-dimethylformamide (DMF) (250 mL) stirred under nitrogen at room temperature was added K2CO3 (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85 C. for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6*100 mL), the organic phase was dried over MgSO4 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D10) (56 g) as a yellow oil. deltaH (CDCl3, 400 MHz): 1.37 (6H, d), 4.52 (1H, m), 6.82 (1H, d), 7.29 (1H, m), 7.50 (1H, d).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;
To a solution of 4-bromo-2-chlorophenol (Compound 27A) (5.0 g, 24.1 mmol)DMF (100 mL) was added K2C03 (10.0 g, 72.5 mmol) and 2-bromopropane (7.5 g, 61.5 mmol) and stirred at 100 C for 16 hours. The mixture was diluted with water (400 mL) and extracted with a mixture of ethyl acetate in petroleum ether (15% v/v, 300 mL x 3). The combined extracts were washed with bine (300 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (petroleum ether) to furnish Compound 27B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
With Cs2CO3 In N,N-dimethyl-formamide at 20 - 100℃; for 2.25h; Inert atmosphere;
27
4-bromo-2-chlorophenol (1.0 g, 4.8 mmol) was dissolved in DMF (35 ml) and water (5 ml) was added followed by sodium chloro(difluoro)acetate (2.0 g, 12 mmol) and cesium carbonate (3.1 g, 9.6 mmol). The mixture was stirred for 15 minutes at room temperature and then heated to 100° C. for 2 hours under nitrogen. The mixture was partitioned between water (50 ml) and tBuOMe (50 ml). The organic phase was separated, washed brine, dried over sodium sulphate, filtered, and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography eluting with 0-30% EtOAc in heptanes to give a title compound (0.83 g, 67% yield) as colourless oil.1HNMR (400 MHz, CDCl3): δ 6.52 (t, 1H), 7.14 (t, 1H), 7.40 (d, 1H), 7.62 (d, 1H).LCMS Rt=1.66 minutes No mass ion detected.
22.4%
With Cs2CO3 In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 100℃; for 2h; Inert atmosphere;
41.1 Step 1) 4-bromo-2-chloro-1-(difluoromethoxy)benzene
A mixture of sodium 2-chloro-2,2-difluoroacetate (8.0 g, 48 mmol), 4-bromo-2-chlorophenol (4.0 g, 19.2 mmol) and Cs2CO3 (12.4 g, 38.4 mmol) in DMF/H2O (120 mL) was stirred for 2 h at 100 oC. The reaction mixture was cooled to room temperature, diluted with H2O (400 mL) and extracted with MTBE (100 mL*2). The combined organic layer was washed with H2O (75 mL) and brine (75 mL*2), dried (MgSO4), filtered and concentrated in vacuum to give crude product, which was purified by silica gel column chromatography with PE/EA = 50/1 to 20/1 to give the title product 4-bromo-2-chloro-1-(difluoromethoxy)benzene (1.1 g, 22.4%) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.63 (d, J = 2.3 Hz, 1 H), 7.42 (dd, J = 2.3, 8.7 Hz, 1 H), 7.15 (d, J = 8.7 Hz, 1 H), 6.75 - 6.32 (m, 1 H) ppm.
22.4%
With Cs2CO3 In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 100℃; for 2h; Inert atmosphere;
41.1 Step 1) 4-bromo-2-chloro-1-(difluoromethoxy)benzene
A mixture of sodium 2-chloro-2,2-difluoroacetate (8.0 g, 48 mmol), 4-bromo-2-chlorophenol (4.0 g, 19.2 mmol) and Cs2CO3 (12.4 g, 38.4 mmol) in DMF/H2O (120 mL) was stirred for 2 h at 100 oC. The reaction mixture was cooled to room temperature, diluted with H2O (400 mL) and extracted with MTBE (100 mL*2). The combined organic layer was washed with H2O (75 mL) and brine (75 mL*2), dried (MgSO4), filtered and concentrated in vacuum to give crude product, which was purified by silica gel column chromatography with PE/EA = 50/1 to 20/1 to give the title product 4-bromo-2-chloro-1-(difluoromethoxy)benzene (1.1 g, 22.4%) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.63 (d, J = 2.3 Hz, 1 H), 7.42 (dd, J = 2.3, 8.7 Hz, 1 H), 7.15 (d, J = 8.7 Hz, 1 H), 6.75 - 6.32 (m, 1 H) ppm.
With potassium carbonate In acetonitrile at 80℃; for 4h;
General procedure: To a solution of 5- bromine -2- chlorophenol (2.9g, 14.3mmol) in 50mL acetonitrile was added K2CO3 (2.5g,17.1mmol), and stirred for 30min intermediate product 10 was added and the solution was heated to 80°C for 4h. The reaction solution was concentrated, water (100mL) was added, and extracted with EtOAc. The organic layer was collected and washed with water and brine for three times, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford intermediate product 11.
Multi-step reaction with 3 steps
1: potassium carbonate / N,N-dimethyl-formamide / 70 °C
2: sodium hydroxide; water / 1,4-dioxane / 20 °C
3: thionyl chloride / N,N-dimethyl-formamide / 3 h / Reflux
Multi-step reaction with 3 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 50 °C
1.2: 12 h / 50 °C
2.1: lithium hydroxide / methanol; water / 12 h / 50 °C
3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 12 h / 20 °C
Multi-step reaction with 3 steps
1: potassium carbonate / N,N-dimethyl-formamide / 70 °C
2: sodium hydroxide / 1,4-dioxane / 20 °C
3: thionyl chloride; N,N-dimethyl-formamide / 3 h / Reflux
With caesium carbonate; In N,N-dimethyl acetamide; at 150℃; for 16h;
Step 1: 4-Bromo-2-chloro- 1-cyclopropoxy-benzene[00281j <strong>[4333-56-6]Bromocyclopropane</strong> (87.5 g, 0.723 mol) was added portionwise over 10 minutes to a stirred solution of 4-bromo-2-chlorophenol (30.0 g, 0.145 mol) and caesium dicarbonate (118 g, 0.362 mol) in dimethyl acetamide (450 mL). The mixture was heated to 150C and stirred at this temperature for 16 hours. After this time, the reaction was cooled to room temperature, poured onto ice-water (600 mL) and extracted with TBME (3 x 400 mL). The organic layers were combined and washed with water (2 x 200 mL) before being dried (MgSO4), filtered and concentrated to give intermediate 1 (31.2 g, 72% yield) as a pale orange oil which was used directly without purification. ?H NMR (500 MHz, CDC13) oe ppm 7.51 - 7.45 (m, 1H) 7.34 (dd, J=8.8, 2.4 Hz, 1H) 7.21 - 7.13 (m, 1H) 3.84 - 3.74 (m, 1H) 0.93 - 0.77 (m, 4H). Tr =2.46 mm (3.5 Minute method) m/z (ESj (M+Hj No ionisation observed.
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 145 - 155℃; for 24h;
[000225j To a solution of Compound El (20 g, 96 mmol) in 1 -methyl-2-pyrrolidinone(300 mL) was added cesium carbonate (62.8 g, 193 mmol) and <strong>[4333-56-6]bromocyclopropane</strong> (24 mL,289 mmol). The mixture was stirred for 24 h while keeping the inner temperature between145 C and 155 C. After the reaction was cooled to ambient temperature, the dark solutionwas diluted with water (400 mL) and extracted with a mixture of ethyl acetate in petroleumether (15% v/v) (300 mL x 3). The combined organic phases were washed with brine (150mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was purified with flash column chromatography on silica gel (petroleum ether) to furnish Compound E2. HPLC: Rt: 1.96 minute. ?H-NMR (CDC13, 400 MHz): 5 (ppm) 0.80-0.88 (m, 4H), 3.67-3.82 (m, 1H), 7.15 (d, J 8.8 Hz, 1H), 7.32 (dd, J 8.8, 2.4 Hz, 1H), 7.47 (d, J 2.4 Hz, 1H).
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 145 - 155℃; for 24h;
[000165] To a solution of Intermediate Al (20 g, 96 mmol) in 1-methyl-2-pyrrolidinone (300 mL) was added cesium carbonate (62.8 g, 193 mmol) and <strong>[4333-56-6]bromocyclopropane</strong> (24 mL, 289 mmol). The mixture was stirred for 24 h while keeping internal temperature between 145C and 155 C. The reaction mixture was cooled to room temperature, diluted with water (400 mL), and extracted with a mixture of ethyl acetate in petroleum ether (15% v/v) (300 mL x 3). The combined organic phases were washed with brine (150 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude product. The crude product was purified with flash column chromatography on silica gel (petroleum ether) to furnish Intermediate A2. HPLC: Rt: 1.96 minute. ?H-NMR (CDC13, 400 MHz): (ppm) 0.80-0.88 (m, 4H), 3.67-3.82 (m, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 8.8, 2.4 Hz, 1H), 7.47 (d, I =2.4Hz, 1H).
1-((4-bromo-2-chlorophenoxy)methyl)cyclopropanecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.24 g
Thionyl chloride (0.92 mL) was added to a solution of <strong>[98730-77-9]1-(hydroxymethyl)cyclopropanecarbonitrile</strong> (0.609 g) in toluene (10 mL) at room temperature. The reaction mixture was stirred at 80C for 2 hr, and the solvent was evaporated. The resulting residue was dissolved in DMF (10 mL), and 4-bromo-2-chlorophenol (1.0 g) and potassium carbonate (2.0 g) were added. The mixture was stirred at 80C overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.24 g) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) delta 1.16-1.24 (2H, m), 1.33-1.46 (2H, m), 4.04 (2H, s), 6.81 (1H, d, J = 8.7 Hz), 7.33 (1H, d, J = 8.7 Hz), 7.53 (1H, s).
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 18.0h;
[000304j Compound P1 (31.lg, 150 mmol), K2C03 (31.lg, 225 mmol) and iodopropane (18 mL, 180 mmol) were stirred at 25 C in DMF (300 mL). After 18 hours, the mixture was diluted with ethyl acetate (600 mL), washed with H20 (300 mL x 4), and dried over anhydrous sodium sulfate. After evaporation, the crude compound was purified with flash column chromatography on silica gel (petroleum ether, 100% v/v) to yield Compound P2. ?HNMR (CDC13, 400 MHz) major characteristic peaks: (5(ppm) 1.36 (d, J= 7.0 Hz, 6H), 4.49- 4.52 (m, 1H), 6.81 (d, J 8.8 Hz, 1H), 7.27 (dd, J 8.8, 2.4 Hz, 1H), 7.49 (d, J= 2.4 Hz, 1H).
Multi-step reaction with 2 steps
1: trifluoroacetic acid / 20 h / 90 °C
2: hydroxylamine hydrochloride; sodium formate; formic acid / 10 h / 100 °C
Multi-step reaction with 2 steps
1.1: trifluoroacetic acid / 20 h / 90 °C
1.2: 2 h / 20 °C
2.1: formic acid; hydroxylamine hydrochloride; sodium formate / 10 h / 100 °C
1-[2-( 4-bromo-2-chlorophenoxy)ethyl]-4-methylpiperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 50℃;Inert atmosphere;
10.373 g (50 mmol) 4-bromo-2-chlorophenol, 14.442 g <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong>(100 mmol) and 26.229 g PPh3 (100 mmol) were dissolved in 250 mL toluene, then 23 .027g diter/butyl azodicarboxylate (100 nimol) was added. The mixture was stirred at 50°Cunder N2 until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOll as eluentsMS (M+H)t 333.0.
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 50℃;Inert atmosphere;
10.373 g 4-bromo-2-chlorophenol (50 mmol), 14.442 g 2-(4-methylpiperazin-l-yl)ethanol (100 mmol) and 26.229 g PPh3 (100 mmol) were dissolved in 250 mL dry toluene under N2 atmosphere, then 23.027 g DTAD (100 mmol) was added. The mixture was stirred at 50 °C until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents. MS (M+H): 333.0
With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 14h;
8 Preparation example 8: preparation of 5-(4-bromo-2-chlorophenoxy)pentan-2-one
Under room temperature, will be sequentially 2-chloro-4-bromophenol (5.0 g, 24.1 millimole), K2CO3(9.97 g, 72.3 mmol) and 5-chloro-pentan-2-one (4.36 g, 36.1 mmol) in DMF (50 ml) in. The obtained mixture is heated to 80 °C, and stirring the reaction 14 hours. The obtained water to the mixture of retrodisplacement at room temperature in (300 ml). The resulting mixture is extracted with ethyl acetate. The resulting organic phase is concentrated to obtain crude product. The resulting crude product is purified by silica gel column chromatography (PE:EA=20:1) to obtain 2.0 g of pale yellow, the target compound (yield: 28.6%).
methyl 4-bromo-2-(4-bromo-2-chlorophenoxy)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;
(1) 4- N bromo-2- chlorophenol (5.0 g), N-dimethylformamide (50 mL) solution at room temperature, potassium carbonate (3.4 g) and <strong>[29547-04-4]2,4-dibromo methyl butyrate</strong>(6. 3g) in that order, and the mixture was stirred for 4 hours at 60 . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, after filtration, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give methyl 4-bromo-2- (4-bromo-2-chlorophenoxy) butanoate (3.8 g, 40%) It was obtained as a colorless oily substance.
With copper(l) iodide; iron(III)-acetylacetonate; potassium carbonate In N,N-dimethyl-formamide for 10h; Inert atmosphere; Heating;
1.1.1.1 Step 1: Synthesis of intermediate A1
Under nitrogen protection, magnetically stirred, 2-bromo-7-iodo-9H-purin-9-one: 46.8 g (122 mmol), 4-bromo-2-chlorophenol: 24.72 g, copper iodide: 2.29 g,Tris(acetylacetonato)iron(III):8.47g, potassium carbonate: 33.2g,N,N-dimethylformamide:240 mL was placed in the flask and heated and stirred for 10 hours.After cooling to room temperature (25 ° C), the reaction solution was filtered, and the reaction solution was extracted with toluene. After removing the aqueous layer, several layers were washed with a saturated aqueous solution of ammonium chloride. Several layers were dried over sodium sulfate, concentrated, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography.31.03 g of a yellow solid were obtained in a yield of 56%.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h;
2.1
4-bromo-2-chloro-phenol (11.56 mmol),Potassium carbonate (17.34 mmol), benzyl chloride(13.87 mmol) was added to 15 mL of DMF, reacted at room temperature for 24 hours, and filtered.The filtrate was added to 200 mL of ethyl acetate, and then respectively 5% sodium hydroxide solution, water,The organic layer was dried over anhydrous sodium sulfate and concentrated.A yellow concentrate was obtained which was used directly in the next reaction.
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
General procedure: To a solution of 5- bromine -2- chlorophenol (2.9g, 14.3mmol) in 50mL acetonitrile was added K2CO3 (2.5g,17.1mmol), and stirred for 30min intermediate product 10 was added and the solution was heated to 80C for 4h. The reaction solution was concentrated, water (100mL) was added, and extracted with EtOAc. The organic layer was collected and washed with water and brine for three times, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford intermediate product 11.
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
General procedure: To a solution of 5- bromine -2- chlorophenol (2.9g, 14.3mmol) in 50mL acetonitrile was added K2CO3 (2.5g,17.1mmol), and stirred for 30min intermediate product 10 was added and the solution was heated to 80C for 4h. The reaction solution was concentrated, water (100mL) was added, and extracted with EtOAc. The organic layer was collected and washed with water and brine for three times, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford intermediate product 11.
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
2.8 1. 4'-butoxy-N-(3-(diethylamino)propyl)biphenyl-3-carboxamide synthesis
General procedure: A mixture of 4-bromophenol (100 mg, 0.58 mmol), bromobutane (160 μL, 1.73 mmol) and potassium carbonate (excess) in DMF (1 mL) was stirred at 90° C. for 3 hours to compound the compound 1 was synthesized, compound 1 (61.4 mg, 0.29 mmol), 3-cyanophenylboronic acid (50.3 mg, 0.34 mmol) and 2N-potassium carbonate (0.2 mL, 0.2 mmol) in degassed THF (1 mL) ) was added to the prepared suspension, and tetrakis (triphenylphosphine) palladium (0) (3 mg, 0.03 mmol) was added and reacted to synthesize compound 2.A mixture of compound 2 (30 mg, 0.13 mmol) and 2N-NaOH (1.5 mL, 6 mmol) dissolved in methanol (3 mL) was refluxed for 20 hours to synthesize compound 3, the compound 3 (15 mg, 0.06 mmol) and oxalyl chloride (20 μL, 0.24 mmol) were dissolved in dichloromethane (2 mL) by adding a drop of DMF as a catalyst to synthesize compound 4, the compound 4, an appropriate amount of primary amine, A mixture of diisopropylethylamine or diethylamine dissolved in THF (anhydrous) was stirred at room temperature for 30 hours.The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous MgSO4, filtered, and the filtrate was concentrated in vacuo. The obtained product was purified by flash column chromatography (CH2Cl2/MeOH = 10-50:1) to synthesize compound 60.
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