* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.583333 h; Stage #2: at -78 - 20℃; for 1.5 h;
Step-1 : Synthesis of 3-bromo-5-hydroxybenzaldehyde: [0135] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 °C was added a 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at - 78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6percent EtOAc in hexane) to yield the desired compound, 3-bromo-5-hydroxybenzaldehyde (1.0 g, 50.12percent) as a white solid. HNMR (400 MHz, DMSO-d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
50%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2.5 h;
A solution of 3,5-dibromophenol (2.5 g, 10 mmol) in THF (25 mL) was cooled to -78 C using the dry ice-acetone bath and a solution of BuLi (9 mL, 22.5 mmol, 2.5 M solution in hexane) was added dropwise. The reaction mixture was stirred for 30 min at this temperature and DMF (15.3 mL) was added. The solution was stirred for 30 min at -78 °C and for 2 h at r. t. The reaction was quenched with sat. NH4C1 and extracted with EtOAc (3 times). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (hexane : EtOAc = 20 : 1 to 4 : 1) yielding 1.0 g (50percent) of a desired product. - 1H NMR (300 MHz, DMSO-d6) 10.55 - 10.39 (m, 1 H), 9.89 (s, 1 H), 7.53 - 7.50 (m, 1 H), 7.29 - 7.24 (m, 2 H). Spectral data are identical to those published in the literature (Yang et al., 2016)
With sulfuric acid; acetic acid; sodium nitrite In water at 0℃; for 3 h; Reflux
To a solution of 15 (0.71 g, 6.0 mmol) in AcOH/H2SO4/H2O(5.0 mL, 8/1/1) was added sodium nitrite aqueous solution (0.24 g,3.5 mmol, 1 mL) dropwise and stirred for 1 h at 0 C. The reactionwas added 10percent sulphuric acid (20 mL) and refluxed for 2 h. Aftercooling to the room temperature, the reaction mixture wasextracted with EtOAc (3 30 mL), washed with saturated sodiumbicarbonate solution (3 30 mL) and brine (30 mL). The combinedorganic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (EtOAc/petroleumether, 1/8) to give 16 (0.47 g, 80percent) as a pale yellow solid. 1H NMR(300 MHz, DMSO-d6) d: 10.43 (s, 1H), 9.88 (s, 1H), 7.51 (s, 1H),7.31e7.18 (m, 2H).
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 116, p. 46 - 58
[2] Journal of the American Chemical Society, 2007, vol. 129, # 15, p. 4512 - 4513
With pyridinium chlorochromate In dichloromethane at 20℃; for 1 h;
Borane-methyl sulfide complex (5.53 ml, 1 1 mmol) was slowly added to a mixture of 3-bromo-5-hydroxybenzoic acid (2 g, 9.22 mmol) and trimethyl borate (2.1 ml, 18 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature overnight. Methanol (25 ml) was then added and the solvents removed. Dichloromethane (60 ml) and then pyridinium chlorochromate (3.77 g, 17 mmol) were added to the crude and the mixture was stirred at room temperature for an hour. The crude was filtered and the mother liquor concentrated in vaccuo. The residue was purified by reverse phase to give 1.85 g (51 percent yield) of the title compound as a white solid. Purity 99percent. LRMS (m/z): 200 (M-1 )"
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 8, p. 3217 - 3227
[2] Patent: WO2014/60431, 2014, A1, . Location in patent: Page/Page column 106
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 2937 - 2957
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 15, p. 4512 - 4513
[2] European Journal of Medicinal Chemistry, 2016, vol. 116, p. 46 - 58
7
[ 355134-13-3 ]
[ 199177-26-9 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 15, p. 4512 - 4513
[2] European Journal of Medicinal Chemistry, 2016, vol. 116, p. 46 - 58
8
[ 99-61-6 ]
[ 199177-26-9 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 15, p. 4512 - 4513
[2] European Journal of Medicinal Chemistry, 2016, vol. 116, p. 46 - 58
9
[ 909854-23-5 ]
[ 199177-26-9 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 15, p. 4512 - 4513
10
[ 140472-69-1 ]
[ 199177-26-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 8, p. 3217 - 3227
[2] Patent: WO2014/60431, 2014, A1,
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 2937 - 2957
11
[ 199177-26-9 ]
[ 74-88-4 ]
[ 262450-65-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;
Example 1 5A: 3 -Bromo-5-methoxybenzaldehyde j00295j 3-Bromo-5-hydroxybenzaldehyde (0.5 g, 2.487 mmol) was dissolved in DMF(14.63 mL) and cooled to 0 °C. NaH (0.119 g, 4.97 mmol) was added in three portions.The flask was immediately allowed to warm to ambient temperature and Mel (0.93 3 mL,14.92 mmol) was added, and the reaction stirred overnight. The reaction was diluted with water and partially concentrated in vacuo. The material was diluted with DCM and washed twice with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (gradientfrom 0 to 100percent EtOAc in hexanes) to yield Example 15A (0.488 g, 2.27 mmol, 9 1percent).‘H NMR (400 MHz, CHLOROFORM-cl) ö ppm 9.91 (1 H, s), 7.58 (1 H, t, J=1.38 Hz), 7.28 - 7.35 (2 H, m, J=2.38, 2.13, 2.01, 2.01 Hz), 3.86 (3 H, s).
With sulfuric acid; acetic acid; sodium nitrite; In water; at 0℃; for 3h;Reflux;
To a solution of 15 (0.71 g, 6.0 mmol) in AcOH/H2SO4/H2O(5.0 mL, 8/1/1) was added sodium nitrite aqueous solution (0.24 g,3.5 mmol, 1 mL) dropwise and stirred for 1 h at 0 C. The reactionwas added 10% sulphuric acid (20 mL) and refluxed for 2 h. Aftercooling to the room temperature, the reaction mixture wasextracted with EtOAc (3 30 mL), washed with saturated sodiumbicarbonate solution (3 30 mL) and brine (30 mL). The combinedorganic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (EtOAc/petroleumether, 1/8) to give 16 (0.47 g, 80%) as a pale yellow solid. 1H NMR(300 MHz, DMSO-d6) d: 10.43 (s, 1H), 9.88 (s, 1H), 7.51 (s, 1H),7.31e7.18 (m, 2H).
A solution of BBr3 (29.1 mL of a 1.0 M solution in DCM, 29.1 mmol) was added slowly to a solution of 170a (2.5 g, 11.62 mmol) in anhydrous DCM (25 mL) maintained under N2 at -78 C. The orange solution was warmed to RT, stirred for 2 h, and poured onto ice. The mixture was extracted with CH2Cl2 (100 mL), and the organic layer was washed with H2O (50 mL) and brine (50 mL). The solvents were evaporated, and the remaining oil was purified by flash chromatography on silica gel eluting with a EtOAc/hexanes gradient (0% to 20% EtOAc) to provide the desired phenol. To a solution of this phenol in pyridine (10 mL) under argon was slowly added acetic anhydride (0.6 mL, 6.33 mmol). After 2 h, the volatile materials were removed to provide 3-bromo-5-formyl-phenyl acetate (170b, 1.02 g, 40%).
With pyridine; for 2h;
step 1-A solution of BBr3 (29.1 mL of a 1.0 M solution in DCM, 29.1 mmol) was added slowly to a solution of 45a (2.5 g, 11.62 mmol) in anhydrous DCM (25 mL) maintained under N2 at -78 C. The orange solution was warmed to RT, stirred for 2 h, and poured onto ice. The mixture was extracted with DCM (100 mL), and the organic layer was washed with H2O (50 mL) and brine (50 mL). The solvents were evaporated, and the remaining oil was purified by flash chromatography on SiO2 eluting with an EtOAc/hexane gradient (0% to 20% EtOAc) to provide the desired phenol. To a solution of this phenol in pyridine (10 mL) under argon was slowly added acetic anhydride (0.6 mL, 6.33 mmol). After 2 h, the volatile materials were removed to provide 3-bromo-5-formyl-phenyl acetate (45b, 1.02 g, 40 %).
With pyridine; for 2h;
A solution of BBr3 (29.1 mL of a 1.0 M solution in DCM, 29.1 mmol) was added slowly to a solution of 62a (2.5 g, 11.62 mmol) in anhydrous DCM (25 mL) maintained under N2 at -78 C. The orange solution was warmed to RT, stirred for 2 h, and poured onto ice. The mixture was extracted with CH2Cl2 (100 mL), and the organic layer was washed with H2O (50 mL) and brine (50 muL). The solvents were evaporated, and the remaining oil was purified by flash chromatography on silica gel eluting with a EtOAc/hexanes gradient (0% to 20% EtOAc) to provide the desired phenol. To a solution of this phenol in pyridine (10 mL) under argon was slowly added acetic anhydride (0.6 mL, 6.33 mmol). After 2 h, the volatile materials were removed to provide 3-bromo-5-formyl-phenyl acetate (62b, 1.02 g, 40%).
With pyridine; for 2h;
A solution of BBr3 (29.1 mL of a 1.0 M solution in DCM, 29.1 mmol) was added slowly to a solution of R-17a (2.5 g, 11.62 mmol, CAS Reg. No. 262450-65-7) in anhydrous DCM (25 mL) maintained under N2 at -78 C. The orange solution was warmed to RT, stirred for 2 h, and poured onto ice. The mixture was extracted with DCM (100 mL), and the organic layer was washed with H2O (50 mL) and brine (50 mL). The solvents were evaporated, and the remaining oil was purified by SiO2 chromatography eluting with a EtOAc/hexanes gradient (0% to 20% EtOAc) to provide the desired phenol. To a solution of this phenol in pyridine (10 mL) under argon was slowly added acetic anhydride (0.6 mL, 6.33 mmol). After 2 h, the volatile materials were removed to provide 3-bromo-5-formyl-phenyl acetate (R-17b, 1.02 g, 40%).
With pyridine; for 2h;
step 1-A solution of BBr3 (29.1 mL of a 1.0 M solution in DCM, 29.1 mmol) was added slowly to a solution of R-17a (2.5 g, 11.62 mmol, CASRN 262450-65-7) in anhydrous DCM (25 mL) maintained under N2 at -78 C. The orange solution was warmed to RT, stirred for 2 h, and poured onto ice. The mixture was extracted with DCM (100 mL), and the organic layer was washed with H2O (50 mL) and brine (50 mL). The solvents were evaporated, and the remaining oil was purified by SiO2 chromatography eluting with a EtOAc/hexanes gradient (0% to 20% EtOAc) to provide the desired phenol. To a solution of this phenol in pyridine (10 mL) under argon was slowly added acetic anhydride (0.6 mL, 6.33 mmol). After 2 h, the volatile materials were removed to provide 3-bromo-5-formyl-phenyl acetate (R-17b, 1.02 g, 40%).
With pyridine; for 2h;
Step 1 Step 2 A solution of BBr3 (29.1 ML of a 1.0 M solution in CH2Cl2, 29.1 mmol) was added slowly to a solution of 119 (2.5 g, 11.62 mmol) in anhydrous CH2Cl2 (25 ML) under nitrogen at -78 C. The orange solution was warmed to RT, stirred for 2 h, and poured onto ice.The mixture was extracted with CH2Cl2 (100 ML), and the organic layer was washed with H2O (50 ML) and brine (50 ML).The solvents were evaporated, and the remaining oil was purified by flash chromatography on silica gel (0% to 20% EtOAc/hexanes) to provide the desired phenol.To a solution of this phenol in pyridine (10 ML) under argon was slowly added acetic anhydride (0.6 ML, 6.33 mmol).After 2 h, the volatile materials were removed to provide 3-bromo-5-formyl-phenyl acetate (120, 1.02 g, 40%).
With pyridine; for 2h;
step 1-A solution of BBr3 (29.1 mL of a 1.0 M solution in DCM, 29.1 mmol) was added slowly to a solution of 27a (2.5 g, 11.62 mmol) in anhydrous DCM (25 mL) maintained under N2 at -78 C. The orange solution was warmed to RT, stirred for 2 h, and poured onto ice. The mixture was extracted with DCM (100 mL), and the organic layer was washed with H2O (50 mL) and brine (50 mL). The solvents were evaporated, and the remaining oil was purified by flash chromatography on silica gel eluting with a EtOAc/hexanes gradient (0% to 20% EtOAc) to provide the desired phenol. To a solution of this phenol in pyridine (10 mL) under argon was slowly added acetic anhydride (0.6 mL, 6.33 mmol). After 2 h, the volatile materials were removed to provide 3-bromo-5-formyl-phenyl acetate (27b, 1.02 g, 40%).
Step 1 : 3-Bomo-5-hydroxybenzaldehyde EPO <DP n="49"/>To a toluene solution (1.6 M) of «-butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at -10 0C rc-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at -10 0C for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at -10 0C over a period of 35 min. After stirring at -10 0C for a further 30 min, the reaction mixture was cooled to -40 0C before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly wanned to RT and allowed to stir at RT for 1 h. The reaction was carefully quenched at 0 0C with 10% aq. HCl and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a yellow solid. Recystallization of the crude product thus obtained from ether - hexane afforded the title compound as a beige powder.
With sodium carbonate;palladium diacetate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 80℃; for 16h;
Step 2: 3-Hydroxy-5-[(liD-3-methoxyprop-l-en-l-yl]benzaldehvde3-Bromo-5-hydroxybenzaldehyde (1 eq.) from the previous step and 2-[(l£)-3- methoxyprop-l-en-l-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 eq.) were combined in DMF <n="22"/>(0.05 M). To this solution was then added palladium acetate (10 mol%), triphenylphosphine (20 mol%), and sodium carbonate (2 M aqueous solution, 4 eq.). The resulting suspension was heated at 80C and stirred for 16 h. The reaction mixture was quenched with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% -> 33% EtO Ac/Hex) to afford the title compound as a yellow oil.
With sodium carbonate;palladium diacetate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 80℃; for 16h;
Step 2: 3-Hydroxy-5-[(lE)-3-(methyloxy)-l-propen-l-yl]benzaldehyde; 3-Bomo-5-hydroxybenzaldehyde (1 eq.) from the previous step and 2-[(lE)-3- methoxyprop-l-en-l-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 eq.) were combined in DMF (0.05 M). To this solution was then added palladium acetate (0.1 eq.), triphenylphosphine (0.2 eq.) and 2 M aq. sodium carbonate (4 eq.). The resulting suspension was heated at 80 0C for 16 h. The reaction mixture was quenched with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a brown tar. Further purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex : EtOAc -> 2:1 (v/v) Hex : EtOAc) afforded the title compound as a yellow oil.
With sodium carbonate; triphenylphosphine;palladium diacetate; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere of nitrogen;
3 -Hydroxy-5 - [( 1 £)-3 -(methy loxy)- 1 -propen- 1 -yl]benzaldehyde .3-Bomo-5-hydroxybenzaldehyde (1 eq.) from the previous step and 2-[(l£)-3- methoxyprop-l-en-l-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 eq.) were combined in DMF (0.05 M). To this solution was then added palladium acetate (0.1 eq.), triphenylphosphine (0.2 eq.) and 2 M0 aq. sodium carbonate (4 eq.). The resulting suspension was heated at 80 0C for 16 h. The reaction mixture was quenched with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed with water, sat. aq. NaHCC>3 and brine. Drying over MgSC^, filtration and concentration of the filtrate in vacuo afforded the crude product as a brown tar. Further purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex : EtOAc -^ 2:1 (v/v) Hex : EtOAc) afforded the title compound as a5 yellow oil.
With sodium carbonate;palladium diacetate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 80℃; for 16h;
Step 2: 3-Hydroxy-5-|Yl£r)-3-methoxyprop-l-en-l-yl]benzaldehvde3-Bomo-5-hydroxybenzaldehyde from the previous step (1 eq.) and 2-[(lE)-3- methoxyprop-l-en-l-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 eq.) were combined in DMF (0.05 M). To this solution was then added palladium acetate (10% loading), triphenylphosphine (20% loading) and sodium carbonate (2 M aqueous solution, 4 eq.). The resulting suspension was heated at 80 0C for 16 h. The reaction mixture was quenched with 10% aq. HCl and extracted with ether. The combined organic extracts were washed with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a brown tar. Purification by way of column chromatography (SiO2, 4: 1 (v/v) Hex : EtOAc -» 2:1 (v/v) Hex : EtOAc) afforded the title compound as a yellow oil.
Step 2: 3-Hvdroxy-5-[(lffi-3-methoxyprop-l-en-l-yl]benzaldehyde3-Bromo-5-hydroxybenzaldehyde (1 eq.) from the previous step and 2-[(lE)-3- methoxyprop-l-en-l-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 eq.) were combined in DMF (0.05 M). To this solution was then added palladium acetate (10 mol%), triphenylphosphine (20 mol%), and sodium carbonate (2 M aqueous solution, 4 eq.). The resulting suspension was heated at 8O0C and stirred for 16 h. The reaction mixture was quenched with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% 33% EtO Ac/Hex) to afford the title compound as a yellow oil.
With sodium carbonate;palladium diacetate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;
3-Bomo-5-hydroxybenzaldehyde (1 eq.) from the previous step and 2-[(E)-3- methoxyprop-l-en-l-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 eq.) were combined in DMF (0.05 M). To this solution was then added palladium acetate (0.1 eq.), triphenylphosphine (0.2 eq.) and 2 M aq. sodium carbonate (4 eq.). The resulting suspension was heated at 80 0C for 16 h. The reaction mixture was quenched with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a brown tar. Further purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex : EtOAc -> 2:1 (v/v) Hex : EtOAc) afforded the title compound as a yellow oil.
Step-1 : Synthesis of 3-bromo-5-hydroxybenzaldehyde: [0135] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 C was added a 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at - 78 C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3-bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. HNMR (400 MHz, DMSO-d6): delta (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
50%
A solution of 3,5-dibromophenol (2.5 g, 10 mmol) in THF (25 mL) was cooled to -78 C using the dry ice-acetone bath and a solution of BuLi (9 mL, 22.5 mmol, 2.5 M solution in hexane) was added dropwise. The reaction mixture was stirred for 30 min at this temperature and DMF (15.3 mL) was added. The solution was stirred for 30 min at -78 C and for 2 h at r. t. The reaction was quenched with sat. NH4C1 and extracted with EtOAc (3 times). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (hexane : EtOAc = 20 : 1 to 4 : 1) yielding 1.0 g (50%) of a desired product. - 1H NMR (300 MHz, DMSO-d6) 10.55 - 10.39 (m, 1 H), 9.89 (s, 1 H), 7.53 - 7.50 (m, 1 H), 7.29 - 7.24 (m, 2 H). Spectral data are identical to those published in the literature (Yang et al., 2016)
Amine 1 Step 1: 3-Bromo-5-hydroxybenzaldehydeTo a toluene solution (1.6 M) of «-butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at -100C r°-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at -100C for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at -100C over a period of 35 min. After stirring at -100C for a further 30 min, the reaction mixture was cooled to -400C before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to it and allowed to stir at rt for 1 h. The reaction was carefully quenched at 00C with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4. Concentration of the filtrate in vacuo afforded a yellow solid. Recrystallization of the crude product in ether/hexane afforded the title compound as a beige powder.
Step 1 : 3-Bomo-5-hydroxybenzaldehyde; To a toluene solution (1.6 M) of w-butyl lithium (2.5 M in hexane, 2.1 eq.) was added at -100C rc-butyl magnesium chloride (2.0 M in THF, 0.6 eq.). The reaction mixture was stirred at -100C for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at - 100C over a period of 35 min. After stirring at - 100C for a further 30 min, the reaction mixture was cooled to -400C before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to RT and allowed to stir at RT for 1 h. The reaction was carefully quenched at O0C with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a yellow solid. Recystallization of the crude product thus obtained from ether - hexane afforded the title compound as a beige powder.
To a toluene solution (1.6 M) of n-butyl lithium (2.5 M in hexane, 2.1 eq.) was added at - 100C n-butyl magnesium chloride (2.0 M in THF, 0.6 eq.). The reaction mixture was stirred at -100C for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at -100C over0 a period of 35 min. After stirring at -100C for a further 30 min, the reaction mixture was cooled to -400C before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to RT and allowed to stir at RT for 1 h. The reaction was carefully quenched at O0C with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a yellow solid. Recy stall ization of5 the crude product thus obtained from ether - hexane afforded the title compound as a beige powder.
Step 1 : 3-Bromo-5-hydroxybenzaldehydeTo a toluene solution (1.6 M) of butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at -10 C fl-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at -1O C for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at -1O C over a period of 35 min. After stirring at -100C for a further 30 min, the reaction mixture was cooled to -40 C before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to rt and allowed to stir at rt for 1 h. The reaction was carefully quenched at 0 C with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4. Concentration of the filtrate in vacuo afforded a yellow solid. Recystallization of the crude product in ether/hexane afforded the title compound as a beige powder.
To a toluene solution (1.6 M) of n-butyl lithium (2.5 M in hexane, 2.1 eq.) was added at -100C w-butyl magnesium chloride (2.0 M in THF, 0.6 eq.). The reaction mixture was stirred at -100C for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at -100C over a period of 35 min. After stirring at -1O0C for a further 30 min, the reaction mixture was cooled to -400C before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to RT and allowed to stir at RT for 1 h. The reaction was carefully quenched at 00C with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a yellow solid. Recystallization of the crude product thus obtained from ether - hexane afforded the title compound as a beige powder.
N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamide[ No CAS ]
[ 199177-26-9 ]
N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3'-formyl-5'-hydroxybiphenyl-3-yloxy)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In water; acetonitrile; at 80℃; for 2h;Inert atmosphere;
Example 66N-((ls,4s)-4-(l,5-dimethyl-lH-pyrazole-3-carboxamido)cyclohexyl)-2-(3'-(((3R,5S)-3,5- dimethylpiperazin-l-yl)methyl)-5'-hydroxybiphenyl-3-yloxy)-5-fluoronicotinamide Step (a) N-((ls,4s)-4-(l,5-dimethyl-lH-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2- (3'-formyl-5'-hydroxybiphenyl-3-yloxy)nicotinamidePalladium acetate (3.89 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (14.22 mg, 0.03 mmol) were added to acetonitrile (4 mL) under nitrogen. The resulting solution was stirred for 10 min. To this solution was added potassium carbonate <n="122"/>(144 mg, 1.04 mmol) dissolved in water (4 rnL), followed by N-(( ls,4s)-4-( 1,5 -dimethyl- 1 H- pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenoxy Nicotinamide (200 mg, 0.35 mmol) and <strong>[199177-26-9]3-bromo-5-hydroxybenzaldehyde</strong> (69.6 mg, 0.35 mmol) and the mixture heated at 80 0C for 2 h. The mixture was poured onto water and extracted into EtOAc (x2). The extractions were combined, washed with brine, dried (MgSO4) and evaporated to give a light brown foam. The crude material was purified by Biotage (eluant = neat EtOAc) to give the sub-title compound as a white foam after evaporation. Yield: 144 mg MS: [M+H]+ = 572 (MultiMode+)
N-((1s,4s)-4-(5-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide[ No CAS ]
[ 199177-26-9 ]
N-((1s,4s)-4-(5-fluoro-2-(3'-formyl-5'-hydroxybiphenyl-3-yloxy)nicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In water; acetonitrile; at 80℃; for 2h;Inert atmosphere;
Example 65N-((ls,4s)-4-(2-(3'-(((3R,5S)-3,5-dimethylpiperazin-l-yl)methyl)-5'-hydroxybiphenyl-3- yloxy)-5-fluoronicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide Step (a) N-((l s,4s)-4-(5-fluor o-2-(3 '-formyl-5 '-hydroxybiphenyl-3- yloxy)nicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamidePalladium acetate (3.87 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (14.14 mg, 0.03 mmol) were added to acetonitrile (4 mL) under nitrogen. The resulting solution was stirred for 10 min. To this solution was added potassium carbonate (143 mg, 1.03 mmol) dissolved in water (4 mL), followed by N-((ls,4s)-4-(5-fluoro-2-(3- (4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)phenoxy)nicotinamido)cyclohexyl)-2- methylthiazole-4-carboxamide (200 mg, 0.34 mmol) and <strong>[199177-26-9]3-bromo-5-hydroxybenzaldehyde</strong> (69.3 mg, 0.34 mmol) and the mixture heated at 80 0C for 2 h. The mixture was poured onto water and extracted into EtOAc (x2). The extractions were combined, washed with brine, dried (MgSO4) and evaporated to give a brown oil. The crude material was purified by Biotage (eluant = neat EtOAc) to give the sub-title compound as a white foam after evaporation. Yield: 102 mg MS: [M+H]+ = 575 (MultiMode+)
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 1h;
Borane-methyl sulfide complex (5.53 ml, 1 1 mmol) was slowly added to a mixture of 3-bromo-5-hydroxybenzoic acid (2 g, 9.22 mmol) and trimethyl borate (2.1 ml, 18 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature overnight. Methanol (25 ml) was then added and the solvents removed. Dichloromethane (60 ml) and then pyridinium chlorochromate (3.77 g, 17 mmol) were added to the crude and the mixture was stirred at room temperature for an hour. The crude was filtered and the mother liquor concentrated in vaccuo. The residue was purified by reverse phase to give 1.85 g (51 % yield) of the title compound as a white solid. Purity 99%. LRMS (m/z): 200 (M-1 )"
With manganese(IV) oxide; In chloroform; ethyl acetate;Reflux;
To a solution of 3-bromo-5-hydroxybenzylalcohol 15 (1.79 g,8.77 mmol, 1.0 eq) in CHCl3 (15 mL) and ethyl acetate (3 mL) wasadded activated MnO2 (5.34 g, 61.4 mmol, 7 eq). The reaction mixturewas heated under reflux for 3 h after which time the reactionwas judged to be complete by TLC analysis. After this time the suspensionwas cooled to rt and filtered through Celite, eluting withCH2Cl2. The volatile components were removed in vacuo, and theresulting solid was purified by silica gel chromatography, ethylacetate: petroleum ether 1:3, to yielded 16 (1.39 g, 78%) as anoff-white solid: Rf (30% EtOAc/petroleum ether) 0.50; mp (fromCHCl3) 137-139 C [lit. mp 137-140 C21]; 1H NMR (400 MHz, D6-DMSO) d 10.45 (1H, s, CHO), 9.86 (1H, s, C(5)OH), 7.52-7.45 (1H,m, CArH), 7.30-7.19 (2H, m, 2 CArH); LRMS m/z (ES) 199 & 201([M(79Br)H] & [M(81Br)H], 31%), 399 & 401 & 403 ([M(79Br)M(79Br)H] & [M(79Br)M(81Br)H] & [M(81Br)M(81Br)H],100%).
potassium (3,5-dimethylisoxazol-4-yl)(trifluoro)borate[ No CAS ]
[ 199177-26-9 ]
[ 1429129-61-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
Na2CO3 (1.41 g, 13.3 mmol, 3.0 eq) was ground to fine powderand added together with 16 (0.890 g, 4.43 mmol, 1.0 eq) and 13(1.36 g, 6.64 mmol, 1.5 eq) into a Schlenk flask. The atmospherein the Schlenk flask was removed by applying a vacuum andreplaced by N2. This process was repeated three times. Ethanol (4mL) was added and the mixture was heated to 80 C for 10-30min. RuPhos (0.394 g, 0.531 mmol, 0.12 eq) and Pd(OAc)2 (60 mg,0.531 mmol, 0.12 eq) were added to a scintillation vial, whichwas capped with a septum. The atmosphere in the scintillation vialwas removed by applying a vacuum and replaced by N2. This processwas repeated three times. Ethanol (2 mL) was added to thescintillation vial and the mixture was stirred until the solutionwas colored deep red. This solution was transferred from the scintillationvial to Schlenk flask using a syringe. Ethanol (2 mL) wasused to transfer the residual catalyst from the scintillation vial toSchlenk flask. The reaction mixture was heated for 1 h at 80 C.After completion, the reaction mixture was cooled to rt and dilutedwith ethyl acetate. The volatile components were removed invacuo. The residue was dissolved in ethyl acetate (50 mL). Theorganic layer was washed with water (3 20 mL). The organiclayer was concentrated in vacuo. Purification by silica gel chromatography,eluting with EtOAc in petroleum ether (gradient elution0 ?50%) yielded 17 (803 mg, 85%) as a yellow solid. Rf (20%EtOAc/petroleum ether) 0.13; mp (from EtOAc) 184-186 C [lit.mp 184-187 C21]; 1H NMR (400 MHz, D6-acetone) d 10.02 (1H,s, CHO), 9.11 (1H, br s, C(5)OH), 7.42 (1H, dd, J = 1.4, 1.4 Hz, C(6)H), 7.36 (1H, dd, J = 2.3, 1.4 Hz, C(2)H), 7.15 (1H, dd, J = 2.3, 1.4Hz, C(4)H), 2.44 (3H, s, C(50)CH3), 2.26 (3H, s, C(30)CH3); LRMS m/z (ES) 216 ([MH], 100%).
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