* 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] Journal of Organic Chemistry, 2014, vol. 79, # 23, p. 11508 - 11516
2
[ 103966-66-1 ]
[ 59557-91-4 ]
Yield
Reaction Conditions
Operation in experiment
2 g
With water; iron; ammonium chloride In tetrahydrofuran at 65℃; for 4 h; Inert atmosphere
Step 3 4-bromo-2-methoxyaniline (Compound 12-5) At room temperature, the reduced iron powder (4.48 g, 80 mmol) and ammonium chloride (2.65 g, 50 mmol) were added to a mixed solution of compound 12-4 (2.3 g, 10.0 mmol) in 60 ml of THF/water (volume ratio of THF and water is 2:1), and vigorously stirred at 65° C. for 4 h. After completion of the reaction, the reaction mixture was filtered, the filtrate was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-5 (2.0 g) which was used directly in the next step. MS m/z (ESI): 201.9 [M+H]+.
Reference：
[1] Tetrahedron, 2009, vol. 65, # 7, p. 1281 - 1286
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 7, p. 1475 - 1491
4
[ 321-23-3 ]
[ 124-41-4 ]
[ 103966-66-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 20℃;
To a solution of 4-bromo-2-fluoro-1-nitro-benzene (2.0 g, 9.09 mmol) in methanol (50 ml) was added sodium methanolate (30 percent in methanol) (1.64 g, 9.09 mmol). The reac.not. tion mixture was stirred at room temperature overnight. The reaction mixture was con- centrated and the residue was dissolved in water (30 ml) and extracted twice with ethyl acetate. The combined organic phases were washed with water. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield a crystalline solid (2.1 g, 99 percent). 1H-NMR (DMSOd6): δ [ppm] 7.9 (d, 1 H), 7.6 (s, 1 H), 7.3 (d, 1 H), 4.0 (s, 3H).
98%
at 60℃; for 1 h;
MeONa (1.0 mL, 5.0 mmol)Was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.01 g, 4.58 mmol)In MeOH (10mL) solution,The reaction was stirred at 60 ° C in an oil bath for 1 h.The solvent was removed under reduced pressure,The residue was dissolved in CH2Cl2 (30 mL)The insoluble material was removed by filtration,The filtrate was concentrated,To give the object as a yellow solid (1.05 g, 98percent).
89.7%
at 20℃;
18.4 g (83.64 mmol) of 2-fluoro-4-bromonitrobenzene (Aldrich) are almost fully dissolved in 300 mL of anhydrous methanol. 19.9 mL (106.22 mmol) of a 30percent solution of sodium methoxide in methanol are added dropwise and the mixture is stirred overnight at room temperature. The methanol is evaporated off under reduced pressure, the medium is taken up in ethyl acetate and water, and the aqueous phase is then acidified by adding aqueous 1N HCl. After separation of the phases by settling, the organic phase is washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. 17.4 g of the expected product are obtained in the form of a yellow solid. Yield=89.7percent.
73%
at 20℃; for 15 h;
4-Bromo-2-methoxy-1-nitrobenzene (4e). To asolution of 4-Bromo-2-fluoro-1-nitrobenzene (400 mg, 2.0 mmol) in methanol (5 mL) wasadded sodium methoxide 5.0Min methanol (480 L, 2.4 mmol) and then stirred at roomtemperature for 15 h. The reaction mixture was diluted with ethyl acetate, washed with waterand brine, and dried over anhydrous MgSO4. The crude material was purified by silica gelchromatography (6percent ethyl acetate in hexanes) to give 4e (380 mg, 73percent). 1H NMR (600 MHz, Acetone-d6) δ 7.80 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H),4.04 (s, 3H); 13C NMR (150 MHz, Acetone-d6) δ 154.1, 139.9, 128.4, 127.3, 124.3, 118.3, 57.6;IR (Neat) (cm-1): 3108, 2990, 2957, 2855, 1611, 1567, 1523, 1441, 1396, 1344, 1304, 1258,1189, 1005, 872, 858. 1H NMR data correspond with those reported in the literature [12].
9.5 g
at 25℃; for 8 h; Inert atmosphere; Reflux
Step 2 4-Bromo-2-methoxy-1-nitrobenzene (compound 12-4) Compound 12-3 (10.0 g, 46 mmol, commercially available) was dissolved in 150 ml of anhydrous methanol at room temperature, sodium methoxide (4.37 g, 81 mmol) was added, and the reaction mixture was heated to reflux and vigorously stirred for 8 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-4 (9.5 g) which was used directly in the next step. MS m/z (ESI): 231.0 [M+H]+.
Stage #1: With sodium In methanol at 0℃; for 1 h; Stage #2: at 20℃;
At 0 ° C, sodium metal (1.0 g) was chopped and slowly added to 30 mL.In anhydrous methanol, after 1 h of reaction, 2-fluoro-4-bromo-1-nitrobenzene (10.0 g) was added.After reacting at room temperature overnight, the target product is obtained by post-treatment and separation and purification.(white solid, 9.8 g).
Reference：
[1] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 4, p. 175 - 179
[2] Patent: CN108276410, 2018, A, . Location in patent: Paragraph 0164; 0165; 0166
6
[ 67-56-1 ]
[ 321-23-3 ]
[ 124-41-4 ]
[ 103966-66-1 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 60℃; for 1 h;
To 4-bromo-2-fluoro-1-nitrobenzene (8.0 g, 36.4 mmol) was added 0.5 N sodium methoxide (105 mL, 52.5 mmol). The mixture was stirred at 60° C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (8.1 g, 34.9 mmol, 96percent) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.61 Hz, 1H), 7.23 (d, J=2.01 Hz, 1H), 7.16 (dd, J=8.61, 1.83 Hz, 1H), 3.95 (s, 3H).
tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In toluene; for 5h;Heating / reflux;
4-Bromo-2-methoxy-1-nitro-benzene (691 mg, 3.14 mmol), tributyl-vinyl-stannane (1.2 g, 3.77 mmol), triphenylphospine (49 mg, 0.19 mmol) and tetrakistriphenylphosphinpal- ladium(O) (73 mg, 0.06 mmol) were dissolved in toluene (25 ml) and stirred for 5 hours at reflux. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (25 ml) and diethyl ether (50 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to yield an oil (2.0 g). The residue was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0 - 25 %). Fractions containing the product were combined, the solvent evaporated to give an oil (435 mg, 72 %).
To a solution of 4-bromo-2-fluoro-1-nitro-benzene (2.0 g, 9.09 mmol) in methanol (50 ml) was added sodium methanolate (30 % in methanol) (1.64 g, 9.09 mmol). The reac¬ tion mixture was stirred at room temperature overnight. The reaction mixture was con- centrated and the residue was dissolved in water (30 ml) and extracted twice with ethyl acetate. The combined organic phases were washed with water. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield a crystalline solid (2.1 g, 99 %). 1H-NMR (DMSOd6): delta [ppm] 7.9 (d, 1 H), 7.6 (s, 1 H), 7.3 (d, 1 H), 4.0 (s, 3H).
98%
In methanol; dichloromethane; at 60℃; for 1h;
MeONa (1.0 mL, 5.0 mmol)Was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.01 g, 4.58 mmol)In MeOH (10mL) solution,The reaction was stirred at 60 C in an oil bath for 1 h.The solvent was removed under reduced pressure,The residue was dissolved in CH2Cl2 (30 mL)The insoluble material was removed by filtration,The filtrate was concentrated,To give the object as a yellow solid (1.05 g, 98%).
89.7%
With methanol; at 20℃;
18.4 g (83.64 mmol) of 2-fluoro-4-bromonitrobenzene (Aldrich) are almost fully dissolved in 300 mL of anhydrous methanol. 19.9 mL (106.22 mmol) of a 30% solution of sodium methoxide in methanol are added dropwise and the mixture is stirred overnight at room temperature. The methanol is evaporated off under reduced pressure, the medium is taken up in ethyl acetate and water, and the aqueous phase is then acidified by adding aqueous 1N HCl. After separation of the phases by settling, the organic phase is washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. 17.4 g of the expected product are obtained in the form of a yellow solid. Yield=89.7%.
73%
In methanol; at 20℃; for 15h;
4-Bromo-2-methoxy-1-nitrobenzene (4e). To asolution of 4-Bromo-2-fluoro-1-nitrobenzene (400 mg, 2.0 mmol) in methanol (5 mL) wasadded sodium methoxide 5.0Min methanol (480 L, 2.4 mmol) and then stirred at roomtemperature for 15 h. The reaction mixture was diluted with ethyl acetate, washed with waterand brine, and dried over anhydrous MgSO4. The crude material was purified by silica gelchromatography (6% ethyl acetate in hexanes) to give 4e (380 mg, 73%). 1H NMR (600 MHz, Acetone-d6) delta 7.80 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H),4.04 (s, 3H); 13C NMR (150 MHz, Acetone-d6) delta 154.1, 139.9, 128.4, 127.3, 124.3, 118.3, 57.6;IR (Neat) (cm-1): 3108, 2990, 2957, 2855, 1611, 1567, 1523, 1441, 1396, 1344, 1304, 1258,1189, 1005, 872, 858. 1H NMR data correspond with those reported in the literature [12].
9.5 g
In methanol; at 25℃; for 8h;Inert atmosphere; Reflux;
Step 2 4-Bromo-2-methoxy-1-nitrobenzene (compound 12-4) Compound 12-3 (10.0 g, 46 mmol, commercially available) was dissolved in 150 ml of anhydrous methanol at room temperature, sodium methoxide (4.37 g, 81 mmol) was added, and the reaction mixture was heated to reflux and vigorously stirred for 8 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-4 (9.5 g) which was used directly in the next step. MS m/z (ESI): 231.0 [M+H]+.
4-(4-fluorobenzyl)-1-piperidinethanethiol[ No CAS ]
[ 103966-66-1 ]
5-[2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanesulfanyl]-2-nitroanisole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
Step B Preparation of 5-[2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanesulfanyl]-2-nitroanisole A mixture of 4-(4-fluorobenzyl)-1-piperidineethanethiol (7.7 g, 30.4 mmol), <strong>[103966-66-1]5-bromo-2-nitroanisole</strong> (7 g, 30.4 mmol) and K2CO, (4.8 g, 35 mmol) in acetonitrile (250 mL) was heated to reflux for 18 hr under nitrogen. After the mixture had cooled, the salts were removed by filtration and the filtrate concentrated to an oil. The compound was purified by chromatography to provide 6 g of an oil.
To 4-bromo-2-fluoro-1-nitrobenzene (8.0 g, 36.4 mmol) was added 0.5 N sodium methoxide (105 mL, 52.5 mmol). The mixture was stirred at 60 C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (8.1 g, 34.9 mmol, 96%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.74 (d, J=8.61 Hz, 1H), 7.23 (d, J=2.01 Hz, 1H), 7.16 (dd, J=8.61, 1.83 Hz, 1H), 3.95 (s, 3H).
With 1,4-diaza-bicyclo[2.2.2]octane;bis(tri-t-butylphosphine)palladium(0); In acetonitrile; at 60℃; for 1h;
To 5-bromo-2-nitrophenyl methyl ether (4.0 g, 17.24 mmol) in 80 mL of acetonitrile was added, Bis(tri-t-butylphosphine)palladium(0) (0.253 g, 0.5 mmol), 2-propyn-1-ol (3.33 g, 59.4 mmol), and DABCO (4.44 g, 39.6 mmol). The mixture was heated to 60 C. for 1 h. The mixture was rotovaped down and then taken up in diethyl ether. The organic layer was washed with H2O, dried (Na2SO4), filtered, and rotovaped. The crude product was purified by flash chromatography to give the title compound of step A (1.7 g, 8.2 mmol, 41%). 1H NMR (400 MHz, CDCl3) delta ppm 7.80 (d, J=8.24 Hz, 1H), 7.12 (d, J=1.65 Hz, 1H), 7.06 (dd, J=8.33, 1.56 Hz, 1H), 4.52 (s, 2H), 3.94 (s, 3H).
With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In propan-1-ol; at 100℃; for 3h;Inert atmosphere;
4.32 g (31.31 mmol) of potassium trifluorovinylborate and 3.12 mL (22.37 mmol) of triethylamine are added to a mixture of 5.19 g (22.37 mmol) of the product prepared in step 4.1 in 56 mL of n-propanol, under argon, and argon is bubbled through for 10 minutes. 0.36 g (0.45 mmol) of PdCl2dppf.CH2Cl2 is added and the mixture is heated under argon at 100 C. for 3 hours. After cooling to room temperature, the reaction mixture is concentrated to dryness and then taken up in a dichloromethane/water mixture. After separation of the phases by settling, the organic phase is washed twice with water and once with saturated aqueous NaCl. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (95/5 to 70/30). 3.1 g of the expected product are obtained in the form of a brown oil, which is used as obtained in the following step. Yield=77%.
58%
With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In propan-1-ol; at 100℃; for 3h;
To 5-bromo-2-nitrophenyl methyl ether (8.0 g, 34.47 mmol) in 80 mL of n-propanol was added, PdCl2(dppf)*DCM (0.5 g, 0.69 mmol), potassium ethenyl(trifluoro)borate (6.47 g, 48.3 mmol), and TEA (3.48 g, 34.47 mmol). The mixture was heated to 100 C. for 3 h. The mixture was poured into 250 mL of H2O and extracted with DCM, dried (Na2SO4), filtered, and rotovaped down, and purified by flash chromatography to give the title compound of step B (3.58 g, 19.98 mmol, 58%). 1H NMR (400 MHz, CDCl3) delta ppm 7.82-7.87 (m, 1H), 7.02-7.07 (m, 2H), 6.70 (dd, J=17.58, 10.80 Hz, 1H), 5.87 (d, J=17.58 Hz, 1H), 5.46 (d, J=10.99 Hz, 1H), 3.97 (s, 3H).
Preparation 37; 2-Methoxy-3- (3-methoxy-4-nitrophenyl) pyrazine (P37); 2,2, 6, 6-Tetramethylpiperidine (0.71 mL, 4.21 mmol) was added to a solution of n- butyllithium (1.6M, 2.6 mL, 4.16 mmol) in tetrahydrofuran (10 mL) at-30C. The mixture was allowed to warm up to 0C and stirred at that temperature for 15 minutes. The solution was then cooled to-70C, a solution of 2-methoxypyrazine (200 mg, 1.80 mmol) in tetrahydrofuran (5 mL) was added and then the mixture stirred at that temperature for 30 minutes. A solution of zinc chloride (500 mg, 3.67 mmol) in tetrahydrofuran (5 mL) was subsequently added at-70C and the mixture was then allowed to warm slowly to room temperature. A solution containing tetrakis (triphenylphosphine) palladium (0) (83 mg, 0.07 mmol) and <strong>[103966-66-1]4-bromo-2-methoxy-1-nitrobenzene</strong> (459 mg, 1.98 mmol) in tetrahydrofuran (5 mL) was added to the organozinc derivative and the mixture heated at 65C for 2 hours. The reaction mixture was then hydrolyse with a solution containing ethylenediaminetetraacetic acid (1.1 g, 3.7 mmol) in water (10 mL) which had been made slightly basic with a saturated aqueous solution of potassium carbonate. The aqueous phase was extracted with dichloromethane (3x100 mL) and the combined extracts dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 0 to 80% ethyl acetate in hexane to yield the title compound as a solid ; MS (APCI+ve) : [M+H] + at m/z 262 (C12H11N304 requires [M+H] + at m/z 262).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;
3-Methoxy-4-bromo nitrobenzene (4.9 g, 21 mmol) was dissolved in 1,2- dimethoxyethane (60 mLl). 2-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- pyridine (5.15 g, 23.5 mmol) was added. Sodium carbonate (5.15 g, 48.5 mmol) was dissolved in minimum amount of water and was added drop wise to the reaction mixture. The reaction mixture was degassed with nitrogen for 45 min. Pd(PPh3)4 (0.732 g, 0.6 mmol) was added under nitrogen. The reaction mixture was then heated overnight at 90 C. After completion of reaction, the reaction mixture was cooled and extracted with ethyl acetate. Purification was done by column chromatography using silica gel (100-200mesh) and 0-2% DCM, MeOH as eluent to give 4-(2-methoxy-4-nitrophenyl)-2-methylpyridine.
At 0 C, sodium metal (1.0 g) was chopped and slowly added to 30 mL.In anhydrous methanol, after 1 h of reaction, 2-fluoro-4-bromo-1-nitrobenzene (10.0 g) was added.After reacting at room temperature overnight, the target product is obtained by post-treatment and separation and purification.(white solid, 9.8 g).
With water; iron; ammonium chloride; In tetrahydrofuran; at 65℃; for 4h;Inert atmosphere;
Step 3 4-bromo-2-methoxyaniline (Compound 12-5) At room temperature, the reduced iron powder (4.48 g, 80 mmol) and ammonium chloride (2.65 g, 50 mmol) were added to a mixed solution of compound 12-4 (2.3 g, 10.0 mmol) in 60 ml of THF/water (volume ratio of THF and water is 2:1), and vigorously stirred at 65 C. for 4 h. After completion of the reaction, the reaction mixture was filtered, the filtrate was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-5 (2.0 g) which was used directly in the next step. MS m/z (ESI): 201.9 [M+H]+.
With ammonium chloride; zinc; In methanol; at 25℃; for 2h;Inert atmosphere;
To a solution of 4-bromo-2-methoxy-1-nitro-benzene (1.07 g, 4.63 mmol, 1 eq) in MeOH (20 mL) was added Zn (3.03 g, 46.30 mmol, 10 eq) and NH4Cl (2.48 g, 46.30 mmol, 1.62 mL, 10 eq). The mixture was stirred at 25 C. for 2 h under N2 atmosphere. The reaction mixture was filtered, concentrated and water (80 mL) was added, extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield 4-bromo-2-methoxy-aniline (830 mg, 4.11 mmol, 88.7% yield, crude) as a black solid which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.89 (d, J=2.2 Hz, 1H), 6.80 (dd, J=2.1, 8.3 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.87 (s, 2H), 3.75 (s, 3H); ES-LCMS m/z 204.0, 206.0 [M+H]+.
7-amino-2-[4-(1-ethylpiperid-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide dihydrochloride[ No CAS ]
7-amino-8-(2-hydroxy-2-methylpropyl)-2-[2-methoxy-4-(piperid-4-yl)phenylamino]-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide dihydrochloride[ No CAS ]
7-amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide dihydrochloride[ No CAS ]
7-amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-methoxyethyl)piperid-4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide dihydrochloride[ No CAS ]
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere;
Argon is bubbled for 10 minutes into a mixture of 4.64 g (20.0 mmol) of the product prepared in step 4.1, 6.25 g (20.2 mmol) of 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (Frontier Scientific) and 8.29 g (60.0 mmol) of potassium carbonate in 125 mL of anhydrous DMF. 0.98 g (1.2 mmol) of PdCl2dppf.CH2Cl2 is added and the mixture is heated under argon at 90 C. for 3 hours. The resulting mixture is diluted with ethyl acetate and washed twice with water and once with saturated aqueous NaCl. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. The crude solid obtained is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (75/25 to 70/30). 6.02 g of a pale yellow solid are obtained, and are triturated in cyclohexane and then drained by suction and dried in an oven. 5.89 g of the expected product are finally recovered in the form of a white solid. Yield=88%.
65%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 90℃;Inert atmosphere;
To a 100 mL flask was added compound 150 <strong>[103966-66-1]4-bromo-2-methoxy-1-nitrobenzene</strong> (1.5 g, 6.46 mmol), 103 N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.199 g, 7.11 mmol), 56 potassium carbonate (2.68 g, 19.39 mmol) and 123 Pd(Ph3P)4 (0.374 g, 0.323 mmol), and then added with 1,4-dioxane. After gas replacement with nitrogen, the mixture was heated under nitrogen atmosphere to 90C and stirred overnight. After TLC indicated the reaction was completed, the reaction mixture was evaporated to remove solvent, diluted with water and extracted with dichloromethane. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and further isolated and purified by column chromatography to give a white solid 151 product (1.72 g, yield 65%). LCMS: t=4.30 min, 279.0 (M-55).
20.6 g
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 100℃; for 5h;Inert atmosphere;
To a mixture of <strong>[103966-66-1]4-bromo-2-methoxy-1-nitrobenzene</strong> (15 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19.99 g), potassium carbonate (9.83 g) and EtOH (150 mL)/toluene (150 mL) was added Pd(PPh3)4 (3.74 g) at room temperature, and the mixture was stirred at 100 C. for 5 hr under argon atmosphere. The impurity was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound (20.6 g). 1H NMR (300 MHz, DMSO-d6) delta1.43 (9H, s), 2.51-2.56 (2H, m), 3.49-3.63 (2H, m), 3.96 (3H, s), 4.00-4.11 (2H, m), 6.33-6.49 (1H, m), 7.16 (1H, dd, J=8.5, 1.7 Hz), 7.30 (1H, d, J=1.6 Hz), 7.87 (1H, d, J=8.5 Hz); MS m/z 235.3 [M+H-Boc]+.
1-[4-(difluoromethoxy)phenyl]prop-2-yn-1-ol[ No CAS ]
[ 103966-66-1 ]
1-(4-(difluoromethoxy)phenyl)-3-(3-methoxy-4-nitrophenyl)prop-2-yn-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 20℃; for 5h;Inert atmosphere;
Under nitrogen protection,A solution of 1- (4- (difluoromethoxy) phenyl) prop-2-yn-l-ol (802 mg, 4.04 mmol)<strong>[103966-66-1]4-bromo-2-methoxy-1-nitrobenzene</strong> (1.05g, 4.52mmol),Pd (PPh3) 2Cl2 (289 mg, 0.40 mmol)And CuI (39.4 mg, 0.20 mmol)Was dissolved in THF (20 mL)Then Et3N (1.20 mL, 8.44 mmol) was added,The reaction was stirred at room temperature for 5 h.The insoluble material was removed by filtration,The filtrate was concentrated,The crude product was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4/1)To give the object as a yellow liquid (1.22 g, 86%).
5-(3-methoxy-4-nitrophenyl)-1-methyl-1H-1,2,3-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.7%
[00112] 1 -Methyl-1 H-1 ,2,3-triazole (41 mg, 0.495 mmol) was dissolved in THF (4.9 mL) and cooled to -78 C. n-Butyllithium solution in hexanes (240 muIota_, 0.594 mmol) was added dropwise and the solution was stirred for further 5 min before zinc(ll) chloride (3.0 mL, 1 .485 mmol) was added. After 30 min at -78 C, the reaction mixture was diluted with DMF (2.0 mL), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and a solution of 4-bromo-2-methoxy-1 -nitrobenzene (1 15 mg, 0.495 mmol) in DMF (500 mu) were added. The solution was stirred at 80 C for 2.5 h. After the mixture was cooled to room temperature, water and EtOAc were added and the phases were separated. The organic phase was washed with water, brine, dried (Na2S04) and the solvent was removed in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc (99/1 to 90/10, 10 g column) to afford the title product as a pale yellow solid (82 mg, 70.7 %). 1 H NMR (500 MHz, CDCI3): <5 4.04 (s, 3H), 4.14 (s, 3H), 7.10-7.13 (m, 2H), 7.82 (s, 1 H), 7.98-8.01 (m, 1 H); LC (Method B)-MS (ESI, m/z) fR 1 .97 min, 235 [(M+H+), 100%].
In 1,2-dimethoxyethane; toluene; at 110℃; for 0.333333h;Microwave irradiation;
General procedure: A mixture of nitrobenzene (0.3 mmol), sodium tert-butoxide (7.0 equiv.), in dry toluene (1.5mL) or in dry toluene/dry DME (9:1) was reacted in a microwave reactor. The reaction mixturewas diluted with DCM, filtered through Celite, and concentrated under reduce pressure.The crude material was purified by flash column chromatography (mobile phase: 0±100%ethyl acetate gradient in hexanes) to give the product.
1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butyl)-1H-imidazole[ No CAS ]
[ 103966-66-1 ]
C20H21N3O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
General procedure: [00128] FiG, SB is a synthetic scheme for various substituted biphenyl linker antifungal compounds, which was used to produce Compounds lOb, lOc, 101, and lOj. Biphenyl linkers in these compounds were substituted ortho to the amidine group, Generally, reagents and conditions for synthesis of compounds according to F1G SB included: a) dibromoalkane, K2C03, CH3CN. refiux; b) imidazole, K2C03, CH3CN. refiux; c) 23a,b, Pd[P(Ph)314, K2C03, DMF, 100C; d) SnCI2.2H20. EtOAc, refiux; e) S-(2-naphthyimethyl)-2-pyridyithioimidate hydrobromide, CH3CN/EtOH (1:3), rt.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
General procedure: FIG. 63B is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds, which was used to produce Compounds 10b, 10c, lOi, and lOj. Biphenyl linkers in these compounds were substituted or (ho to the amidine group. Generally, reagents and conditions for synthesis of compounds according to FIG. 6B included: a) dibromoalkane, K2CO3, CH3CN, reflux; b) imidazole, 2C03, CH3CN, reflux; c) 23a,b, Pd|;P(Ph)3]4, K2C03, DMF, 100C; d) SnCl2.2H20, EtOAc, reflux; e) 5-(2-naphthylmeihyl)-2-pyndylihioimidate hydrobromide, CH3CN/EtOH (1 :3), rt.
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃;
Compound 4j was made according to FIG. 33B. Generally, reagents and conditions for synthesis of compounds according to FIG. 3B included: a) Pd(PPh3)4, dioxane, 90C; b) NBS, DMF, rt; c) K2C03, Cs2C03, DMA, rt; d) Pd(PPh3)4, K2C03, MeOH, toluene, 80C; e) imidazole, NaH, DMF, rt; f) H2, Pd(C), EtOH-EtOAc; g) (1) ,S'-(2-naphthylmethyl)-2- pyndylthioimidate hydrobromide, EtOH; (ii) NaOH.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water;Reflux;
<strong>[103966-66-1]2-methoxy-4-bromo-1-nitrobenzene</strong> (3.0 g),4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)-1,3,2-dioxaborolane(3.8 grams),Pd(dppf)Cl2 (950 mg) and sodium carbonate (3.5 g) were added in sequenceIn a mixed solvent of 1,4-dioxane and water, heated to reflux overnight.The solvent was concentrated under reduced pressure, and the residue was evaporated.After drying and concentration with anhydrous sodium sulfate, the obtained residue was subjected to flash chromatography on silica gel.(petroleum ether: ethyl acetate, 2:1, v/v), isolated and purified to obtain the desired product(yellow solid, 3.5 g).
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