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Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78℃; for 0.5 h;
To a stirred solution of 3-bromo-4-methylthiophene (2.7 g, 15.6 mmol) in THF (35 mL) was added n-BuLi (1.6 M in hexane, 14.6 mL, 23.3 mmol) at -78 °C dropwise over a period of 15 min and the mixture was stirred at -78 °C for 30 min. The C02 (gaseous) was passed through the reaction mixture for 10 min and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was warmed to 0 °C, quenched with aqueous 1 M NaOH (60 mL) and washed with EtOAc (2 x 50 mL). The aqueous layer was acidified to pH ~ 5 and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 8percent MeOH/DCM as eluent) to provide compound A56-1 (1.5 g^ 70percent) as a white solid
The solvent in the washings was distilled off, and to the residue was added 5 ml of water, 5 ml of acetic acid and 5 ml of conc. sulfuric acid, and then the mixture was stirred for 3.5 hours at 135 C. After cooling, the mixture was extracted with ether. The ether layer was extracted with 10% aqueous sodium hydroxide. The aqueous layer was acidified with dilute hydrochloric acid, and extracted again with ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was washed with petroleum ether to obtain 1.57 g of desired compound 19 (total yield: 83%). mp: 137-138 C. 1 H-NMR:delta(CDCl3) 2.49(3 H,d,J=0.8 Hz) 6.94-6.98(1 H,m) 8.24(1 H,d,J=3.6 Hz) ppm. STR53
5
[ 73229-39-7 ]
[ 78071-30-4 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride;
Step 1 (4-Methylthiophen-3-carboxylic acid: 19) A mixture of 8.30 g (67.4 mmol) of 3-cyano-4-methylthiophene [J. W. Terpstra and A. M. von Leusen, J. Org. Chem., 51, 230 (1986)] and 83 ml of concentrated hydrochloric acid was heated under reflux for 40 hours. After cooling, the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was washed with petroleum ether to obtain 6.40 g of desired compound 19.
With potassium carbonate; In N,N-dimethyl-formamide;
4) These compounds were synthesised in the following manner. 5-Chloro-4-methyl-3-thiophenecarboxamide and 2,5-dichloro-4-methyl-3-thiophenecarboxamide <strong>[78071-30-4]4-Methyl-3-thiophenecarboxylic acid</strong> (1.42 g) (synthesised in accordance with the method described in J. Org. Chem., 51, 230 (1986)) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.8 ml) and potassium carbonate (1.38 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water. and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-methyl-3-thiophenecarboxylate (1.7 g).
[00329j Synthesis of compound 9.9. A 250-mL 3-necked round-bottom under nitrogen was charged with bis(propan-2-yl)amine (7.0 g, 69.18 mmol, 2.02 equiv) and tetrahydrofuran (100 mL). To the solution was added n-BuLi (33.2 mL) drop wise while stirring at -30 C. The solution was then warmed up and stirred for 0.5 hours at -10 C. Compound 9.8 (4.88 g, 34.32 mmol, 1.00 equiv) in THF (25 mL) was added then slowly while stirring at -78C, followed by addition of HMPA solution (1.23 g, 6.86 mmol, 0.20 equiv) in THF (5 mL). Reaction was stirred for 1 hour at -78C. To this mixture was added a solution of compound 9.4 (9.2 g, 41.21 mmol, 1.20 equiv) in THF (25 mL) drop wise with stirring at -78C. Reaction was stirred for 45 mm at room temperature and then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3x 100 mL of ethyl acetate, organic layers were combined and solvents were removed under reduced pressure. . The crude was purified using flash column chromatography to provide 10 g (96%) of compound 9.9 as yellow oil.
With water; sodium hydroxide; In methanol; at 20℃; for 2h;
[00328j Synthesis of compound 9.8. A 250-mL round-bottom flask, was charged with compound 9.7 (11.0 g, 64.6 mmol, 1.00 equiv), methanol (60 mL), water (30 mL), sodium hydroxide (6.0 g, 150.01 mmol, 2.32 equiv). The resulting solution was stirred for 2 h at room temperature. Mixture was then concentrated under reduced pressure and the pH value of the solution was adjusted to 3 with HC1. Resulting solids were collected by filtration to provide 8.0 g (87%) of compound 9.8 as a white solid.
trans-4-(4-((3,5-difluorobenzyl)(-2-(2,4-dimethylthiophen-3-yl)-2-hydroxyethyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclohexanecarboxylate[ No CAS ]
trans-4-(4-((3,5-difluorobenzyl)(2-(2,4-dimethylthiophen-3-yl)-2-oxoethyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclohexanecarboxylate[ No CAS ]
trans-4-(4-((3,5-difluorobenzyl)(2-(2,4-dimethylthiophen-3-yl)-2-oxoethyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclohexanecarboxylate[ No CAS ]
To a solution of 4-methylthiophene- 3-carboxylic acid (0.5 g, 3.5 mmol) in THF (20 ml) was added n-butyllithium (1.6 M in hexanes, 5 ml, 8.0 mmol) dropwise at -78C under N2 atmosphere. The resulting reaction mixture was stirred at -78C for 30 min. A solution of iodomethane (0.24 ml, 3.8 mmol) in THF (20 ml) was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at -78C for 30 min then allowed to warm to room temperature. The reaction mixture was poured into saturated ammonium chloride (50 ml) and the resulting solution / suspension concentrated under vacuum. The aqueous was extracted with DCM (70 ml) and filtered under reduced pressure. The filtrate was concentrated under vacuum. The crude was purified by trituration using diethyl ether (2 x 20 ml) then concentrated under vacuum to give the title compound as an off-white solid. Y = 74 %. NMR (400 MHz, DMSO-) delta 12.64 (s, 1H), 6.93 (d, J= 1Hz, 1H), 2.58 (s, 3H), 2.28 (s, 3H).
57%
To a stirred solution of compound A56-1 (390 mg, 2.7 mmol) in THF (4 mL) was added n-BuLi (1.6 M in hexane, 3.8 mL, 6.0 mmol) dropwise at -78 C for 10 min. The mixture was stirred at -78 C for 5 min. A solution of iodomethane (0.4 mL, 6.8 mmol) in THF (1 mL) was added dropwise, and the reaction mixture was stirred at -78 C for 30 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 15 h. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2% MeOH/DCM as eluent) to provide compound A56-2 (246 mg, 57%) as a white solid.
To a stirred solution of 3-bromo-4-methylthiophene (2.7 g, 15.6 mmol) in THF (35 mL) was added n-BuLi (1.6 M in hexane, 14.6 mL, 23.3 mmol) at -78 C dropwise over a period of 15 min and the mixture was stirred at -78 C for 30 min. The C02 (gaseous) was passed through the reaction mixture for 10 min and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was warmed to 0 C, quenched with aqueous 1 M NaOH (60 mL) and washed with EtOAc (2 x 50 mL). The aqueous layer was acidified to pH ~ 5 and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 8% MeOH/DCM as eluent) to provide compound A56-1 (1.5 g^ 70%) as a white solid
ethyl 1-(6-(3-(((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)methyl)-4-methylthiophen-2-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate[ No CAS ]
1-(6-(3-(((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)methyl)-4-methylthiophen-2-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid[ No CAS ]
2-bromo-4-methylthiophene-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Intermediate 3-6-A. 2-Bromo-<strong>[78071-30-4]4-methylthiophene-3-carboxylic acid</strong>To a solution of 1 M LDA in THF (14.77 ml, 14.77 mmol) at -78 C was added a solution of <strong>[78071-30-4]4-methylthiophene-3-carboxylic acid</strong> (CAS 78071 -30-4, 1 g, 7.03 mmol) in THF (5 mL) over 0.25 h, and then the mixture was stirred at -78 C for 0.5 h. To the solution was then added a solution of CBr4 (2.57 g, 7.74 mmol) in THF (8 mL) dropwise over 15 min. The mixture was then stirred at -78 C for 0.5 h, and then allowed to warm to room temperature over 1 h. The reaction was then quenched with 1 N HCI until the pH reached 1 . The mixture was then extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2S04, filtered, and then concentrated. The resulting residue was purified by silica gel flash column chromatography (hexane/EtOAc=1/0 to 0/1 ) to afford the title compound. 1H-NMR (400 MHz, CDCI3) delta 6.92 (s, 1 H), 2.45 (s, 3H).
1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)methyl)-4-methylthiophen-2-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid[ No CAS ]
ethyl 1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenoxy)methyl)-4-methylthiophen-2-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate[ No CAS ]