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Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -65℃; for 0.5 h; Stage #2: With triethylamine In dichloromethane at -65℃; for 0.25 h;
trans-4-Formyl-cyclohexanecarboxylic acid methyl ester To a solution of dimethylsulfoxide (9.53 g, 122 mmol) in dry dichloromethane (400 ml) was slowly added oxalyl chloride (7.74 g, 61.0 mmol) at -78° C. The cooling bath was removed and the reaction mixture was stirred at -50° C. for 5 min. A solution of trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (8.75 g, 50.8 mmol) in dichloromethane (108 ml) was added at -65° C. Stirring for 30 minutes was followed by addition of triethylamine (25.7 g, 254 mmol). The cooling bath was removed 15 minutes after completed addition. The reaction mixture was quenched with 1 M aqueous hydrochloric acid solution (152 ml, 152 mmol) at -10° C. The layers were separated. The organic layer was washed with two 250 ml-portions of water and one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as yellow oil (9.3 g, quantitative), which was used in the next step without further purification. MS m/e: 170 (M+)
91%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60℃; for 1.75 h; Stage #2: With triethylamine In dichloromethane at -60 - 0℃; for 1.5 h;
(4) Under argon gas atmosphere to a solution of oxalyl chloride (4.48 mL) in methylene chloride (50 mL) was added dropwise a solution of dimethysulfoxide (4.55 g) in methylene chloride (5 mL) at -60 °C and the mixture was stirred at the same temperature for 15 minutes. To the mixture was added dropwise a solution of the compound obtained in the above step (3) (5.9 g) in methylene chloride (30 mL) over a period of 30 minutes and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise triethylamine (16.7 mL) at -60 °C and the mixture was stirred at the same temperature for 30 minutes and then stirred at 0 °C for 1 hour. The reaction mixture was diluted with chloroform, washed successively with water, an aqueous 5 percent citric acid, water and brine, dried over sodium sulfate and concentrated in vacuo to give methyl trans-4-formylcyclohexanecarboxylate (5.32 g, yield: 91 percent) as an oil.
Stage #1: With hydrogenchloride In tetrahydrofuran; water at 0 - 5℃; for 4 h; Stage #2: With potassium hydroxide In methanol at 5 - 10℃; for 4 h;
To 1L to three-opening bottle 0.42mol(I-B-c) and 210 ml tetrahydrofuran, three of the salt bath the solution in the bottle cooling to 0 °C; while maintaining the three port to the temperature of the solution in the bottle 0 °C -5 ° C under the condition of, instillment by in the bottle to the three port 50 ml concentrated hydrochloric acid and 50 ml of water, a mixed solution, after dripping maintaining the three port to the temperature of the solution in the bottle 0 °C -5 ° C stirring 4h; to the three-hole bottle is then added to 200 ml of methylene chloride and 200 ml water to liquid processing; finally, the liquid after treatment after the conventional treatment of the product, the formyl cyclohexyl carboxylic acid methyl ester (trans 75percent), the spare. 1L flask was added to the other three 200mL 0.21mol anhydrous methanol and potassium hydroxide, stirring hydroxidePotassium is dissolved, then cooling the solution bottle three to 5 ° C the temperature of the solution bottle holding three T<10 ° C Under the conditions, the three bottle before the dropwise addition of the standby formyl methyl cyclohexyl, aftercompletion of the dropwise addition, Holding three bottles solution temperature T <10 ° C was stirred for 4h After thereaction, the resulting reaction product was subjected to routine We were treated to give the transformylcyclohexylcarboxylate (IBd)0.4mol, yield 95.2percent, GC: 93.2percent.
trans-4-Formyl-cyclohexanecarboxylic acid methyl ester To a solution of dimethylsulfoxide (9.53 g, 122 mmol) in dry dichloromethane (400 ml) was slowly added oxalyl chloride (7.74 g, 61.0 mmol) at -78 C. The cooling bath was removed and the reaction mixture was stirred at -50 C. for 5 min. A solution of <strong>[110928-44-4]trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester</strong> (8.75 g, 50.8 mmol) in dichloromethane (108 ml) was added at -65 C. Stirring for 30 minutes was followed by addition of triethylamine (25.7 g, 254 mmol). The cooling bath was removed 15 minutes after completed addition. The reaction mixture was quenched with 1 M aqueous hydrochloric acid solution (152 ml, 152 mmol) at -10 C. The layers were separated. The organic layer was washed with two 250 ml-portions of water and one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as yellow oil (9.3 g, quantitative), which was used in the next step without further purification. MS m/e: 170 (M+)
91%
(4) Under argon gas atmosphere to a solution of oxalyl chloride (4.48 mL) in methylene chloride (50 mL) was added dropwise a solution of dimethysulfoxide (4.55 g) in methylene chloride (5 mL) at -60 C and the mixture was stirred at the same temperature for 15 minutes. To the mixture was added dropwise a solution of the compound obtained in the above step (3) (5.9 g) in methylene chloride (30 mL) over a period of 30 minutes and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise triethylamine (16.7 mL) at -60 C and the mixture was stirred at the same temperature for 30 minutes and then stirred at 0 C for 1 hour. The reaction mixture was diluted with chloroform, washed successively with water, an aqueous 5 % citric acid, water and brine, dried over sodium sulfate and concentrated in vacuo to give methyl trans-4-formylcyclohexanecarboxylate (5.32 g, yield: 91 %) as an oil.
With Dess-Martin periodane; In tetrahydrofuran; at 0 - 20℃; for 3h;
[00216] Step 2: To a solution of Dess-Martin periodinane (542 mg, 1.28 mmol) in THF (2 mL) was added methyl £raws-4-(hydroxymethyl)cyclohexanecarboxylate (200 mg, 1.18 mmol) at 0 C, and the reaction mixture was then stirred at 20 C for 3 hours before the addition of saturated aqueous sodium thiosulfate solution (50 mL). The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate / petroleum ether) to give methyl iraws-4-formylcyclohexanecarboxylate. MS ESI calc'd. for C9H1503[M + H]+ 171, found 171. *H NMR: (400 MHz, CDC13) delta 9.63 (s, 1H), 3.68 (s, 3H), 2.36 - 2.17 (m, 2H), 2.13 - 2.04 (m, 4H), 1.55 - 1.45 (m, 2H), 1.37 - 1.25 (m, 2H).
Under the protection of argon,DMSO (3.12g, 40mmol) was added to DCM (50ml),After stirring for 10min, cool to -78 ,Add oxalyl chloride (2.54g, 20mmol) dropwise,Add 10 minutes to stir,A solution of compound 4 (3.44g, 20mmol) in DCM was added dropwise,After stirring for 10min,Slowly add triethylamine (5.26g, 52mmol),After stirring for 10 minutes, move to room temperature and continue stirring for about 30 minutes.Add DCM and water to quench, extract, dry, and concentrate to obtain an oily liquid.
methyl trans-4-[(5-chloropyrimidin-2-yl)(hydroxy)methyl]cyclohexanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 2h;
[00217] Step 3 : To a mixture of methyl iraws-4-formylcyclohexanecarboxylate (150 mg, 0.88 mmol) and <strong>[874676-81-0]5-chloro-2-iodopyrimidine</strong> (210 mg, 0.88 mmol) in THF (4 mL) at -78 C was added w-butyllithium (2.5 M in hexanes, 0.35 mL, 0.88 mmol) dropwise. The reaction mixture was stirred at -78 C for 2 hours and then saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate / petroleum ether) to afford methyl £raws-4-[(5-chloropyrimidin-2- yl)(hydroxy)methyl]cyclohexanecarboxylate. MS ESI calc'd for C13H18CI 2O3 [M + H]+ 285, found 285. 'H NMR: (400 MHz, CDC13) delta 8.70 (s, 2H), 4.68 (s, 1H), 3.65 (s, 3H), 2.24 (s, 1H), 2.03 - 1.82 (m, 3H), 1.48 - 1.42 (m, 3H), 1.31 - 1.27 (m, 3H).
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