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With triethylamine; In hexane; water; ethyl acetate;
Synthesis Example 2 Synthesis of 4-methyl-tetrahydro-2H-thiopyran-4-yl methacrylate (thiopyran derivative of the following formula 3) To a 200-mL three-necked flask fitted with a stirrer bar coated with Teflon, were added 5.95 g of 4-hydroxy-4-methyltetrahydrothiopyran (manufactured by SANKYO KASEI Co., Ltd.), 5.08 g of triethyl amine, and 50 mL of dried methylene chloride, and the mixture was stirred under nitrogen atmosphere at 0 C. To the mixture, 5.0 g of methacryloyl chloride was slowly added through a dropping funnel, and the resulted mixture was reacted at 0 C. for 30 minutes, allowed to warm to room temperature, and was further reacted for another 5 hours. After confirming loss of the starting material by TLC, the reaction solution was poured in a 300-mL separatory funnel, washed with 100 mL of water followed by with 100 mL of saturated NaCl solution (brine), and dried with anhydrous sodium sulfate. From the obtained solution, the solvent was removed by an evaporator, to obtain an oily crude product. The crude product was purified by silica gel chromatography using a mixed solution of n-hexane and ethyl acetate to give 5.89 g of 4-methyl-tetrahydro-2H-thiopyran-4-yl methacrylate (thiopyran derivative of the following formula 3) (yield: 59.4%).
6.19 parts of the salt represented by (I-23-a) and 30 parts of chloroform were mixed and stirred at 23 C. for 30 minutes. To the obtained mixed solution, 1.78 parts of the compound represented by the formula (I-1-b) was added, and the mixture was further stirred at 50 C. for 2 hours. To the obtained mixed solution, 1.32 parts of the compound represented by the formula (I-4-c) was added, and the mixture was further stirred at 50 C. for 3 hours and then cooled to 23 C. To the obtained mixture, 15 parts of a 5% aqueous oxalic acid solution was added, and the mixture was stirred at 23 C. for 30 minutes and then separated to remove the organic layer. After adding 15 parts of ion-exchanged water to the obtained organic layer and stirring at 23 C. for 30 minutes, the liquid was separated and the organic layer was taken out. This washing operation was repeated 5 times. The obtained organic layer was concentrated, 30 parts of tert-butyl methyl ether was added to the concentrated residue, and the mixture was stirred at 23 C. for 30 minutes, and then the supernatant was removed and concentrated to obtain the formula (I-24). 2.13 parts of salt represented by.
.36 parts of the salt represented by (I-71-a) and 30 parts of chloroform were mixed and stirred at 23 C. for 30 minutes. To the obtained mixed solution, 1.78 parts of the compound represented by the formula (I-1-b) was added, and the mixture was further stirred at 50 C. for 2 hours. To the obtained mixed solution, 1.32 parts of the compound represented by the formula (I-4-c) was added, and the mixture was further stirred at 50 C. for 3 hours and then cooled to 23 C. To the obtained mixture, 15 parts of a 5% aqueous oxalic acid solution was added, and the mixture was stirred at 23 C. for 30 minutes and then separated to remove the organic layer. After adding 15 parts of ion-exchanged water to the obtained organic layer and stirring at 23 C. for 30 minutes, the liquid was separated and the organic layer was taken out. This washing operation was repeated 5 times. The obtained organic layer was concentrated, 30 parts of tert-butyl methyl ether was added to the concentrated residue, and the mixture was stirred at 23 C. for 30 minutes, and then the supernatant was removed and concentrated to obtain the formula (I-72). 3.33 parts of salt represented by is obtained.
6.72 parts of the salt represented by (I-95-a) and 30 parts of chloroform were mixed and stirred at 23 C. for 30 minutes. To the obtained mixed solution, 1.78 parts of the compound represented by the formula (I-1-b) was added, and the mixture was further stirred at 50 C. for 2 hours. To the obtained mixed solution, 1.32 parts of the compound represented by the formula (I-4-c) was added, and the mixture was further stirred at 50 C. for 3 hours and then cooled to 23 C. To the obtained mixture, 15 parts of a 5% aqueous oxalic acid solution was added, and the mixture was stirred at 23 C. for 30 minutes and then separated to remove the organic layer. After adding 15 parts of ion-exchanged water to the obtained organic layer and stirring at 23 C. for 30 minutes, the liquid was separated and the organic layer was taken out. This washing operation was repeated 5 times. The obtained organic layer was concentrated, 30 parts of tert-butyl methyl ether was added to the concentrated residue, and the mixture was stirred at 23 C. for 30 minutes, and then the supernatant was removed and concentrated to obtain the formula (I-96). 4.01 parts of salt represented by is obtained.
4.92 parts of the salt represented by (I-73-a) and 30 parts of chloroform were mixed and stirred at 23 C. for 30 minutes. To the obtained mixed solution, 1.78 parts of the compound represented by the formula (I-1-b) was added, and the mixture was further stirred at 50 C. for 2 hours. To the obtained mixed solution, 1.32 parts of the compound represented by the formula (I-4-c) was added, and the mixture was further stirred at 50 C. for 3 hours and then cooled to 23 C. To the obtained mixture, 15 parts of a 5% aqueous oxalic acid solution was added, and the mixture was stirred at 23 C. for 30 minutes and then separated to remove the organic layer. After adding 15 parts of ion-exchanged water to the obtained organic layer and stirring at 23 C. for 30 minutes, the liquid was separated and the organic layer was taken out. This washing operation was repeated 5 times. The obtained organic layer was concentrated, 30 parts of tert-butyl methyl ether was added to the concentrated residue, and the mixture was stirred at 23 C. for 30 minutes, and then the supernatant was removed and concentrated to obtain the formula (I-76). 2.69 parts of salt represented by is obtained.
4.38 parts of the salt represented by (I-1-a) and 30 parts of chloroform were mixed and stirred at 23 C. for 30 minutes. To the obtained mixed solution, 1.78 parts of the compound represented by the formula (I-1-b) was added, and the mixture was further stirred at 50 C. for 2 hours. To the obtained mixed solution, 1.32 parts of the compound represented by the formula (I-4-c) was added, and the mixture was further stirred at 50 C. for 3 hours and then cooled to 23 C. To the obtained mixture, 15 parts of a 5% aqueous oxalic acid solution was added, and the mixture was stirred at 23 C. for 30 minutes and then separated to remove the organic layer. After adding 15 parts of ion-exchanged water to the obtained organic layer and stirring at 23 C. for 30 minutes, the liquid was separated and the organic layer was taken out. This washing operation was repeated 5 times. The obtained organic layer was concentrated, 30 parts of tert-butyl methyl ether was added to the concentrated residue, and the mixture was stirred at 23 C. for 30 minutes, and then the supernatant was removed and concentrated to obtain the formula (I-4). 1.98 parts of salt represented by is obtained.
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