반응 #44643

반응 방정식

methylene chloride

3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylic acid methyl ester

→

title compound

(6S,9aR)-6-(4-chlorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one

용매

triethylamine

반응 조건

후처리

1. 1
   온도under reflux for 3 hr
2. 2
   기타The resulting reaction solution
3. 3
   농축concentrated under reduced pressure
4. 4
   온도Similarly, in nitrogen atmosphere, a methylene chloride solution (100 mL) of the high polar isomer (1.10 g) of 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylic acid methyl ester and Grubbs catalyst second generation (268 mg) was heated
5. 5
   온도under reflux for 3 hr
6. 6
   온도to cool to room temperature
7. 7
   workup.ADDITIONtriethylamine (0.44 mL) was added
8. 8
   기타The resulting reaction solution
9. 9
   workup.STIRRINGwas stirred at room temperature for 10 min
10. 10
    농축concentrated under reduced pressure
11. 11
    기타purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system)

실험 절차

Triethylamine (2.20 mL), vinylacetic acid (1.16 mL), and BOPCl (3.47 g) were sequentially added to a THF solution of [(2R,6S)-6-(4-chlorophenyl)piperidin-2-yl]methanol (2.36 g). The resulting reaction solution was stirred at room temperature for 5 hr, and then ethyl acetate and toluene were added thereto. The organic layer was separated, washed with 0.5 N hydrochloric acid, a 0.5 N sodium hydroxide aqueous solution, a saturated sodium hydrogencarbonate aqueous solution, and saturated saline in this order, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-[(2S,6R)-2-(4-chlorophenyl)-6-(hydroxymethyl)piperidin-1-yl]-(3-buten)-1-one. In nitrogen atmosphere, DMSO (1.04 mL) was added to a dichloromethane solution (70 mL) of oxalyl chloride (1.20 mL) over 5 min at −78° C. The resulting reaction solution was stirred at −78° C. for 10 min, and then a dichloromethane solution (10 mL) of the above-given 1-[(2S,6R)-2-(4-chlorophenyl)-6-(hydroxymethyl)piperidin-1-yl]-(3-buten)-1-one was added thereto over 20 min at −78° C. The resulting reaction solution was stirred at −78° C. for 20 min, and triethylamine (7.64 mL) was added thereto over 10 min at −78° C. The resulting reaction solution was stirred for 1 hr at −75° C. to −50° C. Then, the reaction solution was added to water. The resulting mixture was extracted with ethyl acetate, and the obtained extract solution was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. Trimethyl phosphonoacetate (2.73 mL) was added to a THF (50 mL)-DMF (10 mL) solvent mixture of 60% sodium hydride (413 mg) at 0° C. The resulting reaction solution was stirred at room temperature for 30 min. To this reaction solution, a THF solution (10 mL) of the above-given residue (2.41 g) was added at 0° C. The resulting reaction solution was stirred at room temperature for 30 min, and then a cooled ammonium chloride aqueous solution was added thereto. The resulting mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent:heptane-ethyl acetate system) to give 0.65 g of a low polar isomer and 1.10 g of a high polar isomer of 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylic acid methyl ester. In nitrogen atmosphere, a methylene chloride solution (60 mL) of the low polar isomer (0.65 g) of 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylic acid methyl ester and Grubbs catalyst second generation (158 mg) was stirred under reflux for 3 hr. The reaction solution was allowed to cool to room temperature, and triethylamine (0.26 mL) was added thereto. The resulting reaction solution was stirred at room temperature for 10 min and concentrated under reduced pressure. Similarly, in nitrogen atmosphere, a methylene chloride solution (100 mL) of the high polar isomer (1.10 g) of 3-[(2R,6S)-1-(3-butenoyl)-6-(4-chlorophenyl)piperidin-2-yl]acrylic acid methyl ester and Grubbs catalyst second generation (268 mg) was heated under reflux for 3 hr. The reaction solution was allowed to cool to room temperature, and triethylamine (0.44 mL) was added thereto. The resulting reaction solution was stirred at room temperature for 10 min and concentrated under reduced pressure. The residues of both isomers were combined and purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to give 1.09 g of the title compound. The physical property values of this compound were as follows:

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