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Oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride

oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride

4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine

4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl amine

→

N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide

수율 30.5%

용매

toluene

pyridine

반응 조건

후처리

1. 1
   기타then quenched slowly into cold water (3 L)
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   여과The precipitated solid was filtered
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   세척washed with water (3×50 mL)
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   workup.DISSOLUTIONThe solid was dissolved in chloroform (200 mL)
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   세척washed successively with bicarbonate solution (3×200 mL) and brine (200 mL)
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   기타The chloroform layer was separated
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   workup.ADDITIONdiluted with chloroform (800 mL)
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   workup.ADDITIONto this was added neutral alumina (150 g) and charcoal (5 g)
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   workup.STIRRINGThe mixture was stirred for 2 hours at room temperature
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    여과then filtered through celite
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    workup.STIRRINGstirring
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    여과Filtration and concentration
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    기타gave a solid which
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    추출extracted with 25% aqueous acetic acid solution (3×500 mL)
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    추출extracted with diethyl ether (2×300 mL)
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    세척The combined ether extracts were washed with bicarbonate solution (2×200 mL), brine (200 mL)
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    건조dried over sodium sulfate
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    농축concentrated in vacuo
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    기타to give a solid
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    기타This was further purified
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    세척eluting with 30% ethyl acetate in chloroform
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    농축After concentration
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    workup.DISSOLUTIONthe solid was dissolved
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    온도at reflux in ethanol (300 mL)
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    workup.STIRRINGstirred for 15 minutes, whereupon the precipitated solid
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    여과was filtered
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    기타dried on the sinter
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    기타Further drying at 60° C. under high vacuum

실험 절차

Oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 40 g, 0.14 mol) was added portion-wise to a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 94, 18 g, 63.8 mmol) in pyridine (150 mL). The reaction mass was stirred for 1 hour then quenched slowly into cold water (3 L). The precipitated solid was filtered and washed with water (3×50 mL). The solid was dissolved in chloroform (200 mL) and washed successively with bicarbonate solution (3×200 mL) and brine (200 mL). The chloroform layer was separated, diluted with chloroform (800 mL), and to this was added neutral alumina (150 g) and charcoal (5 g). The mixture was stirred for 2 hours at room temperature then filtered through celite. The treatment was repeated with another 75 g of neutral alumina with over night stirring. Filtration and concentration gave a solid which was dissolved in toluene (500 mL) and extracted with 25% aqueous acetic acid solution (3×500 mL). The combined aqueous layers were basified with 25% ammonium hydroxide solution (2 L) to pH ˜7 and extracted with diethyl ether (2×300 mL). The combined ether extracts were washed with bicarbonate solution (2×200 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give a solid. This was further purified by passing through a short silica pad (60-120 silica gel) eluting with 30% ethyl acetate in chloroform. After concentration, the solid was dissolved at reflux in ethanol (300 mL). The solution was cooled to 0° C., and stirred for 15 minutes, whereupon the precipitated solid was filtered and dried on the sinter. Further drying at 60° C. under high vacuum afforded the title compound N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (10.4 g, 30.5%) as a yellow powder.

출처