| Summary: | 碩士 === 國立臺灣大學 === 藥學研究所 === 82 === 2,6-雙取代-4-芳香基-1,4-二氫仳啶-3,5-雙羧酸雙酯類化合物 (1)是當
今最有效的鈣離子通道阻斷劑 (鈣離子拮抗劑)。合成這一類化合物最通
用的方法為Hantzsch 反應，它是一種由乙醯乙酸酯，醛及氨氣等所進行
的縮合反應。有機金屬與啶類衍生物之親核性反應， 在文獻中已有相
當廣泛的研究報導。 但據我們所知，以有機金屬加成至啶類衍生物的
方法，尚未被成功地應用於合成具有活性亦即具有 2,6-雙甲基取代的二
氫啶類化合物.我們為了以親核性反應合成具 2,6-雙甲基取代的二氫仳
啶類化合物，首先合成了 5-(4,4-雙甲基-4,5-二氫-2-愕唑基)-2,6-雙甲
基-菸鹼酸乙酯 (6)。 再以化合物6與苯基鋰反應。但並沒有如同2,6位置
無取代之仳啶類化合物 10一樣得到二氫仳啶類似物11，卻產生
[(5-(4,4-雙甲基-4,5-二氫-2-愕唑基)-2,6-雙甲基-3-仳啶基]-苯基-甲
酮 (13)與 [(5-(4,4-雙甲基-4,5-二氫-2-愕唑基)-2,6-雙甲基-3-仳啶基
]-雙苯基-甲醇 (14) 等與酯基反應的化合物；另一個實驗方向則為利用
四級化仳啶之氮原子來活化仳啶環。我們氧化1,2,6-三甲基-1,4-二氫仳
啶-3,5-雙羧酸雙乙酯 (17)得到氯化仳錠衍生物 18。 再將化合物 18
4-苯基-1,4-二氫仳啶-3,5-雙羧酸雙乙酯 (19)。化合物19的合成，提供
了利用有機金屬與仳啶類衍生物反應,以合成二氫仳啶類化合物的可能路
徑。
2,6-Disubstituted-4-aryl-1,4-dihydropyridine-3,5-dicarboxylic
diesters (1) are the most effective of the calcium antagonists
or calcium channel blockers. Among the many methods for the
synthesis of dihydropyridines, the Hantzsch reaction invloving
condensation of acetoacetic esters with an aldehyde and ammonia
has been conveniently used for the preparation of these The
nucleophilic addition of organometallic reagents to pyridine
derivatives has been well studied. H owever, the pharmacologi-
cally more important dihydropyridines with methyl substituents
in position 2 and 6 have not been synthesized via addition of
organometallics to pyridines. As our first attempt towards the
synthesis of 2,6-disubstituted dihydropyridines, we have
synthesized-4,5-dihydro- oxazol-2-yl)-2,6-dimethyl-nicotinic
acid ethyl ester (6), and reacted it with phenylithium. Unlike
its 2,6-unsubstituted ana- log (10), no dihydropyridine was
formed,and the isolated products [5-(4,4-dimethyl-4,5-dihydro-
oxazol-2-yl)-2,6-dimethyl-pyridin-3- yl]-phenyl-methanone (13)
andl-4,5-dihydro-oxazol- 2-yl)-2,6-dimethylpyridin-3-yl]-
diphenylmethanol (14) resulted from reaction at the ester
group. To test the alternative approach of activating the
pryidine ring via quarternization of the nitrogen, we have
prepared pyridinium chloride 18, the oxidation product of
1,2,6-trimethyl-1,4-dihydropyridine-3,5-di- carboxylic acid
diethyl ester (17). When 18 was reacted with phenylmagnesium
bromide in the presence of cuprous iodide, 1,2,6-trimethyl-4-
phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester
(19) was formed in significant yield. The successful
preparation of dihydropyridine 19 opens up the possibility of
synthesizing pharmacologically meaningful dihydropyridines via
the addition of organometallics to pyridine derivatives.
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