Pyrrolidines. VII. 3-Hydroxy-1-Pyrrolidinecarboxylic Acid Esters
Pyrrolidines. VII. 3-Hydroxy-1-Pyrrolidinecarboxylic Acid Esters
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吡咯烷类。
DOI：
10.1021/jm01239a007
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发表时间：
1962
期刊：
影响因子：
--
通讯作者：
R. Feldkamp
中科院分区：
文献类型：
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作者：
Yao;W. Gould;W. G. Lobeck;H. R. Roth;R. Feldkamp
我们用这两种方法制备了4-氧代-1，3-吡咯烷二甲酸二乙酯。两种方法所得产物的物理常数基本相同。将Kuhn和Osswald方法扩展用于合成十二种4-氧代-1，3-吡咯烷二羧酸烷基乙酯。它们的物理性质列于表I中。与Kuhn和Osswald使用的浓盐酸不同，我们发现，极稀（0.4%）的盐酸是催化这些环状α-酮基酯水解和脱羧所必需的。3-氧代-1-吡咯烷羧酸烷基酯的物理性质在表II中给出。这些3-氧代-1-吡咯烷羧酸烷基酯是稳定的油或低熔点固体。它们与格氏试剂的反应进行顺利，通常得到3-取代的3-羟基-1-吡咯烷羧酸酯，产率相当好。合成了47个在吡咯烷环的2-、3-和5-位具有不同取代基的吡咯烷醇，如表III所示。药理学在禁食的白化病小鼠中筛选表III所列化合物的催眠活性。口服给药后翻正反射的丧失被用作催眠的标准。最有效的化合物按效力降序为5、46、1、37、6、4、3和8号。这8种药物的中位催眠剂量范围为150 - 760 mg/kg。kg.与453 mg相比，kg.水合氯醛作为标准。他们的比例
We have used both processes for the preparation of diethyl 4-oxo-1, 3-pyrrolidinedicarboxylate. The physical constants of the products from the two different methods are essentially the same. The Kuhn and Osswald method was extended for the synthesis of twelve alkyl ethyl 4-oxo-l, 3-pyrrolidinedicarboxylates. Their physical properties are listed in Table I. In contrast to the concentrated hydrochloric acid used by Kuhn and Osswald we found that very dilute (0.4%) hydrochloric acid was all that wras necessary to catalyze the hydrolysis and decarboxylation of these cyclic ß-keto esters. The physical properties of the alkyl 3-oxo-lpyrrolidinecar boxy lates are given in Table II.These alkyl 3-oxo-l-pyrrolidinecarboxylates are stable oils or low melting solids. Their reaction with Grignard reagents goes smoothly and usually gives 3-substituted 3-hydroxy-l-pyrrolidinecarboxylates in fair to good yields. Forty-seven pyrrolidinols havebeen synthe-sized with different substituents at the 2-, 3-and 5-positions of the pyrrolidine ring as shown in Table III. Pharmacology.—Compounds listed in Table III were screened for hypnotic activity in fasted albino mice. Loss of the righting reflex following oral administration was used as the criterion for hypnosis. The most potent of the compounds were No. 5, 46, 1, 37, 6, 4, 3, and 8 in the order of descending potency. The medianhypnotic doses for these eight agents ranged from 150 to 760 mg./kg. incomparison to 453 mg./kg. for chloral hydrate as the standard. Their ratios of