Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-09-15
1994-08-30
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548517, 546281, 540302, 540350, C07D20700, C07D40500, C07D40100, C07D48700
Patent
active
053429630
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
Technical Field
This invention is to provide novel carbapenam derivatives which are useful as preparation intermediates for synthesis of carbapenems which are now developing into various medicines such as .beta.-lactam antibiotics having excellent antibacterial activities, a process for preparing the same, and also novel optically active pyrrolidine derivatives and a process for preparing the same.
Background Art
As for the novel carbapenam derivatives according to the present invention, various derivatives have been synthesized in order to strengthen antibacterial activities of carbapenem antibiotics or heightening the stability against an enzyme DHP-1 which deactivates carbapenems.
It is one of the means of synthesizing derivatives to introduce a hydroxyl group to the 6-position, but almost all the synthetic methods of carbapenems which have heretofore been developed relate to synthesis of 6-hydroxyethylcarbapenems. According to these methods, however, it is difficult to synthesize 6-hydroxy-6-hydroxyethylcarbapenems.
Among preparation methods of 6-hydroxycarbapenems which have heretofore been developed, there is a method where the 6-position of 6-ethylcarbapenems is hydroxylated (Bull. Chem. Soc. Jpn., 60, 2091 (1987)), but there is no method where a hydroxyl group is introduced to the 6-position of 6-hydroxyethyl-substituted carbapenems. Also, as a synthetic method of a 3-hydroxy-3-hydroxyethylazethidinone derivative which can be considered to be an intermediate for synthesis of such carbapenems, there has been known a method by T. Durst (Tetrahdedron Letters, 31, 3249 (1990)). However, this method involves many steps and also requires many further steps for converting it into a final carbapenem.
Under such a technical background, one of the objects of the present invention is to provide intermediates for synthesis of 6-hydroxy-6-hydroxyethylcarbapenems and a process for preparing the same.
Also, as for the novel optically active pyrrolidine derivatives according to the present invention, it is difficult to produce carbapenems by fermentation using bacteria due to their potent antibacterial activities so that it has been desired to develop a synthetic preparation process. As synthetic methods, there have been generally employed those ones where the optically active .beta.-lactam portion is first synthesized and then the 5-membered ring is formed (T. Kametani et al., Heterocycles, 17, 463 (1982) and 25, 729 (1987)). As a more general method for synthesizing various kinds of substituted carbapenems as compared to these methods, the present inventors have developed a method in which L-pyrroglutamic acid derivatives are used as a starting material (S. Nozoe et al., Tetrahedron Letters, 29, 4305 (1988); Japanese Patent Application Laid-Open No. 72667/1988).
The main part of the above method using L-pyrroglutamic acid derivatives as a starting material can be shown by the following figure. ##STR2##
When X.sup.4 is an alkyl group, a desired product can be obtained in a high yield by the said method, but when X.sup.4 is a hydroxyalkyl group represented by the formula: ##STR3## is to be synthesized, a reaction yield of the compound 2 was not satisfactory for practical purposes.
In such a technical background, another object of the present invention is to develop a process for synthesizing, from an inexpensive L-pyrroglutamic acid derivative, 6-hydroxyalkylcarbapenems which are considered to be essential for developing potent antibacterial activities and a wide antibacterial spectrum, and for accomplishing the above, it is necessary to develop a process for synthesizing the compounds 3 and/or 4 in the above figure effectively.
DISCLOSURE OF THE INVENTION
First, the novel carbapenam derivatives of the present invention and a process for preparing the same is to be explained.
The present inventors have intensively studied in view of the above problems and, as a result, found that novel carbapenams represented by the following general formula (I) which are diols and can be useful intermediates
REFERENCES:
patent: 4876383 (1989-10-01), Nozoe
Tetrahedron Letters, vol. 29, No. 34, 1988, pp. 4305-4308, Tomihisa Ohta, et al., "Chirospecific Synthesis of (+)-PS-5 from L-Glutamic Acid".
Bulletin of the Chemical Society of Japan, vol. 60, No. 6, 1987, pp. 2091-2099, Azuma Watanabe, et al., "Total Synthesis of 6-Hydroxy-epi-PS 5 and 6-Methoxy-epi-PS 5".
Abstracts of the 29th Symposium on the Chemistry of Natural Products, 1987, pp. 87-93, K. Izawa.
CA 80(13):70632h, Della et al., 1973.
CA 114(19):1860642, Baxter et al., 1990.
March, Advanced Organic Chemistry, Wiley and Sons, N.Y., 1985, pp. 732-733.
Ineyama Takashi
Izawa Hiroyuki
Izawa Kunisuke
Nozoe Shigeo
Ohta Tomihisa
Ajinomoto Co. Inc.
Cook Rebecca
Richter Johann
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