Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-02-06
1999-11-02
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540358, C07D50120
Patent
active
059773529
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for preparing 3-norcephem compounds. The 3-norcephem compounds of the present invention are useful as a starting material of, for example, ceftizoxime that is widely used as an injection medicine (see Handbook of Latest Antibiotics, 9th ed., Yakuho Jihosha Pub. Co., Ltd., pp. 72-73), or ceftibutene that is widely used as an oral medicine (see the aforementioned Handbook, p85), and they are also in widespread commercial use.
BACKGROUND ART
As a process for preparing 3-norcephem compounds represented by the formula (2), there has been reported a process in which a reducing agent, such as zinc powder, is acted on a 3-halocephem compound or 3-sulfonyloxycephem compound represented by the formula (3) (JP-A-59186/1977, Recent Advances in the Chemistry of .beta.-Lactam Antibiotics, p. 170, 1977, Pure & Appl. Chem., 1987, 59, 1041, etc.) ##STR3## wherein R.sub.1 is a hydrogen atom, amino group or protected amino group, and R.sub.3 is a hydrogen atom or carboxylic acid protective group ##STR4## wherein R.sub.1 and R.sub.3 are as defined above, and X is a halogen atom, C.sub.1 .about.C.sub.3 alkanesulfonyloxy group or toluenesulfonyloxy group.
This process is, however, generally not suitable for a commercial process due to the difficulty in preparing 3-halocephem compounds or 3-sulfonyloxycephem compounds, as a starting material.
Also, there has been reported a process for preparing 3-norcephem compounds in which a 3-hydroxycephem compound is subjected to a catalytic hydrogenation to obtain a 3-hydroxycepham, followed by 1,2-elimination using haloformic acid ester/base (see JP-A-213785/1983, JP-A-34714/1983, Pure & Appl. Chem., 1987, 59, 1041, etc.) ##STR5##
This process is, however, not a commercial process because 3-hydroxycephem whose synthesis is difficult is used as a starting material and further the two steps of catalytic hydrogenation and 1,2-elimination are required.
In addition, Chemistry and Biology of .beta.-Lactam Antibiotics Penicillins and Cephalosporins Volume 1, p. 170, discloses a process in which a 3-formylcephem shown by the following reaction scheme (5) is used as a starting material, and a process employing the Wittig reaction shown by the following reaction scheme (6). ##STR6##
However, the above two processes have difficulties in obtaining their starting materials. In addition, the former requires rhodium complex that is expensive, while the latter has the problem that a large amount of phosphorus-containing waste is formed as a by-product by the Wittig reaction.
An object of the present invention is to overcome the above drawbacks of the conventional processes and provide a process which readily prepares a desired 3-norcephem compound in high yield and purity.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing 3-norcephem compound represented by the formula (2), characterized in that a hydride reagent is acted on a halogenated .beta.-lactam compound represented by the formula (1) in the presence of a cuprous compound ##STR7## wherein R.sub.1 is a hydrogen atom, amino group or protected amino group, R.sub.2 is an aryl or substituted aryl, n is 0 to 2, R.sub.3 is a hydrogen atom or carboxylic acid protective group, X is a halogen atom, and Y is a halogen atom or a leaving group ##STR8## wherein R.sub.1 and R.sub.3 are as defined above.
The present invention was accomplished when the present inventor found the outstanding reaction process. Specifically, without employing cephem compounds whose synthesis is difficult, as in the above conventional processes, a desired 3-norcephem compound can be prepared by a single step in which a halogenated .beta.-lactam compound that can be more easily derived from penicillin is used as a starting material, and a specific reagent is acted thereon in the presence of a specific metal compound so that the reduction and cyclization reaction proceed at the same time.
According to the present invention, it is possible to prepare a desired 3-norcephem compound in a reli
REFERENCES:
patent: 4081595 (1978-03-01), Nagata et al.
patent: 4634697 (1987-01-01), Hamashima et al.
Hideo Tanaka et al., "Synthesis of 2-exo-Methylenepenam and 3-Chloro-.DELTA..sup.3 -cephem through a Sequential Reductive 1,2-Eliminations/S-S Bond Fission or Chloride Ion-Addition/Cyclization of 3,4-Disubstituted 2-Butenoates in Metal Salt/Metal Combination", J. Org. Chem., vol. 62, pp. 3610-3617, 1997.
Hideo Tanaka et al., "Construction of cephem framework via sequential reductive 1,2-elimination-hydride addition in a tributyltin hydride-copper(I) chloride-NMP system: systhesis of 3-norcephalosporin", Chem. Commun., pp. 2705-2076, 1996.
Kameyama Yutaka
Kikuchi Ryo
Sasaoka Michio
Tanaka Hideo
Torii Sigeru
Berch Mark L.
Otsuka Kagaku Kabushiki Kaisha
LandOfFree
Process for preparing 3-norcephem compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for preparing 3-norcephem compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing 3-norcephem compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2137209