Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-12
1999-11-16
Berch, Mark L
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540358, C07D50159, C07D205095
Patent
active
059860910
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The allenyl .beta.-lactam compounds and 3-halocephem compounds of the present invention are important intermediates, from which readily derivable are 3-chlorocephalosporin intermediates, i.e., useful starting materials for cefaclor which has antibacterial activity on a wide variety of gram-positive or gram-negative bacteria and which is widely used as an oral drug. These compounds are in prevalent use industrially.
BACKGROUND ART
The allenyl .beta.-lactam compound of the invention represented by the formula (II) is conventionally prepared, for example, by reacting a tertiary organic base with the starting material in an organic solvent according to the process disclosed in JP-A-282359/1992. However, this compound as contained in the resulting reaction mixture is unstable owing to the presence of an excess of the tertiary organic base or a salt of the base and sulfonic acid, so that the reaction mixture usually requires repetition of a cumbersome procedure involving extraction and concentration after the completion of the reaction. This procedure takes time in the case of quantity production, consequently entailing problems such as a marked reduction in the yield of the isolated product. Thus, a satisfactory feasible process has yet to be developed for preparing the allenyl .beta.-lactam compound.
Reports have been made on widely acceptable processes for preparing 3-halogenated cephem derivatives represented by the formula (III). These processes include a process which uses a 3- hydroxycephem compound represented by the formula (IV) and serving as the starting material and involves conversion of the hydroxyl group to trifluoromesyloxy group and the subsequent reaction with a lithium halide as disclosed in J. Org. Chem., 54, 4962(1989), a process wherein a reactive chlorine or bromine compound (such as phosphorus trichloride, phosphorus oxychloride or thionyl bromide) is reacted with a 3-hydroxycephem compound in dimethylformamide as disclosed in JP-A- 116095/1974, and further a process wherein an alkali metal salt or alkaline earth metal salt of a halogen is reacted with an allenyl .beta.-lactam compound as disclosed in JP-A-282387/1992 ##STR4## wherein R.sub.1 and R.sub.3 are as defined below.
The first of the processes requires the use of the 3-hydroxycephem compound as the starting material which compound itself is difficult to prepared and is therefore in no way practically feasible. The second process inevitably forms 3-sulfonylcephem or 3-thiocephem as a by-product due to the recombination of sulfinate ion or thiolate ion which is released on ring closure, consequently giving the desired 3-halogenated cephem derivative in a yield of as low as up to 70%.
An object of the present invention is to overcome the drawbacks of the foregoing conventional processes and to provide a process capable of readily preparing the desired allenyl .beta.-lactam compound and 3-halogenated cephem compound from the same starting material in a high yield with a high purity merely by using different reaction conditions for the different compounds.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing an allenyl .beta.-lactam compound represented by the formula (II) which process is characterized in that a .beta.-lactam halide compound represented by the formula (I) is reduced with a zero-valent metal ##STR5## wherein R.sub.1 is a hydrogen atom, amino or protected amino, R.sub.2 is aryl which may have a substituent, 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 ##STR6## wherein R.sub.1, R.sub.2, n and R.sub.3 are as defined above.
In solving the problems of the foregoing known processes while developing processes for preparing allenyl .beta.-lactam compounds, we found that the decomposition of the allenyl .beta.-lactam compound is attributable to the presence of a very small excess of the tertiary organic base or a salt of the tertiary organic base and sulfonic acid remaining after
REFERENCES:
patent: 5204458 (1993-04-01), Torri et al.
Patent Abstracts of Japan, Publication No. 08245573 A, Publication Date: Sep. 24, 1996.
Patent Abstracts of Japan, Publication No. 07061967 A, Publication Date: Mar. 7, 1995.
Patent Abstracts of Japan, Publication No. 04211055 A, Publication Date: Aug. 3, 1992.
Patent Abstracts of Japan, Publication No. 04283584 A, Publication Date: Oct. 8, 1992.
Derwent Abstract for Japan 4-282387, Jul. 10, 1992.
Kameyama Yutaka
Sasaoka Michio
Tanaka Hideo
Torii Sigeru
Berch Mark L
Otsuka Kagaku Kabushiki Kaisha
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