Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-11-06
1999-07-27
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540221, 540222, 540358, C07D50108, C07D205095
Patent
active
059292334
DESCRIPTION:
BRIEF SUMMARY
(TECHNICAL FIELD)
The present invention relates to processes for preparing allenyl .beta.-lactam compounds and 3-halogenated cephem derivatives.
The allenyl .beta.-lactam compounds of the present invention are important intermediates for readily giving 3-substituted cephalosporins which are useful as starting materials, for example, for cefaclor, cefprozil or ceftibuten (S. Torni et al, Synlett., 1991, 888; J. Kanto et al, Tetrahedron Lett., 1992, 33, 3563; and S. Torii et al, Tetrahedron Lett., 1992, 33, 7029). The 3-halogenated cephem derivatives of the invention are also important intermediates for giving cephem antibiotics which are useful for oral administration (JP-A-39313/1986).
(BACKGROUND ART)
The allenyl .beta.-lactam compound represented by the general formula (4) given below 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 is unstable when present in the resulting reaction mixture, which therefore usually requires cumbersome repeated procedures for extraction and concentration after the completion of the reaction. These procedures require time in the case of a large scale production, consequently entailing problems such as a marked reduction in the yield of the isolated product. Thus, processes still remain to be developed which are satisfactorily feasible for the preparation of allenyl .beta.-lactam compounds.
Reports have been made on widely acceptable processes for preparing 3-halogenated cephem derivatives represented by the general formula (6) given below. These processes include a process which uses a compound of the general formula (7), i.e., 3-hydroxycephem compound, as the starting material and involves the conversion of hydroxyl group to trifluoromesyloxy group first and the subsequent reaction with a lithium halide as described 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 ##STR1## wherein R.sup.1, R.sup.2 and R.sup.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 prepare, so that the process is 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 provide a process wherein a .beta.-lactam compound represented by the general formula (1) is used as the starting material for preparing an allenyl .beta.-lactam compound of the general formula (4) as isolated with stability and high purity in a high yield by a simplified procedure.
Another object of the invention is to overcome the drawbacks of the conventional production processes described and to provide a widely-useful process for preparing the desired 3-halogenated cephem derivative in a high yield with a high purity.
(DISCLOSURE OF THE INVENTION)
The present invention provides a process for preparing an allenyl .beta.-lactam compound represented by the general formula (4), characterized by reacting the hydroxyl group of a .beta.-lactam compound represented by the general formula (1) with a reactive functional group derivative of sulfonic acid represented by the general formula (2) to convert the compound of the formula (1) to a .beta.-lactam compound represented by the general formula (3), thereafter reacting the resulting .beta.-lactam compound with a basic anion exchange resin o
REFERENCES:
patent: 5162524 (1992-11-01), Farina
patent: 5204458 (1993-04-01), Torii
Tanaka et al, Nippon Kaga Kukai #61, Spring Annual Meeting 1991, Section C 9, #46, p. 1832, with Translation.
Tanaka, Syn Lett 1991, p. 888.
Kukolja, J. Org Chem 41, 2276 (1976).
Abstract for JP 4-282387 (1992).
Amano Yasuhisa
Kameyama Yutaka
Sasaoka Michio
Tanaka Hideo
Torii Sigeru
Berch Mark L.
Otsuka Kagaku Kabushiki Kaisha
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