Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-03
1999-07-06
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D50159
Patent
active
059199245
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for preparing 3-halogenated cephem derivatives.
The 3-halogenated cephem derivative is useful as an intermediate for giving known cephem antibiotics which are administered mainly orally and is converted to cefaclor according to a later-mentioned Reference Example 1 (JP-A-39313/1986).
BACKGROUND ART
Reports have been made on widely acceptable processes for preparing 3-halogenated cephem derivatives represented by the formula (2). These processes include a process which uses a compound of the formula (3), i.e., 3-hydroxycephem compound and involves the conversion of hydroxyl group to trifluoromesyloxy group first and the subsequent reaction with a reactive chlorine or bromine compound (such as phosphorus trichloride, phosphorus oxychloride or thionyl bromide) is reacted with a 3-hydroxycephem compound in dimethylformamide (JP-A-116095/1974). ##STR3## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined below.
These 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 industrially feasible.
Further, a process is known wherein an allenyl .beta.-lactam compound of the formula (1) is reacted with a halogen salt of alkali metal or alkaline earth metal to cyclize the allenyl .beta.-lactam compound to obtain the 3-halogenated cephem compound (JP-A-282387/1992). This process is advantageous in employing the starting material, allenyl .beta.-lactam compound, which is easily available, but inevitably forms 3-sulfonylcephem as a by-product due to the recombination of sulfinate 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 for preparing the desired 3-halogenated cephem derivative in a high yield with a high purity by a safe and simplified procedure without using a starting material which is difficult to prepare.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing a 3-halogenated cephem derivative represented by the formula (2), characterized by causing a halogenating reagent to act on an allenyl .beta.-lactam compound represented by the formula (1) in the presence of a cuprous salt or cupric salt to obtain the 3-halogenated cephem derivative ##STR4## wherein R.sup.1 is a hydrogen atom, amino or protected amino, R.sup.2 is a hydrogen atom, halogen atom, lower alkoxyl, lower acyl, lower alkyl, lower alkyl having at least one selected from hydroxyl and protected hydroxyl as a substituent, hydroxyl or protected hydroxyl, R.sup.3 is a hydrogen atom or carboxylic acid protecting group, R.sup.4 is an aromatic compound residue which may have a substituent or nitrogen-containing aromatic heterocyclic compound residue which may have a substituent, and n is 0 to 2 ##STR5## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, X is a halogen atom.
In the investigation of a widely useful process for preparing 3-halogenated cephem derivatives, we directed attention to the process disclosed in the aforementioned publication JP-A-282387/1992, and continued the investigation under an anticipation of making possible to restrict formation of by-products by converting the sulfinate ion to less-nucleophilic group. As a result, we have found that the sulfinate ion is oxidized to less-nucleophilic sulfonic acid group by conducting a specific oxidation together with the ring closure to obtain the desired 3-halogenated cephem derivative in a high yield.
Namely, we made an intensive investigation on various oxidation reactions, and found an entirely novel fact that use of a hologenating agent in combination with the oxidation reaction using cuprous salt or cupric salt at the same time affords the desired 3-halogenated cephem derivative quantitatively.
Examples of groups mentioned herein are as follows. Examples of halogen atom are fluorine, chlorine, bromine or iodine atom. Exemplary of t
REFERENCES:
Tanaka et al, Bull. Chem. Soc. Japan, (1996) vol. 69, No. 5 pp. 1391-1396.
Tanaka et al, Synlett (1991) No. 12, pp. 888-890.
Kameyama Yutaka
Kikuchi Ryo
Sasaoka Michio
Sorajo Kouichi
Tanaka Hideo
Ford John M.
Otsuka Kagaku Kabushiki Kaisha
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