Process for the preparation of cephem compounds

Details Process for the preparation of cephem compounds Process for the preparation of cephem compounds

2002-02-07

2003-06-10

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S222000, C540S227000

Reexamination Certificate

active

06576761

ABSTRACT:

This application is the National Stage Application of PCT/JP00/05851 filed Aug. 30, 2000.
TECHNICAL FIELD
The present invention relates to a process for preparing a 3-alkenylcephem compound or 3-norcephem compound of the formula (3).
The 3-alkenylcephem compound or 3-norcephem compound of the formula (3) has the basic skeleton of a nonnatural antibiotic substance and is an important intermediate for preparing useful antimicrobial drugs having a wide antibacterial spectrum, such as cefixime and ceftibuten which are oral antibiotics generally in wide use (Katsuharu Sakai, “Handbook of Recent Antibiotics,” 9th ed., pp. 83 and 85, 1994).
BACKGROUND ART
Already known as processes for preparing 3-alkenylcephem compounds are a process for subjecting a 3-halogenated methylcephem compound to Wittig reaction (e.g., JP-A-263990/1986), a process for introducing vinyl into a 3-sulfonyloxycephem compound utilizing a metallic catalyst [Tetrahedron Letters, 29, 6043 (1988), 31, 3389 (1990), 32, 4073 (1991), Journal of Organic Chemistry, 55, 5833 (1990)], a process wherein an allenyl &bgr;-lactam compound or halogenated &bgr;-lactam compound is used as the starting material [Tetrahedron Letters, 33, 7029 (1992), Journal of Organic Chemistry, 59, 4956 (1994), Synlett, 774 (1999)], etc.
However, the Wittig reaction mentioned first inevitably requires the treatment of a very large quantity of phosphorus by-product to be discarded since the reaction mechanism invariably forms a trialkyl or triaryl phosphine oxide in an amount equimolar to the starting material. The process for introducing vinyl into a 3-sulfonyloxycephem compound utilizing a metallic catalyst has a great industrial disadvantage in that the process not only requires the use of an expensive reagent which is sensitive to water in preparing the starting material but also requires an alkenyl tin compound or vinyl cuprate compound which must be used but is harmful to the reagent for alkenylation.
The process wherein an allenyl &bgr;-lactam compound is used as the starting material is difficult to practice industrially because the allenyl &bgr;-lactam compound serving as the starting compound is unstable and further because a combination of copper chloride and vinyltributyl tin or vinyl cuprate prepared from vinyltributyl tin is used as the reaction reagent.
The process wherein a halogenated &bgr;-lactam compound is used as the starting material has the problem of necessitating a multistep reaction procedure for preparing the starting material, requires the use of an organotin compound as an alkenylation reagent for the reaction, and still remains to be improved for realization.
Although these conventional techniques have found application to the preparation not only of 3-vinylcephem compounds but also of 3-alkenylcephem compounds, substantial problems have yet to be overcome.
On the other hand, reports have already been made on a process for preparing 3-norcephem compounds wherein zinc is caused to act, for example, on a 3-halocephem compound or 3-sulfonyloxycephem compound as the starting compound ([JP-A-59186/1977 and Recent Advances in the Chemistry of &bgr;-Lactam Antibiotics, 170(1977), and Pure & Appl. Chem., 59, 1041(1987)]. However, this process requires the use of a large amount of acetic acid, formic acid or trifluoroacetic acid and is difficult to practice.
Reports are also made on a process comprising catalytically hydrogenating first a 3-hydroxycephem compound serving as the starting material to obtain a 3-hydroxycepham compound and thereafter subjecting the compound to 1,2-elimination reaction with use of a haloformic acid ester/base to obtain a 3-norcephem compound (JP-A-213785/1983 and JP-A-34714/1983, or Pure & Appl. Chem., 59, 1041 (1987)]. This process requires the two steps of catalytic hydrogenation and 1,2-elimination reaction for the preparation of the desired compound and can not be a practically useful process.
A report is also made on a process wherein 3-formylcephem is used as the starting material, and a process wherein the Wittig reaction is used (Chemistry and Biology of &bgr;-Lactam Antibiotics, Penicillins and Cephalosporins, Vol. 1, 170), whereas the starting materials for both of these processes are compounds which are very difficult to obtain, the former requires the use of an expensive rhodium complex, and the latter has the problem that the Wittig reaction utilized forms a large amount of phosphorus by-product which must be disposed of.
An object of the present invention is to provide an industrially feasible process for preparing a 3-alkenylcephem compound or 3-norcephem compound from a 3-cephem compound of the formula (1) and serving as the starting material.
Stated more specifically, in a process for preparing with ease a 3-alkenylcephem compound or 3-norcephem compound by causing an alkenyl halide of the formula (2), a nickel catalyst, a metal up to −0.3 (V/SCE) in standard oxidation reduction potential and a compound of a metal having a higher standard oxidation reduction potential than the metal to act on a 3-cephem compound, the invention provides a novel technique capable of selectively producing one of the 3-alkenylcephem compound and the 3-norcephem compound merely by changing the solvent to be used in the process.
DISCLOSURE OF THE INVENTION
The present invention provides a process for selectively preparing a 3-alkenylcephem compound or 3-norcephem compound from a 3-cephem compound of the formula (1) and serving as the starting material.
The invention provides a process for preparing a 3-alkenylcephem compound or 3-norcephem compound of the formula (3) characterized in that an alkenyl halide of the formula (2), a nickel catalyst, a metal up to −0.3 (V/SCE) in standard oxidation reduction potential and a compound of a metal having a higher standard oxidation reduction potential than the metal are caused to act on a 3-cephem compound of the formula (1) in a solvent
wherein R
1
is a hydrogen atom, halogen atom, amino or protected amino, R
2
is a hydrogen atom, halogen atom, lower alkoxyl, lower acyl, hydroxyl, protected hydroxyl, or lower alkyl having or not having hydroxyl or protected hydroxyl as a substituent, R
3
is a hydrogen atom or carboxylic acid protective group, and X is a halogen atom, lower alkylsulfonyloxy having or not having a substituent or an arylsulfonyloxy having or not having a substituent
R
4
—Y  (2)
wherein R
4
is 1-alkenyl having or not having a substituent, and Y is a halogen atom
wherein R
1
, R
2
and R
3
are as defined above, and R
5
is a hydrogen atom or 1-alkenyl having or not having a substituent.
According to the present invention, a 3-alkenylcephem compound can be prepared selectively with a high purity in a high yield by causing an alkenylation reagent, which are relatively safe to the human body and have high universal usefulness, to act on a 3-cephem compound having high stability, readily available and represented by the formula (1). Furthermore, a 3-norcephem compound can be selectively prepared with a high purity and in a high yield by changing the reaction condition. Thus one of the two kinds of nonnatural cephem skeletons can be readily prepared selectively.
Examples of groups referred to in the present invention are as follows. Unless otherwise specified, the term “halogen atom” as used herein refers to fluorine, chlorine, bromine or iodine, and the term “lower alkyl” means a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
The term “aryl” means, for example, phenyl, naphthyl or the like.
Exemplary of the protected amino represented by R
1
are amido groups such as phenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido, p-methoxyphenylacetamido, p-chlorophenylacetamido, p-bromophenylacetamido, phenylmonochloroacetamido, phenyldichloroacetamido, phenylhydroxyacetamido, thienylac

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