Process for preparation of 3-cephem compound

Details Process for preparation of 3-cephem compound Process for preparation of 3-cephem compound

2000-02-29

2002-07-16

Berch, Mark L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S226000, C540S230000, C540S219000

Reexamination Certificate

active

06420554

ABSTRACT:

TECHNICAL FIELD
The cephem compound of the present invention is an important intermediate capable of forming various antibiotics by the introduction of 7-position side chain. For example, a compound of the formula (3) to be described later wherein R
2
=vinyl group enables the preparation of cefixime or cefdinir due to a side chain introduced in 7-position. Now these compounds are commercially available as an oral drug (see Katsuji SAKAI, “Handbook of Latest Antibiotics”, 9th ed., pp.83 and 86).
BACKGROUND ART
It has been commonly practiced to prepare a 3-cephem derivative of the formula (3) by the substitution of 3-position side chain in 7-aminocephalosporanic acid (7-ACA). However, the process gives only limited compounds having a natural cephalosporin skeleton with 3-position side chain and is infeasible for the preparation of antibiotics having a non-natural cephalosporin skeleton which antibiotics are lately regarded as main antibiotics.
To avert these problems, a compound of the formula (3) was prepared usually according to the process disclosed in L. D. Hatfield et al., Recent advances in the chemistry of &bgr;-lactam antibiotics (second international symposium 1980), p.109. The disclosed process comprises reacting a 3-cephem compound of the formula (1) to be described later with a combination of phosphorus halide compound/organic base to give a compound of the formula (2) to be described later, subjecting the compound of the formula (2) to decomposition due to reaction with an alkyl alcohol and to hydrolysis, isolating a compound of the formula (4) or a salt thereof, and removing the protection of carboxylic acid ester of the compound of the formula (4), giving a compound of the formula (3).
wherein R
2
and R
3
are as defined later.
However, the compounds of the formula (4) obtained by the foregoing reaction are mostly unstable and are likely to decompose during isolation and purification. Further, branched aliphatic alcohol has been considered preferable as an alcohol to be used in the decomposition due to reaction with an alcohol because of its reaction mechanism. Yet, the branched aliphatic alcohol is relatively expensive and unsuitable for practical use.
In order to remove the protection of carboxylic acid ester of the compound of the formula (4), it is known to conduct a catalytic reduction using a precious metal catalyst or to treat the compound of the formula (4) with an acid. Known as the latter methods are a method using trifluoroacetic acid [J. Am. Chem. Soc., 91, 5674 (1969)], a method using formic acid [Chem. Pharm. Bull., 30, 4545 (1982)], a method wherein the compound of the formula (4) is reacted with aluminum chloride in the presence of anisole [Tetrahedron Lett., 2793 (1979)] and a method using a phenol [J. Org. Chem., 56, 3633 (1991)].
These conventional methods require the step of isolating the carboxylic acid ester of the formula (4) and the step of removing the protection thereof, namely involve increasing steps. Further, the step of removing the protection poses various problems as described later.
The method involving a catalytic reduction using a precious metal catalyst has a drawback that usually a &bgr;-lactam antibiotic has a sulfide linkage in the molecule which linkage poisons the catalyst, resulting in a need to use an expensive precious metal catalyst in a large amount. In addition, the method is not applicable to a &bgr;-lactam derivative having, in the same molecule, a group which can be reduced such as a nitro group, carbon-carbon multiple bond or the like. Moreover, the method can not remove, in most cases, such protective groups as a benzyl group which has an electron-donating group as a substituent on a phenyl ring, or a diphenylmethyl group which has an electron-donating group as a substituent on a phenyl ring.
The method using an acid has the following drawbacks. The method using an acid such as trifluoroacetic acid usually requires the use of expensive trifluoroacetic acid in a large amount and would entail a large quantity of loss in recovery and reuse of trifluoroacetic acid after the reaction for the removal of protection. Furthermore, the method gives the desired carboxylic acid compound in a low yield because the &bgr;-lactam derivative which is unstable against an acid decomposes during recovery. The method using formic acid necessitates expensive 98-99% formic acid as a solvent in a large excess and gives the desired carboxylic acid compound in a low yield, as is the case with the reaction with trifluoroacetic acid, due to the decomposition of &bgr;-lactam derivative which is unstable against an acid during recovery or reuse.
The method using aluminum chloride in the presence of anisole scarcely give the contemplated compound due to the decomposition of &bgr;-lactam derivative which is unstable against an acid. As described above, the protection-removing reaction commonly practiced is infeasible in most cases for the compounds of the formula (4) which are mostly unstable. Consequently these conventional processes comprising an isolation step would encounter difficulty in preparing the desired compound in a high yield. Thus, a useful process has not been established yet.
An object of the present invention is to provide a process for preparing a cephem compound of the formula (3) stably and in a high yield without isolating an carboxylic acid ester of the formula (4) which is an unstable intermediate.
DISCLOSURE OF THE INVENTION
According to the present invention, there is provided a process for preparing a 3-cephem compound represented by the formula (3), the process comprising the steps of reacting a &bgr;-lactam compound represented by the formula (1) with a phosphorus halide compound in the presence of an organic base to give an imino-&bgr;-lactam compound represented by the formula (2), adding a phenol to the same reaction system to cause decomposition due to reaction with an alcohol and simultaneously to remove the protection of carboxylic acid ester, giving a 3-cephem compound represented by the formula (3) or a salt thereof
wherein R
1
is arylmethyl group or aryloxymethyl group, R
2
is hydrogen atom, halogen atom, hydroxyl group, lower alkoxy group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkenyl group, lower alkynyl group, heterocyclic thiomethyl group or heterocyclic methyl group, and R
3
is benzyl group which may have an electron-donating group as a substituent on a phenyl ring or diphenylmethyl group which may have an electron-donating group as a substituent on a phenyl ring
wherein R
1
, R
2
and R
3
are as defined above and X is halogen atom
wherein R
2
is as defined above.
According to conventional processes, the compound of the formula (4) which is an unstable intermediate is inevitably isolated, consequently making it difficult to obtain the desired compound in a high yield. Further, it is necessary to use a relatively expensive branched aliphatic alcohol for the decomposition due to reaction with an alcohol. For these reasons, these processes are far from practical. The present inventors found that a phenol is comparable or superior to the conventional branched aliphatic alcohol in the capability of decomposition due to reaction with an alcohol. The inventors also established a reaction system in which a phenol is caused to effectively remove the protection. The inventors successfully conducted a reaction for removal of protection in a stable state without isolating the compound of the formula (4), which has been the problem in the prior art.
Stated more specifically, using a phenol as reagents both for the decomposition due to reaction with an alcohol and for the de-esterification in the series of reactions, the inventors established a process wherein de-esterification reaction is caused to proceed substantially at the same time as the formation of a compound of the formula (4) which is an unstable intermediate in the reaction system, ultimately giving a compound of the formula (3) which is a stable interm

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