Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-01
2002-07-09
Berch, Mark L (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S222000
Reexamination Certificate
active
06417351
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a technique with which a stable 3-alkenylcephem compound is prepared in a single step in which an unstable intermediate generated in the reaction system is reacted with a reagent at the same time. The resulting 3-alkenylcephem compound is useful as an intermediate of Cefixime that is a useful antibacterial agent having a wide range antibacterial spectrum disclosed in, for example, Handbook of Latest Antibiotics, 9th ed., Katsuji Sakai P. 83 (JP-B-20435/1988).
BACKGROUND ART
As a process for preparing 3-alkenylcephem compounds, it is generally employed, when taking 3-vinylcephem compounds as example, to conduct Wittig reaction with formaldehyde by using 3-chloromethylcephem derivative or 3-hydroxymethylcephem derivative as a starting material, as described in JP-B-20435/1988 and JP-A-263990/1986. In these processes, it is generally and widely employed that the reactions until phosphonium salt is obtained are conducted in one-pot and, after isolation of the phosphonium salt, ylidation is performed and the reaction with formaldehyde is resumed. In such a series of Wittig reaction, the respective compounds of iodide compound, phosphonium salt and ylide, each being intermediate, are often unstable, and thus it might be impossible to obtain a satisfactory yield. As a matter of fact, the reactions in JP-B-20435/1988 and JP-A-263990/1986 cause the problems that because of a temporal isolation of phosphonium salt, process is complicated and the total yield is low (the total yield of the former is 65%, and that of the latter is 52%). Further, both have many problems in practical production. For example, due to a low yield, by-products are formed in decomposition of the above-mentioned compounds. Accordingly, there has been a desire for an excellent reaction that is a short reaction step applicable industrially, and achieves a short residence time of unstable intermediates.
Process of JP-A-263990/1986:
Alternatively, 3-vinylcephem compounds can be prepared by the reaction of allenyl &bgr;-lactam compound with copper chloride/vinyltributyl tin or vinylcuprate, as described in Tetrahedron Lett., 1992, 33, 7029, and J. Org. Chem., 1994, 59, 4956. In either case, a large amount of copper salt is required, and a significant number of problems may arise with its industrial application from an environmental point of view. Further, since allenyl &bgr;-lactam compound used in these reactions is unstable, there are also handling problems in a large scale reaction.
In the meanwhile, there has been reported a process of preparing 3-vinylcephem compounds by subjecting a 3-trifluoromethane sulfonyloxycephem compound or 3-fluorosulfonyloxycephem compound to coupling reaction or reaction with vinyl cuprate, by using an organic tin compound/palladium catalyst. (Tetrahedron Lett., 1988, 29, Tetrahedron Lett., 1990, 31, 3389, 6043, Tetrahedron Lett., 1991, 32, 4073, and Journal of Organic Chemistry, 1990, 55, 5833).
It is however difficult to industrially apply these processes because, when synthesizing a starting material, 3-trifluoromethanesulfonyloxycephem compound or fluoromethanesulfonyloxycephem compound is required to be prepared by using trifluoromethane sulfonic acid anhydride or fluorosulfonic acid anhydride, the industrial handling of which is difficult. It is also necessary to use an expensive palladium catalyst and copper reagent of not less than equivalent, in these reactions. Thus, there are a number of problems when these processes are put into practice.
Although the foregoing conventional techniques have been applied to not only a process for preparing 3-vinylcephem compounds but also 3-alkenylcephem compounds, there are essential problems remaining unsolved.
An object of the present invention is to provide a novel technique with which 3-alkenylcephem compounds can be prepared in a single easy handling with high yield, by using a 3-chloromethylcephem compound as a starting material, and simultaneously conducting reactions of iodization reagent, alkali metal hydroxide or carbonate, arylphosphine and aldehyde, to decrease the residence time of unstable intermediates in the system.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing 3-alkenylcephem compounds characterized in that 3-alkenylcephem compound of the formula (3) is prepared in a single step by simultaneously conducting reactions of a 3-chloromethylcephem compound of the formula (1) with iodization reagent, alkali metal hydroxide or carbonate, arylphosphine and an aldehyde of the formula (2)
wherein R
1
is a hydrogen atom, halogen atom, amino group, protected amino group, or Ar—CH═N— group where Ar is aryl group which may have a substituent; R
2
is a hydrogen atom, halogen atom, lower alkoxy group, lower acyl group, lower alkyl group, lower alkyl group which has hydroxyl or protected hydroxyl as a substituent, hydroxyl group, or protected hydroxyl group; and R
3
is a hydrogen atom or carboxylic acid protective group
R
4
—CHO (2)
wherein R
4
is a hydrogen atom, or lower alkyl group which may have a substituent
wherein R
1
, R
2
, R
3
and R
4
are as defined above.
With the conventional processes for preparing 3-alkenylcephem compounds by employing Wittig reaction, not only any satisfactory yield is obtained, but also it is time-consuming to purify the desired compound due to the by-product generated in the reactions. The inventor found that the reason for these was to allow unstable intermediates to reside for a long time during the isolation or in the system, and succeeded in preparing 3-vinylcephem compounds at high yield and purity when a reaction system for minimizing the residence time of such intermediates was discovered. Under the reaction conditions of the invention, the unstable intermediates react quickly with the reagents in the system, resulting in a 3-alkenylcephem compound. Therefore, examples of cephem compounds, the existence of which is recognizable in the system, are stable 3-chloromethylcephem compounds and 3-alkenylcephem compounds.
The wavy line bonded to R
4
of the formula (3) of the invention denotes a stereoisomer and means that against the double bond of 3-alkenyl group, R
4
is cis alone, trans alone, or a cis/trans mixture.
Examples of the groups described in the present specification are as follows:
Halogen atom means fluorine, chlorine, bromine, iodine, or the like.
Lower alkyl group means, for example, a straight-chain or branched C
1
~C
4
alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Aryl group means, for example, phenyl, anisyl or naphthyl.
Examples of the protected amino group represented by R
1
are formamido, phenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido, p-methoxyphenylacetamido, p-chlorophenylacetamido, p-bromophenylacetamido, phenylmonochloroacetamido, phenyldichloroacetamido, phenylhydroxyacetamido, phenylacetoxyacetamido, &agr;-oxophenylacetamido, thienylacetamido, benzamido, p-methylbenzamido, p-t-butylbenzamido, p-methoxybenzamido, p-chlorobenzamido, p-bromobenzamido, etc. In addition to these, there are the groups disclosed in “Protective Groups in Organic Synthesis written by Theodora W. Greene, 1981, by John Wiley & Sons. Inc.” (hereinafter referred to merely as the “literature”), Chap. 7 (pp. 218-287), and phenylglycylamido, phenylglycylamido in which amino group is protected, p-hydroxyphenylglycylamido, and p-hydroxyphenylglycylamido in which either of amino and hydroxyl, or both of these are protected. Examples of protective groups for the amino of phenylglycylamido group and p-hydroxyphenylglycylamido group are those disclosed in the literature, Chap. 7 (pp. 218-287). Examples of protective groups for the hydroxyl of p-hydroxyphenylglycylamido are those disclosed in the literature, Chap. 2 (pp. 10-72).
Examples of the aryl of Ar—CH═N— group are phenyl and phenyl groups which may have a substituent, such
Berch Mark L
Otsuka Kagaku Kabushiki Kaisha
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