Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-06
2002-06-04
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S222000, C560S060000, C560S179000
Reexamination Certificate
active
06399770
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing a &bgr;-hydroxyester.
The &bgr;-hydroxyester of the present invention has an active hydroxyl group in the &bgr;-position, and is a very important compound in terms of synthetic chemistry. For example, 3-hydroxycepham compound, which can be readily converted to 3-norcephem skeleton, is an important intermediate of ceftizoxime or ceftibutene both widely used as an injection and an oral drug, respectively (Katsuji SAKAI, “Handbook of Latest Antibiotics”, 9th ed., pp. 72 and 85, 1994) and is in industrially wide use.
BACKGROUND ART
A &bgr;-keto ester is generally unstable under reaction conditions under which hydrolysis tends to occur such as alkaline conditions. The reduction of &bgr;-keto ester under such conditions involves various side reactions, thus making it difficult to give the contemplated product.
For example, a 3-ketocepham compound (3-hydroxycephem compound) is unstable under such reaction conditions and, when reacted, gives a reaction product in low yields, so that the reaction should be conducted at an extremely low temperature. Stated more specifically, known methods include those described in JP-B-59-34714 and Pure & Appl. Chem., 59, 1041 (1987) (hereinafter referred to as “Publication 1”). JP-B-59-34714 discloses a method wherein the reaction is carried out in methanol at 0° C. The reproduced method shows that a product is produced in a yield of only 50 to 60%. On the other hand, Publication 1 discloses a method wherein a 3-hydroxycephem compound is dissolved in a solvent mixture of dichloromethane and methanol and the solution is reduced at −60° C. using sodium borohydride. Since the reaction is performed at a low temperature of −60° C., the method is not industrially advantageous.
Publication 1 states that when the reduction is conducted at 0° C., i.e. a temperature commonly employed, a reaction for removal of substituent R
3
occurs, resulting in production of the contemplated product in a very low yield. The method of JP-B-59-34714 produces a product in a low yield presumably for the same reason.
Helvetica Chimica Acta 57, 1919 (1974) (hereinafter referred to as “Publication 2”) discloses a method in which exomethylene cepham is subjected to ozone decomposition as illustrated below in a scheme, giving a 3-hydroxycephem compound, while ozonide is simultaneously reduced in the same reaction system to produce a 3-hydroxycepham compound. However, the yield of the product is as low as 31.8% which means that the method is not suitable for practical use.
wherein R is benzyl group.
As described above, a practical process has not been established for preparing a &bgr;-hydroxyester from a &bgr;-keto ester of low stability. Currently there is an urgent need for developing an industrially practical process.
An object of the present invention is to provide a process widely applicable for preparing a &bgr;-hydroxyester, the process being free from the drawbacks of conventional processes and capable of giving the contemplated &bgr;-hydroxyester in a high yield and with a high purity.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing a &bgr;-hydroxyester comprising reducing a &bgr;-keto ester in the presence of a salt of ammonium borohydride.
In an attempt to develop the process for preparing a &bgr;-hydroxyester, the present inventor directed attention to the fact that the &bgr;-hydroxyester or &bgr;-keto ester shows a very unstable behavior in reduction under alkaline conditions.
It is known that reduction at a relatively high temperature (e.g. approximately 0° C.) entails side reactions such as hydrolysis, thus giving the contemplated compound in a lower yield and with a lower purity. For example, the reaction of Publication 1 produces (C
6
H
5
)
2
CHOH as a by-product. Publication 1 explains that the by-product is produced due to the attack by hydride when the reaction temperature is elevated to approximately 0° C.
Considering that the by-product is produced due to a high basicity derived from sodium borohydride or due to a great hydride-reducing capability of sodium borohydride, the present inventor attempted to find out a salt of borohydride which does not increase the basicity in the reaction system and which is capable of selectively reducing a &bgr;-keto ester or its ketoenol isomer.
It is already known to produce a salt of borohydride such as aluminum, lithium or zinc salt in the reaction system for use in the reduction. However, such salt failed to achieve the contemplated object. On the other hand, a salt of ammonium borohydride has not been heretofore used for this purpose and was proposed as a useful reagent for the first time in this invention. It was discovered that the foregoing reduction advantageously proceeds in the presence of a salt of ammonium borohydride, giving the contemplated &bgr;-hydroxyester in a high yield and with a high purity. Further, no by-product was produced even when the reaction temperature was raised to 0° C.
In the present invention, a &bgr;-hydroxyester is prepared by reduction of &bgr;-keto ester in the presence of a salt of ammonium borohydride.
The &bgr;-keto ester for use as the starting material in the process of the present invention is not limited and includes conventional compounds. Among useful &bgr;-keto esters, preferred are 3-keto cepham compound represented by the formula (1) and 3-hydroxycephem compound represented by the formula (1′) which is the keto-enol isomer of the 3-keto cepham compound
wherein R
1
is hydrogen atom, halogen atom, amino group, protected amino group or a group —N═CH—Ar (in which Ar is phenyl group optionally having a substituent), R
2
is lower alkyl group optionally having hydroxyl group or protected hydroxyl group as a substituent, hydrogen atom, halogen atom, lower alkoxy group, lower acyl group, hydroxyl group or protected hydroxyl group, and R
3
is hydrogen atom or carboxylic acid-protecting group
wherein R
1
, R
2
and R
3
are as defined above.
Examples of the groups described in the present specification are as follows unless they are otherwise specified:
Halogen atom means fluorine, chlorine, bromine, iodine, or the like. Lower alkyl group means, for example, a straight-chain or branched alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of the lower alkoxy groups are straight-chain or branched alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
Examples of the protected amino group represented by R
1
are 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 as the “Publication 3”), 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 Publication 3, Chap. 7 (pp. 218-287). Examples of protective groups for the hydroxyl of p-hydroxyphenylglycylamido are those disclosed in the Publication 3, Chap. 2 (pp. 10-72).
Examples of phenyl groups represented by Ar in —N═CH—Ar group defined by R
1
are phenyl and phenyl groups such as p-methoxyphenyl, p-nitrophenyl and m-hy
Berch Mark L.
Kubovcik & Kubovcik
Otsuka Kagaku Kabushiki Kaisha
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