Process for producing exo-methylenepenam compounds

Details Process for producing exo-methylenepenam compounds Process for producing exo-methylenepenam compounds

1999-09-07

2002-01-15

Berch, Mark L. (Department: 1611)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06339152

ABSTRACT:

TECHNICAL FIELD
The exo-methylenepenam compound of the present invention is an important intermediate for synthesizing, for example, a &bgr;-lactamase inhibitor (Bawldwin et al, J. Chem. Soc., Chem. Commun., 1987, 81, S. Torii et al., Antibit. Chem. Lett., 1993, 3, 2253).
BACKGROUND ART
A process is already known for preparing the exo-methylenepenam compound of the invention which is represented by the general formula (2), by the decarboxylation Pummerer-type rearrangement reaction of penam-2-carboxylic acid derived from penicillin as illustrated in Diagram (A) (Bawldwin et al., J. Chem. Soc., Chem. Commun., 1987, 81), whereas this process comprises as many as eight reaction steps, and is as low as up to 6% in overall yield and by no means feasible.
(wherein R′═PhOCH
2
CONH, R″═CH
2
C
6
H
4
NO
2
-p)
Also known are a synthesis process wherein an allenyl &bgr;-lactam compound obtained from penicillin is subjected to acid hydrolysis, followed by intramolecular cyclization (S. Torii et al., Tetrahedron Lett., 1991, 32, 7445) as shown in Diagram (B), and a synthesis process wherein an allenyl &bgr;-lactam compound is subjected to a reductive cyclization reaction (S. Torii et al., Synlett., 1992, 878, S. Torii et al., Chemistry Express, 1992, 7, 885, J. Chem. Soc., Chem. Commun., 1992, 1793). These processes nevertheless have various problems such as cumbersomeness of the reaction procedure for industrial operation since the reaction is conducted via an unstable allene compound as an intermediate.
(wherein R
1
~R
3
are same as above, R
4
is aryl group which may have a substituent)
Further known is a synthesis process wherein a halogenated &bgr;-lactam compound derived from penicillin is subjected to reduction for cyclization (Chemistry Letters, 1995, 709, JP-8-245,629 A). However, this process comprises many reaction steps compared with other processes because of use of the halogenated &bgr;-lactam compound as an intermediate. Thus, reactions which are more practical are desired.
(wherein R
1
~R
4
are same as above)
An object of the invention is to provide a process adapted to produce an exo-methylenepenam compound of the formula (2) from the cephem compound of the formula (1) in a high yield with a high purity through a safe and simplified procedure by developing a novel metal reduction system.
DISCLOSURE OF THE INVENTION
The present invention further provides a process for preparing an exo-methylenepenam compound represented by the formula (2) wherein cephem compound represented by the formula (1) is reduced with a metal having a standard oxidation-reduction potential of up to −0.3 (V/SCE) in an amount of at least one mole per mole of the cephem compound and with a metal compound having a higher standard oxidation reduction potential than the metal in an amount of 0.0001 to 10 moles per mole of the cephem compound to obtain the exo-methylenepenam compound
wherein R
1
is a hydrogen atom, amino or protected amino, R
2
is a hydrogen atom, halogen atom, lower alkoxyl, lower acyl, lower alkyl, hydroxyl, protected hydroxyl or lower alkyl having hydroxyl or protected hydroxyl as a substituent, R
3
is a hydrogen atom or carboxylic acid protective group, X is a halogen atom, lower alkylsulfonyloxy, substituted lower alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, halogenated sulfonyloxy or substituted halogenated sulfonyloxy
wherein R
1
, R
2
and R
3
are as defined above.
Examples of groups mentioned herein are as follows.
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, thienylacetamido, phenylacetoxyacetamido, &agr;-oxophenylacetamido, benzamido, p-methylbenzamido, p-methoxybenzamido, p-chlorobenzamido, p-bromobenzamido, phenylglycylamido, phenylglycylamido having protected amino, p-hydroxyphenylglycylamido, p-hydroxyphenylglycylamido having protected amino and/or protected hydroxyl, etc.; imido groups such as phthalimido, nitrophthalimido, etc., in addition to the groups disclosed in Theodora W. Greene, 1981, “Protective Groups in Organic Synthesis” (hereinafter referred to merely as the “literature”), Chap. 7 (pp. 218~287). 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 group are those disclosed in the literature, Chap.2 (pp. 10~72).
Exemplary of the lower alkoxyl represented by R
2
are straight-chain or branched C
1~4
alkoxyl groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.
Exemplary of the lower acyl represented by R
2
are straight-chain or branched C
1~4
acyl groups such as formyl, acetyl, propionyl, butyryl and isobutyryl.
Examples of lower alkyl represented by R
2
are straight-chain or branched C
1~4
alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Examples of protective groups for the protected hydroxyl in the lower alkyl represented by R
2
and substituted with hydroxyl or protected hydroxyl, and for the protected hydroxyl represented by R
2
are those disclosed in the literature, Chap. 2 (pp. 10~72). The substituted lower alkyl represented by R
2
may have as its substituent(s) one or at least two same or different groups selected from among hydroxyl and the protected hydroxyl groups. Such substituent(s) may be positioned on at least one carbon atom of the alkyl.
Exemplary of the carboxylic acid protecting group represented by R
3
are allyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trichloromethyl, tert-butyl, and those disclosed in the literature, Chap. 5 (pp. 152~192).
Examples of halogen atom represented by R
2
and X are fluorine, chlorine, bromine or iodine atom.
Examples of lower alkylsulfonyloxy or substituted lower alkylsulfonyloxy are methanesulfonyloxy, trifluoromethanesulfonyloxy and trichloromethanesulfonyloxy. Examples of arylsulfonyloxy or substituted arylsulfonyloxy are benzenesulfonyloxy and toluenesulfonyloxy. Examples of halogenated sulfonyloxy are fluorosulfonyloxy.
The cephem compound represented by the formula (1) for use as a starting material of the present invention can be prepared for example by the following method.
More specifically, as disclosed in JP 49-116,095 A, the compound of the formula (1) is prepared by reacting 3-hydroxycephem compound of the formula (3) with a reactive chlorine compound (phosphorus trichloride, phosphorus oxychloride, etc.) in dimethylformamide.
(wherein R
1
, R
2
and R
3
are as defined in above.)
The cephem compound of the formula (1) thus obtained can be converted to an exo-methylenepenam compound of the formula (2) by reacting the compound (1) with a metal having a standard oxidation-reduction potential of up to −0.3 (V/SCE) in an amount of at least one mole per mole of the compound (1) and a metal compound having a higher standard oxidation-reduction potential than the metal in an amount of 0.0001 to 10 moles per mole of the compound (1). V/SCE shows oxidation-reduction potential based on a standard caramel electrode.
More specifically, the reaction is conducted in a suitable solvent. Examples of solvents useful in the reaction are lower alkyl esters of lower carboxylic acids such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate and ethyl propionate, ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone and diethyl ketone, ethers such as diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ethe

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