Electrolysis: processes – compositions used therein – and methods – Electrolytic synthesis – Preparing organic compound
Reexamination Certificate
1999-12-10
2001-03-06
Wong, Edna (Department: 1741)
Electrolysis: processes, compositions used therein, and methods
Electrolytic synthesis
Preparing organic compound
Reexamination Certificate
active
06197185
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing &bgr;-lactam halide compounds which are useful as intermediates of antibacterial agents having a cephalosporin skeleton with no carbon atom attached to its 3-position (JP-A-135859/1983). The invention relates also to a process for preparing an exo-methylenepenam compound from the &bgr;-lactam halide compound.
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
The &bgr;-lactam halide compound of the invention represented by the general formula (2) is prepared by reacting halogen molecules with an allenyl &bgr;-lactam compound represented by the general formula (3) as is already known (Can. J. Chem., 1978, 56, 1335). However, this process affords a mixture of &agr;, &bgr;- and &bgr;, &ggr;-position isomers depending on the kind of halogen molecule and is not usable in actuality. This process further gives the product via an unstable allene compound as an intermediate and therefore involves many problems on an industrial scale.
wherein R
1
and R
3
are as defined below, and R
5
is lower alkyl.
It is also reported that as shown in the diagram, a keto-form &bgr;-lactam compound is enolized into an enol ether or vinyl halide, followed by halogenation with N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) in the presence of a radical generating agent (JP-A-135859/1983). Since this process requires use of a hazardous reagent for reaction, processes which are industrially more feasible are desired.
wherein R
8
is phthalimido, aryloxyalkaneamido or alkanoyl, R
7
is thiocyanato, alkanoyl, arylthio, benzothiazolethio, or alkoxycarbonyl which may be substituted with alkoxyl, cycloalkyl or the like, R
8
is alkyl which may be substituted with a halogen, aryl or the like, X is chlorine or the like, and Y is a halogen atom.
Further a process is already known for preparing the exo-methylenepenam compound of the invention which is represented by the general formula (5), by the decarboxylation Pummerer-type transition 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.
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.
An object of the present invention is to provide a process adapted to produce a &bgr;-lactam halide compound represented by the general formula (2) from a &bgr;-lactam halide compound represented by the general formula (1) and readily available industrially, in a high yield with a high purity through a safe and simplified procedure, the process being developed by realizing milder conditions for effecting halogenation and a reaction for introducing the leaving group.
Another object of the invention is to provide a process adapted to produce an exo-methylenepenam compound of the general formula (5) from the &bgr;-lactam halide compound of the general formula (2) in a high yield with a high purity through a safe and simplified procedure by developing a novel metal reduction system and a novel electrolytic reduction system and thereby effecting allenization and conversion to an exo-methylenepenam at the same time efficiently.
DISCLOSURE OF THE INVENTION
The present invention relates to a process for producing a &bgr;-lactam halide compound represented by the general formula (2) which process is characterized in that the hydroxyl group of a &bgr;-lactam halide compound represented by the general formula (1) is substituted with a halogen atom or a leaving group
wherein R
1
is a hydrogen atom, amino or protected amino, R
2
is a hydrogen atom, halogen atom, lower alkoxyl, lower acyl, or lower alkyl having hydroxyl or protected hydroxyl as a substituent, R
3
is a hydrogen atom or carboxylic acid protective group, R
4
is aryl or aryl having a substituent, X is a halogen atom, and n is 0 to 2
wherein R
1
, R
2
, R
3
, R
4
, X and n are as defined above, and Y is a halogen atom or a leaving group.
The present invention further provides a process for preparing an exo-methylenepenam compound represented by the general formula (5) characterized in that a &bgr;-lactam halide compound represented by the general formula (2) 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 halide 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 halide compound, or is subjected to an electrolytic reduction process 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, or lower alkyl having hydroxyl or protected hydroxyl as a substituent, R
3
is a hydrogen atom or carboxylic acid protective group, R
4
is aryl or aryl. having a substituent, X is a halogen atom, Y is a halogen atom or a leaving group and n is 0 to 2
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).
Examples of halogen atom represented by R
2
are fluorine, chlorine, bromine or iodine atom. 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 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 it
Kameyama Yutaka
Sasaoka Michio
Tanaka Hideo
Torii Sigeru
Arent Fox Kintner & Plotkin & Kahn, PLLC
Otsuka Kagaku Kabushiki Kaisha
Wong Edna
LandOfFree
Process for preparing beta lactam compound does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for preparing beta lactam compound, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing beta lactam compound will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2453408