Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-02-15
1991-01-15
Rizzo, Nicholas S.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D50118
Patent
active
049855549
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a new process for the preparation of 3-exomethylene and 3-exohalomethylene cepham derivatives.
These 3-exomethylene cepham compounds (also referred to hereinafter as 3-methylene cepham compounds) are valuable intermediates in the semi-synthetic preparation of various therapeutically useful antibiotics. For example, 3-methylene cepham sulfoxides (also named: 3-methylene-1-oxocepham compounds) can be converted into 7-ADCA and derivatives thereof, into 7-ACA and other 3-acyloxymethyl cephalosporins, and into 3-heteroarylthiomethyl cephalosporins. Some of these compounds can be used as such in pharmaceutical preparations, others have to be converted further before they are suitable for therapeutic use.
Several routes have been known so far to produce 3-methylene cepham compounds, but these routes are almost entirely limited to the preparation of 3-methylene cepham sulfides.
U.S. Pat. No. 4,354,022 discloses a process for preparing 3-methylene cepham sulfides by reacting inter alia 3-halomethyl-3-cephem sulfides with a combination of a metal (zinc, tin or iron) and certain ammonium salts (ammonium halides, ammonium carbonate and ammonium acetate). It is noted that of the 3-halomethyl-3-cephem compounds only chloromethyl is exemplified in this reference.
In Chem. Pharm. Bull. 36(2) 528-591 (1988) the preparation of 7-amino-3-methylenecepham-4-carboxylic acid is described, by reduction of the corresponding 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem compound with zinc either in aqueous acidic or in anhydrous neutral medium.
Other known methods for the preparation of 3-methylene cepham sulfides include the conversion of 3-acetoxymethyl, 3-thiomethyl and 3-carbomoyloxy cephem sulfides.
In Synth. Comm. 16(6) 649-652 (1986) the preparation of 3-methylene-1-oxocepham compounds is described, by reduction of the corresponding 3-acetoxymethyl cephem compounds with activated zinc dust and ammonium chloride.
The present invention now provides a new process for the preparation of 3-methylene and 3-halomethylene cepham compounds of high purity and in good yields.
It has now surprisingly been found that such 3-methylene cepham compounds can be advantageously obtained from the corresponding 3-phosphoniomethyl-3-cephem compounds. Therefore, according to one aspect of the invention, there is provided a process for the preparation of 3-methylene or 3-halomethylene cepham derivatives of the general formula 1: ##STR1## wherein A is an amino group or a protected amino group, formula 2: ##STR2## wherein A, B, X and n are each as defined above, aralkyl groups,
Suitable "protected amino groups" as used in this specification include amino groups substituted with a suitable protective group which are conventionally used in cephalosporin and penicillin chemistry as protective groups at position 7 and position 6, respectively, acylamino, phenyl(lower)alkylamino, (cyclo)alkylamino, (cyclo)alkylideneamino, and the like.
Suitable "acylamino" groups include aliphatic, aromatic and heterocyclic acylamino groups, the acyl group being for example formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzoyl, toluyl, phenylacetyl, phenylpropionyl, phenoxycarbonyl, etc. etc. Basically, the same groups as mentioned in U.S. Pat. No. 4,354,022, herein incorporated by reference, and other groups known to persons skilled in the art of cephalosporin and penicillin chemistry are included within the scope of this invention.
Suitable "protected carboxy groups" as used in this specification include carboxy groups substituted with a suitable protective group, which are conventionally used in cephalosporin and penicillin chemistry as carboxy-protective groups at position 4 and position 3, respectively.
Suitable examples of such protected carboxy groups include esters, such as the methyl ester, ethyl ester, propyl ester, butyl ester, in particular the t-butyl ester, benzyl ester, optionally substituted, such as the 4-nitrobenzyl ester, diphenylmethyl ester, etc. etc. See also
REFERENCES:
patent: 4354022 (1982-10-01), Takaya et al.
Chem. Abstracts, vol. 106, No. 21, 5/25/87.
De Koning Jan J.
Verweij Jan
Witkamp Hendrik A.
Gist-Brocades N.V.
Rizzo Nicholas S.
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