Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1981-08-04
1983-12-27
Lee, Mary C.
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
2602391, C07D49904, C07D49942
Patent
active
044229712
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a novel process for the preparation of 6-aminopenicillanic acid 1,1-dioxide, hereinafter called 6-APA-sulfone, and its salts.
European patent application publ. no. 0002927 describes the use of 6-APA-sulfone and its salts as agents for enhancing the antibacterial activity of .beta.-lactam antibiotics, and its preparation by oxidation of 6-aminopenicillanic acid (6-APA) with a known sulfone generating oxidation agent such as potassium permanganate or 3-chloro-perbenzoic acid. However, the 6-amino group and the 3-carboxylic acid group have to be first protected with suitable groups which are removed after oxidation without affecting the ring structure of the molecule.
In Chemical Abstracts, volume 82 (1975), 156283Y, which corresponds to Japanese patent application Kokai No. 74 82,686, the preparation of 6.beta.-aminopenicillanate 1-oxides is described by treating the methyl or trichloroethyl ester of a 6.beta.-penicillin sulfoxide with an acid halide in an anhydrous solvent, reacting the intermediate with a lower alcohol and hydrolyzing the resulting imino ether with an acid.
In Chemical Abstracts, volume 80 (1974), 95941W, which corresponds to Japanese patent application Kokai No. 74 14,492, the preparation of 6-aminopenicillanic acid 1-oxide (6-APA sulfoxide) and its derivatives at the --COOH group is mentioned by treating 6-acylaminopenicillanic acid 1-oxide or its derivatives at the --COOH group with trialkyloxonium fluoroborate or an iminohalogenating agent and an organic hydroxyl compound or its alkali metal compound followed, if necessary, by hydrolyzing. However, in the examples only the methyl and trichloroethyl ester of benzylpenicillin acid 1-oxide in dichloromethane were treated with dimethylaniline and PCl.sub.5.
Dutch patent application No. 7315579, which corresponds to Japanese patent application No. 72 115,113, describes the preparation of 6-APA sulfoxide derivatives by reacting benzyl or phenoxymethylpenicillanic acid 1-oxide derivatives with PCl.sub.5 in the presence of a base, treating the resulting product with an alcohol and hydrolyzing the product obtained. Among the protecting ester groups mentioned in said patent application are alkyl groups, such as a methyl group, halogenating alkyl groups, such as a 2,2,2-trichloroethyl group, aralkyl groups, such as a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a phenacyl and a benzhydryl group, trialkylsilyl groups such as a trimethylsilyl group, and the like, but in the examples only the use of 2,2,2-trichloroethyl and p-nitrobenzyl groups is demonstrated.
A disadvantage of the prior art methods which potentially may lead to the preparation of 6-APA sulfoxide itself is that the introduction and removal of protecting groups need at least two extra steps in the overall synthesis.
British Pat. Nos. 1,189,022 and 1,224,017 describe a method for preparing 6-aminopenicillanic acid by deacylating a 6-acylaminopenicillanic acid or a salt thereof by preparing a silyl ester of the 6-acylaminopenicillanic acid or a salt thereof, treating it with an agent which forms an imino bond, introducing an --OR group to the carbon atom which is involved in the formation of the imino bond whereby R is an alkyl or arylalkyl group, followed by splitting the imino bridge and the silyl ester group with agents containing a hydroxy group or with water.
After extensive research and experimentation it appeared impossible to isolate 6-APA-sulfoxide using the latter method, in which a 6-acylaminopenicillanic acid 1-oxide was used as the starting material instead of a 6-acylaminopenicillanic acid.
It could not be expected in any way that such a method should lead to reasonable results when used for penicillin sulfones. This appears also, for example, from the method of primary choice according to the aforementioned European patent application publ. No. 0002927 and from Dutch patent application Nos. 7305106 and 7508837, wherein 7-acylaminocephalosporanic acid 1-oxide derivatives are reduced to the corresponding 7-acylamidocephalosporanic
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Akkerboom Piet J.
Oldenhof Christophorus
Gist-Brocades N.V.
Lee Mary C.
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