Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-04-09
1995-08-15
Rizzo, Nicholas
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540215, 540222, 540228, 540310, 540312, 540230, C07D50102, C07D49904
Patent
active
054420580
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the conversion of the 1-(R)-sulfoxides of penicillin and cephalosporin to their corresponding 1-(S)-sulfoxides by treating said 1-(R)-sulfoxides with acid anhydride. The process is carried out in a aqueous medium in a temperature range from -15.degree. to 30.degree. C., the pH of said aqueous medium being maintained between 3.5 and 8. The process may be used to obtain high yields of substantially pure 1-(S)-sulfoxides from various grades of penicillin and cephalosporin at low cost and using shorter reaction times than present processes.
Penicillin-1-(S)-sulfoxide is an intermediate in the synthesis of cephalosporins as is known from R. B. Morin, et al., J. Am. Chem. Soc. 91, 1401 (1969). Penicillin-1-(S)-sulfoxide is commercially produced by the oxidation of natural Penicillin in aqueous medium with commercially available 40% peroxyacetic acid. For example, a procedure is described in, "A Convenient Synthesis of Ampicillin Sulfoxide and 6-Aminopenicillanic Acid Sulfoxide," Micetich, R. G., Synthesis, pp. 264-65 (1976) wherein peroxyacetic acid is employed to produce penicillin sulfoxides in aqueous solutions. However, such preparation processes are costly and extremely dangerous as is evidenced by the communication of A. Noponen, Chem. Eng. News, 21/2/77, p. 5, where Dr. Naponen reported a violent explosion during the preparation of 6-aminopenicillanic acid sulfoxide using the Micetich procedure. Further, the handling of peroxyacetic acid itself is a dangerous task.
Cephalosporin sulfoxides may also be used to produce other useful products as is disclosed in published European Patent Application 0 137 534, for example.
In, A. Mangia, "A Mild and Convenient Synthesis of Penicillin and Cephalosporin Sulfoxides," Synthesis, pp. 361-63 (1978), a number of synthetic methods for preparing penicillin sulfoxides are mentioned. Penicillin sulfoxides, for example, have been prepared by oxidation of penicillins with sodium periodate, ozone, m-chloroperbenzoic acid, and 40% peracetic acid. Although the yields were high, the reagents were expensive or troublesome to handle in large quantities. This communication further states that oxidation with hydrogen peroxide employed along with an organic acid in a large excess had been tried, but often this method led to cleavage of the more sensitive substrates with consequent low yields. The yields are evidenced by, E. Guddal, P. Morch and L. Tybring, Tetrahedron Lett., p. 381 (1962) wherein yields of 34-62% were obtained.
An alternative method of oxidizing penicillin to penicillin sulfoxides with hydrogen peroxide is also suggested in, A. Mangia, Synthesis, pp. 361-3 (1978) wherein the oxidation is carried out in dichloromethane solvent in the presence of a 4 molar excess of acetic or formic acid. However, this reaction suffers from the disadvantage of requiring reaction times of at least 9 hours and the use of an organic solvent which must be subsequently separated from the desired product at great cost and with extreme care in order to preserve the final product in unaltered form.
A similar reaction is suggested by Japanese Patent Application JP 51/56484 published on 18 May 1976, In this reaction, penicillin-(S)-oxides are prepared by oxidizing penicillin with hydrogen peroxide in the presence of maleic anhydride. The reaction requires that the penicillin and maleic anhydride be dissolved in trichloromethane and that a specific form of nitrated penicillin be employed for the reaction. In addition, this reaction is somewhat dangerous due to the addition of the hydrogen peroxide to a solution containing substantial amounts of maleic anhydride which results in the production of large amounts of peroxymaleic acid, used as the in situ generated oxidation agent, in the reaction medium.
A method for the oxidation of penicillin G to penicillin-G-1-(S)-oxide is disclosed in Castellvi and Coil, Afinidad XL 111,406, November-December 1986, wherein the potassium salt of penicillin G is oxidized with hydrogen peroxide in the presence of a t
REFERENCES:
patent: 3275626 (1966-09-01), Morin et al.
Micetich, R. G., Synthesis, pp. 264-265 (1976).
Castellvi et al AFINIDAD XLIII, 406 pp. 505-507 1986.
Chemical Abstracts vol. 92 110912b (1980).
"Chemistry of Cephalosporin Antibiotics. Transformations of Penicillin Sulfoxide, A Synthesis of Cephalosporin Compounds" J. Am. Chem. Soc. vol. 91 No. 6, pp. 1401-1407 (1969).
Mangia, A., "A Mild and Convenient Synthesis of Penicillin and Cephalosporin Sulfoxides", Synthesis, pp. 361-363 (1978).
Guddal, E., et al, Tetrahedron Letters, No. 9, p. 381 (1962).
"Oxidation of Penicillin and Dihydrocephalosporin Derivatives with Ozone" J. Org. Chem. vol. 37, No. 5, p. 793 (1972).
"Conversion of Penicillin to Cephalosporin via a Double Sulfoxide Rearrangement" pp. 5006-5011, J. Am. Chem. Soc. (1970), vol. 92, Spry, D. O.
"Improvements In The Penicillin-Cephalosporin Transformation" Gruszecki, W. et al., Symp. Chem. Nat. Prod., 11th, (1978), 3, pp. 44-46.
Naponen, A., "Chem. Eng. News", Feb. 21, 1977, p. 5.
Flynn, Edwin H., "Cephalosporins and Penicillins," Academic Press, pp. 185-214, 1972.
Akzo Nobel N.V.
Mancini Ralph J.
Morris Louis A.
Rizzo Nicholas
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