Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-03-15
1995-02-07
Rizzo, Nicholas
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540227, C07D50104, A61K 31545
Patent
active
053876792
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel process for preparing derivatives of 7-substituted or unsubstituted aminocephalosporanic acid.
The reaction of a thiol compound with the acetoxy group in 3-position of 7-aminocephalosporanic acid (7-ACA) or a 7-substituted amino derivative thereof is an important reaction in the process to obtain synthetic cephalosporins useful as antibacterial agents.
The 7-amino-3-[(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl]-cephalosporanic acid, an intermediate of Cefazolin and Cefazedone synthesis, is produced on a large scale reacting 7-ACA with 2-methyl-5-mercapto-1,3,4-thiadiazole in the presence of sodium bicarbonate in aqueous acetone, at pH=6-7.
The yield is very low (about 60%) because of the degradation of the cephem nucleus in these conditions. Other publications, for example L. D. Hatfield, et al., Phil. Trans. R. Soc. London B. 1980, 289, 173, report the reaction of a thiol compound with 7-ACA or its acylderivatives in anhydrous solvents, in the presence of strong acids like methanesulfonic acid, trifluoroacetic acid, boron trifluoride etherate or acetate.
U.S. Pat. No. 4,317,907 discloses, inter alia, a method to produce 7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-cephalosporanic acid, reacting 2-methyl-5-mercapto-1,3,4-thiadiazole with 7-aminocephalosporanic acid in acetic acid or nitromethane as solvent, in the presence of boron trifluoride or boron trifluoride etherate with yields of about 86%. The purity of the product obtained by this method is low, 80% max. (see comparative examples a and b) because it contains unreacted 7-ACA and degradation products. The use of an intermediate of low purity affects the yield and the quality of the following step for the production of Cefazolin or Cefazedone.
We have found that the reaction of 7-ACA or 7-substituted aminocephalosporanic acids with a thiol compound proceeds with very high yield when it is effected in dialkyl carbonate, in the presence of a dialkyl carbonate trifluoroborane complex and an aliphatic acid. The product so obtained, can be used without any purification in the following step of the process to produce cephalosporins antibiotics.
A dialkyl carbonate trifluoroborane is a complex of boron trifluoride and a carbonic acid alkyl ester.
The diethyl carbonate trifluoroborane complex has been obtained from boron trifluoride and diethyl carbonate (J. Am. Chem. Soc. 1966, 88, 3058).
The existence of dimethyl carbonate trifluoroborane complex has been demonstrated studying the enthalpy of the complex formation but it has not been isolated. (P. C. Maria et al. J. Phys. Chem. 1985, 89, 1296 and J. Chim. Phys., Phys. Chim. Biol. 1985, 80 (4), 427).
Except the two above reported, no other dialkyl carbonate trifluoroborane complexes are known and they have never been used as catalysts for any reaction.
Another advantage of the invention is the use of dialkyl carbonates as a medium of reaction as far as it concerns environmental hygiene and ecology.
Dialkyl carbonates are, as a matter of fact, substances with a high and greater thermal stability as compared to solvents such as acetonitrile and nitromethane used in the known technique and considered potentially dangerous for the easiness in decomposition.
Dialkyl carbonates have, moreover, a low toxicity, are not mutagenic and they are not therefore dangerous for operators and for the environment.
According to the present invention, there is provided a process for preparing a compound of the formula (I) ##STR4## wherein R is an heterocyclic group which contains at least one nitrogen atom with or without oxygen or sulphur and R.sup.1 and R.sup.2 are both hydrogen atoms or one of them is an hydrogen atom and the other i s an acyl group, or a salt thereof; the process comprising reacting a compound of formula (II) ##STR5## wherein R.sup.1 and R.sup.2 are each as defined above, and wherein, if necessary, any reactive group is protected by a suitable protective group, or a salt thereof, with a compound of formula (III) acid and of a compound of formula (IV) ##STR6
REFERENCES:
patent: 4317907 (1982-03-01), Saikawa et al.
patent: 4385178 (1983-05-01), Saikawa et al.
patent: 4472574 (1984-09-01), Hug
Chemical and Pharmaceutical Bulletin, vol. 33, No. 12, Dec. 1985, Tokyo, Japan, Isamu Saikawa et al.: "An Efficient Method for the preparation of 3-(SUBSTITUTED THIOMETHYL)-7-aminocephalosporins", pp. 5534-5538.
Ribaldone Giuseppe
Sogli Loris
Terrassan Daniele
Antibioticos S.p.A.
Rizzo Nicholas
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