Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-02-25
2000-08-08
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540218, 540222, 540224, 540225, 540226, 540227, 540228, 540229, 540230, 540215, C07B 6300, C07D50112, C07D50110, C07D50122
Patent
active
06100393&
DESCRIPTION:
BRIEF SUMMARY
SCOPE OF THE INVENTION
In this invention the objective sought is the purification of 7-substituted aminodeacetoxycephalosporins through the use of a specific membrane filtering technology avoiding the quality of the final product being insufficient for subsequent use on account of being accompanied by a large number of impurities.
STATE OF THE ART
One of the most important stages of synthesis in the pharmaceutical manufacture of .beta.-lactam antibiotics is the reaction of enlargement of the ring which provides access to the cephalosporin skeleton, which has a 6-membered heterocyclic structure, from penicillins in which the heterocyclic ring contains 5 atoms. ##STR2##
R1 represents H; R2 may be phenylacetyl, phenoxyacetyl, hexenoyl, 2-hexenoyl, 3-hexenoyl or octanoyl; R3 may be H, a monovalent cation, or an alkyl having 1-3 C atoms.
Enlargement is a special case of the Pummerer reaction starting from penicillin sulphoxides (I), which through heating and the elimination of water give rise to the corresponding cephalosporins (II).
There are many publications which study this reaction in detail, based fundamentally on the already classical work by Morin et al. (J. Amer. Chem. Soc. 85, 1986 (1963); ibid. 91, 1401 (1969)), and other subsequent work in which this idea has been developed and commercialized (Chou. Tetrahedron Lett., 725 (1974); Koming et al. J. Org. Chem., 40, 1346 (1975); Claes et al. J. Antibiotics 32820 (1979); Noyori et al. 37, 3899 (1981)).
In all these there is reference to a greater or lesser extent to the coexistence alongside the desired reaction of other side reactions which unfortunately lead to the formation of a wide range of undesired products which appreciably contaminate the final compound.
The fact of bringing about heating which causes opening and subsequent closing in a molecule of extraordinary lability gives rise to great problems with purity of the final product, due to the existence of a large number of by-products, as shown in the extensive bibliography in the field (U.S. Pat. Nos. 3,275,626; 3,947,465; 4,000,129; 4,003,894; 4,159,267), among which mention should be made of:
Because of this, most of the work published on enlargement of the ring centres on efforts to find reagents and reaction conditions which reduce the always high levels of by-products, and therefore increase the yield (EP 0169144 A2).
Ultrafiltration is a technique for separating dissolved molecules according to size by passing a solution through a sufficiently fine filter to retain most of the large molecules, allowing the small molecules and solvents to pass through. In this way ultrafiltration produces a retained fraction which is rich in large molecules and a filtrate which is largely free from such molecules.
One of the especially significant factors when performing selective purification using the ultrafiltration technique is selection of the membrane.
This choice is influenced by the chemical composition of the membrane itself, which makes it possible to work within specific ranges of pH, pressure and temperature, and also the specific molecular weight cut-off value, which brings about the selective separation of the molecules corresponding to the various products present.
As far as chemical composition is concerned, membranes of cellulose acetate, polysulphones, fluoropolymers and polyether sulphones which can be used over wide ranges of pressure, temperature and pH are known. As for the so-called cut-off value (the nominal molecular weight which will not pass) for each of these, the possibilities available cover an enormous range which includes approximate values of this parameter from 2000 to 500,000.
On the other hand the limits within which the technique of ultrafiltration lies are not clearly defined, so that at the lower limit, which depends fundamentally on the size of pore which ensures a specific cut-off value, mention is now made of a new technique called nanofiltration, which basically corresponds to a type of technique which uses membranes having nominal molecular weight cut-off va
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Ferrero Barruego Oscar
Gonzalez de Prado Emiliano
Lopez Ortiz Juan Francisco
Salto Maldonado Francisco
Vitaller Alba Alejandro
Antibioticos S.A.
Berch Mark L.
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