It is known that rifampicin is a compound with very good antibiotic properties which is used particularly as an antitubercular compound.
At present, only three processes for the manufacture of rifampicin are known, these being described in U.S. Pat. Nos. 3,342,810; 3,542,762 and 3,963,705.
According to U.S. Pat. No. 3,342,810, rifampicin is prepared by mildly oxidising a Mannich base of rifamycin SV and then mildly reducing the mixture thus obtained to give 3-formylrifamycin SV which is then reacted with 1-amino-4-methylpiperazine to form rifampicin.
According to U.S. Pat. No. 3,542,762, rifampicin is prepared by reacting rifamycin S with formaldehyde and with a primary aliphatic amine or with a condensation product thereof in the presence of manganese dioxide and then treating the reaction mixture with about 2 equivalents of 1-amino-4-methylpiperazine.
According to U.S. Pat. No. 3,963,705, rifampicin is obtained by reacting rifamycin S with an N-bis-alkoxymethyl-amine or an N-bis-hydroxymethyl-amine to give a well-defined intermediate compound, namely a 1,3-oxazino (5,6-c) rifamycin belonging to a well defined group of compounds specified in this Patent Specification which reacts in distinctly basic medium with the 1-amino-4-methylpiperazine to give rifampicin.
The process described in U.S. Pat. No. 3,342,810 has the disadvantage of requiring four successive reactions, beginning with the starting compound, rifamycin S, which have to be carried out with the isolation of two intermediate compounds, namely the Mannich base of rifamycin SV and of the 3-formylrifamycin SV. This means having to use several reaction vessels for the industrial production, involving high production costs and low yields.
This is also confirmed by the patentee of this U.S. Patent Specification who admits, in subsequent U.S. Pat. No. 3,542,762 that it is not economically advantageous, and defines the second process as being "much more convenient" (line 53, column 1).
The process of U.S. Pat. No. 3,542,762 has the disadvantage of requiring the reactions to be carried out in two different steps: condensation of rifamycin S to give a Mannich base and then oxidation to a Schiff base as the first step; then, after filtering off the manganese dioxide (this filtration is necessary because possible contact of even traces of manganese dioxide with 1-amino-4-methylpiperazine could give rise to explosion and fire), the second step is carried out involving two more reactions, namely, reduction of the Schiff base which is in the quinone form and then transimination of the hydroquinone Schiff base thus obtained to give rifampicin. This again involves high costs and low yields.
Both U.S. Pat. No. 3,342,810 and U.S. Pat. No. 3,542,762 involve oxidation reactions and successive reductions, with intermediate filtration, and, therefore, require the use of different reaction vessels.
According to U.S. Pat. No. 3,963,705, the reaction of rifamycin S with an N-bis-alkoxymethylamine or a N-bis-hydroxymethyl-amine necessarily gives rise to the formation, together with the 1,3-oxazino (5,6-c) rifamycin, of two molecules of alcohol or water which impair the reaction. This is demonstrated by the fact that the use of aprotic dipolar solvents is preferred; in fact, the same reaction carried out in the presence of the aprotic dipolar solvent (Example 14) gave a yield which was three times greater than that obtained with the use of n-propanol (Example 15).
According to the same U.S. Patent Specification, the intermediate compound 1,3-oxazino (5,6-c) rifamycin must be isolated in a solid state or by extraction with water-immiscible solvents and then reacted in a basic medium with 1-amino-4-methylpiperazine, meaning that the entire process is, in practice, carried out in two distinct steps.
As is known (J. Med. Chem., 11, 936/1968), the use of a basic medium can cause desacetylation and/or transacetylation of rifampicin, thus giving derivatives of rifampicin which do not have a useful antimicrobial activity: indeed, the transacetyl derivatives of rifampicin have practically no antibiotic activity in vitro, and the desacetyl derivative, although possessing antibiotic activity in vitro, is not absorbed (see Antibiotica et Chemotherapia, 16, 317/1970). Therefore, the use of basic media gives rise to impure rifampicin which requires purification by successive crystallisation, this decreasing the yield.
Finally, again referring to U.S. Pat. No. 3,963,705, independently of all the above considerations, repetition of the preparations described in the Examples, in spite of using identical experimental conditions, gave substantially lower yields than those reported.
It is an object of the present invention to provide a process for the preparation of rifampicin which can be carried out in one step and in one solvent system, without isolation of any intermediate compounds or phases.
Another object of the present invention is to provide a process by means of which it is possible to produce rifampicin with high yield and purity which, in particular, is substantially free of transacetylation and desacetylation derivatives of rifampicin.
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