Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-03-22
2002-11-19
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500
Reexamination Certificate
active
06482931
ABSTRACT:
A subject-matter of the present invention is a process for the preparation of 9-deoxo-8a-aza-8a-homoerythromycin A and of its 8a-alkylated derivatives from 9-deoxo-9(Z)-hydroxyiminoerythromycin A.
The present invention relates more particularly to the field of macrolide antibiotics of erythromycin type and more particularly their azamacrolide derivatives, which form the subject-matter of Patent EP 508,699 and correspond to the following general formula:
in which R is a hydrogen atom or a C
1
-C
10
alkyl, C
2
-C
10
alkenyl or C
6
-C
12
arylsulfonyl group, if appropriate substituted.
These compounds are obtained from erythromycin A and their synthesis involves two major stages:
the creation of the 8a-azalide macrocycle from the 9-(E)-oxime of erythromycin A, isomerized to the 9-(Z)-oxime, which is subjected to a stereospecific Beckmann rearrangement, and
the modification of the cladinose group at the 4″-position, consisting of the conversion of the 4″(S)—OH to 41, ″(R)—NH
2
.
The present invention relates more particularly to the first stage and is aimed at providing a novel process which makes it possible to prepare optionally 8a-alkylated 9-deoxo-8a-aza-8a-homoerythromycin A directly from 9-(Z)-oximeerythromycin A of formula II given hereinbelow.
The conventional synthetic route can be represented diagrammatically in the following way:
In fact, the current reaction conditions cannot be extrapolated to the industrial scale.
First of all, they require the isolation of the imidate intermediates III and IV. This is because the reduction with sodium borohydride directly on the reaction mixture comprising said imidate intermediates cannot be linked in because of the inhibiting nature of the pyridine. Furthermore, these intermediates are not very stable and readily dehydrate on isolation. This therefore results in a significant drop in the yield.
Furthermore, the imidate of formula IV is sensitive to epimerization at the 10-position, thus resulting in an additional loss of product.
Finally, the reduction conditions currently used, namely sodium borohydride in ethylene glycol or methanol, are not sufficiently effective with regard to the imidate of formula III.
Consequently, it is difficult under current experimental conditions to obtain an overall yield for these two stages, namely Beckmann rearrangement and reduction with sodium borohydride via the intermediate isolation of the two imidates, which is greater than 30%.
A specific object of the present invention is to provide an effective alternative to the synthetic route discussed hereinabove.
More specifically, a subject-matter of the present invention is a process for the preparation of a compound of general formula V
via the stereospecific Beckmann rearrangement, in a reaction mixture using pyridine as main solvent, of a compound of general formula II
into two intermediate imidates III and IV
and then the reduction of said compounds III and IV, characterized in that said compounds III and IV formed in the reaction mixture of the Beckmann rearrangement are not isolated from said mixture and are employed directly in the reduction stage using a sufficient amount of borohydride, after extraction of the pyridine with a hydrocarbon which is miscible with the latter and in which said imidates III and IV, in the salt form, are insoluble.
According to another characteristic, the process according to the invention is additionally characterized in that the compound of formula V formed on conclusion of the reduction reaction is not isolated from the reaction mixture and is directly N-alkylated therein by the addition of an alkylating reagent to said mixture in an amount sufficient to result in the 9-deoxo-8a-aza-8a-alkyl-8a-homoerythromycin A of formula VI.
The inventors have unexpectedly found that it is possible to reduce the intermediate imidate compounds III and IV with a highly satisfactory yield without isolating them beforehand from said Beckmann rearrangement mixture, with the proviso that the pyridine is extracted from this reaction mixture using a hydrocarbon which is miscible with pyridine and in which the imidates III and IV, protonated at the 3′-dimethylamino group, are insoluble.
It is therefore an opposite approach to the conventional route, which consists in extracting the imidates from the reaction mixture with dichloromethane, after partitioning the residue resulting from the rearrangement comprising them in a water/dichloromethane mixture.
Surprisingly, the use of a hydrocarbon makes it possible to extract and remove the pyridine from the mixture without significant decomposition of the imidate IV and thus makes it possible, on the one hand, to effectively dispense with the stage of isolation of the imidate intermediates, which is harmful in terms of yield and of feasibility on the industrial scale, and, on the other hand, to reduce them more efficiently with an alkali metal borohydride in water and/or an organic solvent. This has the advantage of resulting in an overall yield which is markedly improved with respect to the 30% values mentioned above.
Furthermore, the inventors have also demonstrated that it is possible to N-alkylate the reduced compound obtained directly in the reaction mixture by addition of an aldehyde, without it being necessary to isolate it.
This has the advantages, particularly in the case of N-methylation, of avoiding the use of chloroform and formic acid, such as in the Eschweiler-Clarke process used in particular in the abovementioned Application EP 508 699, and of carrying out the reaction under conditions which are simplified from the viewpoint of temperature and duration.
The process according to the invention will be described in more detail hereinbelow with reference to the following reaction schemes:
With reference to Reaction Scheme 1, the 9-(Z)-oxime of formula II is first of all subjected to a Beckmann rearrangement in a pyridine-based mixture, resulting in the formation of the imidate intermediates III and IV, which are not isolated.
This rearrangement is carried out with sulfonyl chloride preferably selected from tosyl chloride, benzenesulfonyl chloride and mesyl chloride.
According to a preferred embodiment of the invention, the 9-(Z)-oxime of formula II is treated in anhydrous pyridine with tosyl chloride, in the solid form or in solution in an organic solvent, for example in toluene. The amount of tosyl chloride is generally between 1 and 10 equivalents with respect to the 9-(Z)-oxime, preferably between 1.5 and 4 equivalents. The organic solvent is generally present in an amount sufficient to dissolve the tosyl chloride. The reaction is carried out at a temperature preferably of between 0 and 5° C.
After reaction, a hydrocarbon is added to the mixture, which hydrocarbon is miscible with pyridine and the other organic solvents present in said reaction mixture and in which hydrocarbon the imidate intermediates, protonated at the dimethylamino group at the 3′-position, are insoluble. The hydrocarbon is preferably selected from linear-, branched- or cyclic-chain hydrocarbons comprising 5 to 15 carbon atoms. Mention may be made, as representative examples, of pentane, cyclohexane, methylcyclohexane and heptane. It is more preferably heptane.
The mixture is subsequently allowed to separate by settling and the upper phase, comprising the organic solvents, including pyridine, is removed.
The solvent for the reduction reaction, which can be water and/or an organic solvent preferably selected from C
1
-C
10
alcohols, preferably methanol or isopropanol, solvents of the amide type, preferably N,N-dimethylformamide or N,N-dimethylacetamide, or solvents of cyclic urea type, preferably 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) or 1,3-dimethyl-2-imidazolinone (DMEU), is then added to the residue.
A borohydride, preferably sodium borohydride or potassium borohydride, is subsequently added, the reaction temperature preferably being maintained between 0 and 5° C. The amount of borohydride is generally between 3 and 15 equivalents with respect to t
Leon Patrick
Lhermitte Frederic
Oddon Gilles
Pauze Denis
Frommer William S.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Merial
Peselev Elli
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