Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-12-18
2004-03-09
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007400, C536S018500
Reexamination Certificate
active
06703372
ABSTRACT:
The present invention relates to macrolides, e.g. azithromycin and similar compounds. Azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A) of formula
is a well-known antibacterial agent, described e.g. in The Merck Index, 12
th
edition (1996), page 157 (946) and may e.g. be produced by
Beckmann rearrangement of erythromycin A 9 oxime to give 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of formula
reduction of a compound of formula II to give 9-deoxo-9a-aza-9a-homoerythromycin A of formula
N-methylation of a compound of formula III to give azithromycin, e.g. of formula I.
Reduction of a compound of formula II to obtain a compound of formula III may be performed e.g. either catalytically under use of hydrogen; or, alternatively, in the presence of borohydrides, e.g. sodium borohydride, which use, however, may result in intermediate borate compounds, e.g. esters of boric acid with one or more of the hydroxy groups of a compound of formula III. The chemical nature of resulting intermediate borate compounds may be dependent on reduction conditions used and different intermediate borate compounds and mixtures thereof may be obtained. E.g. according to data (MS,
11
B and
13
C NMR) e.g. an intermediate borate compound of formula
may be obtained. Hydrolysis of intermediate borate compounds to obtain a compound of formula III may be carried out under acidic conditions which, however, may involve degrading conditions for the macrolide structure. Isolation of the compound of formula III from a reaction mixture resulting from intermediate borate compound-hydrolysis may be performed under neutral or basic conditions and may be complicated because under neutral and basic conditions re-forming of intermediate boron compounds may occur and separation of a compound of formula III from intermediate borate compounds may e.g. afford chromatogrophy. Thus, on industrial scale, reduction of a compound of formula III is preferably carried out catalytically under use of hydrogen.
A process was now found which surprisingly facilitates the isolation of a compound of formula III in a reaction mixture resulting from intermediate borate compound-hydrolysis and which may be carried out on technical scale.
In one aspect the present invention provides a process for the production of a compound of formula III, comprising the steps
i) treating a compound of formula II with a boronated hydride;
ii) hydrolyzing an intermediate borate compound formed in the presence of a polyhydroxylated compound; and, if desired
iii) isolating a compound of formula III from the reaction mixture.
In another aspect the present invention provides a process for the production of a compound of formula III, comprising the steps
i) hydrolyzing an intermediate borate compound formed from a compound of formula II and a boronated hydride in the presence of a polyhydroxylated compound; and, if desired,
ii) isolating a compound of formula III from the reaction mixture.
It was surprisingly found that polyhydroxylated compounds present during hydrolysis of an intermediate borate compound may result in the formation of borate ester, resulting from reaction of boric acid which is generated during hydrolysis, and hydroxy groups of a polyhydroxylated compound. Thus, re-forming of intermediate borate compounds with the macrolide, e.g. a compound of formula III, may be suppressed or avoided and isolation of a compound of formula III may be facilitated.
A process according to the present invention may be carried out as follows:
A compound of formula II which is a known compound may be treated, e.g. stirred, in a solvent, e.g. dissolved, in the presence of boronated hydride, e.g. by addition of boronated hydride to a solution of a compound of formula II (or vice versa). A solution includes a suspension wherein a compound of formula II is at least in part dissolved. A solvent includes solvent appropriate in reduction processes, preferably alcohols such as methanol, ethanol, isopropanol; and ethers, such as tetrahydrofuran; and mixtures of individual solvent, e.g. as cited above. An acid may be present, e.g. may be added to a solution of a compound of formula II, e.g. an acid which is appropriate to accelerate the reduction of imines, e.g. by formation of an iminium ion; including an organic acid, preferably formic acid or acetic acid, and an inorganic acid, preferably hydrochloric acid or sulphuric acid; and mixtures of individual acids, e.g. as cited above. E.g. an acid in aqueous solution may be added to a solution of a compound of formula II. “Boronated hydride” includes a compound containing boron and hydrogen atoms, appropriate to act as a reducing agent, such as
boranes or diboranes, e.g. in the form of stable complexes, such as a complex with tetrahydrofuran, methyl sulfide, pyridine, morpholine, 4-methylmorpholine, 1,4-oxathiane; borane complexes with amines, e.g. including ammonia, tert-butylamine, N,N-diethylaniline, N,N-diisopropylethylamine, dimethylamine, (4-dimethylamino)-pyridine, 4-ethylmorpholine, 2,6-lutidine, triethylamine, trimethylamine; and borane complexes with phosphines e.g. with diphenylphosphine, tributylphosphine, triphenylphosphine;
metal borohydrides, such as sodium and potassium borohydride, sodium and potassium cyanoborohydride and lithium borohydride;
alkylborohydrides, e.g. trialkylborohydrides, e.g tri(C
1-4
)alkyl borohydrides, such as lithium or sodium trimethyl- and triethylborohydride;
alkoxyborohydrides, e.g. trialkoxyborohydrides, such as tri(C
1-4
)alkoxyboro-hydrides, such as sodium trimethoxy-borohydride;
acyloxyborohydrides, e.g. triacyloxyborohydrides, wherein acyl includes (C
2-6
)acyl, such as sodium triacetoxyborohydride;
preferably sodium, potassium and lithium borohydride, sodium and lithium cyanoborohydride; and mixtures of individual boronated hydrides, e.g. as cited above; e.g. in any appropriate form, such as in solid, e.g. powder, pellet, granule form; in solution, e.g. in 2-methyoxyethylether, triethylene glycol dimethyl ether, aqueous solution, e.g. sodium hydroxide solution; e.g. fixed onto a carrier, such as alumina.
An intermediate borate compound, e.g. a borate ester, e.g. such as described above, e.g. of formula IV, may be formed in the reaction mixture and may be isolated, e.g. as conventional, e.g. by evaporating the solvent (system); or e.g. by hydrolyzing an excess of boronated hydride in the reaction mixture, e.g. by treating the reaction mixture with aqueous, e.g. inorganic, acid, adjusting the pH of the mixture obtained to a basic pH, and isolating an intermediate borate compound which may precipitate, e.g. by filtration; or extracting an intermediate borate compound into a solvent which is able to form a two-phase system with water and which is able to dissolve an intermediate borate compound in a two-phase system with water; such as a halogenated hydrocarbon, e.g. methylene chloride; and, if desired evaporating off the solvent.
The amount of a boronated hydrate in respect with a compound of formula II is not critical. An appropriate amount may be easily determined by pre-testing.
An, e.g. isolated, intermediate borate compound obtained may be hydrolized, e.g. in a solvent, e.g. in solution, such as an aqueous solution, e.g. water or an organic solvent which is inert under the reaction conditions and which contains water, e.g. in the presence of an acid, e.g. an inorganic acid, such as hydrochloric acid, sulphuric acid and in the presence of a polyhydroxylated compound, e.g. by addition of a polyhydroxylated compound to a solution (including a suspension) of an intermediate borate compound. An intermediate borate compound obtained in a solution of a solvent which forms a two-phase system with water may e.g. be extracted into an acidic aqueous solvent and a polyhydroxylated compound may be added to the acidic mixture obtained.
A polyhydroxylated compound includes an organic compound having two or more hyroxyl groups, e.g.
linear polyalcohols, such as ethyleneglycol, propyleneglycol, glycerol, 1,2-hexanediol, 1,6-hexanediol, 2,5-hexanediol, 1,2
Bosch Immaculada
Centellas Victor
Diago Jose
Garcia Rafael
Ludescher Johannes
Biochemie S.A.
Furman Diane E.
Lopez Gabriel
Peselev Elli
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