Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-12-06
2001-11-20
Gitomer, Ralph (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S123100, C514S025000, C514S054000
Reexamination Certificate
active
06320044
ABSTRACT:
BACKGROUND
Orthosomycins are a group of complex lipophilic oligosaccharide antibiotics that are active against gram positive bacteria including methicillin resistant Staphylococci and/or vancomycin resistant Enterococci. Lipophilic oligosaccharide antibiotics include, for example, eveminomicins, the flambamycins, the avilamycins and the curamycins which contain at least one acidic phenolic hydrogen, at least one orthoester linkage associated with carbohydrate residues and usually a nitrogen-containing group. Lipophilic oligosaccharide antibiotics are components from fermented cultures of microorganisms. For example, certain everninomicin type compounds can be prepared from the fermentation of
Micromonospora carbonacea
. Various lipophilic oligosaccharide antibiotics and processes for their preparations are known and taught in U.S. Pat. Nos. 4,597,968, 4,735,903, 5,624,914 and 5,763,600; in A. K. Ganguly et al., The Structure of New Oligosaccharide Antibiotics, 13-384 Components 1 and 5, Heterocycles, Vol. 28, No. 1, (1989), pp. 83-88; in A. K. Ganguly et al., Chemical Modification of Everninomicins, The Journal of Antibiotics, Vol. XXXV No. 5, (1982), pp. 561-570; in V. M. Girijavallabhan & A. K. Ganguly, Kirk-Othmer Encyclopedia of Chemical Technology, 4th Ed., Vol. No. 3, (1992) pp. 259-266; in Derek E. Wright, Tetrahedron Report Number 62, The Orthosomycins a New Family of Antibiotics, Tetrahedron Vol. 35, Pergamon Press Ltd., (1979), pp 1207-1237; and in references cited therein. In addition to being complex in their molecular structures, these antibiotics are highly susceptible to degradation. These complex antibiotics are produced in fermentation broths, together with many impurities, precursors and by-products. Thus, the efficient separation of the antibiotic component from the fermentation broth is highly challenging. It would be highly desirable to provide a method which efficiently recovers the desired lipophilic oligosaccharide antibiotics (orthosomycins) from a fermentation broth or mixture wherein the antibiotics are admixed with other impurities, precursors and/or by-products.
SUMMARY OF THE INVENTION
During our studies with lipophilic oligosaccharide antibiotics, we have discovered an unexpectedly and surprisingly efficient method for recovering the desired lipophilic oligosaccharide antibiotics (orthosomycins) from a fermentation broth.
Accordingly, the present invention is directed toward a process for recovering a lipophilic oligosaccharide antibiotic from an aqueous fermentation broth containing the lipophilic oligosaccharide antibiotic admixed with impurities, by-products and/or suspended solids, comprising:
a) combining said fermentation broth with an adsorbent;
b) adjusting the pH of the broth to alkaline in order to solubilize the antibiotic in the broth;
c) allowing sufficient time for the solubilized antibiotic in the alkaline broth to be adsorbed by the adsorbent;
d) adjusting the pH of the broth to about neutral in order to stabilize the antibiotic adsorbed on the adsorbent; and
e) separating the adsorbent to which the antibiotic is adsorbed from the broth.
In another embodiment, the present invention is directed towards a process for recovering a lipophilic oligosaccharide antibiotic from an aqueous fermentation broth containing the lipophilic oligosaccharide antibiotic admixed with impurities, by-products and/or suspended solids, comprising:
i) combining said broth with an adsorbent;
ii) adjusting the pH of the broth to alkaline in order to solubilize the antibiotic in the broth;
iii) allowing sufficient time for the solubilized antibiotic in the alkaline broth to be adsorbed by the adsorbent;
iv) separating the adsorbent to which the antibiotic is adsorbed from the broth; and
v) washing the adsorbent to which the antibiotic is adsorbed with an aqueous wash having an acid pH such that the final pH of the wash-absorbent mixture is about neutral in order to stabilize the antibiotic.
Optionally, the fermentation broth can be pretreated prior to step a) or i), wherein said aqueous fermentation broth is pretreated by separating the suspended solids from the broth and resuspending the suspended solids in an aqueous medium of about neutral pH to provide said resuspended solids as the fermentation broth for subsequent treatment.
Optionally, the process can further comprise step
f) or vi) separating the antibiotic from the adsorbent to which the antibiotic is adsorbed. Preferably the adsorbed antibiotic is separated from the adsorbent by eluting the adsorbent with an organic solvent.
Also, optionally the process can further comprise step
g) or vii) separating the antibiotic from the organic solvent. Preferably, the lipophilic oligosaccharide antibiotic is of the Formula I:
Also preferred is that the lipophilic oligosaccharide antibiotic of the Formula I has the stereoconfiguration of Formula I′ (or Formula I″ as shown in the Example which follows):
wherein (for either the lipophilic oligosaccharide antibiotic of formulas I or I′), X
1
and X
2
independently represent hydrogen (H) or chloro (—Cl), provided at least one of X
1
and X
2
is chloro;
Ring K is as shown or is hydrogen;
R is —NO
2
, —NO, —NHOH and/or —NH
2
,
R
1
is hydrogen or —OH;
R
2
is —OH or —OR
12
,
wherein
R
12
is alkyl or C(O)R
13
wherein R
13
is alkyl;
R
3
is hydrogen,
—C(O)R
14
, —CH(OH)R
15
or
wherein
R
14
is hydrogen or alkyl,
R
15
is alkyl,
R
16
is hydrogen, alkyl or alkenyl,
R
17
is hydrogen, alkyl or alkenyl,
R
4
is hydrogen or OH;
R
5
is hydrogen or methyl;
R
20
is —OH or —OCH
3
;
R
21
is —OH or —OCH
3
; and
R
22
is hydrogen, —CH
3
or —CH
2
OH.
The dashed line indicates a bond whose stereochemistry can be either in the R or S stereoconfiguration. Preferably, X
1
and X
2
are chloro. Preferably, R
1
is hydrogen or —OH. Also preferred is that R
2
is —OH, —OCH
3
or —OCH
2
CH
2
OH. Preferably R
3
is
Also preferred is that R
4
is hydrogen. Preferably, R
5
is hydrogen. Also preferred is that R
20
and R
21
are —OCH
3
and R
22
is —CH
3
. Preferably, R
3
in oligosaccharide antibiotic of formula I and I′ has the
stereoconfiguration.
In another embodiment, the present invention is directed toward a medium for storing an oligosaccharide antibiotic comprising an adsorbent having a lipophilic oligosaccharide antibiotic adsorbed thereon. Preferably the lipophilic oligosaccharide antibiotic is of formula I, more preferably of formula I′ or I″ as shown in the Example which follows. Preferably, the adsorbent is an insoluble material that is capable of adsorbing a lipophilic oligosaccharide antibiotic from an alkaline aqueous solution or suspension, and releasing the antibiotic into an eluting organic solvent. Also preferred is that the adsorbent is polymeric. Also preferred is that the polymeric adsorbent is comprised of a nonionic, polymeric matrix. More preferably, the adsorbent is comprised of a nonionic, polymeric matrix in which the polymer phase of the matrix is an aliphatic, crosslinked polymer. Also preferred is that the aliphatic, cross-linked polymer has a macroreticular structure, which, together with the aliphatic nature of its surface, imparts adsorptive properties to the adsorbent. Most preferably, the aliphatic, crosslinked polymer is an acrylic.
One advantage of the present invention is that it provides a process for efficiently recovering a lipophilic oligosaccharide antibiotic from a fermentation broth in yields as high or even higher than in other known processes.
A second advantage of the present invention is that it provides a process that is more environmentally acceptable than other known processes. The present process avoids contamination of the whole fermentation broth or resuspended solids therefrom, compared with processes that employ direct extraction of a whole fermentation broth or resuspended solids therefrom with organic solvents which otherwise create a large volume of waste that must be disposed of.
A third advantage of the present invention is that it provides a process for recovering a lipop
Alroy Yair
Blaisdell Steven
Eugene Schaefer
Morenberg Allan
Albanese Margaret M.
Gitomer Ralph
Khare Devesh
Majka Joseph T.
Schering Corporation
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