Note: Descriptions are shown in the official language in which they were submitted.
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This invention relates to an improved process for
converting rosamicin to 12,13-desepoxy-12,13-dehy-
drorosamicin.
Rosamicin, formerly known as Antibiotic 67-694 which
antibiotic and certain deri~atives thereof are described
in the British Patent No. 1,302,142 granted May 2, 1973
entitled~ Antibiotic 67-694 and Methods ~or Production
Thereof. Rosamicin is elaborated by Micromonospora
rosaria which is also described in the aforementioned
British Patent. Rosamicin has the following structural
formula
~ ~J ~, 2
0~0~ .
As can be seen from formula I, rosamicin is a dihydroxy
compound ha~ing one hydroxyl group at the 3-position of
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the macrolide ring and another at the 2'-position of the
glycosidically linked sugar moiety. Both hydroxyl groups
are susceptible to esterification. However, it is the
group at the 2'-position which is first to react. Thus,
in order to form a 3-monoester, it i~ necessary to esterify
both hydroxyl groups and employ a selective hydrolysis to
remove the 2'-ester function. Such a hydrolysis is
described in South African Patent 73/8630 granted
August 16, 1974 entitled: Novel Monoesters of Rosamicin.
(The novel hydrolysis process is equally applicable to
the 3,2'-diesters of the compounds of this invention.)
Rosamicin can be converted to 12,13~desepo~y-12,13-dehydro-
rosamicin. According to one process, which is analogous to
processes known in the art, rosamicin is dissolyed in
an organic acid, e.g. (acetic acid) and treated with an
alkali metal iodide, preferably potassium iodide at ele-
vated temperatures for about one hour until a composi-
tion of matter containing 12,13-desepoxy-12,13-dehy-
drorosamicin is formed, separating the reaction prod-
uct, and isolating the individual compounds so produced
by chromatography.
In effecting the above process, it is usually necessary to
heat the reaction mixture to the reflux temperature in an
acidic medium thereby risking the decomposition of the
starting material and~or the decomposition of the product.
, . ,
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Therefore this process gi~es yields of from about 30 % to
about 50 % of theory and its product consists Or substan-
tial amounts of both the `cis and trans isomers.
According to the novel process of this invention rosamicin
can be conYerted to 12,13-desepoxy-12,13-dehydrorosamicin
in yields of about 85 % to 95 %, said compound being about
90 % pure. Further this novel process yields a product
which is rich in the trans isomer and, therefore, daes not
require chromatographic separation of the isomers.
The novel process comprises reducing rosamicin in a
preferably dilute mineral acid solution containing chro-
mous ions in an oxygen free atmosphere. The reducing agent
i.e. the chromous ions are advantageously supplied in the
form of a solution containing a chromous salt wherein the
anion is derived from a mineral acid e.g. chromous chloride,
chromous sulfate, chromous iodide, or the like. The pre-
ferred reducing agent is chromous chloride which may
adYantageously be prepared by the procedure described in
Inorganic Synthesis, Volume III, pages 148-150, published
by McGraw-Hill (1950). It is preferred-that the chromous
chloride solution be freshly prepared immediately before
use to mitigate against chromic ion formation.
Further, for optimum yields of the desired product, the
- ratio of chromous ions to the starting material must be
. .~
.
~..~
.,.~,~. . .
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in the range of from 2.0 to 2.2 moles per mole. When the
ratio o* chromous ions to the starting material is below
2.0, some rosamicin remains unreduced. Conversely, when
the ratio of chromous ion to the starting material is
above 2.2, reduction of the desired product occurs.
The mlneral acids useful for e~fecting this process are
for example hydrohalic (e.g. hydrochloric), phosphoric,
nitric and, preferably, sulfuric. Further, it is pre~erred
that the strength of the acid be ~rom about 0.5N to about
~.ON, preferably about l.ON.-The concentration of rosa~
micin in the reaction mixture may be varied o~er a sub
stantial range, pro~ided the pH of the reaction mixture
does not exceed 2.0 and the range being maintained pre-
ferably between pH o.8 and 2 preferably at a pH o~ about
1Ø Rosamicin being basic reacts with one equivalent of
acid per mole thereby raising the pH of the reaction
mixture. The preferred concentration of resamicin in the
reaction mixture is about 125-175 mgs/ml.
The reaction proceeds at temperatures of from about 10C
to about 40C, about 25C being preferred. The reaction
may be allowed to proceed from about 8 to about 24 hours
with about 15 to 20 hours being preferred.
B~
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After conversion of rosamicin to 12,1~-desepoxy-12,13-
dehydrorosamicin is complete, the product is isolated
by conventional means, preferably by extracting with a
water immiscible organic solvent then basifying the
reaction mixture and re-extracting with a water immis-
cible organic solvent. The product is then finally iso-
lated by evaporation of the solvent,
Rosamicin is preferably reduced at 25C in lN sulfuric
acid under argon with chromous ions derived from chromous
chloride wherein the mole ratio of chromous chloride to
rosamicin is 2.2. to 1 and wherein the reduction is
allowed to proceed for about 18 hours.
The following example is set forth to illustrate the
best mode contemplated for effecting the process of this
invention. However~ it should not be construed as limi-
ting the scope thereof.
'~ .
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Example
12,13-Desepoxy-12,13-dehydrorosamicin
Dissolye 50 gms. of rosamicin in 300 ml. of IN sul-
furic acid under argon. Add 51.5 gms. of chromic chlo-
ride hexahydrate in 80 ml. of water and 20 ml. of sul-
furic acid which has been dripped through a column of
100 gms. of amalgamated zinc thereby forming an equiva~
lent quantity of chromous ions (see Inorganic Synthesis,
~olume 3, pages 148-150). At this point the pH of this
solution should be about 0.8 to 1.2. Allow the reaction
to stand at room temperature (25C) overnight (18 hours)
under argon. Extract the reaction mixture with 500 ml. of
ethyl ether. Adjust the reaction mixture to pH 8 with 8N
sodium hydroxide. Extract the reaction mixture with 2,0 `
liters-of ethyl ether and filter the extract. ~ash the
extract with water and concentrate the extract to a re-
sidue. Dissolve the residue in ethanol; water (1:2) and
lyophilize.
Yield 44.7 gms. (89.4 %) [-~-]D 5 = -29.3 (C=3 % CHC13)
\ CH3OH
~ ~max 283 nm ( ~ =20,420)
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The product of the foregoing example, i.e. 12,13-
desepoxy-12,13-dehydrorosamicin is active against a
broad spectrum of bacteria and is especially useful
against Gram-positive bacteria. Exemplary of the
organisms against which the compound may be used are
strains of such species as Staphylococcus aureus,
Streptococcus pyogenes, Bacillus subtilis, Escherichia
c_ , Proteus vulgaris, Pseudomonas aeruginosa, Diplo-
coccus pneumoniae, Proteus mirabilis, Proteus morganii
and the like.
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