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Description  |
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BACKGROUND OF THE INVENTION
This invention relates to a novel derivative of
11-aza-10-deoxo-10-dihydroerythromycin A useful as an antibacterial agent,
to intermediates therefor, and to processes for their preparation. More
particularly it relates to the N-methyl derivative of
11-aza-10-deoxo-10-dihydroerythromycin A, to pharmaceutically acceptable
acid addition salts thereof, and to certain alkanoyl derivatives thereof
useful as antibacterial agents, to intermediates therefor, and to
processes for their preparation.
Erythromycin A is a macrolide antibiotic produced by fermentation and
described in U.S. Pat. No. 2,653,899. Numerous derivatives of erythromycin
A have been prepared in efforts to modify its biological and/or
pharmacodynamic properties. Erythromycin A esters with mono- and
dicarboxylic acids are reported in Antibiotics Annual, 1953-1954, Proc.
Symposium Antibiotics (Washington, D.C.), pages 500-513 and 514-521,
respectively. U.S. Pat. No. 3,417,077 describes the cyclic carbonate ester
of erythromycin A, the reaction product of erythromycin A and ethylene
carbonate, as an active and antibacterial agent.
U.S. Pat. No. 4,328,334, issued May 4, 1982, describes
11-aza-10-deoxo-10-dihydroerythromycin A, certain N-acyl- and
N-(4-substituted benzenesulfonyl) derivatives thereof having antibacterial
properties, and a process for their preparation.
The alkylation of primary and/or secondary amine groups of compounds which
include a tertiary amine group is generally complicated. However, it is
common practice to protect tertiary amine groups in such compounds by
converting them to N-oxides prior to alkylation (Greene, "Protective
Groups in Organic Synthesis", John Wiley & Sons, Inc., N.Y., 1981, pg.
281).
SUMMARY OF THE INVENTION
It has now been found that the N-methyl derivative of
11-aza-10-deoxo-10-dihydroerythromycin A and its 2'-, 4"- and/or
2',4"-acetyl-, propionyl- and 3-carbethoxypropionyl derivatives are
effective antibacterial agents against gram-positive and gram-negative
bacteria. The compounds have formula I
##STR1##
wherein R.sub.2 is hydrogen, alkanoyl having from 2 to 3 carbon atoms or
3-carbethoxypropionyl; and R.sub.3 is hydrogen, alkanoyl having from 2 to
3 carbon atoms or 3-carbethoxypropionyl.
Also valuable for the same purpose as formula I compounds are the
pharmaceutically acceptable acid addition salts thereof. Included among
said salts, but by no means limited to said salts, are those enumerated
below: hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate,
propionate, butyrate, citrate, glycolate, lactate, tartrate, malate,
maleate, fumarate, gluconate, stearate, mandelate, pamoate, benzoate,
succinate, lactate, p-toluenesulfonate and aspartate.
This invention also includes the intermediates of formulae II, III and
III-A:
##STR2##
The compounds of this invention of formula I can be named as
N-methyl-11-aza-4-O-(L-cladinosyl)-6-O-(D-desosaminyl)-15-ethyl-7,13,14-tr
rihydroxy-3,5,7,9,12,14-hexamethyloxacyclopentadecane-2-ones. However, for
simplicity, they are referred to herein as N-methyl derivatives of
11-aza-10-deoxo-10-dihydroerythromycin A, the nomenclature used in U.S.
Pat. No. 4,328,334.
The compound of formula II (R.sub.2 =R.sub.3 =H) is named in like manner as
N-hydroxy-11-aza-10-deoxo-10-dihydroerythromycin A N'-oxide, the term
"N'-oxide" referring to oxide formation on the dimethylamino group of the
desosaminyl moiety. The alkylated structure of formula III (R.sub.2
=R.sub.3 =H) is named as N-methyl-11-aza-10-deoxo-10-dihydroerythromycin
bis N-oxide. The stereochemistry at the 11-aza atom of formula III is not
yet known. However, said formula III is intended to embrace the
diastereomers.
As an alternative to the nomenclature used above, the parent compound of
formula IV below can be named as 9-deoxo-9a-aza-9a-homoerythromycin A.
Using this system the compounds of formula I wherein each of R.sup.2 and
R.sup.3 is hydrogen is named 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin
A.
Compounds of formula I and pharmaceutically acceptable acid addition salts
thereof are effective antibacterial agents against gram-positive
microorganisms, e.g. Staphylococcus aureus and Streptococcus pyogenes, and
against gram-negative microorganisms, e.g. Pasturella multocida and
Neisseria sicca. Additionally, they exhibit significant activity against
Haemophilus in vitro. The N-methyl derivative (formula I, R.sub.2 =R.sub.3
=H), is superior to erythromycin A and
11-aza-10-deoxo-10-dihydroerythromycin A in its in vitro activity against
Haemophilus.
The N-methyl derivatives (formula I) surprisingly and unexpectedly exhibit
oral activity against gram-positive and gram-negative microorganisms. The
N-methyl derivative of formula I (R.sub.2 =R.sub.3 =H) exhibits
significant oral activity in vivo whereas no practical oral in vivo
activity is exhibited by 11-aza-10-deoxo-10-dihydroerythromycin A.
DETAILED DESCRIPTION OF THE INVENTION
The N-methyl derivative of 11-aza-10-deoxo-10-dihydroerythromycin A
(formula I) is prepared from 11-aza-10-deoxo-10-dihydroerythromycin A
(formula IV) by the following reaction sequence:
##STR3##
The oxidation of 11-aza-10-deoxo-10-dihydroerythromycin A is conducted in a
reaction-inert solvent, i.e., one which does not react with reactants or
products to produce undesired substances, under the conditions of the
reaction, using as oxidizing agent hydrogen peroxide or a per acid such as
peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, permaleic acid
and perphthalic acid.
The choice of solvent depends, in part, upon the oxidizing agent used. When
using a water soluble oxidizing agent such as hydrogen peroxide or
peracetic acid, a water miscible solvent should be used. When using
oxidizing agents of low water solubility, e.g. perbenzoic or
m-chloroperbenzoic acid, an aqueous reaction mixture is generally avoided
in order to maintain a single phase reaction mixture.
Suitable solvents for use with the latter oxidizing agents are methylene
chloride, chloroform, ethers, e.g. dioxane, tetrahydrofuran.
The oxidation is carried out at ambient temperature; i.e., from about
18.degree.-25.degree. C., for reaction periods of up to 24 hours. An
excess of oxidizing agent is used to ensure maximum conversion of
11-aza-10-deoxo-10-dihydroerythromycin A, the limiting reactant. In
general, from about 1.0 mole to about 35 moles of oxidant per mole of said
limiting reactant is used. In practice, for the sake of economy, from
about 5 to about 15 moles of oxidant are used per mole of the limiting
reactant. Hydrogen peroxide is favored as oxidizing agent because of its
availability. The amine oxide of formula II is isolated by extraction
following removal of destruction of the excess oxidizing agent.
The amine oxide of formula II thus produced is then alkylated by reaction
with an appropriate alkylating agent such as methyl iodide or bromide in a
reaction-inert solvent and in the presence of an acid acceptor.
Representative of reaction-inert solvents useful in this step are
methylene chloride, chloroform, tetrahydrofuran and toluene. Suitable acid
acceptors are inorganic bases such as alkali metal hydroxides and
carbonates, and organic amines such as hindered amine bases, e.g.
2,6-lutidine, said substances being used in at least stoichiometric amount
based on the alkylating agent used.
The alkylating agents are generally used in amounts based upon the amine
oxide reactant ranging from equimolar to up to 100% excess.
The alkylation reaction, when methyl iodide is used as alkylating agent, is
conveniently carried out at ambient temperature. Alkylation by means of
methyl bromide is sluggish at ambient temperatures, requiring prolonged
reaction periods of several days. When methyl bromide is used elevated
temperatures, e.g. up to about 120.degree. C., are favored in order to
expedite reaction.
An alternative alkylation procedure comprises the use of dimethyl sulfate
in a reaction-inert solvent in the presence of an inorganic base such as
those enumerated above. The reaction conditions when using dimethyl
sulfate parallel those mentioned above for the methyl halides.
The intermediate products formed by alkylation of the formula II compound
are isolated, if desired, by standard procedures such as evaporation of
the reaction mixture following water wash thereof to remove inorganic
salts. The reduction products (formula I) of said intermediates are also
isolated by standard procedures such as extraction.
It has been found that alkylation of the crude product resulting from the
oxidation of IV, gives rise to two products; the compound of formula III
identified herein as N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A
bis-N-oxide III; and the mono oxide (III-A) wherein oxide formation is at
the desosaminyl nitrogen. Said compound is referred to herein as
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A desosaminyl-N-oxide.
The above-described intermediates need not be purified prior to their use
in subsequent steps of the above reaction sequence. They can be used in
crude form, i.e., as is, following their separation from their respective
reaction mixtures. From the standpoint of convenience and economy the
intermediates are generally not purified prior to their use in the process
of this invention.
The third and final step of the reaction sequence, the reduction step, is
carried out either catalytically or chemically on the crude product of the
alkylation reaction, or on the individual pure alkylated mono- and
bis-oxides (IIIA and III). Catalytic reduction is carried out at ambient
temperature (e.g. 18.degree.-25.degree. C.) at hydrogen pressures of from
about 1 to about 70 atmospheres in a reaction-inert solvent. Higher
temperatures and pressures can be used, if desired, but offer no
advantages.
Suitable catalysts are the noble metal catalysts, preferably supported, and
certain salts thereof such as the oxides. Representative catalysts are
Pd/C, Rh/C, PtO.sub.2 and Raney nickel. The ratio of catalyst to substrate
is not critical, but is generally in the range of from 1:1 to 1:2.
Typical solvents for the reduction step are C.sub.1-4 alcohols, especially
ethanol, ethyl acetate and ethers, e.g. tetrahydrofuran, dioxan.
In addition to the above-mentioned heterogeneous catalytic reduction,
homogeneous catalysis using, for example,
tris(triphenylphosphine)chlororhodium (I), known as the Wilkinson
catalyst, can be used. Suitable solvents for said reaction are those
enumerated above in connection with the heterogeneous catalyst procedure
and in which the homogeneous catalyst is soluble. The concentration of
homogeneous catalyst is not critical but, for reasons of economy, is
generally kept at levels of from about 0.01 mole percent to about 10 mole
percent by weight based on the substrate.
The hydrogen pressure is not critical but, for the sake of convenience, is
generally within the range of from about 1 to about 70 atmospheres.
In the above discussions of heterogeneous and homogeneous catalysis, even
though the amounts of catalyst which would be used are not generally
considered "catalytic" in the normal usage of this term, they are
considered as catalytic here since little or no reaction would occur in
their absence.
The temperature of the catalytic reductions, heterogeneous or homogeneous,
is not critical, but can vary from about 20.degree. C. to about
100.degree. C. The favored temperature range is from 20.degree. to
80.degree. C.
Chemical reduction of the alkylated amine oxides (III-A and III) is
accomplished by means of metal hydrides such as sodium borohydride, sodium
cyanoborohydride, pyridine-SO.sub.3 /potassium iodide, or zinc/glacial
acetic acid.
Compounds of formula I wherein R.sub.2 and/or R.sub.3 are alkanoyl as
herein defined are conveniently prepared by standard acylation procedures
such as those described by Jones et al., J. Med. Chem. 15, 631 (1972), and
by Banaszek et al., Rocy. Chem. 43, 763 (1969). The 2'- and 4"-hydroxy
groups are acylated by means of the appropriate acid anhydride [e.g.
(R.sub.2 CO).sub.2 O] in pyridine. Solvolysis of the 2',4"-ester with
methanol produces the 4"-ester.
Formation of mixed esters, e.g. 2'-acetyl-4"-propionyl-, is readily
achieved by acylating the 4"-ester (R.sub.3 =propionyl) with acetic
anhydride in a reaction-inert solvent in the presence of potassium
carbonate according to the procedure for mixed esters described by Jones
et al. (loc. cit.).
Acid addition salts of the compounds of this invention are readily prepared
by treating compounds having formula I with at least an equimolar amount
of the appropriate acid in a reaction-inert solvent or, in the case of the
hydrochloride salts, with pyridinium hydrochloride. Since more than one
basic group is present in a compound of formula I, the addition of
sufficient acid to satisfy each basic group permits formation of polyacid
addition salts. When preparing acid addition salts of formula I compounds
wherein R.sub.2 is alkanoyl, isopropanol is used as solvent to avoid
solvolysis of the alkanoyl group. The acid addition salts are recovered by
filtration if they are insoluble in the reaction-inert solvent, by
precipitation by addition of a non-solvent for the acid addition salt, or
by evaporation of the solvent.
A variety of gram-positive microorganisms and certain gram-negative
microorganisms, such as those of spherical or ellipsoidal shape (cocci),
are susceptible to compounds of formula I. Their in vitro activity is
readily demonstrated by in vitro tests against various microorganisms in a
brain-heart infusion medium by the usual two-fold serial dilution
technique. Their in vitro activity renders them useful for topical
application in the form of ointments, creams and the like, for
sterilization purposes, e.g. sick-room utensils; and as industrial
antimicrobials, for example, in water treatment, slime control, paint and
wood preservation.
For in vitro use, e.g. for topical application, it will often be convenient
to compound the selected product with a pharmaceutically-acceptable
carrier such as vegetable or mineral oil or an emollient cream Similarly,
they may be dissolved or dispersed in liquid carriers or solvents, such as
water, alcohol, glycols or mixtures thereof or other
pharmaceutically-acceptable inert media; that is, media which have no
harmful effect on the active ingredient. For such purposes, it will
generally be acceptable to employ concentrations of active ingredient of
from about 0.01 percent up to about 10 percent by weight based on total
composition.
Additionally, many compounds of this invention are active versus
gram-positive and certain gram-negative microorganisms in vivo via the
oral and/or parenteral routes of administration in animals, including man.
Their in vivo activity is more limited as regards susceptible organisms
and is determined by the usual procedure which comprises infecting mice of
substantially uniform weight with the test organism and subsequently
treating them orally or subcutaneously with the test compound. In
practice, the mice, e.g. 10, are given an intraperitoneal inoculation of
suitably diluted cultures containing approximately 1 to 10 times the
LD.sub.100 (the lowest concentration of organisms required to produce
100% deaths). Contol tests are simultaneously run in which mice receive
inoculum of lower dilutions as a check on possible variation in virulence
of the test organism. The test compound is administered 0.5 hour
post-inoculation, and is repeated 4, 24 and 48 hours later. Surviving mice
are held for 4 days after the last treatment and the number of survivors
is noted.
When used in vivo, these novel compounds can be administered orally or
parenterally, e.g. by subcutaneous or intramuscular injection, at a dosage
of from about 1 mg/kg to about 200 mg/kg of body weight per day. The
favored dosage range is from about 5 mg/kg to about 100 mg/kg of body
weight per day and the preferred range from about 5 mg/kg to about 50
mg/kg to body weight per day. Vehicles suitable for parenteral injection
may be either aqueous such as water, isotonic saline, isotonic dextrose,
Ringer's solution or non-aqueous such as fatty oils of vegetable origin
(cotton seed, peanut oil, corn, sesame), dimethylsulfoxide and other
non-aqueous vehicles which will not interfere with therapeutic efficiency
of the preparation and are non-toxic in the volume or proportion used
(glycerol, propylene glycol, sorbitol). Additionally, compositions
suitable for extemporaneous preparation of solutions prior to
administration may advantageously be made. Such compositions may include
liquid diluents; for example, propylene glycol, diethyl carbonate,
glycerol, sorbitol, etc.; buffering agents, hyaluronidase, local
anesthetics and inorganic salts to afford desirable pharmacological
properties. These compounds may also be combined with various
pharmaceutically-acceptable inert carriers including solid diluents,
aqueous vehicles, non-toxic organic solvents in the form of capsules,
tablets, lozenges, troches, dry mixes, suspensions, solutions, elixirs and
parenteral solutions or suspensions. In general, the compounds are used in
various dosage forms at concentration levels ranging from about 0.5
percent to about 90 percent by weight of the total composition.
In the Examples presented herein, no effort was made to recover the maximum
amount of product produced or to optimize the yield of a given product.
The Examples are merely illustrative of the process and of the products
obtainable thereby.
EXAMPLE 1
N-Hydroxy-11-aza-10-deoxo-10-dihydroerythromycin A N'-oxide (Formula II)
To a solution of 11-aza-10-deoxo-10-dihydroerythromycin A (10.0 g) in 40 ml
of methanol, a total of 50 ml of 30% aqueous hydrogen peroxide was added
dropwise while stirring over a 5-10 minute period. After stirring
overnight at ambient temperature, the reaction mixture was poured onto a
stirred slurry of ice (200 g), ethyl acetate (200 ml), and water (100 ml).
Excess hydrogen peroxide was quenched by cautious dropwise addition of
saturated aqueous sodium sulfite until a negative starch-iodine test was
indicated. The layers were separated; and the aqueous layer was washed
twice with 200 ml portions of ethyl acetate. The three organic extracts
were combined, dried over anhydrous sodium sulfate, and evaporated to
afford crude N-hydroxy-11-aza-10-deoxo-10-dihydroerythromycin A N'-oxide
as a colorless foam (8.6 g).
While the crude product proved satisfactory for use in the preparative
procedure described below, purification was readily achieved by silica gel
chromatography, eluting with a methylene chloride: methanol:concentrated
ammonium hydroxide system (12:1:0.1). Progress of the column was followed
by thin layer chromatography on silica gel plates using the system
methylene chloride:methanol:concentrated ammonium hydroxide (9:1:0.1). The
plates were developed with a vanillin spray [ethanol (50 ml): 85% H.sub.3
PO.sub.4 (50 ml):vanillin (1.0 g)] indicator with heat. .sup.1 Hnmr
(CDCl.sub.3) delta 3.21
##STR4##
3.39 (3H, s, cladinose CH.sub.3 O-). MS: major peaks at m/e 576 (ion from
desosamine fragmentation), 418 (aglycone ion-minus both sugars). Both
peaks are diagnostic for
##STR5##
moiety within aglycone.
In like manner, but substituting hydrogen peroxide by an equivalent amount
of peracetic acid, the same compound is produced.
EXAMPLE 2
N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide (Formula III)
To a stirred mixture of N-hydroxy-11-aza-10-deoxo-10-dihydroerythromycin A
N'-oxide (4.83 g), methylene chloride (100 ml) and solid anhydrous
potassium carbonate (69.7 g), was added 15.7 ml (35.8 g) of iodomethane
dropwise under nitrogen over two minutes. The mixture was stirred under
nitrogen at ambient temperature for 3.5 hours and the solid which formed
recovered by filtration. The filter cake was washed with methylene
chloride (250 ml), the filtrate and wash solutions were combined, water
(300 ml) was added, and the pH of the vigorously stirred mixture adjusted
to 11. The organic phase was separated, dried with anhydrous sodium
sulfate, and concentrated to afford crude product as a colorless foam
(4.36 g).
While the crude product proved satisfactory for use in the reduction
procedure described below, purification was readily achieved by the
technique commonly known as "Flash" silica gel chromatography [W. Clark
Still, et al., J. Org. Chem. 43, 2923 (1978)] utilizing 230-400 mesh
silica gel (silica gel/crude material about 45/1 by weight), eluting by
the "flash technique" with acetone/methanol=4/1 by volume. The 10 ml
collected fractions shown to be pure bis-N-oxide by thin layer
chromatography (TLC eluting system:methylene
chloride:methanol:concentrated ammonium hydroxide=6:1:0.1; vanillin:85%
H.sub.3 PO.sub.4 :ethanol spray indicator used with heat on silica gel
plates) were combined. From 1 gram of crude product, 128 mg of pure
bis-oxide was obtained. .sup.1 Hnmr (CDCl.sub.3) delta 3.20
##STR6##
3.39 (3H, s, cladinose CH.sub.3 O-); MS: m/e 461, and 431, 415 (these two
peaks are diagnostic for aglycone N-oxide), 159 (cladinosederived
fragment), 115 (desosamine N-oxide derived fragment).
The above-described chromatographic procedure also afforded a second, less
polar product from the crude:
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A desosaminyl-N-oxide (246
mg).
.sup.1 Hnmr (CDCl.sub.3) delta 2.30
##STR7##
3.37 (3H, s, cladinose CH.sub.3 O-); MS: major peaks at m/e 461, 156, 115.
EXAMPLE 3
N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin A
A solution of the crude product of Example 2, comprising
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A desosaminyl-N-oxide and
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide (4.36 g), in
150 ml of absolute ethanol was hydrogenated on a Parr apparatus (3.52
kg/m.sup.2 ; 8.0 g 10% palladium on carbon catalyst; ambient temperature)
for 11/4 hours. The catalyst was filtered, and the resulting filtrate was
evaporated to dryness, affording a colorless foam (4.3 g). The crude
product was taken up in methylene chloride (100 ml) and then stirred with
water (100 ml) while the pH of the mixture was adjusted to 8.8. The
organic and aqueous layers were separated. The aqueous layer was then
extracted twice with 50 ml portions of methylene chloride. The three
organic extracts were combined, dried over anhydrous sodium sulfate and
evaporated to afford a colorless foam (3.0 g). The entire sample was
dissolved in 11 ml of warm ethanol, and water was added until the solution
became slightly turbid. Upon standing overnight, 1.6 g of the title
product crystallized from solution; m.p.136.degree. C., dec. A
recrystallization by the same procedure raised the melting point to
142.degree. C., dec. .sup.1 Hnmr (CDCl.sub.3) delta 2.31 [6H, s,
(CH.sub.3).sub.2 N-], 2.34
##STR8##
.sup.13 Cnmr [CDCl.sub.3, (CH.sub.3).sub.4 Si internal standard] ppm 178.3
(lactone, C=0), 102.9 and 94.8 (C-3, C-5), 41.6
##STR9##
40.3 [(CH.sub.3).sub.2 -N-]; MS: m/e 590, 432, 158.
EXAMPLE 4
N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin A
The pure N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide of
Example 2 (20 mg) was hydrogenated according to the procedure of Example
3. Thin layer chromatography with the system methylene
chloride:methanol:concentrated ammonium hydroxide (9:1:0.1) and the use of
a vanillin spray as indicator (see Example 2) with heat on silica gel
plates showed a single, uniform product. Its .sup.1 Hnmr and TLC Rf values
were identical to those of the product of Example 3. Yield: 60%.
EXAMPLE 5
N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin A
A solution of crude product of Example 2 comprising
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A desosaminyl-N-oxide and
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide (10.0 g) in
150 ml of absolute ethanol was hydrogenated on a Parr apparatus [3.52
kg/m.sup.2 ; 15 g of Raney-Nickel catalyst (water-wet sludge); ambient
temperature] for 11/2 hours. Work-up as described in Example 3 afforded
8.5 g of the title product, with TLC R.sub.f values identical to those of
Example 3.
EXAMPLE 6
N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin A
A solution of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A
desosaminyl-N-oxide (15 mg) in ethanol (5 ml) was hydrogenated at 2 psi
using 5 mg 5% Pd-C catalyst for 3 hours. Filtration of the catalyst and
solvent removal in vacuo produced the title compound (98% yield) as a
colorless foam. Its .sup.1 Hnmr and TLC R.sub.f values were identical to
those of the product of Example 3.
EXAMPLE 7
N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin A Hydrochloride
To a solution of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A (0.2 g,
0.27 mmole) in 50 ml of ethanol (absolute) is added an equimolar amount of
hydrogen chloride and the reaction mixture stirred at room temperature for
one hour. Removal of the solvent by evaporation under reduced pressure
affords the mono-hydrochloride salt.
In like manner, the hydrobromide, acetate, sulfate, butyrate, citrate,
glycolate, stearate, pamoate, p-toluenesulfonate, benzoate and aspartate
salts of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A, are prepared.
Repetition of this procedure but using twice the amount of acid affords the
di-acid salts of said N-methyl derivative.
EXAMPLE 8
N-Methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-Hydrochloride
To a solution of 2.00 g of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin
A in 50 ml of methylene chloride, a solution of 308 mg of pyridinium
hydrochloride in 25 ml of methylene chloride was added dropwise over
several minutes. The mixture was concentrated to a brittle foam (2.35 g),
was thoroughly pulverized in the presence of 125 ml of water. The clear
aqueous solution was decanted from the water-insoluble residue and
lyophilized to afford the bis-hydrochloride salt of
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A as a colorless amorphous
foam (1.21 g).
Analysis: Calc'd. for C.sub.38 H.sub.72 O.sub.12 N.sub.2.2HCl: 8.65% Cl;
Found: 8.89% Cl.
Treatment of a small portion of the water-soluble product with aqueous
sodium bicarbonate afforded a water-insoluble product having identical TLC
Rf characteristics to those described above for
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A free base.
EXAMPLE 9
2',4"-Diacetyl-N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A
A solution of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A (1.5 g, 2
mmole) in pyridine (50 ml) and acetic anhydride (30 ml) is allowed to
stand at room temperature for 3 days. It is then poured over ice and the
pH adjusted to 9 with 20% NaOH (w/w) solution. Extraction of the mixture
with chloroform (3.times.50 ml) followed by drying the combined extracts
(over K.sub.2 CO.sub.3) and evaporation of the solvent under reduced
pressure affords the title compound.
Repetition of this procedure but using propionic anhydride or
3-carbethoxypropionic anhydride as acylating agents affords the
appropriate 2',4"-diacyl derivatives.
EXAMPLE 10
4"-Acetyl-N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A
2',4"-Diacetyl-N-methyl-10-deoxo-10-dihydroerythromycin A (1.0 g) is
dissolved in 100 ml of methanol and allowed to stand 3 days at room
temperature. Evaporation of the methanol under reduced pressure affords
the title product.
Solvolysis of the 2',4"-dipropionyl- and the 2',4"-3-carbethoxypropionyl
derivatives of Example 9 affords the corresponding 4"-propionyl- and
4"-(3-carbethoxypropionyl)-derivatives.
* * * * *
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