Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
6~
This application is divided from applicants copending G~n~ n
application Serial No. 432,606 filed July 18, 1983 which is directed to
a compound oE the formula
0';"~
OCH3
or a pharmaceutically acceptable acid addition salt thereof wherein
R2 is hydrogen, alkanoyl having from 2 to 3 carbon atoms or 3-
carbethoxypropionyl;
R3 is hydrogen, alkanoyl having from 2 to 3 carbon atoms or 3-
carbethoxypropionyl.
This invention relates to a novel intermediate for the
preparation of ll-aza-10-deoxo-10-dihydroerythromycin A a useful anti-
bacterial agent, and to processes for the preparation of the intermediate.
Erythromycin AiS a macrolide antibiotic produced by
fermentation and described in United States Patent 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. United States Patent No. 3,417,077 describes the cyclic
carbonate ester of erythromycin A, the reaction product of erythromycin A
and ethylene carbonate, as an active antibacterial agent.
6~9
United States Patent 4,328,334, issued May 4, 1982, describes
ll-aza-10-deoxo-10-dihydroerythromycin A, certain N-acyl- and N- (4-
substituted benzenesulfonyl) derivatives thereof ~aving 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).
The present invention is useful in the preparation of compounds
of formula I above.
According to the present invention, there is now provided
a process for making a compound having formula (II)
o
UO, ~ )2 (II)
\
OCH3
which comprises reacting a compound of the formula
-- 2 --
~2~2~g
~ HO, ~(CH3)2
HO/,/ ~ (IV~
HO
~ ~ '~
OCH3
with an oxidizing agent in a reaction-inert solvent.
The present invention, together with that of aforementioned
C~rt~fl;~n Application Serial No. 432,606, will now be described in more detail.
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, Eumarate,
gluconate, stearate, r~nd~l~te~ pamoate, benzoate, succinate, lactate, p-
toluenesulfonate and aspartate.
Other intermediates of formula III and IIIA
H (~)n~ H~ ~ )2
HO I III n = 1
~OC
- are described in a further copending divisional application~ 4~-
2~
The compounds of formula I can be named as N-methyl-ll-
aza-4 -O(L-cladinosyl)-6-0-(D-desosaminyl)-15-ethyl-7,13,14-
trihydroxy-3,5,7,9,12,14-hexamethyloxacyclopentadecane-2-ones.
However, for simplicity, they are referred to herein as N-methyl
derivatives of ll-aza-10-deoxo-10-dihydroerythromycin A, the
nomenclature used in U.S. Patent 4,328,334.
The compound of formula II (R2 = R3 = H) is named in
like manner as N hydroxy-ll-aza-10-deoxo-10-dihydroerythromycin A
N'-oxide, the term "Nl-oxide" referring to oxide formation on the
dimethylamino group of the desosaminyl moiety. The alkylated
structure of formula III (R2 = R3 = H) is named as N-metyl-ll-
aza-10-deoxo-10-dihydroerythromycin bis N-oxide. The stereo-
chemistry at the ll-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 R2 and R3 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 micro-organisms, e.g. Staphylococcus aureus
and Streptococcus pyogenes, and against gram-negative micro-
organisms, e.g. Pasturella multocida and Neisseria sicca. Ad-
ditionally, they exhibit significant activity against
Haemophilus _ vitro. The N-methyl derivative (formula I, R2 =
R3 - H), is superior to erythromycin A and ll-aza-10-deoxo-10-
_ D~ --
~z~
dihydroerythromycin A in its in vitro activity against
Haemophilus.
d
- 4a -
6~L9
--5--
The N-methyl derivatives (formula I) surprising-
ly and unexpectedly exhibit oral activity against
gram-positive and gram-negative microorganisms. The
N-methyl derivative of formula I (R2 = R3 = Hj
S exhibits significant oral activity ln vlvo whereas no
practical oral _ vivo activity is exhibited by 11-
aza-10-deoxo-10-dihydroerythromycin A.
The N-methyl derivative of ll-aza-l~-aeoxo-10-
dihydroerythromycin A (formula I) is prepared fromll-aza-10-deoxo-10-dihydroerythromycin A (formula IV)
by the following reaction sequence:
HO N(CH3)2
HO" ~ ",O ~ H2O2
~, ~ " ' ¢~X
OCH3
IV Alkylating
Agent
I ~ Reduction III/III-A
The oxidation of ll-aza-10-deoxo-10-dihydro-
erythromycin 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.
--6--
The choice of solvent depends, in part, upon the
oxidizing agent used. When using a water soluble
oxidizing agent such as hydrogen ~eroxide 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 generallv 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 tempera-
ture; i.e., from about 18-25C, for reaction periods
of up to 24 hours. An excess of oxidizing agent is
used to ensure maximum conversion of ll-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 sa~e 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 or destruction of the excess
oxidizing agent.
The amine oxide of formula I~ 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,
chlorofor~, tetrahydrofuran and toluene. Suitable
:~Z~26~L9
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 120C, are favored in order to
expedite reaction.
An alternative alkylation procedure comprises
the use of dimethyl sulfate in a reaction7inert
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.
Z6~L9
--8--
It has been found that alkylation of tne crude
product resulting from tlle oxidation of IV, gives
rise to two products; the compound of formula I~I
identified herein as N-~ethyl~ aza-10-deoxo-10-
dihydroerythromycin A bis-N-oxide ~II; and the ~ono
oxide (III-A) wherein oxide formation is at the
desosaminyl nitrogen. Said compound is referred to
herein as N-methyl-ll-aza-10-deoxo-10-dihydroerythro-
mycin A desosaminyl-~-oxide.
The ahove-described inter~ediates 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 inter-
mediates 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 catalytical-
ly or chemically on the crude product of the alkylationreaction, or on the individual pure alkylated mono-
and bis-oxides (IIIA and III). Catalytic reduction
is carried out at ambient temperature (e.g. 18-25C)
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. ~epresentative catalysts are Pd/C,
Rh/C, PtO2 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.
~2~)26~
g
Typical solvents for the reduction step are
Cl 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 enumerat-
ed above in connection with the heterogeneous catalyst
procedure and in which the homogeneous catalyst is
soluble. The concentration of homogeneous catalyst
is not critlcal but, for reasons of economy, is
generally kept at levels o from about 0.01 mole
percent to about lO 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 catalysisr 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 catalytlc here since
little or no reaction would occur in their absence.
The temperature of the catalytic reductions,
heterogeneous or homogeneous, is not critical, but
càn vary from about 20C to about 100C. The favored
temperature range is from 20 to 80C.
Chemical reduction of the alkylated amine oxides
(III~A a~d III) is accomplished by means of metal
hydrides such as sodium borohydride, sodium cyano-
borohydride, pyridine-SO3/potassium iodide, or
zinc/glacial acetic acid.
~L2~ 9
-10-
Compounds of formula I wherein ~2 and/or R3 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.
(R2CO)2O] in pyridine. Solvolysis of the 2',4"-ester
with methallol produces the 4"-ester.
Formation of mixed esters, e.g. 2'-acetyl-4"-
propionyl-, is readily achieved by aeylating the 4"-
ester (R3 = propionyl) with acetie anhydride in a
reaetion-inert solvent in the presence o~ pc,tassium
earbonate aceording to the procedure for mi~ed esters
deseribed by Jones et al. (loc. cit.).
Aeid addition salts of the compounds oE for~nula I
are r~adily prepared by treating compounds
having formula I with at least an equimolar amount of
the appropriate aeid in a reaetion-inert solvent or,
in the ease of the hydrochloride salts, with pyri-
dinium hydroehloride. Sinee more than one basie
group is present in a eompound of formula I, the
addition of suffieient aeid to satisfy eaeh basie
group permits formation of polyaeid addition salts.
When preparing aeid addition salts of formula I
eompounds wherein R2 is alkanoyl, isopropanol is used
as solvent to avoid solvolysis of the alkanoyl group.
The acid addition salts are reeovered by filtration
if they are insoluble in the reaetion-inert solvent,
by preeipitation by addition of a non-solvent for the
aeid addi-tion salt, or by evaporation of the solvent.
A variety of gram-positive mieroorsanisms and
eertain gram-negative microorganisms, such as those
of spherieal or ellipsoidal shape (coeei), are
susceptible to eompounds of formula I. Their in
~Z~Z6~
~11-
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
teehnique. Their in vitro activity renders them
useful for topical application in the form of ointments,
ereams and the like, for sterilization ourposes, e.g.
siek-room utensils; and as industrial antimicrobials,
for e~ample, in water tre2tment, slime eontrol, paint
and wood preservation.
For _ vitro use, e.g. for topical application,
it will often be convenient to co~pound the seleeted
produet with a pharmaceutically-acceptable carrier
sueh as vegetable or mineral oil or an emollient
eream. Similarly, they may be dissolved or dis?ersed
in liquid earriers or solvents, such as water,
aleohol, ~lyeols or mixtures thereof or other pharma-
eeutieally-aeceptable inert media; that is, media
whieh have no harmful effect on the active ingredient.
For such purposes, it will generally be acceptable to
employ eoncentrations of active ingre~ient of from
about 0.01 percent up to about 10 percent by weight
based on total eomposition.
Additionally, many of the compou~ds
are aetive versus gram-positive and eertain gram-
negative micraorganisms in vivo via the oral and/orparenteral routes of administration in animals,
ineluding man. Their in vivo aetivity is more
limited as regards susceptible organisms and is
determined by the usual proeedure which eomprises
infecting miee of substantially uniform weight with
the test organism and subsequently treating them
orally or subcutaneously with the test compound, In
praetiee, the mice, e.g. 10, are given an intra-
peritoneal inoculation of suitably diluted eultures
eontaining approximately 1 to 10 times the LDloo
~2~6~
(the lowest concentration of organisms required to
produce 100~ deaths). Control tests are simultaneous-
ly run in which mice receive inoculum of lower
dilu~ions as a check on possible variation in virulence
o~ 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 ln vivo, these novel compounds can be
administered orally or parenterally, e.g. by sub-
cutaneous 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 of 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),
dimethylsuloxide and other non-aqueous vehicl'es
wh'ich will not interfere with therapeutic efficiency
of the preparation and are non-toxic in the volume or
proportion ùsed tglycerol, 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 a~ents, hyaluronidase, local anesthetics
and inorganic salts to afford desirable pharmacological
properties. These compounds may also be combined
with various pharmaceutically-acceptable inert
Z~9
carrlers including solid diluents, aqueous vehicles,
non-toxic organic solvents in the form of capsules,
tablets, lozenges, troclles, 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 praducts obtainable thereby.
~L2C~Z6~9
-14-
EXAMPLE 1
N-Hydroxy~ aza-10-deo~o-10-dihydro-
erythromycin A ~'-oxide (Formula II)
To a solution of ll-aza-10-deoxo-10-dihydro-
erythromycin ~ (10.0 g) in 40 ml of methanol, a totalof 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 hydroyen peroxide was quenched by
cautious dropwise addition of saturated aqueous
sodlum 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 ~-hydroxy-ll-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 ~y 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
H3PO4 (`50 ml):vanillin (1.0 g)] indicator with heat.
Hnmr (CDC13) delta 3.21 [6H, s, (CH3)2~-~o], 3.39
(3H, s, cladinose cH3o~ S: major 2eaks at m/e 576
(ion from desosamine fragmentation), 418 (aglycone
ion-minus both sugars). Both pea~s are diagnostic
for ~ OH moiety within aglycone.
312()26~
-15-
In like manner, but substituting hydrogen
peroxide by an equivalent amount of peracetic acid,
the same compound is produced.
EXAMPLE 2
N-Methyl-ll-aza-10-deoxo-10-dihydro-
erythromycin A bis-N-oxide (Formula III)
To a stirred mixture of N-hydroxy-ll-aza-10-
deoxo-10-dihydroerythromycin A Nl-oxide (4.83 g),
methylene chloride (100 ml) and solid anhydrous
potassium carbonate (69.7 g), was added 15.7 ml
~35.8 g) o~ 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 ad~usted to 11. The organic phase
was separated, dried with anhydrous sodium sul~ate,
and concentrated to afford crude product as a color-
less 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. ~. Chem. 43, 2923
(1978)] utilizing 230-400 mesh silica g~ (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 ~ractions shown to be
pure bis-N-oxide by thin layer chromatography (TLC
eluting system:methylene chloride:methanol:concen-
trated ammonium hydroxide = 6:1:0.1; vanillin:85
H3PO4:ethanol spray indicator used with heat on
~2(~26~9
-16-
silica gel plates) were combined. From 1 gram of
crude product, 128 mg of pure bis-o~ide was obtained.
l~nmr (CDC13) delta 3.20 [9H, broad s, aglycone
CH3-N--~O and (CH3)2 , j, 3.39 (3H, s, cladinose
CH30-); MS: m/e 461, and 431, 415 (these two peaks
are diagnostic for aglycone `N-oxide), 1~9 (cladinose-
derived fragment), 115 (desosamine N-oxide derived
fragment).
The above-described chromatographic procedure
also afforded a second, less polar product from the
crude: N-methyl-ll-a~a-10-deoxo-10-dihydxoerythro-
mycin A desosaminyl-N-oxide (246 mg).
Hnmr (CDC13) delta 2.30 (3H, s, aglycone
CH3-~-), 3.18 [6H, s, (CH3)2-N-~0], 3.37 (3H, s,
cladinose CH30-); MS: major peaks at m/e 461, 156,
115.
EXAMPLE 3
N-Methyl~ll-aza-10-deoxo-
10-dihydroerythromycin A
A solution of the crude prcduct of Example 2,
comprising N-methyl-ll-aza-10-deoxo-10-dihydroerythro-
mycin A desosaminyl-N-oxide and N-methyl-ll-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 ; ~.0 g 10~ palladium on
carbon catalyst; ambient temperature) for 1 1/4
hours. The catalyst was filtered, and the resulting
filtrate was evaporated to dryness, affording a
colorless foam ~4.3 g). The crude produc-t was taken
up in methylene chloride (100 ml) and then stirred
with water (100 ml) while the pH of the mi~ture 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
~2026~9
-17~
colorless foam (3.0 g). The entire sample was
dissolv~d in 11 ml of warm ethanol, and water was
added until the solution became slightly turbid.
~pon standing overni~ht, 1.5 g of the title product
crystallized from solution; m.p. 136C, dec. A
recrystallization by the same procedure raised the
melting point to 142C, dec. lHnmr (CDC13) delta
2-31 [6H, s, (CH3)2N-], 2.34 (3H, s, aglycone CH3-N-);
Cnmr [CDC13, (CH3)4Si internal standard] ppm 178.3
(lactone, C = O), 102~9 and 94.8 (C-3, C-5), 41.6
(aglycone CH3-N-), 40.3 [(CH3)2-N-~; MS: m/e 590,
432, 158.
EXAMPLE 4
N-~lethyl-11-aza-10-deoxo-
10-dihydroerythromvcin A
The pure N-methyl-ll-aza-10-deoxo-10-dihydro-
erythromycin ~ bis-N-oxide of Example 2 (20 mg) was
hydrogenated according to the procedure of Example 3.
Thin layer chromatography ~ith 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 sho~ed
a single, uniform product. Its lHnmr and TLC Rf
values were identical to those of the product of
Example 3. Yield: 60~.
12026~l9
18-
EXAMPLE 5
N-Methyl-ll-aza-lO-deoxo-
10-dihydroervthromycin A
A solution of crude product of Example 2 compris-
ing N-methyl-ll-aza-10-deoxo-10-dihydroerythromycin A
desosaminyl-N-oxide and ~-~ethyl-ll-aza-lO-deoxo-lO-
dihydroerythromycin A bis-N-oxide (10.0 g) in lS0 ml
of absolute ethanol was hydrogenated on a Parr
apparatus [3.52 kg/m2; 15 g of Raney-Mic~el catalyst
(water-wet sludge); ambient temperature] for 1 1/2
hours. Work~up as described in Example 3 af~orded
8.5 g of the title product, with TLC R~ values
identical to those of ~xample 3~
EXAMPLE 6
N-Methyl-ll-aza-lO-deoxo-
lO-dihydroerythromycin A
A solution of N-methyl-ll-aza-lO-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 rernoval ln vacuo produced the
title compound (98~ yield) as a colorless foam. Its
Hnmr and TLC Rf values were identicai to those of
the product of Example 3.
EXAMPLE 7
N-Methyl-ll-aza-lO-deoxo-lO-
dihydroerythromycin A Hydrochloride
To a solution of N-methyl-ll-aza-lO-deoxo-lO-
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.
12~z~L9
--19--
In like manner, the hydrobromide, acetate,
sulfate, butyrate, citrate, glycolate, stearate,
pamoate, p-toluenesulfonate, benzoate and as~artate
salts of N-methyl~ aza-10-deoxo-10-dihydroerythro-
mycin A, are prepared.
Repetition of this prGcedure but using twice the
amount of acid affords the di-acid salts of said
N-methyl derivative.
EXAMPLE 8
N-Methyl-ll-aza-10-deoxo-10-
dihydroerythromcyin ~ bis-Hydrochloride
To a solution of 2.00 g of N-methyl-ll-aza-10-
deoxo-lO-dihydroerythromycin A in 50 ml of methylene
chloride, a solution of 308 mg of pyridinium hydro-
chloride in 25 ml o methylene chloride was added
dropwise over several minutes. The mixture was
concentrated to a brittle foam (2.35 g), was thorough-
ly 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 ll-aza-10-deoxo-
lO-dihydroerythromycin A as a colorless amorphous
foam (1.21 g).
Analysis: Calc~d. for C38H72l2N2.
8.65~ Cl
Found: 8.89~ Cl.
Treatment of a small portion of the water-
soluble product with agueous sodium bicarbonate
afforded a water-insoluble product having identical
TLC Rf characteristics to those described above for
N-methyl~ll-aza-10-deoxo-lO-dihydroerythromycin A
free base.
~Z~Z61g
-20-
EXAMPLE 9
2',4"-Diacetyl-N-methyl-ll-aza-10~
deoxo-10-dihydroerythromycin A
A solution of N-methyl-ll-aza-10-deoxo 10-
dihydroerythromycin ~ (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 ~ith 20%
NaOH (w/w) solution. Extraction of the mixture with
chloroform ~3 x 50 ml) followed by drying the combined
extracts (over K2CO3J 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 2l,4"-diacyl
derivatives.
EXAMPLE 10
4"-Acetyl-N-methyl-ll-aza-10-
deoxo-10-dihydroerythromcyin A
2',4"~Diacetyl-N-methyl-10-deoxo-10-dihydro-
er~thromycin A (1.0 ~) is dissolved in 100 ml of
methanol and allowed to stand 3 days at room temper-
ature. 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
affords the corresponding 4"-propionyl- and 4"-(3-
carbethoxypropionyl)-derivatives.
