U.S. patent application number 14/702004 was filed with the patent office on 2015-08-20 for processes for preparing macrolides and ketolides and intermediates therefor.
The applicant listed for this patent is CEMPRA PHARMACEUTICALS, INC.. Invention is credited to David E. Pereira.
Application Number | 20150232500 14/702004 |
Document ID | / |
Family ID | 44992076 |
Filed Date | 2015-08-20 |
United States Patent
Application |
20150232500 |
Kind Code |
A1 |
Pereira; David E. |
August 20, 2015 |
PROCESSES FOR PREPARING MACROLIDES AND KETOLIDES AND INTERMEDIATES
THEREFOR
Abstract
The invention described herein pertains to processes for the
preparation of macrolide antibacterial agents. In particular, the
invention pertains to processes for preparing macrolides and
ketolides from erythromycin A.
Inventors: |
Pereira; David E.; (Apex,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CEMPRA PHARMACEUTICALS, INC. |
Chapel Hill |
NC |
US |
|
|
Family ID: |
44992076 |
Appl. No.: |
14/702004 |
Filed: |
May 1, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13699020 |
Nov 20, 2012 |
9051346 |
|
|
PCT/US2011/037330 |
May 20, 2011 |
|
|
|
14702004 |
|
|
|
|
61346664 |
May 20, 2010 |
|
|
|
Current U.S.
Class: |
548/218 |
Current CPC
Class: |
A61P 31/04 20180101;
C07H 17/08 20130101 |
International
Class: |
C07H 17/08 20060101
C07H017/08 |
Claims
1.-41. (canceled)
42. A process for preparing a compound of formula (I) ##STR00012##
or a salt thereof, wherein: R.sup.10 is hydrogen, acyl, or a
prodrug moiety; X is H; and Y is OR.sup.7; where R.sup.7 is
monosaccharide, disaccharide, alkyl, arylalkyl, or heteroarylalkyl,
each of which is optionally substituted, or acyl or
C(O)NR.sup.8R.sup.9; where R.sup.8 and R.sup.9 are each
independently selected from the group consisting of hydrogen,
hydroxy, alkyl, heteroalkyl, alkoxy, aryl, arylalkyl, heteroaryl,
and heteroarylalkyl, each of which is optionally substituted, and
dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or
R.sup.8 and R.sup.9 are taken together with the attached nitrogen
to form an optionally substituted heterocycle; or X and Y are taken
together with the attached carbon to form carbonyl; V is C(O),
C(.dbd.NR.sup.11), CH(NR.sup.12R.sup.13), or N(R.sup.14)CH.sub.2;
where N(R.sup.14) is attached to the C-10 carbon; where R.sup.11 is
hydroxy or alkoxy; R.sup.12 and R.sup.13 are each independently
selected from the group consisting of hydrogen, hydroxy, alkyl,
alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl, each of which is optionally substituted, and
dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R.sup.14
is hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, each of which is optionally
substituted, or dimethylaminoalkyl, acyl, sulfonyl, ureido, or
carbamoyl; W is H, F, Cl, Br, I, or OH; A is CH.sub.2, C(O), C(O)O,
C(O)NH, S(O).sub.2, S(O).sub.2NH, or C(O)NHS(O).sub.2; B is
(CII.sub.2).sub.n where n is an integer from 0 to 10; or an
unsaturated carbon chain of 2 to 10 carbons; and C is hydrogen,
hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl,
or heteroarylalkyl, each of which is optionally substituted, or
acyl, acyloxy, sulfonyl, ureido, or carbamoyl; the process
comprising the step (a) contacting a compound of formula (III),
##STR00013## or a salt thereof, wherein Q in combination with the
oxime oxygen forms an acetal or ketal, or Q is tropyl, with an
acylating agent to form a compound of formula (IV) ##STR00014## or
a salt thereof, wherein R is an acyl group; or (b) contacting a
compound of formula (IV), or a salt thereof, with a methylating
agent, to form a compound of formula (V) ##STR00015## or a salt
thereof; or (c) contacting a compound of formula (V), or a salt
thereof, with a deoximating agent to form a compound of formula
(II) or a salt thereof; or ##STR00016## (d) any combination of (a),
(b), and (c); and the step of converting the compound of formula
(IV), (V), or (II) into the compound of formula (I).
43. The process of claim 42 comprising (a) and (b).
44. The process of claim 42 comprising (a) and (c),
45. The process of claim 42 comprising (b) and (c).
46. The process of claim 42 comprising (a), (b), and (c).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application 61/346,664, filed 20 May 2010, which is incorporated by
reference herein.
TECHNICAL FIELD
[0002] The invention described herein pertains to processes for the
preparation of macrolide antibacterial agents. In particular, the
invention pertains to processes for preparing macrolides and
ketolides from erythromycin A.
BACKGROUND AND SUMMARY OF THE INVENTION
[0003] Macrolide antibiotics, characterized by a large lactone ring
to which are attached one or more deoxy sugars, usually cladinose
and desosamine, are antimicrobial drugs that are active against
aerobic and anaerobic gram positive cocci and are prescribed for
the treatment of respiratory tract and soft tissue infections. The
macrolides, which belong to the polyketide class of natural
products, function by reversibly binding to the 50S subunit of the
bacterial ribosome, blocking protein synthesis and preventing
bacterial growth and reproduction. Although this action is
primarily bacteriostatic, at higher concentrations, macrolides can
be bactericidal. Erythromycin and the semi-synthetic derivatives
azithromycin and clarithromycin are among the marketed macrolide
antibiotics.
[0004] Ketolides, which are semi-synthetic derivatives of the
14-membered macrolide erythromycin A, belong to this class of drugs
used to treat respiratory tract infections. These drugs are
effective against macrolide-resistant bacteria because of their
ability to bind to two sites on the bacterial ribosome.
Telithromycin and cethromycin belong to this group of
antibiotics.
[0005] Acquired bacterial resistance to macrolides occurs primarily
through post-transcriptional methylation of the 23S bacterial
ribosome. This results in cross-resistance to macrolides,
lincosamides and streptogramins. Although rare, acquired resistance
also can result from the production of drug-inactivating enzymes
such as esterases or kinases, as well as the production of active
ATP-dependent efflux proteins that transport macrolides out of the
cell. A significant fraction of pneumococci are resistant to
currently available antibiotics. Accordingly, new macrolide and
ketolide antibiotics are needed, along with processes for preparing
them.
[0006] In particular, international patent application publication
No. WO 2004/080391, and its counterpart publication US
2006/0100164, the disclosures of which are incorporated herein by
reference, describes a family of macrolide and ketolide
antibiotics, including fluoroketolide antibiotics, of formula
(I)
##STR00001##
and pharmaceutically acceptable salts thereof, wherein R.sup.10, X,
Y, V, W, A, B, and C are as described herein, and Me indicates
methyl, and Et indicates ethyl. One notable, but non-limiting
example compound of formula (I) is solithromycin, also referred to
as OP-1068 and/or CEM-101. The preparation of CEM-101 and related
compounds is described in WO 2009/055557, the disclosure of which
is incorporated herein by reference. A starting material used in WO
2009/055557 A1 for the preparation of the macrolide antibacterial
agents is clarithromycin. In the processes described therein,
clarithromycin is converted into a clarithromycin derivative in
which the hydroxyl groups of the sugar moieties are protected with
acyl groups, such as clarithromycin dibenzoate, also known as
2',4''-di-O-benzoyl-6-O-methylerythromycin A, to form compounds of
formula (II).
##STR00002##
and pharmaceutically acceptable salts thereof, wherein R is as
described herein.
[0007] Clarithromycin is a semisynthetic antibacterial agent in
which the 6-hydroxy group of erythromycin A has been converted into
a 6-methoxy group to eliminate undesired interaction with the
carbonyl group at the 9-position of the macrolide ring, thereby
stabilizing the antibiotic. Clarithromycin has been prepared by
various processes. The most widely used processes begin with
erythromycin A, which is converted to its oxime and then to a
protected erythromycin A 9-oxime derivative as an intermediate, and
variously involve protection and deprotection of the hydroxyl and
dimethyl groups of the pendant sugar moieties before and after
methylation of the 6-hydroxy group of the macrolide ring (see, for
example, U.S. Pat. No. 6,515,116 for a review of the reported
processes; an alternative approach including protection of the
desosaminyl amino group as an N-oxide is described in U.S. Pat. No.
6,809,188). For the efficient production of a clarithromycin
derivative in which the hydroxyl groups of the sugar moieties are
protected with acyl groups and, subsequently, of a final macrolide
antibacterial agent, there is needed a preparation of the
diprotected derivative from erythromycin A which avoids the
protecting and deprotecting steps used in the prior methodology for
the preparation of clarithromycin. Described herein are processes
for the direct production from erythromycin A of clarithromycin
derivatives of formula (II) in which the hydroxyl groups of the
sugar moieties are protected with acyl groups with a reduced number
of steps. Also described herein are processes for preparing
compounds of formula (I) from compounds of formula (II).
DETAILED DESCRIPTION
[0008] In one illustrative embodiment of the invention, processes
are described for preparing compounds of formula (I)
##STR00003##
and pharmaceutically acceptable salts thereof, wherein:
[0009] R.sup.10 is hydrogen, acyl or a prodrug moiety;
[0010] X is H; and Y is OR.sup.7; where R.sup.7 is monosaccharide,
disaccharide, alkyl, arylalkyl, or heteroarylalkyl, each of which
is optionally substituted, or acyl or C(O)NR.sup.8R.sup.9; where
R.sup.8 and R.sup.9 are each independently selected from the group
consisting of hydrogen, hydroxy, alkyl, heteroalkyl, alkoxy, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl, each of which is
optionally substituted, and dimethylaminoalkyl, acyl, sulfonyl,
ureido, and carbamoyl; or R.sup.8 and R.sup.9 are taken together
with the attached nitrogen to form an optionally substituted
heterocycle; or X and Y are taken together with the attached carbon
to form carbonyl;
[0011] V is C(O), C(.dbd.NR.sup.11), CH(NR.sup.12, R.sup.13), or
N(R.sup.14)CH.sub.2; where N(R.sup.14) is attached to the C-10
carbon; where R.sup.11 is hydroxy or alkoxy; R.sup.12 and R.sup.13
are each independently selected from the group consisting of
hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl, each of which is optionally
substituted, and dimethylaminoalkyl, acyl, sulfonyl, ureido, and
carbamoyl; R.sup.14 is hydrogen, hydroxy, alkyl, alkoxy,
heteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each
of which is optionally substituted, or dimethylaminoalkyl, acyl,
sulfonyl, ureido, or carbamoyl;
[0012] W is H, F, Cl, Br, I, or OH;
[0013] A is CH.sub.2, C(O), C(O)O, C(O)NH, S(O).sub.2,
S(O).sub.2NH, or C(O)NHS(O).sub.2;
[0014] B is (CH.sub.2).sub.n where n is an integer from 0 to 10; or
an unsaturated carbon chain of 2 to 10 carbons; and
[0015] C is hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, each of which is
optionally substituted, or acyl, acyloxy, sulfonyl, ureido, or
carbamoyl.
[0016] In another illustrative embodiment, processes are described
for preparing compounds of formula (II)
##STR00004##
and pharmaceutically acceptable salts thereof, wherein R is an acyl
group. In another embodiment, R is a hindered acyl group, such as
benzoyl.
[0017] In another embodiment, processes are described herein
comprising the step of (a) contacting a compound of formula
(III)
##STR00005##
or an acid addition salt thereof, with an acylating agent to
prepare a compound of formula (IV)
##STR00006##
or an acid addition salt thereof; where in each instance Q in
combination with the oxime oxygen forms an acetal or a ketal, or Q
is tropyl, and R is an acyl group. In another embodiment, the step
(a) of the processes includes a base.
[0018] In another illustrative embodiment, processes are described
herein comprising the step of (b) contacting a compound of formula
(IV), as described herein, or an acid addition salt thereof, with a
methylating agent to prepare a compound of formula (V)
##STR00007##
or an acid addition salt thereof, where Q and R are as described in
the alternative embodiments herein. In another embodiment, the step
(b) of the processes includes a base. In another embodiment, the
step (b) of the processes includes an aprotic polar solvent.
[0019] In another illustrative embodiment, processes are described
herein comprising the step of (c) contacting a compound of formula
(V), as described herein, or an acid addition salt thereof, with a
deoximating agent to form the compound of formula (II),
##STR00008##
or an acid addition salt thereof, where R is described in the
alternative embodiments herein.
[0020] It is to be understood that each of the steps (a), (b), and
(c) may be combined in additional embodiments. It is further to be
understood that the variations of each of the steps (a), (b), and
(c) described herein may be combined without limitation in
additional embodiments. For example, another illustrative process
comprises acylating step (a) and further comprises methylating step
(b), and further comprises deoximating step (c). Another
illustrative process comprises methylating step (b) and further
comprises deoximating step (c). Another illustrative process
comprises acylating step (a) and further comprises methylating step
(b), and further comprises deoximating step (c), and further
comprises steps described in WO 2009/055557 for converting
compounds of formula (II) into compounds of formula (I).
[0021] In another embodiment, processes for preparing compounds of
formula (IV), such as compounds of formula (IV) where R is benzoyl,
or an acid addition salt thereof, are described herein, where the
processes comprise the step of contacting a compound of formula
(III), as described herein, or an acid addition salt thereof, with
an acylating agent, such as benzoyl anhydride, also referred to as
benzoic anhydride, to form a compound of formula (IV), or an acid
addition salt thereof. In one variation, the step is performed in
the presence of a base.
[0022] In another embodiment, processes for preparing compounds of
formula (V), or an acid addition salt thereof, as described herein,
where the processes comprise the step of contacting a compound of
formula (IV), as described herein, or an acid addition salt
thereof, with a methylating agent, to form a 6-O-methyl compound of
formula (V), as described herein, or an acid addition salt thereof.
In one variation, the step is performed in the presence of a base.
In another variation, the step is performed in an aprotic polar
solvent. In another variation, the step is performed in the
presence of a base and in an aprotic polar solvent.
[0023] In another embodiment, processes for preparing compounds of
formula (II), including compounds of formula (II) where R is
benzoyl, or an acid addition salt of any of the foregoing, are
described herein, where the processes comprise the step of
contacting a compound of formula (V), as described herein, or an
acid addition salt thereof, with a deoximating agent to form a
compound of formula (II), or an acid addition salt thereof.
[0024] In another illustrative embodiment of any of the foregoing
processes, Q is an O-protecting group. In one variation, Q in
combination with the oxime oxygen forms an acetal or ketal, or Q is
tropyl. In another illustrative embodiment, R is an acyl group. In
another illustrative embodiment, Q is an O-protecting group. In one
variation, Q in combination with the oxime oxygen forms an acetal
or ketal, or Q is tropyl, and R is an acyl group.
[0025] In another illustrative embodiment of any of the foregoing
processes, Q is C(R.sup.A)(R.sup.C)(OR.sup.B), wherein
[0026] R.sup.A is a group of the formula CH.sub.2R.sup.D, where
R.sup.D is hydrogen, (1-3C)alkyl or (1-6C)alkoxy;
[0027] R.sup.B is (1-6C)alkyl, (5-7C)cycloalkyl; phenyl or
arylalkyl; and
[0028] R.sup.C is hydrogen, (1-4C)alkyl, phenyl or arylalkyl; or
alternatively in any of the foregoing
[0029] R.sup.B and R.sup.D together form an ethylene, propylene or
trimethylene group; or
[0030] R.sup.B and R.sup.D together form a (3-5C)alkanediyl group
which may be further substituted with one to three (1-3C)alkyl
substituents; or
[0031] R.sup.B and R.sup.C together form a (3-4C)alkanediyl
group.
[0032] In another embodiment of any of the foregoing processes, Q
is 2-methoxy-2-propyl, 1-methoxycyclohexyl, or
1-isopropoxycyclohexyl. In another embodiment of any of the
foregoing processes, Q is 2-methoxy-2-propyl.
[0033] Compounds of formula (III), as described herein, may be
prepared by contacting erythromycin A 9-oxime with a corresponding
compound of formula R.sup.E--C(R.sup.A)(R.sup.C)(OR.sup.B) in which
R.sup.E is (1-6C)alkoxy or in which R.sup.A and R.sup.E together
form a group of formula CHR.sup.D connected by a double bond. The
step may be carried out in the presence of an acidic catalyst, for
example in the presence of pyridine hydrochloride. In another
variation, the step is performed using 2-methoxypropene to form a
compound of formula (III) in which Q is 2-methoxy-2-propyl. In
another variation, the step is performed, in dichloromethane at
about 0.degree. C. to about room temperature in the presence of
pyridine hydrochloride using excess 2-methoxypropene. In another
variation, Q is tropyl, and the compounds of formula (III) may be
prepared by reacting erythromycin A 9-oxime with tropylium
tetrafluoroborate in an aprotic polar solvent.
[0034] In another embodiment of any of the processes described
herein, R is a sterically hindered acyl group, such as a benzoyl
group. In another embodiment of any of the processes described
herein, R is not acetyl. Without being bound by theory, it is
believed herein that the use of a sterically hindered group R may
improve the processes and/or the purity of the isolated product of
the processes. It has been discovered that unhindered acyl groups,
such as acetyl groups, present on the C-5 saccharide may migrate to
other positions on the macrolide, for example from the 2'-hydroxy
group of the desosamine moiety to an amino group of a side chain.
Use of a sterically hindered group R decreases and/or precludes
such a migration leading to improved processes and/or improved
purities of the isolated product of the processes
[0035] In another embodiment of any of the processes described
herein, R is benzoyl.
[0036] In another embodiment of any of the processes described
herein, step (a) is performed with an acylating agent is the
anhydride, acid halide, or an activated ester of the corresponding
acyl group R. In another embodiment of any of the processes
described herein, the acylating agent is the anhydride of the acyl
group R. In another embodiment of any of the processes described
herein, about 2 to about 6 equivalents of acylating agent to an
equivalent of the compound of formula (III) is employed. In another
embodiment of any of the processes described herein, a base is
included in step (a), such as a tertiary amine. In another
embodiment of any of the processes described herein, the base is
triethylamine, diisopropylethylamine, or 4-methylmorpholine, or a
combination thereof. In another embodiment of any of the processes
described herein, about 1 to about 4 equivalents of base to an
equivalent of the compound of formula of formula (III) is employed.
In another embodiment of any of the processes described herein, the
acylation is performed in the presence of about 0.5 to about 2.5
equivalents of an acylation catalyst to an equivalent of the
compound of formula of formula (III). In another embodiment of any
of the processes described herein, the acylation catalyst is
4-dimethylaminopyridine.
[0037] In another embodiment of any of the processes described
herein, the methylating agent is methyl bromide, methyl iodide,
dimethyl sulfate, methyl p-toluenesulfonate, or methyl
methanesulfonate. In another embodiment, the methylating agent is
methyl iodide. In another embodiment of a process described herein,
a base is used in combination with the methylating agent, such as
sodium hydroxide, potassium hydroxide, sodium hydride, potassium
hydride, or potassium t-butoxide, or a mixture thereof. In another
embodiment the base used with the methylating agent is potassium
hydroxide. In another embodiment the methylation step is performed
in an aprotic polar solvent, such as dimethyl sulfoxide,
dimethylformamide, 1-methyl-2-pyrrolidone, a mixture thereof, or a
mixture of any of these solvents with one or more of
tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane,
acetonitrile or ethyl acetate. In another embodiment of any of the
processes described herein, the methylating step is performed at a
temperature from about -15.degree. C. to about 60.degree. C.
Another embodiment of processes described herein for the
methylation of a compound of formula (IV) is one wherein the
methylating step is performed at a temperature from about 0.degree.
C. to about 30.degree. C.
[0038] It has been unexpectedly discovered herein that the
methylation step of compounds of formula (IV), where R is benzoyl,
is performed without, any or substantially any, cleavage of the
benzoate ester present on compounds of formula (IV).
[0039] Illustratively, removal of the group Q, such as by
O-deprotection, and/or removal of the oxime group at C-9 to form a
ketone, such as by deoximation, may be performed using any of a
number of conventional processes and/or reagents. Illustrative
deoximation methods include, but are not limited to, hydrolytic,
oxidative and reductive conditions. In one embodiment, the
deoximating agent comprises a reducing agent. Illustrative
embodiments of deoximating agents include, but are not limited to,
inorganic sulfur oxide compounds such as sodium hydrogen sulfite,
sodium pyrosulfate, sodium thiosulfate, sodium sulfite, sodium
hydrosulfite, sodium metabisulfite, sodium bisulfite, sodium
dithionate, potassium hydrogen sulfite, potassium thiosulfate and
potassium metabisulfite, and mixtures thereof. In another
embodiment of any of the processes described herein, the
deoximating agent is sodium metabisulfite or sodium bisulfite, or a
combination thereof. It is to be understood that O-deprotection may
be performed prior to deoximation; or O-deprotection and
deoximation may be performed in a single ("one-pot") step by
treatment, either sequentially, concurrently, contemporaneously, or
simultaneously by using acid, such as formic acid, and a
deoximating agent.
[0040] In another embodiment of any of the processes described
herein, the step of converting the C-9 oxime into a carbonyl is
performed by contacting the compound of formula (V) wherein the
deoximating agent comprises formic acid and sodium metabisulfite in
an aqueous alcoholic solution at a temperature ranging from ambient
temperature to about the boiling point of the solvent.
[0041] It has been unexpectedly discovered that removing the
O-protecting group Q and removing the oxime from a compound of
formula (V) in which R is benzoyl may be performed without, any or
substantially any, cleavage of the benzoate ester present on
compounds of formula (V).
[0042] It is to be understood that the various subgenera, species,
and compounds described herein may be made by the various
embodiments of the processes described herein. For example, in
another embodiment of any of the processes herein, V is C(O);
and/or
[0043] R.sup.7 is an aminosugar or a halosugar; or
[0044] R.sup.7 is 4-nitro-phenylacetyl or 2-pyridylacetyl; or
[0045] X and Y are taken together with the attached carbon to form
carbonyl; and/or
[0046] A is CH.sup.2; and/or
[0047] B is alkenylene; and/or
[0048] B is (CH.sup.2).sup.n; where n is 2 to 6, 2 to 5, or 2 to 4,
or 2 to 3, or 3; and/or
[0049] C is aminophenyl; or
[0050] C is 3-aminophenyl; and/or
[0051] W is fluoro; or
[0052] W is hydrogen; and/or
[0053] R.sup.10 is hydrogen or acyl; or
[0054] R.sup.10 is hydrogen; or
[0055] R.sup.10 is benzoyl.
[0056] In another embodiment of any of the processes described
herein, the compound of formula (I) is CEM-101, or a
pharmaceutically acceptable salt, solvate or hydrate thereof. The
compound CEM-101 has Chemical Abstracts Registry Number
760981-83-7, and structure of the compound is as follows:
##STR00009##
[0057] As used herein, the term "alkyl", alone or in combination,
refers to an optionally substituted straight-chain, optionally
substituted branched-chain, or optionally substituted cyclic alkyl
radical having from 1 to about 30 carbons, more preferably 1 to 12
carbons. Examples of alkyl radicals include methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
tert-amyl, pentyl, hexyl, heptyl, octyl and the like. A "lower
alkyl" is a shorter alkyl, e.g., one containing from 1 to about 6
carbon atoms.
[0058] The term "alkoxy," alone or in combination, refers to an
alkyl ether radical, alkyl-O, wherein the term alkyl is defined as
above. Examples of alkoxy radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy and the like.
[0059] The term "alkenyl," alone or in combination, refers to an
optionally substituted straight-chain, optionally substituted
branched-chain, or optionally substituted cyclic alkenyl
hydrocarbon radical having one or more carbon-carbon double-bonds
and having from 2 to about 30 carbon atoms, more preferably 2 to
about 18 carbons. Examples of alkenyl radicals include ethenyl,
propenyl, butenyl, 1,4-butadienyl and the like. The term can also
embrace cyclic alkenyl structures. A "lower akenyl" refers to an
alkenyl having from 2 to about 6 carbons.
[0060] The term "acyloxy" refers to the ester group OC(O)--R, where
R is H, alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein the
alkyl, alkenyl, alkynyl and arylalkyl groups may be optionally
substituted.
[0061] The term "acyl" includes alkyl, aryl, heteroaryl, arylalkyl
or heteroarylalkyl substituents attached to a compound via a
carbonyl functionality (e.g., CO-alkyl, CO-aryl, CO-arylalkyl or
CO-heteroarylalkyl, etc.).
[0062] The term "heteroalkyl" generally refers to a chain of atoms
that includes both carbon and at least one heteroatom. Illustrative
heteroatoms include nitrogen, oxygen, and sulfur.
[0063] As used herein, the term "aryl" includes monocyclic and
polycyclic aromatic carbocyclic and aromatic heterocyclic groups,
each of which may be optionally substituted. As used herein, the
term "heteroaryl" includes aromatic heterocyclic groups, each of
which may be optionally substituted. Illustrative carbocyclic
aromatic groups described herein include, but are not limited to,
phenyl, naphthyl, and the like. Illustrative heterocyclic aromatic
groups include, but are not limited to, pyridinyl, pyrimidinyl,
pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl,
quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl,
benzisothiazolyl, and the like.
[0064] The term "arylalkyl" refers to an alkyl group substituted
with one or more unsubstituted or substituted monocyclic or
polycyclic aryl groups. Illustrative arylalkyl groups include
benzyl, diphenylmethyl, trityl, 2-phenylethyl, 1-phenylethyl,
2-pyridylmethyl, 4,4'-dimethoxytrityl, and the like.
[0065] The term "alkylaryl" refers to an aryl group substituted
with an alkyl group.
[0066] The term "sulfonyl" refers to SO.sub.2-R where R is H, alkyl
or aryl.
[0067] The term "saccharide" includes monosaccharides,
disaccharides, and polysaccharides, each of which is optionally
substituted. The term also includes sugars and deoxysugars
optionally substituted with amino, amido, ureyl, halogen, nitrile,
or azido groups. Illustrative examples include, glucosamine,
N-acetylglucosamine, desosamine, forosamine, sialic acid, and the
like.
[0068] The term "activated ester" includes carboxylic acid
derivatives in which the hydrogen of the hydroxy group has been
replaced with a residue which results in the formation of a good
leaving group, including the 4-nitrophenyl ester and an activated
ester or anhydride derived from a coupling reagent.
[0069] In another embodiment, compounds of formula (IV) are
described
##STR00010##
and acid addition salts thereof; wherein Q and R are as described
in the various embodiments herein.
[0070] In another embodiment, compounds of formula (V) are
described
##STR00011##
and acid addition salts thereof; wherein Q and R are as described
in the various embodiments herein.
[0071] It is appreciated herein that because compounds of formulae
(I), (II), (III), (IV), and (V) each contain a dimethylamino group
on the desosaminyl moiety, the compounds may form acid addition
salts. Accordingly, it is to be understood that any acid addition
salt of a compound of formulae (I), (II), (III), (IV), and (V)
suitable for use in pharmaceutical manufacturing or for providing a
free base which is suitable for use in pharmaceutical manufacturing
is described herein and to be included in the invention described
herein.
[0072] In each of the foregoing and following embodiments, it is to
be understood that the formulae include and represent not only all
pharmaceutically acceptable salts of the compounds, but also
include any and all hydrates and/or solvates of the compound
formulae. It is appreciated that certain functional groups, such as
the hydroxy, amino, and like groups form complexes and/or
coordination compounds with water and/or various solvents, in the
various physical forms of the compounds. Accordingly, the above
formulae are to be understood to include and represent those
various hydrates and/or solvates. In each of the foregoing and
following embodiments, it is also to be understood that the
formulae include and represent each possible isomer, such as
stereoisomers and geometric isomers, both individually and in any
and all possible mixtures. In each of the foregoing and following
embodiments, it is also to be understood that the formulae include
and represent any and all crystalline forms, partially crystalline
forms, and non crystalline and/or amorphous forms of the compounds.
For example, Illustrative crystal morphologies are described in
co-pending PCT international application No. PCT/US2011/029424, the
disclosure of which is incorporated herein in its entirety.
EXAMPLES
[0073] The following examples further illustrate specific
embodiments of the invention; however, the following illustrative
examples should not be interpreted in any way to limit the
invention. Abbreviations used in the examples include the
following: DCM, dichloromethane; DMAP, 4-dimethylaminopyridine;
DMSO; dimethyl sulfoxide; EA, ethyl acetate; .sup.1H-NMR, proton
nuclear magnetic resonance spectroscopy; MeOH, methanol; Mw,
molecular weight; RT, room (ambient) temperature; THF,
tetrahydrofuran; TLC, thin layer chromatography.
[0074] EXAMPLE. Synthesis of erythromycin A 9-oxime (1). A mixture
of erythromycin A (15 g, 20.4 mmol), NH.sub.2OH.HCl (7.3 g, 105
mmol) and triethylamine (7 g, 69 mmol) in MeOH (23 mL) is heated to
reflux overnight. A white solid forms during the reaction. The
reaction mixture is concentrated to a small volume. To the obtained
residue is added dilute aqueous NH.sub.4OH solution at 0.degree. C.
until the pH of the mixture reaches about 10 to 11. Additional
solid precipitates out from the mixture. The mixture is filtered,
the collected solid is washed with water and dried under vacuum to
give 14.2 g of 1 as white granular solid in 93% yield. TLC analysis
(DCM:MeOH:NH.sub.4OH=90:10:1) of the obtained 1 shows a small
amount of an additional compound (lower spot), corresponding to the
Z-isomer. Mass analysis of the obtained 1 showsd a peak with
Mw=749, corresponding to the title compound. .sup.1H-NMR analysis
of the product is consistent with the title compound, and also
shows a mixture of the (1) and the HCl salt thereof. The product is
used without purification.
[0075] EXAMPLE. Large Scale Preparation of (1). Erythromycin (250
g, 0.34 mol) and hydroxylamine hydrochloride (80.3 g, 1.15 mol) in
methanol (325 ml) are heated under reflux in the presence of
triethylamine (45 g, 0.44 mol). The reaction is monitored by TLC
using toluene/triethylamine (8:2) as eluent. After completion (ca.
24 h), the reaction mass is gradually cooled and stirred at
0-5.degree. C. for 1 h, filtered and washed with cooled methanol
(100 mL). The wet solid (265 g) is suspended in isopropyl alcohol
(350 mL) and heated to 50-55.degree. C. followed by the addition of
aqueous ammonia (650 mL) over a period of 2 h. The solution is
stirred for 1 h at 50-55.degree. C. and gradually cooled to
10-15.degree. C. and maintained for 2 h. The solid was filtered and
washed with water and dried at 80-85.degree. C. for 12 h to isolate
186 g. About 3% of the corresponding Z-oxime isomer is observed by
HPLC. The preparation is repeated as follows with the corresponding
scale of other reagents.
TABLE-US-00001 No. Batch Size Product Yield (%) Purity by HPLC 1
100 g 73 g 74% 93% + 3% of Z-oxime 2 250 g 186 g 73% 95% + 3% of
Z-oxime 3 250 g 187 g 73% 95% + 3% of Z-oxime
[0076] EXAMPLE. Synthesis of a Compound of Formula (III),
Q=2-methoxy-2-propyl (9). To a solution of (1) (3 g, 4 mmol) in
anhydrous dichloromethane (DCM, 21 mL) is added 2-methoxypropene
(1.5 g, 20.8 mmol), followed by pyridine hydrochloride (0.72 g, 6.2
mmol) at 0.degree. C. After the addition, the reaction mixture is
stirred at 0.degree. C. at RT for 30 min. Conversion is monitored
by TLC analysis of the reaction mixture
(DCM:MeOH:NH.sub.4OH=90:10:1). If conversion is incomplete, the
mixture is cooled back to 0.degree. C., and another 0.5 g of
2-methoxypropene (6.9 mmol) is added. The mixture is stirred at
0.degree. C. for another 0.5 h. If conversion is incomplete,
another 0.5 g of 2-methoxypropene (6.9 mmol), followed with another
0.1 g of pyridine hydrochloride (0.86 mmol) is added to the
reaction mixture at 0.degree. C. The reaction mixture was stirred
at 0.degree. C. for another 15 min. Upon complete conversion, the
reaction mixture is diluted with saturated aqueous NaHCO.sub.3
solution. The DCM layer is separated and the aqueous layer is
extracted with DCM. The combined DCM layers are washed with brine,
dried over MgSO.sub.4, concentrated to dryness to give 3.3 g crude
product as a white foam in quantitative yield. Mass analysis of the
product shows Mw=821, corresponding to the title compound, and a
very minor peak with molecular weight of 861. .sup.1H-NMR of the
product is consistent with the title compound, and a small amount
2-methoxypropan-2-ol and pyridine. The product is used without
further purification.
[0077] EXAMPLE. Synthesis of a Compound of Formula (IV),
Q=2-methoxy-2-propyl, R=benzoyl (10). To a solution of (9) (4.1 g,
5 mmol) in ethyl acetate (65 mL) is added benzoyl anhydride (4.5 g,
20 mmol), followed by triethylamine (1.26 g, 12.5 mmol) and DMAP
(0.9 g, 7.4 mmol) at RT. The resulting mixture is stirred at RT for
36 h. The reaction mixture is diluted with saturated aqueous
NaHCO.sub.3 solution. The EA layer is separated and the aqueous
layer is extracted with EA. The combined EA layers are washed with
brine, dried over MgSO.sub.4, filtered to remove the drying agent,
and concentrated to dryness. The obtained residue is subjected to
silica gel column chromatography (DCM:MeOH:NH.sub.4OH=97:3:0.3) to
give 4.2 g of 10 in 80% yield as a white solid. Mass analysis of
the purified product shows Mw=1029, corresponding to the title
compound. .sup.1H-NMR is consistent with the title compound.
[0078] EXAMPLE. Large Scale Preparation of (9). Erythromycin Oxime
(1) (200 g, 026 mol) is dissolved in DCM (1.4 L) and the volume is
reduced to 1 L by distillation under atmospheric pressure. After
cooling the reaction mass to 0-5.degree. C., 2-methoxypropene (80
g, 1.1 mol) and pyridine hydrobromide (50 g, 0.31 mol) are added
and stirred for 3 h at 20-25.degree. C. Mass analysis confirmed the
presence of (9). Without isolation, benzoic anhydride (211 g, 0.93
mol), triethylamine (54 g, 0.53 mol), DMAP (48.8 g, 0.40 mol) are
added and the reaction is continued for 24 h at 30.degree. C. The
reaction is monitored by TLC and analyzed by mass spectrometry.
After completion, saturated sodium bicarbonate (1 L) is added and
stirred for 15 min and allowed to settle. The layers are separated
and the organic layer is concentrated. The material is isolated to
190 g with a purity of 48-51%. The preparation is repeated as
follows with the corresponding scale of other reagents.
TABLE-US-00002 No. Batch Size Unpurified Product Purity 1 200 g 190
g 48% 2 200 g 186 g 50% 3 200 g 184 g 51%
[0079] The unpurified product from successive batches is combined
(450 g) and dissolved in EA (4.5 L) to a clear solution that is
washed with saturated sodium bicarbonate (2.2 L), water (2.2 L),
and brine (2.2 L), and concentrated. The isolated product is
crystallized from IPE/n-Hexane to 360 g (84%).
[0080] EXAMPLE. Synthesis of a Compound of Formula (V),
Q=2-methoxy-2-propyl, R=benzoyl (11). A solution of (10) (3.8 g,
3.7 mmol) in anhydrous THF (15 mL) and anhydrous DMSO (15 mL) is
cooled to 0.degree. C. Powdered KOH (0.46 g, 8.2 mmol) is added,
followed by methyl iodide (1.06 g, 7.5 mmol) at 0.degree. C. The
resulting reaction mixture is stirred at 0.degree. C. for 5 min,
subsequently becoming a thick paste and stopping the stirring. The
mixture is warmed to RT for 5 min, remaining a thick paste, and
diluted with 15 mL of THF and 15 mL of DMSO, to a free flowing
suspension. The mixture is stirred at RT for another 0.5 hr,
diluted with saturated aqueous NaHCO.sub.3 solution, and extracted
with ethyl acetate. The ethyl acetate extract is washed with brine,
dried over MgSO.sub.4 and concentrated to dryness. The isolated
residue is purified by silica gel column chromatography
(DCM:MeOH:NH.sub.4OH=97:3:0.3) to 2.83 g of (11) as a white solid
in 73% yield. Mass analysis shows Mw=1043), corresponding to the
title compound, along with a minor peak Mw=1057. .sup.1H-NMR is
consistent with the title compound.
[0081] EXAMPLE. Large Scale Preparation of (11). Benzoylated oxime
(10) (100 g, 0.09 mol) is dissolved in toluene (1.8 L) and the
solution is distilled under vacuum to remove toluene (300 mL),
cooled to 15.degree. C., and diluted with DMSO (1.5 L). After
cooling to 5.degree. C., methyl iodide (20.5 g , 0.14 mol) is added
followed by KOH (10.8 g, 0.19 mol) and the reaction is continued
for 3 h. The reaction is stopped by the addition of 40%
dimethylamine (22 g) and the temperature of the reaction mass is
raised to RT and diluted with water (500 mL) with stirring. The
layers are separated and the aqueous layer is extracted with
toluene (500 mL). The combined organic layers are washed with water
(2 L) and the organic layer is concentrated by distillation under
vacuum. The isolated product is stirred in IPE (500 mL) for 5 h and
filtered to 82 g of the title compound, which is used without
further purification. The preparation is repeated as follows with
the corresponding scale of other reagents.
TABLE-US-00003 No. Batch Size Product Yield (%) 1 100 g 82 g -- 2
100 g 78 g -- 3 100 g 84 g -- 4 90 g 71 g 80%
[0082] EXAMPLE. Synthesis of a Clarithromycin Dibenzoate, Formula
(II), R=benzoyl. To a solution of (11) (800 mg, 0.78 mmol) in
ethanol (8 mL) and water (8 mL) is added sodium metabisulfite (740
mg, 3.89 mmol) at RT. The resulting mixture is adjusted to pH 2-3
by adding formic acid (1.5 mL). The mixture is heated at 60.degree.
C. for 1 h. Conversion is monitored by mass spectrometry. If
incomplete, or showing a large amount of the deprotected oxime
intermediate (Mw=971), another 2 g of sodium metabisulfite (10.5
mmol) is added. The mixture is stirred at 60.degree. C. for another
7 h, then cooled to RT. A white solid precipitate forms as the
reaction progresses. The reaction mixture is neutralized with
dilute aqueous NaHCO.sub.3 solution to pH of 8-9 and the resulting
mixture is filtered. The isolated white solid is dried under vacuum
to 760 mg of clarithromycin dibenzoate. The unpurified product is
combined with material obtained from other preparations (ca. 200
mg) and purified by silica gel column chromatography to 730 mg of
clarithromycin dibenzoate in 79% yield. Mass analysis shows Mw=956,
corresponding to the title compound, with a minor peak of Mw=970,
which is attributed to the carryover impurity in (11). .sup.1H-NMR
is consistent with the title compound.
[0083] EXAMPLE. Large Scale Preparation of Clarithromycin
Dibenzoate. Methylated oxime (11) (80 g, 0.07 mol) is dissolved in
absolute alcohol (400 mL). Water (400 mL) is added, followed by
sodium bisulfite (72 g, 0.69 mol) and formic acid (21 g). The
reaction mass is heated to reflux for 6 h, cooled to RT, and
diluted with water (400 mL). The reaction mass is cooled to
10-15.degree. C., and 25% NaOH (160 ml) is added slowly. The
mixture is stirred for 2 h and filtered. The isolated solid is
washed with water (500 mL) and dissolved in ethylacetate (400 mL).
The organic layer is washed with water (400 mL), then brine (400
mL), then concentrated. The isolated material is crystallized from
ethyl acetate (1.7 T) to 40.8 g (95% purity). Alternatively, the
isolated material is crystallized from IPA/IPE 89-90% purity. The
preparation is repeated as follows with the corresponding scale of
other reagents.
TABLE-US-00004 No. Batch Size Product Yield (%) 1 80 g 40.8 g 95% 2
70 g 37.8 g 90% 3 70 g 45 g 89%
* * * * *