Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-03-23
2003-08-12
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S007200, C536S018500
Reexamination Certificate
active
06605707
ABSTRACT:
TECHNICAL FIELD
The instant invention relates to a process for the preparation of erythromycin derivatives, or pharmaceutically acceptable salts thereof, which contain an optionally substituted propargyl group at the 6-O-position.
BACKGROUND OF THE INVENTION
Macrolide antibacterial agents are widely used to treat and prevent bacterial infections. However, the discovery of bacterial strains which have resistance or insufficient susceptibility to these agents has promoted development of compounds with modified or improved profiles of antibiotic activity.
Commonly owned U.S. Pat. No. 5,866,549 and commonly owned pending U.S. application Ser. No. 09/273,140, filed Mar. 19, 1999, teach the small scale syntheses of 6-O-propargyl erythromycin derivatives. Large scale production of the same, however, requires a process which avoids complicating factors such as chromatography of intermediates and low-yielding steps, i.e., problems usually associated with macrolide or ketolide synthesis due to the number of reactive groups on the molecule.
Therefore, there is still a continuing need for more efficient and cleaner syntheses of 6-O-propargyl erythromycin derivatives.
SUMMARY OF THE INVENTION
In one embodiment of the instant invention, therefore, is disclosed a process for preparing 6-O-propargyl erythromycin derivatives, or a pharmaceutically acceptable salts thereof, comprising the steps of
(a) simultaneously reacting a compound of formula (I)
wherein
L
1
is selected from the group consisting of halo, trifluoromethanesulfonyl, and optionally substituted phenylsulfonyl; and
R
1
is hydrogen or optionally substituted heteroaryl, a compound of formula (II)
wherein
R
2
and R
3
are taken together and are selected from the group consisting of ═N—O—R
6
, ═N—O—C(O)—R
6
, ═N—O—C(R
7a
)(R
7b
)—OR
8
, ═N—O—Si(R
9
)
3
, ═N—N(R
10a
)(R
10b
), and ═N—N═C(R
11a
)(R
11b
);
R
4
and R
5
are independently hydrogen or a hydroxyl protecting group;
R
6
is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
R
7a
and R
7b
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
R
8
is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl; or
R
7a
and R
7b
together or R
7a
and R
7b
together are alkylene; each R
9
is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
R
10a
and R
10b
are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, and a nitrogen-protecting group; or
R
10a
and R
10b
together are alkylene; and
R
11a
and R
11b
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl; or
R
11a
and R
11b
together are alkylene, and an alkoxide base to provide a compound of formula (III)
a preferred embodiment of which are compounds of formula (III-a)
and
a particularly preferred embodiment of which are compounds of formula (III-b)
Compounds of formula (III) are useful as intermediates in the synthesis of 6-O-propargyl erythromycin derivatives of formula (IV)
a preferred embodiment of which are compounds of formula (IV-a)
Another embodiment of the instant invention, therefore, comprises the step of
(a) reacting the compound of formula (III) with a first acid and sodium nitrite at a pressure of about 15 psi to about 70 psi to provide the compound of formula (IV).
Compounds of formula (IV) are useful as intermediates in the synthesis of 6-O-propargyl erythromycin derivatives of formula (V)
a preferred embodiment of which are compounds of formula (V-a)
and
compounds of formula (V-b)
wherein
R
1a
is optionally substituted heteroaryl,
and
a particularly preferred embodiment of which are compounds of formula (V-c)
Another embodiment of the instant invention, therefore, comprises the steps of
(a) reacting the compound of formula (IV-a) with 1,1′-carbonyldiimidazole and a first base, followed by treatment of the product with ammonia or ammonium hydroxide and a second base to provide the compound of formula (V-a); and
(b) optionally reacting the product of step (a) with a compound of formula L
1
—R
1a
, a palladium catalyst, an additive, and the first base, to provide the compound of formula (V-b).
Compounds of formulas (V) are useful as intermediates in the synthesis of 6-O-propargyl erythromycin derivatives of formula (VII)
preferred embodiments of which are compounds of formula (VII-a)
compounds of formula (VII-b),
and
compounds of formula (VII-c)
and
a particularly preferred embodiment of which are compounds of formula (VII-d)
Another embodiment of the instant invention, therefore, comprises the steps of
(a) reacting the compound of formula (V) with a second acid to provide a compound of formula (VI)
a particularly preferred embodiment of which are compounds of formula (VI-a)
(b) reacting the product of step (a) with an oxidizing agent to provide the compound of formula (VII);
(c) optionally reacting the product of step (b) with the compound of formula L
1
—R
1a
, the palladium catalyst, the additive, and the first base; and
(d) optionally deprotecting the product of step (b) or step (c) to provide the compound of formula (VII-c).
In a particularly preferred embodiment of the instant invention, L
1
—R
1a
is 2-(5-bromo-2-thienyl)pyridine.
Another embodiment of the instant invention, therefore, comprises the step of
(a) reacting 2-(2-thienyl)pyridine and N-bromosuccinimide.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention discloses a method for the synthesis of 6-O-propargyl erythromycin derivatives. As used in the specification, the following have the meanings indicated.
The term “additive,” as used herein, refers to monodentate phosphorus-containing ligands of formulas P(R
C
)
3
(phosphines) and P(OR
D
)
3
(phosphites), wherein each R
C
is independently hydrogen; alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-tolyl; and optionally substitted heteroaryl such as furyl and pyridyl; and wherein each R
D
is independently alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-tolyl; and optionally substituted heteroaryl such as furyl and pyridyl. Specific examples of these additives include tri(alkyl)phosphines such as trimethylphosphine, triethylphosphine, tributylphosphine, and the like; tri(cycloalkyl)phosphines such as tricyclopropylphosphine, tricyclohexylphosphine, and the like; tri(aryl)phosphines such as triphenylphosphine, trinaphthylphosphine, and the like; tri(heteroaryl)phosphines such as tri(fury-2-yl)phosphine, tri(pyrid-3-yl)phosphine, and the like; tri(alkyl)phosphites such as trimethylphosphite, triethylphosphite, tributylphosphite, and the like; tri(cycloalkyl)-phosphites such as tricyclopropylphosphite, tricyclohexylphosphite, and the like; tri(aryl)phosphites such as triphenylphosphite, trinaphthylphosphite, and the like; and tri(heteroaryl)phosphites such as tri(fury-2-yljphosphite, tri(pyrid-3-yl)phosphite, and the like. The term “additive,” as used herein, also refers to bidentate phosphines such as 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(diphenyl-phosphino)ethane (dppe), 1,1-bis(diphenylphosphino)methane (dppm), 1,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1′-bis(diphenylphosphino)ferrocene (dppf), and the like.
The term “alkoxide base,” as as used herein, refers to (M)
+
(OR
1
)
−
, wherein (M)
+
is a cation selected from the group consisting of lithium, sodium, and potassium, and R
1
is alkyl, as defined herein. Examples of alkoxide bases include lithium methoxide, lithium ethoxide, lithium iso-propoxide, lithium tert-butoxide sodium methoxide, sodium ethoxide, sodium iso-propoxide, sodium tert-butoxide, potassium m
Bhagavatula Lakshmi
Chang Sou-Jen
Kerdesky Francis A. J.
King Steven A.
Lallaman John E.
Abbott Laboratories
Donner B Gregory
Peselev Elli
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