Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2003-02-12
2004-03-30
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S007200, C536S007300, C536S018500
Reexamination Certificate
active
06713615
ABSTRACT:
TECHNICAL FIELD PERTINENT TO THE INVENTION
The present invention relates to processes for preparing erythromycin derivatives and to intermediates thereof, and particularly relates to a process for preparing 6-O-substituted ketolide derivatives starting from erythromycin and to intermediates thereof.
PRIOR ART
Macrolide antibiotics including erythromycin A have a strong antibacterial activity against Gram-positive bacteria, some Gram-negative bacteria, Mycoplasmas and the like, and have been widely used as agents for the treatment of infections caused by these bacteria. Furthermore, many erythromycin derivatives have been synthesized for the purpose of the improvement of pharmacokinetic properties of erythromycin A, and some of them have already been clinically used as excellent antibiotics. For example, clarithromycin (6-O-methylerythromycin A, U.S. Pat. No. 4,331,803) has been widely used as a therapeutic agent of respiratory tract infections due to its excellent biological properties. There has been recently reported the derivatives which are generically called ketolides and have a potent antibacterial activity against macrolide-resistant bacteria. The structural features of these derivatives are such that the cladinose group at the 3-position of erythromycin A has been removed, and converted into a carbonyl group, the hydroxyl group at the 6-position has been alkylated, and the hydroxyl groups at the 11- and 12-postions have been converted into a cyclic carbamate. Among these ketolides, there is 3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminyl erythronolide A 11,12-cyclic carbamate (U.S. Pat. No. 5,866,549, and J. Medicinal Chemistry, vol. 43, pp.1045-1049 (2000)), which has a strong antibacterial activity against both of macrolide-sensitive and macrolide-resistant bacteria that cause respiratory tract infections. As mentioned above, this compound is prepared by modifying at three positions, i.e., at the 6-, 3- and 11,12-positions. The preparation process reported is carried out by once converting the carbonyl group at the 9-position into an oxime derivative, modifying at the 6-position and reproducing a carbonyl group at the 9-position, therefore this manufacturing process needs many steps, and is complicated.
Problems to be Solved by the Invention
An object of the present invention is to provide processes for preparing erythromycin derivatives and intermediates thereof, and more particularly to provide preparation processes useful for an efficient synthesis of a 6-O-substituted ketolide derivative.
Means for Solving the Problems
As a result of diligently studies, the present inventors have found a process for leading to a 6-O-substituted ketolide derivatives, which comprises combining a characterized step of introduction of a substituent at the 6-position by selective cleavage of the C—O bond of the cyclic acetal at the 9-position side via a 6,9-cyclic acetal 5-O-desosaminyl erythronolide derivative, a step of conversion into carbonyl groups at the 9- and 3-positions, and a step of 11,12-cyclic carbamation, thereby the present invention have been accomplished. Specifically, this process is useful as a process for the synthesis of 3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminyl erythronolide A 11,12-cyclic carbamate which has been recently reported to have a potent antibacterial activity, and the like.
That is, the present invention is directed to a process for preparing Compound (V) defined below, which comprises the steps of:
(A) providing Compound (I) of the formula:
wherein R
1
and R
2
, which may be the same or different, are a hydrogen atom, formula —CO—R
A
wherein R
A
is a C
1-3
alkyl group, C
1-3
alkyl group substituted with 1-3 halogen atoms, C
1-3
alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3 atoms/substituents selected from the group consisting of C
1-3
alkyl group, C
1-3
alkoxy group, nitro group, cyano group, halogen atom, acetyl group, phenyl group and hydroxy group, or a silyl group substituted with 2-3 substituents selected from the group consisting of C
1-4
alkyl group, phenyl group and benzyl group,
by reaction of erythromycin with ethylene carbonate, subsequent reduction of ketone in 9-position, and optional protection of hydroxy groups in 2′- and/or 4″-positions,
(B) reacting Compound (I) with a compound of the formula:
wherein A is CH═CH or C≡C; R
5
and R
6
, which may be the same or different, are a C
1-7
alkyl group,
and optionally protecting a resulting 3-hydroxy group, to obtain Compound (II) of the formula:
wherein R
3
is the same as R
1
defined above; R
2
and A are as defined above,
(C) reacting Compound (II) with a compound of the formula:
X—R
4
(2)
wherein X is a halogen atom; R
4
is the formula:
wherein R
7
and R
8
are a hydrogen atom or, alternatively, they form a benzene nucleus together with adjacent carbon atoms, or the formula:
wherein Ar is a pyridyl group, quinolyl group or aryl group,
to obtain Compound (III) of the formula:
wherein A, R
2
, R
3
and R
4
are as defined above,
(D) reacting Compound (III) with a compound of the formula:
wherein R
9
is a hydrogen atom, chlorine atom, linear or branched C
1-4
alkyl group, C
1-3
alkoxy group, phenyl or benzyl group; R
10
and R
11
, which may be the same or different, are a chlorine atom, linear or branched C
1-4
alkyl group, C
1-3
alkoxy group, phenyl group or benzyl group,
to obtain Compound (IV) of the formula:
wherein A, R
2
, R
3
and R
4
are as defined above, and
(E) subjecting Compound (IV) to carbonylation at 9-position, carboxylation at 3-position, 11,12-cyclic carbamation and deprotection of 2′-hydroxy group, to obtain Compound (V) of the formula:
wherein A and R
4
are as defined above.
MODE FOR CARRYING OUT THE INVENTION
The present invention is illustrated in more detail as follows.
In the present invention, the term “C
1-7
alkyl group” refers to linear or branched alkyl groups, which include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group and heptyl group. The term “C
1-3
alkoxy group” refers to methoxy, ethoxy and propoxy groups. The term “halogen atom” refers to fluorine, chlorine, bromine, iodine atom and the like.
The present invention relates to a process for preparing Compound (V) from erythromycin A as a starting material, for example, according to the following reaction scheme, and to intermediates thereof.
wherein A and R
1
through R
4
are as defined above, and more particularly, A is CH═CH or C≡C, R
1
is hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group or a triethylsilyl group, R
2
is hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group or a t-butyldimethylsilyl group, R
3
is hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group or a triethylsilyl group, and R
4
is a pyridyl group, a quinolyl group, a pyridylthienyl group or a pyridylimidazolyl group.
Step 1. Compound (I) can be prepared according to a method described in WO9813373. That is, erythromycin A is reacted with ethylene carbonate in the presence of a base in an inert solvent to give an erythromycin A 11,12-cyclic carbonate compound. Here, the inert solvent includes diethyl ether, ethyl acetate, dichloromethane, chloroform, acetone, N,N-dimethylformamide, toluene, tetrahydrofuran and a mixture thereof. The base includes sodium carbonate, potassium carbonate, cesium carbonate and pyridine. Next, the carbonyl group at the 9-position is reduced into a hydroxyl group by a reducing agent in an organic solvent, thereby 9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate can be obtained. The organic solvent used herein includes methanol, ethanol, isopropanol, propanol, tetrahydrofuran and N,N-dimethylformamide. The reducing agent includes lithium borohydride, potassium borohydride, sodium cyanoborohydride and sodium borohydride. The hyd
Adachi Takashi
Kamiyama Hiroaki
Kashimura Masato
Kuwada Takeshi
Suzuki Nobuyuki
Peselev Elli
Taisho Pharmaceutical Co. Ltd.
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