Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-07-30
2004-10-12
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06803469
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for preparing quinolone antibiotic intermediates. The process of the present invention utilizes the surprising result that 3-(2-alkoxyphenyl)-2-enamine-3-oxo-propionic acid ester by-products can be carried forward and are suitable intermediates for the final quinolone products.
BACKGROUND OF THE INVENTION
Quinolone and quinolonyl antibiotics are a recent class of highly potent, broad spectrum antimicrobials and research has been directed at developing this new class of antimicrobials, especially those effective against Gram positive pathogens, inter alia, vancomycin-resistant
Enterococcus faecium
. These quinolone and quinolonyl antibiotics and their preparation are well described in the documents cited herein below.
However, some categories of quinolone antibiotic analogs have substituents along the quinolone ring system which render the synthesis of these analogs cumbersome, indirect, and only achievable in low overall yield. There is therefore a long felt need for a process for making the quinolone and quinolonyl antibiotic intermediates described herein, said process encompassing a direct, high yield, low cost series of reactions thereby benefiting the consumer with effective, affordable antibiotics.
SUMMARY OF THE INVENTION
The present invention relates to the surprising discovery that quinolone antibiotic intermediates having the formula:
wherein R is C
1
-C
2
alkyl, C
1
-C
2
fluoroalkyl, C
2
-C
4
alkenyl, methoxy, chloro, or bromo; R
1
is a unit selected from the group consisting of C
1
-C
2
alkyl, C
2
-C
3
alkenyl, C
3
-C
5
cycloalkyl, and phenyl, each of which can be substituted by one or more fluorine atoms; can be prepared by reacting an admixture of quinolone antibiotic intermediate precursors, said admixture comprising a 2-ethoxy substituted intermediate having the formula:
with a silylating agent as a ring closure reaction catalyst.
In general the present invention relates to a process for preparing quinolone antibiotic intermediates having the formula:
wherein R and R
1
are defined herein; said process comprising the steps of:
a) reacting an acetophenone having the formula:
with diethylcarbonate in the presence of a base to form an admixture of 4-fluoro &bgr;-ketoesters having the formula:
b) reacting said admixture with an amine capable of undergoing a Knoevenagel Reaction, said amine having the formula:
wherein R
2
is C
1
-C
4
linear or branched alkyl, phenyl, and mixtures thereof; X is an aldehyde unit or an aldehyde unit equivalent; to form an admixture of enamine intermediates having the formula:
c) reacting said enamine intermediate admixture with an amine having the formula:
R
1
—NH
2
to form an admixture of quinolone intermediates having the formula:
d) cyclizing said quinoline intermediate admixture in the presence of a silylating agent to form the quinoline antibiotic intermediates according to the present invention.
The present invention further relates to novel compounds having the formula:
and the formula:
wherein R, R
1
, and R
4
are defined herein above, X is a suitable leaving group, said compounds suitable for use as intermediates in the preparation of quinolone antibiotics according to the present invention.
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
REFERENCES:
patent: 4695646 (1987-09-01), Maurer et al.
patent: 5703231 (1997-12-01), Randall et al.
patent: WO 96/04247 (1996-02-01), None
patent: WO 96/04286 (1996-02-01), None
patent: WO 02/48113 (2002-06-01), None
Dentz Bernard
Echler Sr. Richard S.
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