Intermediates useful in the synthesis of quinoline antibiotics

Details Intermediates useful in the synthesis of quinoline antibiotics Intermediates useful in the synthesis of quinoline antibiotics

1999-09-21

2001-03-06

Rotman, Alan L. (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S291000, C548S452000

Reexamination Certificate

active

06198000

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to the antibiotic trovafloxacin having the formula
and its pharmaceutically acceptable salts and prodrugs (hereafter “the active compounds”). More particularly, it relates to a process and compositions useful in the the preparation of compounds of the formula
wherein R
1
, m, o and p are as described below. The compounds of formula III are intermediates in the preparation of the compound of formula I and the pharmaceutically acceptable salts and prodrugs thereof. The antibacterial activity of the aforementioned antibiotic is described in U.S. Pat. No. 5,164,402 (the '402 patent) and U.S. Pat. No. 5,229,396 (the 396' patent) issued Nov. 17, 1992 and Jul. 20, 1993, respectively, the disclosures of which are incorporated herein, by reference, in their entirety. The foregoing patents are assigned in common with the present application.
U.S. Pat. No. 5,256,791 (the '791 patent), issued Oct. 26, 1993, describes a process, for preparing a compound of formula III by adding a base to a solution of a compound of the formula II, described below, and a nitrohalomethane, described below, in an inert, non-aqueous solvent wherein the base consists of 1,8-diazabyclo-[5.4.0]undec-7-ene (DBU) and U.S. patent application Ser. No. 08/181942 (the '942 application), filed Jan. 18, 1994, describes the use of dimethyltetrahydropyrimidine (DMTHP) as the base in a similar process. The foregoing references are assigned in common with the present application and are incorporated herein, in their entirety, by reference.
The methods by which the compounds of formula III may be converted into the compound of formula I are set forth in detail in the aforementioned '791 patent.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the formula
wherein each R
1
is independently selected from hydrogen, optionally substituted (C
1
-C
6
)alkyl or optionally substituted (C
6
-C
10
)aryl wherein said substituents independently are attached to the maximum allowable number of carbon atoms and are each independently selected from halo, nitro, (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, amino and trifluoromethyl or two R
1
groups together with the carbon atom tto which they are attached form a (C
3
-C
8
)cycloalkyl ring,
o is 0 or an integer from 1 to 5;
m is 0, 1 or 2; and
p is 0 or an integer from 1 to 3;
which comprises adding a base of the formula
wherein each R
2
may be different and is independently selected from the group comprising (C
1
-C
16
)alkyl and benzyl;
R
3
is selected from the group described for R
1
; and
each R
4
may be different and is independently selected from (C
1
-C
6
)alkyl
wherein said alkyl group may be a straight chained hydrocarbyl group or, if consisting of more than two carbon atoms may also be branched or cyclic; to a solution comprising a compound of the formula
wherein R
1
, m, o and p are as described above, and a halonitromethane of the formula O
2
NCH
2
X, wherein X is a halogen atom, dissolved in a non-aqueous inert solvent. Preferably, at least one R
4
is a branched (C
4
-C
6
)alkyl group. Most preferably, both R
4
groups are the same.
This invention also relates to a compound having the formula
wherein R
2
, R
3
and R
4
are as described above with the proviso that R
3
cannot be hydrogen or CF
3
when each R
2
is methyl and each R
4
is t-butyl. Preferably, each R
4
is t-butyl, each R
2
is butyl and R
3
is hydrogen.
The term “halo”, as used herein, refers to chloro, fluoro, bromo or iodo.
The term “alkyl” as used herein refers to straight and, if comprised of more than two carbon atoms, cyclic and branched hydrocarbyl chain and combinations thereof.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is illustrated in the following reaction scheme. Except where otherwise indicated, in the reaction scheme and discussion that follow, formulas I, II, III, IV and V substituents X, R
1
, R
2
, R
3
and R
4
are defined as above.
The above reaction scheme illustrates the preparation of the compound of formula III, which is a useful intermediate in the synthesis of the antibiotics, of the formula I, referred to above.
Referring to the above scheme, the compound of formula II is reacted with a halonitromethane V, preferably chloronitromethane (O
2
NCH
2
Cl) or bromonitromethane (O
2
NCH
2
Br), in the presence of the base of the formula IV to yield the compound of formula III. The base is, preferably, tetrabutylammonium 2,6-di-t-butylphenoxide. The reaction is generally effected by dissolving the compound of formula II and the halonitromethane V in a non-aqueous inert solvent and atmosphere and adding the base to the resulting solution. The reaction is, preferably, effected in the presence of a solid support material such as molecular sieves, which are believed to function by absorbing water, and diatomaceous earth, e.g., Celite (trademark), which is believed to function by absorbing undesired byproducts and facilitate filtration and mixtures thereof. Most preferably, the reaction is effected in the presence of a solid support consisting of a mixture of molecular sieves and Celite. Most preferably, the molecular sieves are used in the form of beads. Although a theory has been proposed as to how the solid supports function the invention does not depend on the validity of the theory. Inert solvents useful in the practice of the invention include, e.g., polar, aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or dimethylacetamide (DMAC); ethers such as ethyl ether, glyme or tetrahydrofuran (THF) and aromatic solvents such as optionally halogenated benzene or toluene and mixtures thereof. Toluene is the preferred solvent. Suitable reaction temperatures range from about −78° C. to about 80° C., preferably from about −17 to −19° C. Compounds of the formulae II and V may be obtained commercially or can be prepared by known methods. The compound of formula IV can, generally, be prepared by treatment of the corresponding phenols with tetralkylammonium hydroxides of the formula (R
2
)
4
N
+
OH
−
. (See, e.g., Medebielle, M., et al.
J. Am. Chem. Soc.,
1991, 113, 6872.) The phenols may be used neat or dissolved in a non-aqueous solvent such as those described above for use in dissolving the mixture of compounds II and V, a (C
1
-C
6
)alkanol or acetonitrile. The preferrred solvent is toluene. The reaction is run at a temperature of from about −50 to about 50° C., preferably at room temperature, for a period of from about 5 minutes to two hours. The solvent is removed from the reaction mixture by evaporation, preferably under vacuum, optionally followed by the addition and evaporation of solvents such as toluene to aid in drying. The compounds of formula IV are used without further preparation.
The procedures by which compounds of the formula III may be used to prepare the compound of formula I, related azabicyclo quinoline carboxylic acids and their pharmaceutically acceptable salts and prodrugs thereof are set forth in the '791 patent referred to above and incorporated herein, in its entirety, by reference.
The active compounds are useful in the treatment of animals, including humans, having a broad spectrum of bacterial infections, particularly gram-positive bacterial strains.
The active compounds may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm. They can be injected parenterally, for

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