Process for preparing naphthyridones and intermediates

Details Process for preparing naphthyridones and intermediates Process for preparing naphthyridones and intermediates

1999-01-25

2001-02-06

Kight, John (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S452000

Reexamination Certificate

active

06184380

ABSTRACT:

This application is the nonprovisional application of provisional application Ser. No. 60/071,601, filed Jan. 16, 1998.
This invention relates to a process for preparing the naphthyridone carboxylic acid, trovafloxacin and derivatives thereof, and intermediates of use therein.
Trovafloxacin has the formula
as disclosed in U.S. Pat. No. 5,164,402. The patent also discloses processes for making the compound by using an intermediate of the formula
wherein R′ is a nitrogen protecting group, such as tertiary butyloxycarbonyl.
U.S. Pat. No. 5,475,116 discloses the preparation of other intermediates for use in preparing the naphthyridones of U.S. Pat. No. 5,164,402.
The present invention relates to a process for preparing a compound of the formula
wherein R
1
is benzyl, wherein the phenyl of the benzyl may be substituted by one or more of C
1
—C
6
alkyl, C
1
—C
6
alkoxy, halo, nitro, amino or trifluoromethyl, and
R
2
is C
1
—C
6
alkyl, trifluoromethyl, or phenyl which may be substituted by one or more of C
1
—C
6
alkyl, C
1
—C
6
alkoxy, halo, nitro, amino or trifluoromethyl, which comprises
(a) reducing a compound of the formula
wherein R
1
as defined above, in the presence of iron and a organic solvent under acidic conditions, and
(b) acylating the compound of formula III formed:
with an acylating agent of the formula R
2
C(O)X wherein R
2
is as defined above, and X is a leaving group.
In a preferred embodiment of the invention, the compound of formula III formed in step (a) is not isolated before acylation step (b).
The invention is further related to a process for preparing a compound of the formula
by debenzylating the compound of formula I wherein R
1
and R
2
are as defined above.
In a preferred embodiment, the debenzylation is carried out by reacting a compound of formula I with hydrogen and palladium catalyst in acetic acid and an organic solvent.
The invention also relates to reacting a compound of the formula IV with a compound of the formula
wherein R
3
is C
1
—C
6
alkyl, to form a compound of the formula
wherein R
2
is as defined above with reference to formula 1.
The invention relates to hydrolyzing the compound of formula VI with methanesulfonic acid, water and an organic solvent to form the monomethanesulfonic acid salt of the compound of the formula VII, trovafloxacin.
The invention also relates to hydrolysis of the compound of formula VI with methanesulfonic acid and R
3
OH wherein R
3
is as defined above to form the mono-methanesulfonic acid salt of the compound of the formula
The invention further relates to the intermediates of the formulae
wherein R
2
is C
1
—C
6
alkyl, trifluoromethyl, or phenyl which may be substituted by one or more of C
1
—C
6
alkyl, C
1
—C
6
alkoxy, halo, nitro, amino or trifluoromethyl, and
R
3
is C
1
—C
6
alkyl, and
wherein
R
1
is hydrogen (see formula IV) or benzyl, wherein the phenyl of the benzyl may be substituted by one or more of C
1
—C
6
alkyl, C
1
—C
6
alkoxy, halo, nitro, amino or trifluoromethyl, and
R
2
is C
1
—C
6
alkyl, trifluoromethyl, or phenyl which may be substituted by one or more of C
1
—C
6
alkyl, C
1
—C
6
alkoxy, halo, nitro, amino or trifluoromethyl.
The term “alkyl”, as used herein, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties, e.g. methyl, ethyl.
The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
The processes of the invention are depicted in the following reaction scheme. Unless indicated otherwise, R
1
, R
2
, R
3
and X are as defined above.
The compound of formula III is prepared from the corresponding compound of formula II by reduction in the presence of iron and an organic solvent under acidic conditions. The organic solvent is a C
1
—C
6
alcohol, such as ethanol, or an ether such as tetrahydrofuran (THF), and preferably, an alcohol. The acidic conditions are obtained by use of a mineral acid, such as hydrochloric acid, or an organic acid, such as acetic acid (AcOH). Acetic acid is preferred since it generally results in increased yields.
The compound of formula III may then be isolated from the reaction mixture or may be reacted further in situ, without isolation from the reaction mixture. In either case, the further processing is by acylation with an acylating agent of the formula R
2
C(O)X to form the compound of formula I. The leaving group X is conveniently a halogen, such as chloro, or the acetoxy group. If the compound of formula III is first isolated, then the acylation may be conducted under conventional acylating conditions, for instance, in the presence of an organic solvent of the type discussed above.
The compound of formula I is subjected to debenzylation to form the compound of formula IV. It is understood that in the context of the invention, debenzylation includes removal of R
1
wherein R
1
is benzyl or substituted benzyl. The reaction proceeds in accordance with conventional debenzylation of tertiary nitrogen, conveniently by use of hydrogen and palladium catalyst in acetic acid, and in an organic solvent. The organic solvent may be a C
1
—C
6
alcoholic solvent, such as ethanol, ethyl acetate, THF or water, or a mixture thereof, such as ethanol and water.
The compound of formula VI is obtained by coupling the corresponding compound of formula IV with the bicyclic intermediate ester of formula V. This coupling reaction may be conducted with or without a solvent. The solvent, when used, must be inert under the reaction conditions. Suitable solvents are ethyl acetate, acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, pyridine, and water, and mixtures thereof.
The reaction temperature usually ranges from about 20° C. to about 150° C.
The reaction may advantageously be carried out in the presence of an acid acceptor such as an inorganic or organic base, e.g. an alkali metal or alkaline earth metal carbonate or bicarbonate, or a tertiary amine, e.g. triethylamine, pyridine or picoline.
The mesylate salt of the compound of formula VII, trovafloxacin, is formed by hydrolysis of the compound of formula VI with methanesulfonic acid, water and an organic solvent. Examples of suitable organic solvents include a C
1
—C
6
alcohol, acetone, dimethoxy ethane, glyme, THF, N-methyl-pyrrolidinone, and water, and mixtures thereof.
The mesylate salt of the compound of formula VII is obtained by hydrolysis of the compound of formula VI with methanesulfonic acid and a C
1
—C
6
alcohol of the formula R
3
OH, for example ethanol. The compound of formula VII is an intermediate in the preparation of the mesylate salt of a prodrug of trovafloxacin wherein the amino group is substituted by an amino acid or a polypeptide, e.g. dipeptide, as disclosed in U.S. Pat. No. 5,164,402.
The compound of formula IX in the Reaction Scheme is the intermediate formed in the reaction from compound VI to VII.
The compound of formula VII and the mesylate salt thereof (the active compounds) are useful in the treatment of bacterial infections of broad spectrum, particularly the treatment of gram-positive bacterial strains.
The active compounds may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally or 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 5-5000 ppm, preferably 25-500 ppm. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or flucose to make the solution isotonic. In the case of animals, compounds can be ad

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