Process for preparing trovafloxacin acid salts

Details Process for preparing trovafloxacin acid salts Process for preparing trovafloxacin acid salts

1999-08-26

2002-03-19

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S515000

Reexamination Certificate

active

06359137

ABSTRACT:

1. FIELD OF THE INVENTION
This invention relates to a process for preparing trovafloxacin acid salts. Trovafloxacin acid salts can be obtained from the hydrolysis of an imine intermediate using mild conditions.
2. BACKGROUND OF THE INVENTION
Quinolone and naphthyridone carboxylic acids, zwitterionic salts thereof, and pharmaceutically acceptable salts thereof, are useful as antibacterial agents, and have been prepared according to methods described in, e.g., U.S. Pat. No. 4,738,968 to Matsumoto et al., U.S. Pat. No. 4,382,937 to Matsumoto et al., U.S. Pat. No. 4,382,892 to Hayakawa et al., U.S. Pat. No. 4,571,396 to Hutt et al., U.S. Pat. No. 4,416,884 to Ishikawa et al., U.S. Pat. No. 4,775,668 to Jefson et al., U.S. Pat. No. 5,164,402 to Brighty and U.K Patent Publication No. 2,191,776 to Toyama Chemical Co. Ltd.
(1&agr;,5&agr;,6&agr;)-7-(6-Amino-3-azabicyclo[3.1.0.]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, also known as trovafloxacin, is one type of naphthyridone carboxylic acid having preferred antibacterial properties.
Like trovafloxacin, trovafloxacin acid salts possess antibacterial properties. Trovafloxacin acid salts are aqueous-soluble prodrug forms of trovafloxacin. Trovafloxacin hydrochloride has been previously obtained by coupling ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate:
with [1&agr;, 5&agr;, 6&agr;]-6-tert-butoxycarbonylamino-3-azabicyclo[3.1.0.]hexane:
and hydrolyzing the resulting product with aqueous hydrochloric acid (U.S. Pat. No. 5,164,402 to Brighty, Example 12A).
More recently, trovafloxacin methanesulfonate has been obtained by coupling ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate with [1&agr;,5&agr;,6&agr;]-6-tert-butoxycarbonylamino-3-azabicyclo[3.1.0.]hexane, and hydrolyzing the resulting product with methanesulfonic acid (U.S. Pat. No. 5,763,454 to Handanyan et al.
While the above processes reliably provide usable quantities of trovafloxacin acid salts, the above processes also produce molar equivalents of isobutylene gas as a byproduct of hydrolysis of the tert-butoxycarbonyl protecting groups. Isobutylene is highly combustible, and is believed to exert a deleterious effect on the atmosphere's ozone layer. Accordingly, a process for obtaining trovafloxacin acid salts that does not result in the production of hazardous isobutylene gas would be highly desirable and advantageous.
Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that such reference is available as prior art to the present application.
3. SUMMARY OF THE INVENTION
According to the invention, a process is provided for the preparation of a trovafloxacin acid salt having the formula (IV):
wherein ZH is a mineral acid, comprising the step of contacting a compound of formula (I):
wherein R is a C
1
-C
6
alkyl group; and the benzylidene ring of the compound of formula (I) is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C
6
alkyl or C1-C6 alkoxyl groups, with a composition comprising the mineral acid ZH and water.
The invention further provides novel compounds of formula (I). The compounds of formula (I) are useful as intermediates for the synthesis of trovafloxacin acid salts. In a preferred embodiment of the invention, the compound of formula (I) is ethyl (1&agr;,5&agr;,6&agr;)-7-(6-benzylidenylamino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate:
In addition, the invention provides a process for the preparation of a trovafloxacin acid salt having the formula (IV) comprising the steps of:
(a) contacting, in the presence of a tertiary amine base, a compound of formula (V):
wherein R is defined above, with a compound of formula (II):
wherein the benzylidene ring of the compound of formula (II) is optionally substituted with one or more fluoro, chloro, bromo, iodo, C
1
-C
6
alkyl or C
1
-C
6
alkoxyl groups, to afford a compound of formula (I); and
(b) contacting the compound of formula (I) with a composition comprising the mineral acid ZH and water.
The invention further provides novel compounds of the formula (II) useful as intermediates for the synthesis of compounds of formula (I) and trovafloxacin acid salts. In a preferred embodiment of the invention, the compound of formula (II) is (1&agr;,5&agr;,6&agr;)-6-benzylidenylamino-3-azabicyclo[3.1.0]hexane:
Still further, the invention provides a process for the preparation of trovafloxacin acid salts comprising the steps of:
(a) contacting, under substantially anhydrous conditions, a compound of formula (I) with the mineral acid ZH to afford a compound of formula (III):
wherein R and ZH are defined above; and
(b) contacting the compound of formula (III) with a composition comprising the mineral acid ZH and water.
The invention still further provides novel compounds of the formula (III) useful as intermediates for the synthesis of trovafloxacin acid salts. In a preferred embodiment of the invention, the compound of formula (III) is trovafloxacin ethyl ester methanesulfonate salt:
trovafloxacin ethyl ester methanesulfonate salt.
Since the compounds of formulae (I) and (II) are imines, they exist in either the syn or anti configuration. It is understood, that the invention as claimed includes either configuration or a mixture thereof.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1 Definitions
The term “alkyl” as used herein includes a straight or branched chain hydrocarbyl group such as methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, etc.
The term “aryl” as used herein includes an aromatic hydrocarbyl group, such as phenyl or naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C
1
-C
6
)alkoxy, (C
6
-C
10
)aryloxy, trifluoromethoxy, difluoromethoxy and (C
1
-C
6
)alkyl.
The term “coupling reaction” as used herein means a reaction that results in the formation of a compound of formula (I) via reaction between a compound of formula (II) and a compound of formula (V) in the presence of tertiary amine base.
The term “hydrolysis reaction” as used herein means a reaction between a compound of formula (I), and a composition comprising mineral acid and water.
The term “imine-forming reaction” as used herein means the reaction of (1&agr;,5&agr;,6&agr;)-6-amino-3-azabicyclo[3.1.0]hexane with an optionally substituted aldehyde 5 as shown in Scheme 1.
The term “tertiary amine base” as used herein means an organic compound having a nitrogen atom forming three bonds, each of which being an sp
2
or sp
3
bond, solely with carbon atoms.
The term “trovafloxacin acid salt” as used herein means a mineral acid salt of trovafloxacin.
The term “substantially anhydrous conditions” as used herein means reaction conditions in which water is present in an amount no greater than about 1% by weight of the reaction mixture.
4.2 Compounds of Formula (II)
The compounds of formula (II) can be obtained according to Scheme 1. Nitrocyclopropanation of N-benzylmaleimide (1) affords (1&agr;,5&agr;,6&agr;)-3-N-benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane (2). Reduction of the imino carbonyl groups of 2 with NaBH
4
in the presence of BF
3
-THF provides (1&agr;,5&agr;,6&agr;)-3-N-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane (3). Reduction of the nitro group of 3 to an amino group, with concomitant hydrogenolysis of its N-benzyl group, is accomplished via hydrogenation in the presence of 10% Pd on carbon to afford (1&agr;,5&agr;,6&agr;)-6-amino-3-azabicyclo[3.1.0]hexane (4). (1&agr;,5&agr;,6&agr;)-6-amino-3-azabicyclo[3.1.0]hexane is then reacted with an optionally substituted aldehyde 5 in an imine-forming reaction to afford a compound of formula (II) which bears an imino protecting group on the 6-

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