HK1025318A - Process for preparing trovafloxacin acid salts - Google Patents

Description

Process for preparing acid salts of tonofloxacin

The present invention relates to a process for the preparation of acid salts of trovafloxacin. The acid salt of tonofloxacin may be obtained from the hydrolysis of an imine intermediate using mild conditions.

Quinolone and naphthyridone carboxylic acids, their zwitterionic salts, and pharmaceutically acceptable salts are useful antibacterial agents and have been prepared, for example, by the methods described in the following references: U.S. patent No.4,738,968 to Matsumoto et al, U.S. patent No.4,382,937 to Matsumoto et al, U.S. patent No.4,382,892 to Hayakawa et al, U.S. patent No.4,571,396 to Hutt et al, U.S. patent No.4,416,884 to Ishikawa et al, U.S. patent No.4,775,668 to Jefson et al, U.S. patent No.5,164,402 to Brighty, and british patent application No.2,191,776 to Toyama Chemical co.ltd.

(1 alpha, 5 alpha, 6 alpha) -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 tonofloxacin) is a class of naphthyridonecarboxylic acids with superior antibacterial properties.Tunofloxacin

As with the acid salt of tonofloxacin, the acid salt of tonofloxacin also has antibacterial properties. The acid salt of tonofloxacin is a water-soluble prodrug form of tonofloxacin. The danofloxacin hydrochloride has been previously obtained by the following process: reacting 7-chloro-1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid ethyl ester:

and [1 alpha, 5 alpha, 6 alpha ]]-6-tert-Butoxycarbonylamino-3-azabicyclo [3.1.0]Hexane coupling

The resulting product was then hydrolyzed with aqueous hydrochloric acid (U.S. Pat. No.5,164,402 to Brighty, example 12A).

Recently, the danofloxacin mesylate salt has been obtained by the following method: the resulting product was coupled with ethyl 7-chloro-1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate and [1 α,5 α,6 α ] -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane and hydrolyzed with methanesulfonic acid (U.S. Pat. No.5,763,454 to Handanyan et al).

While the above process reliably provides useful amounts of the acid salt of tonofloxacin, the above process also produces equimolar amounts of isobutylene gas (as a by-product of the hydrolysis of the t-butoxycarbonyl protecting group). Isobutylene is highly flammable and is believed to have a deleterious effect on the atmospheric ozone layer. Therefore, a process for obtaining the acid salt of tonofloxacin without causing the formation of harmful isobutylene gases would be highly desirable and advantageous.

Citation of any document in the background section of the application is not to be construed as an admission that such document is available as prior art to the present application.

The invention provides a method for preparing the acid salt of the tonofloxacin with the structure of the formula (IV):wherein ZH is an inorganic acid, comprising the step of reacting a compound of formula (I):

wherein R is C₁～C₆An alkyl group; and the benzylidene ring of the compound of formula (I) is optionally substituted with one or more of fluoro, chloro, bromo, iodo, C₁～C₆Alkyl or C₁～C₆Alkoxy substituted, with a composition comprising said mineral acid ZH and water.

The invention further provides novel compounds of formula (I). The compounds of formula (I) are useful as intermediates in the synthesis of acid salts of tonorfloxacin. In a preferred embodiment of the invention, the compound of formula (I) is (1 α,5 α,6 α) -7- (6-benzylideneamino-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 ethyl ester:

in addition, the present invention provides a process for preparing an acid salt of tonorfloxacin having the structure of formula (IV), comprising the steps of:

(a) reacting a compound of formula (V):wherein R is as 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 of fluoro, chloro, bromo, iodo, C₁-C₆Alkyl or C₁～C₆Alkoxy substitution to produce a compound of formula (I); and

(b) contacting a compound of formula (I) with a composition comprising the mineral acid ZH and water.

The present invention further provides novel compounds of formula (II) which are useful as intermediates in the synthesis of compounds of formula (I) and acid salts of tonofloxacin. In a preferred embodiment of the invention, the compound of formula (II) is (1 α,5 α,6 α) -6-benzylideneamino-3-azabicyclo [3.1.0]]Hexane:

further, the present invention provides a process for preparing an acid salt of tonofloxacin, comprising the steps of:

(a) contacting a compound of formula (I) with a mineral acid ZH under substantially anhydrous conditions to produce a compound of formula (III):

wherein R and ZH are as previously defined; and

(b) contacting a compound of formula (III) with a composition comprising a mineral acid ZH and water.

The present invention still further provides novel compounds of formula (III) useful as intermediates in the synthesis of acid salts of tonofloxacin. In a preferred embodiment of the invention, the compound of formula (III) is otonorfloxacin ethyl methanesulfonate:

since the compounds of formula (I) and (II) are both imines, they are present in either the cis or trans configuration. It is to be understood that the claimed invention encompasses any configuration or mixture thereof.

Definition of

The term "alkyl" as used herein includes straight or branched chain hydrocarbyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

The term "aryl" as used herein includes aromatic hydrocarbon groups, such as phenyl or naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of: fluorine, chlorine, cyano, nitro, trifluoromethyl, (C)₁～C₆) Alkoxy group, (C)₆～C₁₀) Aryloxy, trifluoromethoxy, difluoromethoxy and (C)₁～C₆) An alkyl group.

The term "coupling reaction" as used herein means a reaction which results in the formation of a compound of formula (I), i.e. a reaction between a compound of formula (II) below and a compound of formula (V) in the presence of a tertiary amine base.

The term "hydrolysis reaction" as used herein means the reaction between a compound of formula (I) and a composition comprising a mineral acid and water.

The term "imine formation reaction" as used herein denotes the reaction of (1 α,5 α,6 α) -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 one bond forming three bonds (wherein each bond is sp²Bond or sp³A bond, separately attached to a carbon atom).

The term "acid salt of tonofloxacin" as used herein means an inorganic acid salt of tonofloxacin.

The term "substantially anhydrous conditions" as used herein means reaction conditions such as: wherein the amount of water present is no greater than about 1 wt% of the reaction mixture.

A compound of formula (II)

The compound of formula (II) can be obtained as shown in scheme 1. Nitrocyclopropanation of N-benzylmaleimide (1) to give (1 alpha, 5 alpha, 6 alpha) -3-N-benzyl-6-nitro-2, 4-dioxo-3-azabicyclo [3.1.0]Hexane (2). In BF₃With NaBH in the presence of THF₄Reduction of the iminocarbonyl group of 2 to give (1 alpha, 5 alpha, 6 alpha) -3-N-benzyl-6-nitro-3-azabicyclo [3.1.0]]Hexane (3). Reduction of the nitro group of 3 to amino group by hydrogenation in the presence of 10% Pd on carbon with hydrogenolysis of the N-benzyl group to give (1 α,5 α,6 α) -6-amino-3-azabicyclo [ 3.1.0%]Hexane (4). Then (1 alpha, 5 alpha, 6 alpha) -6-amino-3-azabicyclo [3.1.0]Reaction of hexane with an optionally substituted aldehyde 5 in an imine formation reaction to produce a compound of formula (II) in the reaction of (1 α,5 α,6 α) -6-amino-3-azabicyclo[3.1.0]Hexane has an imino protecting group on the 6-amino group. Compounds 1 to 4 can be obtained by the methods described later herein or by methods known to those skilled in the art. Compound 3 can be prepared as described by Braish et al, synthetic communications (Synlett)1100 (1996). Aldehyde 5 is optionally substituted with one or more of fluorine, chlorine, bromine, iodine, C₁～C₆Alkyl or C₁～C₆Alkoxy substitution. Aldehyde 5 is commercially available or can be readily synthesized by methods known to those skilled in the art. Suitable aldehydes 5 include, but are not limited to: benzaldehyde, 2-chlorobenzaldehyde, 3-chlorobenzaldehyde, 4-chlorobenzaldehyde, 2-bromobenzaldehyde, 3-bromobenzaldehyde, 4-ethylbenzaldehyde, o-tolualdehyde, m-tolualdehyde, p-tolualdehyde and the like. Preferably, aldehyde 5 is benzaldehyde.

FIG. 1 schematically shows

The reaction leading to the formation of the compound of formula (II) (imine formation reaction) is carried out by contacting (1 α,5 α,6 α) -6-amino-3-azabicyclo [3.1.0] hexane (4) with aldehyde 5. Typically, the molar ratio of (1 α,5 α,6 α) -6-amino-3-azabicyclo [3.1.0] hexane to aldehyde 5 is in the range of about 3: 1 to about 1: 3, preferably in the range of about 1.5: 1 to about 1: 1.5, and most preferably in the range of about 1.1: 1 to about 1: 1.1.

The imine-forming reaction may optionally be carried out in the presence of an inert organic solvent. Suitable organic solvents include, but are not limited to: diethyl ether, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, and simple alcohols such as methanol and isopropanol. When the imine-forming reaction is carried out in the presence of an inert organic solvent, the imine-forming reaction is carried out as a solution in about 1% to about 95% v/v of the inert organic solvent; preferably, it is carried out as a solution in an inert organic solvent at about 5% to about 40% v/v. Preferably, the imine formation reaction is carried out in the absence of an inert organic solvent.

Whether or not an inert organic solvent is used, the imine-forming reaction is preferably carried out in the presence of a tertiary amine base. Without being bound by any particular theory, it is believed that the role of the tertiary amine base is to eliminate any trace of acid present in the reaction medium < which can cause decomposition, e.g., hydrolysis, > of the compound of formula (II). Suitable tertiary amine bases include, but are not limited to: triethylamine, N-diisopropylethylamine, dimethylisopropylamine, methyldibutylamine, triphenylamine, pyridine, 4-dimethylaminopyridine, 2, 6-lutidine, 2, 4, 6-collidine, N' -tetramethyl-1, 8-naphthalenediamine, and the like. Preferably, when a tertiary amine base is used, the tertiary amine base is triethylamine. When a tertiary amine base is used, it is preferably present in an amount in excess of (1 α,5 α,6 α) -6-amino-3-azabicyclo [3.1.0] hexane or aldehyde 5 (whichever is greater). More preferably, the molar ratio of tertiary amine base to (1 α,5 α,6 α) -6-amino-3-azabicyclo [3.1.0] hexane or aldehyde 5 (whichever is greater) is from about 10: 1 to about 2: 1, most preferably from about 5: 1 to about 2: 1.

The imine-forming reaction is carried out at a temperature from about room temperature to about the reflux temperature of any inert organic solvent or tertiary amine base employed, preferably from about room temperature to about 120 ℃, more preferably from about 45 ℃ to about 110 ℃, and most preferably from about 70 ℃ to about 100 ℃.

When the imine-forming reaction is carried out in the absence of an inert organic solvent but in the presence of a triethylamine tertiary amine base, the imine-forming reaction is carried out at about the reflux temperature of triethylamine.

The compounds of formula (II) obtained from the imine-forming reaction can be purified from their reaction mixture using standard recrystallization methods known to those skilled in the art, or can be obtained by simply concentrating the imine-forming reaction mixture (optionally under vacuum) to remove the inert organic solvent or tertiary amine base. Alternatively, the compound of formula (II) may be formed in situ and used as an intermediate without purification to prepare the compound of formula (I) and the acid salt of tonofloxacin.

In a preferred embodiment of the invention, the aldehyde 5 is benzaldehyde and the compound of formula (II) is (1 α,5 α,6 α) -6-benzylideneamino-3-azabicyclo [3.1.0] hexane.

A compound of formula (I)

In general, the compounds of formula (I) are obtained by combining, in no preferred order, a compound of formula (II), a compound of formula (V) and a tertiary amine base. The compounds of formula (II) can be obtained as described in the previous section. The compound of formula (V) may be obtained according to the method of British patent publication No. GB2,191,776.

The tertiary amine base is as described above for the imine-forming reaction. Preferably, the tertiary amine base has the formula (R)²)(R²)(R²) N, wherein each R²Independently is C₁～C₆Alkyl or (C)₆～C₁₀) An aryl group; or the tertiary amine base is an aromatic compound having a bridged ring nitrogen atom. Suitable tertiary amine bases include, but are not limited to: triethylamine, N-diisopropylethylamine, dimethylisopropylamine, methyldibutylamine, triphenylamine, pyridine, 4-dimethylaminopyridine, 2, 6-lutidine, 2, 4, 6-collidine, N' -tetramethyl-1, 8-naphthalenediamine, and the like. Preferably, the tertiary amine base is triethylamine.

The molar ratio of the compound of formula (II) to the compound of formula (V) is in the range of about 1.5: 1 to about 1: 1.5, preferably about 1.3: 1 to about 1: 1.3. The molar ratio of the tertiary amine base to the compound of formula (II) or to the compound of formula (V), whichever is more employed, is generally from about 10: 1 to about 1: 1, preferably from about 6: 1 to about 1: 1.

Without being bound by any particular theory, it is believed that the use of a tertiary amine base substantially avoids the formation of undesirable by-products resulting from imine hydrolysis and subsequent reaction of the primary exocyclic amino group of the compound of formula (II) with the chloro group at the 7-carbon atom in the compound of formula (V). Furthermore, the tertiary amine base promotes the bond formation process between the 7-carbon atom of the compound of formula (V) and the ring nitrogen atom of the compound of formula (II).

If the tertiary amine sufficiently dissolves the compound of formula (II)And a compound of formula (V), the coupling reaction does not have to be carried out in the presence of an additional solvent. However, in some cases it may be desirable to carry out the coupling reaction in the presence of a coupling reaction solvent, for example, to better dissolve reagents or to control reaction exothermicity. Suitable coupling reaction solvents include (C)₁～C₆) Alcohols such as methanol, ethanol and isopropanol; ethers such as Tetrahydrofuran (THF) and diethyl ether; polar aprotic solvents such as dimethyl sulfoxide, acetonitrile, dimethylformamide and N-methylpyrrolidone; and mixtures thereof. The compound of formula (II) and the compound of formula (V) should be at least partially soluble in the chosen coupling reaction solvent; it is therefore within the ability of the person skilled in the art to select a suitable solvent or solvent mixture, if desired.

The coupling reaction is conveniently carried out at a temperature of about 60 ℃ or above, for a reaction time in the range of about 1 hour to about 48 hours, preferably in the range of about 2 hours to about 24 hours. More preferably, the coupling reaction is carried out at the reflux temperature of the tertiary amine base or specific solvent employed, and the reaction time is in the range of about 6 hours to about 20 hours.

The product of the coupling reaction, i.e. the compound of formula (I), can be purified by recrystallization from common laboratory solvents or by other methods known to the person skilled in the art. If the compound of formula (I) is insoluble in the tertiary amine base or the coupling reaction solvent, the compound of formula (I) may be isolated by filtration and optionally recrystallized from usual laboratory solvents or mixtures thereof, or purified using any other method known to those skilled in the art.

The compound of formula (II) used in the coupling reaction may either be isolated and purified from the imine formation reaction described previously, or preferably formed in situ and contacted with the compound of formula (V) and a tertiary amine base. In this regard, the compound of formula (II) is formed as described above in the imine-forming reaction, and the compound of formula (V) is added to the imine-forming reaction mixture. If a tertiary amine base is used in the imine formation reaction, additional tertiary amine base is optionally added to the coupling reaction. If the tertiary amine base is not present in the solution of the compound of formula (V), the tertiary amine base is added to the coupling reaction simultaneously with, before or after the addition of the compound of formula (V).

Acid salt of tonofloxacin

The acid salt of tonofloxacin is obtained by contacting (hydrolysis) the compound of formula (I) with a composition comprising an inorganic acid and water. Without being bound by any particular theory, it is believed that the mineral acid removes the imino protecting group from the compound of formula (I), and the composition comprising the mineral acid and water hydrolyzes the ester group at the 3-carbon atom of the compound of formula (I) to form the tonofloxacin, which forms a stable acid salt with 1 equivalent of the mineral acid used in the hydrolysis reaction.

Suitable inorganic acids include, but are not limited to: methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, acetic acid, maleic acid, and the like. It will be appreciated that the acid salt of tonofloxacin obtained from the hydrolysis reaction is the tonofloxacin salt of the particular inorganic acid used herein.

Generally, the molar ratio of inorganic acid to compound of formula (I) is in the range of about 10: 1 to about 1: 1, preferably about 5: 1 to about 2: 1. The weight ratio of water to the total weight of the compound of formula (I) and the inorganic acid is from about 10: 1 to about 2: 1.

Optionally, a water soluble organic solvent may be added to the hydrolysis reaction to help dissolve the compound of formula (I). Such water-soluble organic solvents are preferably non-nucleophilic and do not form carboxylic acid derivatives with the ester group of the compound of formula (I) or with the carboxyl group of the tonofloxacin group (at the 3-carbon atom). Water-soluble organic solvents suitable for use in this regard include, but are not limited to: tetrahydrofuran, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and the like. If a water-soluble organic solvent is used in the hydrolysis reaction, the water-soluble organic solvent is preferably tetrahydrofuran.

The hydrolysis reaction is carried out at a temperature ranging from about room temperature to about the reflux temperature of water or the water-soluble organic solvent for about 1 hour to about 48 hours. Preferably, the hydrolysis reaction is carried out at the reflux temperature of water or the water-soluble organic solvent for about 12 hours to about 36 hours.

The acid salt of tonofloxacin may be isolated from the hydrolysis reaction by: the hydrolysis reaction mixture is concentrated to a reduced volume, the resulting concentrate is optionally cooled, and the resulting acid salt precipitate of tonofloxacin formed is filtered. The hydrolysis reaction mixture may be pretreated with decolorizing carbon prior to concentration, followed by filtration. In addition, manual granulation or mechanical granulation of the acid salt of tonofloxacin may be required prior to filtration. The filtered acid salt product of tonofloxacin may optionally be recrystallized using conventional laboratory solvents or purified using other methods known to those skilled in the art.

It should be noted that the acid salt of tonofloxacin can also be obtained from the compound of formula (I) via a two-step procedure: a first step of removing the imino-protecting group of the compound of formula (I) without hydrolyzing the ester group at the 3-carbon atom thereof to produce a compound of formula (III); in the second step, the ester group on the 3-carbon atom of the compound of formula (III) is hydrolyzed to obtain the acid salt of the tonofloxacin. Accordingly, the compounds of formula (III) are useful as intermediates in the synthesis of the acid salt of tonorfloxacin, as well as prodrugs of the acid salt of tonorfloxacin.

The compounds of formula (III) are prepared by contacting a compound of formula (I) with a mineral acid, optionally in the presence of an inert organic solvent. Generally, the molar ratio of mineral acid to compound of formula (I) is in the range of about 10: 1 to about 1: 1, preferably in the range of about 5: 1 to about 2: 1. An inert organic solvent may be added to help dissolve the compound of formula (I). If an inert organic solvent is added, the inert organic solvent is preferably tetrahydrofuran.

It will be appreciated that since the compound of formula (III) retains an ester group at the 3-carbon position, the reaction to form the compound of formula (III) is carried out under substantially anhydrous conditions so as to exclude water which would hydrolyze the ester group.

The reaction to produce the compound of formula (III) is carried out at a temperature ranging from about room temperature to about 80 c for a period of time ranging from about 1 hour to about 24 hours. Preferably, the reaction is carried out at a temperature of about 40 ℃ to about 60 ℃ for about 5 hours to about 20 hours.

The resulting compound of formula (III) may be isolated by cooling the reaction mixture to room temperature or below and filtering the product compound of formula (III). If it is desired to isolate the compound of formula (III) in powder form, the compound of formula (III) can be granulated mechanically or manually prior to filtration. Once filtered, the compound of formula (III) may be recrystallized or purified using other methods known to those skilled in the art.

Once the compound of formula (III) is isolated, the compound of formula (III) can be converted to the acid salt of tonofloxacin by contacting the compound of formula (III) with a composition comprising a mineral acid and water. Generally, the molar ratio of mineral acid to compound of formula (III) is in the range of about 5: 1 to about 1: 1, preferably in the range of about 3: 1 to about 1: 1. The weight ratio of water to the total weight of the compound of formula (I) and the inorganic acid is from about 10: 1 to about 2: 1.

Optionally, the aforementioned water-soluble organic solvent may be added to help dissolve the compound of formula (III). If a water-soluble organic solvent is used, the water-soluble organic solvent is preferably tetrahydrofuran.

The conversion of the compound of formula (III) to the acid salt of tonofloxacin is carried out at a temperature in the range of from about room temperature to about the reflux temperature of the water or water-soluble organic solvent for about 1 hour to about 12 hours. Preferably, the reaction is carried out at a temperature of from about 50 ℃ to about 100 ℃ for a period of from about 4 hours to about 8 hours.

The acid salt of tonofloxacin thus obtained can be isolated as described above for the hydrolysis reaction.

Tunorfloxacin zwitterions

Although the acid salt of tonofloxacin is useful as an antibacterial agent, it may be desirable to formulate the acid salt of tonofloxacinIn the form of an active compound having a higher percentage by weight (i.e., no acid salt present). In this case, the acid salt of tonofloxacin obtained as described herein (see international publication No. wo97/07800, example 1A) may be treated with a saturated aqueous solution of sodium bicarbonate to form a zwitterionic form of tonofloxacin having the structure:

method for using acid salt of tonofloxacin

The acid salt of tonofloxacin is useful for the treatment of a wide range of bacterial infections, especially infections with gram-positive strains.

The acid salt of tonofloxacin may be administered alone, but is typically administered in admixture with a pharmaceutical carrier (selected according to the intended route of administration and standard pharmaceutical practice). For example, they may be administered orally or in the form of tablets (containing excipients such as starch or lactose), or in the form of capsules (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 the animal feed or drinking water in concentrations of 5 to 5000ppm, preferably 25 to 500 ppm. They may be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best employed in the form of a sterile aqueous solution which may contain other solutes (e.g., sufficient salts or glucose) to render the solution isotonic. For animals, the acid salt of tonofloxacin may be administered intramuscularly or subcutaneously in a single dose or up to 3 divided doses per day at a dosage level of about 0.1-50 mg/kg/day, advantageously 0.2-10 mg/kg/day.

Bacterial diseases can be treated by oral or parenteral administration of acid salts of trovafloxacin to humans and can be administered orally in a single dose or up to 3 divided doses at dosage levels of about 0.1-500 mg/kg/day, advantageously 0.5-50 mg/kg/day. For intramuscular or intravenous administration, the dosage level is about 0.1 to 200 mg/kg/day, advantageously 0.5 to 50 mg/kg/day. Intramuscular administration may be a single dose or up to 3 divided doses, and intravenous administration may include continuous instillation. As will be appreciated by those skilled in the art, variations will necessarily occur depending on the weight and condition of the subject and the particular route of administration selected.

The antibacterial activity of the acid salt of tonofloxacin was confirmed by testing according to the Streer's replication factor technique, a standard in vitro bacterial test described by e.steers et al in Antibiotics and Chemotherapy (Antibiotics and Chemotherapy), 9, 307 (1959).

The following examples are given to aid in the understanding of the present invention and should not be construed as limiting the invention described and claimed herein. Variations of the invention (including alternatives to all equivalents now known or later developed, which would be within the knowledge of those skilled in the art) are to be considered within the scope of the invention incorporated herein.

Example 1

(1 α,5 α,6 α) -3-N-benzyl-6-nitro-2, 4-dioxo-3-azabicyclo [3.1.0] hexane (2).

N-benzylmaleimide (1) (500g, 2.67 mol), 90% bromonitromethane (831g, 5.34 mol), powdered molecular sieves (200 mesh, 2020g) and toluene (12 dm) were stirred under nitrogen at-10 deg.C³). 1, 2-dimethyl-1, 4,5, 6-tetrahydropyrimidine (616g, 5.49 moles) was added slowly over about 3 hours, maintaining the reaction temperature at < -8 ℃ throughout the addition. After the addition was complete, the reaction mixture was stirred at 25 ℃ for 1.5 hours, filtered through a sealed pressure filter under a nitrogen atmosphere to remove the molecular sieve and the resulting tar, and the molecular sieve was washed with toluene (2L). The combined filtrates were diluted with 2N dilute hydrochloric acid (3X 750 cm)³) Washed, treated with carbon (50g) at 70 ℃ for 1 hour, filtered, concentrated, and mixed with 2-propanol (. about.4 dm³) Trituration to give the title compound as crystals (223g, 34%) mp 116-118 ℃; (found: C, 58.2; H, 4.1; N, 11).3。C₁₂H₁₀N₂O₄Requirement C, 58.5; h, 4.1; n, 11.4%); m/z 246(M +), 200(M + -NO)₂，100％)；δH(300MHz；CDCl₃)7.3(m, 5H, Ph), 4.54(s, 2H, benzyl), 4.45(s, 1H, 6b), 3.35(s, 2H, 3-ring).

Example 2

(1 α,5 α,6 α) -3-N-benzyl-6-nitro-3-azabicyclo [3.1.0] hexane (3).

Tetrahydrofuran (350 cm) was stirred under nitrogen³) Sodium borohydride (14.1g) and (1. alpha., 5. alpha., 6. alpha.) 3-N-benzyl-6-nitro-2, 4-dioxo-3-azabicyclo [3.1.0] obtained above]Hexane (2) (35.0g, mmol) for 0.25 h and then 21.5% BF₃(44.9cm³) The boron trifluoride THF complex was treated dropwise so that the exotherm was controlled at < 40 ℃. After the addition was complete, the reaction mixture was stirred at 40 ℃ for 3 hours, slowly with water/THF (1: 1) (70 cm)³) Quenched to avoid excessive foaming and stirred at 50 ℃ for 0.5 hour to ensure complete quenching of the unreacted diborane formed in situ. The quench formed a salt slurry which was filtered and washed with THF (140 cm)³) Washing; the combined filtrates were partially concentrated with water (350 cm)³) Diluted and concentrated further to remove most of the THF, followed by ethyl acetate (140 cm)³) And (4) extracting. The resulting ethyl acetate solution was concentrated to give the title compound as a clear oil (30.6g, 97%). From its methanesulfonate salt (which is obtained by reacting one equivalent of (1. alpha., 5. alpha., 6. alpha.) -3-N-benzyl-6-nitro-3-azabicyclo [ 3.1.0%]Hexane was mixed with one equivalent of methanesulfonic acid in an alcohol solvent, and the resulting mixture was concentrated) and elemental analysis (found value: c, 49.8; h, 6.0; n, 9.1; and S, 10.2. C₁₂H₁₄N₂O₂·CH₄O₃S required value: c, 49.7; h, 5.8; n, 8.9; s, 10.2%); m/z 218(M +); Δ H (300 MHz; CDCl)₃)7.3(m, 5H, Ph), 4.63(s, 1H, 6b), 3.6(s, 2H, benzylated), 3.14(d, 2H, 5-ring), 2.51(m, 2H, 3-ring).

Example 3

(1 α,5 α,6 α) -6-amino-3-azabicyclo [3.1.0] hexane (4).

Reacting (1 alpha, 5 alpha, 6 alpha) -3-N-benzyl-6-nitro-3-azabicyclo [3.1.0]Hexane (3) (25.2g, 115.5mmol), 10% Pd on carbon (55% water content) (10.0g), Water (125 cm)³) And 2-propanol (250 cm)³) Hydrogenation was carried out in a Parr apparatus at 50 ℃ and 3.5atm for 24 hours. The catalyst was filtered off and the filtrate formed was concentrated in vacuo to give the title compound as an oil (10.4g, 91.7%) with a purity of GC 83%. The material thus obtained was used without further purification. Use 55% CHCl₃、35％CH₃OH and 10% concentrated NH₄OH was purified by column chromatography on silica gel to give the title compound as a clear oil, M/z 96 (M)⁺-2)；δH(300MHz，CD₃OD)4.86(s, NHs and MeOH), 2.97(2H, d, J ═ 11.4Hz), 2.77(2H, dt, J ═ 1.4 and 11.4Hz), 2.06(1H, t, J ═ 2.2Hz), 1.42(2H, td, J ═ 1.4 and 2.2 Hz); Δ C (75.5MHz, CD)₃OD)48.9，32.5，27.5。

Example 4

(1 α,5 α,6 α) -7- (6-benzylideneamino-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 ethyl ester.

The (1 alpha, 5 alpha, 6 alpha) -3-N-benzyl-6-nitro-3-azabicyclo [3.1.0] obtained above]Hexane (3) (30.9g, 142mmol), 2-propanol (310 cm)³) Water (30 cm)³) And 10% carbon supported Pd (50% water content) (12.3g) at 50psi and 50 ℃ in a Parr shaker for 18-24 hours. The Pd catalyst was filtered off and the water was removed by azeotropic distillation at constant volume of the pale yellow filtrate formed. The resulting solution was treated with triethylamine (46g, 456mmol) and heated to reflux. Benzaldehyde (15.0g, 141mmol) was added dropwise over 15 min. Heating the reaction mixture at reflux for 4 hours to form in situ (1 alpha, 5 alpha, 6 alpha) -6-benzylideneamino-3-azabicyclo [3 ].1.0]Hexane. The resulting orange solution was cooled to 40-50 ℃ and ethyl 7-chloro-1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate (42.45g, 111 mmol; see british patent publication No. gb2,191,776) and triethylamine (13.1g, 130mmol) were added. And (3) refluxing and heating the formed slurry for 16-18 hours, cooling to 20 ℃, and stirring for 5 hours. The slurry was filtered and the title compound was isolated as a white solid (75.5% yield based on (1 α,5 α,6 α) -3-N-benzyl-6-nitro-2, 4-dioxo-3-azabicyclo [ 3.1.0)]Hexane; 96.6% yield based on ethyl 7-chloro-1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate). The title compound was recrystallized from acetonitrile and decomposed at mp 148-155 deg.C (real side: C, 63.5; H, 4.4; F, 10.35; N, 10.7. C)₂₉H₂₃F₃N₄O₃·H₂O requirement C, 63.3; h, 4.6; f, 10.35; n.10.2%); m/z533 (M)⁺+1)；δH(300MHz，CDCl₃)8.33(s，1H)，8.29(s，1H)，7.97(d，J＝7.1Hz，1H)，7.58-7.61(m，2H)，7.46(td，J＝5.77，8.6Hz，1H)，7.31-7.35(m，3H)，6.97-7.08(m，2H)，4.31(q，J＝7.1Hz，2H)，3.80(br.s，2H)3.64(br，s，2H)，2.75(t，J＝1.8Hz，1H)，2.13(s，2H)，1.32(t.J＝7.1Hz，3H)；v_{Maximum and minimum}(KBr)cm^-1 1730，1697，1632。

Example 5

Tonofloxacin mesylate (method a).

Adding tetrahydrofuran (250 cm)³) The previously obtained (1. alpha., 5. alpha., 6. alpha) -7- (6-benzylideneamino-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 ethyl ester (25.05g, 47mmol) and water (250 cm)³) Treated with 97% methanesulfonic acid (13.3g, 138mmol) and heated to reflux for 24 h. The resulting solution was cooled to 45 ℃ and treated with activated carbon (2.5g) for 1 hour and then filtered. Vacuum concentrating the filtrate to about 25% of its original volume to form white crystal slurry, cooling to 15-25 deg.C, and granulatingTake 4 hours and filter again to give the title compound (16.86g, 70.0%) as above. mp 253 and 256 ℃ decomposition; (found: C, 49.3; H, 3.75; F, 11.2; N, 11.0; S, 6.3. C)₂₀H₁₅F₃N₄O₃·CH₄O₃S required value C, 49.2; h, 3.7; f, 11.1; n, 10.9; s, 6.3%); Δ H (300 MHz; d)₆-DMSO)8.85(s, 1H), 8.17(br.m, 2H), 8.11(d, 1H), 7.83(m, 2H), 7.62(m, 2H), 7.37(m, 2H), 3.67(br.s, 3H), 2.45(s, 1H), 2.37(s, 3H), 2.08(s, 2H). The compound as above titled may also be isolated as a monohydrate.

Example 6

Danofloxacin zwitterion.

Adding tetrahydrofuran (250 cm)³) The previously obtained (1. alpha., 5. alpha., 6. alpha) -7- (6-benzylideneamino-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 ethyl ester (25.05g, 47mmol) and water (250 cm)³) Treated with 97% methanesulfonic acid (13.3g, 138mmol) and heated to reflux for 24 h. The resulting solution containing the tosufloxacin mesylate was cooled to 45 ℃, treated with activated carbon (2.5g) for 1 hour and filtered. The filtrate was treated with saturated aqueous sodium bicarbonate to pH8 (see PCT publication No. WO97/07800, example 1A) to yield the title compound as above.

Example 7

Otonorfloxacin ethyl ester mesylate.

The previously obtained (1. alpha., 5. alpha., 6. alpha) -7- (6-benzylideneamino-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 ethyl ester (6.02g, 11.3mmol), tetrahydrofuran (90 cm)³) And methanesulfonic acid (1.11g, 11.2mmol) were mixed together to form a slurry. The slurry was heated to 45-55 ℃ for 4 hours at which time additional methanesulfonic acid (2.2g, 22) was added to the reaction mixture.4 mmol). And heating the mixture at the temperature of between 45 and 55 ℃ for 12 hours again to finish the reaction. The reaction mixture was cooled to 0-25 ℃, granulated for 10 hours, filtered, and dried under vacuum at 40-45 ℃ to give the title compound as a white solid (yield 3.76g, 62%).

Example 8

Tonofloxacin mesylate (method B).

With tetrahydrofuran (450 cm)³) Water (50 cm)³) And methanesulfonic acid (13.4g, 139mmol) the otonorfloxacin ethyl ester mesylate (50.0g, 92.5mmol) obtained above was treated to form a slurry. Heating the reaction mixture slurry at 70-80 deg.C for 4 hours, and then removing 250cm by distillation³A solvent. Using water (250 cm)³) Diluting the resulting concentrated reaction mixture to form a solution, and heating the solution at 70-80 ℃ for 2 hours until the reaction is complete. Removing the remaining solvent (200 cm) at 55-65 deg.C under vacuum³). The resulting residue was granulated at 20 to 25 ℃ for 16 hours, filtered and dried under vacuum at 30 to 50 ℃ to give the above-titled compound (yield: 43.8g, (92.4%)). The compound as titled above was consistent with the tonofloxacin mesylate obtained in example 5 above in all material properties.

Some documents have been cited, the entire disclosure of which is incorporated herein by reference.

Claims (21)

1. A process for preparing an acid salt of tonofloxacin having the structure of formula (IV):wherein ZH is an inorganic acid, comprising the step of reacting a compound of formula (I):wherein R is C₁～C₆An alkyl group; and wherein the benzylidene ring of the compound of formula (I) is optionally substituted with one or more of fluoro, chloro, bromo, iodo, C₁～C₆Alkyl or C₁～C₆Alkoxy substituted, with a composition comprising said mineral acid ZH and water.

2. The method of claim 1, wherein R is ethyl.

3. The method of claim 1, wherein the mineral acid is selected from the group consisting of: methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, acetic acid, and maleic acid.

4. The process of claim 1, wherein the process is carried out in the presence of an inert organic solvent.

5. A process for preparing an acid salt of tonofloxacin having the structure of formula (IV):wherein ZH is an inorganic acid, comprising the steps of: (a) reacting a compound of formula (V):wherein R is C₁～C₆Alkyl, with a compound of formula (II):wherein the benzylidene ring of the compound of formula (II) is optionally substituted with one or more of fluoro, chloro, bromo, iodo, C₁～C₆Alkyl or C₁～C₆Alkoxy substitution to produce a compound of formula (I):and (b) contacting the compound of formula (I) with a composition comprising the mineral acid ZH and water.

6. The method of claim 5, wherein R is ethyl.

7. The method of claim 5, wherein the mineral acid is selected from the group consisting of: methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, acetic acid, and maleic acid.

8. The method of claim 5, wherein the tertiary amine base is selected from the group consisting of: triethylamine, N-diisopropylethylamine, dimethylisopropylamine, methyldibutylamine, triphenylamine, pyridine, 4-dimethylaminopyridine, 2, 6-lutidine, 2, 4, 6-collidine and N, N' -tetramethyl-1, 8-naphthalenediamine.

9. The process of claim 6, wherein step (a) of the process is carried out in the presence of an inert organic solvent.

10. The process of claim 6, wherein step (b) of the process is carried out in the presence of a water-soluble organic solvent.

11. A process for preparing an acid salt of tonofloxacin having the structure of formula (IV):wherein ZH is an inorganic acid, comprising the steps of: (a) reacting, under substantially anhydrous conditions, a compound of formula (I):wherein R is C₁～C₆Alkyl, and the benzylidene ring of the compound of formula (I) is optionally substituted with one or more of fluoro, chloro, bromo, iodo, C₁～C₆Alkyl or C₁～C₆Alkoxy substitution, with a mineral acid to produce a compound of formula (III):and (b) contacting the compound of formula (III) with a composition comprising the mineral acid ZH and water.

12. The method of claim 11, wherein R is ethyl.

13. The method of claim 11, wherein the mineral acid is selected from the group consisting of: methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, acetic acid, and maleic acid.

14. The process of claim 11, wherein step (a) of the process is carried out in the presence of an inert organic solvent.

15. The process of claim 11, wherein step (b) of the process is carried out in the presence of a water-soluble organic solvent.

16. A compound of formula (I):wherein R is C₁～C₆Alkyl, and the benzylidene ring of the compound of formula (I) is optionally substituted with one or more of fluoro, chloro, bromo, iodo, C₁～C₆Alkyl or C₁～C₆Alkoxy substitution.

17. The compound of claim 16, wherein R is ethyl.

18. The compound of claim 16, wherein the compound is ethyl (1 α,5 α,6 α) -7- (6-benzylideneamino-3-azabicyclo [3.1.0] hex-3-yl) -1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate.

19. A compound of formula (II):wherein the benzylidene ring of the compound of formula (II) is optionally substituted with one or more of fluoro, chloro, bromo, iodo, C₁～C₆Alkyl or C₁～C₆Alkoxy substitution.

20. The compound of claim 19, wherein the compound is (1 α,5 α,6 α) -6-benzylideneamino-3-azabicyclo [3.1.0] hexane.

21. A compound of formula (III):wherein R is C₁～C₆Alkyl, ZH is an inorganic acid.