DD280530A5 - METHOD FOR PRODUCING L-TERTIAER-ALKYL-SUBSTITUTED NAPHTHYRIDINE AND CHINOLINE-CARBONSAEURES AND CARBONSAFE DERIVATIVES - Google Patents

Abstract

Process for the preparation of 1-tertiary alkyl-substituted naphthyridine and quinoline carboxylic acids. There are described and disclosed novel naphthyridine and quinoline carboxylic acids and carboxylic acid derivatives having a 1-tertiary alkyl substituent and methods for their preparation. In particular, these compounds can be used as intermediates in the preparation of naphthyridine and quinoline carboxylic acids useful in the treatment of bacterial infections in warm-blooded animals.

Description

-C (CH ₃ ) CHRCH ₂ , -C (CH ₃ ) CH ₂ CH ₂ CH ₂ , -C (CH ₃ J = CH ₂ ,

and

wherein R is H or CH ₃ ;

X is selected from the group of halogen groups of F, Cl and Br and trihaloalkyl groups selected from CF ₃ and CCI ₃ ;

X 'is selected from F, Cl, Br and an organic leaving group; Y is selected from CH, CF, CCI, CBr and N; and

M is selected from H, C ₁ -C ₄ alkyl and alkali metal, ammonium and alkaline earth metal ions, characterized in that a compound of the following formula o

"COOK

wherein X, X ', Y and R ^{1 are} as defined above and R is an ester group, is hydrolyzed.

Field of application of the invention

The invention relates to processes for the preparation of novel 4-oxo-naphthyridine> ind 4-oxo-quinol-3-carboxylic acid and -carbonsäurederivaten. The compounds according to the invention are valuable starting materials for agents for combating bacterial infections in warm-blooded animals. In particular, they can be used as intermediates in the preparation of 4-oxonaphthyridine and 4-cxo-quinoline-3-carboxylic acid derivatives having antibacterial activity and in the preparation of compositions containing these derivatives.

Characteristic of the known technical solutions

R. Albrecht, Progress in Drug Research, 21, 9-104 (1977), describes the development of numerous structural variants having antibacterial activity, which the structure of nalidixic acid i1-ethyl-1-4-dihydro-7-methyl-4- oxo-1,8-naphthyridine-3-carboxylic acid) having the following structural formula:

COOH

H ₃ C

Such a variant described by Albrecht is the class of compounds which are useful as quinoline derivatives, in particular as derivatives of 1,1'-dihydro-1-oxo-S-quinolinecarboxylic acids having the following structural forms! be designated:

COOH

rl

Such quinolones, which are unsubstituted in benzene nucleus B (R is H), have been described as having only low antibacterial activity. Numerous quinoline derivatives having the above-mentioned structural formula are described in which the benzene nucleus B has substituents selected from the group consisting of halogen, alkyl, cycloalkyl, unsubstituted and substituted phenyl and pyridyl, piperidinyl and piperazinyl, to name just a few. especially when such substituents are in the 7-position.

There are widely described numerous quinoline derivatives which have the above structural forms! have, wherein the pyridone nucleus A has many substituents in the 1-position, which are selected from unsubstituted lower alkyl groups or lower alkyl groups which are substituted, for example, with halogen and hydroxy groups, lower alkenyl, alkynyl and unsubstituted and substituted phenyl groups. In particular, it is mentioned that in an activity comparison of these quinoline derivatives having an alkyl group in the 1-position, the activity obtained with smaller residues was always the best, and further that usually the best activity is obtained with the ethyl group.

Another variant described by Albrecht is the class of compounds referred to as naphthyridine derivatives, that is 1,8-naphthyridine or especially 1,4-dihydro-4-oxo-1,8-naphthyridine-3-bet .: Arbonsäure derivatives having the following structural formula:

Coou

Among the 1,8-naphthyridine derivatives having the above structural formula, derivatives are described, with piperazinyl and pyrrolidinyl groups in the dtr 7-position and ethyl in the 1-position. As for the substituents in the 1-position, it is described that among the substituents at the 1-position described above, the quinoline derivatives have maximum activity, with ethyl or propyl groups, whereas all the smaller or larger alkyl groups or those with additional double bonds or functional groups reduce efficacy.

MPWentland and JBCornett, Annual Reports In Medicinal Chemistry, 20, 1545-154 (1985) describe modifications and developments in the field of antibacterial quinolones following the abovementioned review by Albrecht, in particular with emphasis on developments of 6-fluoro-7 Piperazinylquinolones for enhanced antibacterial activity against Gram-positive bacteria and against anaerobes as well as Gram-negative bacteria compared to the activity shown by nalidixic acid. Among the newer agents described are those known as norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-7- (1-piperazinylM-oxo-quinoline-3-carboxylic acid) and ciprofloxacin (1-cyclopropyl-6-fluoro-1 , 4-dihydro-7- (1-piperazinyl) -4-oxo-quinoline-3-carboxylic acid).

U.S. Patent No. 3,590,036 describes numerous 1-substituted-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and derivatives thereof having the following formula, including the above-mentioned nalidixic acid, wherein the substituents in FIG Position may be aliphatic hydrocarbon radicals having 1-10 carbon atoms including, for example, alkyl, alkenyl and alkynyl radicals. Exemplary of these grates are methyl, ethyl, n-propyl, i-propyl, 2-butyl, isoamyl and. Like., When it is an alkyl radical, and 2-propenyl (allyl), 2-methyl-2-propenyl, 2-butenyl u. Like., When it is alkenyl. The substituents on the pyridine nucleus, i. in the 5-, 6- and 7-positions of the naphthyridine ring system may be lower alkyl, halogen and lower cycloalkylamino.

COOK

IHC

U.S. Patent 4,284,629 describes the preparation of certain 4-pyridone-3-carboxylic acids and derivatives thereof having the following structural formula:

2a

or a salt thereof, wherein R ¹ 'represents an alkyl, cycloalkyl, aralkyl, aryl or amino group; R ² 'represents a hydrogen atom or an acyl, araikyl or an aryl group; R ^{3a represents} a derivative of a carboxyl group such as a nitrile or ester group; and up to three of the symbols A, B, D and E represent a nitrogen atom and the remaining of the symbols A, B, D and E represent an optionally substituted carbon atom. Although the patent describes that particularly preferred aliphatic groups R ¹ 'are ethyl and tertiary butyl, among the thirty-five examples actually given there is a single example which illustrates tertiary butyl as the radical R ", namely 1-t-butyl-1,4- dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (Example 25), but no data on biological activity are reported in this example

 U.S. Patents 4,359,578 and 4,352,803 describe antibacterial compounds having the following structural formula:

COOR

wherein X is a halo atom, in particular fluorine, R 'is an ethyl or vinyl group and R ^{2 is} a hydrogen atom or a lower alkyl group, as well as non-toxic salts of these compounds.

U.S. Patent 4,146,719 describes the compound 1-ethyl-6-fluoro-1,4-dihydro-7- (1-piperazinyl) -4-oxo-ginoline-3-carboxylic acid (norfloxacin) and the hydrates and addition salts thereof.

German Offenlegungsschrift DE 3142854 describes 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acids, including the specific compound in which the substituent in the 7-position is unsubstituted piperazinyl (Ciprofloxacin) and 4-substituted piperazinyl, wherein the substituent is methyl, ethyl or beta-hydroxyethyl.

European Patent 0,153,163 describes antibacterial compounds having the following structural formula:

wherein X is CH, C-Cl, C-F, C- (H, C-O-alkyl of one to three carbon atoms, C-NH-alkyl of one to three carbon atoms or N; Y is H, F, Cl or Br; Z for heterocyclic substituents having the formula:

or

wherein R ^{3 is} hydrogen, methyl, ethyl, 1- or 2-propyl; R ^{1 is} hydrogen, alkyl of one to six carbon atoms or a cation; and R ^{2 is} an alkyl of one to four carbon atoms, vinyl, haloalkyl or hydroxyalkyl of two to four carbon atoms, or cycloalkyl of three to six carbon atoms. Among the many actual examples is the preparation of two compounds wherein R ^{2 is} a ternary alkyl group, namely I-methylcyclopropyl (see Examples 61 and 68). However, no data are given on the biological activity of these compounds. U.S. Patent 4,571,396 (corresponding to European Patent 0,159,174) discloses certain naphthyridine and quinoline carboxylic acids having antibacterial activity and having the following structural formula:

wherein Z is an amine substituent from the following group:

R-N

N-, R-N

N-

Γ7 \

R-N I N-

R-N

R ¹ HN

VTV.

"XD

in:

wherein R is hydrogen, alkyl of one to three carbon atoms, hydroxyalkyl of two to three carbon atoms, benzyl or p-aminobenzyl; R 'is hydrogen or alkanoyl of one to three carbon atoms; X is CH, CF or N; Y is hydrogen, fluorine or amino; R 'is hydrogen, alkyl of one to six carbon atoms or a cation; and R ^{2 is} an alkyl of one to four carbon atoms, vinyl, haloalkyl or hydroxyalkyl of two to four carbon atoms, or cycloalkyl of three to six carbon atoms, as well as the pharmaceutically acceptable acid addition or base salts thereof. US Pat. No. 4,556,658 describes antibacterial compounds of the following structural formula

OOII

where R ¹ and R ^{2 are} identical or different and denote a C 1 -C 4 -alkyl radical which is optionally substituted by a hydroxyl, amino, methylamines or dimethylamino group, and R ¹ and R ² together with the nitrogen atom, to which they are attached may further form a 5- or 6-membered heterocyclic ring which may additionally contain, as a ring member, the following atoms or group O-, -S-, -SO-, -SO ₂ - or ³ NR ³ . The patented compounds are such as to exhibit low toxicity with a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, particularly against Enterobacteriaceae, especially those that are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides and the like. Like. Are resistant. U.S. Patent 4,573,473 describes an improved process for preparing a compound of the structural formula

where A is a substituted amino group R ¹ R ² N-; X is H or F; and R ^{2 is} C ₁ -C ₃ alkyl or C ₁ -C ₆ cycloalkyl. U.S. Patents 4,059,341 and 4,559,342 describe derivatives of the above-mentioned ciprofloxacin having the structural formula

COOiI

European Patent 0166939 describes antibacterial 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-oxo-1-piperazinyl) -3-quinolinecarboxylic acids having the structural formula

• COOH

European Patent 0167763 describes antibacterial compounds of the structural formula

..1

ι R *

COOH

wherein X 'and X ^{2 are the} same or different and represent Cl or F, provided that both are not F at the same time, and R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- or 6-membered ring, the furthermore -0-, -S-, -SO-, -SO ₂ -,> NR ₃ or -CONR ³

 Spanish Patent 8504767 describes a process for the preparation of compounds of the structural formula

COOH

wherein R _{1 is} hydrogen or lower alkyl, for example methyl, ethyl or isopropyl, and R _{2 is} methyl or ethyl, in which 3-chloro-4-fluoro (N-alkyl) aniline is reacted with ethoxymethyl malononitrile, the intermediate obtained under

Friedel-Crafts conditions is cyclized and the resulting intermediate is reacted with a suitable piperazine

South African Patent Application No. 853954 describes antibacterial compounds of the structural formula

COOH

U.S. Patent 4,563,448 describes a method for controlling plant pathogenic bacteria using a cyclopropyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid derivative of the formula

COOH

British Patent Application 2160519A describes quinolone compound having antibacterial activity with the structural formula

COOR

where R, H or alkyl.

European Patent 0132845 describes antibacterial 1,8-naphthyridine derivatives of the formula

COOH

wherein R ₁ , R ₂ and R _{3 are the} same or different and may be hydrogen or lower alkyl of 1 to 5 carbon atoms. Dio European Patent 0134165 describes antibacterial 7- (pyrrol-1-yl) derivatives of 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-ethyl-1,4-dihydro-4-oxoi1,8 -naphthyridine) -3-carboxylic acid of the formula

COOH

wherein X is a carbon atom or nitrogen atom and R is hydrogen or fluorine. U.S. Patent 4,341,784 describes antibacterial 7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids of the formula

0OH

CLOCK

Although the newly developed compounds show improvements in antibacterial activity as compared to the prior compounds, such as a broader spectrum of activity, increased potency, improved absorbability, increased duration of action and improved stability, there remains a need for compounds that are a beneficial combination of these and other desirable properties. Furthermore, there is a need for suitable compounds which are particularly useful as intermediates in the preparation of the above-mentioned compounds.

Object of the invention

The aim of the invention is the provision and preparation of such compounds with desirable properties. These compounds should be useful in particular for the preparation of 4-oxo-naphthyridine and 4-oxo-quinoline-3-carboxylic acid derivatives having antibacterial activity.

Explanation of the essence of the invention

The invention has for its object to provide processes for the preparation of novel compounds having improved properties, which are particularly suitable as intermediates for the preparation of agents for combating bacterial infections

 The invention relates to the preparation of compounds having the general formula

COOM

(Formula II)

wherein R ^{1 is} a tertiary alkyl group selected from

-C (CH ₃ J ₃ , -C (CH ₃ ) ₂ CH ₂ CH ₃ , -C (C ₆ H ₅ ) (CH ₃ ) ₂ , -C (C ₆ H ₅ ) CHRCH ₂

-C (CH ₃ ) CHRCH ₂ , -C (CH ₃ ) CH ₂ CH ₂ CH ₂ , -C (CH ₃ ) = CH ₂

and

wherein R is H or CH ₃ ;

X is selected from the group of halogen groups of F, Cl and Br and trihaloalkyl groups selected from CF ₃ and CCI ₃ ; X 'is selected from F, Cl, Br and an organic leaving group; Y is selected from CH, CF, CCI, CBr and N and M is selected from H, C, -C ₄ alkyl and alkali, ammonium and alkaline earth ions.

The compounds of the formula II are particularly suitable for the preparation of a general chemical compound of the group of naphthyridine and quinoline carboxylic acids having the following formula

Coou

(Formula I)

in which R ^{1 is} an unsubstituted or substituted tertiary alkyl group, wherein the t-alkyl group 1-3 may contain halogen groups, for. Y is a carbon or a nitrogen atom constituting the quinoline or naphthyridine ring system, and Z is an N-heterocyclic ring selected from the group of piperazinyl, piperidinyl, 3-Amino-1-pyrrolidinyl, 3-aminoalkyl-i-pyrrolidinyl, 2-aminoalkyl-morpholin-4-yl, 2-aminoalkyl-thiomorpholin-4-yl and diazabicycloalkyl groups having 7-9 atoms in diazobicycloalkyl ring system.

Detailed description of the invention

The invention relates to a process for preparing a compound of the formula

COOM

(Formula II)

R ^{1 is} a tertiary alkyl group selected from

-C (CH ₃ ) _3> -C (CH ₃ J ₂ CH ₂ CH ₃₁ -C (C ₆ H ₅ ) (CH ₃ } ₂ , -C (C ₆ H ₅ ) CHRCH ₂ ,

-C (CH ₃ ) CHRCH ₂ , -C (CH ₃ ) CH ₂ CH ₂ CH ₂ , -C (CH ₃ ) = CH ₂ ,

wherein R is H or CH ₃ ;

X is a member of the halogen group F, Cl, Br and trihaloalkyl group in the form of CF ₃ and CCI ₃ ; X 'may have the same meaning as X or is alkyl, aryl or aralkylsulfonyl; Y is selected from CH, CF, CCI, CBr and N; and M is selected from H, C, -C ₄ alkyl and alkali and alkaline earth metal ions and ammonium.

This process is characterized in that a compound of the formula below

IZOOV,

H '

R "

wherein X, X ', Y and R' are as defined above and R is an ester group, hydrolyzed.

The compounds of formula II may contain an asymmetric carbon atom. The shapes! II, representing the various compounds according to the invention, s is to be understood> that it includes all optical isomers of the compounds encompassed by formula dor as well as the racemic mixtures thereof.

Although X 'in the above form! Il may be selected from the same substituents, namely, F, Cl, Br and CF ₃ and CCI ₃ , which define 'X', X 'may also be an organic, separable residue other than CF ₃ and CCI _3. In particular, X' may be selected from F Cl and an organic leaving group such as alkylsulfonyl 'eg methanesulfonyl), arylsulfonyl (eg phenylsulfonyl) and aralkylsulfonyl (eg p-toluenesulfonyl).

The compounds of formula II wherein R 'is a tertiary alkyl group as defined above are novel. They are prepared by hydrolysis of suitable compounds as described above.

The following reaction sequence illustrates a typical mode of preparation of the compounds of formula II (and a preferred further processing to compounds of formula I). In the reaction sequence R = Et or PCHCH ₂ , X = X ¹ = F or C ¹ and Y = CH, CF or N. According to this method, polyhalogenated aromatic acids (1) are converted with sulfuryl chloride to the acid chloride (2), which malonate diester in the presence of magnesium Ethylate to form aroylmalonate (3) acylated.

Portional hydrolysis and decarboxylation of (3) in an aqueous medium using catalytic amounts of p-toluene sulfonic acid gives (4), which is treated with triethyl orthoformate and acetic anhydride to give (5). The reaction of (5) with t-butylamine in ethyl alcohol results in an isomeric mixture of (S) which is cyclized with a slight excess of sodium hydride in dioxane to (7). Compound (10) can be obtained from (7) in two ways: (a) ester (7) is first hydrolyzed under basic conditions to the carboxylic acid (8) which reacts with the appropriate amine to give (10); (b) Ester (7) can be converted to (9) with the appropriate amine, and the ester (9) can be hydrolyzed under basic conditions to (10).

COOH

Χ - ^ - γ "(D

^ X '

Y (2)

(3)

• γ- ^ χ ¹

OZKZCCn

Fv ^ - ^ - COCC

XX, -

OC CCOR

NhOZH,) ^

CCCH

Examples I-XII describe methods of preparation of quinolone and naphthyridone compounds of the invention bearing the t-butyl (1,1-dimethyl-thyl) group.

Example I

Ethyl 3- (2,4-dichloro-5-fluorophenyl) -3-oxo-2 - (((1, oimethyl-ethyl) -amino) -methylene) -propionate A solution of 0.95 ml of tert-butylamine (9 mmol) in 2ml of dry ethanol was added to 3.02g ('J mmol) of 3- (2,4-dichloro-5-fluorophenyl) -3-oxo-2-ethoxymethylene-propionic acid, ethyl ester in 10ml of dry ethanol at -5 ° C.

The resulting mixture was stirred for one hour at room temperature. The resulting precipitate was collected by filtration and washed with 3 ml of ethanol and 5 ml of petroleum ether to give 1.35 g of 3- (2,4-dichloro-5-fluorophenyl) -3-oxo-2 - (((1,1-dimethylethyl) amino methylene) -propionic acid ethyl ester. Melting point 87 ° C.

The residual filtrate was evaporated to dryness. The resulting mixture (oil and solid) was crystallized in 3 ml of isoproparH to give 1.06 g of additional product. Melting point 88-89 ⁰ C.

Example Il

3- {2,3,4,5-Totrafluorophenyl) -3-oxo-2 (((1, 1-i-dimethylethyl) amino) methylene] -propionic acid ethyl ester A solution of 1.77 g (24.2 mmol) tert-Butylamine in 2 ml of ethanol was added to a mixture of 7.05 g (22 mmol) of ethyl 3- (2,3,4,5-tetrafluorophenyl) -3-oxo-2- (ethoxyme'-ethyl) propionate and 9ml of ethanol and cooled in a bath containing ice and salt. More ethanol (2.3 ml) was added and the mixture was stirred for two hours at room temperature. After cooling to 0 ° C, the resulting precipitate was filtered off and washed with ethanol to give 3.72 g of the title compound. Melting point 112 ^° C.

Example IM

3- (2,4,5-trifluorophenyl) -3-oxo-2 - (((1,1-dimethylethyl) -amino) -methylene) -nropionic acid ethyl ester tert -butylamine (6.2 ml, 84.7 mmol) was added to a solution of 13.15 g (43.5 mmol) of 3 (2,4,5-trifluorophenyl) -3-oxo-2- (ethoxymethylene) -propionic acid, ethyl ester in 19 mL of dry ethanol at - IG ⁵ C. After 5 minutes, the mixture was stirred for one hour at room temperature and then concentrated to dryness. The crude residue (10.87 g) was crystallized from 25 mL of hexane to give 7.22 g of the title compound.

-10- 280 53U

Example IV

eye-trifluoro-id.i-dimethyl-ethyl-1-dihydro-1-oxo-S-chloro-1-olcarboxylic acid ester A mixture of 3.5 g (11 mmol) of 3- (2,3,4,5-tetrafluorophenyl) Ethyl 3-oxo-2 - (((1,1-dimethylethyl) amino) methyl-propionate, 35 ml of dioxane and 0.512 g (12.7 mmol) of 60% sodium hydride were stirred at room temperature for 6 hours under nitrogen and then for one hour at 40-50 ⁰ C.

The dioxane was removed. The residue was taken up with cold water, the resulting solid filtered and dried to give a mixture which was chromatographed over 200g of silica gel using toluene / ethyl acetate 80:20 as eluent. 1.54 g of the title compound were collected.

Melting point 146 ^° C.

Bet game V

Methyl ej-DlfluoroM-dihydro-i-bis-dimethyl-methyl-M-oxo-S-chloro-ethyl-carboxylate. 1.1 g (27 mmol) of 60% sodium hydride were added at a temperature between 18 and 22 ° ^C C. To a suspension of 7.22 g (21.9 mmol) of ethyl 3- (2,4,5-trifluorophenyl) -3-oxo-2 - (((1,1-dimethylethyl) amino) -methylene) propionate in 73 ml of anhydrous dioxane , An exothermic reaction took place. After stirring at room temperature for 1 h, the mixture was evaporated to dryness and taken up with CH ₂ Cl ₂ (150 mL) and H ₂ O (200 mL). After decantation, the organic layer was dried over MgSO ₄ . Evaporation of the dichloromethane gave 6.41 g of an amorphous solid which was washed twice with water to give 6.08 g of the title compound.

Example Vl

6-Fluoro-7-chloro (1, VDimethylethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A solution of 3- (2,4-dichloro-5-fluoro) -3-oxo 2 - (((1,1-dimethylethyl) amino) methylbn) propionic acid ethyl ester in 10 ml of dioxane were added at 7 ⁰ C under nitrogen, in portions, 0.34 g (3.45 mmol) of 60% Natriumhyci'rid. During the addition, 9 ml of additional dioxane was added to facilitate stirring. The final mixture was stirred at room temperature for 30 minutes and then refluxed for 2.25 hours. The solvent was evaporated in vacuo to give the crude ethyl ester, the title compound. To this product was added 10 ml of water and 0.6 g of potassium hydroxide. The mixture was refluxed for 1.5 hours, cooled to room temperature and acidified to pH 1-2 with 6N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and recrystallized from water (3 ml) and dioxane (60 ml) to obtain 0.8 g of 6-fluoro-7-chloro- (1,1-dimethylethyl) -1,4 dihydro-4-oxo-3-quinoline-carboxylic acid. Melting point 274 ° C with decomposition. Evaporation of the mother liquor gave a residue which was taken up in 15 ml of boiling dioxane. After cooling and filtration, an additional 0.4 g of the title carboxylic acid was obtained. Melting point 272-273 ° C with decomposition.

Example VII

6,7-Flufluoro-1- (1,1-dimethylmethyl) -1,4-dihydro-4-oxo-3-chloro-n-butylcarboxylic acid hydrochloride A mixture of 6.08 g (19.7 mmol) of ej-difluoro-IO Ethyl diethyl I-dimethylethyl-M-dihydro-oxo-S-quinolinecarboxylate and 19.7 mmol of 2N aqueous sodium hydroxide in 80 ml of ethanol were stirred overnight. The resulting mixture was concentrated in vacuo, taken up with 200 ml of water and extracted with dichloromethane. About 8 ml of 2N HCl was added to the aqueous layer to adjust the pH to 3. The precipitate was collected by filtration, washed with water and dried to give 4.47 g of the title compound. Melting point> 26O ⁰ C.

Example VIII

S ^... Dichloro-S-fluoro-S-pyridinyl-S-oxo ^ -Kd.i-dimethylethyldymnylmethyll-propylsurate ethyl ester A solution of 10.8 g (148 mmol of tert-butylamine in 50 ml of dry ethanol was added dropwise over 30 min Suspension of 50 g (148 mmol) of 3- (2,6-dichloro-3-fluoro-5-pyridinyl) -3-oxo-2 - (((1,1-dimethylethyl) amino) methylene) -propionic acid ethyl ester in 125 ml The mixture was stirred at room temperature for one hour The solvent was evaporated The resulting oil (54.3 g) was stirred in 100 ml of petroleum ether for 0.5 hours with cooling precipitate was filtered, washed with petroleum ether and dried in vacuo over phosphorus pentoxide to obtain 47,7g of the title compound. melting point 78 ⁰ C.

Example IX

7-Fluoro-6-chloro-1,4-dihydro-1 (1,1-dimethylmethyl) -4-oxo-1,8-naphthyridine-3-carboic acid ethyl ester 1.3g (32.4 mmol) 60% Sodium hydride was gradually added at room temperature under nitrogen to a solution of 10 g (27.5 mmol) of 3- (2,6-dichloro-3-fluoro-5-pyridinyl) -3-oxo-2 (((1,1-dimethylethyl) amino methylene) propionic acid ethyl ester in 34ml dry dioxane. DieTemperatui rose by itself at + 6O ⁰ C. After stirring for 15 minutes, the solvent was removed in vacuo. The resulting solid was taken up with 100 ml of dichloromethane and the mixture was cooled in an ice bath. After decantation, the organic layer was washed with cold water and dried over magnesium sulfate to obtain 8.2 g of the title compound. Mp 155 ⁰ C. (A sample washed with hexane had a melting point of 158 ° C.)

Example X

Ethyl e-fluoroethylthiol-i-dihydro-i-i, i-dimethylethoxy-1-oxo-i-naphthyridine-S-carboxylate acetone (90 ml) was added to a mixture of 1.96 g (6 mmol) of ethyl acetate. Fluoro-chloro-id.i-dimethylsthyO-IAdihydro ^ -oxo-i.enaphthyridin-3-carboxylic acid ethyl ester and 2.5 g (18 mmol) of anhydrous potassium carbonate was added. To this suspension was added 1.33 ml (16 mmol) of ethanethiol. After 2.5 hours of heating under reflux, the solvent was removed in vacuo. The residue was taken with ethyl acetate and water. The organic layer was separated, washed with water and brine and dried over magnesium sulfate. The obtained Fe material was treated with ether to give 1.67 g of the title compound. Melting point 15 j-160 ° C.

Example XI

e-fluoro-V-ethylthio-i-dihydro-Vtl.i-dimethyl-ethyl-M-oxo-ie-naphthyridine-S-carboxylic acid A solution of 0.23 g (0.65 mmol D-fluoro-V-ethylthio-li. Dimethyl ethyldi-dihydro-oxo-naphthyridine-carboxylic acid ethyl ester in 1 ml of water was treated with 1.3 ml of 1N aqueous sodium hydroxide and the mixture refluxed for 45 minutes , washed with water and dried in vacuo at 50 ° C to give 0.196 g of the title compound.

Melting point 21BT.

Example XII

e-Fluoro-7-ethylsulfonyM- (1,1-dimethylethyl) -M-dihydro-4-oxo-8-n (phthyridinyl-S-carboxylic acid A suspension of 1.34 g (4.1 mmol) of 7-ethylthio-6 -fluoro-1- (1,1-d mfithylfcthyl) -1,4-dihydro-4-oxo-1,8-naph'hyridine-3-carboxylic acid in 20 ml of acetic acid was cooled to + 5 "C. Then, ι 2 bml added 30% hydrogen peroxide dropwise. After addition, the suspension was gradually heated to 45 ⁰ C until before clear solution! was ehalten. the mixture was kept for 48 hours at room temperature. the f'ederschlag was filtered and washed with water and Ether to give 0.90 g of the title compound Melting point 207 C Unteil decomposition.

The following examples show further methods of preparation of quinolone and naphthyridone compounds according to the invention.

Example XIII

3- (2,6-Dichloro-3-fluoro-5-pyridyl-3-oxo-2 - (((2-phenylthio-1-methylethyl) -amino) -methyl) -propionic acid-ethylene ester 2.09g ( 12.5 mmol) of 2-amino-1-benzenethiopropane were added to a suspension of 4 g (12 mmol) of ethyl 3- (2,6-dichloro-3-fluoro-5-pyridinyl) -3-oxo-2-ethoxymethylene-propionate in 10 ml dry ethanol at -8 ⁰ C under nitrogen.

The mixture was stirred at room temperature for 2.5 hours. The precipitated product was filtered, washed with EtOH, dried in vacuo to yield 3.93 g of the said compound. Melting point 69-70 ⁰ C.

Example XIV

7-Fluoro-6-chloro-1,5-dihydro-1- (2-phenylthio-1-methylethyl) -4-oxo-1,8-naphthyrldin-3-carboxylic acid ethyl ester. A proportion of 0.4 g (10 60% NaH under nitrogen of a solution of 3.92 g (8.55 mM) of 3- (2,6-dichloro-3-fluoro-S-pyridyl) -3-oxo-2 - (((2-phenylthio) 1-methylethyl) amino) methylene) -propionic acid ethyl ester with external cooling added to keep the temperature below 40 ^c C. After stirring at room temperature for 25 minutes, the solvent was removed in vacuo.

The resulting mixture was taken up in 50 ml of dichloromethane and 10 g of ice. After decantation, the inorganic layer was extracted with dichloromethane (3x 10 ml). The combined organic layer was washed with water (10 ml) and dried over magnesium sulfate to obtain 3.5 g of a product which was triturated with 50 ml of diisopropyl oxide to give 2.75 g of the title compound. Melting point VO ⁰ C.

Example XV

7-Fluoro-6-chloro-1,4-dlhydro-1- (2-phenylsulfinyl-1-methyl-ethyl-1-oxo-1,8-naphthyridine-citrate-9-ethyl ester. 1.03g (6 mmol 2.18 g (5.25 mmol) of 7-fluoro-6-chloro-1,4-dihydro-1- (2-phenylthio-1-methylethyl) -4-oxo-1, metachloroperbenzoic acid is gradually added to a solution. 8-Naphthyr! Din-3-carboxylic acid ethyl ester at 5 ⁰ C added.

After stirring for 30 minutes at room temperature, 25m ^{1 of} 10% sodium carbonate was added. The aqueous phase was extracted with dichloromethane (2x10ml). The collected organic phases were washed with water and dried over magnesium sulfate.

The residue (2.26 g) was chromatographed over silica gel using ethyl acetate as the eluent, urr. To give 1.5 g of the indicated compound. Melting point 170 ^c C-172 ° C.

Example XVI

3- (2,4-Dlchloro-5-fluorophenyl) -3-oxo-2 - (((2-d-methylamino-1-methylethyl) nmir-3-methylene) -propionic acid ethyl ester A solution of 1, 29 ml (10 mmol) of 1-methyl-1- (dimethylamino) -ethylamine in 5 ml of ethanol was added to a solution of 3.35 g (10 mmol) of 3- (2,4-dichloro-5-fluorophenyl) -3-oxo in 10 min. 2- (ethoxymethylene) propionic acid ethyl ester in 10ml Ethariolbei -8 ⁰ C given.

After stirring for 2 hours and 30 minutes at room temperature, the mixture was evaporated to dryness to give 3.98 g of the title compound as an oil.

Example XVII

7-Chloro-6-fluoro-1,4-dihydro-1- (2-dimethylmethyl) -1-methyl-ethyl-4-oxo-3-chanolamine-carboxylic acid ethyl ester To a solution of 10 mmol of 3- (2,4 -Dichloro-5-fluorophenyl) -3-oxo-2 - (((2- (dimethamino) -1-methylethyl) amino) -mcthylenepropionic acid ethylenes in 4CmI dioxane were 0.5 g Ί 2 mmoles) 60% NaH in a portion added.

The mixture was heated at reflux for two hours g, evaporated to dryness, and the residue was taken up in diethyl ether and water. Dieorgi 'he layer gave 3.3 g crude product which was aulgelöst in 29 ml of acetone. To this solution was added an excess of SN eti ^. added hydrochloric acid. That received? Hydrochloric!

was filtered and washed with acetone.

1.77 g of this hydrochloride was dissolved in 35 ml of water and sodium hydroxide was added to adjust to pH> 11. After saturation with sodium chloride, this solution was extracted with diethyl ether. The solvent was evaporated to dryness to give 1.22 g of the indicated compound as an amorphous solid.

Example XVIIt

7-chloro-8-fluoro-1,4-dlhydro-1: 2-dimethylmethyl) -1-methyl-ethyl) -4-oxo-3-chloro-n-butylcarboxylic acid A suspension of 1.8 mmol 7-chloro-6- Ethyl fluorool-1,4-dihydro-1- (2-dimethylamino) -1-methylethyl) -4-oxo-3-quinolinecarboxylate in 2.5 ml of N NaOH was heated at reflux for 2 hours.

After cooling, the mixture was washed with ethyl acetate (2 × 2 ml), and the pH was adjusted to 6-6.5 with hydrochloric acid. The precipitated compound was filtered, washed with 2 ml of water, 2 ml of ethyl acetate, 2 × 5 ml of petroleum ether to give 0.31 g of the indicated compound. Melting point 238 ° C.

Example XIX

N, N-trimethyl-IS-ethoxycarbonyl-y-chloro-S-fluoro-oxy-i-dihydro-i-chlorolinyl-propanaminium-iodine To a solution of 1.2 g (3.35 mmol) of chloro-6 2.1 ml (33.5 mmol) of dimethyl-1-fluoro-1,4-dihydro-1- (2- (dimethylamino) -1-methylethyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester in 10 ml of acetone was added was stirred at room temperature for 5 hours and 5 ml of diethyl ether was added to aid precipitation.

The precipitate was filtered off and washed with diethyl ether to obtain 1.8 g of the title compound.

Melting point 21O ⁰ C.

Example XX

7-Chloro-6-fluoro-1,4-dihydro-1-oxo-1- (1-methyl-ethenyl) -3-chloro-carboxylate To a hot solution of 2.4 g of N, N-trimethyl-β-ethoxycarbonyl -chloro-e-fluoM-oxo-i ^ -dihydro-i-quinoleinyl) -propanaminium-iodo in 75ml methanol was treated twice with Dowex 1 (OH form) (prepared from 9.6g Dowjx 1 (CI-Forml). the resin was washed with 30 ml of methanol. the methanol was evaporated in vacuo and the residue was heated for 1 hour under vacuum at 190 ⁰ C.

The product obtained was chromatographed over silica gel using chloroform: methanol 97: 3. The crude methyl ester was rubbed in boiling diisopropyl ether. After cooling, the solvent was separated by filtration to obtain 0.3 g of the title compound. RF = 0.41 (chloroform-methanol 97: 3).

Example XXI

7-chloro-6-fluoro-1,4-dlhydro-4-oxo-1- (1-methylethenyl) -3-quinolene-carboxylic acid A mixture of 0.3 g (1.07 mmol) of 7-chloro-6-fluoro Methyl 1,4-dihydro-4-oxo-1- (1-methylethenyl) -3-quinolinecarboxylate, 1 ml of methanol and 2.14 ml (2.14 mmol) of sodium hydroxide were refluxed for 1.5 hours.

More sodium hydroxide (1 ml) was added and heating was continued for 30 minutes.

The solution was diluted with 2 ml of water, acidified with 6N hydrochloric acid, saturated with sodium chloride, extracted with ethyl acetate and dried over magnesium sulfate to obtain 0.25 g of the title compound. Melting point 229 ° C.

Claims (1)

Invention claim: 1. A process for preparing a compound of the formula COOM (IO X ¹ Y R ^{1 is} a tertiary alkyl group selected from -C (CH ₃ ) ₃ , -C (CH ₃ J ₂ CH ₂ CH ₃ , -C (C ₆ H ₅ ) (CH ₃ ) ₂ , -C (C ₆ H ₅ ) CHRCH ₂