CS270598B2 - Method of 1-tertiary alkylsubstituted naphthyridine and quinoline carboxylic acids preparation - Google Patents

Abstract

4-Oxo-naphthyridine- and 4-oxo-quinoline-3- carboxylic acid derivs. of formula (I) and pharmaceutically acceptable acid addn. and base salts are new. In (I), R1=tert. alkyl from tBu, -C(Me)2Et, -C(Ph)Me2, -CMe=CH2 and gps. of formulae (a)-(d), all opt. contg. 1-3 halogens; R=H or Me; X=F, Cl, Br, CF3 or CCl3; Y=CH, CF, CCl, CBr or N; W=NR2, S or O; R2=H, 1-6C alkyl (opt. substd. by 1-3 OH, F, Cl, NH2, alkylamino, trifluoroacetylamino or phenyl gps.), 3-6C cycloalkyl or 3-6C cycloalkenyl; A, B, C, D=H, 1-4C alkyl (opt. substd. as above), NH2, OH, F, Cl or phenyl; n=0, 1, 2 or 3; and when N(R2)2 is present and is not NH2, then R2=Me or Et; provided that when R1= (b), then Z is not gp. (f) where one R2 is H and A-D=H. - Among pref. cpds. the following are typical; 1-(1,1-dimethylethyl)-1,4- dihydro-6-fluoro-7 piperazinyl-4-oxo-3-quinoline carboxylic acid, methanesulphonate (IA); 7-(8-methyl-3,8-diazabicyclo (3.2.1)octan-3-yl)-1- (1,1-dimethylethyl)-1,4 dihydro-6-fluoro-4-oxo-3- quinolinecarboxylic acid, hydrochloride; and 7-(trans-3-amino-4- methylpyrrolidin-1-yl) -1-(1,1-dimethylethyl)- 1,4-dihydro-6-fluoro-4 oxo-1,8-naphthyridine-3- carboxylic acid.

Description

The invention also relates to a process for the preparation of novel 4-oxo-naphthyridine-4-oxo-quinoline-3-carboxylic acid derivatives which are used as intermediates in the production of antibacterially active substances.

In our related Czechoslovak Pat. No. 270,597, a process for the production of antibacterially active compounds of formula I is described.

(AND)

in which

R ¹ represents a tertiary alkyl group selected from radicals of the formula -C (CH3) _3> -с (сн _{3) 2} сн2СНр -с _(с б н ₅₎ (сн _{3) 2>}

-CCCHpCHRCHg,

or -C (C ₆ H _{5) 2 --CH>}

-C (CH ₃ ) = CH ₂ and

where

R represents a hydrogen atom or a methyl group, the tertiary alkyl group having 1 to 3 halogen atoms, e.g. fluorine

X. Represents a halogen atom selected from the group consisting of fluorine, chlorine and a bromine or a trihaloalkyl group selected from the group consisting of trifluoromethyl and trichloromethyl

Y is CH CF _{t t f} CCl CBr, or N, and

Z represents a substituent selected from the group consisting of radicals of formulas

CS 270 598 B2

B ² 2N- (CH ₂ )

R ² 2H- (CH ₂ ) o wherein V represents NH, sulfur or oxygen,

in which

R is independently hydrogen or optionally substituted alkyl of 1 to 6 carbon atoms, wherein the optional substituents are independently selected from the group consisting of 2 and ± 3 hydroxyl groups, fluorine and chlorine atoms, aodo groups, alkylamino groups, C 1 -C 4, trifluoroacetylamino and phenyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl,

CS 270 598 B2

A, В, С and D are each independently hydrogen »optionally substituted alkyl of 1 to 4 carbon atoms» wherein the substituents are independently selected from the group consisting of 1 to 3 hydroxyl groups »fluorine and chlorine atoms, amino groups» C 1-4 alkylamino groups »trifluoroacetylamino and phenyl groups» furthermore amino group »hydroxyl group» fluorine atom »chlorine atom or phenyl group an

with the restriction je is an integer of 0 1 1 2 2 or 3 že that when R ^{1 is a} radical of the formula

-С (СН ₃ ) СНасНг »then Z does not represent the rest of the formula

R ² HN (CH ₂ ) ---- L and their pharmaceutically acceptable acid addition and base salts »consisting of the reaction of compounds of formula II

in which

R ¹ "X and Y have the above meanings»

M represents a hydrogen atom, a (C1 -C4) alkyl group, an alkali metal or alkaline earth metal ion, or an ammonium ion, and

X * represents a radical X as defined above or an organic leaving group »such as a C1 -C6 alkylsulfonyl group» an arylsulfonyl or C1 -C4 aralkylsulfonyl group in the alkyl moiety »wherein the aryl moieties are phenyl moieties» optionally substituted by an alkyl group в C 1 -C 4 or C 1 -C 4 haloalkyl having a cyclic amine of formula III

Z - H (III) in which

Z is as defined above and in the event of subsequent conversion of the product to a salt.

Thus, the basic intermediates for the above-described synthesis »are compounds of the above general formula (II).

CS 270 598 B2

Accordingly, the invention provides a process for the preparation of compounds of formula II

T

R ¹ (II) ·.

in which

R ¹ represents a tertiary alkyl group selected from the group consisting of radicals of the formulas -C (CH _{3) p} -С (СН _{3) 2} СЙ2СН _3> -C (C ₆ H _{5) 3} LCH) _2,

-C _{(CH3) 2 --CH>}

-CÍC ^CHCHCHCH ^

wherein R is hydrogen or methyl, represents fluorine or chlorine or bromine, trifluoromethyl or trichloromethyl, represents fluorine, chlorine or bromine or an organic leaving group selected from the group consisting of alkylsulfonyl groups of 1 to 6 carbon atoms, arylsulfonyl and aralkylsulfonyl groups ? 1-4 carbon atoms in the alkyl moiety in which the aryl moieties are phenyl moieties optionally substituted by a C1-C4 alkyl group or a C1-C4 haloalkyl group represent CH, SC, CCl, CBr or H; and represents a hydrogen atom, an alkali metal ion or an alkaline earth metal ion, characterized in that a compound of formula IV is hydrolyzed

IQOR (IV)

X

CS 270 598 B2 in which

X, Ϊ and R ¹ are as defined above and;

j 1

R represents an ester-forming group, such as an alkyl group having from 1 to 6 carbon atoms, a phenyl group or a phenyl group having from 1 to 4 carbon atoms in the alkyl moiety.

The hydrolysis according to the invention is preferably carried out under basic conditions and the reaction conditions are in no way different from those generally known for carrying out this type of reaction.

The compounds of the above formulas II and IV may contain an asymmetric carbon atom. It should be emphasized that formulas II and IV include all optical isomers as well as racemic mixtures of compounds falling within the scope of these formulas.

Preferred compounds of the invention are those compounds of formula (II) above wherein:

R ¹ is a remainder of the formula -C (CH 3) 8 CH 2 CH p -CH 2 Cl 2,

I ^: III — C (CH3CH3CH3CH3), —S (CH3CH3) CH3CH3CH3 or

-C (CH ₃ ) = CH ₂ ,

X represents a fluorine atom,

Y represents CH, OT or a nitrogen atom; and

X * is as defined above ·

Particularly preferred are those compounds of formula II according to the invention wherein:

R ¹ is -C (CH ₃ > ₃₎ ,

X represents a fluorine atom,

Y is CH and

X * is as defined above ·

Other particularly preferred compounds of the invention are those compounds of formula (II) wherein:

R ¹ is -C (CH 3) p

X represents a fluorine atom,

Y represents a nitrogen atom and

X 'is as defined above ·

The starting materials of formula (IV) may be prepared from known starting materials by standard or conventional methods or variations thereof. Representative processes of this type are described, for example, in U.S. Patent No. 4,571,396.

The following reaction scheme illustrates a typical process for the preparation of compounds of formula (II) and their conversion to the active compounds of formula (I) by the method described in our above-cited related Czechoslovak patent specification. In this reaction

CS 270 598 B2 represents R is ethyl or benzyl, X and X ¹ are fluorine or chlorine and X is CH ₉ CF or nitrogen *

(3 ⁾

CS 270 598 B2

According to this process, the polyhalogenated carboxylic aromatic acid (1) is converted by treatment with sulfuryl chloride to the acid chloride (2) by which it is acylated in the presence of magnesium malonic acid diester to produce aroyl malonate (3).

Partial hydrolysis and decarboxylation of aroyl malonate (3) in aqueous medium using a catalytic amount of p-toluenesulfonic acid gives the ester (4) which is reacted with triethyl orthoformate and acetic anhydride to give compound (5). Reaction of compound (9) with t »butylamine in ethanol gives a mixture of isomers (6) _t which is derivatized with a slight excess of sodium hydride in dioxane cyclised to compound (7) · Compound (10) can be produced from compound (7) prepared in two ways:

a) Ester (7) is first hydrolyzed in basic conditions to carboxylic acid (8) by reacting that _t and the respective amine and provide the desired compound (10);

b) the ester (7) is converted by the action of the corresponding amine to the ester (9) which is hydrolyzed. . under basic conditions to give the desired compound (10);

The invention is illustrated by the following non-limiting Examples. Unless otherwise indicated, parts and percentages are by weight and parts by weight, unless otherwise indicated.

Example 1

Synthesis of 7-chloro-6-fluoro-4 _{t-dihydro-4-oxo-l-} (l-methylethenyl) -3-quinolinecarboxylic acid

3- (2,4-Dichloro-5-fluorophenyl) -3-oxo-2 - (((2-dimethylaaino-1-methylethyl) amino) methylene) propanoic acid ethyl ester

To a solution of 3- (2,4-dichloro-5-fluorophenyl) -3-oxo-2- (ethoxymethylene) -propanoic acid ethyl ester (35 ml, 10 mmol) in ethanol (10 ml) was added at -8 ° C during 10 minutes solution of 1 »29 ml (10 mmol) of 1-methyl-1- (dimethylamino) ethylamine in 5 al ethanol ·

The reaction mixture is stirred at room temperature for 2 _t 5 hours and then evaporated to dryness. 3 »98 g of the title compound are obtained» as an oil ·

7-Chloro-6-fluoro-1,4-dihydro-1- (2- (dimethylamino) -1-methylethyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester

To a solution of 10 mmol of 3- (2,4-dichloro-5-fluorophenyl) * 3 * oxo-2 - (((2- (dimethylamino) -1-methylethyl) amino) methylene) propanoic acid ethyl ester in 40 mL of dioxane was added to a solution of 10 mmol. adds 0 in a single dose. »5 g (12 mmol) of 60% sodium hydride ·

The reaction mixture is refluxed for 2 hours »then evaporated to dryness and the residue is taken up in diethyl ether and water. 3» 3 g of crude product are obtained from the organic layer »which is dissolved in 29 ml of acetone and excess is added. 5N ethanolic hydrochloric acid. The resulting hydrochloride was filtered off and washed with acetone.

CS 270 598-2

1.77 g of this hydrochloride are dissolved in 35 ml of water and the solution is made alkaline to pH greater than 11 with sodium hydroxide solution. After saturation with sodium chloride, extraction is carried out with diethyl ether and the solvent is evaporated from the extract. 1.22 g of the title compound is obtained as a solid. ·

7-chloro-6-fluoro-1,4-dihydro-1- (2- (dimethylamino) -1-methylethyl) -4-cis-3-quinolinecarbonyl acid

A suspension of 1.8 mmol of 7-chloro-6-fluoro-1,4-dihydro-1- (2- (dimethylamino) -1-methylethyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester in 2.5 µL of 1N hydroxide The reaction mixture was heated at reflux for 2 hours.

After cooling, the mixture is washed twice with 2 ml of ethyl acetate each time and the pH is adjusted to 6 to 6.5 with hydrochloric acid. The precipitated mother liquor was filtered off and washed successively with 2 ml of water, 2 ml of ethyl acetate and twice with 5 l of petroleum ether each time. 0.31 g of the title compound of melting point 238 DEG C. is obtained.

Ν, Ν, Ν-trimethyl-1- (3- (ethoxycarbonyl) -7-chloro-8-fluoro-4-oxo-1,4-dihydro-1-quinolinyl) propanaminium iodide

To a solution of 1.2 g (3.35 mmol) of 7-chloro-6-fluoro-1,4-dihydro-1- (2- (dimethylamino) -1-methylethyl) -4-oxo-3-quinolinecarboxylic acid ethyl ester in Methyl iodide (2.1 ml, 33.5 mmol) was added, acetone (10 ml) was added, and the mixture was stirred at room temperature for 5 hours, followed by diethyl ether (5 ml) to stimulate product precipitation.

Filtration with washing of the precipitate with diethylletter gave 1.80 g of the title compound, m.p. 210 ° C.

7-Chloro-6-fluoro-1,4-dihydro-4-oxo-1- (1-methylethyl) -3-quinolinecarboxylic acid methyl ester

To a hot solution of 2.4 g of N, N, N-tarimethyl-2- (3- (ethoxycarbosyl) -7-chloro-6-fluoro-4-oxo-1,4-dihydro-1-quinolinyl) propanaminium iodide in 75 ml of methanol are treated twice with Dowex 1 (OH-cycle) ion exchanger prepared from Dowex 1 (C1-cycle). The ion exchanger is washed with 30 ml of methanol, the methanol is evaporated off under vacuum and the residue is heated under vacuum at 190 ° C for 1 hour.

The resulting product is chromatographed on silica gel using chloroform / methanol (97: 3). The crude methyl ester is then triturated in boiling diiaopropyl ether. After cooling, the mixture was filtered to give 0.3 g of the title compound which had a 0.41 mp.

7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- (1-methylethenyl) -3-quinclinecarboxylic acid

A mixture of 0.3 g (1.07 mmol) of 7-chloro-6-fluoro-1,4-iihydro-4-oxo-1- (1- (nethylethenyl) -3-quinolinecarboxylic acid methyl ester), 1 mL of methanol and 2. 14 ml (2.14 mmol) of 1N sodium hydroxide are heated at reflux for 1.5 hours, then another 1 ml of sodium hydroxide is added and heating is continued for 3 minutes.

The resulting solution was diluted with 2 [mu] l of water, acidified with 6 N hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. After drying over magnesium sulfate, 0.25 g of the title compound of melting point 229 DEG C. is obtained from the extract.

CS 270 598 B2

Example 2 j

6-fluoro-7-chloro-1- (1,1-dimethylethyl) -1,4-dihydroxy-4-oxo-3-quinolinecarboxylic acid.

To a solution of 3- (2,4-dichloro-5-fluoro) -3-oxo-2 - (((1,1-diaethylethyl) amino) methylene) propanoic acid ethyl ether in 10 mL of dioxane at 7 ° C under nitrogen 0.34 g (8.45 amol) of 60% sodium hydride was added portionwise. An additional 9 ml of dioxane was also added during the addition to facilitate stirring. The resulting mixture was stirred at room temperature for 30 minutes and then heated under reflux for 2.25 hours. The solvent was evaporated in vacuo to give the crude ethyl ester of the acid. 10 ml of water and 0.6 g of potassium hydroxide are added to this product, the mixture is heated at reflux for 1.5 hours, then cooled to room temperature and 65 hydrochloric acid is acidified to pH 1-2. The precipitate formed is filtered off, washed with water and recrystallized from a mixture of 3 ml of water and 60 ml of dioxane to give 0.8 g of 6-fluoro-7-chloro-1- (1,1-dimethylethyl) -1,4. -dihydro-4-oxo-3-quinolinecarboxylic acid melting at 274 ° C with decomposition. The residue from evaporation of the mother liquors is taken up in 15 ml of boiling dioxane and the solution is cooled. melting at decomposition at 272 to 273 ° C *

Example 3

6,7-Difluoro-1- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

6.08 g (19.7 mmol) of 6,7-difluoro-1- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ether and 19.7 mmol of 25 aqueous hydroxide sodium hydroxide in 80 ml of ethanol is stirred overnight. The resulting mixture is concentrated in vacuo, the residue is taken up in 200 ml of water and extracted with dichloromethane. The pH of the aqueous layer is adjusted to 3 by adding approximately 8 ml of 25 hydrochloric acid. The water wash was dried. 4.47 g of the title compound melting above 260 ° C were obtained.

Example 4

6-fluoro-7-ethylthio-1,4-dihydro-1- (1,1-dimethylethyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid

To a suspension of 0.23 g (0.65 mmol) of 6-fluoro-7-ethylthio-1- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ether yl ester _r mL of water was added 1.3 ml of 15 aqueous sodium hydroxide and the mixture was heated for 45 minutes к reflux · the reaction mixture was acidified with 1 ml of 25 hydrochloric acid, the precipitate filtered, washed with water and dried in vacuo at 50 ° C to give 0 * 396 g of the title compound, m.p. 215 ° C.

CS 270 598 B2

Example 5

6-fluoro-7-ethylsulfonyl-1- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

Suspension 1.34 g (4.1 mmol) of 7-ethylthio-6-fluoro-1- (1,1-diethylethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid acid in 20 «1 acetic acid is cooled to + 5 ° C and 2.5 1 1 30% hydrogen peroxide is added dropwise. · After the addition, the suspension is carefully heated to 45 ° C until it becomes clear. The reaction mixture is allowed to stand at room temperature for 48 hours, then the precipitate formed is filtered off and washed with water and ether to give 0.90 g of the title compound, melting at 207 ° C with decomposition,

The following examples describe the preparation of starting materials for the preparation of the compounds of the invention.

Example 6

3- (2,4-Dichloro-5-fluorophenyl) -3-oxo-2 - (((1,1-diethyl ethyl) amino) methylene) propanoic acid ethyl ester

A solution of t-butylamine (0.95 mL, 9 mmol) in dry ethanol (2 mL) was added to 3.02 g (9 mmol) of 3- (2,4-dichloro-5-fluorophenyl) -3 ethyl ester at -5 ° C. -oxo-2-ethoxymethylenepropanoic acid in 10 ml dry ethanol ·

The resulting mixture is stirred at room temperature for 1 hour, the precipitate formed is filtered off and washed with 3 ml of ethanol and 5 ml of petroleum ether. 1.35 g of ethyl ester are obtained.

3- (2,4-dichloro-5-fluorophenyl) -3-oxo-2 - (((1,1-dimethylmethyl) amino) methylene) propanoic acid, m.p. 87 ° C.

The filtrate from the above filtration was evaporated to dryness, and the oily solid residue was crystallized in 3 ml of isopropanol. An additional 1.06 g of product was obtained, m.p. 88-89 ° C.

Example 7

3- (2,3,4,5-Tetrafluorophenyl) -3-oxo-2 - (((1,1-dimethylethyl) amino) methylene) propanoic acid ethyl ester

To a mixture of 7.05 g (22 mmol) of 3- (2,3,4,5-tetrafluorophenyl) -3-oxo-2- (ethoxymethylene) propanoic acid ethyl ester and 9 ml of ethanol was added, while cooling in an ice / salt mixture. solution of 1.77 g (24.2 mmol) of t-butylamine in 2 ml of ethanol. After an additional 2.3 ml of ethanol was added, the reaction mixture was stirred at room temperature for 2 hours and then cooled to 0 ° C. The precipitate formed is filtered off and washed with ethanol to give 3.72 g of the title compound, m.p. 112 ° C.

CS 270 598 B2

Example 8

3- (2,4,5-Trifluorophenyl) -3-cis-2 - (((1'-1-dimethylethyl) amino) methyl) propanoic acid ethyl ester · ‘

To a solution of 13.15 g (43.5 mmol) of 3- (2,4,5-trifluorophenyl) -3-oxo-2- (ethoxymethylene) propanoic acid ethyl ester in 19 ml of dry ethanol is added at -15 ° C. Tert-butylamine, 2 ml (84.7 mmol) · After 5 minutes from the end of the addition, the reaction mixture is stirred at room temperature for 1 hour and then concentrated to dryness. The crude residue (10.87 g) is crystallized from 25 ml of hexane. 7.22 g of the title compound.

Example 9

6,7,8-Trifluoro-1- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

A mixture of 3.5 g (11 mmol) of 3- (2,3,4,5-tetrafluorophenyl) -3-oxo-2 - (((1,1-dimethylethyl) amino) methylene) propanoic acid ethyl ester, 35 ml of dioxane and 0.512 g (12.7 mmol) of 60% sodium hydride was stirred at room temperature under nitrogen for 6 hours and then at 40-50 ° C for 1 hour.

The dioxane is evaporated, the residue is taken up in cold water, the solid material is filtered off and dried. This material is chromatographed on 200 g of silica gel. using a mixture of toluene and ethyl acetate (:0: 20) as the eluent, 1.54 g of the title compound, m.p. 146 ° C.

Example 10

6,7-Difluoro-1,4-dihydro-1- (1,1-dimethylmethyl) -4-oxo-3-ehino-linkarboxylic acid ethyl ester

To a suspension of 7.22 g (21.9 mmol) of 3- (2,4,5-trifluorophenyl) -3-oxo-2 - (((1,1-dimethylethyl) amino) methylene) propanoic acid ethyl ester in 73 mL of anhydrous of dioxane at 18-22 ° C was added portionwise 1.1 g (27 mmol) of 60% sodium hydride, causing an exothermic reaction. The reaction mixture is stirred at room temperature for 1 hour, then evaporated to dryness and the residue is taken up in 150 ml of dichloromethane and 200 ml of water. After separation by decantation, the organic layer is dried over magnesium sulphate and evaporated.

6.41 g of an amorphous solid is obtained, which after washing with water twice gives 6.08 g of the title compound.

CS 270 598 B2

Example 11

3- (2,6-Dichloro-3-fluoro-5-pyridinyl) -3-oxo-2 - (((1,1-dimethylethyl) amino) methylene) propanoic acid ethyl ester ·

To a suspension of 50 g (148 mmol) of 3- (2,6-dichloro-3-fluoro-5-pyridinyl) -3-oxo-2 - (((1,1-dimethylethyl) amino) methylene) propanoic acid ethyl ester in 125 ml of dry ethanol is added dropwise a solution of 10.8 g (148 mmol) of t-butylamine in 50 ml of dry ethanol under nitrogen at -5 ° C over about 30 minutes. After stirring at room temperature for 1 hour, the solvent was evaporated. The oily residue (54.3 g) was stirred in 100 ml of petroleum ether under cooling for 0.5 hour. The yellow precipitate formed is filtered off, washed with petroleum ether and dried in vacuo over phosphorus pentoxide. This gives 47.7 g of the title compound, m.p. 78 ° C.

Example 12

7-Fluoro-6-chloro-1,4-dihydro-1- (1,1-dimethylethyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester

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) propanoic acid ethyl ester In 34 ml of dry dioxane, 1.3 g (32.4 mmol) of 60% sodium hydride are gradually added under nitrogen atmosphere at room temperature, the temperature spontaneously rising to * 60 ° C. After stirring for 15 minutes, the solvent was evaporated in vacuo, the solid residue was taken up in 100 ml of dichloromethane and the mixture was cooled in ice. After decantation, the organic layer was washed with cold water and dried over magnesium sulfate. 8.2 g of the title compound melting at 155 ° C is obtained. A sample of this product melts at 158 ° C after washing with hexane.

Example 13

6-Fluoro-7-ethylthic-1,4-dihydro-1- (1,1-dimethylethyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester

To a mixture of 1.96 g (6 mmol) of 6-fluoro-7-chloro-1- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and Anhydrous potassium carbonate (2.5 g, 18 mmol) was added with acetone (90 ml) and ethanethiol (1.33 ml, 18 mmol) was added. The reaction mixture was heated under reflux for 2.5 hours and then the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and water, the organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The solid residue gave, after crystallization from ether, 1.67 g of the title compound, m.p. 159-160 ° C.

Claims (1)

D L D 1LĚ1. VTKlLEÍir Production Method 1-tert. alkyl substituted naphthyridine- and quinoc1-6-methoxy-left; of acids of formula II COOM OD in which it represents a tertiary alkyl group selected from radicals of the formula -c (ch ₃ ) _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₎ CH ₂ CH ₂ CH _2> -C (CH ₃ ) CHRCH _2> wherein R is hydrogen or methyl, X represents a fluorine, chlorine or bromine atom, a trifluoromethyl or trichloromethyl group, X * represents a fluorine, chlorine or bromine atom or an organic leaving group selected from the group consisting of alkylsulfonyl groups of 1 to 6 carbon atoms, arylsulfonyl and aralkylsulfonyl groups of 1 to 4 carbon atoms in the alkyl moiety in which aryl moieties are phenyl moieties optionally substituted by C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, Y is CH, CF, CCl, CBr or Na M represents a hydrogen atom, an alkali metal ion or an alkaline earth metal ion, characterized in that the compound of formula IV is hydrolyzed CS 270 598 B2 (IV) in which X, X ', Ϊ and R ¹ are as defined above and R represents an ester-forming group such as a C 1 -C 6 alkyl group, a phenyl group or a C 1 -C 4 phenylalkyl group in the alkyl moiety.