NO168101B - 6-FLUORO-5-METHYL-1,2,3,4-TETRAHYDROKINALDINE FOR USE AS OUTSTANDING MATERIAL FOR THE PREPARATION OF THERAPEUTIC ACTIVE COMPOUNDS - Google Patents

Description

The present invention relates to 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine of formula

This compound is the starting material for the preparation of therapeutically active 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo-thij]-quinolizine-2-carboxylic acid of formula

or a pharmaceutically acceptable Na salt thereof, as described in NO 160782. These compounds are useful anti-microbial substances.

The therapeutically active, acidic compound according to the invention can be prepared as described in the following reaction core:

in which alk and each group R"^ are independent of each other and denote alkyl groups with 1-4 carbon atoms, preferably 1-2 carbon atoms.

In the first step of the reaction sequence, 5-amino-2-fluorobenzoic acid of formula II is reacted with the shown crotonaldehyde of formula III or a precursor for crotonaldehyde which forms crotonaldehyde under the acidic reaction conditions. Suitable precursors for crotonaldehyde which can be used in step (1) include acetaldehyde, acetal or paraldehyde. The product from step (1) is the hitherto unknown compound 5-carboxy-6-fluoroquinaldine of formula (IV). The reaction is carried out in the presence of a dilute aqueous acid such as sulfuric acid or hydrochloric acid, hydrochloric acid being preferred. The reaction is carried out at a temperature between approx. 50°C and the reflux temperature of the reaction mixture. It is advantageous to carry out the reaction in the presence of a reagent pair consisting of a weak oxidizing agent and a weak reducing agent. Suitable oxidizing agents include alkali metal-alkaline earth metal salts of the organic acid Eieta -nitrobenzenesulfonic acid. The sodium and potassium salts are preferred. The free acids can also be used as oxidizing agents. Suitable reducing agents include ferrous sulphate, ferric sulphate, ferric chloride and the like. The currently preferred reagent pair is the sodium salt of m-nitrobenzenesulfonic acid as the oxidizing agent and ferrous sulfate as the reducing agent. Use of at least theoretical amounts of the oxidizing agent and reducing agent (ie at least 0.25 mol of each per mol of the aminobenzoic acid of formula II) is preferred. If catalytic amounts of the reducing agent are used, the reaction proceeds, but at a lower rate.

Steps (2) and (3) of the reaction scheme involve reduction of the carboxyl group in the intermediate of formula IV. The intermediate of formula IV is reduced in step (2) to form the hitherto unknown intermediate 1,2-dihydro-6-fluoro-5-hydroxy-methylquinaldine of formula V. This reduction is carried out using diborane in a suitable solvent such as tetrahydrofuran . The mixture is heated under reflux for several hours.

In step (3), the 1,2-dihydro-6-fluoro-5-hydroxy-methylquinaldine of formula V is reduced to form the hitherto unknown intermediate 6-fluoro-5-methyl-1,2,3,4-tetrahydro-quinaldine of formula VI. This reduction is carried out using hydrogen gas and a mixture of palladium on carbon and platinum on carbon. Alternatively, the reduction can be carried out in two consecutive steps, where the first step includes the use of one catalyst and the second step the other. In each case, the reduction is carried out in a solvent such as ethanol, using a Paar apparatus.

The 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine of formula VI is condensed with a dialkyl alkoxymethylene malonate of formula VII in step (4). The preferred dialkyl alkoxy methylene malonate is diethyl ethoxy methylene malonate, as this is the most readily available. The condensation reaction requires heating the reactants until the reaction is complete, as determined by chromatographic analysis. The reaction is carried out in the absence of solvent at a temperature of 100 - 200°C for several hours. It is preferred that the reaction is carried out at a temperature of 140 - 150°C for 2 hours. Alternatively, the reaction can be carried out in the presence of an inert organic solvent which forms an azeotropic mixture with the formed alcohol after condensation of dialkyl alkoxy methylene malonate (e.g. ethanol, where diethyl ethoxy methylene malonate is used in step (4)). The reaction mixture is heated to its reflux temperature and the azeotropic mixture comprising the alcohol and the organic solvent is collected, e.g. in a Dean-Stark trap. Fresh organic solvent is usually added to the reaction mixture as the solvent is used during distillation. Removal of the alcohol from the reaction mixture usually drives the condensation reaction completely and increases the yield. The product from step (4) is the hitherto unknown intermediate of formula VIII. This intermediate can be isolated, e.g. as an oil or a solid, or the product from step (4) can be used directly in step (5) without isolation of the intermediate product.

Alternatively, an N-cycloisopropylidenyl alkoxymalonate of formula in which alk is an alkyl group with 1-4 carbon atoms can be used as the diester of alkoxymethylenemalonic acid in step (4) instead of the shown dialkylalkoxymethylenemalonate of formula VII.

In step (5), the intermediate product of formula VIII is cyclized to form the ester of formula IX. The cyclization step is carried out by heating the intermediate of formula VIII in the presence of polyphosphoric acid. The reaction temperature is preferably 150 - 160°C. Alternatively, cyclization of the intermediate of formula VIII is carried out in the presence of phosphorus oxychloride under reflux for several hours, evaporation of excess phosphorus oxychloride and reflux in the presence of water.

The ester of formula IX is saponified in step (6) in the usual manner to form 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo-1^ijj-quinolizine-2- carboxylic acid of formula I.

When the above-mentioned N-cycloisopropylidenyl alkoxymalonate is used in step (4), step (5) usually results directly in the formation of 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo-JjLj"| -quinolizine-2-carboxylic acid and no separate hydrolysis step is required.

The invention is illustrated in the following examples.

Example 1 (starting material)

Preparation of 5-carboxyl-6-fluoroquinaldine

A mixture of 95.2 g 5-amino-2-fluorobenzoic acid (0.60 mol), 74.3 g (0.33 mol) sodium meta-nitrobenzenesulfonate, 46.2

g (0.17 mol) of ferrous sulfate heptahydrate and 660 ml of 9 N hydrochloric acid were heated to 90-95°C. 77 g (1.0 mol) of crotonaldehyde (96%) was added dropwise over 2.5 hours with vigorous stirring, keeping the temperature just below the reflux temperature. After further stirring for 0.5 hour, the hot solution was filtered through a plug of glass wool. The filtrate was cooled to 30°C, treated with decolorizing charcoal and filtered. The clear filtrate was cooled on ice with stirring to form a yellow solid. The solid was separated by filtration, washed with acetone and dried. The solid was then dissolved in 400 ml of hot water, and a solution of 50 g of sodium acetate in 100 ml of water was added. The product was 58.2 g of cream-colored crystals of 5-carboxyl-6-fluoroquinaldine. The structure

was confirmed by infrared analysis and nuclear magnetic resonance spectrum analysis.

Example 2

Preparation of the hitherto unknown intermediate 1,2-dihydro-6-fluoro-5-hydroxymethylquinaldine

To a stirred slurry of 20.0 g (97.6 mol) of 5-carboxyl-6-fluoroquinaldine in 400 ml of tetrahydrofuran, 300 ml of 1 M diborane in tetrahydrofuran (0.3 mol) was added dropwise. The solution was stirred at 20°C for 1 hour, was heated to the reflux temperature for 2 hours and then allowed to cool. A mixture of 150 ml of water and 100 ml of tetrahydrofuran was added and the mixture was stirred for 30 minutes on a steam bath and then cooled. The aqueous layer was saturated with sodium carbonate by stepwise addition of the salt. The organic layer was separated and the aqueous layer was extracted with 200 ml of diethyl ether. The extracts were combined with the organic and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was dissolved in a solution of 400 ml of ethanol and 15 ml of concentrated hydrochloric acid. After heating this mixture under reflux for 1 hour, the solvent was evaporated to form a solid. The solid was dissolved in 200 ml of water and the solution basified with aqueous sodium hydroxide to give a solid which was predominantly 1,2-dihydro-6-fluoro-5-hydroxymethylquinaldine as determined by nuclear magnetic spectral analysis. Other isomers were also present.

Claims (1)

Chemical connection, characterized in that this is 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine of the formula