HU207517B - Process for producing flumecvine derivatives - Google Patents

Abstract

The present invention relates to a novel process for the preparation of the flumequine (chemical name: 6,7-dihydro-9-fluoro-5-methyl-1-oxolH, 5H-benzoquinolizine-2-carboxylic acid) of formula (I). -fluoro-tetrahydroquinaldine condensation with ethoxymethylene-malonic acid diethyl ester, ring closure of the resulting diester () and the resulting procedure (Π) for the preparation of flumequine by hydrolysis of benzoquinolizine carboxylic acid ester. According to the present invention, the ring closure of the diester compound of formula (III) is carried out without separation, with a mixture of acetic anhydride and concentrated sulfuric acid (1.8-2.2): (0.8-1.2), followed by the mixture (II). The hydrolysis of the compound of formula (II) is carried out without isolation in the presence of water at 90-95 ° C. EN 207 517 A F Scope of the description: 4 pages (inside / page figure)

Description

The present invention relates to a process for the preparation of flumequine of the formula I (6,7-Dihydro-9-fluoro-5-methyl-1-oxolH, 5H-benzoquinolizine-2-carboxylic acid).

Flumequine is known to be an effective antimicrobial agent and is used as an active ingredient in many human and veterinary formulations.

The preparation of tricyclic compounds containing methyl, fluorine, oxo and carboxyl groups was first described in U.S. Patent 3,896,131. According to the procedure disclosed therein, the appropriately substituted tetrahydroquinoline derivative is condensed with diethyl ether of ethoxymethylenemalonic acid in the absence of a solvent at 100200 ° C for 1-5 hours, and then added with polyphosphoric acid. It is further reacted at 140 ° C. The resulting benzoquinolizine carboxylic acid ester is hydrolyzed with 10% w / w aqueous sodium hydroxide and the desired end product is isolated.

Substantially the same process for the preparation of flumequine is disclosed in Hungarian Patent No. 168,927. In the process described therein, the cyclization of the diester of formula (III) formed by the condensation of the 6-fluoro-tetrahydroquinaldine of formula (IV) with the ethoxymethylenemalononic acid diethyl ester is carried out in the presence of polyphosphoric acid of 10 to 10% by weight. then the resulting compound of formula II is hydrolyzed alkaline.

A process analogous to the above for the preparation of flumequine is disclosed in U.S. Patent No. 4,301,289. In the process described therein, tetraphosphoric acid is used for ring closure. The ring closure step provides the compound of formula (II) in 82.3% yield; Flumequine is obtained in a total yield of 62.5% relative to the starting material of formula IV.

A disadvantage of the described processes is that the reaction mixture formed by condensation of the starting material of formula IV with the diethyl ester of ethoxymethylenemalonic acid produces numerous unfavorable by-products at the relatively high temperature required. These by-products, when left in the reaction mixture, cause further by-reactions and also make the isolation of the final product significantly difficult. A further disadvantage is the presence of an immiscible sticky substance in the reaction mixture, the reaction is exothermic and difficult to handle, and the aqueous decomposition of the sticky product is dangerous. The use of large amounts of polyphosphoric acid is environmentally unfavorable, and alkaline hydrolysis also leads to the formation of environmentally polluting by-products.

It is an object of the present invention to provide an industrially feasible process for overcoming the above disadvantages.

The present invention is based on the recognition that a particular composition of acetic anhydride / concentrated sulfuric acid may be used to form the tricyclic ring system. It has been found that when the diester of formula (III) is ring-closed with a mixture of acetic anhydride and concentrated sulfuric acid (1.8-2.2) (0.8-1.2), the ring closure is as described above at 100-140 ° C. Instead of C, it is already carried out at 80-85 ° C and a much smaller amount of the acid mixture, about 3-4 times the weight of the diester of formula III, is used for the ring closure. The use of a specially formulated acetic anhydride / concentrated sulfuric acid mixture thus significantly reduces the energy demand and the environmental impact of the process. More importantly, due to the homogeneity of the reaction mixture, the reaction is well controlled, which increases operational safety and reduces the risk of by-product formation. It has also been found that by freezing the reaction with a certain amount of water during the ring closure phase, the side reactions can be completely eliminated, and the loss of yield is merely the otherwise usual isolation loss. Dilution of the acetic anhydride / concentrated sulfuric acid mixture with water allows the hydrolysis to be carried out directly, so that no hydrolysis is required. Flumequine, which is obtained from the reaction mixture during hydrolysis, can also be used directly in some cases, but if necessary, the resulting flumexin can be purified in a known manner, preferably converted to the base salt and then liberated again.

The present invention therefore relates to a process for the preparation of flumequine of formula (I) by condensation of 6-fluoro-tetrahydro-quinaldine of formula (IV) with ethoxymethylene-malonic acid diethyl ester, cyclization of the resulting diester of formula (III) and by hydrolysis of the benzoquinolizine carboxylic acid ester of formula (II). According to the invention, the cyclization of the diester compound (III) is carried out without isolation with a mixture of acetic anhydride and concentrated sulfuric acid (1.8-2.2): (0.8-1.2) to hydrolyze the resultant compound (II). without isolation in the presence of water at 90-95 ° C, the resulting compound of formula (I) is isolated and, if desired, purified by conventional means, preferably the base salt, and the compound of formula (I) precipitated with acid.

The tetrahydroquinolizine derivative of formula (IV) used as starting material can be prepared as described in U.S. Patent No. 4,301,289. The condensation of the compound of formula (IV) with the diethyl ester of ethoxymethylene malonic acid is carried out at a conventional temperature of 120-140 ° C. In a preferred embodiment, an acid addition salt of the compound of formula (IV) is started, from which the compound of formula (IV) is liberated with a base and subsequently reacted with diethyl ethoxymethylenemalonic acid after removal of the solvent.

A 2: 1 by volume mixture of acetic anhydride and concentrated sulfuric acid is particularly preferred for ring closure.

The following example further illustrates the process of the invention.

Example

6-tetrahydro-quinaldine hydrochloride (101 g, 0.5 mol) was suspended in 700 cm ³ of methanol or ethanol and the base is liberated with solid sodium hydroxide (20 g, 0.5 mol). The precipitated sodium chloride was filtered off and the solvent was evaporated from the filtrate. 129.6 g (0.6 mol) of ethoxymethylenemalonic acid diethyl ester are added to the residue and the mixture is condensed under vacuum at 130 ° C for 4 hours while the ethanol is removed.

HU 207 517 A

To the condensate was added 300 cm ^{3 of} acetic anhydride and 150 cm ^{3 of} concentrated sulfuric acid was added dropwise over 2 hours at room temperature. The resulting mixture was stirred at 80-85 ° C for 1 hour. Water (2000 cm ³ ) was then added dropwise to the reaction mixture, and the residue was added suddenly. The resulting mixture was heated at 90-95 ° C for 4-5 hours. The precipitate was filtered off and washed with 1000 cm ^{3 of} water. Yield: 97 g (74%) of crude flumequine as a buttery solid.

The crude product was suspended in 700 cm ^{3 of} water, the solid was dissolved in 80 cm ^{3 of} 25% w / w ammonia solution and the resulting solution was clarified with 10% w / w activated carbon. To the clarified solution was added concentrated hydrochloric acid (about 70 cm ³ ) in an amount sufficient to neutralize the ammonia. Flumekvint The precipitated was filtered off, washed chloride-free with 1000 cm ³ of water and then dried. Yield: 94.5 g (72.1%) of flumequine as a white solid, m.p. 253-255 ° C.

Claims (1)

Patent Claim Point A process for the preparation of 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H, 5H-benzoquinolizine-2-carboxylic acid of formula (I) using ethoxymethylene of 6-fluoro-tetrahydro-quinaldine of formula (IV). condensation of the malonic acid with diethyl ester, cyclization of the resulting diester of formula (III) and hydrolysis of the resulting benzoquinolizinecarboxylic acid ester of formula (II), characterized in that the diester compound of formula (III) is ring-closed without isolation; acetic anhydride and concentrated sulfuric acid (1.8-2.2) (0.81.2), hydrolyzing the resultant compound (II) in the presence of water at 90-95 ° C without isolation and The resulting compound of formula (I) is isolated and, if desired, purified by treatment in a known manner, preferably with a base, followed by purification of the compound of formula (I) by acid precipitation.