HU185285B - Improved process for producing 1-ethyl-4-oxo-1,4-dihydro-7-methyl-1,8-naphtiridine derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of the naphthyridine derivatives of the formula I by reacting the naphthyridine derivatives of formula II with triethyl phosphate and potassium carbonate at 200-220 ° C where R is 1 or 2 alkoxy or alkyl - by reacting a naphthyridine derivative of formula II wherein R is as defined above with potassium carbonate at 140-170 ° C in the presence of an apolar aliphatic hydrocarbon which forms an azeotrope with water, the water formed and optionally the alcohol present are removed by azeotropic distillation the potassium salt of Formula III, wherein R is as defined above, is reacted with triethyl phosphate at 200-220 ° C in the same mixture and regenerates the ethylating agent. In the process in a homogeneous phase, the alkylation reaction occurs rapidly. -1-

Description

The present invention provides an improved process for the preparation of 1,8-naphthyridine derivatives of formula I.

In the general formulas, R is always C 1 or C 2 alkoxy or alkyl.

1-Ethyl-4-oxo-7-methyl-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, commonly known as nalidixic acid, is known to be a potent antibacterial agent (J. Med. Pharm. Chem. 1962] 1063).

It can be used as a direct starting material

Synthesis of 3-ethoxycarbonyl-4-hydroxy-7-methyl-1,8-naphthyridine (hereinafter naphthyridine ester) and 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid (hereinafter naphthyridine carboxylic acid) known (J. Am. Chem. Soc. 70, 3348, 1948). Nalidixic acid was prepared primarily by N-ethylation of these compounds.

Nalidixic acid was also prepared by:

-ethyl-3-acetyl-7-methyl-4-oxo-1,4-di-hydro-1,8-naphthyridine was subsequently converted to the carbonyl group (Hungarian Patent Nos. 171,651, 171,869, 173,574). ). An intermediate step in these latter procedures was the

3-acetyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine

N-ethylation (Hungarian Patent Application No. 171,996).

In the first embodiments, the naphthyridine ester or naphthyridine carboxylic acid was reacted with ethanol in the presence of potassium hydroxide with a large excess of ethyl iodide for several days. Thus, low yields of nalidixic acid were obtained (Belgian Patent No. 612,258).

N-ethylation of the naphthyridine ester was carried out with a significantly shorter reaction time with 2.5- to 3.5-fold excess triethyl phosphate, without acid binder, at 200-225 ° C for 30-40 minutes, with a 80% laboratory yield. Hungarian Patent No. 153,292). In the industrial realization of this process, the highly impure product obtained by direct hydrolysis of the reaction mixture was recrystallized several times to obtain nalidixic acid in accordance with pharmacopoeial requirements.

The preparation of a purer product was described when it was reported that naphthyridine ester was hot prepared using aromatic hydrocarbons as a solvent (Japanese Patent No. 7,524,292). This was ethylated with double excess of trifluoromethanesulfonic acid ethyl ester in ether for 1-3 hours and then the resulting complex was hydrolyzed with alkali. Thus, nalidixic acid was obtained in a yield of 60-87%. In the examples given, metal potassium and potassium amide were used as salt-forming agents; they are expensive and their large-scale use is disadvantageous from a safety point of view. Salt formation and N-alkylation were carried out in two separate steps in different solvents.

The alkylating agent used was the expensive and difficult to prepare trifluoromethanesulfonic acid ethyl ester, and the solvent was also a disadvantageous ether. A further disadvantage of the process is that no intermediate purification step was used, so that crude nalidixic acid which was difficult to purify by recrystallization was obtained at the end of the reaction.

In the processes described for the N-ethylation of 3-acetyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine, five times the molar excess of triethyl phosphate was used as ethylating agent in the presence of moles of potassium carbonate. with boiling for one minute, without solvent. However, the crude product obtained in about 90% yield has a low melting point. Product lasts approx. After recrystallization from 20-fold i-propanol, ca. In a yield of 50%, a product with a suitable melting point can be obtained (Hungarian Patent Application Nos. 171,996, 171,561). thus, the process, especially at the plant scale, was still not economical enough.

The present invention was based on the assumption that, due to the electron structure of the 1,8-naphthyridine backbone (J. Org. Chem. 53, 1384 (1968); J. Chem. Soc. 971 (1949)) at a rate comparable to N-alkylation. parallel reactions occur which result in the formation of the 8-alkyl and 1,8-dialkyl derivatives in addition to the formation of the 1-alkylated product.

It has been found that the rate of the 1-alkylation reaction can be efficiently enhanced by pre-deprotonation of the compound to be alkylated, i.e., by the production of basic salts of the alkylated compound using basic substances. Instead of the previously known salt formation methods, however, a more economical solution has been sought.

It has also been found that alkylation in a heterogeneous phase with a high excess of a strong alkylating agent, on the other hand, results in an acceleration of side reactions, whether or not an acid acceptor is present.

It has further been found that the preparation of highly purified 1-ethyl-4-oxo-7-methyl-1,4-dihydro-3-ethoxycarbonyl-1,8-naphthyridine (nalidixic acid ester) is highly preferred for the preparation of high purity nalidixic acid. isolation during technology.

The present invention is based on the discovery that in a suitable polar mixture of high boiling, less active alkylating agent and also high boiling, nonpolar, water azeotropic solvents, the same reaction mixture can be used to lower the 1,8-naphthyridine derivative and then at higher temperatures the N-alkylation operation.

The present invention relates to a process for preparing naphthyridine derivatives of formula I by reacting naphthyridine derivatives of formula II with triethyl phosphate and potassium carbonate at 200-220 ° C by reacting naphthyridine derivatives of formula II with potassium carbonate. At 170 ° C, in the presence of an apolar aliphatic hydrocarbon which is azeotropic with water, the water formed and optionally the alcohol present is removed by azeotropic distillation, and the potassium salt of Formula III formed is reacted with triethyl phosphate in the same mixture at 200-220 ° C. regenerating the ethylating agent.

Water formed during the reaction at the temperature of the salt formation with the aid of the apolar solvent component and azeotropic distillation of crystalline alcohol with the 1,8-naphthyridine compound prior to the start of the N-alkylation reaction

185,285 are removable, so that side reactions associated with hydrolysis and ether formation are severely limited.

The use of the non-polar solvent component can significantly reduce the amount of alkylating agent required without reducing the conversion of the alkylation reaction. Reducing the concentration of the alkylating agent and using a less active alkylating agent advantageously reduces the rate of the dialkylation side reaction.

After salt formation and distillation of water and alcohol by distillation of a portion of the apolar solvent component, the polarity of the solvent mixture is increased so that the alkali salt of the 1,8-naphthyridine derivative is completely dissolved in the solvent mixture. Thus, the 1-alkylation reaction proceeds rapidly in the homogeneous phase in the absence of side-inducing agents. Crystallization from the reaction mixture provides a directly purified nalidixic acid ester.

According to the present invention, it is advantageous to use a suitable boiling point aliphatic hydrocarbon fraction as the apolar solvent component and solvent, preferably petroleum, the polar solvent component and the alkylating agent triethyl phosphate, and the salt forming agent potassium carbonate.

The salt formation and 1-alkylation operation can be carried out in a single batch reactor. The reactor is equipped with a glass phase separation vessel connected to a reflux condenser. At lower temperatures, preferably 140-170 ° C, the salt formation and water and alcohol removal operations can be carried out, and the polarity of the mixture is increased by gradually increasing the temperature and continuously distilling off some of the non-polar solvent component. Thus, the alkali salt of the 1,8-naphthyridine derivative is completely dissolved.

Next, the N-alkylation step is carried out at elevated temperature, preferably 200 to 220 ° C, for 30 minutes to 2 hours, preferably 45 minutes. At the end of the reaction, the residue of the nonpolar solvent component and the unreacted alkylating agent can be recovered by vacuum distillation and reused without purification.

Crystallization of the reaction mixture from water gives the 1-alkylated product directly.

Preferably, 1 to 1.5 moles of alkylating agent and 0.5 to 0.6 moles of alkali carbonate are used to alkylate 1 mole of the 1,8-naphthyridine derivative.

It is convenient to carry out the salt formation at 140-170 ° C and the 1-alkylation at 200-220 ° C for 30 minutes to 2 hours.

Thus, the present invention improved the conversion of the N-alkylation reaction and the purity of the resulting product, significantly reduced the amount of alkylating agent used, reduced reaction time with the use of cheap, readily available alkylating agent, simplified technology, and enabled immediate recovery of unreacted chemicals.

Further details of our process are given in the Examples.

Example I

a) 75 kg (0.32333 km) of 3-ethoxycarbonyl-4-hydroxy-7-methyl-1,8-naphthyridine (m.p. 265-267 ° C), 90 kg (0.489 km) of triethyl phosphate, A mixture of 100 kg (0.167 km) of potassium carbonate and 30 kg of petroleum was refluxed for one hour in a reflux distillation apparatus (140-160 ° C). During this time, the reaction water completely distils off. The system is then set to distillate and the temperature is raised to 210 ° C. The reaction mixture was stirred at 210 ° C for 30 minutes and then the unreacted triethyl phosphate was recovered by vacuum distillation. The residue was cooled, diluted with 400 L of water, filtered at 0 ° C, and the filtrate washed with 50 L of water and dried.

The product was 76 kg (0.2 kmol) 1-ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-7-methyl-1,8-naphthyridine. Mp: 84 'C. Pink crystal. Yield 90%.

The crude product was recrystallized from aqueous ethanol. The product was 68.4 kg of white crystals. Mp 110 'C. (Alternatively, unreacted triethyl phosphate can be regenerated by vacuum distillation of aqueous mother liquor instead of vacuum distillation.)

(b) The above intermediate may be used to prepare pure nalidixic acid as follows:

i-Ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-7-methyl-1,8-naphthyridine (0.15777 mol) (m.p. 110 ° C) was added to 150 ml of water and 7 g of (0.175 mol) in sodium hydroxide solution, refluxed for 4 hours, diluted with ethanol (300 ml), cooled to 80 ° C, clarified with 2 g of charcoal, filtered and the pH of the filtrate adjusted to 6 with acetic acid the resulting slurry was filtered at 20 ° C and the precipitate was washed with water (50 ml) and ethanol (50 ml) and dried to constant weight at 70 ° C. The product was 30 g (0.1293 mol, 1-ethyl-3-carboxy-4-oxo-1,4-dihydro-7-methyl-1,8-naphthyridine, 82% yield, m.p. 230-231 ° C). White crystal with active ingredient content above 99% The product is in full compliance with BPC 73 and NF XIV Specifications: 65.6%.

Example 2 3-Acetyl-4-hydroxy-7-methyl-1,8-naphthyridine (0.2475 mol) (m.p. 300 ° C), 70 g (0.3804 mol) triethyl phosphate, 21 g. A mixture of potassium carbonate (0.1522 mol) and petroleum (70 ml) was stirred at 150-170 ° C until gas evolution ceased. The resulting water is distilled off. The residue is stirred at 200-210 ° C for 30 minutes, the unreacted triethyl phosphate and petroleum are distilled off in vacuo, the residue is cooled to 100 ° C, diluted with 800 ml of water and 100 ml of ethanol, cooled to 0 ° C and filtered. The filtrate was washed with water (50 ml) and dried at 60 ° C under vacuum to constant weight. The product was 48 g (0.2087 mol) of 1-ethyl-3-acetyl-4-oxo-1,4-dihydro-7-methyl-1,8-naphthyridine. Yield: 84.3%. M.p .: 182-184 'C. Yellow crystal.

Claims (3)

A process for preparing naphthyridine derivatives of formula I by reacting naphthyridine derivatives of formula II with triethyl phosphate and potassium carbonate at 200-220 ° C. - where in the formulas R is an alkoxy or alkyl group having 1 or 2 carbon atoms, characterized in that it is a naphthyridine derivative of formula II. - wherein R is reacted with the above potassium carbonate at 140-170 ° C in the presence of an apolar aliphatic hydrocarbon which is azeotropic with water, the resulting water and optionally an alcohol present is removed by azeotropic distillation, the potassium salt of formula III formed wherein R is reacted with triethyl phosphate in the same ⁵ mixture at 200-220 ° C and regenerating the ethylating agent. 2. A process according to claim 1, wherein the solvent is petroleum ¹⁰ . 3. A process according to any one of claims 1 to 4, characterized in that after completion of the ethylation reaction, the unreacted ethylating agent is regenerated by vacuum distillation.