HU196072B - New process for production of oxoline acid - Google Patents

Abstract

Field of the Invention The present invention relates to an improved process for the preparation of a potent chemotherapeutic agent known as oxolic acid by a compound of formula (III) by hydrogenation or by alkylation of an alkyl group or salt thereof, and disruption of the resulting compound of formula (II) by alkyl ester (II). As an ester and a byproduct of Formula III, a mixture comprising a compound of Formula III and an acid amine is treated with an aqueous mineral acid in an alcoholic or ketone solution to convert the ester of Formula II to oxolinic acid, and the unreacted ester and acid amide to an acid which decarboxylates and \ t dissolves in the reaction mixture, and then, after isolation, the mixture containing oxolinic acid and the by-products of formulas IV and VI is subjected to further separation steps to remove the impurity (IV): a) the mixture dissolved in a biphasic system, the organic phase is separated at pH 6.5-7.5 and the iron complex dissolved in the organic phase is separated from the system by crystallization of the compound (VI) which crystallizes from the system, or (b) the mixture is formic acid. dissolved in an amide, then the oxo · Hnic acid containing the compound of formula (V1) is crystallized and the contaminated oxolic acid is dissolved in water at pH = 9-11 and treated with a cation-exchange absorbent. u (u <XO * (Μ • <XO "-1-

Description

The present invention relates to the preparation of 1-ethyl-6,7-methylenedioxy-4-oxo-1,4-dihydro-4-dinoline-3-carboxylic acid (hereinafter referred to as "oxollic acid") in a very pure form.

As used herein, the variable substituents in the general formulas have the following meaning:

R is alkyl,

R 1 is alkyl,

Price meaning of anion.

There have been many processes for the preparation of oxolinic acid, by alkylating the compound of formula (III), which differ in the alkylating agents, in the method of alkylation, and in the methoxy of the process (J. Med. Chem. 11,160 (1968): M 4148). . There are two ways to obtain the desired quality product: either by purification of the ester (II) or by the carboxylic acid (I).

The ester purification can also be carried out in aqueous or other solvent media (e.g., J. Med. Chem. 11, 160). The advantage of the aqueous method is that the purification efficiency is good, but it has the disadvantage of having to work in very large volumes since no more than 3% solution can be prepared in this medium.

It is a solvent for the purification of oxolinic acid of formula (I). they suggest ancient digging.

The efficiency of the solvent processes is poor, only a few purifications can be made with a material of sufficient purity, and the solvents used require special attention both from health (eg chloroform) and fire (eg light petroleum), and should therefore be avoided in large-scale commercial practice.

The present invention, which is described below, is based on the experiments carried out to chromatographically isolate and determine the properties of the impurities resulting from the acid treatment of the ester of formula (ΊΙΙ) after triethylphosphate, ethyl iodide, diethyl sulfate and p-toluenesulfonic acid.

We identified some color impurities and developed systematic technologies to eliminate by-products. The following contaminants are worth highlighting:

It is an intensely orange iron complex of formula q (IV) with very high stability. The solubility properties of the complex at pH range of 1-13 in aqueous media are quite similar to oxolinic acid and therefore cannot be removed by diluting the acidic or alkaline solution of oxolinic acid.

The starting compound of formula (III) always contains the yellow carboxylic acid of formula (V), which has a complexing tendency similar to that of oxolinic acid. Since the quinoline ring is formed at high temperatures (230 ° C to 320 ° C) and devices operating in this temperature range can only be made of an iron alloy, it is already possible to form an iron complex.

The substance of formula (V), due to its amphoteric nature, cannot be removed from the like product by treatment with alkaline or acid. This must always be taken into account, since the alkylation reaction always leaves unreacted ester of formula (III), from which the compound of formula (V) is formed during hydrolysis after aliquotation.

A further impurity is the quaternary ammonium salt of formula VI, which varies in color from orange to dark brown depending on the anion. It is formed during the alkylation reaction and can be separated only by very long (more than 24 hours) alkaline cooking.

With the above data, we have set ourselves the task of selectively separating the valuable drug substance from the above by-products and, if successful, incorporating the resulting separation steps into the manufacturing technology.

The present invention is based on the discoveries which enable the above contaminants to be completely removed from the oxolinic acid:

It has been found that the oxolinic-iron complex is more soluble in certain solvents than oxolinic acid or one of its salts and is thus selectively soluble.

It has now been found that the dye of formula VI (the cation is the dye ion) can be bound to certain cation exchange adsorbents and thus removed from the oxolinic acid by ion exchange adsorption. It was found that the color depends on the anion present: in the presence of a phosphate ion, the intensity of the color is stronger than that of sulfate or chloride (medium brown).

It has also been found that the acidic boiling decarboxylates the carboxylic acid of formula (V) and simultaneously converts the decarboxylated product into a solution of varying composition of the reaction medium in water with various alcohols or ketones. In this case, the amount of lanolin (VII) that accompanies the starting material used in the alkylation reaction is also dissolved. A further advantage of the said acidic treatment is that it also keeps in solution tar materials which may be formed during the ethylation.

According to the present invention, we have obtained an oxdinic acid having a purity higher than ^that required in ^the pharmacopoeias and, to the best of our knowledge in the chemical literature, have been able to isolate pure white oxolinic acid.

The present invention relates to a process for the preparation of oxolinic acid (I) by ethylation of an ester (III) or a salt (VIII) and decomposition of the resulting ester (II). The mixture of the ester (II) obtained as a result of the ethylation and the by-product (III) and the acid amide (IX) is treated with 1-10% aqueous mineral acid in an alcoholic or ketone solution at 50-100 ° C. on 0.5-6 hours. The ester (II) is converted to the oxolinic acid (I), the unreacted ester (III) is converted to the acid (V), the acid (V) is decarboxylated and the compound (VII) thus obtained is reacted. dissolves in the mixture. After isolation, the resulting mixture of oxolinic acid of formula (I) and by-product of formula (V) and (V) is subjected to the separation steps listed below to remove the complex of formula (IV)

(a) Dissolve the mixture in a biphasic system containing water and a low miscible organic solvent at pH 9-11 and then at pH 6.5-21

At -7.5, the organic phase is separated and the complex (IV) dissolved in the organic phase is separated from the still impure oxolinic acid which crystallizes from the system, or

b) dissolving the mixture at 100-140 ° C in a formic acid amide and then cooling the solution to crystallize the oxolinic acid still contaminated with the compound of formula VI to isolate it from the complex remaining in the solution; contaminated oxolinic acid is dissolved in water at pH 9-11 and treated with a cation exchange adsorbent. Thereby, the dye of formula (VI) is bound together with other impurities of a polar nature. Pure white oxolinic acid is isolated from the reaction mixture at pH 4.5-7.5.

Preferred solvents for the preparation of the oxolinic acid complex of the invention include: ethers (diethyl ether, diisopropyl ether, dichloroethyl ether, etc.) amides (formamide, dimethylformamide, etc.) alcohols (butyl alcohol, isobutyl alcohol, amyl alcohol).

Preferably, the dye is separated from the oxolinic acid by dissolving the material obtained after the aforesaid de-ironing processes in dilute alkaline solution and stirring the selected adsorbent in a suitable amount for 0.5 to 3 hours. Various minerals can be used as adsorbents: permutates, zeolites, minerals, glauconites, and synthetic resins. Thus preferred are cabazite, kaolinite, perlite, halloysite, montmorillonite, pyrrophyllite, fullerland, neopermutite and supemeopermutite. It has been found that the above-mentioned purification operations are particularly effective when the acid hydrolysis of the oxolinic acid ester (II) obtained after alkylation is carried out in an aqueous solution of 5-50% methanol or ethanol or acetone or methyl ethyl ketone, preferably 0.5- 5 hours.

An aqueous solution of sodium hydroxide, especially ammonium hydroxide and potassium carbonate, is preferably used to remove the iron complex by process a) or to remove the coloring compound of formula VI.

The advantages of the process of the present invention compared to other methods are summarized below:

1. The material specificity of the 6,7-methylenedioxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester (II) and the alkylating agent used is 20-25% better due to the smaller losses resulting from the simpler processing.

2. The amount of specific adsorbent used to produce a given amount of product is about. half the amount of bleaching agents used in other processes.

3. The natural adsorbents we use are available indefinitely from domestic sources and the goods are very favorable.

4. In our process, all filtration operations can be performed at room temperature, so there is no need for cold energy.

5. The required specific volume requirement is 30-50% of previous methods.

6. The great advantage of our process is that it contains both purification steps in acidic and alkaline milieu, so that both highly acidic and basic substances can be completely removed from the amphoteric oxolinic acid.

Example 1 6 g of 6,7-methylenedioxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester, 80 g of triethylphosphate and 15 g of potassium carbonate are refluxed for 1 hour. The reaction mixture was cooled to below 100 ° C and water (250 mL) and methanol (250 mL) were added.

To the resulting solution was added 40 ml of 50% sulfuric acid and heated at reflux for 5 hours. The resulting slurry was cooled to room temperature, filtered, washed with water to neutral, and resuspended in 2 x 50 mL methanol.

Obtained: 50-54 g of a damp substance. This was dissolved in a mixture of 300 ml of water and 7 g of sodium hydroxide.

200 ml of isobutanol are added and the mixture is heated to boiling. During reflux, ρΗ is slightly acidified with acetic acid. The resulting slurry is filtered at room temperature, the crystals are well washed with water and covered with methanol. The material thus obtained was dissolved in a solution of 1000 ml of water and 40 g of potassium carbonate. The solution was stirred at 80 ° C for half an hour with 0.5 g of perlite and then for a further half hour with 3 g of carbon and finally filtered hot. The clarification operation is repeated in a similar manner. The filtered clear solution was diluted with 250 mL of methanol and the solution was slightly acidified with acetic acid. After refluxing for a further half an hour, the suspension was filtered at room temperature. The crystals were well washed with water and dried under infra-hemp.

We get. 32-35 g of white oxolinic acid (m.p. 313-315 C).

Example 2

Same as in Example 1 except that 200 ml of isobutyl alcohol is replaced by 200 ml of amyl alcohol or 200 ml of diethyl ether or 200 ml of dichloroethyl ether or 200 ml of isopropyl ether or 200 ml of butyl alcohol.

Example 3

Same as Example 1 except that instead of 0.5 g perlite, either 1.0 g cabazite or 1.5 g kaolinite or 1.0 ghalloysite or 1.0 g montmorollinite or 5 g fullerite or 0.5 g of neopermutite or 0.5 g of superneopennutite or 0.5 g of cation exchange resin in the hydrogen phase.

Example 4 Ethyl 6,7-methylenedioxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester, 80 g triethyl phosphate and 15 g potassium carbonate were refluxed for one hour, then the reaction mixture was cooled to 100 ° C and treated with 250 ml water and 250 ml of methanol. To the resulting solution was added 40 ml of 50% sulfuric acid and heated at reflux for 5 hours. The resulting slurry was cooled to room temperature and filtered through a pad.

The filtered crystals were washed to neutral with water and resuspended in methanol (2 x 50 mL).

50-54 g of crude nucleus wet oxolinic acid are obtained.

To this was added 140-150 g of formamide and heated to 140 ° C4g. After being maintained at this temperature for half an hour, the mixture is cooled to 20 ° C and the suspension is filtered. The crystals remaining on the nucleus were twice covered with methanol.

The material thus obtained was dissolved in a mixture of 1000 ml of water and 50 g of potassium carbonate. The resulting solution was stirred with 0.5 g of perlite for half an hour, then with 3 g of clarifying charcoal for another half hour, and then filtered warm. The clarification operation is repeated in a similar manner. The filtered clear solution was diluted with 250 mL of methanol and the acid was slightly acidified with acetic acid at reflux. After stirring for half an hour at this temperature, the resulting suspension was cooled to 20 ° C and filtered. The filtered crystals were washed well with water, covered with methanol, and dried under an infrared lamp.

Yield: 30-32 g of white oxalic acid. Mp: 313-315 ^b C.

The formamide mother liquor was evaporated, diluted with 100 ml of acetone or methanol, boiled, cooled, filtered with 4 to 10 g of oxollic acid II. generation.

Example 5

Same as in Example 4 except that 104-110 g dimethylformamide is used instead of 140-150 g formamide.

Example 6

Same as in Example 4 except that 250 ml of methanol or 250 ml of acetone or 250 numylethylketone are used instead of 250 ml of methanol to hydrolyze the ester.

Claims (9)

PATENT CLAIMS A process for the preparation of an oxolinic acid of formula (I): A compound of formula (III) R is hydrogen or ethyl or a salt of formula (VIII) and the resulting compound of formula (Π) R ¹ is alkyl ester disruption, characterized in that the obtained etUezés ester (II) of the formula R ¹ is a mixture of the above and by-product (ΙΠ) ester and (IX) acid amide of formula is of the formula in an alcoholic or ketonic solution with a 1-10% aqueous solution of a mineral acid 50 to 100 ^o C 0.5-6 hr and thus the ester of formula (II) ^R1 is oxolinsavvá formula (I) above, the ester (IX) with an amide of formula of formula unreacted (III): - R is as defined above - and (V) is converted to the acid of formula (V) acid of formula decarboxylation and thus the resulting compound (VII) is dissolved in the reaction mixture, and after isolation, the resulting mixture of oxolinic acid (I) and by-product (TV) and (VI) is subjected to the separation steps listed below: to remove the complex (IV) a) The mixture is dissolved in a biphasic system containing water and a water-immiscible organic solvent at pH 9-11 and then the organic phase is separated at pH = 6.5-7.5 to dissolve in the organic phase (IV). ) is separated from the oxolinic acid which crystallizes from the system and contains a compound of formula VI, or b) dissolving the mixture at 100-140 ° C in a formic acid amide, and then cooling the solution to crystallize the oxolinic acid containing the compound of formula VI and separating it from the complex remaining in the solution, and then oxalic acid, which is still contaminated, is dissolved in water at pH 9-11 and treated with a cation exchange adsorbent to thereby bind the dyestuff of formula VI - A - anion, and isolate the pure white oxolinic acid at pH 4 - 7 3 from the reaction mixture. A process for the decarboxylation of the by-product of formula (V) and the hydrolysis of an ester of formula (II) as defined above, according to claim ¹ , characterized in that the aqueous acid treatment is carried out with hydrochloric acid or sulfuric acid. The process for separating the complex of formula (IV) according to claim 1, wherein the water-immiscible alcohols or ethers are used to prepare the biphasic system. 4. The process of claim 3 wherein the alcohol is isobutyl alcohol. The process for separating the complex of formula (IV) according to claim 1, wherein the formic acid is formamide or dimethylformamide. 6. Process according to any one of claims 1 to 3, characterized in that the organic solvent is used in an amount of 3 to 10 times the amount of the product to be purified. 7. A process for separating a dye of the formula VI as defined in claim 1, characterized in that it is capable of cation exchange as an adsorbent of minerals of natural origin such as zeolites, clays, glauconites, permutites, preferably cabazite, kaolinite, perlite, halloysite, monmorillonite, pyrophyllite, fuller earth, neopermutite or supemeopermutite are used. The process according to claim 7, wherein the adsorbent is present in an amount of 0.1 to 20% by weight, based on the final product, and the adsorption is carried out at 20-100 ° C. Process according to claim 7 or 8, characterized in that the adsorption is carried out at a pH above 7, preferably in the presence of ammonium hydroxide.