PL141326B1 - Method of obtaining /d/-2-/6-metoxy-2-naphtyl/-propionic acid or its pharmacologically admissible salts - Google Patents

Description

The subject of the invention is a process for the preparation of (d) -2- (6-methoxy-2-naphthyl) -propionic acid or its pharmacologically acceptable salts. (D) -2- (6-methoxy-2-naphthyl) -propionic acid, known under the name naproxen, it is a well-known anesthetic and antipyretic. Naproxen and its salts are optically active substances, usually prepared in the form of mixtures of enantiomers (d) and (1). European Patent Application Nos. 79102502.6 and 80105828.2 describe the preparation of naproxen and its salts using as resolving agent for glucamine derivatives of the formula NRd-glucamine, in which R is an alkyl radical of 1-56 carbon atoms or a cycloalkyl radical of 5-8 carbon atoms, and these derivatives can also be used in the form of a salt. According to these publications, the process of separating the mixtures of both enantiomers of naproxen consists in preparing the salts of these mixtures with N-R-d-glucamine and subjecting them to fractionated crystallization and separating the less soluble naproxen salt from the more easily dissolving salt. British Patent No. 1,274,271 discloses the preparation of d, 1-2- (5-halo-6-methoxy-2-naphthyl) propionic acids and their separation using alkaloids such as cinchonidine. It has surprisingly been found that glucamine derivatives of formula NRd-glucamine in which R is an alkyl radical of 1-18, preferably of 2-18 carbon atoms, or a cycloalkyl radical of 5-8 atoms, especially NRd-glucamines containing 5-8 Carbon atoms, or the salts of these glucamines, can be used as resolving agents in the preparation of certain naproxen precursors which are then easily converted to naproxen. Accordingly, the invention relates to a process for using N-R-d-glucamines or their salts as resolving agents in the preparation of naproxen precursors. These resolving agents form diastereomeric (dl) salts with the naproxen precursors, and the salts of the naproxenf precursors can be isolated from these salts preferably by fractionated crystallization of diastereomeric salts. According to the invention, separation of the naproxen precursors which have the same acid functional group is used. propionic as naproxen, but they are characterized by having substituents on that part of the naproxen molecule which is remote from the chiral center of the molecule. These substituents can then easily be converted into substituents peculiar to naproxen. Preferably, the distance from the point of attachment of these convertible substituents with the naphthalene ring to the chiral center, i.e. the carbon atom to which the methyl radical is bound, is 0.58-0.66 nm. According to the invention, halogen atoms in the 5-position of the naphthalene ring and the hydroxyl group in the 6-position of the molecule are particularly preferred as these substituents. Both of these types of substituents can be easily transformed into the substituents present in the naproxene, i.e. the hydrogen atom in the 5-position and the methoxy group in the 6-position, while keeping the spatial arrangement of the molecule unchanged. The naproxen precursors used in the invention are represented by the general formula 1 where X is a halogen atom, such as chlorine or bromine, n is zero or 1 and when n is zero then R is hydrogen, and when n is 1 then R is hydrogen or methyl (formula 1a ) * These precursors may also appear in the form of salts of the compounds of formula 1 described above. The compounds of formula I in the form of racemic mixtures are known compounds. For example, (d, 1) -2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, i.e. the compound of formula I, where R is methyl, X is bromine and n is the number 1 is known from the German patent specification No. 1,934,460, and the compound of formula 1, in which R is a methyl radical, X is a chlorine atom, and n is the number 1, is listed in the form of a ricemic mixture in Belgian Patent Specification No. 752 627 * Compounds of formula 1, in which R is hydrogen, X is halogen and n is zero or 1, are in the form of their racemic mixtures stated in the application of the invention of the Federal Republic of Germany No. 1,793,825. Salts of these compounds However, according to the invention, mixtures of enantiomers (d) and (1) of the compounds of the formula I or their soluble salts with NR-] glucamine or a salt thereof, in which R is an alkyl radical of 1-18, preferably 2-18, z especially with 6-18 carbon atoms, or a cycloalkyl radical with 3-8 carbon atoms, is subjected to separation, producing a product with an increased content of naproxen free precursor, which can then be converted into naproxen or its pharmacologically acceptable salt / As starting products in The process of the invention preferably uses racemic mixtures of the compounds of formula I in the form in which they are produced by known methods * The term "alkyl" as used herein denotes straight or branched chain radicals containing 1-18 carbon atoms * Examples of such substances are radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexy, n-octyl, n-dodecyl and n-octadecyl radicals. The term "cycloalkyl" denotes cycloaliphatic hydrocarbon radicals with 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl and cyclooctyl radicals. Preferred radicals here are the cyclohexyl and cycloheptyl radicals. According to the invention, the resolving agents are preferably N-alkylglukaaines in which the alkyl radical R contains 2-18, and in particular 6-18 carbon atoms * and the clades of such glucamines. sa: N-ethyl-D-glucamine, NN-propyl-D-glucamine, .Nn-butyl-] -glucamine, Nn-octyl-1-glucamine, Nn-decyl-Iglucamine and F ^ n-hexadecyl-Iglucam 1 na.141 326 3 A particularly preferred resolving agent is N-methylglucamine with respect to the naproxen precursors of formula I, where R is hydrogen, X is chlorine or bromine and n is 1, or R is hydrogen and n is zero The separation process according to the invention is carried out in an inert organic solvent in which there is a marked difference in the solubility of the naproxene precursor salt of formula I with the separating agent and the solubility of the salt of the second enantiomer with this agent at room temperature to the boiling point of the solvent used under reflux. The solubility of the naproxen precursor salt with a resolving agent, e.g. from N-methyl] glucamine, Nn-propyl-D-glucamine, Nn-butyl-1-glucamine or Nn-octyl-EH-glucamine, in the selected solvent should be much lower than the solubility of the salt of the second of the enantiomer with this agent so that, on cooling the heated solution, usually to room temperature, primarily the naproxen precursor salt with the resolving agent crystallizes. Suitable solvents are water, monohydric alcohols with 1 to 10 carbon atoms, in particular (C 1 -C 4) alkanols, e.g. methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, cyclohexanol, 2-ethylhexanol, benzyl alcohol and furfuryl alcohol, dihydric alcohols with 2-6 carbon atoms, e.g. * ethylene glycol, 1,2-propylene glycol and 1,3-propylene glycol, trihydric alcohols with 3 or 4 carbon atoms, e.g. glycerin , ketones with 3-11 carbon atoms, e.g. acetone, acetylacetone, ethylmethyl ketone, diethyl, di-n-propyl, diisopropyl and diisobutyl ketone and other solvents, such as lower ethylene glycol 1, diethylene glycol or diethylene glycol dialkyl ethers sulfolanes, formamide, dimethylformamide, N-methylpyrrolidone, pyridine, dioxane and dimethylacetamide. Preferably, alcohols with 1 to 3 carbon atoms are used in particular, e.g. methanol or isopropanol, especially methanol. ¥ in order to dissolve all the substances contained in the mixture, you can use the addition of water in an appropriate amount. As a solvent, you can also use mixtures of polar solvents with aromatic hydrocarbons, such as toluene or benzene, e.g. methanol from toluene. Most often methanols are used as a solvent. the naproxen precursor with its other enantiomer, or a mixture of soluble salts of both enantiomers, is heated, usually to a temperature of 60-100 ° C or to the reflux temperature of the solvent together with the enantiomer separation agent, causing all substances to dissolve. added substances in the solvent. If necessary, the mixture is kept at an elevated temperature for a longer period of time so as to obtain a solution. The solution is then cooled slowly to room temperature, and it is preferable to seed the naproxen precursor salt solution with the resolving compound to obtain a crystalline precipitate enriched in naproxen precursor salt with the separation compound. The final temperature to which the solution is cooled is selected based on practical considerations, but should be low enough for the temperature difference to allow good yield crystals to be obtained. The crystallizing mixture is kept at this lowest temperature until the end of the crystallization, usually from about 30 minutes to several hours, after which the crystalline precipitate is filtered off and washed. The resulting product is subjected to a further process. Namely, if this product is made with water-soluble NR-Iglucamine, then it is dissolved in water and acidified with a mineral acid, e.g. sulfuric or hydrochloric acid, or with an organic acid, e.g. acetic acid, sucked off the precipitate, washed it and dried, yielding the naproxen precursor. If the product was made with a water-insoluble GDR-glucamine, then it is treated with a strong base, such as potassium hydroxide or some other base with a pH greater than 10, causing salt splitting and then the separating agent is separated by filtration and the filtrate is acidified with a mineral or organic acid as mentioned above, and the crystalline precipitate is then filtered off, washed and dried to obtain naproxen precursor.4 141 326 In order to obtain an optically pure naproxen precursor, it is preferable to dissolve the product with a high content of naproxen precursor with a separating agent again in the cleavage process solvent and warm, then cool using seeding as described above. This procedure can be repeated, since each time a product is obtained with a higher content of naproxen precursor salt with a separating compound. If N-methyl-EH-glucamine, N-ethyl-D-glucamine, Nn-propyl-Iglukamine, Nn-butyl-D-glucamine, Nn-hexyl-EH-glucamine or Nn-octyl-D-glucamine is used as the separating agent then it is sufficient to repeat the redissolution and acidification treatment once and the resulting naproxen precursor is about 97-99% pure. Preferably, in particular, as a separating agent, N-methyl-D-glucamine, N-ethyl-] glucamine or Nn- is used. octyl-D-glucamine, since they provide easily drainable salts with naproxen precursors, from which, even without repeating the re-dissolution and acidification treatment described above, a high purity naprpxen precursor of about 97-98% can be obtained. Besides, the cleavage of the salt can be carried out in an alkaline or acidic environment. N-n-octyl-D-glucamine is essentially insoluble in water, so it can be recovered from the aqueous system with high efficiency. The same applies to the other glucamine derivatives of the formula -NR-Iglucamine, in which R is an alkyl radical of at least 6 carbon atoms, i.e. an alkyl radical of 6-18 carbon atoms, and a product with a high content of the second enantiomer of the compound of formula I or its The NR-Iglucamine salt can be processed to recover this enantiomer, which can then be racemized by known methods, e.g. the method known from U.S. Patent No. 3,686,183. "According to the invention, the resolving agent is used in an amount of about 50- 100% on a molar basis to the amount of d, l-acid of formula I processed. The theoretically necessary amount is only 50% on the above-mentioned molar ratio, and the remaining amount, usually about 40-50% on the molar ratio, can be replaced by a less expensive base, e.g. an alkali metal hydroxide, e.g. sodium hydroxide or potassium, or an organic base with a pH of at least 8, e.g. a tertiary amine such as triethylamine, triethanolamine, tributylamine, etc. The term "mixture of enantiomers (d) and (1) of the compound of formula 1n also includes salts of these compounds that are soluble in the solvent used for separation in the process of the invention These salts include, for example, the corresponding sodium, potassium and lithium salts. These salts can be prepared by adding a base such as an alkali metal hydroxide, for example sodium or potassium hydroxide, to a solution of the mixture ( d) and (1) of the acid enantiomers of formula I and the resulting mixture of the (d) -2- (6-methoxy-2-naphthyl) -propionic acid salt with the (1) -2- (6-methoxy) acid salt -2-naphthyl) -propi of the resolving agent salt which reacts to give the salt of (d) -2- (6-methoxy-2-naphthyl) propionic acid with NR-Iglucamini. Suitable salts of glucamine are those with inorganic or organic acids, e.g. * with hydrochloric acid or acetic acid. It is also possible to use salts with propionic acid, butyric acid, isobutyric acid, sulfuric acid, nitric acid, maleic acid, etc. Accordingly, the term nN-R-] glucamate, in which the formula R has the above meaning, also includes the salts of these compounds which used with a mixture of (d) and (1) of 2- (6-methoxy-2-naphthyl) -propionic acid causes separation of this mixture. Acids of formula 1 are prepared by known methods, described in German Patent Specification No. 1,934,460, in Belgian in German Patent Specification No. 752,627, in German Patent Specifications DOS No. 1,668,654 and 1,793,825,141,326. The naproxen precursor obtained in optically pure or raw form can be converted into naproxen or into its pharmacologically acceptable salts. Formula I, in which R is hydrogen or methyl, X is halogen and n is 1, the conversion to naproxen is by dehalogenation of the compound of Formula 1f and that is replacement of a halogen atom with a hydrogen atom. When R is hydrogen, X is halogen and n is the number 1, it is preferred to first methylate such a compound as described below and then remove the halogen from the 5-position; The 2- (5-halo-6-methoxy-2-naphthyl) propionic acid precursor to naproxenut can be subjected to dehalogenation reactions that do not affect the rest of the molecule ^ Such a suitable method is to react the separated 5-halogen compounds of formula 1 with a metal alkoxide alkaline earths such as magnesium alkoxide, e.g., magnesium methoxide, and a tertiary amine, such as a lower trialkylamine, e.g., triethylamine, in an inert solvent such as an alcohol or an alkanol from which the alcoholate used, e.g., an alkanolate, is derived. Reactions are carried out at a temperature from 30 ° C. to the reflux temperature of the solvent. For example, a mixture of powdered magnesium, methanol and triethylamine in a molar excess is stirred under an inert gas, e.g. nitrogen, and a solution of separated 2- (5-halo-6-methoxy-2-naphthyl) propionic acid in anhydrous After the reaction is complete, that is, after about 1 hour, while the mixture has been boiled under reflux, hydrochloric acid is added to the mixture to dissolve the remaining magnesium, and naproxen is isolated by conventional methods. For example, the mixture is poured into water and extracted with a suitable solvent such as methylene chloride, the organic layer is separated, washed with water, and crystallized to give pure naproxen. Using another variant of the process, the naproxen precursor of formula 1 is reacted with at least 2, and preferably with 2 to 50 equivalents of a nickel-aluminum alloy or cobalt-aluminum (the equivalent is calculated on the alum content, in the presence of at least 2 , preferably 2-50 equivalents of an alkali metal hydroxide in an inert solvent and reacted until the halogen is removed from the 5th position. Preferably nickel or cobalt aluminum alloys having particles less than 1 mm are used, and the aluminum content in the alloy should be at least 10 The alkali metal hydroxide used is, for example, sodium, potassium or lithium hydroxide, and the reactions are carried out in an inert solvent, preferably methanol, ethanol, propanol, isopropanol, tertiary, butanol, tetrahydrofuran or dioxane at a temperature of from 0 ° C to the boiling point of the solvent, preferably at a temperature of at least 40 ° C, the reaction takes from 15 minutes to 12 hours. The 5-halogen compounds of formula I can also be reacted directly with a mixture of ground magnesium, preferably powdered magnesium with particles smaller than 1 mm, with a lower alkanol and possibly a molar excess of an aliphatic amine. Such reactions are carried out at a temperature of 0 ° C. to the boiling point of the reaction mixture, preferably at a temperature of at least 20 ° C, in an inert gas atmosphere, e.g. nitrogen, The time required for the removal of halogen from position 5 depends on the temperature and ranges from 10 minutes to 12 hours, and when carried out at a temperature If the mixture is refluxed under reflux, the reaction is complete within 1 hour. Or the 5-halogen compound of formula I can be treated with Raney nickel in an inert organic solvent such as a lower alkanol, an ester with up to 6 carbon atoms, e.g. ethyl acetate, or a lower acid an alkanoic carboxylic acid, for example acetic or propionic acid, optionally under a hydrogen atmosphere. These reactions are carried out at a temperature of at least 0 ° C, preferably greater than 20 ° C, and most preferably at reflux temperature. The reaction takes from 10 minutes to 24 hours. 6 141 326 According to another variant, the 5-halogen compounds of formula I are treated with hydrogen in the presence of palladium on charcoal, platinum or platinum oxide in an inert solvent, such as that used in the test. reaction in the presence of Raney nickel. The reaction temperature is from 0 ° C to the reflux temperature of the mixture, preferably at room temperature. The reaction takes 10 minutes to 12 hours. The crude precursor of naproxen of formula 1, in which R is hydrogen and n is zero, can be converted directly into naproxen # PD. Likewise, the product can be purified by crystallization and purified, having a given optical refractivity, By treating naproxen by treatment with a suitable methylating agent. Methylation involves the treatment of the naproxen precursor of formula I, in which R is hydrogen, with dimethyl sulfate, dimethyl carbonate or methyl halide in an alkaline environment in a solvent such as water or lower aliphatic alcohol. To create an alkaline environment, sodium or potassium hydroxide or carbonate is used and the reaction is carried out at a temperature of 40 ° C to the boiling point of the mixture, preferably at 40-70 ° C. The reaction time depends on the temperature and is usually 1-10 hours. The produced naproxen is isolated by treating the cooled reaction mixture with strong organic or inorganic acid in order to acidify it, then the separated precipitate is filtered off, washed and dried at a temperature that does not have a negative effect. on naproxen. The naproxen precursor of formula I, where R is hydrogen, X is halogen and n is 1, can be methylated and then halogenated as described above. Naproxen obtained by dehalogenating the 5-halogen compound of the formula I or by methylating the compound 6- The hydroxyl group of the formula I can be recrystallized to obtain a product of high optical purity, namely with a value of? 7 "d of 62-67 ° (chloroform). Naproxen according to the invention can be converted into its pharmacologically acceptable salts by reaction with at least the equivalent amount of an organic or inorganic base, preferably sodium hydroxide These reactions are carried out in an inert solvent at a temperature of 0 ° C to the boiling point of the solvent, whereupon the naproxen salt crystallizes out, optionally after some or all of the solvent is evaporated. the crystalline salt may be recrystallized again to increase its purity i. Example I. 50 g of d, 1- 2- (6-hydroxy-2-naphthyl) propionic acid are heated in 215 ml of methanol and 13.8 ml of toluene until a solution is obtained, then 67.8 g of Nn-octyl-D-glucamine, cooled to 40 ° C, seeded with crystals of d-2- (6-hydroxy-2-naphthyl) -propionic acid salt with Nn-octyl-D-glucamine and stirred overnight at room temperature, to give the salt of d-2- (6-hydroxy-2-naphthyl) -propionic acid in Nn-octyl-D-glucamine. This salt, after cleavage, yields 11.5 g of d-2- (6-hydroxy-2-naphthyl) -propionic acid with a specific specificity of + 91.3 ° in chloroform. The yield of the process is 23.096 theoretical and 10.5 g. The resulting naproxen precursor is dissolved in 60 ml of acetone, 100 ml of 1.5N aqueous potassium hydroxide solution and 4 g of methyl iodide are added, and the solution is kept at 0-20 ° C for 14 hours. The obtained naproxen methyl ester is hydrolyzed in situ in an alkaline environment, yielding naproxen with a yield of 90.3% of theoretical yield. • The specificity of the obtained naproxen is + 63.5 ° in chloroform. Example Ii 17.0 g of d acid, 1-2- (6-hydroxy-2-naphthyl) -prcpionic acid and 15.34 g of N-methyl-D-glucamine are dissolved in 150 ml of boiling methanol containing * \ 0% by weight of water, the solution is filtered and slowly cooled while stirring to 45 ° C, yielding the salt of the 6-hydroxy naproxen precursor from N-methyl-iglucamine. This salt is crystallized three times from the same solvent, and then split, yielding 3.1 g (18.3% of the theoretical yield of d, -2- (6-hydroxy-2-naphthyl) -propionic acid with optical precision +91 , 7 ° in chloroform * By proceeding as described in example 1, this product gives d-2- (6-methoxy-2-naphthyl) -propionic acid with a specificity of + 63.8 ° in chloroform. III. 25 g of d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid, 23.7 g of Nn-octyl-D-glucamine and 60 ml of 10% toluene in methanol are kept at under reflux until the solids dissolve, and then for 20 minutes more, then it is cooled slowly and at 30 ° C it inoculates a small amount of d-2- (5-bromo-6-methoxy-2) acid salt -Naphthyl / propionate with Nn-octyl-Englucamine and left overnight at room temperature The precipitate was filtered off with suction and washed with 30 ml of cold methanol, yielding 16.7 g of product. here with a high content of d-2- (5-boro-6-methoxy-2-naphthyl) -propionic acid salt with N-n-octyl-E4-glucamine. 1.0 g of this product is mixed with 50 ml of water, the suspension is heated to 80 ° C and acidified with concentrated Hd to give a precipitate of a product with a high content of d-2- (5-bromo-6-aethoxy-2-acid). naphthyl / propionic acid. This erythema is filtered off at 50 ° C, washed with water and dried under reduced pressure, obtaining a product with specificity JcC / '- ^ - + 28.2 ° (c = 0.5% in chloroform). Other 15.7 g of the product with a high content of d-2- / 5-bromo-6-methoxy--2-naphthyl / propionic acid salt is dissolved in 2 ml of toluene and 18 ml of methanol at the boiling point of the solvent, then cooled to 25 ° C , seed the salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid with Nn-octyl-iglukahin and leave overnight * The precipitate is filtered off, washed with 20 ml of cold methanol, mixed with 100 ml water, heated the suspension to 80 ° C, acidified with hydrochloric acid and the precipitate was separated, giving 5.5 g of essentially pure di-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, + 42.5 ° (c »0.5% in chloroform). The obtained naproxen precursor is de-bromination as described above, obtaining naproxen with specific conductivity + 64 ° (in chloroform). Example IV. 15 g of d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid is mixed with 2f42 g of triethylamine, 7.03 g of Nn-octyl-glucamine and 30 ml of 10% toluene solution in methanol and boiled under reflux for 20 minutes, then slowly cooled and at 30 ° C inoculated with a small amount of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid salt, and then is left overnight at room temperature and the precipitate is filtered off and washed with 20 ml of cold methanol to give 4.47 g of product with a high content of d-2- (5-bromo-6-methoxy-2-naphthyl / propionic acid salt) and 4.47 g of the product obtained is dissolved in a mixture of 9 ml of methanol and 1 al of toluene at the boiling point of the solvent, the solution is cooled to 30 ° C, and the salt of d-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid is grafted. with Nn-octyl-iglukamine and left overnight. The separated precipitate is filtered off, washed with 10 ml of cold methanol, mixed with 75 ml of water, heated to 80 ° C and acidified with hydrochloric acid, then the precipitate is separated, obtaining 1.2 g of a product with a high content of d-2- / 5 acid. -broa-6-methoxy-2-naphthyl) -propionic acid, F <4> D- + 42 ° (c-0.5% in chloroform). From the obtained 5-bromo-precursor naproxen, bromine is cleaved as described above. Example V * 5f 30 g of d, 1- 2- (5-chloro-a-ethoxy-2-naproxy-propionic acid and 1.01 g of triethylamine (0 , 5 eq.) Is heated in 35 ml of isopropanol to about the boiling point of the solvent, to obtain a solution to which 2.09 g of Tylylglucamine (0.5 eq.) Is then added and cooled to room temperature. obtaining 4 g of the product, enriched in salt of the less soluble naproxen precursor with N-ethyl-D-glucamine. A sample of this product is dissolved in about 25 ml of water, heated to a temperature of about 80 ° C, acidified with hydrochloric acid and the separated precipitate enriched in acid which is a precursor of naproxem is filtered off 1.00 g of the above-mentioned product with a high content of N-ethyl-D salt. -glucamine is dissolved in 19.5 ml of isopropanol and 1.5 ml of water at about the boiling point of the solvent, and the solution is cooled to room temperature, yielding 0.50 g of recrystallized salt. This salt is treated with hydrochloric acid as described in the preceding paragraph to obtain a product which is even more enriched in d-2- (5-chloro-6-methoxy--2-naphthyl) propionic acid, 1 g of this acid in 20 ml. 1096 aqueous sodium hydroxide solution is heated to 90 ° C., 3 g of nickel aluminum alloy are added in small portions, stirred for 2 hours, filtered, treated with dilute hydrochloric acid and extracted with methylene chloride. The extract was evaporated to dryness and the residue was recrystallized from methylene chloride with hexane to give 2- (6-methoxy-2-naphthyl) -propionic acid with the value / ° C = * 60 (in chloroform). In an analogous manner to that described above, but using the appropriate compound substituted with bromine at the 5-position, naproxen o / o ^ / ^ = + 61 ° (in chloroform) and Example VI are obtained. 6.2 g of d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid and 1.01 g of triethylamine (0.5 eq.) Are heated in 30 ml of isopropanol and 1.5 ml of water to almost the boiling point of the solvent under reflux until a solution is obtained, then 2.09 g of N-ethylglucamine are added and the solution is cooled to room temperature, obtaining 4.32 g of the product enriched in N-ethyl-iglucamine salt with the said above with acid * A sample of this salt is dissolved in about 25 ml of water, heated to a temperature of about 80 ° C and acidified with hydrochloric acid, yielding a product enriched in acid, which is a naproxen precursor. 1.00 g of the product enriched in salt with N-ethyl-glucamine is dissolved in 20 ml of a 5% aqueous solution of isopropanol with the addition of 1.0 ml of water at a temperature close to the boiling point of the solvent, then the solution is cooled to room temperature. yielding 0.6 g of first-feed recrystallized product. A sample of this product was treated with hydrochloric acid as described in the preceding paragraph to obtain a product more enriched in the salt of the naproxen precursor. 0.50 g of the above-mentioned first feed product is dissolved in 10 ml of 5% isopropanol aqueous solution and 0.5 ml of water at about the boiling point of the solvent, and cooled to room temperature, yielding 0.43 g of recrystallized second feed product. A sample of this product is treated with hydrochloric acid as described in the first paragraph of this example, to obtain a product of higher optical purity, 0.33 g of the second-line product is dissolved in 12 ml of 5% aqueous isopropanol and 1.0 ml of water in about the boiling point of the solvent and then cooled to room temperature to give the recrystallized tertiary product. This product is treated with hydrochloric acid as described in the first paragraph of this example, yielding a substantially pure naproxem 5-bromo precursor. In a 250 ml flask equipped with a reflux condenser and a nitrogen bubbler, 60 g of powdered magnesium are placed, 50 ml of anhydrous methanol and 10 g of triethylamine, flushing the flask with nitrogen and maintaining a nitrogen atmosphere throughout the reaction. 0.1 mole of the above-mentioned 5-bromo-precursor naproxen in 15 g of methanol is slowly added to the mixture in the flask, and after the addition is complete, the mixture is kept under reflux for 1 hour, then cooled and mixed with 6N hydrochloric acid until until the disappearance of magnesium. The mixture is then poured into water, extracted with methylene chloride, the extract is rinsed with water, concentrated, hexane is added and it is left to crystallize. Naproxen is obtained, which, after recrystallization into optical scissibility / ^ / n = 64 [deg.] (In chloroform). In an analogous manner, by using the appropriate naproxen 5-chloroprecursor, naproxen with an optical precision of 62 ° (in chloroform) is obtained * 141 326 9 Example VII. 3 g of d, -1-2- (5-chloro-6-methoxy-2-naphthyl) propionic acid and 0.50 g of triethylamine (0.5 eq) in 15 ml of isopropanol and 0.5 ml of water are heated to the boiling point of the solvent under reflux and after obtaining a solution, 1.32 g (0.5 eq.) of N-cyclonexyl-glucaniin is added. A precipitate is immediately formed which dissolves after adding 15 ml of isopropanol and 1.15 ml of water and heating to reflux temperature . The solution is then cooled to room temperature, yielding a product enriched in the salt of the N-cyclohexylglucamine precursor naproxen. A sample of this product is dissolved in about 25 ml of water, heated to a temperature of about 80 ° C and acidified with hydrochloric acid, causing precipitation a product with a high content of naproxen precursor. 1.00 g of the above-mentioned salt-enriched N-cyclohexyl-D-glucamine precursor naproxen product is dissolved in 20 ml of a 5% aqueous isopropanol solution at the boiling point of the solvent under reflux and cooled to room temperature, yielding by filtration. 0.79 g of first-line recrystallized product * A sample of this product is treated with hydrochloric acid as described in the preceding paragraph to obtain a product with a higher content of d-2- / 5-chloro-6-methoxy-2-naphthyl / propionic acid than in pro The product obtained in the previous paragraph * 1.0 g of this product is dissolved in 10 ml of anhydrous methanol, mixed with 1 g of Raney nickel and boiled under reflux for 12 hours, then filtered, diluted with water, the precipitate is filtered off, dried and recrystallized from acetone with hexane, obtaining naproxen. In a similar way, naproxen with the specific conductivity / <* £ / '= 60 ° (in chloroform) is obtained from a suitable 5-bromo compound. and e). By proceeding in an analogous manner, but using N-methyl-Iglucamine or N-n-octyl-Iglucamine or N-n-octyl-Iglucine as separating agent, we obtain naproxen with a specificity of 60-65 ° (in chloroform). Example VIII. 6.2 g of d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid and 1.01 g (0.5 eq.) Of triethylamine in 30 ml of isopropanol and 1.5 ml of water heat to the boiling point of the solvent and after the solution has been obtained, 2.93 g (0.5 eq.) of Nn-octyl-D-glucamine are added, cooled to room temperature and 4.5 g of the Nn-octyl salt-enriched naproxen precursor product is drained. -Iglucamine. A sample of this product is dissolved in about 25 ml of water at a temperature of about 80 ° C, acidified with hydrochloric acid and the precipitate is filtered off, which is a product enriched in d-2- (5-bromo-6-methoxy-2-naphthyl) acid. propionic. 1.00 g of the above-mentioned product enriched in the salt of the Nn-octyl-D-glucamine precursor naproxen is dissolved in 9f5 ml of isopropanol and 0.5 ml of water at the reflux temperature of the solvent, then cooled and drained to give 0, 85 g of recrystallized salt. This salt is treated with hydrochloric acid as described in the previous paragraph to give essentially pure d-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid in a 200 ml flask equipped with 60 g of powdered magnesium, 50 ml of anhydrous methanol and 10 g of triethylamine are placed in the reflux cooler and the nitrogen bubbler, and 0.1 mole of d-2- / 5-bromo-6- acid is added dropwise to the flask. methoxy-2-naphthyl / propionic acid as a solution in 15 g methanol * The mixture is then refluxed for 1 hour, then cooled to room temperature and treated with 6N hydrochloric acid until the magnesium disappears. The mixture obtained is diluted with water and mixed with methylene chloride, the organic layer is separated, washed with water, concentrated and hexane is added, then the crystallized product is filtered off, obtaining naproxen with a melting point of 155 ° C and I ° C 1-65 °. In an analogous manner, using d, 1- (5-chloro-6-methoxy-2-naphthyl) -propionic acid as a starting product, naproxen with a melting point of 154 ° C and / n. 62 ° (in chloroform) .10 141 326 Example IX. 2.16 g of df1-2- (6-hydroxy-2-naphthyl) propionic acid and 0.50 g (0.5 eq) of triethylamine are heated in 30 ml of ethylene glycol to 90 ° C and, after dissolving the propionic acid 1.47 g of Nn-octyl-D-glucamine is added, the solution is cooled to 40 ° C, the salt of d-2- (hydroxy-2-naphthyl) -propionic acid is inoculated with Nn-octyl-D-glucamine with crystals and mixed with overnight at room temperature. By filtering off the precipitate, 1.47 g of a product enriched in d-2- (6-hydroxy-2-naphthyl) -propionic acid salt with Nn-octyl-D-glucamine is obtained. A sample of this product is dissolved in about 25 ml of water at a temperature of about 80 ° C. and treated with hydrochloric acid, then the precipitate, which is a product enriched in d-2- (6-hydroxy-2-naphthyl) propionic acid, is filtered off. 2 g of the product obtained is dissolved in 30 ml of a 1N aqueous solution of sodium hydroxide, 3.8 g of dimethyl sulphate are added and kept at a temperature of 60 ° C for 2 hours, then cooled to room temperature and acidified with diluted hydrochloric acid. The precipitate formed is filtered off and it was washed with water until it was neutral, obtaining 1.5 g of naproxen, the specific content of which after recrystallization was / a VD = 62 °. D, 1- 2- (6-hydroxy-5-bromo-2-naphthyl) -propionic acid is separated and methylated in an analogous manner, and the product obtained is bromine as described in Example IV, giving naproxen / cef /D=60°. Example X, 3.1 g of d, 1- 2- / 5-bromo-6-methoxy-2-naphthyl / propionic acid and 0.50 g (0.5 eq) of triethylamine in 15 ml isopropanol and 0.75 ml of water are heated to the reflux temperature of the solvent, and after dissolving the propionic acid, 1.75 g of Nn-dodecyl-D-glucamine (0.5 equiv) are added, cooled to room temperature and drained 2.50 g of product enriched in d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid salt with Nn-dodecyl] glucamine. A sample of this product is mixed with about 25 ml of water and 300 mg of potassium hydroxide and kept at room temperature for 1 hour, then the precipitate is filtered off and the filtrate is acidified with hydrochloric acid, causing precipitation of the product enriched in d-2- / 5 acid. -bromo-6-methoxy-2-naphthyl) -propionic. 1.00 g of the above-mentioned product enriched in Nn-dodecyl-D-glucamine di-2- (5-bromo-6-methoxy-6-methoxy-2-naphthyl) -propionic acid salt is dissolved in 20 ml of a 5% solution isopropanol at a temperature close to the reflux temperature of the solvent and then cooled to room temperature to give 0.88 g of first-line recrystallized product. A sample of this product is treated with potassium hydroxide and then with hydrochloric acid as described in the preceding paragraph to give a product with a higher content of d, 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, from of the product obtained in the manner mentioned in the preceding paragraph. 0.62 g of the first-line product described in the preceding paragraph, which is a product enriched in the salt of d-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid from Nn- dodecyl] glucamine, dissolves in 15 ml of a 3% aqueous solution of isopropanol at a temperature close to the boiling point of the solvent, and then cooled to room temperature to give 0.5 g of recrystallized product of the second line. * In a 250 ml flask equipped with a reflux cooler and a bubbler for for the introduction of nitrogen, 60 g of powdered magnesium, 50 ml of anhydrous methanol and 10 g of triethylamine are placed and, while maintaining a nitrogen atmosphere in the flask, 0.1 mole of the product enriched in d-2- / 5-bromo acid mentioned in the first paragraph of this example is added dropwise. -6-methoxy-2-naphthyl) -propionic acid in 15 g of methanol, then reflux the mixture for 1 hour with continued nitrogen purge. The mixture is then cooled and treated with 6N hydrochloric acid until the magnesium disappears, then poured into water and extracted with methylene chloride. The extract is rinsed with water, concentrated, hexane is added and the precipitate is filtered off. Fb of recrystallization of this precipitate, naproxen is obtained with an optical skewness of 141 326 11 / c ^ / D = 62 ° #. In an analogous manner, from d, 1- 2- (5-chloro-6-methoxy-2-naphthyl / propionic acid) is obtained naproxen with optical rotation 60 • Example XI. 135 mg of sodium salt of d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid and 100 mg of Nn-butyl-D-glucamine hydrochloride in 2 ml of 5% aqueous isopropanol solution is heated to temperature close to the boiling point of the solvent under a reflux condenser, then cooled slowly and inoculated with a small amount of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid salt with Nn-butyl-] glucamine and further cooling to room temperature. By filtering off the precipitate formed and washing it with water, 1.10 g of product enriched in the salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid from N-n-butyl-iglukainin are obtained. A sample of this product is dissolved in water, acidified with hydrochloric acid and the separated product, enriched in d-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid, is filtered off. Solution of 1 g of the product obtained in 10 ml of anhydrous methanol It is mixed with 1 g of Raney nickel and, by introducing hydrogen, it boils the mixture under reflux for 14 hours, then it is filtered, diluted by filtration with water and the separated precipitate is recrystallized from acetone with hexane, obtaining naproxen with an optical specificity of 65 °. Example XII. 2.1 g of d, 1- 2- (6-hydroxy-2-naphthyl) -propionic acid and 1.46 g (0.55 eq.) Of Nn-hexyl-D-glucamine in 15 ml of water are heated to about 80 ° C, then 0.17 g (0.45 eq.) Of potassium hydroxide is added and the pH of the solution is adjusted to 8 with potassium carbonate. The solution is then seeded with a small amount of d-2- (6-hydroxy-2-naphthyl) -propionic acid salt with Nn-hekyyl-D-glucamine and cooled to obtain 1.25 g of the product enriched in d-2-acid salt after draining. (6-hydroxy-2-naphthyl) -propionic acid from Ito-hexyl-glucamine. The obtained product is dissolved in 15 ml of dioxane, 15 ml of 20% aqueous sodium hydroxide solution are added, the mixture is heated and saturated with methyl bromide, and then it is cooled to room temperature, continuing to introduce methyl bromide * The resulting mixture is cooled, acidified with 1N aqueous hydrochloric acid solution and extracted with diethyl ether. EXAMPLE XIII 4.60 g of d, 1- 2- (6-hydroxy-2-naphthyl) propionic acid is mixed with 25 ml of water and 0.60 g (0.45 eq.) Of potassium hydroxide and kept at at 70 ° C for 10 minutes, then 3.22 g (0.55 eq.) of Nn-octyl-Ig is added ukamine and slowly cool the solution to 50 ° C. Then a small amount of d-2- (6-hydroxy-2-naphthyl) -propionic acid salt of n-octyl -glucamine is added and the solution is stirred at room temperature overnight, and the precipitate is filtered off to obtain 4.0 g of enriched product. into the salt of d-2- (6-hydroxy-2-naphthyl) -propionic acid with Nn-octyl-D-glucamine. A sample of this product is mixed with 25 ml of water and 300 mg of potassium hydroxide at room temperature for 1 hour, then the precipitate is filtered off and the filtrate is acidified with hydrochloric acid, causing precipitation of the product enriched in d-2- (6-hydroxy) acid. 2-naphthyl / propionic acid # 2 g of the product obtained is dissolved in 35 ml of 1N aqueous sodium hydroxide solution, 4 g of dimethyl sulfate are added and the solution is kept at 65 ° C for 2 to 5 hours, then it is cooled to room temperature and acidified with diluted solution. with hydrochloric acid * The resulting precipitate is filtered off and washed with water until it is neutral, yielding 1.6 g of naproxen with an optical skewness of 64 ° (in chloroform). 12 141 326. Example 14, 433 g (2 moles) ) racemic 2- (6-hydroxy-2-naphthyl) -propionic acid and '390f5 g (2 moles) of N-methyl-D-glucamine are dissolved in 4 liters of boiling methanol, filter the solution and slowly stirring slowly to a temperature of 45 C. Then 1 g of acid salt is added su d-2- (6-hydroxy-2-naphthyl) -propionic acid from N-methyl-D-glucamine, obtained in a separately conducted test, by rubbing the vessel walls with a glass stick, sucking off the sediment and washing it with a small amount of methanol. Immediately after seeding, crystallization takes place rapidly, initially maintaining the temperature of the mixture at 45 ° C and slowly lowering it to 15 ° C. The crystalline precipitate is filtered off, washed with a little methanol and dried to give 300 g of N-methyl-D-glucamine d-2- (6-hydroxy-2-naphthyl) propionic acid salt. The salt obtained is dissolved in water, acidified with dilute hydrochloric acid and the precipitate of d-2- (6-hydroxy-2-naphthyl) propionic acid is filtered off. 200 g of the product obtained are dissolved in 350 ml of 1N aqueous sodium hydroxide solution, 40 g of dimethyl sulfate are added, kept at 60 ° C for 2 hours, then cooled to room temperature and acidified with dilute hydrochloric acid. The precipitate formed is filtered off and washed with water until neutral, yielding 175 g of naproxen, which, after recrystallization, has an optical performance of 62. Example XV. 6.2 g of d, 1-2- (5-bromo-6-methoxy-2-naphthyl) propionic acid and 1.01 g (0.5 eq.) Of triethylamine in 20 ml of 6% toluene in methanol are retained is boiled under reflux and after dissolving the propionic acid, 1.95 g (0.5 eq.) of N-methyl-D-glucamine is added and cooled to room temperature * R) by filtering off the precipitate, 3.52 g of the product enriched in d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid salt with N-methyl-D-glucamine. This salt is dissolved in about 25 ml of water, acidified with hydrochloric acid and the product enriched with acid is filtered off. -2- (5-bromo-6-methoxy-2-naphthyl) propionic acid. 1.00 g of the above-mentioned product with an increased content of naproxen precursor with N-methyl] glucamine is recrystallized from a mixture of 10 ml of methanol with 20 ml of ethanol by dissolving hot and evaporating 5 ml of solvent and then cooling. The resulting 0.85 g of salt is treated with with hydrochloric acid as described in the preceding paragraph to give substantially pure d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid. 1 g of this acid in 10 ml of anhydrous methanol is mixed with 100 mg of palladium on charcoal and, by introducing hydrogen, kept at room temperature for 12 hours and then filtered. The filtrate is diluted with water by extraction with methylene chloride, the extract is evaporated to dryness and the residue is recrystallized from methyl chloride with hexane to give naproxen with an optical precision of 58 °. In another variant of this process, in a 250 ml flask equipped with a cooler and a nitrogen bubbler are placed, 60 g of powdered magnesium, 50 ml of anhydrous methanol and 10 g of triethylamine are placed, and a solution of 0.1 mole of naproxen precursor prepared as described in the first part of Example XI, in 15 g of methanol, then the mixture is boiled under reflux for 1 hour. The mixture is then cooled and treated with 6N hydrochloric acid until the magnesium disappears, then poured into water and extracted with methylene chloride. The mixture is rinsed with water, concentrated, hexane is added and the crystalline precipitate is filtered off. If this precipitate is crystallized, naproxen with an optical skewness of 64 ° (in chloroform) is obtained and, in a similar manner, naproxen with an optical skewness of 62 ° is obtained from naproxen 5-chloro-precursor. 2- (6-methoxy-2-naphthyl) -propionic acid, prepared as described in Example 1, is mixed with 4 g of sodium hydroxide in 500 ml of aqueous methanol and stirred at room temperature for 3 hours, then evaporated. to give the sodium salt of d-2- (6-methoxy-2-naphthyl) -propionic acid. This product is mixed with toluene, centrifuged, washed with hexane and dried to give a product having a melting point of 255 ° C (signs of decomposition). The infrared spectrum of the product shows maxima at 1260, 1600, 1625 and 1725 cm. The yield of the process, based on the starting acid, is 95% of theoretical. Claims 1. Method for the preparation of (d) -2- (6-methoxy-2-naphthyl) propionic acid or its pharmacologically acceptable salts, characterized by the fact that the compound of the formula I, in which R is a hydrogen atom or a methyl radical, X is a chlorine atom or a bromine atom, and n is a number zero or 1, and when n is a number zero, then R is a hydrogen atom or a salt of this compound is subjected to the environment of an inert solvent by resolution of the enantiomers by reaction with a glucamine derivative of the formula NRd-glucamine, in which R is an (O.-O-8) alkyl radical or a (C1-C6) cycloalkyl radical, or a salt of the derivative, and the obtained precursor of (d (-2- (6-methoxy-2-naphthyl) -propionic acid) is converted into (d-2- (6-methoxy-2-naphthyl) -propionic acid, which, if necessary, is transformed into its pharmacologically an acceptable salt, and the resulting left-tail enantiomer of the obtained precursor even the racemate is then racemized and the resulting racemate is separated into the enantiomers. 2. The method according to claim A compound according to claim 1, characterized in that the compound of formula I, i &lt; &gt; in which R is methyl, X is bromine or chlorine and n is. Number 1 is reacted in a mixture of toluene and methanol with a compound of formula N-R-d-glucamine, in which R is a methyl radical. 3. The method according to p. A compound according to claim 1, characterized in that the compound of formula I, in which R is a methyl radical, X is a bromine or chlorine atom, and n is the number 1, is reacted with a compound of formula NRd-glucHmin, in which R is a methyl radical, to carry out these reactions in an inert organic solvent, other than a mixture of toluene and methanol. 4. The method according to p. A compound according to claim 1, characterized in that a compound of formula I, wherein R is hydrogen, X is bromine or chlorine, and n is zero, is reacted with a compound of formula N-R-d-glucamine, in which R is methyl. 5. The method according to p. A compound according to claim 1, characterized in that a compound of formula N-R-d-glucamine is used, in which R is an alkyl radical of 2-18 carbon atoms or a cycloalkyl radical of 3-8 carbon atoms. 6. The method according to p. A compound according to claim 5, characterized in that a compound of formula N-R-d-glucamine is used, in which R is an alkyl radical of 6-18 carbon atoms or a cycloalkyl radical of 3-8 carbon atoms. 7. The method according to p. A process according to any of the preceding claims, characterized in that d-2- (6-hydroxy-2-naphthyl) -propionic acid or a salt thereof is converted into d-2- (6-methoxy-2-naphthyl) -propionic acid. 8. The method according to p. A process as claimed in any one of the preceding claims, characterized in that d-2- (5-halo-6-methoxy-2-naphthyl) propionic acid or its salt is converted to d-2- (6-) Methoxy-2-naphthyl / propionic acid and 141 326 9H3 CH-COOH Second and CH.CH-COOH Ifliór la Pracownia Poligraficzna LT PR1. Mintage i00 e & z Price PLN 220 PL

Claims (8)

Claims 1. A process for the preparation of (d) -2- (6-methoxy-2-naphthyl) -propionic acid or its pharmacologically acceptable salts, characterized by the compound of formula I, wherein R is hydrogen or methyl, X is chlorine or bromine and n is zero or 1, where n is zero, then R is a hydrogen atom, or a salt of this compound, is subjected to enantiomer separation in an inert solvent by reaction with a glucamine derivative of formula NRd -glucamine, in which R is an (O.-O-8) alkyl radical or a (C ~ -C6) cycloalkyl radical, or from a salt of this derivative, whereupon the obtained precursor of the acid / d (-2- / 6-methoxy-2) -naphthyl-propionic acid is converted to (d-2- (6-methoxy-2-naphthyl) -propionic acid, which is optionally converted into its pharmacologically acceptable salt, and the resulting leftwin enantiomer of the precursor obtained is optionally racemized and separated the enantiomers of the racemate produced. 2. The method according to claim A compound according to claim 1, characterized in that the compound of formula I, i &lt; &gt; in which R is methyl, X is bromine or chlorine and n is. Number 1 is reacted in a mixture of toluene and methanol with a compound of formula N-R-d-glucamine, in which R is a methyl radical. 3. The method according to p. A compound according to claim 1, characterized in that the compound of formula I, in which R is a methyl radical, X is a bromine or chlorine atom, and n is the number 1, is reacted with a compound of formula NRd-glucHmin, in which R is a methyl radical, to carry out these reactions in an inert organic solvent, other than a mixture of toluene and methanol. 4. The method according to p. A compound according to claim 1, characterized in that a compound of formula I, wherein R is hydrogen, X is bromine or chlorine, and n is zero, is reacted with a compound of formula N-R-d-glucamine, in which R is methyl. 5. The method according to p. A compound according to claim 1, characterized in that a compound of formula N-R-d-glucamine is used, in which R is an alkyl radical of 2-18 carbon atoms or a cycloalkyl radical of 3-8 carbon atoms. 6. The method according to p. A compound according to claim 5, characterized in that a compound of formula N-R-d-glucamine is used, in which R is an alkyl radical of 6-18 carbon atoms or a cycloalkyl radical of 3-8 carbon atoms. 7. The method according to p. A process according to any of the preceding claims, characterized in that d-2- (6-hydroxy-2-naphthyl) -propionic acid or a salt thereof is converted into d-2- (6-methoxy-2-naphthyl) -propionic acid. 8. The method according to p. A process as claimed in any one of the preceding claims, characterized in that d-2- (5-halo-6-methoxy-2-naphthyl) propionic acid or its salt is converted to d-2- (6-) methoxy-2-naphthyl / propionic acid and CH. 326 9H3 CH-COOH Second and CH. CH-COOH Ifliór la Pracownia Poligraficzna LT PR1. Mintage i00 e & z Price PLN 220 PL