FI65773C - FOERFARANDE FOER SEPARERING AV D-2- (6-METOXY-2-NAPHTHYL) PROPIONYRA - Google Patents

Description

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Fetwo oeh reghterstyiehei ^ AmMcm iitEJToehudj ^ nftM30.03.84 (32) (33) (31) Pyr ** «y moHwii l» | M ptoriut 06.07.79 USA (US) 055258 (71) Syntex Pharmaceuticals International Limited, Global House,

Church Street, Hamilton 5, Bermuda (BM) (72) Percy G. Holton, Menlo Park, California, USA (74) Leitzinger Oy (54) Method d-2- (6-methoxy-2-naphthyl) prop The present invention relates to a process according to claim 1 of Finnish patent 64 796, d-2- (6-methoxy-2-naphthyl) propionic acid (61) Addition to patent 64796 - Tfllägg till patent 64796 To separate 6-methoxy-2-naphthyl) propionic acid in the form of the free acid or its N-alkyl-glucamine salt or a pharmaceutically acceptable salt thereof from a mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acid or its salts.

d-2- (6-methoxy-2-naphthyl) propionic acid is a well-known anti-inflammatory, analgesic and antipyretic agent described and claimed in U.S. Patent 3,904,682. Methods for preparing d-2- (6-methoxy-2-naphthyl) propionic acid are described in U.S. Patents 3,651,106; 3,652,683; 3,658,858; 3,658,863; 3,663,584; 3,904,682; 3,904,683 and 3,975,432.

The main patent application discloses a separation method in which the N-methyl-D-glucamine salt is used as the separation agent. This method can now also be performed with the N-alkyl-D-glucamine salt.

The process of this invention is characterized in that 2 65773 (a) is heated with d- and 1-2- (6-methoxy-2-naphthyl) propionic acid or a salt thereof and NRD glucamine, wherein R is an alkyl group having 2 to 18 carbon atoms, or A cycloalkyl group having 8 carbon atoms or a salt thereof and optionally an organic or inorganic base in an inert solvent at an elevated temperature to form a glucamine salt of d- and 1-2- (6-methoxy-2-naphthyl) propionic acid; and (b) crystallizing the glucamine salt of d-2- (6-methoxy-2-naphthyl) propionic acid by cooling the heated mixture; and optionally (c) cleaving the d-acid salt with an acid or base to liberate the d-acid and crystallizing the d-acid; and optionally (d) converting said d-acid to a pharmaceutically acceptable salt.

Preferred resolving agents are N-n-propyl-D-glucamine, N-n-butyl-D-glucamine and N-n-octyl-D-glucamine.

The separation according to the present invention is carried out in an inert organic solvent in which the salt of d-2- (6-methoxy-2-naphthyl) propionic acid with the separating agent and the salt of 1-2- (6-methoxy-2-naphthyl) propionic acid with the separating agent are significantly differently soluble, generally at temperatures between room temperature or ambient temperature and an elevated temperature, up to the reflux temperature of the solvent usually used, the salt of d-2- (6-methoxy-2-naphthylpropionic acid with a resolving agent (e.g. Nn-propyl-D-glucamine, With Nn-butyl-D-glucamine or Nn-octyl-D-glucamine) should dissolve significantly less in the solvent than the salt of 1-2- (6-methoxy-2-naphthyl) propionic acid with a separating agent, whereby when its hot solution cools, usually to or near ambient temperature, such a salt of d-2- (6-methoxy-2-naphthyl) propionic acid is crystallized primarily with a resolving agent. alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, cyclohexanol, 2-ethylhexanol, benzyl alcohol, furfuryl alcohol and the like, C2-C8 dihydric alcohols such as 1,2-ethylene glycol propylene glycol, 1,3-propylene glycol and the like, C3 to C4 trihydric alcohols such as glycerol and the like, ketones such as aceto, acetylacetone, ethylmethyl ketone, diethyl ketone, di-n-propyl ketone, diisopropyl ketone, di -isobutyl ketone and the like. Other solvents include ethylene glycol and diethylene glycol mono- and di (lower) alkyl ether, dimethyl sulfoxide, sulfolanes, formamide, dimethylformamide, N-methylpyrrolidone, pyridine, dioxane, dimethylacetamide and the like. At present, alcohols, for example methanol and isopropanol, especially raethanol, are considered to be the best solvents. If necessary, so much water can be added to the solvent that all the substances added to it are soluble.

Starting material / i.e. a mixture of d-2- (6-methoxy-2-naphthyl) propionic acid and 1-2- (6-methoxy-2-naphthyl) propionic acid or their soluble salts / is heated to an elevated temperature, generally between about 60 ° C and about 100 ° C, or to the reflux temperature of the solvent, in the presence of a separating agent, whereby all the substances added to the solvent are made to dissolve. If desired, the solvent can be kept at an elevated temperature until all the substances have dissolved. After maintaining the solution at an elevated temperature for the desired time, it is slowly cooled to ambient temperature. During cooling, it is recommended to seed the solution with a salt of d-2- (6-methoxy-2-naphthyl) propionic acid and a separating agent / for example d-2- (6-methoxy-2-naphthyl) -propionic acid with Nn-propyl-D-glucamine. / with salt. The resulting crystalline precipitate is enriched in d-2- (6-methoxy-2-naphthyl) propionic acid and a separating agent. The final temperature to which the solution is heated is selected on the basis of practical considerations, but is generally chosen so that the temperature difference is sufficient to produce high-yield crystals. The crystallizing mixture can be kept at a lower temperature until crystallization has occurred completely or almost completely, usually about 30 minutes to several hours. The resulting crystalline precipitate is removed by filtration and washed.

The crystalline substance / so obtained in this step of the process. a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and a salt of a separating agent / after filtration and washing can be added to 4,677,73 in water and, if necessary, heated to redissolve the crystalline substance. In the case of N-R-D-glucamines which are soluble in water, the solution obtained is acidified with, for example, a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as acetic acid and the crystalline precipitate thus obtained is filtered off, washed and dried. This gives a white crystalline product which is substantially enriched in d-2- (6-methoxy-2-naphthyl) propionic acid, or, in the case of NRD-glucamines which are insoluble in water, a substance enriched in d-2- (6- methoxy-2-naphthyl) propionic acid and a salt of such a separating agent, can be treated with a strong base such as potassium hydroxide or another strong base having a pKa of more than 10, whereby the salt cracks, then the separating agent is removed by filtration and the filtrate is acidified with hydrochloric acid or with sulfuric acid or an organic acid such as acetic acid to give, after filtration, washing and drying, a white crystalline product substantially enriched in d-2- (6-methoxy-2-naphthyl) propionic acid.

Before cleaving a substance enriched in d-2- (6-methoxy-2-naphthyl) propionic acid and a salt of a separating agent to d-2- (6-methoxy-2-naphthyl) propionic acid, it is generally recommended to redissolve the enriched salt material in an additional portion of solvent, heat the solvent to the desired (usually elevated) temperature, inoculate the resulting solution with a salt of d-2- (6-methoxy-2-naphthyl) propionic acid and a separating agent, and cool the resulting solution. Thus, one or more recrystallizations can be performed. Each such recrystallization further increases the amount of d-2- (6-methoxy-2-naphthyl) propionic acid and the salt of the separating agent in the recrystallized material. Particularly suitable resolving agents according to the present invention are Nn-propyl-D-glucamine, Nn-butyl-D-glucamine and Nn-hexyl-D-glucamine, since by using only one recrystallization step before redissolving the obtained crystalline product and subsequent acidification, to obtain a product having a purity of the order of d-2- (6-roethoxy-2-naphthyl) propionic acid of the order of about 97-99%.

However, Nn-octyl-D-glucamine is currently considered to be the best resolving agent because, using Nn-octyl-D-glucamine, the salt of d-2- (6-methoxy-2-naphthyl) propionic acid with Nn-octyl-D-glucamine is 657773. can be easily recovered by filtration, d-2- (6-methoxy-2-naphthyl) propionic acid of sufficient optical purity can be obtained without the need for one or more recrystallizations before the bleaching step, and the separating agent can be recovered directly by filtration and in high yield (on the order of about 97-98%). ). In addition, cleavage can be performed under either temporal or acidic conditions. Alkaline cleavage results in a N-n-octyl-D-glutamine precipitate, while d-2- (6-methoxy-2-naphthyl) propionic acid is present in alkaline medium in solution. Acid cleavage results in a d-2- (6-methoxy-2-naphthyl) propionic acid precipitate, while N-h-octyl-D-glutamine remains in acidic medium solution.

N-n-octyl-D-glucamine is substantially insoluble in water, allowing it to be recovered from aqueous systems in high yields. This is also the case for other resolving agents of the present invention in which R is alkyl / having at least 6 carbon atoms, for example those resolving agents in which R is alkyl having 6 to 18 carbon atoms.

A substance enriched in 1-2- (6-methoxy-2-naphthyl) propionic acid or its NRD-glucamine salt (when R is as defined above) can be treated to recover 1-2- (6-methoxy-2-naphthyl) propionic acid. which can then be racemized by known methods to a substance containing more d-2- (6-methoxy-2-naphthyl) -propionic acid. See, e.g., Dyson U.S. Patent 3,686,183.

This material can be recycled, either alone or in combination with other d, 1-2- (6-methoxy-2-naphthyl) propionic acid, to provide additional starting material for the separation process of this invention.

The amount of resolving agent used in accordance with the present invention (in moles of d, 1-2- (6-methoxy-2-naphthyl) propionic acid to be separated) is between about 50 and 100%. However, since only about 50% / mole of d / 2- (6-methoxy-2-naphthyl) propionic acid to be separated is required to form its more insoluble salt with d-2- (6-methoxy-2-naphthyl) propionic acid, the remainder the separating agent (usually on the order of about 40 to 50 mol%) may, if desired, be replaced by a cheaper base, including, for example, an inorganic inorganic base such as an alkali metal hydroxide, e.g. sodium hydroxide or

Aqueous mother liquors obtained from the separation of d-2- (6-methoxy-2-naphthyl) propionic acid and 1-2- (6-methoxy-2-naphthyl) propionic acid contain, for example, salts of the separating agent with the acid used in the acid mixture. These mother liquors can be treated with an inorganic base to give the corresponding insoluble salt with N-R-D-glucamine. For example, treatment with a suspension of calcium hydroxide precipitates the corresponding calcium salt, which can be recovered by filtration. The filtrate is concentrated to dryness in vacuo at elevated temperatures, first removing any other salt, for example the calcium salt, which is formed during the initial stages of concentration. The residue is dissolved in a suitable solvent at elevated temperature, up to the reflux temperature of the solvent, and then cooled to room temperature to give a separating agent as a crystalline precipitate which can be reused in the separation method of this invention, either alone or in combination with a new agent. Alternatively, the release agent can be recovered using an anion exchange resin and recycled for reuse.

The term "mixture of d-2- (6-methoxy-2-naphthyl) propionic acid and d-2- (6-methoxy-3-naphthyl) propionic acid" also includes those salts which are soluble in the solvent used in the separation process of this invention. Such salts include, for example, the corresponding sodium salts, potassium salts, lithium salts and the like. 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 a mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acid. The resulting mixture of salts of d-2- (6-methoxy-2-naphthyl) propionic acid and 1-2- (6-methoxy-2-naphthyl) propionic acid can be separated according to the present invention using a salt of a resolving agent which reacts to form d-2- (6-methoxy-2-naphthyl) propionic acid. -methoxy-2-naphthyl) propionic acid salt with NRD-glucamine. Suitable glucamine salts include, for example, the hydrochloride salt and the acetate salt. Other salts include propionate salt, butyrate salt, isobutyrate salt, sulfate salt, nitrate salt and the like. The term "NRD-glucamine" (where R is as defined above) thus encompasses those salts which cause the separation referred to herein when used in a mixture of d- and 1-2- (6-methoxy-2-naphthyl) propionic acid 7 / cnn7

with the salt in question. Ό3 f f O

The N-R-D-glucanamine salts of d-2- (6-methoxy-2-naphthyl) propionic acid are useful as anti-inf Lamina inhibitors, analgesic and / or antipyretic agents, antiplatelet agents, fibrinolytic agents and smooth muscle relaxants.

The above salts are also useful in the treatment of dysmenorrhea and may alleviate postmenopausal symptoms.

Such salts may thus be useful in the treatment and treatment of inflammation. These include inflammatory conditions of the musculoskeletal system, skeletal joints, and other tissues. For example, they can be used to treat inflammatory conditions such as rheumatism, concussions, tears, arthritis, fractures, post-traumatic conditions, and gout. In cases where the above conditions are associated with pain and pyrexia associated with inflammation, these salts may be useful in alleviating these conditions as well as the inflammation.

The above salts may be administered in a suitable pharmaceutical composition by any acceptable route of administration for the treatment of inflammation, pain or pyrexia. Thus, for example, administration may be oral, narenteral (e.g., by injection or topical in solid, semi-solid, or liquid dosage forms such as tablets, suppositories, pills, capsules, powders, liquid solutions, suspensions, creams, lotions, ointments, or the like). Such pharmaceutical compositions contain a conventional pharmaceutical carrier or excipient and a salt of NRD-glucamine with d-2- (6-methoxy-2-naphthyl) -propionic acid and may additionally contain other drugs, pharmaceuticals, carriers , excipients, etc.

The recommended route of administration is oral, using an appropriate daily dose range that can be adjusted according to the degree of disease. Usually the daily dose is · 2 to 20 mg of the above salt per kilogram of body weight. For such oral administration, a pharmaceutically acceptable non-toxic mixture is formed by the addition of any commonly used excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate. These compositions may be in the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, and the like.

By using, for example, polyalkylene glycols such as polypropylene glycol as a carrier, a suppository can be formulated. Liquid pharmaceutically acceptable compositions may be prepared, for example, by dissolving, dispersing, etc. the above salt and optional pharmaceutical excipients in a carrier such as water, saline, aqueous dextrose, glycerol, ethanol and the like to give a solution or suspension. The pharmaceutical composition to be administered may, if desired, also contain minor amounts of toxicants such as wetting or emulsifying agents, pH buffers and the like, such as sodium acetate, sorbitan monolaurate, trimethanolamine oleate, etc.

The actual methods of preparation of such dosage forms are known or will be apparent to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition, 1970. However, the composition to be administered must contain a pharmaceutically effective amount of the above salt (s). the state treated according to its teachings is alleviated.

The aforementioned salts are also relaxants for uterine smooth muscle. They are thus useful substances for maintaining the pregnancy of a pregnant mammal, the mother and / or the fetus, until it is medically desirable or more desirable for the mother and / or fetus to terminate the pregnancy. However, it should be noted that in some cases, for example when synnvtvft has already begun (i.e., the mother feels uterine contractions, especially near due date), administration of the aforementioned salts may not indefinitely preserve the pregnancy. Most likely, pregnancy in such cases tends to be slightly "delayed", a factor that may be beneficial to either the mother and / or the fetus.

The above-mentioned salts are also used as agents for delaying or delaying the onset of labor. As used herein, the term "delaying the onset of labor" encompasses the delay in labor caused by the administration of any of the aforementioned salts at any time prior to the onset of uterine muscle contractions. The above term thus encompasses the prevention of miscarriage during pregnancy (i.e., before the fetus is "alive") and the delay of preterm delivery. The term preterm labor is sometimes used to refer to premature birth burns that are experienced later in pregnancy, when the fetus is considered "alive." In either case, the agents are administered as prophylactic agents in such a way that their administration is intended to prevent the onset of labor. This route of administration is particularly useful in the treatment of women who have had a spontaneous miscarriage or premature delivery (i.e., prenatal delivery). Such a route of administration is also useful when there are clinical signs that the pregnancy may be terminated before the time considered appropriate by the mother and / or fetus.

The term "postponement of labor" as used in this application encompasses the delay in labor caused by the administration of any of the aforementioned salts after the onset of uterine muscle contractions. The results achieved are affected by the patient's condition, including the time of pregnancy when the contractions began, the intensity of the contractions, and how long the contractions continued. The effect may be, for example, a reduction in the intensity and / or duration of the contractions (the actual delivery "lengthens"), or a complete cessation of the contractions. In either case, the effect prolongs the gestational age, although depending on the patient's condition, as described above, the effect may be either mild or somewhat greater under appropriate conditions. Such administration may prevent spontaneous miscarriage, facilitate labor and / or make it more painless for the mother or at a more appropriate time and / or location.

In animals, this treatment can cause the birth of a group of pregnant animals to occur at the same time or at about the same time or at a desired time or near it and / or at a desired location so that the births can be better equipped.

10 65773

In all cases, administration should be in accordance with best and / or accepted medical (or veterinary) practice so as to maximize the benefits to the mother and fetus.

For example, administration should not be continued until full time that the fetus dies in utero.

In carrying out this aspect of the present invention, a therapeutically effective amount of any of the aforementioned salts or a pharmaceutical composition comprising the aforementioned salt is administered to a pregnant animal by any method known and acceptable in the art. The salt may be administered either alone or in combination with another compound or compounds as defined above, or with other pharmaceutical agents, carriers, excipients, and the like. Such salt (s) or mixtures may be administered orally or parenterally in the dosages and forms (including oral tablets, vaginal or uterine tablets or suppositories, etc.) set forth above for anti-inflammatory, etc. activities. Administration may be as a single daily dose or up to three or four smaller doses regularly throughout the day. The actual amount of salt administered will, of course, depend on its relative activity for that particular use.

The preparation of the glucamine salt used in the process of the invention is illustrated in the following Preparation Examples A-J.

Preparation A

18 g of D-glucose, 20 ml of 70% ethylamine in water and 1 g of Raney nickel in 140 ml of methanol and 30 ml of water are treated with hydrogen for two 2 times at a pressure of 11.2 kg / cm 2 at 60 ° C. The catalyst is removed from the solution by filtration, the solvent is concentrated under reduced pressure, the precipitate is dissolved in 50 ml of water and the resulting solution is filtered and cooled to give 15.5 g of N-ethyl-D-glucamine. 132-134 ° C | <x] D - 15.4 ° (water) J as a precipitate.

Preparation B 65773 18 g of D-glucose, 20 ml of n-propylamine and 1 g of Raney nickel in 140 ml of methanol and 40 ml of water are treated for 2 hours with hydrogen at a pressure of 11.2 kg / cm 2 at 60 ° C. The precipitate is dissolved by adding 40 ml of water, the solution is filtered to remove the catalyst, the solution is concentrated under reduced pressure, the precipitate is dissolved in 100 ml of methanol and the resulting solution is cooled to give 14.6 g of N-n-propyl-Dglucamine ISp. 141-143 ° C; o (] D - 15.2 ° (water).

Preparation C

9 g of D-glucose and 9 g of isopropylamine are stirred for two hours, 5 ml of ethanol are added and the mixture is stirred overnight. Excess isopropylamine and ethanol are removed under reduced pressure, the residue is dissolved in 180 ml of methanol and treated overnight at 50 ° C with 1 g of 5% palladium on carbon and hydrogen (12.3 kg / cm 2). The catalyst is removed from the methanol solution by filtration, concentrated under reduced pressure and the residue obtained is recrystallized from ethanol to give 5.7 g of N-isopropyl-D-glucamine. 134-136 ° C; £ <*] D -13.15 ° (water)].

Preparation D

18 g of D-glucose and 21.9 g of n-butylamine and 180 ml of methanol are stirred for 1 hour under reflux, the excess n-butylamine and methanol are removed under reduced pressure and the residue is dissolved in 180 ml of methanol. The solution is treated overnight at 60 ° C with 1.5 g of 5% palladium on carbon and hydrogen (12.6 kg / cm 2). The catalyst is removed from the solution by filtration, concentrated under reduced pressure and the residue obtained is recrystallized from ethanol to give 13.3 g of N-n-butyl-D-glucamine | 129-131 ° C [α] D - 14.30 ° (water)].

Preparation D

18 g of D-glucol, 22 g of iso-butylamine and 1 g of Raney nickel in 140 ml of methanol and 40 ml of water are treated with hydrogen for 2 hours at a pressure of 11.2 kg / cm2 and at 60 ° C. The catalyst is removed by filtration and the solution is kept overnight at -10 ° C to give a precipitate which is collected by filtration. 6.6 g of N-iso-butyl-12 65773 are obtained

li-D-glucamine CSp. 138-143 ° C. JD -18.8 ° (dimethyl sulfoxide) l. Preparation E

18 g of D-glucose, 9.9 g of cyclohexylamine and 1 g of Raney nickel in 140 ml of methanol and 40 ml of water are treated with hydrogen at a pressure of 11.2 kg / cm 2 at 60 ° C for 2 hours. The catalyst is removed from the solution by filtration. The solution is stored overnight at -10 ° C to give a precipitate which is collected by filtration. 2.35 g of N-cyclohexyl-D-glucamine CSp are obtained. 144-146 ° C; IJx] D -20.4 ° (dimethyl sulfoxide)].

Preparation G

18 g of D-glucose, 25 ml of n-octylamine and 1 g of Raney nickel in 140 ml of methanol and 40 ml of equal water are treated with 11.2 kg / cm2 of hydrogen at 60 ° C for 2 hours. Most of the precipitate formed is dissolved by slurrying the reaction mixture in 300 ml of dichloromethane. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to give 9.2 g of N-n-octyl-D-glucamine | 120-122 ° C; δJD - 16.6 ° (dimethyl sulfoxide) J.

Preparation H

18 g of D-glucose, 18.5 g of n-dodecylamine and 1 g of Raney nickel in 140 ml of methanol and 40 ml of water are treated with 11.2 kg / cm2 of hydrogen at 60 [deg.] C. for 2 hours. The catalyst is removed from the solution by filtration. The solution is kept overnight at -10 ° C and the resulting precipitate (20.35 g) is collected by filtration. 10 g of precipitate 1 g of Raney nickel in 200 ml of methanol are treated overnight with hydrogen at 12.6 kg / cm2 at 60 ° C. The reduction with hydrogen is then continued for a further 3.5 hours at a pressure of 12.6 kg / cm2 and 105 ° C. The reaction mixture is heated to dissolve the precipitate formed and the mixture is filtered to remove the catalyst. The reaction mixture is cooled to room temperature, kept at this temperature for 2 hours and then filtered to give 4.59 g of N-n-dodecyl-D-glucamine. 122-125 ° C; [α] D -14.0 ° (dimethyl sulfoxide)].

Preparation I

18.0 g of glucose and 27.0 g of n-octadecylamine are stirred in 500 ml of 13,657,773 methanol for about 60 hours. The precipitate formed is collected, washed with 250 ml of methanol and then dried in vacuo (low stream of nitrogen) at about 53 [deg.] C. to recover 39.5 g of product. 2.0 g of product and 0.5 g of 5% palladium on carbon are mixed in 200 ml of isopropanol and treated with hydrogen (21 kg / cm2) overnight at 50 ° C. The precipitate formed is dissolved by heating the solvent. The catalyst is removed from the reaction mixture by filtration through celite. The filtrate is cooled to give 1.5 g of N-n-octadecyl-D-glucamine (m.p. 124-126 ° C). 0.4 g of the latter is dissolved in 20 ml of hot isopropanol, filtered and cooled to give 0.36 g of pure N-n-octa-decyl-D-glucamine mp · 123-126 ° C; 8 * JD - 10.6 ° (pyridine) J.

Preparation J

18.0 g of glucose and 10.1 g of n-hexylamine are stirred at room temperature for about 60 hours in 145 ml of methanol. 1.0 g of 5% palladium on carbon is stirred into the reaction mixture and the mixture is treated with hydrogen (7 kg / cm 2) overnight at 45-50 ° C. The precipitate formed is collected and redissolved in 200 ml of methanol. The catalyst is removed by filtration through celite and the filtrate is cooled to give 15.03 g of N-n-hexyl-D-glucamine precipitate | 125-126 ° C? C <-DJD -18.6 ° (dimethyl sulfoxide) J.

The following examples illustrate the invention and its implementation in more detail.

Example 1 4.60 gd, 12- (6-methoxy-2-naphthylpropionic acid and 1.01 g of triethylamine (0.5 equivalents) in 35 ml of isopropanol are heated close to the solvent reflux temperature d, 1-2- ( To dissolve 6-methoxy-2-naphthyl) propionic acid, 2.09 g of N-ethyl-D-glucamine (0.5 equivalents) are added and the solution is cooled to room temperature (i.e. about 20-23 ° C) to give 4 , 42 g of a substance enriched in the salt of d-2- (6-methoxy-2-naphthyl) propionic acid and N-ethyl-D-glucamine (mp 153-161 ° C), the sample being dissolved in about 25 ml about 80 ° C water, acidified with hydrochloric acid to precipitate the d-2- (6-methoxy-2-naphthyl) propionic acid from the solution and recover.

14 65773 by filtration (/ a / D + 27.7 ° (chloroform)).

1.00 g of the substance enriched in the d 2- (6-methoxy-2-propionic acid and N-ethyl-D-glucamine salt) are dissolved in a mixture of 19.5 ml of isopropanol and 1.5 ml of water at approximately the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.65 g of recrystallized salt (m.p. 167-169 ° C) This material is treated as described in the previous paragraph with hydrochloric acid to give a substance which is further enriched in d 2- (6-methoxy-2- naphthyl) propionic acid (α / D + 56.0 ° (chloroform)).

Example 2 4.60 gd of 1-2- (6-methoxy-2-naphthyl) propionic acid and 1.01 g of triethylamine (0.5 equivalents) in a mixture of 30 ml of isopropanol and 1.5 ml of water are heated near the reflux temperature of the solvent to dissolve d, 1-2- (6-methoxy-2-naphthyl) propionic acid. 2.09 g of N-ethyl-D-glucamine are added and the solution is cooled to room temperature to give 4.32 g of a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and N-ethyl-D-glucamine. salt (m.p. 149-156 ° C). A sample of the latter is dissolved in about 25 ml of water at about 80 ° C, treated with hydrochloric acid to give an acid enriched in the solution, which is enriched in d-2- (6-methoxy-2-naphthyl) propionic acid, and this material is recovered by filtration. ([α] D + 35.9 °).

1.00 g of the substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and N-ethyl-D-glucamine are dissolved at approximately the reflux temperature of the solvent * in a mixture of 20 ml of 5% aqueous isopropanol and 1.0 ml of water. The solution is cooled to room temperature to give 0.70 g of once recrystallized material (m.p. 167-168 ° C). From this, the sample is treated with hydrochloric acid as given in the previous paragraph to give a substance which is further enriched in d-2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 55.4 °).

15 65773 0.50 g of the material recrystallized once from the previous paragraph / m.p. substance »1 enriched in the salt of d-2- (6-methoxy-2-naphthyl) -propionic acid and the salt of N-ethyl-D-glucamine / is dissolved at approximately the reflux temperature of the solvent in a mixture of 10 ml of 5% aqueous isopropanol and 0 , 5 ml of water. The solution is cooled to room temperature to give 0.43 g of doubly recrystallized material (m.p. 169-170 ° C). A sample of the latter is treated with hydrochloric acid as described in the first paragraph of this example to give a substance which is even more enriched with respect to d-2- (6-methoxy-2-naphthyl) propionic acid ([ot / D + 62.0 °).

0.33 g of the doubly recrystallized material from the previous paragraph (i.e. a substance further enriched in the salt of d-2- (6-methoxy-2-naphthyl) propionic acid and N-ethyl-D-glucamine / is dissolved in substantially the solvent. at reflux to a mixture of 12 ml of 5% aqueous isopropanol and 1.0 ml of water, and the solution is cooled to room temperature to give 0.27 g of three times recrystallized material, the latter being treated with hydrochloric acid as described in the first paragraph of this example to give substantially pure d- 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 67.1 °).

Example 3 2.30 gd of 1-2- (6-methoxy-2-naphthyl) propionic acid and 0.5 g of triethylamine in 23 ml of denatured alcohol are heated close to the reflux temperature of the solvent d, 1- 2- (6-methoxy). 2-naphthyl) to dissolve propionic acid. 1.05 g of N-ethyl-D-glucamine are added and a small amount of d-2- (6-methoxy-2-naphthyl) propionic acid salt with N-ethyl-D-glucamine is inoculated into the solution, followed by cooling to room temperature. 1.95 g of material enriched in d-2- (6-methoxy-2-naphthyl) propionic acid and N-ethyl-D-glucamine salt are obtained (m.p. 157-160 ° C). A sample of the latter is dissolved in about 25 ml of water at about 80 ° C, the solution is acidified with hydrochloric acid to precipitate a substance enriched in d-2- (6-methoxy-2-naphthyl) propionic acid and collected by filtration (/ ot (D + 38.1 °).

16 65773 1.0 g of the substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-ethyl-D-glucamine is dissolved in 15 ml of denatured alcohol near the reflux temperature of the solvent. The solution is slowly cooled, inoculated with a small amount of the salt of 2- (6-methoxy-2-naphthyl) propionic acid with N-ethyl-D-glucamine.

It is then cooled to room temperature to give, after filtration, 0.65 g of material enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and N-ethyl-D-glucamine salt (m.p. 167-168 ° C). ). From the latter, the sample is dissolved in about 25 ml of water heated to about 80 ° C. The solution is treated as acidic with hydrochloric acid, whereupon a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid precipitates out of solution, which is recovered by filtration (o / D + 61.6 °).

Example 4 4.60 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 1.01 g of triethylamine (0.5 equivalents) in 35 ml of isopropanol are heated close to the reflux temperature of the solvent d, 1 2- (6 -methoxy-2-naphthyl) propionic acid. 2.23 g of N-propyl-D-clucamine (0.5 equivalents) are added and the solution is cooled to room temperature to give 4.68 g of 2- (6-methoxy-2-naphthyl) -propionic acid and Nn-propyl-D-clucamine. a substance enriched in glucamine salt (m.p. 173-175 ° C). A sample of the latter is dissolved in about 25 any water heated to about 80 ° C, the solution is acidified with hydrochloric acid to precipitate a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration (/ a (Q + 46.4 °).

1.00 g of the substance enriched in d- (6-methoxy-2-naphthyl) propionic acid and the salt of Nn-propyl-D-glucamine are dissolved in a mixture of 19.5 ml of isopropanol and 2.5 ml of water, close to the reflux temperature of the solvent. . The solution is cooled to room temperature to give 0.82 g of recrystallized salt (m.p.

180-181 ° C). This material is treated with hydrochloric acid as described in the previous paragraph to give substantially pure ‘2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 68.0 °).

17 65773

Example 5 4.60 gd of 1, 2- (6-methoxy-2-naphthyl) propionic acid and 1.01 g of triethylaminif (0.5 equivalents) in 35 ml of isopropanol are heated close to the reflux temperature of the solvent d, 1 2- (6-methoxy). To dissolve -2-naphthyl) propionic acid. 2.23 g of N-isopropyl-D-glucamine (0.5 equivalents) are added and the solution is cooled to room temperature to give 4.43 g of 2- (6-methoxy-2-naphthyl) propionic acid and N-iso- a substance enriched in the salt of propyl D-glucamine. A sample of the latter is dissolved in about 25 ml of water at about 80 ° C, the solution is acidified with hydrochloric acid to precipitate a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid, which is collected by filtration (/ a / D + 28 8 °).

1.00 g of the substance enriched in d- (6-methoxy-2-naphthyl) propionic acid and the salt of N-isopropyl-D-glucamine are dissolved in 21 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.85 g of recrystallized salt. This is treated with hydrochloric acid as described in the previous paragraph to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid (<VD + 42.7 °).

Example 6 4.60 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 1.01 g of triethylamine (0.5 equivalents) in a mixture of 30 ml of isopropanol and 1.5 ml of water are heated close to the reflux temperature of the solvent. d, 12 to dissolve 2- (6-methoxy-2-naphthyl) propionic acid. 2.23 g of N-isopropyl-D-glucamine are added and the solution is cooled to room temperature to give 4.38 g of 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-isopropyl-D-glucamine. enriched material (m.p. 146-148 ° C). A sample of the latter is dissolved in about 25 ml of water at about 80 degrees, the solution is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) -propionic acid, which is recovered by filtration (/ a / D + 26.9 °).

«18 65773 1.00 g of a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-isopropyl-D-glucaine are dissolved in 20% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.76 g of the first recrystallized material (m.p. 151-152 ° C). From this, a sample is dissolved in hydrochloric acid as described in the previous paragraph to give a substance which is further enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 43.0 °).

0.50 g of the first recrystallized material from the previous paragraph / m.p. a substance enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and N-isopropyl-D-glucamine / is dissolved in 10 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.43 g of a second recrystallized material (m.p. 153-154 ° C). The latter is treated with hydrochloric acid as described in the first paragraph of this example to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 53.2 °).

0.32 g of the second substance to be recrystallized from the previous paragraph / m.p. a substance which is even more enriched in respect of the salt of 2- (6-methoxy-2-naphthyl) propionic acid and N-isopropyl-D-glucamine /! is dissolved in 10 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.29 g of a third recrystallized material (i.e. 153-154 ° C). The latter is treated with hydrochloric acid as described in the first paragraph of this example to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid (/ a / D + 57.9 °).

Example 7 4.60 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 1.01 g of triethylamine (0.5 equivalents) in 18 ml of ethanol are heated close to the reflux temperature of the solvent d, 12- (6-methoxy). -2-naphthyl) propionic acid. 2.37 g of N-n-butyl-D-glucamine and a further 18 ml of ethanol are added. The solution is cooled to room temperature to give 4.28 g of d (2- (6-methoxy-2-naphthyl) propionic acid and 19 65773 of N-n-butyl-D-glucamine salt (m.p. 155-156 ° C). The latter is dissolved in 1.0 g of about 25 ml of water, which must be heated to about 80 ° C. The solution is treated with acidic acid, whereupon a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid precipitates out of solution, which is recovered by filtration (/ a / D + 27.4 °).

3.0 g of the substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-butyl-D-Glu-amine are dissolved in a mixture of 48 ml of ethanol and 1 ml of water near the reflux temperature of the solvent. The solution is cooled to room temperature to give 2.64 g of recrystallized salt (m.p. 157.5-158 ° C). The latter is treated with 1.0 g of hydrochloric acid as described in the previous paragraph to give substantially pure d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 65.8 °).

Example 8 0.28 g of potassium hydroxide is dissolved in 18 ml of methanol, followed by the addition of 2.30 g of d, 1,2- (6-methoxy-2-naphthyl) propionic acid and 1.18 g of N-n-butyl-D-glucamine. The methanol solution is heated close to the reflux temperature of the solvent to dissolve 2- (6-methoxy-2-naphthyl) propionic acid. The solution is slowly cooled, seeded with a small amount of the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and Nn-butyl-D-glucamine, followed by recooling to room temperature to give 1.18 g after filtration and washing. enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and Nn-butyl-D-glucamine salt. The latter is dissolved in 15 ml to give about 80 degrees water.

The solution is acidified with hydrochloric acid to precipitate 0.56 g of a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration (α / D + 56.8 °).

Example 9 2.30 g of d, 12- (6-methoxy-2-naphthyl) propionic acid and 0.50 g of triethylamine (0.5 equivalents) are dissolved in 25 ml of acetone. 1.19 g of N-n-butyl-D-glucamine are heated to 50 ° C in another 25 ml batch of acetone. N-n-butyl-D-glucamine is dissolved by adding 3.5 ml in 0.5 ml portions. A solution of nn-butyl-D-glucamine is added at 50 ° C and 65773 with stirring to a solution of 1,1'-2- (6-methoxy-2-naphthyl) propionic acid, followed by cooling to room temperature to give 1.83 g of 2- (6-methoxy). -2-naphthyl) propionic acid and Nn-butyl-D-glucamine salt (m.p. 157-158 ° C). From the latter, the sample is dissolved in about 25 ml of water at about 80 ° C. The solution is acidified with hydrochloric acid, whereupon a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid precipitates out of solution, which is recovered by filtration (/ a / D + 61.1 °).

Example 10 4.60 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 1.01 g of triethylamine (0.5 equivalents) in a mixture of 40 ml of isopropanol and 2.0 ml of water are heated to near the reflux temperature of the solvent to dissolve 2- (2- (6-methoxy-2-naphthyl) propionic acid. 2.37 g of N-iso-butyl-D-glucamine are added and the solution is cooled to room temperature to give 4.53 g of a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and N-iso-butyl. -D-glucamine salt (m.p. 150-152 ° C). From the latter, the sample is dissolved in about 25 ml of water at about 80 ° C. The solution is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration ([α] D + 30.2 °).

1.00 g of a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-iso-butyl-D-glucamine are dissolved in 20 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.85 g of the first recrystallized material (m.p. 154-156 ° C). From the latter, a sample is dissolved in hydrochloric acid as described in the previous paragraph to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 40.3 °).

0.80 g of the first reconstituted material from the previous paragraph / so. the substance enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and N-iso-butyl-D-glucamine / is dissolved in 16 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature 65773 21 to give 0.77 g of a second material to be recrystallized (m.p. 156-157 ° C). The latter is treated with hydrochloric acid as described in the first paragraph of this example to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 47.9 °).

0.67 g of the second material to be recrystallized from the previous paragraph / m.p. a substance which is even more enriched in the salt of d 2- (6-methoxy-naphthyl) propionic acid and N-iso-butyl-D-glucamine / is dissolved in a mixture of 16 ml of 5% aqueous isopropanol and 1.0 ml of water, near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.39 g of a third recrystallized material (m.p. 157-158 ° C). The latter is treated with hydrochloric acid as described in the first paragraph of this example to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid (+ ct / D + 54.3 °).

Example 11 2.60 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 0.50 g of triethylamine (0.5 equivalents) are heated in a mixture of 15 ml of isopropanol and 0.5 ml of water the reflux temperature of the solvent to dissolve d, 2- (6-methoxy-2-naphthyl) propionic acid.

When 1.32 g of N-cyclohexyl-D-glucamine (0.5 equivalents) is added to the heated solution, a precipitate immediately forms.

Add another 15 ml of isopropanol and 1.5 ml of water. The mixture is heated close to the reflux temperature of the solvent to dissolve the precipitate. The solution is cooled to room temperature to give 2.24 g of material enriched in d-2- (6-methoxy-2-naphthyl) propionic acid and N-cyclohexyl-D-glucamine salt (m.p. 157-158 ° C). From the latter, the sample is dissolved in about 25 ml of water at about 80 ° C. The solution is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration ([+] + 38.7 °).

1.00 g of a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-cyclohexyl-D-glucamine are dissolved in 20 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.779 g of the first recrystallized material (m.p. 159-160 ° C). From the latter, a sample is treated with hydrochloric acid as described in the previous paragraph to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid (/ ct / D + 51.7 °).

0.20 g of the first recrystallized material from the previous paragraph / m.p. the substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and N-cyclohexyl-D-glucamine salt / is dissolved in 4 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.18 g of a second material to be recrystallized (m.p. 160-161 ° C). The latter is treated with a sample of hydrochloric acid as described in the first paragraph of this example to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 60.3 °).

0.15 g of the second recrystallized material obtained from the previous paragraph / m.p. substance * which is even more enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and N-cyclohexyl-D-glucamine / is dissolved in 5 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.13 g of a third recrystallized material (m.p. 161-162 ° C). The latter is treated with hydrochloric acid as described in the first paragraph of this example to give essentially purified d 2- (6-methoxy-2-naphthyl) -propionic acid ([α] D + 65.5 °).

Example 12 4.60 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 1.01 g of triethylamine (0.5 equivalents) are heated in a mixture of 30 ml of isopropanol and 1.5 ml of water the reflux temperature of the solvent to dissolve 2- (2- (6-methoxy-2-naphthyl) propionic acid. 2.93 g of Nn-octyl-D-glucamine (0.5 equivalents) are added and the solution is cooled to room temperature to give 4.42 g of 2- (6-methoxy-2-naphthyl) propionic acid and Nn-octyl-D-glucamine. salt-enriched material (m.p. 139-140 ° C). From the latter, the sample is dissolved in about 25 ml of water at about 80 ° C. The solution is acidified with hydrochloric acid to precipitate a substance contaminated with 2- (6-methoxy-23,677,73-2-naphthyl) propionic acid, which is recovered by filtration ([α] D + 54.8 °).

1.00 g of a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-octyl-D-glucamine are dissolved in a mixture of 9.5 ml of isopropanol and 0.5 ml of water, close to the reflux temperature of solvent t. The solution is cooled to room temperature to give 0.85 g of recrystallized salt (m.p. 140-141 ° C).

This material is treated with hydrochloric acid as described in the previous paragraph to give substantially pure d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 65.8 °).

Example 13 0.10 g of the material obtained from the first paragraph of Example 12 enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and the salt of Nn-octyl-D-glucamine and 0.3 g of potassium hydroxide are stirred for 1 hour at room temperature. at 25 ml in water. The precipitate is removed by filtration. The filtrate is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration (/ α / β + 55.3 °).

Example 14 2.30 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 0.50 g of triethylamine (0.5 equivalents) in 30 ml of ethylene glycol are heated to 90 DEG C. To dissolve (6-methoxy-2-naphthyl) propionic acid. 1.47 g of N-n-octyl-D-glucamine are added and then the solution is cooled to 40 ° C and seeded with crystals of 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-octyl-D-glucamine. The reaction mixture is stirred overnight at room temperature to give 1.47 g of a substance enriched in d-2-methoxy-2-naphthyl) propionic acid and the salt of N-n-octyl-D-glucamine (m.p. 115-122 ° C). A sample of the latter is dissolved in about 25 ml of water at about 80 ° C. The solution is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration ([α] D + 65.5 °).

24

Example 15 65773 2.30 gd, l 2- (6-methoxy-2-naphthyl) propionic acid and 0.50 g of triethylamine (0/5 equivalent) are heated in a mixture of 15 ml of isopropanol and 0.75 ml of water, near the reflux temperature of the solvent to dissolve 2- (6-methoxy-2-naphthyl) propionic acid. 1.75 g of Nn-dodecyl-D-glucamine (0.5 equivalents) are added and the solution is cooled to room temperature to give 2.50 g of 2- (6-methoxy-2-naphthyl) propionic acid and Nn-dodecyl-D-glucamine. enriched in salt (m.p. 133-135 ° C). Of the latter, a sample of about 25 in any room temperature water is suspended in the presence of 300 mg of potassium hydroxide, and the suspension is kept at this temperature for 60 minutes. The precipitate is removed by filtration. The filtrate is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration ([α] D + 56.1 °).

1.00 g of a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and the N-n-dodecyl-D-glucamine salt are dissolved in 20 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.88 g of the first recrystallized material (mp 135-137 ° C). A sample of the latter is treated with potassium hydroxide followed by hydrochloric acid as described in the previous paragraph to give a substance which is also enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 58.9 °).

0.62 g of the first recrystallized material from the previous paragraph / m.p. a substance which is also enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and N-n-dodecyl-D-glucamine / is dissolved in 15 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.59 g of a second recrystallized material (m.p. 135-137 ° C).

0.51 g of the second recrystallized material obtained from the previous paragraph / m.p. a substance further enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and N-n-dodecyl-D-glucamine / is dissolved in 10 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature 65773 to give 0.43 g of a third recrystallized material (m.p. 135-137 ° C). The latter is treated with potassium hydroxide followed by hydrochloric acid as described in the first paragraph of this example to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid (/ ot / D + 67.5 °). .

Example 16 1.15 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 0.25 g of triethylamine (0.5 equivalents) are heated in 10 ml of isopropanol near the reflux temperature of the solvent d, 12- (6 -methoxy-2-naphthyl) -propionic acid. 1.09 g of Nn-octadecyl-D-glucamine (0.5 equivalents) are added and the solution is filtered hot to remove slight turbidity, cooled slightly and then seeded with a small amount of 2- (6-methoxy-2-naphthyl) propionic acid and Nn -octadecyl-D-glucamine salt. It is then cooled to room temperature to give 1.55 g of a substance enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and N-n-octadecyl-D-glucamine (m.p. 123-127 ° C). From the latter, a sample of about 25 in any room temperature water is suspended in the presence of 300 mg of potassium hydroxide, and the suspension is kept at this temperature for 60 minutes. The precipitate is removed by filtration. The filtrate is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration (/ α / β + 57.9 °).

1.0 g of the substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-octadecyl-D-glucamine is stirred in 10 ml of isopropanol at the reflux temperature of the solvent. The solution is cooled to room temperature over 2 hours to give 0.95 g of the first recrystallized material (m.p. 129-130 ° C). The latter is treated with a sample of potassium hydroxide followed by hydrochloric acid as described in the previous paragraph to give a substance which is even more enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 68.1 °).

26

Example 17 65773 100 mg of the sodium salt of d, l 2- (6-methoxy-2-naphthyl) propionic acid and 100 mg of the hydrochloride salt of N-butyl-D-glucamine are heated in 2 ml of 5% aqueous isopropanol near the reflux temperature of the solvent. The reaction mixture is slowly cooled, seeded with a small amount of d 2- (6-methoxy-2-naphthyl) propionic acid and Nn-butyl-D-glucamine salt and re-cooled to room temperature to give 1.10 g of 2- (6 -methoxy-2-naphthyl) propionic acid and Nn-butyl-D-glucamine salt (m.p. 143-145 ° C). From the latter, a sample is dissolved in water and acidified with hydrochloric acid to precipitate a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration (/ a / D + 54.9 °).

Example 18

The following table gives the solubilities of d 2- (6-methoxy-2-naphthyl) propionic acid and 1 2- (6-methoxy-2-naphthyl) propionic acid and diastereoisomeric salt pairs of various N-R-D-glucamines in methanol at room temperature and reflux temperature:

table 1

Solubility in methanol (g / 100 ml solvent) d 2- (6-methoxy-2-naphth-12- (6-methoxy-2-naphthyl) propionic acid style) propionic acid with NRD-glucamine NRD-glucamine _R_23 ° C reflux lt._23 ° C reflux lt.

ethyl 0.83 5.1 n-propyl 0.31 1.7 6.8 iso-propyl 2.3 6.4 6.7 95 n-butyl 1.3 9.2 5.0 90 iso-butyl 1, 2 10.8 cyclohexyl 2.1 23.1 n-octyl 1.8 21.1 21.7 n-dodecyl 0.32 8.7

Example 19 65 77 3 27 2.30 gd, 2- (6-methoxy-2-naphthyl) propionic acid and 0.45 g of triethylamine (0.45 equivalents) are heated in a mixture of 40 ml of isopropanol and 1.0 ml of ml of water, to about 80 ° C to dissolve d, l 2- (6-methoxy-2-naphthyl) propionic acid. 1.46 g of Nn-hexyl-D-glucamine (0.55 equivalents) are added and the solution is cooled to room temperature to give 2.48 g of 2- (6-methoxy-2-naphthyl) propionic acid and Nn-hexyl-D-glucamine. salt-enriched material (m.p. 131-132 ° C). From the latter, a sample of about 25 is suspended in any room temperature water, acidified with hydrochloric acid and stirred at this temperature for about 60 minutes. The resulting bag, enriched in d 2- (6-methoxy-2-naphthyl) -propionic acid, is collected by filtration (/ α / β + 37.2 °).

1.00 g of a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-hexyl-D-glucamine are dissolved in 10 ml of 5% isopropanol near the reflux temperature of the solvent. The solution is cooled to room temperature to give 0.75 g of the first recrystallized salt (m.p. 130-131 ° C). This material is treated with hydrochloric acid as described in the previous paragraph to give substantially pure d 2- (6-methoxy-2-naphthyl) -propionic acid (± 6.2 °).

Example 20 1.00 g of the material obtained from the first paragraph of Example 19 enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-hexyl-D-glucamine are suspended in 10 ml of water. 0.15 g of potassium hydroxide is added and then the mixture is stirred at room temperature for 1.5 inches. The precipitate obtained is collected, washed with 5 ml of water and dried to give 0.38 g of N-n-hexyl-D-glucamine (m.p. 124-126 ° C). D 2- (6-methoxy-2-naphthyl) propionic acid is recovered from the filtrate by treatment with hydrochloric acid as described in the first paragraph of Example 19.

28 65773

Example 21 1.00 g of the substance obtained from the first paragraph of Example 19 enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-hexyl-D-glucamine are suspended in 8 ml of water. 0.15 g of potassium hydroxide is added and the mixture is stirred at room temperature for 45 minutes. The precipitate obtained is collected, washed with 2 ml of water and dried in vacuo (weak stream of nitrogen) at 45 [deg.] C. to give 0.47 g of N-n-hexyl-D-glucamine (m.p. 122-124 ° C). D 2- (6-methoxy-2-naphthyl) propionic acid is recovered from the filtrate by treatment with hydrochloric acid as described in the first paragraph of Example 19.

Example 22 2.30 gd of 12- (6-methoxy-2-naphthyl) propionic acid and 1.46 g of Nn-hexyl-D-glucamine (0.55 equivalents) in 15 ml of water are heated to about 80 ° C . 0.17 g of potassium hydroxide (0.45 equivalents) is added and the pH of the solution is adjusted to 8 with potassium carbonate.

The solution is inoculated with a small amount of the salt of 2- (6-methoxy-2-naphthyl) propionic acid and Nn-hexyl-D-glucamine and cooled to give 1.25 g of 2- (6-methoxy-2-naphthyl) propionic acid and Nn- hexyl-D-glucamine salt-enriched substance (m.p.

125-127 ° C).

Example 23 4.60 gd, 12- (6-methoxy-2-naphthyl) propionic acid and 0.91 g of triethylamine (0.45 equivalents) in 60 ml of isopropanol are heated close to the reflux temperature of the solvent d, l 2- (6 -methoxy-2-naphthyl) to dissolve propionic acid. 3.22 g of N-n-octyl-D-glucamine (0.55 equivalents) are added. The solution is cooled slightly and then seeded with a small amount of a salt of 2- (6-methoxy-2-naphthyl) propionic acid and N-n-octyl-D-glucamine to give a precipitate. The reaction mixture is kept at 60 [deg.] C. for 1.5 hours, then cooled to room temperature overnight and washed with 20 ml of isopropanol.

4.9 g of a substance enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and N-n-octyl-D-glucamine are obtained (m.p.

138-139 ° C). The latter is suspended in about 25 ml of room temperature water in the presence of 300 mg of potassium hydroxide.

29 65773

The suspension is kept at this temperature for about 60 minutes. The precipitate obtained is removed by filtration. The filtrate is acidified with hydrochloric acid to precipitate a substance enriched in d-72- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration (/ a / D + 64.3 °).

Example 24 4.60 gd of 2- (6-methoxy-2-naphthyl) propionic acid is slurried at 70 ° C for 10 minutes in a mixture of 25 ml of water and 0.60 g of potassium hydroxide (0.55 equivalents). . 3.22 g of N-n-octyl-D-glucamine (0.55 equivalents) are added and the solution is slowly cooled to 50 ° C. A small amount of the salt of d 2- (6-methoxy-2-naphthyl) propionic acid and Nn-octyl-D-glucamine is added and the solution is cooled overnight while stirring to room temperature to give 4.0 g of 2- (6 -methoxy-2-naphthyl) propionic acid and Nn-octyl-D-glucamine salt (m.p. 138-140 ° C). From the latter, the sample is suspended in about 25 ml of room temperature water in the presence of 300 mg of potassium hydroxide. The suspension is kept at this temperature for about 60 minutes. The precipitate obtained is removed by filtration. The filtrate is acidified with hydrochloric acid to precipitate a substance enriched in 2- (6-methoxy-2-naphthyl) -propionic acid, which is recovered by filtration ([α] D + 62.9 °).

Example 25

The procedure of Example 24 is repeated using 20 ml of water to give 0.45 g of a substance enriched in the salt of 2- (6-methoxy-2-naphthyl) propionic acid and N-n-octyl-D-glucamine (m.p. 138-140 ° C). The latter is treated with potassium hydroxide followed by hydrochloric acid as described in Example 24 to give a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid (/ α / β + 65.1 °).

Example 26

Repeat Examples 1) 24 using 15 ml of water to give 4.45 g of a substance enriched in 2- (6-methoxy-2-naphthyl) propionic acid and the salt of Nn-octyl-D-glucamine (m.p. 138-3065773 140 ° C). ). The latter is treated with potassium hydroxide followed by hydrochloric acid as described in Example 24 to give a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid ([α] D + 63.5 °).

Example 27 44.5 g of a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and N-n-octyl-D-glucamine are treated with 6.2 g of a volume of potassium hydroxide in 445 ml of water. The reaction mixture is stirred for 2 hours at 46 ° C, after which it is slowly cooled to 36 ° C over 1 hour with stirring. The reaction mixture is maintained at this temperature for about 60 hours.

The precipitate obtained is collected by filtration and washed with 150 ml of water to give 24.6 g (99% of theory) of N-n-octyl-D-glucamine (m.p. 121-123 ° C).

The filtrate is treated with 12 ml of concentrated hydrochloric acid to give a fine thick precipitate. This precipitate is aged with stirring with 350 ml of water, then filtered, washed with water and dried at 45 ° C to give 19.4 g (99% of theory) of d 2- (6-methoxy-2-naphthyl) propionic acid. (mp 147-150 ° C).

Example 28 2.30 gd, 12 2- (6-methoxy-2-naphthyl) propionic acid is heated in a mixture of 27.3 ml of isopropanol and 2.7 ml of water to near the reflux of the solvent at a temperature of d, 2- (6-methoxy). -2-naphthyl) propionic acid. 2.93 g of N-n-octyl-D-glucamine (1.0 equivalent) are added and the solution is cooled to room temperature. Wash with 2 mL of aqueous isopropanol to give 2.57 g of a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid and the salt of N-n-octyl-D-glucamine (m.p. 138.5-140 ° C). From the latter, the sample is suspended in about 25 ml of room temperature water in the presence of 300 mg of potassium hydroxide. The suspension is kept at this temperature for about 60 minutes. The precipitate obtained is removed by filtration. The filtrate is acidified with hydrochloric acid to precipitate a substance enriched in d 2- (6-methoxy-2-naphthyl) propionic acid, which is recovered by filtration (± D + 61.7 °).

Example 29 31 65773 2.0 kg of d, l 2- (6-methoxy-2-naphthyl) propionic acid are added to a mixture of 9.08 l of methanol and 0.92 l of toluene. This mixture is heated to 55 ° C and 2.54 kg of N-n-octyl-D-glucamine are added. The slurry is heated to reflux, at which temperature all solids dissolve. The mixture is cooled to 56 [deg.] C. and 2.5 g of the salt of 2- (6-methoxy-2-naphthyl) propionic acid and N-n-octyl-D-glucamine are added. The slurry is kept at 55-56 ° C for 1 hour, then cooled to 25 ° C at a cooling rate of 10 ° C / hour. By filtration, the salt of 2- (6-methoxy-2-naphthyl) propionic acid and N-n-octyl-D-glucamine is recovered as a wet cake weighing 2.0 kg and washed with 6.0 liters of methanol. The wet cake from the previous step is added to a mixture of 1.0 L of water and 0.25 L of hexane. The wet cake from the previous step is added to a mixture of 1.0 L of water and 0.25 L of hexane and the solution is heated to 50 ° C. 300 g of potassium hydroxide are added and the mixture is kept at 50 [deg.] C. for 1 hour. The lifete is cooled to 25 ° C at a rate of 10 ° C / hour. The precipitated N-n-octyl-D-glucamine is filtered off, washed with 3 l of water and dried (yield: 1.11 kg).

The combined filtrate and washings from the previous step are added to a mixture of 100 ml of toluene and 420 ml of concentrated hydrochloric acid (less than 1.0 nH). The slurry is heated to 70 ° C, aged for 1 hour and cooled to 25 ° C at a rate of 10 ° C / hour. The precipitated 2- (6-methoxy-2-naphthyl) propionic acid is collected by filtration and washed with 2.0 l of water. This material is so pure that it is not necessary to recrystallize it to increase the optical purity.

d 2- (6-methoxy-2-naphthyl) propionic acid is dissolved in 4.40 liters of acetone and 22.5 g of carbon are added. The solution is stirred for 1 hour, then filtered. The filtrate is washed with 2.0 liters of acetone. The combined filtrate and washings are concentrated under reduced pressure to about 1.0 liter and 60 ml of concentrated hydrochloric acid in 400 ml of water are added. An additional 5.3 L of water is then added. The slurry is aged for 1 hour at 20 ° C and the precipitated d 2- (6-methoxy-2-naphthyl) propionic acid is collected by filtration, washed with 5.0 l of water and dried (yield 838.0 g; 41.9 w / w). % by weight based on the addition of d '2- (6-methoxy-2-naphthyl) -propionic acid (mp 153.5-156.0 ° C; [α] D + 66.6 °). The sole purpose of this recrystallization is to remove any excess insoluble matter and to improve the color of the precipitated product.

The filtrates and washings from the previous step are combined and distilled to 5.5 liters. Distillation is continued by adding water to keep the volume at 5.5 liters. When all the methanol has been distilled off, 1 l of water is added, followed by 334 g of potassium hydroxide. The mixture is cooled to 60 ° C and seeded with a small amount of N-n-octyl-D-glucamine, followed by cooling to 25 ° C. The precipitated N-n-octyl-D-glucamine is collected by filtration, washed with 1 liter of water and then a second time with 4 liters of water. It is then dried (yield: 1.31 kg). The total amount of N-n-octyl-D-glucamine recovered (i.e., at this point and from the step in the second paragraph of this example) is 2.42 kg (95.2%).

431 g of potassium hydroxide are added to the combined filtrates of the previous step and the first washing solution, and the mixture is heated to 130 ° C. The solution is cooled to 50 ° C at 2.1 kg / cm 3 over 3 hours. 130 ml of toluene are added, followed by 1.4 l of concentrated hydrochloric acid. The slurry is heated to 80 ° C, aged for 1 hour at this temperature and cooled to 25 ° C at a rate of 10 ° C / hour. The precipitated d, 1,2- (6-methoxy-2-naphthyl) propionic acid is collected by filtration, washed with 10 liters of water and dried (yield: 1122 g (56.1%)).

Claims (1)

A process according to claim 1 of Finnish Patent 64,796 for the separation of d-2- (6-methoxy-2-naphthyl) propionic acid in the form of the free acid or its N-alkyl-glucamine salt or a pharmaceutically acceptable salt thereof, d- and 1-2 - A mixture of (6-methoxy-2-naphthyl) -propionic acid or its salts, characterized in that (a) d- and 1-2- (6-methoxy-2-naphthyl) -propionic acid or its salt and NRD glucamine are heated, in which R is an alkyl group having 2 to 18 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, or a mixture thereof, and optionally an organic or inorganic base in an inert solvent at an elevated temperature to form a glucamine salt of d- and 1-2- (6-methoxy-2-naphthyl) propionic acid; and (b) crystallizing the glucamine salt of d-2- (6-methoxy-2-naphthyl) propionic acid by cooling the heated mixture; and optionally (c) cleaving the d-acid salt with an acid or base to liberate the d-acid and crystallizing the d-acid; and optionally (d) converting said d-acid to a pharmaceutically acceptable salt.