SI7911736A8 - Process for separation of (+) and (-)-6-methoxy-alpha-methyl-2-naphtaleneacetic acid and its salts - Google Patents

Description

D-2- (6-methoxy-2-yl) propionic acid / is an effective antiflogist / analgesic / antipyretic #.

According to Germany, Report 2,039,602, for example, is obtained from racemates by selective biological degradation or by making diastereoisomeric salts of 6-methoxy-α-methyl-2-naphthalenesacetic acid with a decomposed, optically active amine base such as cinchonidine, and then separating the resulting diastereoisers fractions by ion crystallization.

The military diastereoisomeric salts are then hydrolyzed with strong acids to give the corresponding (+) - or (-) -6-methoxy-amethyl-2-naphthalenesacetic acid.

The racemate of 6-methoxy-α-methyl-2-naphthalic acid cannot be decomposed by spontaneous separation and preferential selective crystallization of one of the enantiomers.

In addition to cinchonidine, the following compounds have been proposed, among others, in German Applications 2,007,177 and 2,008,272 as optically active amine bases for the separation phase: naturally occurring alkaloids, anabazine, brucine, conesin, cinchonioln, cinchonin, D-deoxyiefedrine, L-efoxifedrin, L , epichinine, morphine, quinidine, hlinin, strychnine, dehydroabietilamine and solanidine as well as cholesterylamine, D-men ti lamin, glucosamine, such primary, secondary and tertiary amines as L-2-amino-l-propanol, L-2 -amino-butanol, D-2-aminobutanol, D-threo-2-amino-β-nitrophenyl-1,3-propanediol, D-amphetamine, L-2-benzylamino-1-propanol, D-4-dimethylamino-1 , 2-di-enyl-3-methyl-2-butanol, Do- (1-naphthyl) ethylamine, L-α- (1-naphthyl) -ethylamine, Da-methylbenzylamine and L-amethylbenzylamine.

The alkaloids cinchonidine, dehydroabietilamine and hlinin are preferred according to German Applications 1,934,460, 2,013,641, 2,007,177, 2,005,454, 2,008,272 1 2,039,602.

Other alkaloids and bases are mentioned in Example 7 of German Application 2,007,177 and in Example 3 of German Application 2,008,272.

Germany 2,005,454 Protects pharmaceutically acceptable salts of 6-methoxy-a-methyl-2-naphthaleneacetic acid suitable for the treatment and alleviation of inflammation, fever,

etc. Among the salts that are widely protected but not described de mel j are the N-methyl-D-glucamine salts. N-Methyl-O-glucamine salt of (+) 6-methoxy- _e -raethyl-2-naphthalenic acid is mentioned in Example 26 of German Application 2,005,454 as a possible end product. This salt is made by reacting (+) - 6-methoxy- _e- methyl-2-naphthalenic acid with N-methyl-D-glucamine. However, the N-methyl-D-glucamine salts of the racemic mixture of 6-methoxy-α-methyl2-naphthalenic acid have not been described previously.

Asymmetric bases with the structure of carbohydrates are generally known as decomposers (c £. NL Allinger and EL Eliel, Topic in Stereochemistry, Vol. 6, WileaInterscience, Nev. 1971 Chapter: Resolving Agent and Reeolution in Organic Chemiatry by SH Milen; and SH Milen, Tabes of Resolving Agent and Optical Resolutions, Edited by EL Eliel, 1972, Uhiversity of Notre Dame Press) and, prior to the present invention, were considered ineligible for this purpose.

Germany Application 2,007,177 proposed glucosamine for the decomposition of 6-methoxy - «- methylnaphthaleneir <acetic acid. However, it does not contain a specific example.

Glucosamine (2-amino-2-deoxy-D-glucose) is very difficult to synthesize, can be obtained practically only from chitin and is relatively unstable. The solubility of its salts with (+) .- and (-) - A (where A is 6-methoxy-e-methyl-2naphthalic acid) was determined to explain the suitability of this material as a decomposition agent (Table 1).

Table 1

The solubility of glucosamine salts

Solvent So (+, A with D-glu- So (-) A with D-glucosamine Cosaminosis · 38.95 ° / a / * ° - 37.41 °

m.p. · 60-63 ° C (dec.) mp · 90-100¾ (dec. 20 ° C boiling point 20¾ boiling point

b ₂ 0 nerast. dec. 1 break · CE ^ OH 50 dec. 3.3 coll. C ₂ H ₅ OR, 95 » 2.5 dec. 1 rasp. C ₂ Hg * H abs. 1 dec. 1 rasp.

Table 1 shows that the undesirable isomer, i.e., the ·, (-) A form, could perhaps be isolated by the use of a glucosamine salt. Even at temperatures as low as 40 ° C, which are unfavorable in practice, glucosamine salts are unstable as they decompose. This makes it difficult to make, isolate and possibly regenerate. In fact, from a cosertional atanos, glucosamine is inappropriate as a decomposition agent for mixtures of (+) - and (-) - 6 ^ -methoxy-2-methyl-2-acetic acid, which supports the view that asymmetric bases with a carbohydrate structure very poor means of decomposition.

Unexpectedly, Nmethyl-D-glucamine has been found to be commercially suitable for the decomposition of (+) - and (-) - 6-methoxy-methyl-2-naphthalene acetic acid mixtures into their enantiomers.

The present invention is therefore a process for decomposing mixtures of (♦) - and (-) - 6-methoxy-α-methyl-2-naphthalenic acid,

111 of its soluble salts, into its enantiomers, characterized in that N-Rethyl ethyl-O-glucamine (-1-deoxy-1- (methylamino) D-gluchitol), 111 its salt, is used as a disintegrant.

For this purpose, the mixture of (+) - and (-, - 6-methoxy-a-methyl-2naphthalen ir of the acid acid is reacted with N-methyl-D-glucamine and the resulting pair of salts (+) - and (-) - 6- methoxy-α-methyl-2-naphthalenesacetic acid with N-methyl-D-glucamine undergoes fractional crystallization and.

Alternatively, the soluble salts of (+) - and (-) - 6-methoxy-methyl-2-naphthalenesacetic acid can be decomposed with the corresponding salts of N-methyl-D-glucamine.

The resulting salts of (+) - and (-) - 6-methoxy-a-methyl-2-naphthalenesacetic acid with N-methyl-D-glucamine are broken down by pyoidinafino acid cleavage, for example, with a mineral acid, where acid is deposited , or by breaking with the bases and then acidifying them to form the free acids. Selective (+) - can be obtained in fillet form.

Then, using known methods, the (-) - form is rheoemized and N-methyl-D-glucamine is isolated from acidic mother liquors.

It has been noted that the salts of the N-methyl-D-glucamyl / 1-deoxy-1- (methylamino) -D-glucitol / s (+) - and (-) - 6methoxy-a-methyl-2-naphthalenesetricone active base salt acid has extremely large solubility differences, which is ideal for separating diastereoisomers. The desired (+) -6-methoxy-α-raethyl-2-naphthalenic acid with N-methyl-D-glucamine is much less soluble than the corresponding salt of (-) - 6-methoxy-α-methyl- 2n Phthalicacetic acid and so can be easily obtained by cu fillet form. The decomposition of the vapors of diastereoisomeric pairs ^: - 6 - - / salts of (+) - and (-) - 6-methoxy-o-methyl-2-naphthalenic acid with N-methyl-D-gluamine in various solvents have been established in Table 2 where λ is as defined above.

Table 2

Solubilities of N-Rethyl-D-glucamine salts

Solvent Sal (+) A with N-methyl- So (-) A with N-methyl- D-glucamine D-glucamine 20 ° C temp. key. 20¾ temp. key. h ₂ o 25 100 70 100 ch ₃ oh 1.3 6.5 18 100 (CH2) ₂ CH0H 0.02 0.16 ¹ 0.16 1.7 ¹

on reflux

The solubility differences are highly emphasized by Sak and in water, which was not the case for makoji from other studied pairs.

The solubility differences in cold 1 hot methanol are significant. They are 1.3: 18 (1:14) at room temperature r

and 6.5: 100 (1: 15.4) at boiling point, and favor the isolation of the desired Isomer (+) A form. This favorable condition and the higher absolute value of the solubility of salt (-) A with Nmethyl-D-glucamine allow economical separation with minimal solvent consumption and maximum decomposition effect, i.e., with the highest Som optical purity of the desired product and at the same time in high yield.

The use of N-methyl-o-glucamine with the decomposition of 6 N -methoxy-methyl-2-naphthalenesartic acid is appropriate for the additional reason that N-methyl-D-glucamine is a very readily available reduction in cm D-glucose (grape shader), which not expensive and affordable

- - ί is in unlimited quantities, in the presence of methylamine.

The decomposition of the present invention is carried out in an inert organic solvent having a marked difference between the solubility of the (+) - 6-methoxy-α-raethyl-2-naphthalenic acid acetic acid salt of N, N-methyl-D-glucosamin and the salt (-) - 6- methoxy ia-methyl 1-2-naphthalic acid with N-methyl-O-glucamine, quenched at temperatures between room temperature 111 at an elevated temperature 1, quenched to a reflux temperature of a buffer solvent. Salt (+) - € -methoxy-a-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine should be significantly less soluble in the solvent than the salt of (-) - 6-methoxy-e-methylβ-naphthalene of acetic acid with N-methyl-O-glucamine and, therefore, after cooling the heated solution to an approximately ordinary or ambient temperature, such a salt of (+) - 6-methoxy-a-methyl-2naphthaleneacetic acid with N-methyl-O-glucamine if the preferences crystallize clearly. Suitable solvents include C 1 to monohydroxyl alcohols, such as, for example, methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, cyclohexanol, 2-ethylhexanol, benzyl alcohol, furfuryl alcohol and the like, C ₂ to C _g dlhydroxyl alcohols , such as, for example, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol and the like, up to trihydroxyl alcohols, such as, for example, glycerol and the like, C ₃ to ketones, such as, for example, acetone , acetylaoetone, ethylmethylketone, diethylketone, di-n-propylketone, diisopropylketone, diisobutylketone and the like. Other solvents include mono- and dl (lower) alkylether of ethylene glycol 1 dlethenyl glycol, dimethylformamide, sulfolanes, formamide, dimethylsulfoxide, N-methylpyrrolidone, pyridine, dioxane, dimethylacetamide and the like. Cj to C ₃

-5 alcohols, for example, methanol 1 Isopropanol, especially methanol, solvents currently desired. Enough water can be added to the solvent to dissolve any added materials.

The starting material, i.e., a mixture of (+) - € -methoxy-e-methyl-2naphthalic acid and (-) - 6 "methoxy-α-methyl-2-naphthalenic acid / is heated at elevated temperature, generally at a temperature in the range of about 60 ° C to about 100 ° C, or to the reflux temperature of the solvent, in the presence of N-methyl-D-glucamene so that all the materials but which have been added to the solvent are dissolved. If necessary, the solvent ae may be kept at elevated temperature until all the materials have gone into solution. As the solution is kept at elevated temperature for the desired period of time, it is slightly cooled to ordinary temperature.

During the cooling process, the solution is preferably pelleted with (N) -6-methoxy-α-methyl-2-naphthalenic acid acid salt with N-methyl-D-glucamine. The resulting crystalline precipitate was enriched with aa salt of (+) - 6-methoxy-α-methyl-2-naphthalenic acid with N-methyl-D-glucamine. The final temperature at which the solution is taken is chosen on the basis of practical considerations but is generally chosen so that the temperature difference will be sufficient to ensure a high crystal yield. The crystalline lust can be maintained at a lower temperature until crystallization is complete, 111 almost complete, usually from about 30 minutes to about several hours 111 like. The crystalline precipitate which is removed removes the ee by filtration of 1 wash.

The crystalline material obtained at this stage in the process (i.e., the material enriched with (+) - 6methoxy * ethyl-2-naphthalenic acid salt with N-methyl-Dglucamine), after separation by filtration and evaporation, may be add to water and heat, as necessary, to reconstitute the solution

ο. 9 crystalline material. The resulting solution was acidified, for example, with a mineral acid, such as sulfuric acid or hydrochloric acid, or an organic acid such as sulfuric acid or p-toluenesulfonic acid, and the resulting crystalline precipitate was separated by trituration and washed with 1 dried. A white crystalline product substantially enriched with (+) - 6-methoxy-α-methyl-2-naphthalenesulfuric acid was obtained. Alternatively, the material with the salt (+) - 6-methoxy-oiaeti 1-2-naphthalenic acid with N-methyl-D-glucamine can be treated with a strong base, such as potassium hydroxide or other strong base having a pKa value of 10, so that the salt breaks down, followed by acidification with some strong acid such as hydrochloric acid or sulfuric acid or some organic acid such as the following acid, so I get it after filtration. rinsing and drying, a white crystalline product substantially enriched with (+) - 6-methoxy-e-methyl-2-naphthalenic acid.

Before re-dissolving the material enriched with (+) - 6-methoxy-? -Methyl-2-naphthalenic acid acid with N-methyl-D-glucamine and subsequently acidifying to give (+) - 6-methoxy-e-methyl- It is generally preferable to re-dissolve the enriched salt material in a still more soluble material, to warm the solution to the desired temperature, and then to dissolve the resulting solution with (+) - 6-methoxy-e-methyl-2 salt. -naphthalenesulfuric acid with N-methyl_D-glucamine, 1 to cool so that one or more new recrystallizations are carried out. All such recrystallizations further increase the ratio of the (+) -6methoxy-α-raethyl 2-naphthalineuric acid salt to N-methyl-D-glucamine in the recrystallized material. A product having an order of about 97-99% (+) - 6-methoxy-α-methyl-2-naphthalenesodic acid can be obtained with only one recrystallization phase before re-dissolving the resulting crystalline product 1 at a later acidification.

A material enriched with (-) - 6-methoxy-a-methyl-2-naphthalene-diacetic acid or its N-methyl-O-glucamine salt can be processed to isolate (-) - 6-methoxy-a-methyl-2- naphthalene is an acidic acid that can then be racemized according to the prior art to produce a material having a higher content of (+) - 6-methoxy-o-methyl-2-naphthalene-8-acetic acid. See, for example, Dyson o.S. Patent Mo. No. 3,686,183. This material may be recomposed 111 eamoetally or in combination with other mixtures of (+) - and (-) -6-methoxy-α-methyl-2-naphthaleneacetic acid, so that additional starting material is provided for the decomposition process of this invention.

The amount of N, N-methyl-D-glucamine used, on a molar basis, with respect to (+) - and (-) - 6 ^ netokei-e-methyl-2-naphthalenic acid, which decomposes / according to the present invention varies from about 50% and 100%. However, since only about 50% / on a molar basis with respect to (+) - and (-) -6-methoxy-amethyl-2-naphthalenesorbic acid which is decomposed / N ^ -methyl-Dglucamine is required for trimming its soluble salts with (+) - 6-methoxy-α-methyl-2-naphthalenic acid, the residue of N-methyl-D-glucamine (generally up to about 40-50 molar%) can be replaced by, if necessary, an inexpensive base. including, for example, some inorganic base such as an alkali metal hydroxide, or some tertiary amine such as trie ti lamin, triethanolamine, tri-n-butylamine,

- η Aqueous mother liquors resulting from the isolation of oL · (+) - 6-methoxy-methyl-2-naphthalenic acid and (-) - 6methoxy-methyl-2-naphthalenic acid contain, for example, N-methyl- D-glucamine with an acid used in the acidification phase. Such mother liquors may be treated with a non-organic base to form an insoluble inorganic salt, leaving N-methyl-D-glucamine in solution, such as by treatment with a suspension of calcium hydroxide so as to precipitate the corresponding calcium salt. which is separated by filtration. The filtrate is concentrated in vacuo at elevated temperatures to dryness, removing any further salt, e.g., calcium salt, which is formed during the early stages of the concentration process. The residue is dissolved in a suitable solvent at elevated temperature up to the reflux temperature of the solvent, so as to obtain a decomposable crystalline precipitate, either alone or in combination with a new material, in the decomposition process of the present invention. Alternatively, N-methyl-D-glucamine can be regenerated for use as an anion exchange resin and recycled for reuse.

The terms mixture of (+) - 6-methoxy-methyl-2-naphthalenesacetic 4, acid and (-) - 6-methoxy-methyl-2-naphthalenesacetic acid are also intended to include its salts which are soluble in the solvent used. in the decomposition process of the present invention. Such salts include, for example, the corresponding sodium salts, potassium salts, lithium salts and the like. Such salts can be made by adding a base, such as an alkali metal hydroxide, for example, sodium or potassium hydroxide, to a solution of (+) - and (-) - 6-methoxymethyl-2-naphthalenesacetic acid. The resulting mixture (+) - and (-) - 6 *

- 12 Methoxy-α-methyl-2-naphthalenesacetic acid in the form of a salt can be decomposed according to the present invention by using a salt of a decomposing agent which will react to form the salt of (+) - 6-methoxy-α-methyl-2-naphthalic acid with Nmethyl-D-glucamine. Suitable salts of N-methyl-D-glucamine include, for example, the chlorhydrate salt and the acetate salt. Other salts include propionate salt, butlrate salt, isobutlate salt, sulfate salt, nitrate salt and the like. According to Torn, the term N-methyl-D-glucamine is intended to include those salts thereof which, when used with the corresponding salt of a mixture of (+) - and (-) -6-methoxy-araethyl-2-hydroxyacetic acid. perform the decomposition described here.

Examples

Example 1 (+) -6-roethoxy-α-methyl-2-naphthalenesulfonic N-methyl-o-glucan

460.7 g. racemic 6-raetoxy-α-methyl-2-naphthalenesacetic acid (2 moles) and 390.5 g N-methyl-D-glucamine / 1-deoxy1- (methylamino) -D-glucitol / (2 moles) were dissolved in 4 liters of boiling water. methanol.

The solution was filtered to be clear and cooled carefully to 45 ° C with gentle agitation. 1 g is now added. (+) - 6-Methoxy-methyl-2-naphthalenesulfonated N-methylHS-glucamine salt in the form of crystals (crystals were obtained in a preliminary test by cooling and rubbing with glass Staple filtration in vacuum 1 by washing with a little methanol). Massive crystallization of the (+) -6-methoxy-α-methyl-2-naphthalenesulfonated N-methyl-D-glucamine salt occurs immediately after plating. The temperature is held at 45 ^C hr and then is slowly SNIŽENO at 15 ° C.

—13 -

The precipitated crystals were filtered off and washed with a little methanol

Yield: 360 g. (+) - 6-Methoxy-α-methyl-2-naphthalinair <5etene

N-methyl-D-glucamine salts, i.e., 84% of theory.

Melting point: 156-158 ° C.

Specific rotation at 20 ° C) conc. lt in water

Wavelength λ 589 546 436 365 / ej [ ²⁰ o -18.59 -22.85 -42.53 -80.63

The resulting product (360 g) was redissolved in 4.4 liters of boiling methanol, filtered, slightly cooled, pelleted with authentic material, allowed to crystallize, cooled, filtered and washed.

Yield: 278 g. pure (+) - 6-methoxy-α-methyl-2-naphthalenesulfonate N-methyl-D-glucamine salts, i.e., 65% of theory.

Melting point: 169-161 ° C.

Specific rotation at 20 ° C) conc. «1% in water

Wavelength 1 589 546 436 365 / e / J ⁱⁿ o -20 -23.95 -44.83 -87.19

Microanalysis: ^C 21®31 ^ ° 8 ^: calc. C 59.28%) N 3.29% asl. C 59.58%) N 3.42%.

The mother liquors evaporate completely so that the ee regenerates methanol.

The evaporation residue was dissolved in water and dilute hydrochloric acid was added to acidify the solution.

Precipitation of (-) - 6-methoxy- * ^1- methyl-2-naphthalene-cheese acetic acid.

Quantity: 228 g. (-) - 6-Methoxy-N-methyl-2-naphthalenesacetic acid, i.e., 99.lt of theory.

Melting point: 145-146 ° C.

/ * / 2 ° «-45.8 ° (conc. 1% in chloroform) · (589) Optical purity: 67.15%

The product can be translated by racemization back into the racemate, i.e., the starting material, and then reused in further batches during the decomposition process.

Example 2

Reusing mother liquors

The methanol mother liquor can be used immediately before regeneration in further decomposition operations.

The decomposition operation as described in Example 1 is performed with the same quantities of starting material. However, instead of fresh methanol, the methanol mother liquor from the previous equal lot is used.

The first product obtained was:

431 g. (+) - 6-Ethoxy-d * methyl-2-naphthalene m.p. &apos; acid N-methyl-D-glucamine salt, i.e. 100% of theoretical.

Melting point: 155 * 158%.

Specific rotation at 20 ° Cj conc. «1% in water Wavelength X 589 546 436 365 o -18.52 -21.41 -40.5 -76.6

After recrystallization from 4.4 liters of fresh methanol, the product was:

- 15 326 g. (+) - C-Methoxy-α-raetyl-2-arylacetic acid N- (2-ethyl) -D-glucamine salt, i.e., 76% of theory.

Melting point »159-160 ° C.

Specific rotation at 20%; conc. “1% in water Wavelength λ 589 546 436 365 / / ²⁰ o -20.02 -24.12 -45.88 -88.41 λ

The decomposition of racemic 6-methoxy-α-methyl-2-naphthalenesacetic acid was continued 3 more times, always using the mother liquor from the previous operation.

The following material balances were obtained. Used: 2,303.5 g. racemic 6-methoxy-e-methyl-2-naphthalenesacetic acid.

Obtained: 1,613.5 g. (+) - 6-Methoxy-α-methyl-2-naphthalenesacetic acid Nmethyl-O-glucamic acid salt, i.e., 75.8% of theory.

1,120 g. (-) - 6aethoxyBi-α-methyl-2-naphthalenesacetic acid, / e / ²⁰ - -47 + 2 °, optical purity 69%.

D "

Example 3 (+) -6-Methoxy-α-roetyl-2-naphthalenic acid

460.7 g of racemic 6-methoxy-α-methyl-2-naphthalic acid (2 mol) and 390 g. N-methyl-D-glucamine is dissolved in 4 liters of boiling methanol. The resulting diastereoisomeric pairs were separated by the procedure described in Example 1. Obtained: 370 g. (+) - 6-Methoxy-α-raethyl-2-naphthyl acetic acid N-methyl-D-glucamine salt, i.e., 86.9% of theory.

1 «Melting point 158-159 ° C.

/ a / * ⁰ - -19.1 °, / «/ 355 - -83.7 ° (c - 1% in water).

Methanol l mother liquors use ee to regenerate (-) - 6-methoxy-α-methyl-2-naphthalenesacetic acid and N-methylD-glucamine.

The precipitated salt (370 g) was dissolved in 1750 ml. water, and the solution was heated to 80 ° C and filtered to be a clear filtrate. The solution was acidified by the light addition of 250 ml. 4n sulfuric acid at 80 ° C with stirring. The usual suspension was cooled to 20 ° C, the product was filtered and washed with water. The mother liquor is collected. The filtered product was washed with acidified water (0.001 N hydrochloric acid) until the sulfate ion was gone.

Obtained t 196.3 g. (+) -6-methoxy-α-methyl-2-naphthalenic acid, i.e., 98% of theory relative to used salt 1 85.16% of theory of used racemate.

Melting point: 156-157 ° C / / a / * ° - + 65.2 °.

Content: 99.4%

By-products - negligible (DC)

Dry loss: 0.1%.

The quality of the product obtained directly in this way (naproxen) already meets the requirements of the optical rotation of the Health Authorities, eg · as published in the British Pharmacopoeia (Addendum 75), which requires +63 to + 68.5 ° .

17 Example 4

Isolation of (-) - 6TOethoxy-a-tnetyl-2-naphthalene ir acetic acid (A) 1 Isolation of N-methyl-D-glucamine (B)

Insulation (A)

The methanol mother liquors from isomer separation according to Example 3 were evaporated to dryness. The residue was dissolved in 2300 ml. of water at 80 ° C. By clogging the ea 290 ml. 4n sulfuric acid, by cooling, filtration and drying, analogous to the procedure described in detail in Example 3, yields 255 g.

(-) - 6-Methoxy-α-methyl-2-naphthalenesacetic acid, which is then racemized according to techniques known for recycling.

yield of (+) - and (-) - 6- ^ non-oxy-? -methyl2-naphthalenesacetic acid

Mat. bal. '»- - - - - —— - - 98%

Starting material (racemate)

Isolation (B)

Aqueous mother liquors of (+) - and (-) - form insulation

6-Methoxy-α-methyl-2-naphthalenesacetic acid of Example 3, containing N-methyl-D-glucamine sulfate, were combined and gently added with potassium hydroxide suspension / obtained by stirring

63.7 g of calcium oxide (i.e., 105% of theory, relative to sulfuric acid used) with 250 ml. water. Calcium sulfate is formed, most of which is precipitated and filtered and washed with water. The filtrate was concentrated to a small volume, the newly precipitated calcium sulfate was filtered and washed with little water. The filtrate is now concentrated by evaporation at 85-95 ° C. in a vacuum to dry.

The evaporation residue was dissolved in 2400 ml. 95% ethanol with reflux cooking, filtered to a clear filter in the hot state, and cooled to 15 ° C. N-methyl-O-gluamine crystallizes.

Quantity:

- 18 351 g. N-methyl-D-glucamine

Yield: 90% of theory

Content: 99%

Melting point: 127-128 ° C «H / * ° - -16.95 °.

Example 5

Isolation of N-methyl-D-glucamine using an ion-exchange resin

For the decomposition of (+) - and (-) -6-methoxy-N-methyl-2-naphthalenesulfonic acid N-raethyl-D-glucamine salts and the precipitation of (+) - and (-) -6-methoxy-N-methyl-2- naphthalenesacetic acids, it is also possible to use hydrochloric acid and the sulfuric acid used in Examples 3 and 4 (A). The N-methyl-D-glucamine chloride hydrate is then hydrated by a phase from which the chloride ions can be easily removed by ion-exchange agents than would be possible with sulfate ions.

From 2 moles of false preparation, mother liquors which 4.

obtained from the precipitation of (+) - and (-) - 6-methoxy-methyl-2-naphthalenesacetic acid containing N-methyl-D-glucamine hydrochloride, neutralized with ammonia at pH 7 and then percolated through an ion exchange column coated with

R

1.6 liter Amberlite IR-120. The exchange resin is then washed with 3.2 liters of deionized water. The expiration containing the chloride ion was discarded.

N-methyl-D-glucamine was dissolved from the resin by percolation with 2400 ml. aqueous ammonia (2.5 N) and 3.2 1 deionized water. The spouts were combined and concentrated to evaporation to dryness. As described in Example 4, the evaporation residue was recrystallized from 2400 ml. 95% ethanol.

Quantity:

351 g. N-methyl-D-glucamine

Yield:

90 «

99.1 «

Content: 99.1 «

Melting point: 127-128 ° C

EXAMPLE 6

4.60 g. d, 1-2- (6-methoxy-2-naphthyl) propionic acid was heated with 1.01 g. of triethylamine (0.5 eq.) in 20 ml.

6 "toluene in methanol to reflux the solvent temperature by dissolving d, l 2- (6-methoxy-2-naphthyl) propionic acid · Add 1.95 g. N-methyl-D-glucamine (0.5 eq) and the solution was cooled to room temperature (i.e., about 20-23 ° C) to give 3.52 g. of the material enriched with 2- (6-methoxy-2-naphthyl) propionic acid with N-methyl-Dglucamine. The latter is dissolved in about 25 ml. of water, treated with hydrochloric acid to acid reaction 1 at that point, the material enriched with d 2- (6-toethoxy-2-naphthyl) propionic acid precipitated from the solution and isolated by filtration (/ _D / 48.8 °).

1.00 g. of the material enriched in the salt of 2- (6-methoxy-2naphthyl) propionic acid with N-methyl-D-glucamine was recrystallized from 10 ml. methanol and 20 ml. of ethanol, refluxed to remove 5 ml. of the solvent, and cooled to give 0.85 g. recrystallized salts. This material is treated with hydrochloric acid as shown in the previous paragraph to give the dried pure 2- (6-methoxy-2-naphthyl) propionic acid (/ <* / _D + 64.6 °).

_β '20 -

EXAMPLE 7

Mr Rücker d, l 2- (6-Methoxy-2-naphthyl) propionic acid was suspended with 432 ml. methanol and 21.1 ml. toluene 1 was then added to the suspension 42.36 g. N-methyl-D-glucamine.

The mixture was heated to reflux and the solution became clear.

The solution was then cooled to 50 [deg.] C. and pelleted with N- (6-methoxy-2-naphthyl) propionic acid N-methyl-D-glucamyl salt. Crystallization begins to occur when the solution is cooled to 45 ° C.

The temperature was lowered by 10 ° C per hour for 3 hours and the solution was kept at 15% for 30 minutes. The solution was filtered, and the resulting cake was washed with 21 ml. of fresh methanol to give 84.20 g. wet cake.

The wet cake is then mixed directly into 451 ml. methanol and 21.3 ml. toluene and heated at reflux with stirring, cooled to 50 [deg.] C., pelleted with N-methyl-O-glucamine salt of 2- (6-methoxy-2-naphthyl) propionic acid, then _r cooled to 15 % for 2 hours, then kept at 15 ° C for 30 minutes. The solution was filtered and the wet cake was washed with 50 ml. 5% toluene in methanol and partially dried to give 38.77 g. partially dried cake.

The partially dried cake is bathed in 184 ml. of water and warmed to 80 ° C with stirring. The solution was treated with 0.97 g. decolorizing coal for 20 minutes. The solution is then filtered through a celite filter 1 the solution temperature rises to

85 ° C

- 21 Adds 51 ml. 3.3 N sulfuric acid for 30 minutes to give a precipitate which is enriched in 2- (6methoxy-2-naphthyl) propionic acid. The solution was kept at 85 ° C for 30 minutes, then cooled to 15 ° C for 30 minutes, filtered, washed to neutrality and dried. 18.84 g is obtained. (direct yield "37.68%) d 2- (6-Methoxy-2-naphthyl) -propionic acid </ a / ₃ + 64.6 °).

EXAMPLE 8

After one step, it was repeated from Example 7 to give 20.02 g (direct yield 40.%) of 2- (6-methoxy-2-naphthyl) propionic acid (/ o / _D + 65.4 °).

Claims (22)

PATENT REQUIREMENTS 1. A process for decomposing mixtures of (+) - and (-) - methoxy-o-methyl2-naphthalenesacetic acid or its salts into their enantiomers, using N-methyl-D-glucamine / l- deoxy-1- (methylamino) -D-glucitol / iii. 2. The method of claim 1, wherein the mixture of (+) - and (-) -6-methoxy-? -Methyl 1-2-naphtha lins and hydrochloric acid is reacted with N-raethyl-D-glucamine to give the resulting pair The (+) 1 (-) - 6-methoxy-e-methyl-2-naphthyl acetic acid salt with N-methylD-glucamine was separated by fractional crystallization. 3. The process of claim 2, wherein the salt treatment and separation of the diastereoisomers is carried out by fractional crystallization in methanol. 4. The process of claim 2, wherein the (+) - and (-) - 6-methoxy-o-methyl-2-naphthalic acid salts of N-methyl-D-glucamine are individually digested individually by the addition of a mineral acid. The (+) - abundance is isolated as a pure compound, then the (-) - form is racemized by known methods, and N-methyl-D-glucamine is isolated from acidic mother liquors. 5. A process according to claim 1 or 2, wherein a solvent is used in which the solubility of (-) - 6-methoxy-a-methyl-2-naphthalenesacetic acid with N-methyl-D-glucamine is at least 10 times greater from the solution of the salt of (+) - 6-methoxy-ame ti 1-2-naphthalic acid with N-methyl-D-glucamine at decomposition temperature. - 23: - A process for the separation of (+) - 6-methoxy-e-methyl-2-naphthalenic acid from a mixture of (+) - and (-) - 6-methoxy-α-methyl-2-naphthaleneacetic acid or their salts, Which includes: making a mixture of (+, -, and (-) - 6-methoxy-a-methyl-2-naphthalenate and hydrochloric acid or their soluble salts and N-methyl-Dglucamine or its salts in an inert solvent to form salts (+) - and (-) - 6-methoxy-e-methyl-2-naphthalenesacetic acid with N-methyl-D-glucamine, with (+) - 6-methoxy-o-methyl-2-naphthalene being the acid of N -methyl-D-glucamine is significantly less soluble in an inert solvent than (-) - 6methoxy-α-methyl-2-naphthalenesacetic acid salt with N-methyl-Dglucamine at crystallization temperature, and crystallization of (+) - 6-methoxy- α-methyl-2-naphthalenesacetic acid with N-methyl-D-glucamine from said mixture to give the product in the form of a salt which is enriched with the salt (+) -6-methoxy-e-methyl-2-naphthalenesacetic acid with N -methylD-glucamine. 7. A process according to claim 6, wherein said mixture is heated to dissolve the (+) - and (-) - 6-methoxy-6-methyl-2-naphthalenesacetic acid salts from the N, N-methyl-D-glucamine in said inert solvent , and said (+) - 6-methoxy-a-methyl2-naphthalic acid with N-methyl-D-glucamine is crystallized by cooling said heated mixture to subject said mixture to crystalline crystallization to give said product in the form of a salt which is enriched with the salt (+) - 6-methoxy-α-rne ti 1-2-naphtha lina ir acetic acid ea N-methyl-D-glucamine. .- 24 The process according to claim 8 or 7, further comprising the steps of dissolving said product in the form of a salt enriched with ea aol (+) - 6-methoxy-a-methyl-2-naphthalene acetic acid with N-raethyl-D -glucamine in an inert solvent for this salt, decomposing said salt to give (+) - 6-methoxy-e-oethyl-2-naphthalene acetic acid, and from there crystalline substantially pure (+) - 6methoxy-o-methyl-2-naphthalene ether acid. 9. The method of claim 6, wherein said mixture comprises about 50 to 100 molar percent of said N-methyl-D-glucamine based on (+) - and (-) -6-flux si-a-methy 1- 2naphthalicacetic acid in said mixture. The method of claim 6, wherein said mixture comprises about 50-60 molar percent of said M-methyl-D-glucamine 1 about 40-50 molar percent of inorganic or organic base, wherein said molar percent is based on (+ ) - and (-) - 6-methoxy-α-methyl-2-naphthalenic acid in the aforementioned mixture. The process of claim 10, wherein the inorganic base is potassium hydroxide. 12. The process of claim 10, wherein the organic bass is tralalkylamine. what was mentioned that was mentioned 13. The process according to the request organic bass triethylamine. 10, characterized in. Which is mentioned 14. The process of claim 6 or 7, wherein the solvent is alcohol. - 25 A process according to claim 6 111 7 wherein the solvent is methanol or isopropanol. 16. The process of claim 14 or 15, wherein the solvent comprises water. 17. The method of claim € 7, further comprising the step of treating mother liquors to isolate N-methyl-D-flucamine for recycling. 18. The process according to claim 6 or 7, further comprising the steps of isolating the non-racemic mixture of (+) - and (-) 6-methoxy-a-methyl-2-naphtha lins and hydrochloric acid from the mother liquors, wherein the mixture is enriched with (-) -6 * ^ aetoxy-? -methyl2-naphthalenesacetic acid, this one is racemized and the said racemized mixture is recycled. 19. The method of claim 6, further comprising the steps of subjecting said product in the form of a salt enriched with (+) - 6 ^ -methoxy-α-methyl-2-naphthalenesacetic acid with N-raethyl-D-glucamine at least further recrystallization to give a product further enriched with (+) - 6-methoxy-α-raethyl-2-naphthalenesacetic acid salt with N-methyl-D-glucamine, and then the said product is further enriched with salt (+) - 6me stream si-o-me ti 1-2-naphtha lins ir of acidic acid with N-methyl-D-gluca min in inert solvent for it, break said product to give (+) - 6- retoxy-o-methyl-2-naphthalenesacetic acid and from there crystallized essentially pure (+) - 6methoxy-α-raethyl-2-naphthalenesacetic acid. - 26 20. The process according to claim 8 or 19, further comprising subjecting said substantially pure (+) - 6methoxy-methyl-2-naphthalenicacetic acid to at least one additional recrystallization to further increase its purity. 21. A mixture of (+) - 6-methoxy- [ ^alpha] -methyl-2-naphthalenic acid acid salt with N-methyl-D-glucamine. 22. A decomposition medium comprising a mixture of (+) -6-methoxy-methyl-2- methyl-2-naphthalenic acid acid salt from N-methyl-D-glucosamin and a solvent in which the solubility of (-) -6- methoxy-methyl-2-naphthalenesacetic acid with N-methyl-D-glucamine at least 10 times the solubility of the (+) - 6-methoxy®-meth 1-2-naphthalic acid with N-methyl-D-glucamine at temperature interpretations.