DK157003B - Use of N-methyl-D-glucamine, or salts thereof, as cleaving agent when preparing (+)-6-methoxy-alpha-methyl- 2-naphthaleneacetic acid - Google Patents

Description

DK 157003 B

(+) - 6-methoxy-o-methyl-2-naphthalene acetic acid [= D-2- (6-methoxy-2-naphthylpropionic acid] is an effective antiphlogistic / analgesic / antipyretic agent.

5 According to DE Publication No. 2,039,602, it is obtained e.g. from the racemate by selective biodegradation or by preparing diastereoisomeric salts of 6-methoxy-cc-methyl-2-naphthalene acetic acid with a cleaved optically active amine base such as cinchonidine and then separating the resulting 10 diastereoisomers by fractionated crystal . The separated diastereoisomeric salts are then hydrolyzed with strong acids to give the corresponding (+) - or (-) - 6-methoxy-α-methyl-2-naphthalene acetic acids.

The racemate of 6-methoxy-o-methyl-2-naphthalene acetic acid cannot be cleaved by spontaneous separation and preferential selective crystallization of one of the enantiomers.

In addition to cinchonidine, among others, the following compounds in DE Publication Nos. 2,000,177 and 2,008,272 are proposed as optically active amine bases for the separation step:

The naturally occurring alkaloids, anabasin, brucine, cones sin, cinchonicin, cinchonin, D-deoxyoxyhedrin, L-ephedrine, epiquinin, morphine, quinidine, quinine, strychnine, dehydroabiethylamine and solanidine as well as cholesterylamine, D-mentamine , primary, secondary and tertiary amines such as L-2-amino-1-propanol, L-2-aminobutanol, D-2-aminobutanol, D-threo-2-amino-no-1β-ni-trophenyl-1,3-propanediol, D-amphetamine, L-2-benzylamino-1-propanol, D-4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol, D-α- (1-naphthyl) ethylamine, Lo- (1-naphthyl) -ethylamine, O-α-methylbenzylamine and La-methylbenzylamine.

The alkaloids cinchonidine, dehydroabiethylamine and quinine are prepared according to DE Publication Nos. 1,934,460, 35,013,641, 2,007,177, 2,005,454, 2,008,272 and 2,039,602.

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2

The other alkaloids and bases were named in Example 7 of OE Publication No. 2,007,177 and in Example 3 of DE Publication 2,008,272.

DE Publication No. 2,005,454 discloses pharmaceutically acceptable salts of 6-methoxy-α-methyl-2-naphthalene acetic acid suitable for the treatment and relief of inflammation, fever, etc .. Among the salts which are included in the broad definition but not described in more detail are the 10 N-methyl-D-glucamine salts. The N-methyl-D-glucamine salt of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid is named in Example 26 of DE Publication No. 2,005,454 as a possible end product. This site was prepared by the reaction of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-15 glucamine. However, the N-methyl-D-glucamine salts of the racemic mixture of 6-methoxy-α-methyl-2-naphthalene acetic acid have not been previously described.

Asymmetric bases with a carbohydrate structure are not generally known as decomposers (cf. NL Allinger and EL Eliel, Topîcs in Stereochemistry, Vol. 6, Wiley-Interscience, New York, 1971, chapter: Resolving Agents and Resolution in Organic Chemistry by SH Wilen and SH Wilen, Tables of Resolving Agents and Optical Resolutions, edited by EL Eliel, 1972, 25 University of Notre Dame Press) and have been considered unsuitable for this purpose prior to the present invention.

Publication No. 2,007,177 has proposed glucose amine for cleavage of 6-methoxy-α-methylnaphthalene acetic acid. However, it does not contain any specific examples at all.

35 3 (

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It is very difficult to synthesize glucosamine [= 2-amino-2-deoxy-D-glucose] # in practice it can only be obtained from chitin and it is relatively unstable. The solubility of its salts with (+) - and (-) - A (where A is 6-methoxy-α-methyl-2-naphthalene acetic acid) was determined to elucidate the suitability of this substance as cleavage agent (Table 1).

Table 1 Solubility of the glucosamine salts q / 100 ml 10 Solution Sait of (+) A with Sait of (-) A with mean D-glucosamine D-glucosamine [a] 20 = 38.95 ° [a] 20 = 37.41 °

0 D

Mp. = 60-63 ° C, m.p. = 90-100 ° C, decomposition decomposition _20 ° C boiling temperature 20 ° C boiling temperature H2O insoluble decomp. 1 decomp.

CH3OH 50 "3.3" C2H50H, 95% 2.5 "1 C2H50H absolute 1" 1 "20 L 0

Table 1 shows that the unwanted isomer, i.e. (-) The A form may be isolated using the g 1 ucosamine acid. Even at 25 temperatures down to 40 ° C, which is inevitable in practice, the glucosamine salts are unstable as they decompose. This greatly impairs their manufacture, insulation and perhaps re-generation. From a commercial point of view, glucosamine is in fact unsuitable as the decomposition agent for mixtures of 30 (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid, which supports the view that asymmetric bases with a carbohydrate structure are very poor cleavage agents.

S. H. Wilen points out in the chapter on cleavage agents and 35 cleavage in organic chemistry in Topics and Stereochemistry, Volume 6, Wiley-Interscience, New York, 1971, on page 114, that

A

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cleavages involve unpredictable variables. It is thus surprising that N-methyl-D-glucamine is an excellent cleavage agent with very large differences in readability between the (+) - acid salt and (-) - the acid salt. The (+) acid salt has a substantially sterile insolubility than the (-) acid salt and can therefore most easily be recovered from the solution subjected to fractional crystalization. Since this relationship could not be expected on the basis of the prior art, even when considering the occurrence of structurally different glucosamine, it was entirely unexpected that the choice of N-methyl-D-glucamine as a cleaving agent should give the shown advantage.

The present invention thus relates to the use of N-methyl-D-glucamine [= 1-deoxy-1- (methylamino) -D-glucitol] or a site thereof as a decomposing agent in the preparation of (+) - 6-methoxy-α- methyl-2-naphthalene acetic acid. In a preferred embodiment, the use is made by the preparation comprising fractional crystallization, especially of a mixture of (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid.

In the preferred application, a mixture of (+) - and (-) - 6-nithoxy-α-methyl-2-naphthalene acetic acid is combined with N-methyl-D-glucamine, and the resulting mixture of (+) - and {-) -6-Methoxy-α-meth-25-yl-2-naphthalene acetic acid-N-methyl-D-glucamine salt is subjected to fractional crystallization.

Alternatively, soluble salts of (+) and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid can be cleaved with appropriate salts of 30 N-methyl-D-glucamine.

The (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid N-methyl-o-glucamine salts are individually decomposed by acid cleavage or with a mineral acid as the acids flow out, or by base cleavage. followed by acidification

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5 formation of the free acids. The desired (+) form can be obtained in pure form. Using known methods, the (-) form ·; .-;. is then racerized and N-methyl-D-glucamine is extracted from the acidic mother liquor.

5

It has been found that the salts of the optically active base N-: methyl-D-glucamine [= 1-deoxy-1- (methylamino) -D-glucitol] with (+) - and (-) - 6-methoxy- α-methyl-2-naphthalene acetic acid has extrenite large solubility differences / which is ideal for separating the diastereoisomers.

The salt of the desired (-i-) - 6-methoxy-α-methyl-2-naphthalene = acetic acid with N-methyl-D-glucamine is much more difficult to dissolve than the corresponding site of (-) - 6-methoxy- α-methyl-2-naphthalene acetic acid and can thus be very easily obtained in pure form. The solubilities of the diastereoisomeric salt pairs of (+) - and (-) '6-methoxy-o-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine in various solvents are given in Table 2, where A has the above defined meaning.

Table 2.

Solubilities of the N-methyl-D-glucamine salts g / 100 ml

Solution Sait of (+) A with Sait of (-) A with agent N-methyl-D-glucamine N-methyl-D-glucamine 20 ° C boiling temperature 20 ° C boiling temperature H20 25 100 70 100 CH30H 1.3 6, 5 18 100 (CH 3) 2 CHOH 0.02 0.161 0.16 1.71 30 reflux.

The solubility differences are very pronounced even in water, which was not the case for any of the other 35 pairs studied.

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The solubility differences in cold and hot methanol are substantially greater. They are 1.3: 18 (1:14) at room temperature and 6.5: 100 (1: 15.4) at boiling temperature and favor the isolation of the desired isomer of the (+) A form. This favorable ratio and the higher absolute value of the solubility of the salt of (-) A with N-methyl-D-glucamine allow economic separation with a minimum solvent consumption and a maximum cleavage effect, ie. with the highest optical purity of the desired product and at the same time with high yield.

10

The use of N-methyl-D-glucamine for the cleavage of 6-methoxy-α-methyl-2-naphthalene acetic acid is advantageous and also for the reason that N-methyl-D-glucamine is very readily available in reducing D -glucose (grapes sugar), which is affordable and available in unlimited quantities, in the presence of methylamine.

The preparation of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid is carried out in an inert organic solvent with a pronounced difference between the solubilities of the salt of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid. with N-methyl-D-glucamine salt and the salt of (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine, generally at temperatures between room temperature or ambient temperature. and an elevated temperature, usually up to the reflux temperature of the solvent used. The salt of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine should be substantially less soluble in the solvent than the salt of (-) - 6-methoxy-α-methyl-2 -naph = 30 thalenacetic acid with N-methyl-D-glucamine, and consequently, upon cooling a heated solution thereof, generally to about ambient temperature or room temperature, such as (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid acid with N-methyl-D-glucamine is preferably crystallized therefrom. Suitable solvents include monohydric alcohols such as methanol, ethanol, n-propa = 7

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nol, isopropanol, butanol, pentanol, hexanol, cyclohexanol, 2-ethylhexanol, benzyl alcohol and furfuryl alcohol C₂ C Cg divalent alcohols such as ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, C ^-C ^ tri = 5 valent alcohols glycerol, C ^-C ^ ketones such as acetone, acetylacetone, ethylmethyl ketone, diethyl ketone, di-n-propyl ketone, diisopropyl ketone and diisobutyl ketone. . Other solvents include mono- and di (lower) alkyl ether of ethylene glycol and diethylene = 10 glycol, dimethyl sulfoxide, sulfolanes, formamide, dimethylformamide, N-methylpyrrolidone, pyridine, dioxane and dimethyl = acetamide. The C 3 alcohols, for example, methanol and isopropanol, especially methanol, are currently the preferred solvents. Sufficient water may be added to the solvent, if necessary, to dissolve all the substances which have been added. thereto.

In the preferred embodiment, the starting material is heated [i.e. the mixture of (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid] in the solvent to an elevated temperature, usually to a temperature in the range of about 60 ° C to approx.

100 ° C or to the reflux temperature of the solvent, in the presence of N-methyl-D-glucamine to dissolve all of the substances which have been added to the solvent. If desired, the solvent can be kept at the elevated temperature until all the substances have dissolved. After the solution has been kept at the elevated temperature for the desired period, it is slowly cooled to ambient temperature. During the cooling process, the solution is preferably seeded with a site of (+} - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine. The resulting crystalline precipitate is enriched in the salt of (+) -6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine The final temperature at which the solution is brought is chosen according to practical considerations, but is generally selected such that the temperature difference will be sufficient to give a high

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8 is kept at the lower temperature until the crystallization is complete or almost complete, usually for approx.

30 minutes to several hours. The resulting crystalline precipitate is filtered off and washed.

5

The crystalline substance thus obtained at this stage of the process [i.e., a substance enriched in the salt of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine] can after filtration and washing, 10 is transferred to water and heated if necessary to redissolve the crystalline substance. For example, the resulting solution is acidified. with a mineral acid, such as sulfuric acid or hydrochloric acid, or an organic acid, such as acetic acid or p-toluenesulfonic acid, and the crystalline precipitate thus obtained is filtered off, washed and dried. A white crystalline product is obtained which is substantially enriched in (+) - 6-methoxy-α-methyl-2-naph = thaleneacetic acid. Alternatively, the substance enriched in the salt of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine may be treated with a strong base, such as e.g. potassium hydroxide, or another strong base having a pKa value above 10, for cleavage of the salt, followed by acidification with e.g. a mineral acid, such as hydrochloric or sulfuric acid, or an organic acid, such as acetic acid, to obtain after filtration, washing and drying a white crystalline product substantially enriched in (+) - 6-methoxy-α-methyl 2-naphthaleneacetic acid.

Before redissolving the material enriched in the salt of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-

3 O

methyl D-glucamine, and subsequent acidification to obtain (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid, it is generally desirable to redissolve the enriched salt material in additional solvent, heating the solvent to the Desired temperature, inoculate the resulting solution with the salt of (+) - 6-methoxy-α-methyl-2-naphthalene = acetic acid with N-methyl-D-glucamine and cool to give one or more additional recrystallizations. Every 9

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of these recrystallizations further increases the amount of the salt of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid with N-methyl-D-glucamine in the recrystallized substance. Product with an order of magnitude approx. 97-99% (+) - 6-methoxy-5? -Methyl-2-naphthalene acetic acid can be obtained with only one recrystallization step before the dissolution of the resulting crystalline product and subsequent acidification.

The (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid or the 0 N-methyl-D-glucamine salt thereof enriched can be treated to recover (-) - 6-methoxy-α-methyl-2-naphthalene vinegar. Acid acid may be racemized in accordance with known methods to obtain a substance with a higher content of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid. See e.g. U.S. U.S. Patent No. 3,586,183. This substance can be recycled, either alone or in combination with other mixtures of (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid to obtain additional starting material.

The amount of N-methyl-D-glucamine used [on a molar basis relative to (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid cleaved] varies widely. between 50% and 100%.

However, since only approx. 50% [on a molar basis relative to the (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid cleaved] of N-methyl-D-glucamine to give it more insoluble sites thereof with (+) - 6-methoxy-o-methyl-2-naphthalene acetic acid / the remainder of the N-methyl-D-glucamine (usually of the order of about 40-50 mol%) may be replaced if desired. a cheaper base, including.

eg. an inorganic base, such as an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, or an organic tertiary amine such as triethylamine, triethanolamine and tri-n-butylamine.

The aqueous mother liquor obtained after the isolation of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid and (-) - 6-methoxyacetic acid

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10 <x -methyl-2-naphthalene acetic acid, e.g. salts of N-methyl-D-glucamine with the acid used in the acidification step. Mother liquor of this type can be treated with an inorganic base to form an insoluble, inorganic site, while N-methyl-D-glucamine remains in solution, such as e.g. treatment with a suspension of calcium hydroxide to precipitate the corresponding calcium salt which is filtered off. The filtrate is concentrated in vacuo at elevated dryness temperatures, first removing any additional sites, e.g. the calcium salt, which is formed during the first steps of the concentration process. The residue is dissolved in a suitable solvent at an elevated temperature up to the reflux temperature of the solvent and then cooled to room temperature, whereby the decomposition agent is obtained as a crystalline precipitate which can be re-used either alone or in combination with new substance in the decomposition process of the invention. Alternatively, the N-methyl-D-glucamine can be recovered using an ion exchange resin and recycled for use again.

20

The terms "mixture of (+) - and (-) - 6-methoxy-α-methyl-2-naphtha-glacial acetic acid" shall also include the salts thereof which are soluble in the solvent used in the decomposition process of the invention. Such salts include e.g. the corresponding 25 sodium salts, potassium salts, lithium salts and the like. Such salts can be prepared by the addition of base, such as alkali metal hydroxide, e.g. sodium or potassium hydroxide, for a solution of the mixture of (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid. The resulting mixture of (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid salts can be cleaved in accordance with the present invention using a site of the cleavage agent which will react to form a site of (+) - 6-methoxy-α-methyl-2-n aph th a = lenacetic acid with the N * »methyl-D-glucamine. Suitable N-methyl-D-

w O

glucamine salts include e.g. the hydrochloric salt © g aeetat = the salt. Other salts include the propionate salt, butyrate salt, r? rtm aV a *> n ir »η / s Λ A 1 fi» / m. In rsa «ο e £ C2. JL · i? / '·. ô Λ »cra m« * k I iem A »· 11

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Accordingly, "N-methyl-D-glucamine" comprises the salts thereof which, when used with an appropriate site e.g. the mixture of (+) - and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid will give the cleavage contemplated thereby.

5

Examples. . .

Example 1.

(+) - 6-methoxy-α-methyl-2-naphthalene acetic acid-N-methyl-D-glucaroic salt.

460.7 g of racemic 6-methoxy-α-methyl-2-naphthalene acetic acid (2 moles) and 390.5 g of N-methyl-D-glucamine [= 1-deoxy-1- (methyl = 15 amino) -D-glucitol ] (2 moles) was dissolved in 4 liters of boiling methanol.

The solution was filtered for clarity and gently cooled to 45 ° C with slow stirring. Now 1 g of 20 (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid N-methyl-D-glucamine salt crystals (obtained in a preliminary test by cooling and rubbing with a glass spatula, filtering under suction and washing with some methanol). Solid crystallization of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid-N-25 methyl-D-glucamine salt was demonstrated immediately after inoculation.

The temperature was kept at 45 ° C and then slowly lowered to 15 ° C.

The precipitated crystals were filtered off and washed with a small amount of methanol.

Exchanges: 360 g (+) - 6-methoxy-α-methyl-2-naphthalene vinegar = acid N-methyl-D-glucamine salt, i.e. 84% of the theoretical yield.

Melting point: 156-158 ° C.

35

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12

Specific rotation at 20 ° C; concentration = 1% in water Wavelength λ 589 546 436 365 20 5 [α] + υ ο -18.59 -22.85 -43.53 -80.63

The obtained product (360 g) was dissolved again in 4.4 liters of boiling methanol, filtered, slowly cooled, seeded with authentic substance, and allowed to crystallize and cooled, filtered and washed.

Yield: 278 g of pure (+) - 6-methoxy-α-methyl-2-naphthalenedetic acid N-methyl-D-glucamine salt, i.e. 65% of the theoretical yield.

Melting point: 160-161 ° C.

Specific rotation at 20 ° C; concentration = 1% in water 20 Wavelength λ 589 546 436 .365 20 [α] χ © -20 -23.95 -44.83 -87.19 2S Microanalysis: C21H31N08:

Calculated C 59.28%; N, 3.29%; found C, 59.58%; N, 3.42%.

The mother liquor was completely evaporated to recover the methanol.

The evaporation residue was dissolved in water and dilute hydrochloric acid was added to acidify the saline solution. The (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid was precipitated.

Amount: 228 g of (-) - 6-inethoxy-α = irethylethyl 2-iaphthaleneduic acid, i.e. 99.1% of theoretical yield.

35

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13

Melting point: 145-146 ° C.

Λ Λ - [α.] + = -45.8 (concentration = 1% in ehloroform).

optical purity: 67%.

5

Product. can-v-ed - racemization is generated by the tri-racemate, i.e. the starting material and then used again in additional batches during the cleavage process.

Example 2.

Recycling of the mother liquor.

The methanolic mother liquor can be used directly> before regeneration> in further cleavage operations.

A cleavage operation described in Example 1 was carried out with the same amounts of starting materials. However, instead of fresh methanol, the methanolic 20 mother liquor from a previous similar charge was used.

The first product obtained was: 431 g (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid N-25 methyl-D-glucamine salt, i.e. 100% of theoretical yield.

Melting point: 155-158 ° C.

Specific rotation at 20 ° C; concentration = 1% in water.

Wavelength λ 589 546 436 365 [α] + ° ο -18.52 -21.41 -40.5 -76.6 35 After recrystallization from 4.4 liters of fresh methanol, the product was:

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14,326 g of (+) - 6-methoxy-α-methyl-2-naphthalene acetic acid N-methyl-D-glucamine salt, i.e. 76% of the theoretical yield.

Melting point: 159-160 ° C.

Specific rotation at 20 ° C concentration * 1% in water Wavelength λ 589 546 436 365 [a] J o -20.02 -24.12 -45.88 -88.41 10 -

The cleavage of racemic 6-methoxy-α-methyl-2-naphthalene = acetic acid was continued for a further 3 tints, always using the mother liquor from the previous operation.

15

The following material balance was obtained:

Used: 2,303.5 g of racemic 6-methoxy-α-methyl-2- 'naphthalene acetic acid.

Obtained: 1 613.5 g (+) - 6-methoxy-α-methyl-2-naphthalene = acetic acid N-methyl-D-glucamine salt, i.e.

75.8% of theoretical yield, 1 120 g (-) - 6-methoxy-α-methyl-2-25 naphthalene acetic acid, ta] + = -47-2 °, optical purity 69%.

Example 3

(+) - 6-methoxy-g-methyl-2-naphthalene acetic acid.

460.7 g of racemic 6-methoxy-α-methyl-2-naphthalene acetic acid (2 moles) and 390 g of N-methyl-D-glucamine are dissolved in 4 liters of boiling methanol. The obtained diastereoisomeric pairs are separated by the method described in Example 1.

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15

Obtained: 370 g of (+) -6-methoxy-α-methyl-2-naphthalene vinegar = acid N-methyl-D-glucamine salt, i.e. 86.9% of the theoretical yield.

Melting point: 158-159 ° C.

[.Alpha.] D @ 20 = -19.1 DEG, [.alpha. @ 2 D @ 5 = -83.7 ° (c = 1% in water).

The methanolic mother liquor is used for the extraction of (-) - 6-methoxy-α-methyl-2- * naphthalene acetic acid and N-methyl-D-glucamine.

10

The obtained solution (370 g) is dissolved in 1750 ml of water and the solution is heated to 80 ° C and filtered clear. The solution is acidified by slowly adding 250 ml of 4N sulfuric acid at 80 ° C with stirring. The suspension obtained is cooled to 15 ° C, the product is filtered off and washed with water. The mother liquor is separated. The filtered product is washed with acidified water (0.001 N hydrochloric acid) until the sulfate ions disappear.

Obtained: 196.3 g (+) - 6-methoxy-α-methyl-2-naphthalene = acetic acid, i.e. 98% of the theoretical yield compared to the site used and 85.16% of the theoretical yield compared to the used racemate.

Melting point: 156-157 ° C; [α] D + 65.2 °.

Purity: 99.4%.

By-products = insignificant.

Thin layer chromatography shows a dry loss of 0.1%.

30

The quality of the product obtained directly in this way (naproxen) already meets the health authorities' requirements for optical rotation, ie. as stated in British Pharmacopeia (Addendum 75), requiring 35 [a] p ° be from +63 to + 68.5 °.

Example 4

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16 * «recovery of (-) - 6-methoxy-g» methyl-2 ~ naphthalene acetic acid (A) and recovery of N-methyl-D-glucamine (B).

5 recovery of (A).

The methanolic mother liquor from the isomeric separation of claim 3 is evaporated to dryness. The residue is dissolved in 2300 ml of water at 80 ° C. Acidification with 290 ml of 4N sulfuric acid, decolorization, filtration and drying, analogous to the method described in detail in Example 3, gives: 255 g of (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid can be racemized according to known methods of recycling.

15

Yield of (+) and (-) - 6-methoxy-Material Balance - α-methyl-2-naphthalene acetic acid = 98%

Starting material (racemate) Extraction of (B).

The aqueous mother liquor from the isolation of the (+} - and (-1-forms of 6-methoxy-α-methyl-2-naphthalene acetic acid from Example 3 containing N-methyl-D-glucamine sulfate is combined, and to this 2S is slowly added a suspension of calcium hydroxide [obtained by quenching 63.7 g of calcium oxide (ie, 105% of theoretical value with respect to the sulfuric acid used) with 250 ml of water] Calcium sulphate is formed, the majority of which precipitates and is filtered off and washed with water. The filtrate 30 is concentrated to a low volume, the newly precipitated calcium sulfate is filtered off and washed with a small amount of water, and the filtrate is concentrated by evaporation at 85-95 ° C in a vacuum to dryness.

The evaporation residue is dissolved in 2400 ml of 95% ethanol by refluxing, which is clearly filtered in the hot state and cooled to 15 ° C. N-methyl-D-glucamine crystal- 1 * f βΑν-ΛΥ · 11 / ^

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* f 17 Quantity:. 351 g of N-methyl-D-glucamine

Yield: 90% of theoretical yield

Purity: 99%

Melting point: 122-128 ° C [α] 1 ° = -16.95 °.

Example 5

Extraction of N-methyl-D-glucamine by the aid of anion exchanger-10 resins. · - -

For the decomposition of the (+) and (-) - 6-methoxy-α-methyl-2-naphthalene acetic acid N-methyl-D-glucamine salts and the precipitation of the (+) α-methyl-2-naph = 15 thalenacetic acids, it is also possible to use hydrochloric acid instead of the sulfuric acid used in Examples 3 and 4 (A). N-methyl-D-glucamine hydrochloride "dissolves" in the aqueous phase, from which chloride ions can be more easily recovered by ion exchange than would be possible with sulfate ions.

20 üd from a 2 mole starting composition, the rudder liquor obtained is thereby neutralized from the precipitation of (+) - and {-) - 6-methoxyarmethyl-2-naphthalene acetic acid containing N-methyl-D-glucamine hydrochloride, with ammonia to pH 7 and per-25.

is then cooled through an ion-exchange column coated with 1.6 liters of "Amberlite" ® IR-120. The exchange resin is then washed with 3.2 liters of deionized water. The chloride ion-containing effluent is discarded.

30 N-methyl-D-glucam is dissolved out of the exchange resin by percolation with 2400 ml of aqueous ammonia (2.5 N) and 3.2 liters of deionized water. The drains are combined and concentrated by evaporation to dryness. As described in Example 4, the residue is recrystallized from 2400 ml of 95% ethanol.

3 5

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Amount: 351 g of N-methyl-D-glucamine

Yield: 9 0%

Content: 99.1%

Melting point: 127-128 ° C

rni 20 -j 70 5 ia] D “17 *

Example 6

4.60 gd, 1- 2- (6-methoxy-2-naphthyl) propionic acid is heated with 10 1.01 g of triethylamine (0.5 equivalent) in 20 ml of 6% toluene in methanol to reflux the solvent to dissolve d, l -2- (6-methoxy-2-naphthyl) propionic acid.

1.95 g of N-methyl-D-glucamine (0.5 equivalent) is added and the solution is cooled to room temperature (i.e., about 20-23 ° C) to obtain 3.52 g of an enriched substance on the salt of d 2- (6-methoxy-2-naphthyl) propionic acid with N-methyl-D-glucamine. The latter is dissolved in approx. 25 ml of water are treated with hydrochloric acid until acidification, during which time a material enriched in 2- (6-methoxy-2-naphthyl) propionic acid is precipitated by the solution and filtered from ([α] β +48, 8 °).

1.00 g of the material enriched in the salt of d 2- (6-methoxy-2-naphthyl) propionic acid with N-methyl-D-glucamine> is recrystallized from 10 ml of methanol and 20 ml of ethanol, conc. 25 is refluxed to remove 5 ml of solvent and cooled to obtain 0.85 g of a crystallized site. This substance is treated with hydrochloric acid, as indicated in the previous section, to obtain substantially pure d 2- (6-methoxy-2-naphthyl) propionic acid ([a] D + 64.6 °). Yield 30 is 98% of theoretical yield. (0.85 g of the salt is dissolved in 12 ml of water. To this is added 1 ml of concentrated HCl. The precipitate (0.45 g) is d 2- (6-methoxy-2-naphthyl) propionic acid with the above optical rotation).

35

Example 7

DK 157003 B

19 50 g of d-1- (6-methoxy-2-naphthyl) -propionic acid are slurried with 432 ml of methanol and 21.1 ml of toluene and 42.36 g of 5 N-methyl-D-glucamine are added to the slurry. The mixture is heated to reflux and the solution becomes clear. The solution is then cooled to 50 ° C and seeded with the N-methyl-D-glucamine salt of d 2- (6-methoxy-2-naphthyl) -propionic acid. Crystallization begins to appear as the solution is cooled to 45 ° C.

10

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

15

The wet cake is then transferred directly to 451 ml of methanol and 21.3 ml of toluene and heated to reflux with stirring, cooled to 50 ° C, seeded with the N-methyl-D-glucamine salt of d 2- (6-methoxy-2-naphthyl) ) propionic acid, further cooled to 20 15 ° C for 2 hours, is then kept at 15 ° C for 30 minutes. The solution is filtered and the wet cake washed with 50 ml of 5% toluene in methanol and partially dried to yield 38.77 g, partially dried cake.

The partially dried cake is transferred to 184 ml of water and heated to 80 ° C while stirring. The solution is treated with 0.97 g of decolorizing carbon for 20 minutes. The solution is then filtered through Celite filter aid and the solution is raised to 85 ° C.

30 ml of 3.3 N sulfuric acid were added over 30 minutes to form a precipitate which is substantially enriched in 2- (6-methoxy-2-naphthyl) propionic acid. The solution is kept at 85 ° C for 30 minutes, then cooled to 15 ° C over 2 hours.

The solution is evaporated at 15 ° C for 30 minutes, filtered, washed to neutral reaction and dried. 18.84 g (direct yield = 37.68%) d 2- (6-methoxy-2-naphthyl) propionate are obtained

Example 8.

DK 157003 B

20

The procedure of Example 7 is repeated to obtain 20.02 g (direct yield = 40.0%) d 2- (6-methoxy-2-naphthyl) -prop = 5 pionic acid ([a] Q + 65.4 °).

Example 9

4.60 gd, 1- 2- (6-methoxy-2-naphthyl) propionic acid is heated with 1.95 g of N-methyl-D-glucamine (0.5 equivalents), 23 ml of acetone 10 and 3 ml of water to the reflux temperature of the solvent to dissolve d, l-acid. The solution is cooled to room temperature and seeded with crystals of d- (6-methoxy-2-naphtyl) propionic acid N-methyl-D-glucamine salt to give 2.93 g (i.e.

68% of theoretical yield of d 2- (6-methoxy-2-naphthyl) pro

Λ 5 - Q

pionic acid N-methyl-D-glucamine salt, mp 154-155 C.

The one obtained therefrom in a yield of 98% of the theoretically obtained crude 2- (6-methoxy-2-naphthyl) propionic acid had a specific rotation at 20 ° C [α] + 52.6 °.

Example 10.

4.60 gd, 1- 2- (6-methoxy-2-naphthyl) propionic acid is heated with 2.34 g of N-methyl-D-glucamine (0.6 equivalents), 21 ml of methanol and 2 ml of water until obtained. a solution. The pH of the solution is between 7 and 8. The solution is cooled to room temperature and seeded with crystals of d 2- (6-methoxy-2-naphthyl) propionic acid N-methyl-D-glucamine salt to obtain 2.28 g (i.e.

54% of the theoretical yield of d 2- (6-methoxy-2-naphthyl) propionic acid N-methyl-D-glucamine salt, mp 148-150 ° C.

The crude 2- (6-methoxy-2-naphthyl) propionic acid obtained therefrom in a yield of ca. 96% of theoretical yield has a specific rotation at 20 ° C [a) j = 48.9 °.

Example 11.

DK 157003 E

21 4.60 gd, 1- 2- (6-methoxy acid 2-naphthyl) propionic acid, 1.95 g N-methyl-D-glucamine, and 46 ml isopropanol are subjected to fractional crystallization as described in Example 9 to give 4.04 g of the N-methyl-D-glucamine salt of the d-acid (96% of theoretical yield) melting point of the salt is 150-152 ° C.

The raw acid obtained therefrom in a yield of 98% of the theoretical yield has a "specific rotation of 48.6 °.

Example 12.

Example 11 is repeated except that the isopropanol is replaced with 46 ml of isopentyl alcohol. d-acid salt is obtained in a yield of - 94% of the theoretical yield with a melting point of 150-153 ° C.

The crude acid obtained in yield of 96% of theoretical yield has a specific rotation of 47.7 °.

20

Example 13

100 mg of d, l 2- (6-methoxy-2-naphthyl) propionic acid are heated with 100 mg of HCl salt of N-methyl-D-glucamine in 1.5 ml of methanol 25 until a solution is obtained. The solution is cooled to room temperature and inoculated with crystals of d 2- (6-methoxy-2-naphthyl) propionic acid N-methyl-D-glucamine salt to give 20 mg of d 2- (6-methoxy-2-naphthyl) propionic acid-N -methyl-D-glu = camine salt, m.p. 142r44 ° C.

30

The one obtained therefrom in a yield of 96% of the theoretical yield obtained by raw d-acid has a specific rotation at 20 ° C at [a] + ° = 61.0 °.

35

Claims (2)

Use of N-methyl-D-glucamine or its salts as cleavage agent in the preparation of {+) - 6-methoxy-α-methyl-2-naphthalene acetic acid. Use according to claim 1, characterized in that the preparation comprises fractional crystallization. 35