SI8210720A8 - New process for preparing d-2-(6-methoxy-2-naphthyl)-propionic acid - Google Patents

Description

Field of the Invention (MPK: CO7C65 / 18; A61K31 / 19)

The invention relates to the field of organic chemistry and relates to a new process for the preparation of d-2- (6-methoxy and 2-naphthyl) -propionic acid (naproxen), which is known for its excellent anti-inflammatory properties.The compound is useful in the pharmaceutical industry as a drug preparation substance.

A technical problem

There is a constant need to prepare a right-handed isomer from a mixture of d- and 1-2- (6-methoxy'-2-naphthyl) -propionic acid in a technologically advantageous process.

The state of the art

The compound d-2- (6-methoxy-2-naphthyl) -propionic acid (naproxen, an international unprotected name) is known in the literature for its excellent anti-inflammatory properties. It was first described in U.S. Patent No. 3,904,682. Several processes are known for its preparation that address the synthesis of the racemic mixture of d- and 1- (2- methoxy-2-naphthyl) propionic acid (see, e.g., U.S. Pat. 658 863,

658 858, 3 663 584 and 3 694 770), which are then separated into both optically active antipodes by forming salts with optically active organic bases (see, e.g., French Publication 2 035 846 and U.S. Patent 3 683 015). On the other hand, some procedures are known to deal with the synthesis of racemic. mixtures of d- and 1- 2- (5-halo-6-methoxy-2-naphthyl) -4pr6p ± oishkilx ^and icishlin by separating them into optically active antipodes and finally dehalogenating the d-isomer into the desired end product. British patents 1 274 271, 1 274 272 and 1 274 273 describe e.g. synthesis of compound II as a racemic mixture, but no example is given for separating this mixture into optically active antipodes or for dehalogenating the d-isomer.

Description of solution to a technical problem with implementation examples

The present invention relates to a novel process for the preparation of d-2- (6-methoxy-2-naphthyl) -propionic acid of formula I

The process of the invention can be schematically presented as follows.

I and I halo = halogen, preferably chromium or chlorine

- ή. In accordance with step A, optical separation of the racemic mixture of 2- (5-halo-6-methoxy-2-naphthyl) -propionic acids is carried out via the formation of salts of both isomers with optically active organic bases, taking advantage of the different solubilities of these salts in predetermined systems solvents.

Several optically active organic bases are known from the literature, which have proven to work more or less satisfactorily with a separate mixture of d- and 1- 2- (6-methoxy-2-naphthyl) propionic acid into the corresponding optical antipodes. As an example, alkaloids such as inhonidine or other bases such as h-phenyl-til-aminyl or widely used in such operations are widely used.

dehydroabietylamine, but you have never reported in the literature specific cases of optical separation of a mixture of d- and 12- (5-halo-6-methoxy-2-yl) -propionic acid ·

Surprisingly, we have found that special conditions are required in order to obtain the desired d-2- (5-halo-6-methoxy-2-naphthyl) -propionic acid of the above Formula III in high yields and optical purity. In terms of solvent as the solvent to be used, excellent separation is actually achieved when used as a separating agent N-methyl-D-glucamine, and a solvent system comprising toluene and methanol in different volume ratios.

In the actual embodiment, perform optical separation according to step A of the above scheme by dissolving or

- 5 · suspended in a solvent system formed by a mixture of toluene and methanol, preferably in a volume ratio of toluene / methanol = 4/1 or 3/1, the mole fraction of the substantially racemic mixture of d- and

1-, 2- (5-Lalo-6-methoxy-2-naphthyl) -propionic acid, preferably d- and 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid, half a mole fraction or a slight excess over this amount of Jf-methyl-D-gluamine and an optically inactive organic or inorganic base, such as e.g. triethylamine or sodium or potassium hydroxide. The reaction mixture thus obtained was stirred at substantially room temperature until clear. The solution is then cleaved with a small amount of d-2- (5-halo-6-methoxy-2-naphthyl) -propionic acid, preferably D-2- (5-bromo6-methoxy- 2-naphthyl) -propionic acid to accelerate the precipitation of the desired d-isomer (as the N-methyl-D-glucamine salt) of formula III. This is also advantageous by heating the dense suspension formed after vaccination at a temperature between about 40 and about 65 ° C, preferably at 55 ° C, and allowing the resulting solution to cool to about room temperature. The resulting precipitate, which, as stated above, is N-methylD-glucamine salt of d-2- (5-halo-6-methoxy-2-naphthyl) -propionic acid, preferably d-2- (5-bromo-6 salt -methoxy-2-naphthyl) propionic acid, then treated in a manner known per se,

- 6 e.g. with a strong mineral acid at room temperature to give the desired compound of formula III, in which the bale preferably represents a bromine atom.

The yield of this step is generally greater than 90% (calculated from the molar amount of the d-isomer present in the starting mixture), with the resulting d-isomer being substantially free of the 1-isomer. In fact, the d-isomer of the Formula III dehalogenation reaction can be subjected to the dehalogenation reaction according to step B of the above scheme without undergoing any further purification by recrystallization or analogous methods of operation.

Step B of the above reaction scheme is carried out by treating a molar amount of d-2- (5-halo-6-methoxy-2-naphthyl) propionic acid, preferably 5-bromo compounds, with a suitable hydrogenation system to remove the halogen in position 5- Hydrogenation systems can be diverse. As an example, a hydrogenation system is a hydrogenation catalyst, such as e.g. palladium carbon or finely divided platinum dioxide alone or in admixture with mixed metal hydride, such as e.g. sodium borohydride. Other hydrogenation systems that have produced satisfactory results include a mixture of different proportions of mixed metal hydride and transition metal salts, e.g. sodium borohydride and copper sulphate pentahydrate, sodium borohydride and nickel sulphate, sodium borohydride and cobalt sulphate and the like. Another suitable hydrogenation system is the Devard alloy, i.e. an alloy containing 50 weights. parts of copper, 45 weights. parts of aluminum and 5 weights. parts of zinc, in the presence of mixed metal hydride. A further suitable hydrogenation system, which * has been shown to give the best results in terms of both the final yields of the desired product and the ease of reaction, is a nickel-aluminum alloy, generally in a weight ratio of 50: 50, and hydrazine hydrate , or Ni / Raney and hi irritated hydrate in different proportions.

In the actual embodiments, the dehalogenation reaction (step B of the above scheme) is carried out by storing, under alkaline conditions, the amount of d-2- (5-halo-6-methoxy-2-naphthyl) propionic acid, preferably d-2- (5-bromo) -6-methoxy-2-naphthyl) -propionic acid, in contact with a suitable amount of one of the hydrogenation systems shown above.

Generally, this amount is selected in such a way as to ensure complete replacement of the halogen atom in position 5 of the compound of formula III with a hydrogen atom. The reaction is carried out at a temperature between about room temperature and about 100 ° 0, but it has been found that a lower temperature interval between about room temperature and about 50 ° C can be used if 50:50 (weight) alloys are used as hydrogenation systems nickel with aluminum and hydrazine ^; hiiirat \ Mi3iii /

Raney and hydrazine hydrate. In general, a time interval of about 1 to about 4 hours is sufficient to complete the reaction.

- 8 -

Stage B is practically quantitative yields and the resulting end product, i.e., d-2- (6-methoxy2-n-phthyl) -propionic acid _t, exhibits a specific entity that fully complies with the standards shown in Appendix 1978 to the British Pharmacopoeia .; 1975 · Given that even the gains of Grade A are never less than 90% (calculated from the amount of d-isomer present in the starting. ^ bil— mixture), it can be seen that the present invention provides a new and useful process for the preparation of valuable pharmaceutical compounds, namely d-2- (6-methoxy-2-naphthyl) -propionic acid. Finally, it should be emphasized that the above-described dehalogenation process can be carried out under the same reaction conditions if we proceed from a substantially racemic mixture of d- and 12- (5-halo-6-methoxy-2-naphthyl) -propionic acid, a mixture of d- and 1- 2- (6-methoxy-2-aftyl) -propionic acid can then be separated into the corresponding optically active antipodes according to the procedure described in Italian application 3492 A / 80, filed July 30 * 198θ · In accordance a solution of a mixture of d- and 1- 2- (6-methoxy-2-naphthyl) propionic acid and an optically active organic base, e.g. cinchonidine by dissolving substances in an organic solvent selected from formamide, mono- and dimethylformamide, monoin diethylformamide, mono- and dimethylacetamide, at a temperature between about 70 and about 90 ° 0. The solution thus obtained

- 9 is slowly cooled and is cleaved at a predetermined temperature by a small amount of a salt of d-2- (6-methoxy-2-naphthyl) propionic acid with an optically active organic base, containing this salt by weight of the amount of reaction solvent used. varies from about 9.5% to Ί4%. A precipitate is formed consisting essentially of a salt of the d-isomer with an optically active organic base, and this salt still contains the amount of reaction solvent used that varies within the upper percentages from which it is obtained by conventional methods of working d-2- ( 6-Methoxy-2-naphthyl) -propionic acid in practically pure form.

The starting compound of formula II, namely d, 1-2 (5-halo-6-methoxy-2-naphthyl) -propionic acid, can be prepared according to various methods of operation. One of these comprises a multi-step process derived from 1-halo-2-methoxynaphthalene of the formula

in which the halo represents a halogen atom and is carried out according to the following reaction scheme:

Thus, according to the above scheme, the compound IV is molar with an excess of acetyl chloride at a temperature between about 0 and 10 ° in the presence of a halogenated hydrocarbon as a reaction solvent. These are typical conditions for a Priedel-Orafts reaction, even if it is not advantageously used as a nitrobenzene reaction solvent. In addition, greater yields of the acetylated compound were observed. The 2-acetyl-5-halo6-methoxy-naphthalene thus obtained is converted by Darzens reaction into a compound

- 11 VI, which is first hydrolyzed at room temperature for about 46 hours with an aqueous solution of alkali metal hydroxide and then decarboxylated to compound VII, i.e. d, 1-2- (5halo-6-methoxy-2-naphthyl) -propionaldefecid *, The fading stages deal with the formation of an oxime of formula VIII by treating an aldehyde of formula VII with hydroxylamine hydrochloride and then treating the oxime with a strong alkali agent, such as · potassium hydroxide in the presence of ethylene glycol at a temperature between about 100 and about 140 ° C for a period of about 5 to about 8 hours. The benefits of this multi-level way of working are virtually quantitative. Another useful process for preparing the starting compound d, 1-2- (5halo-6-methoxy-2-naphthyl) -propionic acid comprises hydrolysis of a compound of the formula

CH-COi ICH

I

CH

n.

halo 'namely, d-1- (5-halo-6-methoxy-2-naphthyl) propionic acid halo'-ethyl ester, in which each halo and halo' represent each independently a halogen atom, under mild alkaline conditions. Compound IX, however, is prepared as described in European

- 12 published application 35305. Other obvious processes for preparing the starting compound of formula II fall within the scope of the present invention.

In order to better illustrate the invention, the following examples are given.

- 13 EXAMPLE 1

Preparation of a starting compound of formula II in which the halo is a chromium atom, namely d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid

k) 2-acetyl-3-chromo-6-methoxy-naphthalene (Compound V)

A suspension of 43 g of alkaline AlCl ^ and 24.6 g (0.313 mol) of acetyl chloride in 200 ml of 1,2-dichloroethane at 10 ° 0 was cooled to 0 ° C and a solution of 59.25 g (0.250 mol) was added dropwise. Of 1-bromo-2-methoxy-naphthalene in 150 ml

1,2-dichloroethane. The resulting solution was stirred for 15 minutes, then poured into a cold solution of 300 ml of water and 100 ml of 22N hydrochloric acid. The organic phase was separated, washed first with 100 ml of 1 N hydrochloric acid and then with 100 ml of water, dried under vacuum and the resulting residue was crystallized from 2-butanol. Yield 68.11 g (98%).

B) d »j: 7'5- ^ ^{) rol31o} ' ^l ' ^ '~ ^me ^ oxy-2-naphthyl-prepionaldehyde d (compound VII)

To a mixture of sodium 2-butoxide (prepared from 9 »28 g of sodium and 164 ml of 2-butanol) and 120 ml of toluene maintained at 10 ° 0 was added 55» 8 S (0.2 mol) of the compound prepared under A), and 42.4 ml of ethyl chloroacetate. The resulting mixture was stirred for 3 hours at 10 ° C, then 200 ml of water was added, the organic layer was separated and a solution of 45 g of 85% potassium hydroxide was added under vigorous stirring.

After stirring at room temperature for 5 hours, a solid precipitate was obtained, which was filtered, washed with 100 ml of 50:50 (v / v) toluene / 2-butanol and suspended in 200 ml of water.

- 14 The aqueous suspension was heated at 100 ° C for 0 hour and then cooled to room temperature, yielding 57 S (almost quantitative yield) of compound VII.

0) d <yl-2- (5-bromo-6-niethoxy-2-naphthyl) -propionaldoxine (compound VIII)

49.8 g (0.170 mol) of aldehyde VII was dissolved at room temperature in 100 ml of water and 100 ml of chloroform and then a solution of 15.9 g of hydroxylamine hydrochloride in 50 ml of water was added while maintaining the pH of the reaction mixture between 6 and 7 with aqueous sodium carbonate solution. The resulting mixture was stirred for 50 minutes, precipitating the title compound obtained by filtration. After concentrating the chloroform mother liquors, further yield of the title compound was collected. Yield 50.25 g (96%).

D) d, 1- 2- (5-Bromo-6-methoxy-2-naphthyl) -propionic acid (compound II)

A solution of 22.5 g of 85% potassium hydroxide in 55 ml of ethylene glycol was heated to 70 ° and then 45 g (0.146 mol) of oxime prepared under C) was added. The solution was then heated at 120 ° C for 7 hours, cooled to 90 ° 0, and 450 ml of water was added. After extraction with 500 ml (2x150 ml) of methylene chloride, the aqueous phase was first warmed to 90 ° C and then brought to pH 4 with acetic acid.

- 15 The resulting suspension was cooled to 25 ° 0, filtered, and the solid obtained was washed extensively with water and dried. Yield 45 g (98%) of d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid.

EXAMPLE 2

Preparation of a starting compound of formula II in which the halo is a bromine atom, namely d, 1- 2- (5-bromo-6-methoxy-2-naphthyl) propionic acid

37j4 g (0.0905 mol) of 2-bromoethyl ester of d, 1- (2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid was suspended in 100 ml of methanol and 27.5 ul of water to form a suspension. 12.5 S of 90% potassium hydroxide was added and the whole was heated to 30 ° C. The mixture was stirred vigorously for 2 hours, then concentrated to low volume and taken up with 100 ml of water. The aqueous solution was washed with 150 ml of 1,2Bchloroethane, then adjusted to a pH of about 2 by the addition of concentrated hydrochloric acid at 50 ° C. After cooling to room temperature, the precipitate obtained was filtered, washed with water and dried. Profit?

27 »3 g (98%) of the title compound.

- 16 EXAMPLE 3 d-2- (5-Bromo-6-methoxy-2-naphthyl) -propionic acid

To a flask containing 360 ml of toluene, ml of methanol and 26 ml of triethylamine, 116 g (0.376 mol) of d, 1-2- (5-bromo-6-methoxy-2-naphthyl) was added at room temperature while stirring. -propionic acids and 36.5 S (0.186 mol) of N-methyl-D-glucamine. The clear solution thus obtained was then cleaved with 0.5 g of N-methyl-Dglucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid; after 3θ minutes a thick suspension was formed. This suspension was heated to 55 ° C and slowly cooled to 20 ° G, then filtered and the resulting solid was washed with 180 ml of 80:20 (v / v) mixture of toluene and methanol.

The wet solid was dissolved in 500 µL of water and 600 ml of ethyl acetate, the pH of the solution was adjusted with concentrated hydrochloric acid to 3, the organic layer was then washed with water and then concentrated to dryness in vacuo. Yield 56.26 g (97% of theory) of d? 2- (5bromo-6-methoxy-2-naphthyl) -propionic acid · [a] | ° ₈ = +47.5 ⁰ (o = o, 5% in OHOlj).

EXAMPLE 4 d-2- (6-Methoxy-2-naphthyl) -propionic acid

To a solution of 8 <g sodium hydroxide in 150 ml of water was added 35 "5 g (0.109 mol) of d-2- (5-bromo6-methoxy-2-naphthyl) -propionic acid and 2 g of 5%

- 17 palladium on charcoal. The reaction temperature was lowered to 50 ° C, then a solution of 3 S sodium borohydride in 30 ml of slightly alkaline water was added dropwise over 1 hour. After stirring for 13 minutes and cooling to 30 ° C, the catalyst was removed by filtration on Dicalite and 400 ml of ethyl acetate were added to the filtrate. The solution of jpH was concentrated to 3 with concentrated hydrochloric acid and the organic phase separated, washed with water until neutral and dried under vacuum.

Yield of 23.7 S (95% theoretical) of d-2- (6-methoxy-2naphthyl) -propionic acid.

Ca] f ° »+65.5 ⁰ (C = 1% v- OHOip, mp = 154 · to 155 ° 0.

EXAMPLE 5 d-2- (6-Methoxy-2-naphthyl) -propionic acid

To a solution of 2.5 g copper sulphate pentahydrate, 12.5 g 90% potassium hydroxide and 30.9 g (0.1 mol) of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic of acid in 150 ml of water was first added 1 g of charcoal and then dropwise while stirring a solution of 3.8 g of sodium borohydride in 40 ml of slightly alkaline water. During the addition of the first third of this sodium borohydride solution, the temperature of the reaction mixture was gradually raised to 80 ^Q 0, then a further 5.1 g of 90% potassium hydroxy was added.

- 18 and the remaining sodium borohydride solution was added at the same temperature for about 2 hours. After the addition was complete, the reaction mixture was stirred for $ 0 minutes, cooled to 50 ° C and the catalyst filtered off. The resulting filtrate was heated to 50 DEG C., the pH was adjusted with concentrated hydrochloric acid to 2, the solution was cooled to 20 DEG C. to form a solid obtained by filtration, washed with water until dry and dried. Yield 22.4 g (97% of theory) j Coo3§ ° = +66 ⁰ (0 = 1% and CH01 ₅ ). Tal. = 154 to 155 ° C.

EXAMPLE 6 d-2- (6-Methoxy-2-naphthyl) -propionic acid

A mixture of 25 ml of 40% (w / v) aqueous sodium hydroxide solution and 150 ml of water was heated to 40 ° 0 and 50.9 S (0.1 mol) of d-2- (5-chromo-6-methoxy2) was added. -Naphthyl) -propionic acid, After 5 minutes a clear solution was added and added to it under a nitrogen atmosphere

1.2 g 50% aqueous Ni / Raney suspension. The reaction temperature was brought to 50 ° C, then a solution of 4 ml of 100% hydrazine hydrate in 40 ml of water was added dropwise in about 90 minutes. After cooling and filtration of the catalyst, 150 ml of water was added to the filtrate, the resulting solution was heated to 80 ° C and adjusted to a concentrated concentration.

- 1.9 Hydrochloric acid pH to 2. After cooling to room temperature, the precipitate formed is obtained by filtration, washed with water until neutral and dried. Yield 22.5 6 (98% of theory).

[<x3 ^ ° = +68,4 ⁰ (C = 1% in OHOip. m.p. 155 to 156 ° 0.

EXAMPLE 7 d-2- (6-Methoxy-2-naphthyl) -propionic acid

We poured 11.4 l of water into a 54 liter container,

1.7 kg of aqueous 40% (w / v) sodium hydroxide solution and 1560 kg of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid and the resulting solution warmed to 50 ⁰ under a nitrogen atmosphere and 60 g of 5θ ^: 5Ο (»te / m) nickel alloy with aluminum was added. After stirring for 50 minutes at the same temperature, a solution of 0.128 11100% hydrazine hydrate in 1.28 l of water was added dropwise over 2 hours while stirring.

Stirring was continued for a further 50 minutes and then, after addition of 80 g of Dicalite and adjusting the pH to 9 with concentrated hydrochloric acid, the whole was filtered. The filtrate was heated to 80 DEG C., concentrated with concentrated hydrochloric acid to pH 5 ", cooled to 55 DEG C. and the solid obtained by filtration. After washing with water to neutrality and drying, 1,140 kg of the title compound were obtained. Profit

- 20 98% of theory.

[οϋβθ = +67 ⁰ (C = 1% in CHCip. m.p. 155 to 156 ° C.

EXAMPLE 8 Compound d, l-2- (6-Methoxy-2-naphthyl) -propionic acid was prepared following essentially the same methods as in Examples 4 to 7, starting from d, l-2 - (5-Bromo-6-methoxy-2-naphthyl) -propionic acid. Tal. 154- to 155 ° θ ·

Optical separation to give d-2- (6-methoxy2-naphthyl) -propionic acid was performed as described in Italian Patent Application 54-92 A / 80. Tal. of the final product: 155 ° C> La3 ^ ° = +66.5 ⁰ (0 = 1% in OHCl ^).

Citation for the best applicant known method for economically exploiting the claimed invention d-2- (5-'bromo-6-methoxy-2-naphthyl) -propionic acid

To a flask containing 360 ml of toluene, ml of methanol and 26 ml of triethylamine were added at room temperature while stirring 116 g (0.576 mol) of d, 1-2- (5-br omo-6-me t oxy-2- naphthyl) -propionic saliva and 56.5 S (0.186 mol) of N-methyl-D-glucamine. The clear solution thus obtained was then cleaved with 0.5 g of N-methyl-Dglucamine salt of d-2- (5-bromo-6-methoxy-2-naphthyl) -propionic acid; after 50 minutes a thick suspension was formed. This suspension was heated to 55 ° ^C and cooled slowly to 20 ° C, then filtered and the solid was washed with 180 ml of 80:20 (v / v) mixture of toluene and methanol.

The wet solid was dissolved in 5θθ ml water and 600 ml e til acetate, and the pH of the solution was adjusted with concentrated hydrochloric acid to 5 »organic layer, then washed with water and then concentrated to dryness in vacuo. Yield 56.26 g (97% of theory) of d * 2- (5bromo-6-methoxy-2-naphthyl) -propionic acid.

[α] | θθ = +47.5 ⁰ (C = 0.5% in CHOip.

d-2- (6-Methoxy-2-naphthyl) -propionic acid

A mixture of 25 ml of 40% (w / v) aqueous sodium hydroxide solution and 15θ ml of water was heated to 40 ° C and 50.9 g (0.1 mol) of d-2- (5-bromo-6-methoxy2) was added. -naphthyl) -pr opic acid, After 5 minutes a clear solution was added and added to it under a nitrogen atmosphere.

- ² ζ1.2 g 50% Ni / Raney aqueous suspension. The reaction temperature was brought to 50 ° C, then a solution of 4 ml of 100 ^c / e-hydrazine hydrate in 40 ml of water was added dropwise over about 90 minutes. After cooling and filtration of the catalyst, 150 ml of water was added to the filtrate, the resulting solution was heated to 80 ° C and adjusted with concentrated hydrochloric acid to pH 2. After cooling to room temperature, a precipitate formed, which was obtained by ^: * ~~ filtration. washed with water to neutrality and dried. Yield 22.5 S (98% of theory).

[<x] 2 ° = +68.4 ⁰ (C = 1% in CHOip. mp 155 to 156 ° C.

Claims (3)

PATENT APPLICATIONS A process for the preparation of d-2- (6-methoxy-2-naphthyl) -propionic acid of the formula characterized in that a racemic mixture of d- and 1- 2- (5-bromo-6methoxy-2-naphthyl) is treated - propionic acid of formula X d, 1 with N-methyl-D-gluamine in the presence of a toluene / methanol mixture and in the presence of triethylamine at a temperature between about room temperature and about 55 ° C, the less soluble N-methyl-D-glucamine salt d-2 is separated - (5-Bromo-6-methoxy-2-naphthyl) -propionic acid, treat this salt with a strong mineral acid such as hydrochloric acid to give the free acid of formula XI Nr d. and catalytically dehalogenize this free acid with a hydrogenation catalyst such as 5% palladium on carbon and sodium borohydride or copper sulfate pentahydrate and sodium boro-2 ^ hydride or a nickel and aluminum alloy and 100% hydrazine hydrate or Raney 100% nickel or hydrazine hydrate in an aqueous solution of sodium or potassium hydroxide at a temperature between about room temperature and about 100 ° C. A process according to claim 1, characterized in that the lumetric ratio of toluene to methanol is 4: 1 or 3: 1 Process according to claim 1 or 2, characterized in that about half a mole fraction of N-methyl-D-glucamine is used.