HU203896B - Process for producing glycosides of aromatic amines - Google Patents

Abstract

The present invention is directed to a new process for preparing anomer pure N-glycosides or acid additon salts thereof of general formula (I), wherein R stands for a glycosyl group, n stands for 1, 2 or 3, A stands for an aromatic system, selected from a benzene ring, a 5-membered ring containing 1 heteroatom, the heteroatom being nitrogen and a 6-membered ring containing 2 heteroatoms, the heteroatoms being nitrogen or nitrogen and sulfur, a 6-membered ring containing 3 heteroatoms, the heteroatoms being nitrogen, a condensed ring system consisting of 2 or 3 rings, one member of which is the above ring, with the provision that the glycoside nitrogen atom(s) is (are) attached to aromatic nucleus (nuclea), S stands for an acid residue, p stands for 1, 2 or 3, m stands for 0 or 1, R1 and R2 are the same or different, and stand for hydrogen, halogen, amino-, sulfonamido-, nitro-, C1-4 straight or branched saturated or unsaturated alkyl or alkoxy group, carboxyl, C1-4 carbalkoxy, phenyl, substituted phenyl, heterocyclic or substituted heterocyclic group, by reacting a compound of general formula (II) or an acid addition salt thereof, wherein R1, R2, A, X, n, p and m are as given above, with the provision that the amino group(s) to be glycosylated is (are) attached to aromatic nucleus (nuclea) - with hexose, pentose, desoxy-, desoxy-amino, hexose or pentose derivatives or oligosaccharides in the presence of a protic acid catalyst which comprises carrying out the reaction in water preferably in the presence of hydrochloric acid in a catalytic amount at a temperature of 18-90 DEG C and isolating the product preferably by a direct filtration of the reaction mixture, or by separating first with an organic solvent, preferably ethanol, acetone or a mixture of ethanol and acetone and drying the product subsequently.

Description

The present invention relates to a process for the preparation of compounds of the formula R-NH-A-Ri wherein A is phenylene or naphthylene,

R is β-D-glucopyranosyl, β-D-xylopyranosyl, β-L-arabinopyranosyl, α-L-rhamnopyranosyl, β-D-galactopyranosyl, β-D-mannosopyranosyl, β-lactosyl,

R 1 is hydrogen, sulfonamido, nitro, C 1 -C 4 alkyl, or -COOR 2

- wherein R 2 is hydrogen,

To form a C 1 -C 4 alkyl group or an alkali metal atom by reacting a compound of formula H 2 N-A-R 1 '

- in the formula

A has the meaning above,

R 1 'is hydrogen, sulfonamido, nitro, C 1 -C 4 alkyl, or -COOR 2' where R 2 'is hydrogen or C 1 -C 4 alkyl and glucose, xylose, arabinose, rhamnose, galactose, mannose, or lactose reacting in the presence of a protic acid catalyst by reaction in an aqueous medium, reacting 1-4 moles of mono- or disaccharide per mole of the amino-containing compound at a temperature of 20-95 ° C, and recovering the product in a known manner and optionally reacting a compound of formula R-NH-A-R 1 wherein R and A are as defined above, R 1 is -COOR 2, wherein R 2 is hydrogen, with an alkali metal hydroxide.

N-glycosides or N-glycoside derivatives of aromatic amines include a number of compounds having broad pharmacological properties or having significant biological activity.

Several methods are known in the art for the preparation of N-glycosides. For example, secondary glycopyranosylamines or their peracylated derivatives can be prepared by acid-catalyzed condensation of primary amines and sugars in an organic solvent medium or by the Koenigs-Knorr reaction of acyl halogen sugars in an alkaline medium [Chem. Wage. 34, 957 (1901)].

According to the Kuhn process, aromatic amines are boiled with the corresponding sugar in methyl or ethyl alcohol in the presence of a catalytic amount of ammonium chloride, hydrochloric acid or sulfuric acid [Chem. Wage. 68. 1765 (1935) 73. 1745 (1940)].

The main disadvantage of the method is that sugars are poorly soluble in anhydrous alcohols, which causes an increase in reaction time and can lead to the formation of O-glycosides.

In Weygand's method, which is particularly suitable for the preparation of N-glycosides of highly aromatic amines, the aromatic amine and sugar are homogeneously melted in the presence of a catalytic amount of acid, and the product crystallized by addition of alcohol [Chem. Wage. 72, 1663 (1939), 73, 1239 (1940)].

The yield of the process is between 44 and 92%, depending on the reaction partners. The disadvantage is that anomeric mixture is formed at the end of the reaction.

Pigman describes an aqueous alcoholic solvent system for the preparation of N-glycosides. However, since the reaction is carried out without the use of a catalyst, the reaction time is extremely increased [J. OIG. Chem., 22, 1727 (1957)].

N-glycosides can also be prepared by overglycosylation by reacting a readily available N-glycoside with the amine component of the desired new N-glycoside to produce the desired N-glycoside simultaneously with the release of the old alkaline (amine) [R. Bognár, P. Nánási, Natúre 171,475 (1953).

Saponification of acylated N-glycosides also leads to N-glycosides. However, this method assumes relatively easy availability of the starting material. The acylated derivative can be prepared either by the modified Koenigs-Knorr reaction by reacting the acyl halide sugar with the desired amine in an inert solvent or solvent mixture, such as potassium hydroxide, silver oxide, mercuric cyanide, and the like. sugars or peracylated sugars according to Frerejacque are treated with an excess of amine per aglycone in the presence of little acetic acid. At different rates depending on the basicity of the amines, the C 1 -acetyl group is converted to the amine by transacylation, whereupon the C 1 -hydroxy group is regenerated and then reacts with the free amine on the free semacetal or glycosidic group. (Evans et al., Advances in Carbohydrate Chem. 6.41 (1951); M. Frerejacque, Compt Rend. 202, 1190 (1936)].

Pharmacologically significant and commercially valuable N-glycoside derivatives are prepared by the above-mentioned processes or modified versions thereof.

For example, glycopyranosyl derivatives of aminobenzoic acid are prepared in 95-100% ethyl alcohol or methanol in the presence of ammonium chloride according to Belgian Patent Nos. 875,399 and 2,056,856.

In each of the processes described, anomeric mixture of N-glycosides is formed. The preparation of pure anomers requires various purification operations and isolation! means difficulties.

A further disadvantage is that O-glycoside formation also occurs as a competitive reaction in processes employing a solvent system containing alcohol. The purification of the by-product O-glycoside requires further purification.

In addition, glycosylation reactions in solvent mixtures will in all cases result in a hardly identifiable "polar product", the removal of which will result in the production of pure product in low yields only.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a simple and economical process for the preparation of N-glycosides of aromatic amines in which the desired product is obtained in high yield and in anomerically pure form.

On the one hand, the present invention is based on the surprising discovery that, unlike prior art, the reaction is carried out in a purely aqueous solution without the use of an organic solvent.

On the other hand, it takes place selectively in such a way that the desired N-glycoside is formed in anomerically pure form and can be recovered from the reaction mixture.

According to the present invention, compounds of the formula R-NHA-Ri, wherein A is phenylene or naphthylene,

R is β-D-glucopyranosyl, β-D-xylopyranosyl, β-L-arabinopyranosyl, α-L-rhamnopyranosyl, β-D-galactopyranosyl, β-D-mannopyranosyl, β-lactosyl,

R 1 is hydrogen, sulfonamido, nitro, C 1 -C 4 alkyl or -COOR ₂ where R 2 is hydrogen, C 1 -C 4 alkyl or alkali metal to form a compound of formula H 2 N-A-R 1 'in which

A has the meaning above,

R f is hydrogen, sulfonamido, nitro, C 1 -C 4 alkyl, or -COOR? a group of the general formula wherein R ₂ 'is hydrogen or (C 1 -C 4) alkyl, and glucose, xylose, arabinose, rhamnose, galactose, mannose or lactose are reacted in the presence of a protic acid catalyst by reacting the amino group with an aqueous medium. 1-4 moles of mono- or disaccharide per mole of the compound at a temperature of from 20 to 95 ° C and recovering the product in a manner known per se, and optionally R-NH-A-Ri wherein R and A are above, R 1 is -COOR? wherein R 1 is hydrogen is reacted with an alkali metal hydroxide.

A further feature of the process is that the reaction is carried out in a very short time in the presence of a catalytic amount of acid, preferably hydrochloric acid.

In the event that any of the reaction partners 40 is poorly soluble in water, it is advisable to warm the initial suspension to 80-90 ° C for a few minutes, and continue to bubble until the reaction mixture becomes a homogeneous solution. The reaction takes place in a short time. 45

The target product can be isolated by direct filtration as long as the target product is insoluble in water.

By optimizing the amount of water used as the reaction medium for the particular reaction partners, the target product can be obtained in 60-90% yield and 95-100% purity. If necessary, the product may be recrystallized from a few drops of water containing ammonia solution.

Example 1 55

4- (beta-D-glucopyranosyl-amino) benzenesulfonamide

4-Aminobenzenesulfonamide (deseptyl) (1.72 g, 10 mmol) and D-glucose monohydrate (2.18 g, 11 mmol) were suspended in water (20 mL). 0.5 ml of 2N hydrochloric acid was added. The reaction mixture was heated to 80 ° C, then allowed to cool, and crystallization was initiated by seed crystals. The crystals were filtered and air dried. The crude product was recrystallized from water containing little ammonia.

Yield: 2.65 g (79.3%)

M.p. 211-212 ° C [α] 20 DEG -85.6 ° [c-0.48, dimethylformamide (DMF)]

Example 2

3- (β-D-Glucopyranosylamino) nitrobenzene 138 g (10 mmol) m-nitroaniline and 3.96 g (20 mmol)

D-glucose monohydrate was suspended in 4 ml of water. 1 ml of 2N hydrochloric acid solution was added and the reaction mixture was heated at 60 ° C for 5 minutes. After cooling, a thick mass was obtained which was triturated with 2 ml of water and the solid filtered. It was recrystallized from ethanol.

Yield: 1.13 g (37.6%)

M.p. 183 'C [α] g -124.9' (c-0.46, DMF)

Example 3

4- (ss-D-glucopyranosyl-amino) -benzoic acid methyl ester

141 g (10 mmol) of methyl 4-aminobenzoic acid and 2.38 g (12 mmol) of D-glucose monohydrate were suspended in 20 ml of water. 2N HCl (03 mL) was added and the reaction mixture was heated at 60 for 5 min. After cooling, the crystals were filtered off and air dried.

Yield: 1.90 g (60.6%)

M.p. 192-196 ° C [α] D -102.8 '(c-0.33, DMF)

Example 4

4- (| i-D-glucopyranosyl-amino) -toluene

1.07 g (10 mmol) of p-toluidine and 3.96 g (20 mmol) of D-glucose monohydrate were suspended in 8 mL of water. 0.2 ml of 2N hydrochloric acid was added and the reaction mixture was heated at 80 ° C for 2 minutes. After cooling, the crystals were filtered and air dried.

Yield: 1.54 g (57.2%)

120-130 ° C [α] g> -85.2 '(c-0.41, DMF)

Example 5

4- (3-D-xylopyranosyl) -benzoic acid methyl ester

141 g (10 mmol) of methyl 4-aminobenzoic acid and 3.0 g (20 mmol) of D-xylose were suspended in 8 ml of water and 0.2 ml of 2N hydrochloric acid was added. The reaction mixture was kept at 90 ° C for 2 minutes and then allowed to cool. Crystallization started under mechanical influence. The precipitated crystals were filtered off and air dried.

Yield: 2.60 g (91.8%)

M.p. 168-172 ° C [α] D -38.2 '(c-0.17, DMF)

Example 6

4- (ss-D-xylopyranosyl) benzoic acid

141 g (10.0 mmol) of 4-aminobenzoic acid and 3.0 g (20 mmol) of D-xylose were suspended in 30 ml of water. THE

The reaction mixture was heated to 90 ° C and maintained at this temperature for 5 minutes. After cooling, the crystals were filtered off and air dried.

Yield: 2.18 g (80.9%)

180 DEG C. (with decomposition) [.alpha.] D @ ³ to -38.3 DEG (c 0.29, DMF).

Example 7

Sodium 4- (p-D-xylopyranosyl) benzoate

8 g of 4- (P-D-xylopyranosylamino) benzoic acid prepared according to Example 6 were suspended in 20 ml of water. Under vigorous stirring, 20% sodium hydroxide solution was added dropwise until the material was dissolved. With continued stirring, after slowly adding 300 ml of ethanol, the resulting precipitate was filtered off and air dried.

Yield: 8.42 g (97.3%)

172-176 'C (with decomposition) [<x] 8> - 41.29' (c-0.39, water)

Example 8

4- (3-lactosyl-amino) -benzoic acid methyl ester

1.51 g (10.0 mmol) of methyl 4-aminobenzoic acid and 7.20 g (20 mmol) of lactose monohydrate are suspended in 20 ml of water. 0.2 ml of 2N hydrochloric acid was added and the reaction mixture was heated at 80 ° C for 10 minutes. After cooling, excess lactose was precipitated by addition of 150 ml of acetone and filtered. The filtrate was neutralized with ammonia solution and evaporated. The residue was crystallized from ethanol.

Yield: 1.46 g (30.7%)

200-206 'C [<x] g> -72.6' (c-0.41, DMF)

Example 9

4- (3-L-arabinopyranosyl) -benzoic acid

A mixture of 1.37 g (10 mmol) of p-aminobenzoic acid and 3.0 g (20 mmol) of L-arabinose was suspended in 12 mL of water. The reaction mixture was heated at 80 ° C for 5 minutes and then allowed to cool. Crystallization was initiated by mechanical action. The precipitated crystals were filtered off and air dried.

Yield: 2.04 g (75.8%)

146-152 'C (with decomposition) [?] 2> -23.9' (c-0.37, DMF)

Example 10

4- (a-L-rhamnopyranosyl-amino) -benzoic acid methyl ester

A mixture of 1.51 g (10 mmol) of methyl 4-aminobenzoic acid and 3.64 g (20 mmol) of L-rhamnose monohydrate was suspended in 20 ml of water. 0.2 ml of 2N hydrochloric acid solution was added and the reaction mixture was heated at 60 ° C for 8 minutes. After cooling and standing for 2 hours, the crystals were filtered off and air dried.

Yield: 2.80 g (94.2%)

M.p .: 204-208 'C

- +154.8 '(c-0.73, DMF)

Example 11 (β-D-Galactopyranosylamino) benzene

To a mixture of 0.93 g (10 mmol) of aniline, 3.60 g (20 mmol) of D-galactose and 8 ml of water was added 0.2 ml of 2N hydrochloric acid 5 and the reaction mixture was heated at 60 ° C for 5 minutes. After cooling, the crystals were filtered and air dried. Yield: 1.28 g (50.2%)

M.p .: 158-160 ° C [a] # ¹ --71,5 ° (c = 0.95, DMF)

Example 12

- (p-D-mannopyranosyl -propionic naphthalene

1.45 g (10 mmol) of 1-aminonaphthalene and 3.60 g (20 mmol) of D-mannose were suspended in 8 ml of water. 0.4 ml of 2N hydrochloric acid was added and the reaction mixture was heated at 80 ° C for 5 minutes. After cooling, crystallization was initiated by mechanical action. After standing for two hours, the crystals were filtered off and air dried. Yield: 2.11 g (69.1%)

M.p. 190-193 'C [α] g * -104.6' (c-0.48, DMF)

Claims (1)

1. A process for the preparation of compounds of formula R-NH-A-Ri A is phenylene or naphthylene, R is β-D-glucopyranosyl, β-D-xylopyranosyl, 30 β-L-arabinopyranosyl group, α-L-rhamnopyranosyl group, β-D-galactopyranosyl group, β-D-mannopyranosyl group, β-lactosyl group, 35 R, is hydrogen, sulfonamido, nitro, C 1-4 alkyl or -COOR 2 - wherein R ₂ is hydrogen, C1-4 alkyl or alkáli40 metal atom - of producing a H ₂ NA-R 'compounds of the formula: - wherein A has the meaning above, R 1 'is hydrogen, sulfonamido, nitro, C 1 -C 4 alkyl, or 45 'COOR ₂ * - wherein R ₂ ' is a protic acid catalyzed reaction of a hydrogen or C 1 -C 4 alkyl group with glucose, xylose, arabinose, rhamnose, galactose, mannose or lactose in an aqueous medium At last, 1-4 moles of mono- or disaccharide per mole of compound containing the amino group are reacted at a temperature of 20-95 ° C, and the resulting product is recovered in a known manner and optionally R-NH-A-R 1 Wherein R and A are as defined above, R 1 is -COOR ₂ wherein R ₂ is hydrogen is reacted with an alkali metal hydroxide.