PROCESS FOR THE PREPARATION OF ANOMER PURE GLYCOSIDES OF AROMATIC AMINES

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: Process for the preparation of aπomer pure glycosides of aromatic amines The present invention is directed to a new process for the preparation of N-glycosides or acid addi¬ tion salts thereof of aromatic amines. The N-glycosides can be characterized by the general formula (I) where in R stands for a glycosyl group, n stands for 1, 2 or 3, A stands for an aromatic system, selected from benzene ring, a 5-mernbered 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 hetero¬ atoms, the heteroatoms being nitrogen, a con¬ densed 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, R, and R 2 are the same or different, and stand for hydrogen, halogen, amino-, sulfonamido-, nitro-, C, . straight or branched saturated or unsaturated alkyl or alkoxy group, carboxyl, C, . carbalkoxy, phenyl, substituted phenyl, heterocyclic or substituted heterocyclic group. The compounds of the general formula (I) can be prepared by reacting a compound of the general formula (ID or an acid addition salt thereof - wherein R, , R ? , A, S, 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) - and hexose- pentose-, desoxa-, desoxy-amino-, hexose- or pentose- derivatives or oligosacharides in the presence of a protic acid catalyst by carrying out the reaction in water, prefer ably in the presence of hydrochloric acid in a catalytic amount and isolating the product by filtration or by adding organic solvent, preferably ethanol, acetone or ethanol and acetone followed by filtration. As opposed to the so far known processes the process according to the present invention results in an anomer pyre endproduct and by the new process the pharmacologically active or more active anomer can be isolated by a simple method avoiding the expensive separa¬ tion from the other anomer. Among the N-glycosides or N-glycoside derivatives of aromatic amines many compounds exhibit pharmacological properties or significant biological activity. There are many processes known for the prepara¬ tion of N-glycosides. Thus, for instance secondary glyco- pyranozyl amines or peracylated derivatives thereof can be prepared by the condensation of primary amines and sugars in the presence of an acid catalyst in organic solvents or by Koenigs-Knorr reaction of acyl-halo sugars carried out in alkaline medium (Che . Ber. 34 957 1901). According to Khuπ-process aromatic amines and the corresponding sugars are reacted in methanol or ethanol in the presence of ammonium chloride, hydrochloric acid or sulfuric acid by boiling the reaction mixture (Chem. Ber. 6B. 1765 (1935); 69. 1745 (1940)). The disadvantage of this method is the poor solubility of sugars in anhydrous alcohols and this property leads to the in¬ crease of the reaction time and to the formation of 0-glycoside. According to the method of eygaπd which is suitable for N-glycosides of aromatic amines of particularly strong basic character, the aromatic amine and sugar are converted to a homogeneous melt in the presence of an acid in catalytic amount and the crystal¬ lization of the formed product is promoted by the addi¬ tion of alcohol (Chem. Ber. 72. 1663 (1939); 73. 1239 (1940)). Pigmaππ described for the preparation of N-glycosides a solvent system of aqueous alcohol, but the reaction is carried out without any catalyst, there¬ fore the reaction time is extremely long (3. Org. Chem. 22. 1727 (1957)). N-glycosides can also be prepared by trans- -glycolysatioπ (R. Bogπar, P. Nanasi Nature 171. 475 (1953)), or by saponificatioπ of acylated N-glycosides. (Evans et. al., Advances in Carbohydrate Chem. 6. 41. (1951); M. Frerejacque, Comt. Rend. 202. 1190 (1936)). The N-glycoside derivatives which are sigπi- ficaπt from pharmacological point of view and which are of commercial value as well are prepared by the above mentioned processes or some modified version thereof . Amiπo-benzoic acid pyraπosides can be prepared according to Belgian patent specification No.87 .399 and British patent specification 2.056.B56 in ethanol or methanol in the presence of ammonium chloride with a yield of 95 - 100 %. According to Hungarian patent specification No. 186.383 N-glycosiαes of heteroaromatic mono- and diamines are prepared in a mixture of ethanol - water or acetone-water. According to all of the mentioned processes the glycosylation is carried out in an organic solvent or solvent mixture or in a water-containing organic solvent. The main disadvantage of said processes is that an aπomer mixture of the N-glycosides is formed. The preparation of the pure anomers requires various purification methods and is accompanied by the diffi¬ culties of isolation. A further disadvantage of the processes using an alcohol containing solvent system is the 0-glycoside formation as a side reaction. The removal of the 0- -glycoside being a by-product requires further purifi¬ cation steps. Further, during the glycozylation reactions carried out in an organic solvent-containing solvent mixture in all cases a hardly identifiable" "polar product" is formed, the removal of which is accompanied by further steps and therefore the prepa¬ ration of a pure product can be performed only with a very law yield (Hungarian patent specification No. 186 383). The present invention is aimed at the prepara¬ tion of N-glycosides of aromatic amines by a simple and economic process and at the preparation of aπomer pure form of the desired product. We have surprisingly found that the reaction can be carried out without the use of an organic solvent in a pure aqueous medium and the reaction takes place selectively as the desired N-glycoside is formed in aπomer pure form and it can be isolated from the reaction mixture in this pure form. The process according to the invention is suitable for the preparation of pyranozyl amines or acid addition salts thereof in an aqueous medium with the proviso that the amino group of the starting com- pound is attached to aromatic nucleus. The reaction is further characterized by the short reaction time in the presence of an acid catalyst, preferably hydrochloric-acid. If the reactaπts are well soluble in water usually no heat treatment is needed as the reaction takes places within a few minutes at room temperature. If any of the reactants is not well soluble in water, the initial suspension is preferably heated for a few minutes to 80 - 90 °C in order to start the reaction and the heating should be continued until the reaction mixture becomes a homogeneous solution. Even in this case the reaction is completed within a short time, that is within a few hours. The end product can be isolated by direct filtration and if the end product is not soluble in water then the product is first isolated with a suit- able solvent, such as ethanol, acetone or the mixture thereof, followed by filtration. By optimalization of the amount of the water used as reaction medium depending on the given reactants the end-product can be obtained with a yield of 60 - 90 in a purity of 95 - 100 %. If desired, the product can be recrystallized from water containing a few drops of ammonia solution. The further details of the present invention are illustrated in the following examples. Example 1 4-( p -D-glucopyranozyl-amino)-benzene-sulfon- a ide 1.72 g (10 mmoles) of 4-amino-benzene-sulfon- amide (deseptyl) and 2.18 g (11 mmoles) of D-glucose monohydrate are suspended in 20 ml of water. 0.5 ml of 2 N hydrochloric-acid solution is added. The reaction- -mixture is heated to 80 °C and allowed to cool. Crystal¬ lization is initiated by a seed crystal. The crystals are filtered and air-dried. The crude product Is recrystallized from water containing some ammonia. Yield: 2.65 g (79.3 %) Mp.: 211 - 212 °C /^7p° = -85.6° (c = 0.48, DMF) Example 2 3-( β-D-glucopyranozyl-amino)-nitro-benzene 1.38 g (10 mmoles) of m-nitro-aπiline and 3.96 g (20 mmoles) of D-glucose monohydrate are sus¬ pended in 4 ml of water. 1 ml of 2N hydrochloric acid solution is added and the reaction mixture is kept at 60 °C for 5 minutes. After cooling a dense mass is obtained which after trituration with 2 ml of water results in a solid which is filtered and recrystallized from ethanol. Yield: 1.13 g (37.6 %) Mp. : 183 °C / 7p° = -124.9° (c = 0.46, DMF) Example 3 Methyl 4-( β> -D-glucopyraπozyl-amino)-benzoate 1.51 g (10 mmoles) of methyl 4-amino-benzoate and 2.38 g (12 mmoles) of D-glucose monohydrate are suspended in 20 ml of water. 0.2 ml of 2N hydrochloric acid solution is added and the reaction mixture is kept at 60 °C for 5 minutes. After cooling the crystals are filtered and air-dried. Yield: 1.90 g (60.6 %) Mp.: 192 196 U C l 0 = -102.8° (c = 0.33, DMF) 13 C-NMR spectrum (DMSO) (see enclosure 1) Example 4 4-( /^-D-glucopyranozyl-amiπo)-toluene 1.07 g (10 mmoles) of para-toluidine and 3.96 g (20 mmoles) of D-glucose monohydrate are sus¬ pended in 8 ml of water. 0.2 ml of 2N hydrochloric acid is added and the reaction mixture is kept at 80 °C for 2 minutes. After cooling the crystals are filtered and air-dried. Yield: 1.54 g (57.2 %) Mp. : 120 - 130 °C / p = -85.2° (c = 0.41, DMF) Example 5 Methyl i-( > -D-xylopyraπozyl-amino)-benzoate 1.51 g (10 mmoles) of methyl 4-amino-benzoate and 3 g D-xylose are suspended in 8 ml of water and 0.2 ml of 2N hydrochloric-acid is added. The reaction mixture is kept at 90 C for 2 minutes and allowed to cool. Upon mechanic influence the mixture crystal- lizes. The precipitating crystals are filtered and air-dried. Yield: 2.60 g (91.8 %) Mp.: 168 - 172 °C /^7p° = -38.2° (c = 0.17, DMF) Example 6 4-( > -D-xylopyranozyl-amino)-benzoic acid 1.34 g p-amino-benzoic acid and 3.0 g D-xylose are suspended in 30 ml of water. The reaction mixture is heated to 90 °C and kept for 5 minutes at this tem¬ perature. After cooling the crystals are filtered and air-dried. Yield 2.18 g (80.9 %) Mp.: 180 °C (decomposition) /?7 Q ° = -38.3° (c = 0.29, DMF) Example 7 4-( ft -D-xylopyraπozyl-amiπo)-sodium-benzoate 8 g of 4-(|_? -D-xylopyraπozyl-amino)-beπzoic acid prepared according to Example 6 are suspended in 20 ml of water. Under intensive stirring a 20 % sodium hydroxide solution is added dropwise until the substance is completely dissolved. By continuing the stirring after slowly adding 300 ml of ethanol the formed precipitated product is filtered and air-dried. Yield: 8.42 g (97.3 %) Mp.: 172 - 176 C (decomposition) Λ 7p° = +60.6 → -15.6 (c = 1.07, water) Example 8 Methyl - -lactosyl-amino)-beπzoate 1.51 g (10.0 mmoles) of methyl 4-amiπo-benzoat and 7.20 g (20 mmoles) of lactose monohydrate are sus¬ pended in 20 ml of water. 0.2 ml of 2N hydrochloric acid is added and the reaction mixture is kept for 10 minutes at 80 °C. After cooling the excess of lactose is precipitated by adding 150 ml of acetone and filtered The filtrate is neutralized by ammonia solution and evaporated. The residue is crystallized from ethanol. Yield: 1.46 g (30.7 %) Mp.: 200 - 206 °C /^7§° = -72.6 (c = 0.41, DMF) Example 9 4- p-L-arabinopyraπozyl-amiπo-benzoic acid 1.34 g (10 mmoles) of p-amino-beπzoic acid and 3 g (20 mmoles) of L-arabinose are suspended in 12 ml of water. The reaction mixture is kept at 80 °C for 5 minutes and allowed to cool. The crystallization is started by mechanic influence. The precipitating crystals are filtered and air-dried. Yield: 2.04 g (75.8 %) Mp.: 146 - 152 °C (decomposition). Λ 7 Q 0 = -23.9 (c = 0.37, DMF) Example 10 Methyl 4-( -K-L-ramnopyranozyl-amiπo)-benzoate 1.51 g (10 mmoles) of methyl 4-amino-beπzoate and 3.64 g (20 mmoles) L-ramnose monohydrate are suspende in 20 ml of water. 0.2 ml of 2N hydrochloric acid is added and the reaction mixture is kept at 60 C for 8 minutes. After cooling and standing for 2 hours the crystals are filtered and air-dried. Yield: 2.80 g (94.2 %) Mp. : 204 - 208 °C /<_f7 [ j 0 = +154 . 8 ( c = 0 . 73 , DMF ) 1 C-NMR spectrum (DMS0) (see Enclosure 2) Example 11 (b -D-galactopyranozyl-amino-beπzene 0.93 g (10 mmoles) of anilin, 3.60 g (20 mmoles) of D-galactose and 8 ml of water are admixed and to the mixture 0.2 ml of 2N hydrochloric acid is added and the reaction mixture is kept for 5 minutes at 60 °C. After cooling the crystals are filtered and air-dried. Yield: 1.28 g (53 %) Mp.: 158-160 °C / - 7 20 = -71.5 (c = 0.95, DMF) Example 12 2-Acetamido-2-desoxy- β -D-glucopyranozyl- -amino-benzene 0.93 g (10 mmoles) of aniline and 4.42 g (20 mmoles) of N-acetyl-D-glucose-amine are suspended in 8 ml of 'water. 0.2 ml 2N hydrochloric acid solution is added and the reaction mixture is kept at 90 °C for 2 minutes. After cooling the precipitating crystals are filtered and air-dried. Yield: 2.23 g (75.3 %) Mp.: 198 - 202 °C 13 C-NMR (DMS0) (see Enclosure 4) Example 13 l-(e^,-D-mannopyraπozyl-amino)-πaph aline 1.43 g (10 mmoles) of 1-amino-naphtaliπe and 3.60 g (20 mmoles) of D-mannoze are suspended in 8 ml of water. 0.4 ml of a 2N hydrochloric acid solu¬ tion is added and the reaction mixture is kept at 80 C for 5 minutes. After cooling on mechanical effect the crystallization starts. After 2 hours standing the crystals are filtered and air-dried. Yield: 2.11 g (69.1 %) Mp. : 190 - 193 °C /^7 Q ° = -104.6 (c = 0.48, DMF) Example 14 3.6-Di-( ft -D-galactopyraπozyl-amiπo)-acridi- nium-chloride 9.84 g (3x10 mole) of 3 , 6-diamiπo-acridiπium -chloride and 28.8 g (l,6xl0 ~ mole) of D-galactose are suspended in 40 ml of water. 0.8 ml of 2N hydro¬ chloric acid is added. The suspension is stirred at room temperature until a homogeneous solution is ob¬ tained. The reaction is monitored by thin-layer chroma- tography. After 6 hours the reaction mixture is diluted with 10 ml of water, and to the vigorously stirred solution 200 ml of ethanol is added dropwise. The powder precipitated product is filtered and washed with 2x30 ml of acetone, 2 x 30 ml of ethyl-acetate and 2x30 ml of ether. Thereafter a 10 percent by weight aqueous solution is added dropwise to a sixfold volume of an acetone-ethanol mixture of 8:2. The precipitated substance is filtered and washed with ethyl-acetate and ether and dried. Yield: 18.0 g (79 %) Mp . : 190 °C (decomposition) Example 15 3,6-di-( p -D-glucopyranozyl-amino)-acridiπium- -chloride 24.6 g (0.1 mole) of 3 ,6-diamiπo-acridiήium- -chloride,80 g (0.4 mole) of D-glucose-moπohydrate are " suspended in 70 ml of water. 7 ml of 2N hydrochloric acid are added and the suspension is stirred at room temperature until the reaction mixture becomes homoge¬ neous. The reaction is monitored by chromatography . After 7 hours the reaction mixture is diluted with 70 ml of water. The orange powdery precipitate is filtered and washed with 2x50 ml of ether and air-dried. A 10 % by weight of aqueous solution is prepared from the crude product to which under intensive stirring a sixfold volume of a 8:2 mixture of acetone and ethanol is added dropwise. Yield: 36.2 g (63.0 °.) Mp.: 210 °C (decomposition) / 7 D° = "225.8° (c = 0.25, DMF) C-NMR spectrum (DMS0) (see enclosure 3) Example 16 ,6-Di-C_ -D-ribopyranozyl-amino)-10-N-methyl- -acridinium-chloride 20 g (0.08 mole) of 3 , -diamino-10-N-methyl- -acridiπium-chloride and 34.6 g (0.23 mole) of D-ribose are suspended in 120 ml of water. 2 ml of 2N hydrochloric acid are added and the suspension is stirred at room temperature until a homogeneous solution is obtained. The reaction is monitored by thin layer chromatography. After 6 hours the mixture is diluted with 360 ml of water and under intensive stirring 2.4 liters of aceton are a'dded dropwise. The precipitated product is filtered and washed with 2x50 ml of acetone, 2x50 ml of ethyl- -acetate and 2x50 ml of ether and air-dried. The crude product is dissolved in 300 ml of water and precipitated with an 1:1 mixture ' of 1.5 liters of acetone and ethanol. The precipitated product is filtered, dried and dissolved in 220 ml of hot water. After cooling and standing overnight the precipitated product is filtered and dried. Yield: 22 g (54.7 % Mp.: 220 °C (decomposition) /<* Q° = +194° (c = 0.165, DMF) Example 17 5-Ethyl-6-pheπyl- ,8-di-p -D-glucopyranozyl- -pheπaπtridium-bro ide A suspension , of 3.95 g (10 mole) ethidium- -bromide (3,8-diamino-5-ethyl-6-phenyl-pheπantridium- -bromide), 8.1 g (4x10 mole) of D-glucose-moπohydrate, 5 ml of water and 0.2 ml of 2N-hydrochloric acid solu¬ tion is stirred at room temperature. The reaction mix- ture is diluted with 60 ml of -water. After adding 700 ml of acetone under stirring an oily product is obtained, which is dissolved again in 50 ml of water. By adding 100 ml of ethanol and 500 ml of acetone a powdery precipitated product is obtained in an amount of 8.19 g. The precipitation is repeated and a chroma- tographically homogeneous product is obtained. Yield: 6.44 g (89.6 %) Mp . : &7l ϋ •216.4° (c = 0.21, water)

Claims: C l a i m s 1. Process for the preparation of anomer pure N-glycosides or acid addition salts thereof of the 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 hetero¬ atoms, the heteroatoms being nitrogen, a con¬ densed 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, R, and R-, are the same or different, and stand for hydrogen, halogen, amino-, sulfoπa ido-, nitro-, C,_ 4 straight or branched saturated or uπsaturated alkyl or alkoxy group, carboxyl C-_ carbalkoxy, phenyl, substituted phenyl, heterocyclic or substituted heterocyclic group - by reacting a compound of the general formula (II) or an acid addition salt thereof, wherein R, , R«, 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 deriva¬ tives or oligosacharides 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 C and isolating the product preferably by - a direct filtration of the reaction mixture, or - by separating first with an organic solvent, prefer¬ ably ethanol, acetone or a mixture of ethanol and acetone and drying the product subsequently. 2. Process as claimed in claim 1 which com¬ prises carrying out the reaction in case of water soluble reactants at 18 - 40 °C. 3. Process according to claim 1 which com¬ prises carrying out the reaction in case of reactants not well soluble in water by heating the reaction mix¬ ture to 80-90 C until the product is dissolved,

Inventors: CSERNUS ISTVAN, HARANGI JANOS, JANCSO SANDOR, JANOSSY LORANT, KEREKGYARTO JANOS, KOVACS ANTAL, KOVACS KATALIN, LIPTAK ANDRAS, MAROSSY KATALIN, NANASI PAL, SZURMAI ZOLTAN, TAKACS ERZSEBET, CSERNUS, ISTVAN, HARANGI, JANOS, JANCSO, SANDOR, JANOSSY, LORANT, KEREKGYARTO, JANOS, KOVACS, ANTAL, KOVACS, KATALIN, LIPTAK, ANDRAS, MAROSSY, KATALIN, NANASI, PAL, SZURMAI, ZOLTAN, TAKACS, ERZSEBET
Applicants: BIOGAL GYOGYSZERGYAR
Application year: 1989
Main classification: C07H15
IPC codes: C07H15, C07H17