CS249097B1 - Process for the preparation of 1,6-anhydro-4- O- (8-hydroxy-5,6-dioxaoctyl) -D-glucopyranose - Google Patents

Abstract

The proposed method for the production of 1,6-anhydro- -4-O-/-hydroxyoxa-alkyl/- Λ-D-glucopyranose of the general formula VI, where n = 0 to 5, consists in that 1,6:5,4-dianhydro-2-O-p-toluenesulfonyl-/> -D-galactopyranose of the formula I, where Ts denotes a p-toluenesulfonyl group, is treated with a glycol of the general formula II, where n = 0 to 5, in the presence of p-toluenesulfonic acid as a catalyst, the resulting 1,6-anhydro- -4-O-/-hydroxyoxaalkyl/-2-O-o-toluenesulfonyl-/O-D-glucogyrazone of the general formula III, where n = 0 to 5, is converted by reaction with a base, preferably sodium methanolate, into the corresponding anhydro derivative of the general formula V, where n = 0 to 5, which is hydrolyzed with water in the presence of an alkaline hydroxide to form the 1,6-anhydro derivative of general formula VI, and the by-product formed in the first reaction stage, 1,6-anhydro-2,4-di-O-p-toluenesulfonyl- / 5 -D-glucopyranose of formula IV, when reacted with a base, gives back the starting 1,6: J,4-dianhydro- -2-O-p-toluenesulfonyl- / 5 -D-galactopyranose of formula I. The substances produced in this way have potentially cryptogenic properties.

Description

The present invention relates to a process for the preparation of 1,6-anhydro-4-O- (8-hydroxy-3,6-dioxaalkyl) -4-D-glucopyranose and analogs thereof of the formula VI wherein n-0- to 3, potentially cryptogenic properties.

Several dozen compounds of the D-glucose cyclic polyether type have been described in recent years (see, for example, M. Pietraszkiewicz, J. Jurczak, Tetrahedron 40, 2967 (1985) and references cited therein). In either case, the free electron pairs of the oxygen atom of 0-5, the oxygen atom of the tetrahydropyran ring, could not be used to further enhance the stability of metal cation complexes. The reason was their disadvantageous steric orientation with respect to the macrocyclic polyether skeleton, usually comprising oxygen atoms 0-2 and 0-3, respectively. 0-3 and 0-4 carbohydrate. In our studies, we found that the effect of free electron pairs of the oxygen atom on 0-5 is surprisingly high. However, this requires the existence of a carbohydrate in a usually less stable conformation of ^ C ^ (D), in which case the oxygen atoms 0-2 and 0-4 are involved in the formation of the complex. The present invention is concerned with the synthesis of compounds in which oxygen atom 0-5 permanently secured, specifically by the synthesis of 1,6-anhydro-4-D-glucopyranosyte derivatives.

Unsymmetrical polyethers have hitherto been prepared exclusively by the Williamson reaction, which in polyhydroxy compounds such as carbohydrates requires a number of extra steps associated with the introduction and removal of protecting groups to achieve the necessary regiorespective stereospecificity.

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The aforementioned disadvantages are overcome by the process for the preparation of 1,6-anhydro-4-O- (6'-hydroxy-oxaalkyl) - N -D-glucopyranose of the formula VI, wherein n = 0 to 3, according to the invention, which comprises: at 1.6, 3 _F 4-dianhydro-2-0-p-toluenesulfonyl - /? - D-galactopyranose pattern CE · I, where TS represents a tosyl group, treated with a glycol of the formula II, wherein n = 0-3, in the presence of p-toluenesulfonic acid catalyst, the resulting 1,6-anhydro-4-O- (N-hydroxyoxyaalkyl) -2-O-p-fluorenesulfonyl 1- (5-D-glucopyranose) of formula (II) wherein n = 0 1-3, by reaction with a base, preferably sodium methoxide, is converted to the corresponding anhydro derivative of formula V, wherein n = 0-3, which is hydrolyzed with water in the presence of an alkali hydroxide to form the 1,6-anhydro derivative. of formula (VI), and the by-product of the first reaction step, 1,6-anhydro-2,4-di-Op-toluenesulfonyl-N-D-glucopyranose of formula (IV), reacts with the base to give a starting 1,6: 3,4-dianhydro-2-O-p-toluenesulfonyl- N -D-galactopyranose of formula I.

The process of the present invention, wherein the asymmetric polyether is formed by opening the epoxide, i.e. the oxirane ring, with a suitable diol of the type OK / (CH 2 O / n) CH 3 OH, where n = 0 to 3, does not have such disadvantages. As starting material, we used the readily available 1,6: 3,4-dianhydro-2-O-p-toluenesulfonyl-N-D-galactopyranose (1) M. Cerny, V. Gut, J. Pacak, Collect. Czechoslov. Chem. Commun. 26, 2542 (1961), whose oxirane ring is cleaved by nucleophilic reagents exclusively diaxially (M. Cerny, J. Stanek jr., Advan. Carbohydr. Chem. Biochem. 34, 23 (1977) // Also, using diodes 0H / CH 2 CH 2 O / _n CH 2 CH _p OH, where n = 0 to 3, the opening of epoxide I proved to be stereospecific. In all cases, the dominant product after several hours of boiling was the 4-O-alkyl derivative of the β-D-glucose configuration, a derivative with an axial alkyl group. The other possible isomer, the product of the attack on the C-3 carbon atom, having the N-D-glucose configuration, could not be detected in the reaction mixture. Reaction of 1,6: 3,4-dianhydro-2-O-p-toluenesulfonyl-β-D-galactopyranose of formula I with triethylene glycol of formula II, where n = 2, gives 1,6-anhydro-4-O- (8-Hydroxy-3,6-dioxaoctyl) -2-O-p-toluenesulfonyl-1H-D-glucopyranose of formula III, where n = 2, were prepared analogously

The reaction was possible to carry out the reaction, in contrast to all the previous polyether preparations by Williamson synthesis and under acid catalysis. In this case, it has proven to be particularly advantageous for suppressing the subsequent reactions due to the interaction of the product with the alkoxides. It also facilitates the isolation, which in such a case is not complicated by the interaction of polyethers with excess cations. Of the acids, p-toluenesulfonic acid has proven to be the best. In this case, 1,6-anhydro-2,4-di-Op-toluenesulfonyl-4-D-glucopyranose of formula IV, which is a common precursor in the preparation of the starting material I, was isolated as a by-product. Stanek jr., Advan. Carbohydr. Chem. Biochem ₀ 54, 25/1977 //

We have therefore advantageously treated the crude reaction mixture with sodium methoxide, in which the by-product of formula IV is quantitatively converted to the excellent crystallizing 1,6: 5,4-dianhydro-2-O-p-toluenesulfonyl-.beta.-D-galactopyranose of formula I At the same time, the p-toluenesulfonic acid in the compound of formula III is cleaved to give 1,6: 2,3-dianhydro-4-O- (hydroxyoxaalkyl) -4-D-mannopyranosyl of the formula V, starting from compound I easily separated. The compound of formula (V) is identical to the product obtained by reacting the compound of formula (III) with a base previously isolated by liquid chromatography.

The oxirane ring cleavage of the 1,6-anhydride derivatives of the general formula V in potassium hydroxide again proceeded mainly diaxially, in accordance with the PURST-Plattner rule. Thus, alkaline hydrolysis of 1,6: 2,3-ianhydro-4-O- (8-hydroxy-5,6-dioxaoctyl) -? - D-manno pyranose (V, where n = 2) gave the desired 1,6-anhydro -4-O- (8-hydroxy-5,6-dioxaoctyl) - ₍ [beta] -D-glucopyranose) (VI, where n = 2), wherein the groups at positions 2 and 4 have the correct orientation for complexing with metal cations . Similarly, isomers of formula VI were prepared wherein n = 0, 1, and 5.

Example 1

1,6: 2,5-Dihydroxy-4-O- (8-hydroxy-5,6-dioxa-octyl) -4-D-mannopyranose (V, where n = 2)

A mixture of 10 g of 1,6: 3,4-dianhydro-2-O-p-toluenesulfonyl- (5-D-galactopyranose A), 13.3 ml of triethylene glycol (II, n-2), 1.0 g

4,249,097 anhydrous p-toluenesulfonic acid and 100 ml benzene were refluxed for 18 hours. To the mixture was added dropwise at room temperature JO mL of 1M sodium methoxide solution, followed by JO min of 100 mL of water. The benzene layer was separated, the aqueous portion was shaken with 4 x 100 ml of chloroform, the combined chloroform fractions were evaporated to a partially crystalline mixture of I and V, where n - 2 from which the starting compound was separated by crystallization. For analytical purposes, the compound of formula V wherein n = 4 was purified by chromatography on silica gel with chloroform as the mobile phase. In addition to 1.2 g of starting material I, 6.8 g (7.7%) of a syrupy compound of formula V are obtained, where n = 2, which has not been crystallized. For G ₁₂ ^H 20 ° 7/276, J / calculated: 52.17% C, 7.1 JO% H, Found: 52.66% C, 7.16% H.

In a similar manner, a derivative of formula V wherein n = 0 was obtained by reaction with ethylene glycol in a yield of 82%, a derivative of formula V wherein n = 1 _f by a reaction with diethylene glycol in a yield of 70%. J, in a yield of 60 with properties corresponding to the proposed structures.

Example 2

1,6-Anhydro-4-O- (8-hydroxy-1,6-dioxaoctyl) - (Z-D-glucopyranose) VI, where n = 2)

An anhydride of formula V wherein n - 2 (10.1 g) was dissolved in 100 ml of 5% potassium hydroxide and heated to reflux for 12 hours. After cooling, the mixture was neutralized with Amberlite IR 120 H ⁺ , the product was purified by chromatography on a 100 mL Amberlite IR 120 H + column. 10 g (96%) of a chromatographically uniform compound of formula VI, where n = 2, were obtained as a colorless syrup. For C 12 H 22 ° 8/294, J / calculated: 48.97% G, 7.5J% H; Found: 48.82% C, 7.67% H, in a completely analogous way were prepared the isomers of formula VI, where n = 0, 1, _J? generally as syrupy compounds with properties corresponding to the proposed structures.

Example J

1,6-Anhydro-4'-O- (5-hydroxy-1-oxapentyl) -2-O-p-toluenesulfonyl-D-glucopyranose (III, where n = 1)

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A mixture of 10 g of 1,6-N-dianhydro-4-O-p-toluenesulfonyl-X-D-galactopyranose (1), 10 g of diethylene glycol, 1.0 g of p-toluenesulfonic acid and 100 ml of benzene was heated under reflux for 20 hours. After evaporation of the benzene, the residue was purified by column chromatography on silica gel with chloroform / 2% methanol. The compound of formula III obtained, where η - 1 (72%), m.p. 109-111 [deg.] C., had identical properties to the substance disclosed in the literature [J. Dolezalova, T. Trnka, Li.Cerny, Collect Czechoslov. Chem. Commun. 47, 2415 (1982).

Claims (1)

A process for the preparation of 1,6-anhydro-4-O - [(i) -hydroxy-alkoxy] -? - D-glucopyranose of formula VI wherein n = 0 to 3, characterized in that it is 1.6: 3.4 -dianhydro-2-O-p-toluenesulfonyl- [4-D-galactopyranose] of formula I, where Ts is a p-toluenesulfonyl group, acts with a glycol of formula II wherein n = 0-3 in the presence of p-toluenesulfonic acid as a catalyst, the resulting 1,6-anhydro-4-O- (6α-hydroxyoxyalkyl) -2-O-p-toluenesulfonyl-4-p-glucopyranose of formula III wherein n-0 to 3 is reacted with a base, preferably with sodium methoxide, is converted to the corresponding anhydride of formula V wherein n-0-3 is hydrolyzed with water in the presence of an alkali hydroxide to give the 1,6-anhydride of formula VI and the by-product formed in the first reaction step, 1,6-anhydro-2,4-di-Op-toluenesulfonyl-4 H -D-glucopyranose of formula. IV reacts with the base to give the starting 1,6: 3,4-dianhydro-2-O-p-toluenesulfonyl-X-D-galactopyranose of formula (I).