CA2057001A1 - Process for producing 1-fluoro-glycuronic acids and their salts and such new 1-fluoro-glyconic acids and their salts - Google Patents
Process for producing 1-fluoro-glycuronic acids and their salts and such new 1-fluoro-glyconic acids and their saltsInfo
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- CA2057001A1 CA2057001A1 CA002057001A CA2057001A CA2057001A1 CA 2057001 A1 CA2057001 A1 CA 2057001A1 CA 002057001 A CA002057001 A CA 002057001A CA 2057001 A CA2057001 A CA 2057001A CA 2057001 A1 CA2057001 A1 CA 2057001A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/02—Acyclic radicals
- C07H7/033—Uronic acids
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
Abstract of the disclosure:
Process for the preparation of 1-fluoro-glycuronic acids and salts thereof, and such novel 1-fluoro-glycuronic acids and salts thereof Process for the preparation of 1-fluoro-glycuronic acids, which can contain protected amino groups, and salts thereof, characterized in that glycopyranosyl fluorides of mono- or oligosaccharides which carry at least one primary OH function are oxidized with oxygen as the oxidizing agent in an aqueous solution in the pH range from 6 to 9 in the presence of a catalyst which contains at least one platinum metal, and the 1-fluoro-glycuronic acids formed are at least partly neutralized.
The invention furthermore relates to compounds of the general formula (I)
Process for the preparation of 1-fluoro-glycuronic acids and salts thereof, and such novel 1-fluoro-glycuronic acids and salts thereof Process for the preparation of 1-fluoro-glycuronic acids, which can contain protected amino groups, and salts thereof, characterized in that glycopyranosyl fluorides of mono- or oligosaccharides which carry at least one primary OH function are oxidized with oxygen as the oxidizing agent in an aqueous solution in the pH range from 6 to 9 in the presence of a catalyst which contains at least one platinum metal, and the 1-fluoro-glycuronic acids formed are at least partly neutralized.
The invention furthermore relates to compounds of the general formula (I)
Description
2~7~
HOECHST AKTIENGESELLSCHAFT HOE ~/F 149 Dr. gLR/gm Description Process for the preparation of l-fluoro-glycuronic acids and salts thereof, and such nov~ fluoro-glycuronic acids and salts thereof The present invention relates to a process for tha preparation of l-fluoro-glycuronic acids (= l-~luoro-l-deoxyglycopyranuronic acids = glycopyranuronosyl fluorides) by catalytic oxidation of the corresponding glycosyl fluorides and conversion thereo~ into the corresponding salts. It furthermore relates to novel 1-fluoro-glycuronic acids and salts thereof.
Since the aldehyde group in aldoses is very readily oxidized to the carboxyl function, the anomeric center (the hemiacetal group) must be protected, usually as glycoside, for the synthesis of uronic acids. Oxida~tion of such glycosides with oxygen in the presence of platinum/charcoal to give glycuronic acid is known (US-PS 2 562 200). After the primary OH group has been oxidized to carboxylic acid, the glycoside bond is split under acid conditions, during which considerable losses in yield may occur because of the drastic reaction conditions (S.A. Barker, E.J. Bourne, M. Stacy, Chem. and Ind. 1951, 970). Only then is activation and use of the uronic acids possible, for example for glycosylation reactions. Although from the acetals alternatively used, for example 0l,02-isopropylidene-~-D-glucofuranose (C.L. Mehltretter, B.H. Alexander, R.L. Mellis, C.B. Rist, J. Am. Chem. Soc. 73, 2424 (1951)) or 0',0 cyclohexylidene-~-D-glucofuranose(C.L. Mehltretter,Adv.
Carbohydr. Chem. 8, 244 (1953)), the free uronic acids can be obtained imply and smoothly the [sic] product obtained by oxidation, these acetates [sic] are considerably more troublesome and expensive to prepare.
- 2 ~ 7~ ~
The isolation of uronic acids from naturally occurring substances is often associated with considerable purifi-cation steps and low yields (R.L. Whistler, M.L. Wolfrom, Meth. Carbohydr. Chem. 2, 27 ~1963)).
Surprisingly, it has now been found that the bonding of the fluorine atom of glycosyl fluorides is astonishingly stable under the conditions of catalytic oxidation with oxygen in the presence of noble metal catalysts in neutral solution, so that such glycosyl fluorides can be converted into the corresponding l-fluoro-glycuronic acids without hydrolysis of the C-F bond.
The invention thus relates to a process for the prepara-tion of 1-fluoro-glycuronic acids, which can contain protected amino groups, and salts thereof, which is characterized in that glycopyranosyl fluorides of mono-or oligosaccharides which carry at least one primary OH
function are oxidized with oxygen as the oxidizing agent in an aqueous solution in the pH range from 6 to 9 in the presence of a catalyst which contains at least one platinum metal, and the 1-fluoro-glycuronic acids formed are at least par$1y neutralized.
~everal advantages over the conventional procedures are achieved at the same time by the invention: the 1-fluoro-glycuronic acid can be used directly as a glycosyl donor in glycosidation reactions or enzymatic syntheses under suitable conditions, such as are described, for example, in EP-OS 168723 = US-PS 4 749 785 and ~P-OS 298438. The hydrolysis to give the free glycuronic acid in an acid medium can also be brought to completion rapidly and without side reactions. Oxidation with oxygen also avoids the often considerable disadvantages of other oxidation methods, such as, for example, the unavoidable formation of undesirable by-products such as nitrous gases or sulfur compounds, disposal of which requires considerable expense, or the difficult removal of excess oxidizing agent. With the oxidation according to the invention, in _ 3 _ 2~7~
contrast, only water, which is in any case used as the solvent, is unavoidably fonmed alongside the desired products.
Suitable glycosyl fluorides are the fluorid~s o~ mono-and oligosaccharides which carry at least one primary OH
function, for example ~-D-glucopyranosyl fluoride, ~-D-galactopyranosyl fluoride, ~ mannopyranosyl fluoride, ~-D-lactosyl fluoride, ~-D-cellobiosyl fluoride, ~-D-maltobiosyl fluoride, maltotriosyl fluoride, maltotetro-syl fluoride and the like. ~lycosyl fluorides of thosesaccharides which also contain amino groups (although these m~st be protected in a suitable manner, for example by acyl, alkyl, aryl or aralkyl radicals having up to 10 carbon atoms,) are also suitable, especially those having up to 2 such amino groups, such as 2-acetamido-2-deoxy-~-D-glucopyranosyl fluoride. Although glycosyl fluorides which are partly or completely protected on the secondary OH groups can also be oxidized, unprotected glycosyl fluorides are preferably used.
It is another advantage of the process according to the invention that by using as starting substances the glycosyl fluorides of carbohydrates which are unprotected or partly protected on the amino groups, the expensive introduction of protectiYe groups and splitting off of these again later can be avoided.
Suitable catalysts are those which con~ain platinum metals, ~hat is to say osmium, iridium, rhodium, ruthen-ium, palladium and/or platinum. Catalysts which contain a combination of palladium and platinum, and in particu-lar only platinum, are preferred. The platinum metals arepreferably applied to a support, such as Al703 or SiOz, but in particular active charcoal. The metal content of the catalyst is in general 1 to 15, preferably 5 to 10 %
by weight.
It may occasionally be appropriate, particularly if 2~a~
protected glycosyl fluorides of relatively poor water-solubility are used as starting substances, to add a solubilizing agent which is inert under the reaction conditions, preferably in a concentration of 10 to 75 ~
by weight, in particular 30 to 50 ~ by weight, based on the amount of water and solubilizing agent. Those solu-bilizing agents which have a :Low volatility when oxygen is passed through the aqueous solution, so that an explosion hazard in the vapor space is avoided, are suitable above all; on the other hand, the solubilizing agent should be easy to remove after the oxidation, for example by distillation. Examples of suitable solubiliz-ing agents are glycol ethers containing no free OH
groups, such as those of the formula RlO(CHRCH2O)nR2, in which n denotes a number from 1 to 4, R denotes H or CH3 and Rl and R2 i.n each case independently of one another denote Cl-C~-alkyl. Particularly suitable agents are the dimethyl, diethyl and methyl ethyl ethers of the general formula mentioned having boiling points in the range from ~0 about 100 to about 250C, for example di- and triethylene glycol dimethyl and diethyl ether and dipropylene glycol dimethyl and diethyl ether, of which diethylene glycol dimethyl ether is preferred.
At the start of the oxidation, the aqueous solution advantageously contains 5 to 30 ~ by weight, preferably 10 to 20 % by weight, based on the sum of water and solubilizing agent, of glycosyl fluorid~.
The preferred oxidizing agent is commercially available, industrially pure oxygen. However, it is also possible to use mixtures of oxygen with gases which are inert under the reaction conditions, for example mixtures of oxygen with inert gases. Air i~self is of course also suitable.
As a rule, the reaction is carried out under an overall pressure of 0.5 to 100 bar. As the pressure increases, the rate of reaction increases significantly as the oxygen partial pressure increases; however, the advantage 2~7~
of the higher rate of reaction can be overcompensated in respect of profitability by the higher expenditure on apparatus needed when a higher pressure is used. A
pressure range from atmospheric pressure to 10 bar (absolute) is preferred, the procedure under atmospheric pressure being particularly elasy to carry out.
As a rule, the process according to the invention is carried out at a temperature of 5C to 80C, preferably lO~C to 60C, in particular 20 to 40C.
The reaction must be carried out in an approximately neutral to weakly alkaline medium, that is to say from pH 6 to 9, preferably from 6.5 to 8.5 and in particular from 7 to 8, since the glycosyl fluorides are not stable in the acid range. The carboxylic acids formed during the oxidation must therefore be trapped, for example by suitable buffer substances or advantageously by the addition of aqueous bases, for example alkali metal hydroxide solutions or alkaline earth metal hydroxide solutions, these being metered in such that the pH of the reaction sys~em remains in the range from 6 to 9 during the oxidation. If neutralization is complete, the oxida-tion products are obtained as salts.
The process according to the invention can be carried out - in all apparatuses which are suitable for carrying out reactions in the liquid phase with or without application of increased pressure. Examples of this are the procedure in a stirred kettle or in a bubble column with suspended catalyst. However, the oxidation can also be carried out over a fixed bed of granular catalyst in a trickle phase reactor.
The reaction time required is advantageously determined by taking and analyzing samples of the reaction solution at certain intervals of time. For example, the yield of the reaction products can be determined continuously in a simple manner by analysis of a sample with the aid of _ 6 ~ 7~
high pressure liquid chromatography in comparison with standard solutions. Optimization of the reaction tLme is to b8 advised, since an unneces arily prolonged introduc-tion of oxygen may lead to supexoxidations and therefore~
for example, to decarboxylationæ and to a reduction in the yield of the desired reaction products.
The reaction mixture can be worked up by customary methods. For example, the water and any solubilizing agents present are first removed by distillation. The product is then purified, for example by chromatography, crystallization or precipitation. The product can also be separated off from the solution obtained in the oxidation via a basic ion exchanger in the OH- form.
Compared with the conventional methods mentioned at the beginning, the process according to the invention has the further advantage that no protective group~ are introduced on the anomeric center and the product~ can be used directly as activated carbohydrates.
The invention also relates to compounds of the general 20formula I
COOM
~0 RX ~ F (I) RX XR
in which M represents a cation, such as that of Li, Na, K, Mg or Ca, or H or NH4, but in particular represents H
25or an alkali metal cation and X denotes oxygen or NH, independently of one another, wherein, if X = oxygen, R denotes hydrogen or a glycosidically bonded monosaccharide and if X = NH, R represents an acyl, alkyl, aryl or aralkyl protective group radical having up to 10 carbon atoms, - 7 ~ 7~
but wherein only one of the groups RX has a meaning other than OH.
The l-fluoxo-glycuronic acids are useful starting sub-stances for the preparation of biologically acti~e di-and oligosaccharides which for example as constituents of cell surface saccharides and glycoproteins, can have a biological activity, for example for stimulation of immune reactions and antibody formation. It is also possible, for example by simple glycosylation reactions, for surface-active deri~atives to be obtained or the dissolving and transpor~ation properties of naturally occurring substances and active compounds to be improved.
~amples 1) 10 standard liters of oxygen per hour were introduced from below, through a glass frit and at a temperature of 30C, into a vertically positioned glass tube (diameter 25 mm, length 600 mm) which could be heated externally and was filled with a mixture of 10 g of ~-D-glucopyranosyl fluoride, 90 g of wat~r and 5 g of a commercially available catalyst (5 % by weight platinum-on-acti~e charcoal, F 196 RAW from Degussa, Frankfurt, Germany). The pH was kept at 7 to 7.5 by continuous addition of 30 ~ strength agueous sodium hydxoxide solution. After 6 hours, the solution contained 10.2 g of sodium ~-D-glucopyranuronatosyl fluoride (85 ~ of the-ory). The product can be isolated and purified by cus~om-ary proces~es.
White, amorphous powder:(~) D: +71.2 (c = 1.08, water) lH-NMR (D2O): ~ = 5.71 (dd, H-1), 3.67 (ddd, H-2), 3.77 (dd, H-3), 3.58 (dd, H-4), 4.09 (d, H-5~; J1F = 53 4~
J12 = 2.9, J2F = 26.6, J23 9.8, J3,4 ~ 4,5 = 10.2 Hz.
Mass spectroscopy (MS) (after silylation): M~ = 484 (ClBH4lFO6Si4, silylated 4-fold) 2) 10 g of ~-D-galactopyranosyl fluoride were oxidized 2~7~
with oxygen at 10C under the conditions described in Example 1 in a 10 ~ strength aqueous solution in the presence of 5 g of the catalyst mentioned in that ex-ample. After 4 hours, the reaction mixture contained 9.3 g of sodium ~-D-galactopyranuronatosyl fluoxide (78 %
of theory), which can be isolated and purified by cus-~omary processes.
White, amorphous powder: (~)D: +37.1 (c = 0.98, water) lH-NMR (D20): ~ = 5.73 (dd, H-l), 4.05 (mc, 4 H-2,3,4,5);
J1,F = 53-7, J1.2 = 2.2 Hz.
(MS3 ~after silylation): M+ = 484 (C18H41F06Si4, silylated 4-fold) 3) A mixture of 10 g of 2-acetamido-2-deoxy-~-D-gluco-pyranosyl fluoride, 90 g of water and 5 g of the catalyst mentioned in Example 1 was reacted with oxygen at 40C in the device described in that example. The pH was kept at 7 to 7.5 by continuous addition of 30 % strength sodium hydroxide solution. After 6 hours, the solution contained 7.4gofsodium2-acetamido-2-deoxy-~-D-glucopyranuronato-syl fluoride, corresponding to a yield of 70 ~ of theory, which can be isolated and purified.
White, amorphous powder: (~)D: +23.5~ (c = 1.14, water) H-NMR (D20): ~ = 5.67 (dd, H-1), 4.06 (ddd, H-2), 3.81 (dd, H-3), 3.67 (dd, H-4), 4.11 (d, H-5), 2.07 (s, CH3);
1,F 52.9, J12 3-0~ J2,F = 27-8, J23 = 9.9, J3 4 = 9 1, J4 5 = 10.0 Hz.
(MS) (after silylation): M+ = 453 (C,7H36FN06Si3, silylated 3-fold).
HOECHST AKTIENGESELLSCHAFT HOE ~/F 149 Dr. gLR/gm Description Process for the preparation of l-fluoro-glycuronic acids and salts thereof, and such nov~ fluoro-glycuronic acids and salts thereof The present invention relates to a process for tha preparation of l-fluoro-glycuronic acids (= l-~luoro-l-deoxyglycopyranuronic acids = glycopyranuronosyl fluorides) by catalytic oxidation of the corresponding glycosyl fluorides and conversion thereo~ into the corresponding salts. It furthermore relates to novel 1-fluoro-glycuronic acids and salts thereof.
Since the aldehyde group in aldoses is very readily oxidized to the carboxyl function, the anomeric center (the hemiacetal group) must be protected, usually as glycoside, for the synthesis of uronic acids. Oxida~tion of such glycosides with oxygen in the presence of platinum/charcoal to give glycuronic acid is known (US-PS 2 562 200). After the primary OH group has been oxidized to carboxylic acid, the glycoside bond is split under acid conditions, during which considerable losses in yield may occur because of the drastic reaction conditions (S.A. Barker, E.J. Bourne, M. Stacy, Chem. and Ind. 1951, 970). Only then is activation and use of the uronic acids possible, for example for glycosylation reactions. Although from the acetals alternatively used, for example 0l,02-isopropylidene-~-D-glucofuranose (C.L. Mehltretter, B.H. Alexander, R.L. Mellis, C.B. Rist, J. Am. Chem. Soc. 73, 2424 (1951)) or 0',0 cyclohexylidene-~-D-glucofuranose(C.L. Mehltretter,Adv.
Carbohydr. Chem. 8, 244 (1953)), the free uronic acids can be obtained imply and smoothly the [sic] product obtained by oxidation, these acetates [sic] are considerably more troublesome and expensive to prepare.
- 2 ~ 7~ ~
The isolation of uronic acids from naturally occurring substances is often associated with considerable purifi-cation steps and low yields (R.L. Whistler, M.L. Wolfrom, Meth. Carbohydr. Chem. 2, 27 ~1963)).
Surprisingly, it has now been found that the bonding of the fluorine atom of glycosyl fluorides is astonishingly stable under the conditions of catalytic oxidation with oxygen in the presence of noble metal catalysts in neutral solution, so that such glycosyl fluorides can be converted into the corresponding l-fluoro-glycuronic acids without hydrolysis of the C-F bond.
The invention thus relates to a process for the prepara-tion of 1-fluoro-glycuronic acids, which can contain protected amino groups, and salts thereof, which is characterized in that glycopyranosyl fluorides of mono-or oligosaccharides which carry at least one primary OH
function are oxidized with oxygen as the oxidizing agent in an aqueous solution in the pH range from 6 to 9 in the presence of a catalyst which contains at least one platinum metal, and the 1-fluoro-glycuronic acids formed are at least par$1y neutralized.
~everal advantages over the conventional procedures are achieved at the same time by the invention: the 1-fluoro-glycuronic acid can be used directly as a glycosyl donor in glycosidation reactions or enzymatic syntheses under suitable conditions, such as are described, for example, in EP-OS 168723 = US-PS 4 749 785 and ~P-OS 298438. The hydrolysis to give the free glycuronic acid in an acid medium can also be brought to completion rapidly and without side reactions. Oxidation with oxygen also avoids the often considerable disadvantages of other oxidation methods, such as, for example, the unavoidable formation of undesirable by-products such as nitrous gases or sulfur compounds, disposal of which requires considerable expense, or the difficult removal of excess oxidizing agent. With the oxidation according to the invention, in _ 3 _ 2~7~
contrast, only water, which is in any case used as the solvent, is unavoidably fonmed alongside the desired products.
Suitable glycosyl fluorides are the fluorid~s o~ mono-and oligosaccharides which carry at least one primary OH
function, for example ~-D-glucopyranosyl fluoride, ~-D-galactopyranosyl fluoride, ~ mannopyranosyl fluoride, ~-D-lactosyl fluoride, ~-D-cellobiosyl fluoride, ~-D-maltobiosyl fluoride, maltotriosyl fluoride, maltotetro-syl fluoride and the like. ~lycosyl fluorides of thosesaccharides which also contain amino groups (although these m~st be protected in a suitable manner, for example by acyl, alkyl, aryl or aralkyl radicals having up to 10 carbon atoms,) are also suitable, especially those having up to 2 such amino groups, such as 2-acetamido-2-deoxy-~-D-glucopyranosyl fluoride. Although glycosyl fluorides which are partly or completely protected on the secondary OH groups can also be oxidized, unprotected glycosyl fluorides are preferably used.
It is another advantage of the process according to the invention that by using as starting substances the glycosyl fluorides of carbohydrates which are unprotected or partly protected on the amino groups, the expensive introduction of protectiYe groups and splitting off of these again later can be avoided.
Suitable catalysts are those which con~ain platinum metals, ~hat is to say osmium, iridium, rhodium, ruthen-ium, palladium and/or platinum. Catalysts which contain a combination of palladium and platinum, and in particu-lar only platinum, are preferred. The platinum metals arepreferably applied to a support, such as Al703 or SiOz, but in particular active charcoal. The metal content of the catalyst is in general 1 to 15, preferably 5 to 10 %
by weight.
It may occasionally be appropriate, particularly if 2~a~
protected glycosyl fluorides of relatively poor water-solubility are used as starting substances, to add a solubilizing agent which is inert under the reaction conditions, preferably in a concentration of 10 to 75 ~
by weight, in particular 30 to 50 ~ by weight, based on the amount of water and solubilizing agent. Those solu-bilizing agents which have a :Low volatility when oxygen is passed through the aqueous solution, so that an explosion hazard in the vapor space is avoided, are suitable above all; on the other hand, the solubilizing agent should be easy to remove after the oxidation, for example by distillation. Examples of suitable solubiliz-ing agents are glycol ethers containing no free OH
groups, such as those of the formula RlO(CHRCH2O)nR2, in which n denotes a number from 1 to 4, R denotes H or CH3 and Rl and R2 i.n each case independently of one another denote Cl-C~-alkyl. Particularly suitable agents are the dimethyl, diethyl and methyl ethyl ethers of the general formula mentioned having boiling points in the range from ~0 about 100 to about 250C, for example di- and triethylene glycol dimethyl and diethyl ether and dipropylene glycol dimethyl and diethyl ether, of which diethylene glycol dimethyl ether is preferred.
At the start of the oxidation, the aqueous solution advantageously contains 5 to 30 ~ by weight, preferably 10 to 20 % by weight, based on the sum of water and solubilizing agent, of glycosyl fluorid~.
The preferred oxidizing agent is commercially available, industrially pure oxygen. However, it is also possible to use mixtures of oxygen with gases which are inert under the reaction conditions, for example mixtures of oxygen with inert gases. Air i~self is of course also suitable.
As a rule, the reaction is carried out under an overall pressure of 0.5 to 100 bar. As the pressure increases, the rate of reaction increases significantly as the oxygen partial pressure increases; however, the advantage 2~7~
of the higher rate of reaction can be overcompensated in respect of profitability by the higher expenditure on apparatus needed when a higher pressure is used. A
pressure range from atmospheric pressure to 10 bar (absolute) is preferred, the procedure under atmospheric pressure being particularly elasy to carry out.
As a rule, the process according to the invention is carried out at a temperature of 5C to 80C, preferably lO~C to 60C, in particular 20 to 40C.
The reaction must be carried out in an approximately neutral to weakly alkaline medium, that is to say from pH 6 to 9, preferably from 6.5 to 8.5 and in particular from 7 to 8, since the glycosyl fluorides are not stable in the acid range. The carboxylic acids formed during the oxidation must therefore be trapped, for example by suitable buffer substances or advantageously by the addition of aqueous bases, for example alkali metal hydroxide solutions or alkaline earth metal hydroxide solutions, these being metered in such that the pH of the reaction sys~em remains in the range from 6 to 9 during the oxidation. If neutralization is complete, the oxida-tion products are obtained as salts.
The process according to the invention can be carried out - in all apparatuses which are suitable for carrying out reactions in the liquid phase with or without application of increased pressure. Examples of this are the procedure in a stirred kettle or in a bubble column with suspended catalyst. However, the oxidation can also be carried out over a fixed bed of granular catalyst in a trickle phase reactor.
The reaction time required is advantageously determined by taking and analyzing samples of the reaction solution at certain intervals of time. For example, the yield of the reaction products can be determined continuously in a simple manner by analysis of a sample with the aid of _ 6 ~ 7~
high pressure liquid chromatography in comparison with standard solutions. Optimization of the reaction tLme is to b8 advised, since an unneces arily prolonged introduc-tion of oxygen may lead to supexoxidations and therefore~
for example, to decarboxylationæ and to a reduction in the yield of the desired reaction products.
The reaction mixture can be worked up by customary methods. For example, the water and any solubilizing agents present are first removed by distillation. The product is then purified, for example by chromatography, crystallization or precipitation. The product can also be separated off from the solution obtained in the oxidation via a basic ion exchanger in the OH- form.
Compared with the conventional methods mentioned at the beginning, the process according to the invention has the further advantage that no protective group~ are introduced on the anomeric center and the product~ can be used directly as activated carbohydrates.
The invention also relates to compounds of the general 20formula I
COOM
~0 RX ~ F (I) RX XR
in which M represents a cation, such as that of Li, Na, K, Mg or Ca, or H or NH4, but in particular represents H
25or an alkali metal cation and X denotes oxygen or NH, independently of one another, wherein, if X = oxygen, R denotes hydrogen or a glycosidically bonded monosaccharide and if X = NH, R represents an acyl, alkyl, aryl or aralkyl protective group radical having up to 10 carbon atoms, - 7 ~ 7~
but wherein only one of the groups RX has a meaning other than OH.
The l-fluoxo-glycuronic acids are useful starting sub-stances for the preparation of biologically acti~e di-and oligosaccharides which for example as constituents of cell surface saccharides and glycoproteins, can have a biological activity, for example for stimulation of immune reactions and antibody formation. It is also possible, for example by simple glycosylation reactions, for surface-active deri~atives to be obtained or the dissolving and transpor~ation properties of naturally occurring substances and active compounds to be improved.
~amples 1) 10 standard liters of oxygen per hour were introduced from below, through a glass frit and at a temperature of 30C, into a vertically positioned glass tube (diameter 25 mm, length 600 mm) which could be heated externally and was filled with a mixture of 10 g of ~-D-glucopyranosyl fluoride, 90 g of wat~r and 5 g of a commercially available catalyst (5 % by weight platinum-on-acti~e charcoal, F 196 RAW from Degussa, Frankfurt, Germany). The pH was kept at 7 to 7.5 by continuous addition of 30 ~ strength agueous sodium hydxoxide solution. After 6 hours, the solution contained 10.2 g of sodium ~-D-glucopyranuronatosyl fluoride (85 ~ of the-ory). The product can be isolated and purified by cus~om-ary proces~es.
White, amorphous powder:(~) D: +71.2 (c = 1.08, water) lH-NMR (D2O): ~ = 5.71 (dd, H-1), 3.67 (ddd, H-2), 3.77 (dd, H-3), 3.58 (dd, H-4), 4.09 (d, H-5~; J1F = 53 4~
J12 = 2.9, J2F = 26.6, J23 9.8, J3,4 ~ 4,5 = 10.2 Hz.
Mass spectroscopy (MS) (after silylation): M~ = 484 (ClBH4lFO6Si4, silylated 4-fold) 2) 10 g of ~-D-galactopyranosyl fluoride were oxidized 2~7~
with oxygen at 10C under the conditions described in Example 1 in a 10 ~ strength aqueous solution in the presence of 5 g of the catalyst mentioned in that ex-ample. After 4 hours, the reaction mixture contained 9.3 g of sodium ~-D-galactopyranuronatosyl fluoxide (78 %
of theory), which can be isolated and purified by cus-~omary processes.
White, amorphous powder: (~)D: +37.1 (c = 0.98, water) lH-NMR (D20): ~ = 5.73 (dd, H-l), 4.05 (mc, 4 H-2,3,4,5);
J1,F = 53-7, J1.2 = 2.2 Hz.
(MS3 ~after silylation): M+ = 484 (C18H41F06Si4, silylated 4-fold) 3) A mixture of 10 g of 2-acetamido-2-deoxy-~-D-gluco-pyranosyl fluoride, 90 g of water and 5 g of the catalyst mentioned in Example 1 was reacted with oxygen at 40C in the device described in that example. The pH was kept at 7 to 7.5 by continuous addition of 30 % strength sodium hydroxide solution. After 6 hours, the solution contained 7.4gofsodium2-acetamido-2-deoxy-~-D-glucopyranuronato-syl fluoride, corresponding to a yield of 70 ~ of theory, which can be isolated and purified.
White, amorphous powder: (~)D: +23.5~ (c = 1.14, water) H-NMR (D20): ~ = 5.67 (dd, H-1), 4.06 (ddd, H-2), 3.81 (dd, H-3), 3.67 (dd, H-4), 4.11 (d, H-5), 2.07 (s, CH3);
1,F 52.9, J12 3-0~ J2,F = 27-8, J23 = 9.9, J3 4 = 9 1, J4 5 = 10.0 Hz.
(MS) (after silylation): M+ = 453 (C,7H36FN06Si3, silylated 3-fold).
4) A mixture of 10 g of ~-lactosyl fluoride (4-0-(A-D-galactopyranosyl)-~-D-glucopyranosyl fluoride), 90 g of water and 5 g of the catalyst mentioned in Example 1 was reacted with oxygen at 30C in the device described in that example. The pH was kept at 7 to 7.5 by continuous addition of 30 ~ strength sodium hydroxide solution.
After 5 hours, the solution contained, in addition to the two monocarboxylic acids, 4.g g of 1-fluoro-lactodiuronic acid salt (disodium 4-o-(~-D-galactopyranuronatosyl)-Q
- 9 - 2~70~1 D-glucopyranuronatosyl fluoride), corresponding to a yield of 45 ~ of theory, which can be isolated and purified.
Colorless syrup lH-NMR (D20): ~ = 5.65 (dd, H 1); J1,z = 2.7, J1,F = 53.2 Hz.
(MS) (after silylation): M+ = 876 (C33Hl3FOl2Si7, silylated 7-fold).
After 5 hours, the solution contained, in addition to the two monocarboxylic acids, 4.g g of 1-fluoro-lactodiuronic acid salt (disodium 4-o-(~-D-galactopyranuronatosyl)-Q
- 9 - 2~70~1 D-glucopyranuronatosyl fluoride), corresponding to a yield of 45 ~ of theory, which can be isolated and purified.
Colorless syrup lH-NMR (D20): ~ = 5.65 (dd, H 1); J1,z = 2.7, J1,F = 53.2 Hz.
(MS) (after silylation): M+ = 876 (C33Hl3FOl2Si7, silylated 7-fold).
Claims (10)
1. Process for the preparation of 1-fluoro-glycuronic acids, which can contain protected amino groups, and salts thereof, characterized in that glycopyranosyl fluorides of mono- or oligosaccharides, which carry at least one primary OH function, are oxidized with oxygen as the oxidizing agent in an aqueous solution in the pH
range from 6 to 9 in the presence of a catalyst which contains at least one platinum metal, and the 1-fluoroglycuronic acids formed are at least partly neutralized.
range from 6 to 9 in the presence of a catalyst which contains at least one platinum metal, and the 1-fluoroglycuronic acids formed are at least partly neutralized.
2. Process according to Claim 1, characterized in that the glycosyl fluorides employed are glycosyl fluorides in unprotected form.
3. Process according to Claim 1 or 2, characterized in that the catalyst contains as the platinum metal a combination of palladium and platinum, in particular only platinum.
4. Process according to one or more of Claims 1 to 3, characterized in that the catalyst comprises 1 to 15 % by weight, preferably S to 10 % by weight, of the platinum metal and a support, preferably active charcoal.
5. Process according to one or more of Claims 1 to 4, characterized in that the oxidation is carried out in a pressure range of 0.5 to 100 bar, preferably atmospheric pressure to 10 bar, in particular under atmospheric pressure, and preferably using industrially pure oxygen.
6. Process according to one or more of Claims 1 to 5, characterized in that the aqueous solution contains a solubilizing agent which is inert under the reaction conditions, preferably in an amount of 10 to 75 % by weight, in particular 30 to 50 % by weight, the solubil-izing agent preferably being a glycol ether containing no hydroxyl groups, in particular diethylene glycol dimethyl ether.
7. Process according to one or more of Claims 1 to 6, characterized in that the oxidation is carried out at a temperature of 5 to 80°C, preferably 10 to 60°C, in particular 20 to 40°C.
8. Process according to one or more of Claims 1 to 7, characterized in that, at the start of the oxidation, the aqueous solution contains 5 to 30 % by weight, preferably 10 to 20 % by weight, based on the sum of water and solubilizing agent, of glycosyl fluoride.
9. Process according to one or more of Claims 1 to 8, characterized in that the oxidation is carried out at a pH of 6.5 to 8.5, preferably 7 to 8.
10. Compounds of the general formula (I) in which M represents hydrogen or a cation, in particular an alkali metal, and X denotes oxygen or NH, independently of one another, wherein, if X = oxygen, R denotes hydrogen or a glycosidically bonded monosaccharide and if X = NH, R represents an acyl, alkyl, aryl or aralkyl protective group radical having up to 10 carbon atoms, but wherein only one of the groups RX has a meaning other than OH.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3916206A DE3916206A1 (en) | 1989-05-18 | 1989-05-18 | METHOD FOR PRODUCING 1-FLUOR-GLYCURONIC ACIDS AND THEIR SALTS, AND SUCH NEW 1-FLOUR-GLYCURONIC ACIDS AND THEIR SALTS |
| DEP3916206.0 | 1989-05-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2057001A1 true CA2057001A1 (en) | 1990-11-19 |
Family
ID=6380895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002057001A Abandoned CA2057001A1 (en) | 1989-05-18 | 1990-05-11 | Process for producing 1-fluoro-glycuronic acids and their salts and such new 1-fluoro-glyconic acids and their salts |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0472556B1 (en) |
| JP (1) | JPH06104676B2 (en) |
| CA (1) | CA2057001A1 (en) |
| DE (2) | DE3916206A1 (en) |
| WO (1) | WO1990014350A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4307388A1 (en) * | 1993-03-10 | 1994-09-15 | Zuckerindustrie Verein | Method and device for producing mono-oxidized products from carbohydrates, carbohydrate derivatives and primary alcohols |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2845439A (en) * | 1949-08-19 | 1958-07-29 | Corn Prod Refining Co | Preparation of uronic acids and derivatives thereof |
| DE3426074A1 (en) * | 1984-07-14 | 1986-01-23 | Hoechst Ag, 6230 Frankfurt | METHOD FOR THE PRODUCTION OF GLYCOSIDES FROM GLYKOSYLFLUORIDES |
| DE3528654A1 (en) * | 1985-08-09 | 1987-02-19 | Hoechst Ag | METHOD FOR PRODUCING ALKYLATED HYDROXYL GROUP-FREE GLYCOSYL FLUORIDES |
| DE3535720A1 (en) * | 1985-10-07 | 1987-04-09 | Hoechst Ag | SACCHAROSE TRICARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| DE3722812A1 (en) * | 1987-07-10 | 1989-01-19 | Hoechst Ag | DISACCHARIDFLUORIDES, METHOD FOR THE ENZYMATIC PRODUCTION WITH (ALPHA) -GLYCOSYLFLUORIDES AS SUBSTRATES |
-
1989
- 1989-05-18 DE DE3916206A patent/DE3916206A1/en not_active Withdrawn
-
1990
- 1990-05-11 WO PCT/EP1990/000760 patent/WO1990014350A1/en active IP Right Grant
- 1990-05-11 DE DE59007648T patent/DE59007648D1/en not_active Expired - Fee Related
- 1990-05-11 CA CA002057001A patent/CA2057001A1/en not_active Abandoned
- 1990-05-11 EP EP90906997A patent/EP0472556B1/en not_active Expired - Lifetime
- 1990-05-11 JP JP2506935A patent/JPH06104676B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE59007648D1 (en) | 1994-12-08 |
| EP0472556B1 (en) | 1994-11-02 |
| WO1990014350A1 (en) | 1990-11-29 |
| JPH04505320A (en) | 1992-09-17 |
| EP0472556A1 (en) | 1992-03-04 |
| JPH06104676B2 (en) | 1994-12-21 |
| DE3916206A1 (en) | 1990-11-22 |
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