MXPA00010829A - Process for selective oxidation of primary alcohols - Google Patents

Abstract

Primary alcohols, especially in carbohydrates, can be selectively oxidised to aldehydes and carboxylic acids in a low-halogen process by using a peracid in the presence of a catalytic amount of a di-tertiary-alkyl nitroxyl (TEMPO) and a catalytic amount of halide. The halide is preferably bromide and the process can be carried out at nearly neutral to moderately alkaline pH (5-11). The peracid can be produced or regenerated by means of hydrogen peroxide or oxygen. The process is advantageous for producing uronic acids and for introducing aldehyde groups which are suitable for crosslinking and derivatisation.

Description

PROCESS FOR THE SELECTIVE OXIDATION OF PRIMARY ALCOHOLS FIELD OF THE INVENTION The invention relates to the selective oxidation of primary alcohols using an oxidation agent in the presence of a catalytic amount of a di-tertiary alkyl nitroxyl compound, especially 2, 2, 6, 6-tetramethylpiperidin-1-oxyl (TEMPO).

BACKGROUND OF THE INVENTION This process is known as Tetrahedron Le t t. 34, 1181-1184 (1993), which describes the oxidation of monosaccharides, where the non-primary hydroxyl groups are partially protected, using sodium hypochlorite, potassium bromide and TEMPO in a two-phase solvent system (dichloromethane and water) to produce the corresponding uronic acid. WO 95/07303 describes a process for oxidizing carbohydrates with hypochlorite / TEMPO, using a pH of 9 to 13 in an aqueous medium. Oxidation of carboxymethyl and hydroxyethyl derivatives of starch and cellulose and other starch ethers with TEMPO is described in WO 96/38484. These oxidations of the prior art have the advantage of being selective, since the oxidation of the primary alcohol groups is strongly favored over the oxidation of the secondary alcohol groups. However, known processes utilize hypochlorite as the actual oxidizing agent and therefore chloride and some chlorinated byproducts are produced; for the complete oxidation of the primary alcohols in carboxylic acids, two or more molar equivalents of hypochlorite are used and two molar equivalents of chloride are produced. This is a serious problem as there is an increasing need for oxidation processes with low chlorine content or even without chlorine. It has now been found that the oxidation of the primary alcohol functional groups can be carried out without using equivalent amounts of chlorine compounds and with the possibility of using hydrogen peroxide as the final oxidizing agent. The process of the invention is defined by the particular features of the appended claims.

DETAILED DESCRIPTION OF THE INVENTION In the following description, reference is made to TEMPO, only for reasons of simplicity, but it should be understood that other tertiary dialkyl nitroxyls, for example 4,4-dimethyloxazolidin-N-oxyl (DOXYL), 2.2 , 5,5-tetramethylpyrrolidin-N-oxyl (PROXYL) and 4-hydroxy-TEMPO and derivatives thereof, and those described in WO 95/07303, can be replaced by TEMPO. The catalytic amount of nitroxyl is preferably 0.1 to 2.5% by weight, based on the primary alcohol or 0.1 to 2.5 mole% with respect to the primary alcohol. The halide present in the process of this invention serves to regenerate TEMPO. The halide can be chlorine, but preferably is bromine. The halide can be added to the reaction mixture as such, but it can also be added as an equivalent thereof or as a molecular halogen. Halide ions are oxidized to molecular halogen by peracids, and molecular halogen regenerates TEMPO. Therefore, both TEMPO and halide need to be present in a catalytic amount only. The catalytic amount of the halide can be from 0.1 to 40, preferably from 0.5 to 10 mol%, with respect to the primary alcohol. The peracid can be any peralkanoic acid, for example peracetic acid, perpropionic acid, perluric acid, etc., a substituted alkanoic acid, for example peroxytrifluoroacetic acid, an optionally substituted aromatic peracid such as for example perbenzoic acid or m-chloroperbenzoic acid, or a Inorganic peracid, for example salts or persulphuric acids of any of the above peracids, for example potassium peroxymonosulfate, which are commercially available under the name Oxone®. The peracids can be formed in themselves from a precursor, for example from the corresponding aldehyde, amide, ester, acid anhydride or (carboxylic) acid, for example tetra-acetyl-ethylenediamine, with a suitable halogen-free oxidizing agent, for example oxide or hydrogen peroxide, either before the oxidation reaction or during the oxidation reaction. The process of the invention results in the oxidation of primary alcohols, initially to the corresponding aldehydes and, optionally, to the corresponding carboxylic acids. In general, the second oxidation step, from the aldehyde to the carboxylic acid, proceeds at a faster rate than the first step, ie the oxidation of the alcohol to the aldehyde. Under normal experimental conditions, the maximum fraction of the aldehyde function present will be between about 10 and 15% (based on the number of primary hydroxyl available for oxidation). This process is especially favored for the selective oxidation of the primary hydroxyl groups in alcohols having a secondary alcohol function, in addition to the primary alcohol, for example 1,6-octanediol, 1,9-octadecanediol, sugar alcohols, glycosides and particular carbohydrates that have primary alcohol functions, for example glucans (starch, cellulose), furanofructans, galactans (galacto) mannans and the like. A particular group of compounds suitable for oxidation with the processes of the present invention are hydroxyalkylated, especially hydroxylated, carbohydrates, for example hydroxyethyl starch or hydroxyethyl inulin. These derivatives are obtained alternatively to produce formylmethyl and carboxymethyl carbohydrates. Oxidation of carbohydrates containing primary hydroxyl groups results in the corresponding carbohydrates containing carboxylic acid and / or aldehydes, with intact ring systems. Examples include α-1,4-glucan-6-aldehydes, β-2, 1-fructan-6-aldehydes and β-2,6-fructan-1-aldehydes, with the corresponding carboxylic acids. When these products still contain the aldehydes, they are useful intermediates for functional carbohydrates, wherein the aldehyde groups further function with, for example, the amine compounds and the like. They are also useful intermediates for crosslinked carbohydrates, wherein the aldehyde groups further react with, for example, diamine reagents.

Example 1: Oxidation of methyl-D-gl-copyranoside (MGP) One gram of MGP (5.15 mmol) was dissolved in 60 ml of water at room temperature. To this solution were added 200 mg of NaBr (1.94 mmol), 20 mg of TEMPO (0.13 mmol), 10 mg of EDTA (to stabilize the oxidizing agent) and 2.5 g of NaHCO3. Peracetic acid (1.32 mmol / ml) was added at a rate of 200 μl for 10 minutes, to an excess amount calculated on a theoretical basis for 100% oxidation to 6-carboxylic acid (14.6 mmol). The pH was maintained at 7 by the addition of 1 M NaOH using a pH-stat. The reaction time was 8 hours. The degree of oxidation, determined with the Blumenkrantz method with galacturonic acid as a reference, was 95%. High resolution anion exchange chromatography (HPAEC) showed that the degree of oxidation is greater than 95%. No other peaks other than uronic acid and a trace of starting material were detected.

Example 2: Oxidation of aD-gl ucopyranosyl phosphate (-Gl c-1 -P) 1.97 g of a-Glc-1-P (2K + .C6Hn09P2".2H20, 5.5 mmol) was dissolved in 60 ml of water To this solution were added 210 mg KBr (1.76 mmol), TEMPO 20 mg (0.13 mmol), EDTA 10 mg and KHC03 2.5 g .. Peracetic acid (10 ml, 1.69 mmol / ml) was added under a regimen. 200 μl for 10 minutes The pH was maintained at 8 by the addition of 2M KOH using pH-stat After 16 hours the reaction was completed The product crystallized from the mixture after addition of MeOH to obtain monophosphate of aD-glucopyranuronic acid (3K + .C6H8O? 0P3".5H20, 1.90 g, 4.0 mmol, 73%). NMR (500 Mhz, D20, in ppm): XH d 3.32 (dd, H-4, J3.4 = 9.5 Hz, J4.5 = 9.9 Hz), 3.35 (m, H-2, Jp, H2 = 1- 8 Hz, Jl? 2 = 3.4 Hz, J2.3 = 9.5 Hz), 3.62 (dd, H-3, J2.3 = 9.5 Hz, J3 / 4 = 9.5 Hz)), 3.99 (d, H-5, J4.5 = 9.9 Hz), 5.30 (dd, Hl, JP / H? = 7.3 Hz, Jlf2 = 3.4 Hz), 13C d 71.4 (C-2), 71.5 (C-3, C-4), 72.4 ( C-5), 93.0 (Cl), 176.6 (C-6).

Example 3: Oxidation of D-glucuronic acid with 1.94 g of D-glucuronic acid (10 mmol) was dissolved in 50 ml of water at room temperature. To this solution were added 196 mg of KBr (1.65 mmol), 30 mg of TEMPO (0.20 mmol), 10 mg of EDTA and 1.0 g of KHC03. Peracetic acid (8 ml, 1.69 mmol / ml) was added at a rate of 200 μl for 10 minutes. The pH was maintained at 8 with the addition of 2M KOH using pH-stat. After 16 hours the reaction ended. The reaction mixture was acidified with concentrated HCl to a pH of 3.4 and the product was crystallized to obtain D-glucaric acid in monopotassium salt (K + .C6H908, H20, 1.55 g, 0.62 mmol, 62%).

FT-IR (in cm-1): 3379 (s), 3261 (s), 2940 (m), 1738 (s), 1453 (m), 1407 (m), 1385 (m), 1342 (m), 1267 (m (, 1215 (m), 1108 (s), 1050 (m), 862 (m), 657 (m).

Example 4: Oxidation of allyson at pH 5 1 gram of potato starch (6.17 mmol) was gelatinized in 60 ml of water at 100 ° C. To this solution were added 200 mg of NaBr (1.94 mmol), 20 mg of TEMPO (0.13 mmol), 10 mg of EDTA and 2.5 g of sodium acetate at room temperature. Peracetic acid (1.51 mmol / ml) of 200 μl for 10 minutes to an excess amount, calculated on a theoretical basis for 100% oxidation in 6-carboxylic acid (13.6 mmol). The pH was maintained at 5 with 1.0 M NaOH using a pH-stat. The reaction time was 8 hours. The degree of oxidation (Blumenkrant z - polygalacturonic acid) was 26% of 6-carboxyl starch.

Example 5: Oxidation of starch at pH 6 1 gram of potato starch (6.17 mmol) was gelatinized in 60 ml of water at 100 ° C. To this solution were added 200 mg of NaBr (1.94 mmol), 20 mg of TEMPO (0.13 mmol), 10 mg of EDTA, 1.25 g of NaH2P04 and 1.25 g of Na2HP04 at room temperature. Peracetic acid (1.30 mmol / ml) was added at a 200 μl regimen for 10 minutes until an excess amount had already been added, calculated on a theoretical basis for 100% oxidation to 6-carboxylic acid (13.8 mmol). The pH was maintained at 6 with 1.0 M NaOH using pH-stat. The reaction time was 8 hours. The degree of oxidation (Blumenkrant z - polygalacturonic acid) was 40% 6-carboxyl starch.

Example 6: Oxidation of allyson at pH 7 1 gram of potato starch (6.17 mmol) was gelatinized in 60 ml of water at 100 ° C. To this solution were added 200 mg of NaBr (1.94 mmol), 20 mg of TEMPO (0.13 mmol), 10 mg of EDTA and 2.5 g of NaHCO 3. Peracetic acid (1.35 mmol / ml) was added at a rate of 200 μl for 10 minutes until an excess amount was obtained, which was calculated on a theoretical basis for 100% oxidation to 6-carboxylic acid (18.4 mmol) . The pH was maintained at 7 with 1.0 M NaOH using a pH-stat. The reaction time was 11.5 hours. The degree of oxidation, determined using the Blumenkrantz method with polygalacturonic acid as reference, was 95% 6-carboxyl starch. The degree of oxidation determined with HPAEC was 86% 6-carboxyl starch.

Example 7: Oxidation of allyson at pH 8 Example 6 was repeated keeping the pH of the reaction at 8. The consumption of peracetic acid was 13.9 mmol. The degree of oxidation (Blumenkrantz-polygalacturonic acid) was 91% 6-carboxyl starch.

Example 8: Oxidation of allyson at pH 9 Example 6 was repeated keeping the pH of the reaction at 9. The consumption of peracetic acid was 11.9 mmol. The degree of oxidation (Blumenkrantz-polygalacturonic acid) was 90% 6-carboxyl starch.

Example 9: Oxidation of starch at pH 10 Example 6 was repeated (using 2.5 g of Na2HP04 instead of NaHCO3). The peracetic acid intake (1.42 mmol / ml) was 14.3 mmol. The degree of oxidation was 37% 6-carboxyl starch.

Claims (8)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property; A process for oxidizing a primary alcohol using an oxidizing agent in the presence of a catalytic amount of a di-alkyl tertiary nitroxyl, characterized in that the oxidation agent is a peracid or a precursor thereof and the oxidation is carried out in the presence of 0.1-40 mol% of halide, in relation to the primary alcohol.
2. 2. A process according to claim 1, wherein the halide is bromide.
3. 3. A process according to claim 1 or 2, wherein the di-alkyl tertiary nitroxyl is 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO).
4. 4. A process according to any of claims 1 to 3, wherein a pH of
5. 5 to 11 and especially from 7 to 10. A process according to any of claims 1 to 4, wherein the peracid is a peralkanoic acid, especially peracetic acid.
6. 6. A process according to any of claims 1 to 5, wherein the peracid is produced in itself from hydrogen peroxide.
7. 7. A process according to any of claims 1 to 6, wherein the primary alcohol is a carbohydrate.
8. 8. A process according to any of claims 1 to 6, wherein the primary alcohol is a hydroxyalkylated carbohydrate.