WO2009111915A1

WO2009111915A1 - Bromide-free tempo-mediated oxidation of the primary alcohol in carbohydrate under two-phase conditions

Info

Publication number: WO2009111915A1
Application number: PCT/CN2008/070482
Authority: WO
Inventors: Yujin Yang
Original assignee: Chongqing Shengkai Science & Technology Co., Ltd.
Priority date: 2008-03-12
Filing date: 2008-03-12
Publication date: 2009-09-17
Also published as: CN101952237B; CN101952237A

Abstract

A process of selective oxidizing primary alcohols in carbohydrate by means of a hypohalite in the presence of catalytic amount of a di-tertiary-alkyl nitroxyl, the process is characterized in that the oxidation is under a two-phase and bromide-free condition in the presence of phase transfer catalyst.

Description

Bromide-free TEMPO-mediated oxidation of the primary alcohol in carbohydrate under two-phase conditions

Field:

The present invention relates to a process of selectively oxidizing primary alcohols, in particular the primary alcohol in carbohydrate under bromide-free two-phase conditions.

Background:

Selective oxidation of primary alcohols to carboxylic acids is one of the long standing problems of organic chemistry. Although a huge number of methods of oxidation are known, it is difficult to find a procedure which is selective, cheap, efficient, and easy to work up.

Recently the use of metal-free catalysts for selective oxidation of organic compounds is attracting more and more attention because these metal-free catalysts are beneficial from both economic and environmental viewpoints. Moreover, they are readily able to tether to a support covalently and obviate the problem of metal leaching.

A promising method for the selective oxidation of primary alcohols in the presence of secondary ones originates from the work of Semmelhack et al. ( M. F. Semmelhack, CS. Chou, and D.A. Cortes, /. Am. Chem. Soc, 105 (1983) 4492-4494.) . These authors used the stable organic nitroxyl radical 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO) as a mediator.

Anelli et al., /. Org. Chem. 52, 2559(1987),and 54,2970(1989), reported the oxidation of alcohols and diols with sodium hypochlorite, potassium bromide and 2,2,6, 6-tetramethyl-l-piperidinyloxy (TEMPO) or 4- methoxy-TEMPO in two-phase solvent system(dichloromethane and water) at pH 9.5.

Davis and Flitsch, Tetrahedron Lett. 34, 1181-1184(1993), reported the oxidation of monosaccharide wherein the acetal hydroxyl groups are protected, using the same oxidation system.

De Nooy et al. (WO950733) have described the oxidation of polysaccharide and monosaccharide using TEMPO, hypohalite and sodium bromide in the presence of a catalytic amount of TEMPO in an aqueous reaction medium at pH between 9 and 13.

All of above methods use sodium bromide as cocatalyst which may be cause serious environment problems. From an industrial point of view, a process without sodium bromide would be more attractive, since its presence in the waste stream is highly undesired, due to environmental and corrosion concerns.

Petter L. B. et al. Carbohydrate Research 328 (2000) 355-363 reported the bromide-free TEMPO: (H)OCl system, the reaction rates is first-order in methyl a-Dglucopyranoside and first-order in TEMPO. But the method mentioned in this paper isn't under the two phase conditions, so the reaction rate is slight low. Only increasing the concentration of substrate or the concentration of catalyst TEMPO or , alternatively , increasing the reaction temperatures, can good product properties and higher reaction rates be obtained.

Another drawback of all aforementioned methods is using harmful solvent such as dichloromethane, moreover , those methods need more acute reaction conditions such as higher temperatures.

Description:

This invention provides a novel method for oxidizing primary alcohols in carbohydrate which does not have the drawbacks mentioned above and has a higher specificity and selectivity , as well as has little environmental issues than those known methods.

The method according to the invention can be employed for the production of carboxyl carbohydrate and its derivatives which widely used in biology research and biotechnology.

The method according to the invention for oxidizing primary alcohols in carbohydrate is performed by means of a hypohalite, which is used as oxidant, in the presence of catalytic amount of a di-tertiary-alkyl nitroxyl , the process is characterized in that the oxidation is under a two-phase and bromide-free condition in the presence of phase transfer catalyst.

Wherein said carbohydrate is preferably monosaccharide or disaccharide.

The di-tertiaaryl nitroxyl is acyclic or cyclic compound, but is preferably a cyclic compound which satisfies the formula below:

In this formula, A represents a chain of preferably two or three atoms, in particular carbon atoms or a combination of one or two atoms with an oxygen or nitrogen atom. Chain A may be substituted by one or more groups such as alkyl, aryl, aryloxy, amino, amido or oxo groups, or by a divalent or multivalent group which is bound to one or more other groups.

The amount of used nitroxyl compound larger than 10% by weight does no harm, but is unattractive because of the higher costs. Preferably the catalytic amount of nitroxyl is 0.001-5% by weight, more preferably 0.05-2.0% by weight and especially 0.1-1% by weight, based on the carbohydrate.

The said phase transfer catalyst can be cationic surface active agent such as tridodecyl methyl ammonium chloride, tetrabutyl ammonium chloride, triethyl phenyl ammonium chloride. And the phase transfer catalyst also can be non-ionic surfactant such as Triton-X 100 and PEG-400.

The amount of phase transfer catalyst larger than 5% by weight does no harm, but is unattractive because of the higher costs. Preferably the catalytic amount of phase transfer catalyst is 0.00001-5% by weight, more preferably 0.0001-0.1% by weight and especially 0.001-0.01% by weight, based on the carbohydrate.

The oxidation can be carried out in water and organic solvent which can't soluble in water. The organic solvent is preferably esters such as ethyl acetate. Hypohalite , used as oxidant , can be hypochlorite salt, preferably in the form of a salt thereof, such as lithium hypochlorite, sodium hypochlorite, and potassium hypochlorite. As a molar ratio, the amounts of oxidant to be used are 1.6~2.4 mol per mol of carbohydrate.

The method according to the invention is carried out in a little basic reaction medium with a pH of higher than 7 up to 9.5, preferred a pH of 7.5-9.2 is employed; preferably a pH of 8.0-9.0 is employed. The pH of the reaction mixture can be adjusted by adding NaOH.

The reaction temperature can vary from approximately -5°C to about 50⁰C . Preferably, the reaction is carried out at temperature of below 20⁰C, more preferably at approximately 0-10°C

After the reaction, the product, oxidized carbohydrate can be isolated from the reaction mixture by ion exchange. The yields of the product , carboxyl carbohydrate, in general are above 92%. And the di-tertiary-alkyl nitroxyl used as the catalyst can be recovered from the reaction mixture, for example by extraction with ethyl acetate.

Examples:

Example 1

Trehalose 3 g was suspended in 200 ml of water and 10 ml ethyl acetate, the suspension was added with 0.03 g TEMPO and O.OOlg tetrabutyl ammonium chloride. The suspension was cold to 0°C, the pH of the reaction mixture was adjusted to 8.5 by adding 20%NaOH and 65 ml 4% sodium hypochlorite was added. By means of a pH stat, the pH was maintained at 8.0-9.0 during the reaction by the addition of 2M NaOH. The reaction was terminated after 3 hours at 0°C by addition of 50 ml ethyl acetate to extract the TEMPO out. The mixture was concentrated and isolated by ion exchange. D-glucuronyl-D-glucuronic acid was obtained , as white solid, in a yield of 92%. ESI-MS: 385.1 (M+H) .

Example 2

Methyl glucopyranoside 250 Kg and 4-acetoxy- TEMPO 0.8 kg, tetrabutyl ammonium chloride 2Og were dissolved in 500 kg water and 10 kg ethyl acetate. The solution was cooled to 3°C, and the temperature was maintained at 0-20 °C the reaction was initiated by the addition of sodium hypochlorite, and during the reaction the pH is maintained at 8.0-9.0 by the addition of 2M NaOH. After the reaction is completed, 50 kg ethyl acetate was added to extract the TEMPO. The mixture was concentrated and isolated by ion exchange. The yield of colorless oil methyl glucopyranosiduronic acid is 92%. ESI-MS: 209.2(M+H)

Example 3

Methyl alloside 5 g was suspended in 200 ml of water and 10 ml ethyl acetate, the suspension was added with 0.03 g 4-ethelyamido-2,2,6,6-tetramethylpiperidin-l-oxy and O.OOlg Triton-X 100. The suspension was cold to 0°C, and 70 ml 4% lithium hypochlorite at pH 8.5 was added. By means of a ph stat, the ph was maintained at 8.0-9.0 during the reaction by the addition of 2M NaOH. The reaction was terminated after 3 hours at 0°C by addition of 50 ml ethyl acetate to extract the 4-ethelyamido-2,2,6,6-tetramethylpiperidin-l-oxy out. The mixture was concentrated and isolated by ion exchange. The methyl alloopyranosiduronic acid was obtained as colorless oil and was determined by HPLC. ESI-MS: 209.5(M+H), the yield is 93%.

Example 4

Ethyl altroside 4.2 g was suspended in 200 ml of water and 10 ml ethyl acetate, the suspension was added with 0.03 g 4-propionyloxyl-2,2,6,6-tetramethylpiperidin-l-oxy and O.OOlg PEG-400. The suspension was cold to 0°C, and 60 ml 4% sodium hypochlorite at pH 8.5 was added. By means of a ph stat, the ph was maintained at 8.0-9.0 during the reaction by the addition of 2M NaOH. The reaction was terminated after 3 hours at 0°C by addition of 50 ml ethyl acetate to extract the4- propionyloxyl -2,2,6,6-tetramethylpiperidin-l-oxy out. The mixture was concentrated and isolated by ion exchange. The yield of colorless oil ethyl altropyranosiduronic acid is 92%. ESI-MS: 223.4(M+H).

Example 5

Methyl galactofuranoside 240 Kg and 4- hydroxy -TEMPO 0.7 kg, triethyl phenyl Ammonium Chloride 2Og were dissolved in 500 kg water and 10 kg ethyl acetate. The solution was cooled to 3°C, and the temperature was maintained at 0-10°C the reaction was initiated by the addition of sodium hypochlorite, and during the reaction the pH is maintained at 8.0-9.0 by the addition of 2M NaOH, after the reaction completely. 40 kg ethyl acetate was added to extract the A- hydroxy -TEMPO. The mixture was concentrated and isolated by ion exchange. The The yield of colorless oil methyl galactofuranouronic acid is 96%. ESI-MS: 209.5(M+H).

Example 6

Methyl gulopyranoside 3 g was suspended in 200 ml of water and 10 ml butyl acetate, the suspension was added with 0.03 g TEMPO and O.OOlg tetrabutyl ammonium chloride. The suspension was cold to 0°C, and 65 ml 4% potassium hypochlorite at pH 8.5 was added. By means of a ph stat, the ph was maintained at 8.0-9.0 during the reaction by the addition of 2M NaOH. The reaction was terminated after 3 hours at 0°C by addition of 50 ml butyl acetate to extract the TEMPO out. The mixture was concentrated and isolated by ion exchange. The yield of colorless oil methyl gulopyranouronic acid is 97%. ESI-MS: 209.1(M+H).

Example 7

Methyl mannofuranoside 3.5 g was suspended in 200 ml of water and 10 ml butyl acetate, the suspension was added with 0.03 g 4-ethelyamido-2,2,6,6-tetramethylpiperidin-l-oxy and O.OOlg Triton-X 100. The suspension was cold to 0°C, and 70 ml 4% potassium hypochlorite at pH 8.5 was added. By means of a ph stat, the ph was maintained at 8.0-9.0 during the reaction by the addition of 2M NaOH. The reaction was terminated after 3 hours at 0°C by addition of 50 ml ethyl acetate to extract the 4-ethelyamido-2,2,6,6-tetramethylpiperidin-l-oxy out. The mixture was concentrated and isolated by ion exchange. The yield of colorless oil methyl mannofuranouronic acid is 94%. ESI-MS: 209.2(M+H).

Example 8

Methyl sorboside 250 Kg and 4-acetoxyl -TEMPO 0.5 kg, Tridodecyl Methyl Ammonium Chloride 20g were dissolved in 500 kg water and 10 kg ethyl acetate. The solution was cooled to 3°C, and the temperature was maintained at 10-30°C the reaction was initiated by the addition of sodium hypochlorite, and during the reaction the pH is maintained at 8.0-9.0 by the addition of 2M NaOH, after the reaction completely. 50 kg ethyl acetate was added to extract the 4-acetoxyl -TEMPO. The mixture was concentrated and isolated by ion exchange. The yield of colorless oil methyl sorbouronic acid is 98%. ESI-MS: 209.3(M+H).

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable.

Claims

1. A process of selective oxidizing primary alcohols in carbohydrate by means of a hypohalite in the presence of catalytic amount of a di-tertiary-alkyl nitroxyl , the process is characterized in that the oxidation is under a two-phase and bromide-free condition in the presence of phase transfer catalyst.

2. The process according to claim 1, wherein said carbohydrate is monosaccharide or disaccharide.

3. The process according to claim 1 or 2, wherein said phase transfer catalyst is selected from the group consisting of tridodecyl methyl ammonium chloride, tetrabutyl ammonium chloride, triethyl phenyl ammonium chloride, Triton-X 100 or PEG-400; said catalytic amount of phase transfer catalyst is 0.00001-5% by weight, based on the carbohydrate.

4. The process according to claim 3, the catalytic amount of phase transfer catalyst is 0.0001-0.1% by weight, based on the carbohydrate.

5. The process according to claim 3, the catalytic amount of phase transfer catalyst is 0.001-0.01% by weight, based on the carbohydrate.

6. The process according to claim 1 or 2, wherein said di-tertiary-alkyl nitroxyl is 4-hydrooxy-2,2,6,6-tetramethylpiperidin-l-oxyl or an ester thereof, or 4-alkanoylamido2,2,6,6-tetramethylpiperidin-l-oxyl; said catalytic amount of di-tertiary-alkyl nitroxyl is 0.001-5% by weight based on the carbohydrate.

7. The process according to claim 6, wherein said catalytic amount of di-tertiary-alkyl nitroxyl is 0.05-2.0% by weight , based on the carbohydrate.

8. The process according to claim 6, wherein said catalytic amount of di-tertiary-alkyl nitroxyl is 0.1-1% by weight, based on the carbohydrate.

9. The process according to claim 1 or 2, as a molar ratio, the amounts of oxidant to be used are 1.6~2.4 mol per mol of monosaccharide.

10. A process according to claim 1 or 2, the organic solvent is preferably esters such as ethyl acetate, butyl acetate.

11. A process according to claim 1 or 2, little basic reaction medium with a pH of 7.5-9.2 is employed and the reaction temperature is from approximately -5°C ~50°C .