WO2009067847A1

WO2009067847A1 - Catalyst and method for selectively oxidizing primary hydroxy of protected monosaccharide

Info

Publication number: WO2009067847A1
Application number: PCT/CN2007/071144
Authority: WO
Inventors: Yongsheng Li
Original assignee: Chongqing Shengkai Science & Technology Co., Ltd.
Priority date: 2007-11-28
Filing date: 2007-11-28
Publication date: 2009-06-04

Abstract

The present invention provides catalysts and methods for selectively oxidizing primary hydroxyl of protected monosaccharides. The present invention uses 4-alkyloxy or acyloxy substituted 2,2,6,6-tetramethylpiperidinyl-N-oxy as catalyst, reacts protected monosaccharides to be oxidized with hypohalite solution, without any adjuvant catalyst being required and primary hydroxyl of the protected monosaccharides can be selectively oxidized to carboxyl and the reaction yield can reach above 95%.

Description

Catalyst and method for protecting selective oxidation of monosaccharide primary hydroxyl groups

The present invention relates to a catalyst for the selective oxidation of primary hydroxyl groups of monosaccharides, and to a method for the selective oxidation of primary hydroxyl groups of monosaccharides. Background technique:

Monosaccharides are polyhydroxy compounds, and the selective oxidation of primary hydroxyl groups in their structures to monoglycosides is of great importance because it is an important intermediate for the synthesis of many physiologically active substances.

The catalysts and methods for selectively oxidizing primary hydroxyl groups in monosaccharides have been reported as follows:

1. GB670929 uses nitric acid and sodium nitrite as oxidants. This method consumes a large amount of nitric acid. The yield is low, and there are many by-products. It will produce a large amount of nitrogen dioxide (known as “Huanglong” in the industry), causing significant pollution to the environment.

2. US2592249, US2683150 is a nitrogen dioxide gas as an oxidant, but the nitrogen dioxide gas is inconvenient to operate, and also causes serious pollution to the environment.

3. US2845439 and US2627520 use oxygen as the oxidant in the presence of precious metals. This method requires the use of expensive platinum, palladium and other metals as catalysts.

4. Use 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) as a catalyst, such as:

1) TEMPO + sodium hypochlorite + sodium bromide, see Tetrahedron Lett. 34, 1181-1184, 1993 and WO9507303; 2) TEMPO + sodium hypochlorite + hydrogen peroxide, see WO0134657;

3) TEMPO+ sodium hypochlorite, see PL Bragd: J. Mol. Cata. A: Chem, 170, 35-42, 2001 Some of the above methods using TEMPO require the use of an auxiliary oxidant, which can cause problems: such as the addition of sodium bromide, products It will introduce impurities such as Br—the hydrogen peroxide is easy to explode in the post-treatment, and the safety of the operation is very high. In addition, the pH range of the reaction is narrow and the reaction conditions are harsh. Moreover, the above method has a low reaction yield.

SUMMARY OF THE INVENTION The ultimate object of the present invention is to provide a convenient and economical method for selectively oxidizing primary hydroxyl groups to protect monosaccharides. The immediate aim is to find a new catalyst and find the most suitable reaction conditions to make the selective oxidation reaction more efficient and economical.

In order to achieve the above object, the inventors synthesized and screened a series of TEMPO derivatives by molecular design, and respectively used them for the selective catalytic oxidation test of primary hydroxyl groups of hydroxyl groups, and finally found the compound of formula I: 4- Alkoxy or Acyloxy substituted -2,2,6,6-tetramethylpiperidine-N-oxide, such a novel compound can be used as a catalyst alone, and can selectively oxidize and protect the primary hydroxyl group of the monosaccharide into a carboxyl group without an auxiliary oxidizing agent. Moreover, the reaction yield can reach more than 95%.

Formula I

In formula I: R is selected from the group consisting of a chain alkyl group, a cycloalkyl group or an acyl group, preferably a tert-butyl group, an isopropyl group, a cyclohexyl group, a propionyl group, a butyryl group or a valeryl group, preferably a tert-butyl group, an isopropyl group, a cyclohexyl group. Butyryl. The present invention provides a novel method for protecting a primary hydroxyl group from monosaccharide protection:

The protective monosaccharide to be oxidized is reacted with a 1% to 20% (w/w) hypohalite solution using the compound of the formula I as a catalyst; the amount of the compound of the formula I is 0.1% of the protected monosaccharide~ 5.0% (W/W)o

The protective monosaccharide includes alenose, glucopyranoside, alloside, glucopyranoside, glucoside, glucose glucoside, glucose glucoside, glucose glucoside, Azhuo glycoside, arboside, azhuo glucoside, azhuo glucoside, mannose glucoside, mannose glucoside, mannose glucoside, mannose glucoside, gulose Glycoside, gulose glycoside, gulose aglycone, gulose glucoside, galactosylglycoside, galactose, galactoside, galactoside.

The hypo-acid salt includes hypochlorite, hypobromite, preferably sodium hypochlorite or sodium hypobromite. The present invention has the following advantages over the prior art:

1. No need for auxiliary oxidizer

It not only saves raw materials but also eliminates the opportunity to introduce impurities into the product.

2. Loose reaction conditions

It is not necessary to carry out the reaction under acidic conditions, and it can be carried out in an environment of pH 4-10.

3. Low cost

The catalyst is directly used for the catalytic reaction, the reaction step is small, the reaction speed is fast, the manpower is saved, and it is particularly suitable for large-scale production on an industrial scale.

4. High efficiency

The reaction yield can reach more than 95%. detailed description:

The invention will be further clarified by the following examples, and the present invention may be more fully understood by those skilled in the art, but without limiting the invention in any way.

Example 1 Preparation of 4-tert-butoxy- 2,2,6,6-tetramethylpiperidine-N-oxide

In a 1 L three-necked flask, 300 ml of dichloromethane, 60 ml of pyridine, 30 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxide were added at 0 ° C, and then 66 g of a pair was added dropwise. A solution of tosyl chloride dissolved in 200 ml of dichloromethane was reacted for 180 minutes. Further, a solution of 50 g of sodium t-butoxide dissolved in 200 ml of dichloromethane was added dropwise to the solution, and the reaction was stirred for 120 minutes. After completion of the reaction, the reaction mixture was washed three times with water, dried over anhydrous sodium sulfate, evaporated, evaporated, evaporated. Red crystals of tetramethylpiperidine-N-oxide 34go 1H NMR (CDC1 ₃ , 300 ΜΗζ, δ) 1.22 (s, 9H) 1.73 (s, 12H) 1.95-2.20 (m, 4H) 2.83 (m, 1H) Elemental analysis: C, 68.36; H, 11.43; N, 6.07; 0, 14.03; ESI-MS: found: 228.1965 (calu: 228.1964) This catalyst is used directly in the catalytic reaction. Example 2 Preparation of 4-isopropoxy-2,2,6,6-tetramethylpiperidine-N-oxide

In a 1 L three-necked flask, 300 ml of dichloromethane, 60 ml of pyridine, 30 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxide were added at 0 ° C, and then 66 g of a pair was added dropwise. A solution of tosyl chloride dissolved in 200 ml of dichloromethane was reacted for 180 minutes. Further, a solution of 46.5 g of sodium isopropoxide dissolved in 200 ml of dichloromethane was added dropwise to the solution, and the reaction was stirred for 120 minutes. After completion of the reaction, the reaction mixture was washed three times with water and dried over anhydrous sodium sulfate. Red crystals of tetramethylpiperidine-N-oxide 28go 1H NMR (CDC1 ₃ , 300 ΜΗζ, δ) 1.17 (s, 6H) 1.71 (s, 12H) 1.95-2.20 (m, 4H) 2.83 (m, 1H) 3.20 (m, 1H); Elemental analysis: C, 67.24; H, 11.30; N, 6.58; 0, 14.90; ESI-MS: found: 214.1810 (calu: 214.1807). This catalyst is used directly for the catalytic reaction. Example 3 Preparation of 4-cyclohexyloxy-2,2,6,6-tetramethylpiperidine-N-oxide

In a 1 L three-necked flask, 300 ml of dichloromethane, 60 ml of pyridine, 30 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxide were added at 0 ° C, and then 66 g of a pair was added dropwise. A solution of tosyl chloride dissolved in 200 ml of dichloromethane was reacted for 180 minutes. Further, a solution of 52.4 g of sodium cyclohexoxide in 200 ml of dichloromethane was added dropwise to the solution, and the reaction was stirred for 120 minutes. After completion of the reaction, the reaction mixture was washed three times with water and dried over anhydrous sodium sulfate. Red crystals of tetramethylpiperidine-N-oxide 32go 1H NMR (CDC1 ₃ , 300 ΜΗζ, δ) 1.39-1.46 (m, 8H) 1.71 (s, 12H) 1.73 (m, 2H) 1.95-2.20 (m , 4H) 2.79 (m, 1H) 2.83 (m, 1H); Elemental analysis: C, 70.81; H, 11.10; N, 5.54; 0, 12.57; ESI-MS: found: 254.3881 (calu: 254.3883). This catalyst is used directly for the catalytic reaction. Example 4 Preparation of 4-propionyloxy-2,2,6,6-tetramethylpiperidine-N-oxide

Add 500 ml of dichloromethane to a clean and dry 1 L three-necked flask, add 127 ml of pyridine, 172 g of 4-OH-TEMPO, and add 101 ml of propionyl chloride in 200 ml of dichloromethane solution after cooling to below 0 ° C. Stir for 30 min. The reaction mixture was transferred to a 2 L sep. funnel, and the methylene chloride layer was washed three times (150 ml X 3 ) with EtOAc. The dichloromethane was evaporated to dryness under reduced pressure at 35 ° C to yield 284 g of brown liquid. After filtration, the filter cake was washed three times with 100 ml of ice-hexane, to give an orange-yellow crystal 4 (t, 3H) .16 (s, 12H) .78.53 (m, 4H) 2.29 (q, 2H) 3.97 (m, 1H) Elemental analysis: C, 63.12; H, 9.72; N, 6.13; 0, 21.04; ESI-MS: found: 228.1601 ( calu: 228.1600). This catalyst is used directly for the catalytic reaction. Example 5 Preparation of 4-butyryloxy-2,2,6,6-tetramethylpiperidine-N-oxide

Add a clean and dry 1L three-necked flask to 500ml of dichloromethane, and add 127ml of pyridine, 172g of 4-OH-TEMPO, and add 112ml of butyryl chloride in 200ml of dichloromethane solution after cooling to below 0 °C. Stir for 30 min. The reaction mixture was transferred to a 2 L sep. funnel, and the methylene chloride layer was washed three times (150 m 3 ) with 0.5 N EtOAc. Dichloromethane was evaporated to dryness under reduced pressure at 35 ° C to yield 290 g of brown liquid, which was then taken to 100 ml of n-hexane and chilled overnight in a freezer. Filtration, the filter cake was washed three times with 100 ml of ice-hexane, to give an orange-yellow crystal of 0.96 (t, 3H) .16 (s, 12H) .72 (m, 2H) .78.53 (m, 4H) 2.26 (q, 2H) 3.97 (m, 1H); Elemental analysis: C, 64.44; H, 9.96; N, 5.74; 0, 19.83; ESI-MS: found: 242.1757 ( calu: 242.1756). This catalyst is used directly for the catalytic reaction.

Example 6 Selective oxidation of galactose to galactosidate

2000 ml of water was added to a 20 L three-necked flask at 0 ° C, then 1000 g of dried galactoside, 10 g of 4-butyryloxy-2,2,6,6-tetramethylperazine was added with stirring. pyridine-N-oxide, start adding 16% NaC10 solution and 2 N hydrochloric acid at the same time, keep the pH between 5~8, keep the temperature at 0-30 °C, when adding about 1800 ml NaCIO solution, Stop adding hydrochloric acid and add 2N NaOH solution until 6750 ml NaCIO solution is added dropwise. The yield of galactosidic acid was 93% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 95%. Example 7 Selective Oxidation of Glucosinate to Glucose Glycinate

2000 ml of water was added to a 20 L three-necked vial at 0 ° C, then 1000 g of dry dextrose glucoside, 10 g of 4-tert-butoxy-2,2,6,6-tetramethylpiperidine was added with stirring. -N-oxide, and at the same time start adding 16% NaC10 solution and 2 N hydrochloric acid, keep the pH between 6~10, keep the temperature at 0-30 °C, when adding about 1800 ml NaCIO solution, stop adding hydrochloric acid, add 2N NaOH solution until 6750 ml NaCIO solution drops The addition is completed. The yield of glucose glycylate was 92% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 94%. Example 8 Selective Oxidation of Glucose Adenosine to Glucose Mesylate

2000 ml of water was added to a 20 L three-necked flask at 0 ° C, then 1000 g of dried dextrose glucoside, 2 g of 4-isopropoxy-2,2,6,6-tetramethylpiperidine were added with stirring. -N-oxide, start adding 20% NaBrO solution and 2 N hydrochloric acid at the same time, keep the pH between 4~8, keep the temperature at 0-30 °C, stop when adding about 1850 ml NaBrO solution Add hydrochloric acid and add 2 N NaOH solution until 5400 ml of NaBrO solution is added dropwise. The yield of glucose-based acid was 90% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 95%. Example 9 Selective Oxidation of Glucose Adenosine to Glucose Mesylate

2000 ml of water was added to a 20 L three-necked flask at 0 ° C, then 1000 g of dried dextrose glucoside, 5 g of 4-acetoxy-2,2,6,6-tetramethylpiperidine - was added with stirring. N-oxide, start adding 20% NaBrO solution and 2 N hydrochloric acid at the same time, keep the pH between 4~8, keep the temperature at 0-30 °C, when adding about 1850 ml NaBrO solution, stop adding Hydrochloric acid, add 2 N NaOH solution until 5400 ml NaBrO solution is added dropwise. The yield of glucose-based acid was 90% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 95%. Example 10 Selective oxidation of aglucoside to aglucoside

2000 ml of water was added to a 20 L three-necked flask at 0 ° C, and then 1000 g of dried aloe glucoside, 45 g of 4-cyclohexyloxy-2,2,6,6-tetramethyl was added with stirring. Piperidine-N-oxide, start adding 10% NaClO solution and 2 N hydrochloric acid at the same time, keep the pH between 6-10, keep the temperature at 0-30 °C, when adding about 2900ml NaCIO solution, Stop adding hydrochloric acid and add 2 N NaOH solution until 10800 ml of NaCIO solution is added dropwise. The Blumenkrantz analysis method was used to analyze the yield of aglucosyl isocyanate by 93%, and the selectivity of primary hydroxyl oxidation was above 96%. Example 11 Selective oxidation of aglucoside to aglucoside

2000 ml of water was added to a 20 L three-necked flask at 0 ° C, and then 1000 g of dried aloe carboside, 10 g of 4-propionyloxy-2,2,6,6-tetramethyl was added with stirring. Piperidine-N-oxide, start adding 10% NaClO solution and 2 N hydrochloric acid at the same time, keep the pH between 6-10, keep the temperature at 0-30 °C, when adding about 2900ml NaCIO solution, Stop adding hydrochloric acid and add 2 N NaOH solution until 10800 ml of NaCIO solution is added dropwise. The yield of alopose-based acid was 95% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 96%. Example 12 Selective Oxidation of Galactose-Aglycone to Galactose-Based Acid

2000 ml of water was added to a 50 L three-necked flask at 0 ° C, and then 1000 g of dried galactosylglycoside, 20 _§ 4-tert-butoxy-2,2,6,6-tetramethyl was added with stirring. Piperidine ^-oxide, and then start adding 5% KC10 solution and 2 N hydrochloric acid, keep the pH between 4-7, keep the temperature at 0-30 °C, when adding about 5760ml KC10 solution, stop Add hydrochloric acid and add 2 N NaOH solution until 21600 ml of KC10 solution is added dropwise. The yield of galactosylformate was 92% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 95%. Example 13 Selective Oxidation of Mannose Aglycone to Mannosyl Glucuronide

2000 ml of water was added to a 20 L three-necked flask at 0 ° C, then 1000 g of dried mannoside was added with stirring, 15 _§ 4-isopropoxy-2,2,6,6-tetramethyl Piperidine ^-oxide, then start adding 16% KBrO solution and 2 N hydrochloric acid, keep the pH between 5-9, keep the temperature at 0-30 °C, when adding about 1800ml KBrO solution, stop adding Hydrochloric acid, add 2 N NaOH solution until 6750ml KBrO solution is added dropwise. The yield of mannose-based acid was 93% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 94%. Example 14 Selective Oxidation of Mannose Adenosine to Mannose

2000 ml of water was added to a 20 L three-necked flask at 0 ° C, then 1000 g of dried mannoside was added with stirring, 15 g of 4-butyryloxy-2,2,6,6-tetramethylperidine. Acridine-N-oxide, start adding 16% KBrO solution and 2 N hydrochloric acid at the same time, keep the pH between 5-9, keep the temperature at 0-30 °C, when adding about 1800ml KBrO solution, stop adding Hydrochloric acid, add 2 N NaOH solution until 6750ml KBrO solution is added dropwise. The yield of mannose-based acid was 93% by the Blumenkrantz analysis method, and the selectivity of primary hydroxyl oxidation was above 96%.

Claims

Rights request

Compound of formula I

Formula I

In formula I: R is selected from the group consisting of a chain alkyl group, a cycloalkyl group or an acyl group.

2. A compound of formula I according to claim 1 wherein R is selected from the group consisting of t-butyl, isopropyl, cyclohexyl, propionyl, butyryl or valeryl.

3. A compound of formula I according to claim 2, wherein R is selected from the group consisting of t-butyl, isopropyl, cyclohexyl, butanoyl.

4. Use of a compound of formula I according to any one of claims 1 to 3 as a catalyst for the selective oxidation of primary hydroxyl groups of monosaccharides.

5. The use according to claim 4, wherein the protective monosaccharide comprises algose, glucopyranoside, alopyranoside, allose glucoside, altoside, altrose Ethyl glycoside, atropine, aglucone, glucoside, glucoside, glucoside, glucoside, mannose, mannose, mannose, mannose, mannose Isopropyl glucoside, gulose glycoside, gulose glycoside, gulose aglycone, gulose glucoside, galactosylglycoside, galactose, galactoside, galactoside.

A method for protecting a primary hydroxy group of a monosaccharide, which comprises the use of a compound of the formula I according to any one of claims 1 to 3 as a catalyst for protecting a monosaccharide to be oxidized. %~20% (WAV) hypohalite solution is reacted; the compound of formula I is used in an amount of 0.1% to 5.0% (W/W) of the protected monosaccharide.

7. The method for protecting a primary hydroxy group of a monosaccharide according to claim 6, wherein the protective monosaccharide comprises glucose methyl glycoside, glucose ethyl glucoside, glucose glucoside, glucose glucoside, aglucoside, alo Glycoside, alenose, glucopyranoside, alte glycoside, altrose glycoside, adradine, aglucoside, mannose, mannose Glycoside, mannose, mannose, gulose, gulose, gulose, gulose, glucopyranoside, galactose, galactoside , galactoside, galactose isopropyl glycoside.

8. A method of protecting a primary hydroxyl group for selective oxidation of a monosaccharide according to claim 6, wherein the hypohalite is selected from the group consisting of hypochlorite and hypobromite.

9. A method of protecting a primary hydroxy group of a monosaccharide according to claim 8, wherein the hypohalite is sodium hypochlorite or sodium hypobromite.