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Electrochemical Method for the Production of Betulin Aldehyde

Inactive Publication Date: 2008-12-18
RGT UNIV OF MINNESOTA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The present invention provides a relatively cost effective, safe and efficient maimer to convert a primary alcohol (e.g., betulin) to the corresponding aldehyde (e.g., betulin aldehyde). Specifically, the present invention provides a relatively cost effective, safe and efficient manner to convert betulin to betulin-28-aldehyde. The synthesis is a one-step method that typically affords up to about 90 wt. % aldehyde, and about 10 wt. % unreacted starting material. The oxidation employs an oxoammonium ion, which can be electrochemically produced from, e.g., compound of formula (XXV), e.g., TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl). The crude aldehyde can be converted to the corresponding carboxylic acid (betulinic acid), where it can be separated from the unreacted starting material (e.g., betulin) employing, e.g., an acid-base washing.

Problems solved by technology

Due to the length of time required to carry out this process and the yield it provides, it is not ideal for the commercial scale (e.g., kilogram) production of betulinic acid.
Additionally, the process uses solvents and reagents that are hazardous and expensive, and the disclosed purification steps are not feasible on a commercial scale.
The main obstacle for employing this method is the preparation of starting material (i.e., betulin-3-acetate).
Additionally, the cost of magnesium alcoholates is fairly high.
As such, this method is not attractive for the commercial scale production of betulinic acid.

Method used

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  • Electrochemical Method for the Production of Betulin Aldehyde
  • Electrochemical Method for the Production of Betulin Aldehyde
  • Electrochemical Method for the Production of Betulin Aldehyde

Examples

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Effect test

example 1

Preparation of Betulin Aldehyde from Betulin

[0139]450 ml of N,N-dimethylformamide, 20 g of betulin and 4 g of tetra-n-butylammonium perchlorate were loaded into a 500 ml Duran reaction vessel equipped with a heating mantle, mechanical stirrer, reflux condenser, glass-jacketed thermocouple and electrode bank of 3 flat platinum gauze anodes (50×50 mm) and 2 copper plate cathodes of the same size, clamped through 3 mm Teflon spacers. The mixture was heated up to 65° C. with stirring, then 20 ml of water and finally 1 g of TEMPO were added to mixture. After this, sufficient voltage was applied to the electrodes to maintain a 350-400 mA current. The process started at 2.9 V, then the voltage increased to 3.4-3.8 V and remained in this range for about 10 hours. At the end of the process the mixture turned from orange to colorless, and the voltage increased rapidly to 4 V and higher. The mixture was removed from the reactor to a flask, evaporated to about 200 ml, then diluted with 400 ml o...

example 2

Preparation of Betulin Aldehyde from Betulin

[0140]2500 ml of N,N-dimethylformamide, 120 g of betulin and 20 g of tetraethylammonium p-toluenesulfonate were loaded into a 2500 ml Duran reaction vessel equipped with a heating mantle, mechanical stirrer, reflux condenser, glass-jacketed thermocouple and an electrode bank of a cylindrical platinum gauze anode of total surface area 550 cm2 and 2 coaxial copper gauze cathodes, clamped through 4 mm Teflon rings. The mixture was heated up to 70° C. with stirring, then 100 ml of water and finally 5 g of TEMPO were added to the mixture. After this, sufficient voltage was applied on the electrodes to get a current of 3 A. The process started at 2.9 V, then the voltage increased to 3.4-3.8 V and remained in this range for about 25 hours. At the end of the process the mixture turned from orange to colorless, and the voltage increased rapidly to 4 V and higher. The mixture was removed from the reactor to a flask and diluted with 4 L of water with...

example 3

Preparation of Betulin Aldehyde from Betulin

[0141]2500 ml of N,N-dimethylacetamide, 120 g of betulin and 20 g of tetraethylammonium p-toluenesulfonate were loaded into the reaction vessel of Example 2. The mixture was heated up to 60° C. with stirring, then 60 ml of water and finally 5 g of TEMPO were added to mixture. After this, sufficient voltage was applied to the electrodes to get a current of 1.7 A. The voltage started at 2.6 V, then increased to 3.1±0.1 V and maintained in this range for about 35 hours. After the voltage further increased to 3.5 Volts, the process was maintained 8 hours more at constant voltage. At the end of process the mixture turned from orange to colorless. The mixture was removed from the reactor to a flask and diluted with 4 L of water with stirring. The white deposit was filtered after the mixture cooled down, washed with water, and dried at 70° C. Yield: 120 g of a mixture of 92% betulin aldehyde and 8% betulin.

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Abstract

The present invention provides a method for manufacturing betulin aldehyde from betulin. The method includes: (a) electrochemically forming a oxoammonium ion from a nitroxyl radical; and (b) contacting betulin with the oxoammonium ion, for a period of time effective to provide the betulin aldehyde. The betulin aldehyde can subsequently be converted to betulinic acid, employing, e.g., NaClO2 or KClO2. The betulinic acid can be purified from from any unreacted betulin by converting the betulinic acid into a corresponding salt (Na, K, Li, Na, Ca, Mg, Ba, or Al), and separating the salt from the unreacted betulin.

Description

BACKGROUND OF THE INVENTION[0001]Betulinic acid is useful as a potential therapeutic agent. For example, Pisha, E. et al., (1995) J. M. Nature Medicine, 1, 1046-1051 disclose that betulinic acid has antitumor activity against melanoma, e.g., MEL-1, MEL-2 and MEL4. In addition, Fujioka, T. et al., J. Nat. Prod., (1994) 57, 243-247 discloses that betulinic acid has anti-HIV activity in H9 lymphocytic cells.[0002]Betulinic acid can be manufactured from betulin, which is present in large quantities in the outer birch bark of numerous species of birch trees. For example, a single paper mill in northern Minnesota generates nearly 30-70 tons of birch bark per day. Approximately 230,000 tons of birch bark are generated per year. Outer bark of Betula verrucosa (European commercial birth tree) contains nearly 25% betulin (Rainer Ekman, 1983, Horzforschung 37, 205-211). The outer bark of Betula paparifera (commercial birch of northern U.S. and Canada) contains nearly 5-18% betulin (see, U.S. P...

Claims

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Application Information

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IPC IPC(8): C25B3/00C25B3/23
CPCC07J63/00C25B3/02C25B3/23
Inventor KRASUTSKY, PAVEL A.RUDNITSKAVA, ANNAKHOTKEVYCH, ANDRIV B.
Owner RGT UNIV OF MINNESOTA
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