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Method for manufacturing betulinic acid

a manufacturing method and technology for betulinic acid, applied in the field of betulinic acid manufacturing, can solve the problems of unsatisfactory commercial scale (e.g., kilogram) production of betulinic acid, unfavorable disclosure of purification steps, and inability to meet the requirements of a commercial scale, etc., to achieve less toxic, less time, and less expensive

Inactive Publication Date: 2001-07-12
RGT UNIV OF MINNESOTA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006] The present invention provides a method for preparing betulinic acid and precursors thereof. The methods of the present invention require less time and require reagents that are less expensive, less toxic, or less flammable than known methods for preparing betulinic acid and the precursors thereof.

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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  • Method for manufacturing betulinic acid
  • Method for manufacturing betulinic acid
  • Method for manufacturing betulinic acid

Examples

Experimental program
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Effect test

example 1

[0065] Betulin-3-acetate (III) 9

[0066] Acetic anhydride (85 ml) and acetic acid (800 ml) were introduced into round bottom flask (3 L). Betulin (I) (100 g, 0.2259 mol) was added to the stirred solution and refluxed for 3 hours. The reaction mixture was allowed to cool to 50.degree. C. and acetic acid was evaporated under reduced pressure (25-30 mm Hg). Cream-white crystals of intermediate betulin-3,28-diacetate (II) were obtained after storage in vacuo (118.8 g, 0.2257 mol, 50-60.degree. C., 0.1 mm Hg).

[0067] Isopropanol (i.e., i-PrOH) (2.5 L) and powdered aluminum iso-propoxide (i.e., Al(O-i-Pr).sub.3) (100 g, 0.223 mol) were added to the flask and the mixture was refluxed for 1.5 hours. Isopropyl alcohol was then removed under reduced pressure (100 mm Hg) at 30-33.degree. C. The resulting white-orange crystals were dissolved in dichloromethane (1 L) and water (60 ml) was added to the solution. After stirring (10-15 minutes) the precipitated material was filtered, extracted with di...

example 2

[0068] Betulinic aldehyde-3-acetate (VI) 10

[0069] Oxalyl chloride (15.72 g, 0.1237 mol) in methylene chloride (i.e., CH.sub.2Cl.sub.2) (500 ml) was placed in a round bottom two-neck flask (2 L). After cooling to -50 to -60.degree. C. (dry ice bath) and with efficient stirring was added dimethylsulfoxide (i.e., DMSO) (12.87 g, 0.165 mol) in methylene chloride (500 ml) drop-wise over 5 to 10 minutes. The mixture was stirred for an additional 5 to 10 minutes (until gas evolution stops). Betulin-3-acetate (III) (powdered) (0.0825 mol, 40 g) was then added and allowed to stand for 45 minutes. After triethylamine (41.67 g, 0.4126 mol) was added, the cooling bath was removed and temperature allowed to increase to 10.degree. C. Cold water (200 ml) was added and the mixture was extracted with methylene chloride (3.times.100 ml). The combined organic extracts were washed with water (5.times.100 ml), 5% HCl (2.times.100 ml) and brine (2.times.100 ml). After drying over sodium sulfate (10 g), e...

example 3

[0070] Betulinic aldehyde-3-acetate (VI) 11

[0071] Oxalyl chloride (7.86 g, 62 mmol) in trifluoromethylbenzene (250 ml) was placed in a round bottom two-neck flask (2 L). After cooling to -30 to -35.degree. C. (i-PrOH-dry ice bath) and with efficient stirring was added dimethylsulfoxide (6.44 g, 83 mmol) in trifluoromethylbenzene (250 ml) drop-wise over 5 to 10 minutes. The mixture was stirred for an additional 5-10 minutes (until gas evolution stops). Powdered 3-O-acetyl-betulin (III) (40 g, 41 mmol) was then added. The resulting mixture was allowed to stand for 45 minutes. After triethylamine (41.67 g, 206 mmol) was added, the cooling bath was removed and the temperature was allowed to increase to 10.degree. C. Cold water (100 ml) was added and the mixture was extracted with trifluoromethylbenzene (3.times.50 ml). The combined organic extracts were washed with water (5.times.50 ml), 5% HCl (2.times.50 ml) with brine (2.times.50 ml). After drying over sodium sulfate (5 g), evaporati...

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Abstract

The present invention provides a method for preparing betulin-3-acetate including alcoholyzing betulin 3,28-dibenzoate; a process for preparing betulin-3-acetate including: (1) acylating betulin to provide betulin 3,28-dibenzoate and (2) alcoholyzing betulin 3,28-dibenzoate to provide betulin-3-acetate; and a process for preparing betulinic acid including: (1) acylating betulin to provide betulin 3,28-dibenzoate; (2) alcoholyzing betulin 3,28-dibenzoate to provide betulin-3-acetate; (3) oxidizing betulin-3-acetate to provide betulinic aldehyde-3-acetate; (4) oxidizing betulinic aldehyde-3-acetate to provide betulinic acid-3-acetate; and (5) deprotecting betulinic acid-3-acetate to provide betulinic acid.

Description

BACKGROUND OF THE INVENTION[0001] Betulinic acid is useful as a 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 MEL-4. 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, 205-21 1). The outer bark of Betula paparifera (commercial birch of northern U.S. and Canada) contains nearly 5-18% betulin (see, U.S. patent ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C45/64C07C47/46C07C67/29C07C51/16C07C51/235C07C51/367C07C62/06C07C62/32C07C69/00C07C69/16
CPCC07C51/16C07C51/367C07C62/32C07C67/08C07C67/14C07C67/29C07C2103/52C07C69/013C07C69/16C07C69/78C07C69/14C07C2603/52
Inventor KRASUTSKY, PAVEL A.CARLSON, ROBERT M.NESTERENKO, VITALIY V.
Owner RGT UNIV OF MINNESOTA
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