The method of obtaining betulinol acid

 

(57) Abstract:

The invention relates to an improved method of obtaining Betulinol acid. The method is based on the oxidation of betulin with subsequent restoration betulone acid and recrystallization and characterized in that the oxidation of betulin as oxidant used pyridinediamine complex (PDHC) with acetic anhydride (AA) in dimethylformamide (DMF) at a ratio of DMF : UA = 2,5 : 1-3 : 1, obtained betulonovoi acid to restore to(5%) and(95%) of the isomers Betulinol acid with sodium borohydride in alcohol WITH2-C4natural isomer of Betulinol acid is separated from the isomer by recrystallization Betulinol acid from alcohol2-C4while the crystals contain natural isomer, and the filtrate contains the mixture of isomers from which the oxidation can be obtained again belanova acid.

The invention relates to the field of chemistry and can be used in the processing of birch bark to obtain Betulinol acid.

You know getting Betulinol acid according to the method Ružička. (Ruzicka von L. , A. H. Lamberton & Christie C. W. Zur kenntnis der tritepene oxydation des betulin-mono-acetates mit chromtrioxyd zu of redukten//Helv. Chim. Acta, 1938, 21, pp.1706-1717). The way zaklyuchennii of the reaction, excess UA is distilled off under vacuum, the residue is washed and dried to constant weight. The yield of betulin diacetate - 99%. Then, the betulin diacetate omelet alcohol-benzene solution of potassium hydroxide, after the reaction the solution is added a solution of 0.1 N hydrochloric acid and evaporated. The crystals precipitated upon cooling, is filtered off, washed with alcohol, dried and receive acetate betulin. A big disadvantage of the method is that benzene is a highly toxic substance. Then carry out the oxidation of acetate betulin with chromic anhydride in acetic acid and get the acetate Betulinol acid, which amyraut 1.5 N alcoholic solution of potassium hydroxide. The resulting solution was concentrated in vacuo, mixed with HCl and with water and extracted with ether. From the ether layer falls clean the sediment Betulinol acid, which is filtered off. The remainder of Betulinol acid is produced by evaporation of the ether. After removal of the solvent Betulinol acid is recrystallized from ethanol. The method is complex because of the complexity of Otdelenia salts of chromium from the ether solvent.

A method of obtaining Betulinol acid through betulonovoi acid (Kim D. S. H. L, Chen Z., Nguyen T., Pezzuto J. M., Lu Z-Z betulone acid. To a solution of betulin (1 g, 2.26 mmol) in acetone is added dropwise a freshly prepared Jones reagent at 0oC. the Solution is stirred for 1.5 h at 0oWith, then add 25 ml of methanol, stirred for 5 min, add 40 ml of water. The organic solvent is removed under vacuum and the aqueous residue broekstraat with ethyl acetate (2 x 40 ml). The organic layer is separated and washed with water (20 ml), then a salt solution (15 ml). The organic layer is dried over MgSO4, filtered and evaporated under vacuum. The residue is purified by chromatography on silica gel (60-200), as eluent, a mixture of ether with ethyl acetate (4:1). Output betulone acid was 75%. Melting point 247-249oC.

Preparation of Betulinol acid. To tetrahydrofuran (20 ml) containing betulonovoi acid (500 mg, 1.10 mmol), was added NaBH4(400 mg) at 0oC and stirred at room temperature for 10 hours. The reaction is stopped by adding 2 N HCl solution (3 ml), tetrahydrofuran is distilled off under vacuum to half volume. The solution is diluted with ethyl acetate (80 ml), washed with water (3 times 5 ml) and a solution of salt (5 ml). The organic layer is dried over MgSO4sucked and pack for the recrystallization of Betulinol acid (375 mg, 75%). Melting point 291-292oC.

The disadvantage of this method is that the solvent used tetrahydrofuran, which was weak properties as a solvent in the preparation of Betulinol acid.

The challenge which seeks the invention consists in the further improvement of the method of obtaining Betulinol acid.

The problem is solved in the following way.

The method of obtaining Betulinol acid based on the oxidation of betulin with subsequent restoration betulone acid and recrystallization and characterized in that the oxidation of betulin as oxidant used pyridinediamine complex (PDHC) with acetic anhydride (AA) in dimethylformamide (DMF) at a ratio of DMF:UA 2.5:1-3:1, obtained betulonovoi acid to restore to(5%) and(95%) of the isomers Betulinol acid with sodium borohydride in alcohol WITH2-C4natural isomer of Betulinol acid is separated from the isomer by recrystallization Betulinol acid from alcohol C2-C4while the crystals contain natural isomer, and the filtrate contains the mixture of isomers from which the oxidation can be obtained again b oxidation of betulin important is the choice of oxidant. According to the invention it is proposed to use as the oxidizer pyridinediamine complex (PDHC) with acetic anhydride (AA) in dimethylformamide (DMF) (the ratio of DMF:UA equal to 2.5:1-3:1, which allows easy separation of chromium salt from the reaction products. Output betulone acid is 60%, and the final output of Betulinol acid 55% of the original betulin.

Belanova acid is easily restored to(5%) and(95%) of the isomers Betulinol acid with sodium borohydride in alcohol C2-C4.

Natural isomer of Betulinol acid is separated from the isomer by recrystallization Betulinol acid from alcohol C2-C4. When the crystals contain natural isomer, and the filtrate contains the mixture of isomers from which the oxidation can be obtained again belanova acid.

The method of obtaining Betulinol acid through oxidation of betulin to betulone acid is as follows.

Betulin is dissolved in a mixture of UA with DMF. The oxidant PDHC in a solution of DMF was added to the obtained solution and stirred for 30 minutes After the reaction betulonovoi acid is extracted with a solvent that is not miscible with water: prevedoros adding to the water extractor. The resulting solution betulone acid washed with water, then add to it a solution of alkali based on 1 mol betulone acid is not less than 1 mole of dry alkali. In this case the obtained Sol betulone acid is not soluble either in water or in an organic solvent, and forms an intermediate layer, which is then filtered. When filtering salt betulone acid is separated from the solvents and aqueous alkali solution, then it is acidified with an organic acid WITH2-C4or mineral acid to a pH of 1-4. Belanova acid is filtered and washed with water.

To obtain Betulinol acid is necessary to restore betulonovoi acid with sodium borohydride. As the solvent used alcohols WITH2-C4. Recovery betulone acid is quantitatively within three hours. After adding mineral acids, removal of the solvent, adding water and filtering receive a product that contains - and - isomers of Betulinol acid, it is recrystallized from alcohol2-C4while-isomer precipitates, and the mixture of isomers is in the filtrate.

Example 1. Oxidation of betulin. 10 g of betulin is dissolved in 175 ml D, the maximum temperature is 45oC. After the reaction betulonovoi acid is extracted with petroleum ether. The ether solution is washed with water, then add with stirring a 10% aqueous solution of KOH (10 ml), the formed intermediate layer of salt betulone acid is filtered and acidified with 5% aqueous solution of N2SO4.

Betulonovoi acid is filtered off and washed with water. Output betulone acid is 30% of the original betulin.

Recovery betulone acid. 1 g betulone acid dissolved in 30 ml of propanol, add sodium borohydride and stirred for 3 hours. After the reaction is added 2 N Hcl solution, the solvent is distilled off, add water, the precipitation is filtered off, washed with water. The output of Betulinol acid - 98% of betulone acid.

Recrystallization Betulinol acid. 1 g of Betulinol acid is recrystallized from ethyl or methyl alcohol. After cooling of the solution falls-isomer Betulinol acid, which is filtered off, washed with water and dried. The melting point of Betulinol acid - 295-297oC. From the filtrate the solvent is distilled off and the residue, containing the body take in two times less. Received betulonovoi acid restore.

Example 2. Oxidation of betulin. The difference from example 1 in that PDHC add in the form of a solution in DMF. 10 g of betulin dissolved in 117 ml of DMF (2/3 of the total) and 60 ml of UA. To the resulting solution was added 29 g PDHC in 58 ml of DMF (1/3 of the total), stirred for 30 minutes while cooling. Removing betulone acid, recovery, recrystallization is carried out as in example 1. Output betulone acid is 60% of the original betulin and exit Betulinol acid 55% of the original betulin.

The method of obtaining Betulinol acid oxidation of betulin and subsequent reduction of the obtained betulone acid sodium borohydride and recrystallization, characterized in that the oxidation of betulin performed using pyridinediamine complex (PDHC) with acetic anhydride (AA) in dimethylformamide (DMF) at a ratio of DMF : UA= 2,5: 1-3: 1, and recovering Betulinol acid to obtain -(5%) and(95%) of the isomers Betulinol acid is carried out in2-C4alcohol, natural-isomer Betulinol acid is separated from the isomer by recrystallization from C2-C4the alcohol.

 

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