The method of producing monoether succinic acid from 17 - oxosteroid and succinic anhydride

 

(57) Abstract:

The invention relates to the field of organic chemistry, the method of production of monoether from 17-oxosteroid and succinic anhydride. The method comprises the acylation of 17-oxosteroid using succinic anhydride in the environment bipolar aprotic solvent at 20-110oC in the presence of catalytic amount or an excess of base. As reaction medium used dimethylformamide, dimethylacetamide, dimethylsulfoxide, and other similar solvents. As the catalyst used for various reasons: calcined potash, tetramin. Excess base without adversely affects the yield of the target product, the yield of the target product is 91%. The process is carried out in mild conditions.

The invention relates to the field of organic chemistry - the way to get monoether succinic acid and 17-oxosteroid.

A known method of producing monoether succinic acid by acylation of 17-oxosteroid, for example trenbolone (östra-4,9,11-triene-17-hydroxy-3-one) (I) based on heating it with succinic anhydride in the environment pyridine:

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However, the conditions of the reaction, the heating in pyridine in 75o

It should be noted that the pyridine is among the highly toxic compounds and does not have a sufficiently high dissolving ability.

In addition, when the selection of the target product, in the case of pyridine there is a need to neutralize it with a strong mineral acid, which creates an additional inconvenience.

The aim of the invention is to develop a new method of obtaining monoether succinic acid from 17-oxosteroid and succinic anhydride in a more mild and environmentally friendly conditions, simplifying selection and increase the yield of the target product, expanding the range of the used solvents. This goal is achieved by the fact that the acylation of 17-oxosteroid with succinic anhydride is carried out in the environment bipolar aprotic solvent at 20-110oIn the presence of catalytic amount or an excess of the base.

The proposed method for the acylation of trenbolone (I) is of a General nature and can be used in the acylation other 17-oxosteroid, for example, 19-nortestosterone (III).

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As reaction medium in the proposed method can be used dimethylformamide, dimethylacetamide, dimethylsulfoxide and the number is the R bipolar solvents and goes without the use of a catalyst, however, the output of the respective monoamino succinic acid (II, IV) small (2-3%).

As a catalyst can be used various reasons (calcined potash, triethylamine). Organic Foundation it is better to apply at lower temperatures the reaction (20-60oC), inorganic elevated temperatures (60-100oC).

The acylation is successfully using catalytic amounts of base. Excess base without adversely affects the yield of the target product.

Monetary succinic acid (II, IV) synthesized by acylation of the corresponding 17-oxosteroid (I, III) succinic anhydride, are important for obtaining antigens that are widely used for the determination of trace quantities of these steroids, anabolic action [2, 3].

The course of the reaction and purity of the products is checked by thin layer chromatography on plates with silica gel "Silufol UV-254". As the mobile phase at chromatographicaliy use a mixture of chloroform and acetone in a ratio of 10: 1. Plate viewed in UV light or sprayed with a 0.1% alcoholic solution of bromophenol blue.

When conducting realspectrum shoot at the unit SF-16 in ethanol, IR-spectrum - on the UR-20 instrument in vaseline oil.

The invention is illustrated by the following examples.

Example 1. A mixture of 135 mg (0.5 mmol) of trenbolone (östra-4,9,11-triene-17-hydroxy-3-one) (I), 200 mg (2 mmol) of succinic anhydride, 1.2 cm3dimethyl sulfoxide and 20 mg (0.15 mmol) of potassium carbonate are heated 4 h at 80oC. the Reaction mixture is cooled to 20oWith and treated while cooling with ice to 10 cm32% hydrochloric acid. Dropped the precipitate was separated by filtration and pound on the glass filter three times with 3 cm3water. The precipitate is dried in air. The output of monoether succinic acid (II) 170 mg (92%), So pl. 152-153oS, Rfether (II) - 0,23, Rftrenbolone (I) - (0,3,max320 nm ( 20 500).

After recrystallization from methanol So pl. 155-156oC. According to literature data melting point of monoether succinic acid (II) 155-157oWITH [I].

Target product examples 2-6 allocate the same way as in example 1.

Example 2. A mixture of 13.5 mg (0.05 mmol) of trenbolone (östra-4,9,11-triene-17-hydroxy-3-one) (I), 20 mg (0.2 mmol) of succinic anhydride, 0,12 cm3dimethylacetamide and 2 mg (0.015 mmol) of potassium carbonate are heated for 3 h at 75oC. the Yield of ester (II) is 89%.

Example 3. A mixture of 13.5 mg (0.05 mlocked and 8 mg (0.07 mmol) of potassium carbonate are stirred at 20oWith three days. The yield of ester (II)- 32%.

Example 4. A mixture of 13.5 mg (0.05 mmol) of trenbolone (östra-4,9,11-triene-17-hydroxy-3-one) (I), 20 mg (0.2 mmol) of succinic anhydride, 0,06 cm3dimethylacetamide and 0.06 cm3triethylamine stand for one week at room temperature. The yield of ester (II) is 91%.

Example 5. A mixture of 13.5 mg (0.05 mmol) of trenbolone (östra-4,9,11-triene-17-hydroxy-3-one) (I), 20 mg (0.2 mmol) of succinic anhydride, 0,06 cm3dimethylacetamide and 0.003 cm3(0.02 mmol) of triethylamine are heated in a sealed tube at 60oWith four hours. The yield of ester (II)- 65%.

Example 6. The mixture is 27.4 (0.1 mmol) 19-nortestosterone (III), 15 mg (0.15 mmol) of succinic anhydride and 0.1 cm3dimethylacetamide and 8 mg (0.07 mmol) of potassium carbonate are heated for 10-15 minutes at 110oC. the Yield of the ester (IV) is 90%,max239 nm (16,5). IR-spectrum: 1728 (C=O,-OR), 1645 (PINE=C), 1605 (C=C).

The method of producing monoether succinic acid from 17-oxosteroid and succinic anhydride, characterized in that the acylation is carried out in the environment bipolar aprotic solvent at 20-110oIn the presence of catalytic or excess basis.

 

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