Method for synthesizing androstenedione (2,2,4,6,6,16,16-D<7>) through deuterium exchange

Abstract

The invention relates to a method for synthesizing androstenedione (2,2,4,6,6,16,16-D<7>) through deuterium exchange. The preparation method comprises the following steps: (1) dissolving androstenedione into deuterated methanol (D4 or OD, wherein 0.2-10 mL of the deuterated methanol is used for dissolving each 100 mg of androstenedione); adding a formed solution into an aqueous deuterated hydrochloric acid solution (wherein the concentration of the aqueous deuterated hydrochloric acid solution is 1-35 w%, or 2.5-60% of deuterated sulfuric acid, or anhydrous thionyl chloride, sulfonyl chlorideand the like is used for reacting with deuterium water to prepare deuterated hydrochloric acid or deuterated sulfuric acid, and a usage amount ratio of deuterated acid to androstenedione is 0.1-50mL / 100mg), carrying out heating to 45-100 DEG C, and performing reacting for 12-5 days in the presence of inert gas; and (2) after the reaction is finished, cooling a reaction solution, carrying out vacuum spin-drying on deuterated methanol, and successively performing refrigerating, standing and crystallizing so as to allow a solid to be slowly separated out, or directly carrying out vacuum spin-drying on all solvents (the solvents can be supplemented and then exchanged under the condition that a small amount of the solvents are exchanged each time and exchanged a plurality of times), then recrystallizing a solid, and carrying out filtering and drying to obtain a pure product.

Description

technical field [0001] The invention relates to a synthetic androstenedione (2,2,4,6,6,16,16-D 7 ) method, especially related to a kind of direct androstenedione (2,2,4,6,6,16,16-D 7 )Methods. Background technique [0002] Congenital Adrenal Hyperplasia (CAH) is a relatively common autosomal recessive genetic disease, which is mainly caused by inborn defects in the enzymes required for the synthesis of corticosteroids. The internal standard method of tandem mass spectrometry can be used to screen for CAH by measuring the content of steroids in plasma, urine and other body fluids. The NSK-S-CAH congenital adrenal hyperplasia reference standard is generally used as a standard for screening and diagnosing this disease. There are five stable isotope-labeled compounds, androstenedione (2,2,4,6 ,6,16,16-D 7 ) is one of the important internal standard compounds, can high-purity, high-abundance androstenedione (2,2,4,6,6,16,16-D 7 ) is the basis for whether the detection kit ca...

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Problems solved by technology

[0006] This method adopts alkali as a catalyst to directly carry out hydrogen-deuterium exchange to androstenedione, but the reaction solution must be neutralized during post-treatment, and the neutralization process must also be strictly controlled to isolate the air and be carried out at low temperature. The method is cumbersome, and deuterated acid needs to be used to neutralize the alkali, and the cost is high; when performing a large number of exchanges, if multiple exchanges are used, each treatment needs to be neutralized, and then fresh deuterated solvent is added for exchange , there will be frequent neutralization and extraction processes, and too many operations will make it difficult to control the abundance of the product, so this method can only be used for a very small amount of one-time exchange, and the process is cumbersome, which is not conducive to mass production

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