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

A technology for androstenedione and deuterium exchange, applied in organic chemistry methods, chemical instruments and methods, steroids, etc., can solve the problems of cumbersome treatment methods, cumbersome processes, and high costs, and achieve the effect of saving deuterated reagents

Pending Publication Date: 2020-07-03
无锡贝塔医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

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  • Method for synthesizing androstenedione (2,2,4,6,6,16,16-D&lt;7&gt;) through deuterium exchange
  • Method for synthesizing androstenedione (2,2,4,6,6,16,16-D&lt;7&gt;) through deuterium exchange

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 100mg androstenedione to a 50ml single-necked flask connected with argon protection gas and a condenser tube, replace it with an oil pump three times, then add 1.5mL deuterated methanol-OD, after the dissolution is complete, slowly add 10% deuterated hydrochloric acid 5 mL of deuterium aqueous solution was heated to 55° C. under argon atmosphere, and the reaction was monitored by LC-MS, and the reaction was completed in about 10 to 12 hours. After the reaction, deuterated methanol (recyclable) was distilled off under reduced pressure, and the reaction solution was cooled, then left to refrigerate to crystallize, and a white solid was precipitated. Filter, dry, obtain about 85mg of product, about 85% of productive rate, product purity >98% (HPLC), LC-MS and 1 HNMR determined deuterium abundance >98%.

Embodiment 2

[0032] Add 200mg androstenedione to a 25ml single-necked flask connected with argon protective gas and a condenser tube, replace the oil pump three times, then add 1.5mL deuterated methanol-OD, after the dissolution is complete, slowly add 10% deuterated hydrochloric acid 3 mL of deuterium aqueous solution was heated to 55°C under argon atmosphere, and the reaction was monitored by LC-MS. After about 10 to 12 hours, the abundance stopped increasing. After the reaction, deuterated methanol (recyclable) was distilled off under reduced pressure, and the reaction solution was cooled, then left to refrigerate to crystallize, and a white solid was precipitated. Filter and dry, then add the same amount of deuterated methanol-OD and deuterated deuterium hydrochloride aqueous solution, continue to heat up and exchange, after 10 to 12 hours of reaction, spin dry deuterated methanol, refrigerate and crystallize, precipitate a white solid, filter and dry to obtain Product about 165mg, pro...

Embodiment 3

[0034] Add 980mg androstenedione to a 25ml single-necked flask connected with argon protective gas and a condenser tube, replace it three times with an oil pump, then add 3mL deuterated methanol-OD, after the dissolution is complete, slowly add 8% deuterated deuterated hydrochloride Aqueous solution 9mL, heated to 56°C under argon atmosphere, LC-MS to monitor the reaction, after the reaction was completed, deuterated methanol was evaporated under reduced pressure, and then the oil pump was spun to dry the water to obtain a solid, and then an equal amount of deuterated methanol was added- OD and deuterated deuterium hydrochloride aqueous solution, continue to heat up and exchange, perform three exchanges in total as above, after the last time, deuterated methanol is spin-dried, refrigerated and crystallized, a white solid is precipitated, filtered and dried to obtain about 910 mg of the product, and the yield is about 91%. Product purity>98.6% (HPLC), LC-MS and 1HNMR confirmed d...

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00C07B59/00
CPCC07B59/001C07B2200/05C07J1/0011
Inventor 蔡定龙李刚
Owner 无锡贝塔医药科技有限公司
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