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Synthesis method of spironolactone intermediate testosterone lactone

A testosterone lactone and synthesis method technology, applied in the field of chemical drug synthesis, can solve the problems of cumbersome operation, many reaction steps, and low yield, and achieve the effects of simple post-processing, easy operation, and high yield

Active Publication Date: 2015-02-04
ZHEJIANG SHENZHOU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, the traditional spironolactone synthesis process has many reaction steps, cumbersome operation, and low yield. Therefore, starting from the raw material 4-androstenedione, a more concise construction of 17,21-carboxylactone spirocycle is developed. The new method of structure will have extremely important economic value and practical value

Method used

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  • Synthesis method of spironolactone intermediate testosterone lactone
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: addition deprotection reaction

[0033] The reaction formula is as follows:

[0034]

[0035] In reaction flask A, under nitrogen protection, add 100mL dry tetrahydrofuran (after strict anhydrous treatment KF<0.05%), 60mL n-butyllithium (1.6M n-hexane solution), and cool to -60°C. Slowly add (3-bromopropoxy)trimethylsilane (12.6 g), keep stirring at -60°C for 30 minutes, and set aside.

[0036]In reaction flask B, under the protection of nitrogen, the dried compound I (3 g) was dissolved in 30 mL of tetrahydrofuran (after strict anhydrous treatment KF<0.05%), and cooled to -40 °C. The pre-prepared LDA (12 mL, 2M tetrahydrofuran solution) was slowly added dropwise to the aforementioned reaction system, kept at -40° C. and stirred for 10 minutes, and set aside.

[0037] The solution system in reaction bottle A was slowly added dropwise to the solution system in reaction bottle B, warmed up to room temperature and reacted for 1 hour, TLC showed that the ...

Embodiment 2

[0038] Embodiment 2: addition deprotection reaction

[0039] In reaction bottle A, under nitrogen protection, add 100mL dry tetrahydrofuran (after strict anhydrous treatment KF<0.05%), 65mL sec-butyllithium (1.3M solution in cyclohexane), and cool to -78°C. Slowly add (3-bromopropoxy)triethylsilane (13.2 g), keep stirring at -60°C for 30 minutes, and set aside.

[0040] In reaction flask B, under the protection of nitrogen, the dried compound I (3 g) was dissolved in 30 mL of tetrahydrofuran (after strict anhydrous treatment KF<0.05%), and cooled to -40 °C. The pre-prepared LDA (12mL, 2M solution in tetrahydrofuran) was slowly added dropwise to the aforementioned reaction system, kept at -40°C and stirred for 10 minutes, and set aside.

[0041] The solution system in reaction bottle A was slowly added dropwise to the solution system in reaction bottle B, warmed up to room temperature and reacted for 1 hour, TLC showed that the reaction was complete, and 80 mL of water was add...

Embodiment 3

[0042] Example 3: Oxidative cyclization reaction

[0043] The reaction formula is as follows:

[0044]

[0045] Dissolve 10g of compound (II) in 150mL of dichloromethane, add 0.05g of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) and 7g of potassium bromide in sequence, add 40mL of 10% Sodium hypochlorite aqueous solution and 0.5g phase transfer catalyst tetrabutylammonium chloride were stirred at 10-15°C for about 6 hours. After the reaction was complete, sodium sulfite solution (9g / 9mL water) was added to neutralize the oxidant, and the water layer was separated. Concentrate until there is no dichloromethane, add 30mL methanol and 10mL 10% dilute hydrochloric acid, stir at 20-25°C for 0.5 hours, neutralize with 0.5N sodium hydroxide solution to pH about 6.5, reduce the pressure to no methanol, add 100mL water, stir After 0.5 hour, filter and dry at 60° C. for 24 hours to obtain 8.7 g of testosterone lactone (III), the mass yield is about 87%, and the HPLC purity i...

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Abstract

The invention relates to a synthesis method of a chemical medicine, and concretely relates to a synthesis method of a spironolactone intermediate testosterone lactone. The method is characterized in that a compound I 4-androstenedione (4AD) undergoes a two-step reaction of addition siloxane removal and oxidation cyclization to obtain the compound III testosterone lactone, and the reaction route is shown in the specification. Compared with traditional methods adopting a traditional raw material 16-dehydropregnenolone acetate with high price, the method provided by the invention adopting the cheap and easily available 4-androstenedione (4AD, I) as an initial raw material has extremely high production application and economic values under the affection of market supply and demand.

Description

technical field [0001] The invention relates to a synthesis method of chemical medicines, in particular to a synthesis method of spironolactone intermediate testosterone lactone. Background technique [0002] The chemical name of spironolactone is: (7α,17α)-7-(acetylmercapto)-17-hydroxyl-3-oxopregna-4-ene-21-carboxylic acid-γ-lactone, which is produced by Pfizer of the United States The aldosterone competitive inhibitor developed by the company is now on the market in many countries and is clinically used as a diuretic. Its chemical structure is as follows: [0003] [0004] In the synthesis method of spironolactone, one of the key technical links is to construct the 17,21-carboxylactone spiro ring structure. At present, according to the generation method of its spirocycle, the synthesis process of spironolactone can be roughly divided into two categories: 1) taking 4-androstenedione (4AD) as raw material, utilizing Corey epoxidation reagent to convert the C17-keto group...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J21/00
CPCC07J21/001
Inventor 王荣
Owner ZHEJIANG SHENZHOU PHARMA
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