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Preparation method of canrenone intermediate

An intermediate, canrenone technology, which is applied in the field of preparation of canrenone intermediates, can solve problems affecting production efficiency, quality and yield, and achieve the effects of low production cost, less environmental pollution, and increased concentration

Inactive Publication Date: 2018-05-29
GUANGXI WANDE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There is no relevant report on the treatment of this impurity in the disclosed patent literature. In actual production, about 10-15% of the double-etherified impurities need to be refined before they can be reacted, which greatly affects the efficiency, quality and yield of subsequent production. Rate

Method used

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  • Preparation method of canrenone intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Such as figure 1 The method for preparing a canrenone intermediate includes the following steps: adding 30 g of 4-androstenedione, 120 ml of tetrahydrofuran, and 0.9 g of p-toluenesulfonic acid to a three-necked flask under nitrogen protection, and heating to 30°C, Slowly add 60ml of trimethyl orthoformate, stir at 38°C for 3h, cool to -5°C, add 15ml of water at -5°C, hydrolyze for 6min, immediately add 30ml of 2% sodium carbonate solution to stop the reaction, and pour into the reaction solution Put into 240ml ice water, stir for 1h, filter with suction, wash with a small amount of water, and dry.

[0028] 30.84 g of the product (Compound I) was obtained, with a yield of 102.8% and a purity of 99.5%.

Embodiment 2

[0030] Such as figure 1 The method for preparing a canrenone intermediate includes the following steps: adding 50 g of 4-androstenedione, 200 ml of tetrahydrofuran, and 2.5 g of p-toluenesulfonic acid into a three-necked flask under the protection of nitrogen, and heating to 35°C, Slowly add 200ml of trimethyl orthoformate, stir at 45°C for 4h, cool to -10°C, add 50ml of water and stir for 10min, immediately add 50ml of 5% sodium carbonate solution to stop the reaction, pour the reaction solution into 400ml of ice water and stir for 1h. Filter by suction, wash with a little water, and dry.

[0031] The product (Compound I) 51g was obtained with a yield of 101% and a purity of 99.2%.

Embodiment 3

[0033] Such as figure 1 The method for preparing a canrenone intermediate includes the following steps: under the protection of nitrogen, add 100g of 4-androstenedione, 400ml of tetrahydrofuran, and 1g of p-toluenesulfonic acid into a three-necked flask, and raise the temperature to 30°C slowly. Add 400ml of trimethyl orthoformate, stir at 30°C for 2h, cool to 10°C, add 100ml of water at 10°C and stir for 3min, immediately add 100ml of 1% sodium carbonate solution to stop the reaction, pour the reaction solution into 800ml of ice water and stir for 1h , Suction filtration, washing with a little water, and drying.

[0034] Obtain 100g of the product (Compound I) with a yield of 100%, such as figure 2 Said, the purity of the prepared compound I is 98.8%, as image 3 The purity of the standard sample is 98.02%.

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Abstract

The invention provides a preparation method of a canrenone intermediate. The preparation method comprises the following steps: taking 4-androstenedione as a substrate, adding tetrahydrofuran, p-toluenesulfonic acid and trimethyl orthoformate into the substrate, stirring the mixture until complete reaction, cooling, adding a small amount of water for a hydrolysis reaction, stirring the mixture, adding weak base solution to terminate the hydrolysis reaction, performing crystallization and filtering separation in the water, and drying, so as to obtain a compound I. In the preparation method, by optimizing reaction conditions and adding a small amount of water for a differentiation reaction after an anhydrous reaction is ended, a dual etherification phenomenon when a protection reaction is simultaneously performed on a 3-ketone group and a 17-ketone group in the prior art can be overcome, so that the purity of a product is effectively improved, the production cost is lowered, and the operation difficulty in production is lowered.

Description

Technical field [0001] The invention belongs to the field of medicine manufacturing, and specifically relates to a preparation method of canrenone intermediate. Background technique [0002] Canrenone, whose chemical name is 17β-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid-Y-lactone, is a commonly used diuretic and also a synthetic aldosterone An important intermediate for the receptor antagonist spironolactone. Canrenone can also be widely used in the preparation of important steroid raw materials such as eplerenone, a cardiovascular disease drug. [0003] Chinese patent CN104327142A discloses a method of protecting the 3-ketone group with 4-androstenone as the substrate. It uses trimethyl orthoformate or triethyl orthoformate for protection under the action of a catalyst, but the following side reactions will occur [0004] [0005] There is no relevant report on the treatment of this impurity in the published patent documents. In actual production, about 10-15% of the d...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0003C07J1/0011
Inventor 蒋青锋李家宝
Owner GUANGXI WANDE PHARMA
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