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A technology of eplerenone and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of unpublished separation of eplerenone intermediates, difficult separation of eplerenone intermediates and main impurities, etc., and achieve high reaction Yield effect
Active Publication Date: 2017-08-25
JIANGSU JIAERKE PHARMA GRP CORP
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[0004] While adopting the above method to obtain the eplerenone intermediate, the impurity 17α-pregna-4,11(12)-diene-7α,21-dicarboxylic acid-17β-hydroxyl-3-oxygen will inevitably be produced Generation-γ-lactone-7-methyl ester (hereinafter referred to as the main impurity), and the eplerenone intermediate is difficult to separate from the main impurity, and the prior art does not disclose any separation of the eplerenone intermediate and Literature of the main impurity
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Embodiment 1）
[0013] The preparation method of the eplerenone intermediate of this embodiment includes elimination reaction and catalytic hydrogenation reaction.
[0014] ① Elimination reaction:
[0015] Put 20.0 g of 17α-pregn-4-ene-7α, 21-dicarboxylic acid-11α, 17β-dihydroxy-3-oxo-γ-lactone-7-methyl ester and 100 mL of acetonitrile into the reaction flask After stirring, add 12mL of Ishikawa reagent (N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine) dropwise, and after the drop is completed, put it at room temperature (15-25°C, the same below). After about 8.5 hours of reaction, stop the reaction.
[0016] After the reaction, add sodium bicarbonate solution dropwise, stir for several minutes, add dichloromethane, separate layers, extract the water layer with dichloromethane, combine organic phases, recover dichloromethane at normal pressure to dryness, add water, cool, and centrifuge , spin-dried, and dried at 80°C to obtain 18.5 g of crude eplerenone intermediate, with a content of 94.41%...
Embodiment 2～ Embodiment 6）
[0022] The preparation method of each embodiment is basically the same as that of Example 1, except that the amount and content of the palladium carbon catalyst in step ②, see Table 1 for details.
[0023] Table 1
[0024] Palladium carbon catalyst dosage and content Refined product weight and weight yield Intermediate content in refined products Content of main impurities in refined products Example 1 0.2g, 5wt% 9.7g，89.7% 98.01% 0.50% Example 2 0.01g, 5wt% 9.8g，90.7% 97.60% 0.86% Example 3 0.03g, 5wt% 9.7g，89.7% 97.90% 0.59% Example 4 0.1g, 5wt% 9.6g，88.8% 98.01% 0.50% Example 5 0.2g, 10wt% 9.6g，89.7% 98.12% 0.47% Example 6 0.2g, 3wt% 9.8g，90.7% 97.85% 0.56%
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Abstract
The invention discloses a preparation method of an eplerenone intermediate, which is based on 17α-pregna-4-ene-7α, 21-dicarboxylic acid-11α, 17β-dihydroxy-3-oxo-γ- Lactone-7-methyl ester is the starting material, first obtains the crude product of eplerenone intermediate through elimination reaction, then refines the crude product of eplerenone intermediate to obtain the refined product of eplerenone intermediate; the refining is Catalytic hydrogenation is carried out to the crude product of the eplerenone intermediate, and then the refined product of the eplerenone intermediate is separated. The catalyst used in the catalytic hydrogenation is 3wt%-10wt% palladium carbon catalyst. The catalytic hydrogenation is carried out in the presence of ethanol, ethyl acetate or tetrahydrofuran. The method of the invention does not reduce the content of the eplerenone intermediate while reducing the content of main impurities, so that not only can the refined product of the eplerenone intermediate with higher content be obtained, but also have a higher reaction yield.
Description
technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, in particular to an eplerenone intermediate 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxyl-3 - Process for the preparation of oxo-γ-lactone-7-methyl ester. Background technique [0002] Eplerenone is a selective aldosterone receptor antagonist, used for the treatment of hypertension, and has almost no side effects such as menstrual disorders and male feminization, 17α-pregna-4,9(11)-diene -7α,21-Dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester is an important intermediate in the synthesis of eplerenone. [0003] For 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (hereinafter referred to as Epleil ketone intermediate), the method disclosed in the prior art is mainly composed of 17α-pregn-4-ene-7α, 21-dicarboxylic acid-11α, 17β-dihydroxy-3-oxo-γ-lactone- 7-Methyl ester is prepared by esterifica...
Claims
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