Preparation method of drospirenone impurity

A drospirenone and impurity technology, which is applied in the preparation of compounds and progesterone drospirenone impurities, can solve the problems of difficult removal and easy residue, and achieve the effects of convenient purification, high reaction efficiency and reasonable process design

Pending Publication Date: 2022-08-09
TLC NANJING PHARMA RANDD CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As one of its most important impurities, it is easy to have residues in the production process, and it is difficult to remove. Therefore, obtaining pure impurities is helpful to study the pharmacology of drospirenone, the toxicity of impurities, the harm to the human body, and its metabolism. The mechanism has important medical research value, and there is no report about the synthesis method of the two drospirenone (Drospirenone EPImpurity I VII, Drospirenone Impurity 13VI) impurities reported in this paper

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  • Preparation method of drospirenone impurity
  • Preparation method of drospirenone impurity
  • Preparation method of drospirenone impurity

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Embodiment 1

[0033] The preparation method of described drospirenone impurity, its preparation technological process is as follows figure 1 shown, including the following steps:

[0034] (1) Raw material 70g Drospirenone (I, the structure is as follows Figure 4 ) was dissolved in acetone, concentrated hydrochloric acid was added dropwise to the ice bath, and then the temperature was raised to 70 °C for 3 hours. TLC spot plate showed no starting material remaining. The reaction solution was cooled to room temperature, adjusted to pH 8 with 17.5 g of sodium carbonate dissolved in 250 ml of water, and then spin-dried. 0.5 L of water was added to the system, and extracted with dichloromethane (200 mL x 3). The organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized with ethyl acetate to obtain a solid, which was filtered and dried to obtain 58 g of intermediate II (mixture of IIa and IIb) with a yield of 75.36%.

[0035] MS ...

Embodiment 2

[0046] The preparation method of described drospirenone impurity, its preparation technological process is as follows figure 1 shown, including the following steps:

[0047] (1) 50 g of the raw material Drospirenone was dissolved in acetone, 19 ml of concentrated hydrochloric acid was added dropwise in an ice bath, and then the temperature was raised to 70° C. to react for 3 hours. TLC spot plate showed no starting material remaining. The reaction solution was cooled to room temperature, adjusted to pH 8 by dissolving 16.5 g of sodium carbonate in 220 ml of water, and then spin-dried. 0.35 liter of water was added to the system, and the mixture was extracted with dichloromethane (160 mL×3). The organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized with ethyl acetate to obtain a solid, which was filtered and dried to obtain 45.6 g of intermediate II (mixture of IIa and IIb). The structures of structural formu...

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Abstract

The invention discloses a preparation method of drospirenone impurity, which is characterized in that a preparation process with optimal reactant dosage, reaction temperature, reaction time, reaction solvent and the like is screened out through a large number of experiments, the whole preparation process is strong in operability, high in preparation efficiency and low in production cost, and industrial mass production can be realized; the purity of the prepared drospirenone impurity can reach 96%, the yield can reach 30% or above, and the drospirenone impurity can be widely applied to tests for comprehensively analyzing and researching pharmacology, pharmacokinetics, toxicology and the like of drospirenone.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of a progestogen drospirenone impurity, and belongs to the technical field of medicine. Background technique [0002] Drospirenone (English name: Drospirenone, CAS: 67392-87-4, chemical name (4aR, 4bS, 6aS, 7S, 7aS, 8aS, 8bS, 8cR, 8dR, 9aR)-4a, 6a-dimethyl-3' ,4,4a,4b,4',5,6,6a,7a,8,8a,8b,8c,8d,9,9a-hexadecahydro-5 'H-spiro[cyclopropa[4,5]cyclopenta[1, 2-a]cyclopropa[l]phenanthrene-7,2'-furan]-2,5'(3H)-dio ne), drospirenone is a fourth-generation oral contraceptive developed by a German company. A novel synthetic progesterone with corticosteroid and anti-androgenic activity, without androgenic, estrogenic, glucocorticoid and anti-glucocorticoid activities, and its pharmacological action spectrum is similar to that of natural progesterone. Combined oral contraceptives composed of drospirenone and ethinylestradiol are safe, effective and well-tolerated lo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J53/00
CPCC07J53/008Y02P20/55
Inventor 魏德胜纵权张池刘春杨石崔希林
Owner TLC NANJING PHARMA RANDD CO LTD
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