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Ethinyloestradiol crude drug impurity, and preparation method and application thereof in serving as standard substance

A technology of butyne and alcohol magnesium bromide, which is applied in the direction of material separation, analysis of materials, steroids, etc., and can solve problems such as unexamined

Inactive Publication Date: 2012-11-28
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The impurity mentioned in the present invention 3-hydroxy-19-nor-17α-pregna-1,3,5(10)-triene-20-(3-hydroxy-3-methylbutynyl-1-yl )-17-alcohol is not included in EP and USP, and through the comprehensive search of Scifinder database, at present, there are no reports of this kind of substance and its synthesis method in the patents and journal documents about ethinylestradiol at home and abroad, so the substance’s Research is an innovative technical field

Method used

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  • Ethinyloestradiol crude drug impurity, and preparation method and application thereof in serving as standard substance
  • Ethinyloestradiol crude drug impurity, and preparation method and application thereof in serving as standard substance
  • Ethinyloestradiol crude drug impurity, and preparation method and application thereof in serving as standard substance

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Chromatographic conditions for the analysis of related substances of ethinyl estradiol:

[0025] Column: Agilent ZORBAX SB C 18 Chromatographic column (150mm×4.6mm i.d., 5μm); mobile phase: water (A) and acetonitrile (B); gradient elution, phase B gradient: (0~20min, 30%~40%, 20~20.5min, 40 %~45%20.5~28min, 45%~50%); flow rate: 1.0mL min -1 ; Column temperature: 30° C.; Injection volume: 10 μL; Detection wavelength: 280 nm.

[0026] Mass Spectrometry Conditions:

[0027] LC-MS analysis: APCI ion source, using negative ion detection mode; nebulizer temperature: 500°C; sheath gas (N 2 ) flow rate: 50arb; auxiliary gas (N 2 ) flow rate: 5arb; exhaust gas sweep (N 2 ) flow rate: 0arb; dissociation current: 4μA; capillary temperature: 150°C; capillary voltage: -12V; tubular lens voltage: -84.28V.

[0028] sample handling

[0029] Accurately weigh 3.0 mg of EE fine drug, dissolve it in 1 mL of methanol, vortex and mix well, and filter through a 0.45 μm microporous memb...

Embodiment 2

[0037] Magnesium (2640mg, 110mmol) was placed in a dry 500ml three-necked bottle, added to 50ml of anhydrous THF, and N 2 , add a small amount of bromoethane, then add a grain of I 2 , heated to 50°C, until bubbles appeared, and the color of the solution gradually disappeared, continued to add dropwise anhydrous THF diluent of ethyl bromide (7.5ml, 100mmol), kept the solution slightly boiling, and continued the reaction until the magnesium chips were basically After disappearing, add 2-methyl-3-butyn-2-ol (9.6ml, 100mmol) dropwise in anhydrous THF diluent under heating to reflux, and the reaction solution releases gas. After cooling down to room temperature, a solution of estrone (13.5 g, 50 mmol) in anhydrous THF was added dropwise, and the color of the reaction solution gradually turned milky yellow, and the reaction was continued for 3 hours. After the reaction is complete, add NH 4 The aqueous solution of Cl was quenched, THF was distilled off, and ether was added for ex...

Embodiment 3

[0042] The specific method is as example 1, magnesium (2640mg, 110mmol) is put in the dry 500ml three-neck bottle, is added in 50ml anhydrous THF, feeds N 2 , add a small amount of bromoisopropane, then add a grain of I 2 , heated to 50°C, until bubbles appeared, and the color of the solution gradually disappeared. Continue to add the anhydrous THF diluent of bromoisopropane (7.5ml, 100mmol) dropwise, keep the solution slightly boiling, and continue the reaction after the dropwise addition is completed. After the magnesium chips basically disappear, add 2-methyl - Anhydrous THF dilution of 3-butyn-2-ol (9.6ml, 100mmol), the reaction solution emits gas, after reacting for 1 hour, after no longer emitting gas, it is cooled to room temperature, and estrone (13.5g , 50mmol) in anhydrous THF solution, the color of the reaction solution gradually turned milky yellow, and the reaction was carried out for 3h. After the reaction is complete, add NH 4 The aqueous solution of Cl was q...

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Abstract

The invention discloses a novel byproduct produced by an ethinyloestradiol synthesis process and a synthesis method thereof. The byproduct is as shown in a formula I, and the chemical name is 3-hydroxy-19-nor-17alpha-pregna-1,3,5(10)-triene-20-(3-hydroxy-3-methylbutynyl-1-yl)-17-ol. The invention also provides a preparation method of the byproduct. The substance can be simply and conveniently obtained by performing Grignard exchange on alkyl magnesium bromide and 3-methyl-1-butynyl-3-ol and then performing Grignard exchange on estrone. The compound can be used as a standard substance for controlling impurities in an ethinyloestradiol production process.

Description

technical field [0001] The invention relates to a new related substance in the synthesis process of contraceptive ethinyl estradiol and its synthesis method, which belongs to the field of medicinal chemistry. Background technique [0002] Ethinylestradiol (Ethinylestradiol) is a sex hormone drug, which is mainly used clinically as an ovulation suppressing drug, and is also used for children with cryptorchidism, androgen excess, and pituitary tumors. Its chemical name is 3-hydroxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-17-ol: [0003] [0004] Ethinyl estradiol has positive and negative feedback effects on the pituitary gland of the hypothalamus. Small doses can stimulate the rate-limiting secretion of stimulants; large doses can inhibit its secretion, thereby inhibiting ovarian ovulation and achieving anti-fertility effects. This product can stimulate the pituitary gland to synthesize and release gonadotropins (FSH and LH), and gonadotropins stimulate the gonads to rele...

Claims

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Application Information

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IPC IPC(8): C07J1/00G01N30/02
Inventor 王冬梅李静雅郑焱胡彪田卫学吴松
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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