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Ulipristal acetate intermediate product and preparation method thereof

A technology for hydrochloric acid and compounds, applied in the preparation of intermediates of ulipristal acetate and the field of preparation thereof, can solve the problems of low product purity, difficult product purification, many side reactions and the like

Active Publication Date: 2014-05-21
JIANGSU PUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] This method has avoided using acetone cyanohydrin, but the side reaction of every step reaction is many, and product is not easy to purify, and the purity of gained product is low

Method used

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  • Ulipristal acetate intermediate product and preparation method thereof
  • Ulipristal acetate intermediate product and preparation method thereof
  • Ulipristal acetate intermediate product and preparation method thereof

Examples

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preparation example Construction

[0114] The present invention provides the preparation method of the intermediate of the present invention. It should be understood that the intermediates of the present invention can also be prepared by methods or conditions commonly used in the art.

[0115] Preferably, the preparation method of the intermediate compound of formula I comprises the steps of: in an ether solvent, in the presence of hydrogen halide / ether solvent, at -20-0°C, estro-4,9-diene-3, 17-diketone and diol derivatives (HO-(CHR 1 ) n -OH, R 1 Defined as above) to react, so as to obtain the compound of formula I;

[0116]

[0117] In the formula, R is as defined above.

[0118] Wherein, the ether solvent can be selected from: ethylene glycol dimethyl ether, ethylene glycol diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, or a combination thereof; the hydrogen halide / ether solvent can be Selected from: hydrogen chloride / oxane, hydrogen chloride / tetrahydrofuran, hydrogen bromide / tetrahydrofu...

Embodiment 13

[0147] Example 13, Preparation of 3-(2-methylethylenedioxy)-estro-5(10), 9(11)-dien-17-one (I-1)

[0148] Add estro-4,9-diene-3,17-dione (100.0g, 0.37mol), ethylene glycol dimethyl ether 1l, 1,2-propanediol (30.0ml, 0.41mol), 1N Hydrogen chloride in dioxane (11.0 ml) was reacted at -20°C for 4 hours. Triethylamine (200ml) was added to terminate the reaction, and the solvent was removed by concentration. The residue was dissolved in ethyl acetate, water was added for extraction, the layers were separated, and the organic phase was concentrated to dryness. The residue was crystallized from isopropyl ether, the solid was collected by filtration and dried to give the title compound (89.0 g).

[0149] MS(m / z):328.20; 1 H-NMR(DMSO):δ1.30( 3 H,18-CH 3 ),3.73-4.07( 6 H,-O-CH(CH 3 )CH 2 O-),5.50( 1 H,H-11); 13 C-NMR: 145.4(C-5), 136.8(C-9), 132.8(C-10), 124.1(C-11), 118.0(C-3), 81.5(C-17), 71.5(-O -CH 2 -), 75.2 (-O-CH-).

Embodiment 23

[0150] Example 23, Preparation of 3-(2-methylethylenedioxy)-17α-ethynyl-17β-hydroxyl-estro-5(10), 9(11)-diene (II-1)

[0151] Tetrahydrofuran (700ml) and potassium tert-butoxide (35.0g, 0.31mol) were added to the reaction flask, the temperature was lowered to -2-2°C, and acetylene gas was passed through for 15 minutes. Add I-1 (70.0 g, 0.21 mol) and continue to pass acetylene for 1 hour. After the reaction was complete, 25% ammonium chloride aqueous solution (550ml) was slowly added dropwise, and the temperature was controlled not to exceed 25°C. Ethyl acetate (300ml) was added for extraction, and the layers were separated. The organic layer was concentrated to dryness under reduced pressure to obtain the title compound.

[0152] MS(m / z):354.22; 1 H-NMR (DMSO): δ1.04 ( 3 H,18-CH 3 ),3.52(H,20-C≡CH),3.73-4.07( 6 H,-O-CH(CH 3 )CH 2 O-),5.50( 1 H,H-11); 13 C-NMR: 145.4(C-5), 136.8(C-9), 132.8(C-10), 124.1(C-11), 118.0(C-3), 87.6(C-19), 81.5(C- 17),74.0(C-20),71.5(-O-CH ...

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PUM

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Abstract

The invention relates to an ulipristal acetate intermediate product and a preparation method thereof. In particular, the invention discloses multiple intermediate products for preparing 3,3,20,20-bis (ethylene dioxy)-17 alpha-hydroxy-19-norpregna-5(10),9(11)-diene (namely, a compound represented as formula VII), and a preparation method thereof, wherein structures of the intermediate products are represented as formula I, formula II, formula III, formula IV or formula V. Furthermore, the invention discloses a method for preparing the compound represented as formula VII. The method disclosed by the invention is easily available in raw material, mild in reaction condition, high in yield, relatively low in cost, low in byproduct content in reaction process, high in target product purity and applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy. Specifically, the invention discloses an intermediate for preparing ulipristal acetate and a preparation method thereof. Background technique [0002] Ulipristal acetate is a selective progesterone receptor modulator (SPRM) developed by HRA Pharmaceuticals for emergency contraception within 5 days (120 hours) of unprotected intercourse or contraceptive failure. The mechanism of contraception is to prevent the combination of progesterone and its receptor, thereby inhibiting the normal gene transcription stimulated by progesterone, so that it cannot synthesize the protein required for the initiation and maintenance of pregnancy, so as to achieve the effect of contraception. [0003] 3,3,20,20-bis(ethylenedioxy)-17α-hydroxyl-19-norpregna-5(10), 9(11)-diene (hereinafter referred to as the compound of formula VII) is a synthetic acetic acid The key intermediate of Ulipristal has a structural formula...

Claims

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Application Information

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IPC IPC(8): C07J21/00C07J7/00
Inventor 安晓霞张伟黄成军
Owner JIANGSU PUXIN PHARMA CO LTD
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