Preparation method of key intermediate of Ulipristal acetate

A technology of ulipristal acetate and an intermediate, applied in the field of medicine, can solve problems such as strict requirements for post-processing methods, increase reaction steps and the like, and achieve the effects of simple steps, easy operation and high yield

Inactive Publication Date: 2013-05-01
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is the use of highly toxic cyanation reagents in chemical quantities, and the post-processing method requires strict
In addition, the hydroxyl group needs to be protected and deprotected, which increases the reaction steps

Method used

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  • Preparation method of key intermediate of Ulipristal acetate
  • Preparation method of key intermediate of Ulipristal acetate
  • Preparation method of key intermediate of Ulipristal acetate

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Example 1. Take a 3-liter one-necked flask, add 39 grams (0.35 moles) of potassium tert-butoxide, 130 grams (0.35 moles) of triphenylethylphosphorus bromide and 1 liter of toluene, and stir at room temperature for 1 hour. 100 g (0.32 mol) of compound III was added, the temperature was raised to 60°C, and the reaction was stirred for 1 hour. Add 200 ml of n-hexane and 100 ml of water, stir for 10 minutes and separate the layers. The aqueous layer was extracted with n-hexane, and the organic layers were combined, washed with 200 ml of saturated brine, and dried over anhydrous sodium sulfate. Concentrate after filtration, add 1 liter of n-hexane, stir for 30 minutes, and filter the precipitate. The filtrate was concentrated to obtain 90 g of a white solid (compound IV), with a yield of 85% and a purity of 98% by HPLC. Compound Ⅳ, melting point: 120-125℃; MS: 327.22(M+1); 1 H NMR (600MHz, CDCl 3 ):5.57(s,1H),5.20(quart,1H),3.99(s,4H),0.84-2.58(m,24H).

Embodiment 2

[0037] Example 2. Take a 3-liter single-necked flask, add 11.5 grams (0.48 moles) of sodium hydride, 178 grams (0.48 moles) of triphenylethylphosphorus bromide and 1 liter of toluene, and stir for 1 hour. 100 g (0.32 mol) of compound III was added, the temperature was raised to 60°C, and the reaction was stirred for 1.5 hours. Add 250 ml of n-hexane and 120 ml of water, and stir for 10 minutes. The layers were separated, the aqueous layer was extracted with n-hexane, the organic layers were combined, washed with 200 ml of saturated brine, and dried over anhydrous sodium sulfate. Concentrate after filtration, add 1 liter of n-hexane, stir for 30 minutes, and then filter the precipitate. The filtrate was concentrated to obtain 88 g of white solid (compound IV), with a yield of 83% and a purity of 96% by HPLC.

Embodiment 3

[0038]Example 3. Take a 3-liter one-necked flask, add 178 grams (0.48 moles) of triphenylethylphosphonium bromide and 1 liter of tetrahydrofuran, cool to -78 ° C, add 48 milliliters (0.48 moles) of n-butyllithium, and stir the reaction 30 minutes. 100 g (0.32 mol) of compound III was added, and the reaction was stirred for 1.5 hours. Add 200 ml of n-hexane and 100 ml of saturated sodium bicarbonate solution, and stir for 10 minutes. The layers were separated, the aqueous layer was extracted twice with 100 ml of n-hexane, the organic layers were combined, washed with 200 ml of saturated brine, and dried over anhydrous sodium sulfate. Concentrate after filtration, add 1 liter of n-hexane, stir for 30 minutes, and then filter the precipitate. The filtrate was concentrated to obtain 95 g of a white solid (compound IV), with a yield of 90% and an HPLC purity of 97%.

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Abstract

The invention discloses a preparation method of a key intermediate of Ulipristal acetate. The key intermediate of the Ulipristal acetate has a structure of a formula II. A compound IV is prepared through Wittig reaction by using a compound III, a compound V is prepared through selective oxidization, and finally secondary alcohol at a No.20 site is oxidized into carbonyl by using oxidant to obtain the key intermediate of the Ulipristal acetate. The synthesis route and the synthesis steps of the key intermediate of the Ulipristal acetate are simple and convenient, and the operation is easy to conduct; the obtained product has the advantages of low cost, high yield and high purity; and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of a compound, in particular to a preparation method of a key intermediate of Ulipristal Acetate (Ulipristal Acetate), an emergency contraceptive. Background technique [0002] The compound with the structure shown in formula I is the oral emergency contraceptive ulipristal acetate, which is a selective progesterone receptor modulator developed by HRA company in France. It mainly exerts the emergency contraceptive effect by inhibiting ovulation and has been marketed in Europe and the United States. , for the prevention of pregnancy within 120 hours of unprotected sex or known or suspected contraceptive failure, is an effective and safe emergency contraceptive. [0003] [0004] The compound of formula II is its key intermediate 3-(ethylenedioxy)-17αhydroxy-19-norpregna-5(10),9(11)-dien-20-one. [0005] Related reports prepared the key intermediate 3- (Ethy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J21/00
Inventor 刘兆鹏张灿飞周义刚
Owner SHANDONG UNIV
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