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Preparation method of ulipristal acetate and intermediate thereof

A technology for ulipristal acetate and compounds, which is applied in the directions of steroids, organic chemistry, etc., can solve the problems of high cost, unsuitability for industrial production, dangerous large acetylene, etc., and achieves low cost, convenient for industrial scale production, The effect of less environmental pollution

Inactive Publication Date: 2015-04-22
CHENGDU ORGANOCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] This method uses acetylene which is more dangerous. In addition, new impurities will be produced by heating at high temperature for a long time during crystallization. The total yield of this method is 13.8%-15.8%. The cost is high and it is not suitable for industrial production.

Method used

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  • Preparation method of ulipristal acetate and intermediate thereof
  • Preparation method of ulipristal acetate and intermediate thereof
  • Preparation method of ulipristal acetate and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The preparation of 3-(ethylenedioxy)-17α-ethynyl-17β-hydroxyl-estra-5(10), 9(11) diene (compound III) mainly comprises the following steps:

[0055] Under nitrogen protection and 0°C, add 3-ketal (5.00Kg, 15.93mol) and anhydrous tetrahydrofuran (63L) into the reaction kettle, stir for 20 minutes, 3-ketal is completely dissolved, add sodium acetylene (1.61Kg , 33.45mol), stirred at -2 to 0°C for 6 hours, then added saturated ammonium chloride solution (30L) and stirred the reaction mixture for 30 minutes, separated the organic layer, and extracted the aqueous phase with tetrahydrofuran (4L×3) , combined organic layers;

[0056] The obtained organic layer was washed with saturated ammonium chloride solution (6L), the washed product was concentrated to 2.5L and then poured into ice water (16L), and the resulting mixture was stirred at -2 to 0°C for 3 hours, and then filtered into the The resulting precipitate was filtered and dried at 45°C to obtain 5.36 Kg (yield 99%, HP...

Embodiment 2

[0059] Preparation of 3-(ethylenedioxy)-17α-ethynyl-17β-hydroxy-estra-5(10),9(11) diene (compound III):

[0060] Under nitrogen protection and -2°C, add 3-ketal (5.00Kg, 15.93mol) and 2-methyltetrahydrofuran (50L) into the reaction kettle, stir for 30 minutes, 3-ketal is completely dissolved, and add potassium acetylide (2.05Kg, 31.86mol), stirred at -2 to 0°C for 8 hours, then added saturated ammonium chloride solution (30L) and stirred the reaction mixture for 40 minutes, separated the organic layer, and washed with 2-methyltetrahydrofuran (content 99%) after extracting the aqueous phase, combine the organic layers;

[0061] The obtained organic layer was washed with saturated ammonium chloride solution (5.5L), the washed product was concentrated to 2.2L and then poured into ice water (15.6L), the resulting mixture was stirred at -2 to 0°C for 3 hours, and then filtered The precipitate produced in the mixture was filtered and dried at 45° C. to obtain 5.33 Kg (yield 98%, HP...

Embodiment 3

[0064] Preparation of 3-(ethylenedioxy)-5α,10α-epoxy-17α-ethynyl-17β-hydroxy-19-norpregna-9(11)-ene (compound IV):

[0065] At 4°C, compound III (5.03Kg, 14.78mol) was dissolved in 50L of dichloromethane, and 1,1,1-trifluoroacetone (2.20L, 25mol), disodium hydrogen phosphate (8.75Kg, 62.5 mol) and 50% hydrogen peroxide (3.84L, 62.5mol), stirred and reacted at constant temperature for 18 hours, added 15L of saturated sodium sulfite solution, and continued to stir for 2 hours, separated the organic layer, and extracted with dichloromethane (5L×2) The organic layer in the water layer, each organic layer of gain is combined;

[0066] After the combined organic layer was washed with 20L saturated sodium chloride solution, the washed product was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to 3L, then 12L of isopropyl ether was added, stirred slowly for 15 hours and then filtered, and the filtered precipitate was heated at 50°C Drying under low te...

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Abstract

The invention discloses a preparation method of ulipristal acetate and an intermediate thereof, and belongs to the field of pharmaceutical synthesis. The preparation method of the ulipristal acetate comprises the following steps: by taking 3,3-(ethylenedioxy)-19-methylestra-5(10),9(11)-diene-3,17-diketone as raw material, enabling the raw material to react with sodium acetylide or potassium acetylide to obtain a compound III, carrying out high-selectivity epoxidation by oxide to obtain a compound IV, subsequently enabling the compound IV to react with 4-(N,N-dimethyl amino) phenyl magnesium bromide Grignard reagent to obtain a compound V, then enabling the compound V to react with phenyl sulfonic acid chloride to obtain a compound VI, enabling the compound VI to respectively react with sodium methoxide and trimethyl phosphate to obtain a compound VII, hydrolyzing and removing a protection group to obtain a compound VIII, finally carrying out acetylation reaction to obtain the ulipristal acetate, wherein the reaction formulae are as shown in the description. The method is short in synthetic route, mild in reaction conditions, high in yield and purity of products, low in cost, stable and controllable in quality, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a medicine for antiprogestin and antiglucocorticoid, in particular to a preparation method of ulipristal acetate and an intermediate thereof, belonging to the field of medicine synthesis methods. Background technique [0002] Ulipristal acetate (compound I), chemical name: 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19norpregna-4,9-diene-3, As a potent antiprogestin and antiglucocorticoid drug, 20-diketone can safely and effectively realize emergency contraception, so it is widely used. Its structural formula is as follows: [0003] [0004] At present, the preparation methods of ulipristal acetate mainly include the following: [0005] 1. As the reaction formula disclosed in U.S. Patent No. 4,954,490: [0006] [0007] The method has long processing steps, cumbersome operation, and the starting material (3-methoxy-19-norpregna-1,3,5(10),17(20)-tetraene) is not easy to obtain, and the reaction conditions are complicate...

Claims

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Application Information

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IPC IPC(8): C07J41/00
CPCC07J41/0083
Inventor 曾超资炎王海洋
Owner CHENGDU ORGANOCHEM CO LTD
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