Novel synthesis method of Ulipristal acetate

A technology of Eulyst acetate and a synthesis method, applied in the directions of steroids, organic chemistry, etc., can solve the problems of increased α addition ratio, increased steric hindrance, long steps, etc., and achieves simplified operation and low cost. , cleverly conceived effect

Inactive Publication Date: 2014-02-26
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The steps of this method are slightly longer, because the β-acetyl group is first introduced at the 17th position, resulting in greater steric hindrance, and when the format is added, the proportion of α addition becomes larger, making the overall yield low

Method used

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  • Novel synthesis method of Ulipristal acetate
  • Novel synthesis method of Ulipristal acetate
  • Novel synthesis method of Ulipristal acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 compound 3 Synthesis

[0061]

[0062] Add 11.5g of disodium hydrogen phosphate dodecahydrate into dichloromethane, add 8.8mL of hexafluoroacetone and 15.8mL of 30% hydrogen peroxide in turn, stir at 0°C for 1 hour, add 10g of the compound 2 , the solution was orange-yellow, and continued to stir at 0°C for 18 hours. TLC monitored that the reaction was complete. Add 50 mL of 10% sodium sulfite to the reaction solution, stir for 15 minutes, separate the dichloromethane layer, and then wash the water layer with 2*30 mL of dichloromethane Extract, combine the dichloromethane layers, wash with 10% sodium sulfite (2*50mL), wash with water (2*50mL), dry with 20g of anhydrous sodium sulfate, and concentrate to obtain 10.6g of pale yellow foamy solid. (Theory: 10.5g yield is 100%) HPLC measured 5α, 10α / 5β, 10β as 81:19. 1 HNMR {400 MHz, CDCl 3 (TMS), δ (ppm)}: 0.874 (s, 3H, CH 3 ), 1.214-2.509 (m, 18H), 3.876-3.966 (m, 4H, OCH 2 CH 2 O), 5β,10β: 5.860 (d,...

Embodiment 2

[0063] Example 2 compound 4 Synthesis

[0064]

[0065] 10g compound 3 After heating and dissolving with 20ml of acetone cyanohydrin, add 0.1ml of 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene (DBU) and stir at room temperature for 24h, a large amount of white solids precipitated , and then add 100ml of isopropyl ether and stir for 30min, then filter, wash the filter cake with isopropyl ether (2×20ml), collect the filter cake, and dry under reduced pressure at 50°C to obtain 5.95g (55%) of white solid. 1 HNMR {400 MHz, CDCl 3 (TMS), δ (ppm)}:0.935 (s, 3H, CH 3 ), 1.177~2.520 (m, 18H), 2.609 (s, 1H, OH), 3.882~3.969 (m, 4H, OCH 2 CH 2 O), 6.081 (t, 1H, J =2.8, =CH).

Embodiment 3

[0066] Example 3 Compound 5 Synthesis of (R 1 , R 2 , R 3 for methyl)

[0067]

[0068] 3.9g imidazole and 5g compound 4 After dissolving with 50ml of dry tetrahydrofuran, slowly add trimethylchlorosilane (5.5ml) dropwise at 0°C. After the addition is complete, continue to stir at this temperature for 3h. After the reaction is complete, a white needle-like solid precipitates out. Add 100ml of water , the solid was dissolved, extracted with ethyl acetate (3×40 ml), the combined ethyl acetate layers were washed with water (3×30 ml), dried over anhydrous sodium sulfate, and concentrated to give a white solid 6.1g (100%) mp: 160- 162°C. 1 HNMR {400 MHz, CDCl 3 (TMS), δ (ppm)}:0.219 (s, 9H, Si-CH 3 ), 0.879 (s, 3H, CH 3 ), 1.182~2.555 (m, 18H), 3.879~3.930 (m, 4H, OCH 2 CH 2 O), 6.082 (t, 1H, J =2.8, =CH).

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Abstract

The invention provides a novel method for synthesizing a progesterone receptor regulator, namely Ulipristal acetate (represented by a formula I shown in the specification). According to the method, Ulipristal acetate is prepared from a compound 2 through reaction in six steps, namely epoxidation, cyanation, hydroxyl protecting, Grignard reaction, methylation and acetylation. The method provided by the invention is ingenious in conception and has the characteristics of short steps, simplicity in operation and high product yield and purity, and the cost is reduced greatly, so that the method is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a new method for synthesizing progesterone receptor regulator Ulistat acetate. Background technique [0002] Compound Ulistat Acetate (Formula I), chemical name: 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene- 3,20-Diketone, common name: Ulipristal acetate, has the following formula: [0003] [0004] On August 13, 2010, the U.S. Food and Drug Administration (FDA) approved a new molecular entity emergency contraceptive tablet named Ella, and its drug name is Ulipristal acetate, which is an acetate salt. This emergency contraceptive tablet can be taken within 120 hours (5 days) after intercourse without measures. Ella is a progesterone receptor blocker / antagonist whose main function is to inhibit or delay female ovulation. In June 2010, the FDA's Advisory Committee for Reproductive Health Drugs discussed the drug. Members of the committee voted u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00
Inventor 吴勇管玫郝文梅海俐余永国李晓岑
Owner SICHUAN UNIV
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