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Synthesis method of ulipristal acetate

A technology of ulipristal acetate and a synthetic method, which is applied in the direction of steroids, organic chemistry, etc., can solve the problems that cannot meet the requirements of residual solvents and limits, and achieve the effect of high product yield and high purity

Active Publication Date: 2018-01-26
广州市桐晖药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] For the solvent-based crystals of ulipristal acetate, the crystals obtained directly by the solvent evaporation method often cannot meet the residual solvent and limit requirements stipulated in the 2015 edition of the Pharmacopoeia of the People's Republic of China

Method used

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  • Synthesis method of ulipristal acetate
  • Synthesis method of ulipristal acetate
  • Synthesis method of ulipristal acetate

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preparation example Construction

[0033] The invention provides a synthetic method of ulipristal acetate, which uses commercially available pregnanodienol as a starting material, and undergoes keto group protection, oxidation, Grignard addition, hydrolysis and esterification in sequence to finally obtain acetic acid Ulistat. In this method, the reaction conditions for obtaining ulipristal acetate from ulipristal are relatively mild, and it is difficult to produce demethylated ulipristal or nitric oxide ulipristal, and the final ulipristal has high purity.

[0034] A kind of synthetic method of ulipristal acetate, is characterized in that, reaction formula is as follows:

[0035]

[0036] The method comprises the steps of:

[0037] 1) Pregnodienol generates compound VI under the action of ethylene glycol, p-toluenesulfonic acid and trimethyl orthoformate;

[0038] This step is to protect the two ketone groups to avoid destroying the ketone groups during the next step of oxidation;

[0039] 2) compound VI ...

Embodiment 1

[0046] Embodiment 1: the preparation of compound VI

[0047] Take 62.8g (0.20mol) pregnanodienol, 80mL (1.44mol) ethylene glycol, 55mL (0.5mol) trimethyl orthoformate and dissolve in 500mL dichloromethane, add 7.6g (0.04mol) P-toluenesulfonic acid monohydrate, heat up to 35°C, stir the reaction until TLC shows that the reaction of pregnodienol is complete, add saturated aqueous sodium bicarbonate solution to neutralize, separate the organic phase, extract the aqueous phase with 300mL dichloromethane each time, and dry , add 0.5mL of pyridine, distill under reduced pressure to obtain a thick substance, add 300mL of methanol to the thick substance, stir at 0-5°C for 45min, filter, wash the filter cake with ice methanol, and dry in vacuo to obtain 66.3g of compound VI (0.167 mol), yield 83%.

Embodiment 2

[0048] Embodiment 2: the preparation of compound VII

[0049]Dissolve 60.3g (0.15mol) of compound VI, 7.6mL (0.05mol) of hexachloroacetone, and 1.5mL (0.019mol) of pyridine in 200mL of dichloromethane, and add 90mL (1.5mol) of 50% hydrogen peroxide dropwise at 0-5°C , keep stirring at 0-5°C, until TLC monitors that compound VI disappears, separate the organic phase, extract the aqueous phase with 100mL of dichloromethane, combine the organic phases, quench with aqueous sodium thiosulfate until the aqueous phase is neutral, dry, reduce Concentrate under reduced pressure to obtain compound VII, which is directly used in the next reaction.

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Abstract

The invention discloses a synthesis method of ulipristal acetate. The synthesis method comprises the following steps: 1), producing a compound VI from gestadienol under the action of ethylene glycol,p-toluenesulfonic acid and trimethyl orthoformate; 2), oxidizing the compound VI by using hydrogen peroxide to obtain a compound VII; 3), preforming a reaction on the compound VII and a 4-(N, N-dimethylamino) phenylmagnesium bromide Grignard reagent to obtain a compound VIII; 4), hydrolyzing a compound VIII to obtain a compound XI; 5), preforming a reaction on the compound XI, glacial acetic acidand acetic anhydride under the catalytic action of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine and iron perchlorate to obtain the ulipristal acetate. In the synthesis method, reaction conditions for obtaining the ulipristal acetate from ulipristal are relatively mild, demethylated ulipristal or ulipristal oxynitride is unlikely to produce, and the production process is more controllable.

Description

technical field [0001] The invention relates to a synthesis method of western medicine, in particular to a synthesis method of ulipristal acetate. Background technique [0002] Ulipristal acetate (ulipristal acetate), its molecular formula is C 30 h 37 NO 4 , relative molecular mass 475.62, systematically named 17α-acetoxy-11β(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione , is a progesterone agonist / antagonist with the following structural formula: [0003] [0004] There are many synthetic routes of ulipristal acetate at present, and more commonly used is the Dancsi method as shown in the following equation: [0005] [0006] [0007] Taking this method as an example, in the synthesized ulipristal acetate, in addition to intermediates 8 and 9 (ulipristal), common impurities also have specific related substances specified, such as demethylated ulipristal acetate He and ulipristal nitric oxide, and the isomers of ulipristal, as shown in the follow...

Claims

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Application Information

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IPC IPC(8): C07J41/00
Inventor 张彤丽
Owner 广州市桐晖药业有限公司
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