Novel preparation method of ulipristal acetate key intermediate

A technology of ethylenedioxy and norpregna, which is applied in the direction of steroids and organic chemistry, can solve the problems of unfavorable product quality, many by-products, and improvement, and achieve high yield and selectivity, and easier reaction The effect of control

Active Publication Date: 2013-06-12
CHANGZHOU YABANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This route needs to use metal lithium when preparing 17α-hydroxyl-19-norpregna-4,9-diene-3,20-dione (IV), and metal lithium is a very high chemical reaction Alkali metal will burn violently when it meets water or acid, releasing hydrogen and heat, which is extremely unsuitable for large-scale industrial production
Secondly, this route uses cuprous chloride catalyst in the 1,4-conjugated addition reaction of last step, and the yield of reaction is only 76%, and by product is more, causes difficulty to the purification of final product, is unfavorable for product quality improvement

Method used

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  • Novel preparation method of ulipristal acetate key intermediate
  • Novel preparation method of ulipristal acetate key intermediate
  • Novel preparation method of ulipristal acetate key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: 3,3-ethylenedioxy-17β-cyano-17α-chloromethyl (dimethyl) siloxyestradiol-5 (10), the preparation of 9 (11) diene (III )

[0022] Add 3,3-ethylenedioxy-17β-cyanoestro-5(10), 9(11)dien-17α-alcohol (II) 170.5g and 5L tetrahydrofuran into the reaction flask in sequence, and start stirring , the temperature was lowered to 5°C, 12.2 g of 4-dimethylaminopyridine and 96.5 mL of triethylamine were added, 79.0 mL of chloromethyldimethylsilyl chloride was added dropwise, and the reaction was stirred at room temperature for 12 hours. Concentrate to dryness under reduced pressure at room temperature, add 1500 mL of dichloromethane, and pour the reaction solution into 800 mL of saturated aqueous sodium bicarbonate solution while stirring. The liquid was separated, and the organic phase was concentrated to dryness under reduced pressure, 500 mL of isopropyl ether was added, filtered, and the filter cake was air-dried to obtain 219.5 g of off-white solid, with a yield of 98....

Embodiment 2

[0023] Example 2: Preparation of 17α-hydroxy-19-norpregna-4,9-diene-3,20-dione (IV)

[0024]Add 219.5 g of 3,3-ethylenedioxy-17β-cyano-17α-chloromethyl (dimethyl) siloxyestradiol-5(10), 9(11) diene (III) to In a mixed solvent of 500mL toluene and 500mL tetrahydrofuran, after stirring at room temperature for 15min, 7.0g of cuprous bromide was added and added dropwise at room temperature. After the dropwise addition, continue to stir the reaction for 23h, evaporate the solvent under reduced pressure, slowly add 300mL of 5% dilute hydrochloric acid, continue to stir at room temperature for 30min, and extract twice with dichloromethane (500mL×2), and the organic phase is sequentially washed with 300mL Wash once with saturated saline and water, dry over anhydrous magnesium sulfate, and filter. The filtrate is concentrated to dryness to obtain 142.2 g of the product, with a yield of 92.3%.

Embodiment 3

[0025] Example 3: Preparation of 3,3,20,20-bis(ethylenedioxy)-17α-hydroxyl-5α, 10α-epoxy-19-norpregna-9(11)-ene (V)

[0026] Mix 17α-hydroxy-19-norpregna-4,9-diene-3,20-dione 138.7g (IV), 122.9mL ethylene glycol and 1500mL dichloromethane, start stirring, add dropwise at room temperature A solution of triethyl orthoformate (220.4 mL) in 200 mL of dichloromethane. After the dropwise addition, 5.1 g of p-toluenesulfonic acid was added, and after stirring at room temperature for 18 hours, 700 mL of saturated sodium bicarbonate solution was slowly added dropwise. After dropping, the liquid was separated, and the organic phase was washed with saturated brine and 700 mL of water successively. After drying the organic phase over anhydrous magnesium sulfate, filter, add 71.2 g of hexafluoroacetone to the obtained dichloromethane filtrate, start stirring and cool to 4 ° C, dropwise add 30% hydrogen peroxide (125 mL) and disodium hydrogen phosphate (25 g) to mix After the solution wa...

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Abstract

The invention discloses a novel preparation method of ulipristal acetate key intermediate 3,3,20,20-double (ethylenedioxy group)-5 alpha, 17 alpha- dihydroxyl-11 bata-[4-(N,N- dimethyl amidogen)- phenyl]-19-norprogesterone-9(11)-alkene, namely 3,3- ethylenedioxy group-17 beta-cyangroup female steroid-5(10), 9(11) diene-17 alpha-alcohol is used as a raw material, through the protection of hydroxyl, the addition of Grignard reagent and cyangroup, and the protection of ketal, and the target compound is obtained finally through 1,4 addition of alpha, beta unsaturation epoxide under the catalysis of a system of cuprous halides and dimethyl sulfide. The raw materials used in the method are safe and reliable, reaction is easy to control, reaction yield and stereoselectivity are high, and the method is applicable for industrial production.

Description

technical field [0001] The present invention relates to the key intermediate 3,3,20,20-bis(ethylenedioxy)-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino) of uliplast acetate Process for the preparation of -phenyl]-19-norpregna-9(11)-ene. Background technique [0002] Uliplast acetate is a progesterone receptor modulator developed by HRA Pharmaceuticals and approved by the European Commission in May 2009 for unprotected sexual intercourse or oral use within 120 hours of contraceptive failure. contraceptive pills. The chemical name of uliplast acetate is 17α-(acetoxy)-11β-[4-(dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20- Diketones, the structure of which is shown below: [0003] [0004] 3,3,20,20-Bis(ethylenedioxy)-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino)-phenyl]-19-norpregna -9(11)-ene is a key intermediate for the synthesis and preparation of uliplast acetate, and its structure is shown in the following formula (I): [0005] [0006] 3,3,20,20-Bis(ethylenedio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J21/00
Inventor 陈再新夏正君张明光王明林林送吉小龙马堰启臧路杰袁满龙
Owner CHANGZHOU YABANG PHARMA
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