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New preparation method of 5,7-pregnadiene-3,20-dione-diethyl ketal

A technology of pregnane and ethylene diketal, which is applied in 5 fields, can solve the problems of tetrabutylammonium fluoride instability, high production and operation costs, and difficulty in long-term storage, and achieve economical and environmentally friendly synthesis routes and good overall recovery. rate effect

Active Publication Date: 2015-07-08
TAIZHOU HISOUND PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the yield of this synthetic route has been greatly improved, solid waste hydantoin will be produced in the bromination process. At the same time, because the industrial tetrabutylammonium fluoride contains three crystal waters and the price is relatively high, and it needs to pass The freeze-drying process turns tetrabutylammonium fluoride trihydrate into tetrabutylammonium fluoride monohydrate, which will greatly increase the cost, and tetrabutylammonium fluoride becomes unstable after dehydration and is not easy to store for a long time. Therefore, this Route industrial production operation cost is high, no actual production value

Method used

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  • New preparation method of 5,7-pregnadiene-3,20-dione-diethyl ketal
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  • New preparation method of 5,7-pregnadiene-3,20-dione-diethyl ketal

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Embodiment 1

[0027] Embodiment 1: the preparation of compound D

[0028]Put 5.0L of anhydrous ethylene glycol, 3.0g of p-toluenesulfonic acid, and 250g (0.795mol) of progesterone into the reaction bottle. After switching nitrogen three times, turn on the vacuum and start heating, keeping the reaction temperature at 75-80 ℃, while distilling out ethylene glycol. After approximately 3.0L of ethylene glycol has been evaporated, the reaction solution is cooled to room temperature and emptied, and 300ml of ethanol solution with a mass percentage of 20% KOH is added, and stirring is continued for 20 minutes, and 1.7L of dichloromethane is added to dilute the reaction solution, and the layer, the lower layer of dichloromethane was separated, and the upper layer was extracted once with 1.0 L of dichloromethane. Combine the dichloromethane layers, wash the dichloromethane solution with 900ml of water three times, dry over anhydrous sodium sulfate, filter, distill off the dichloromethane under red...

Embodiment 2

[0029] Embodiment 2: the preparation of compound D

[0030] 200g (0.496mol) of compound B, 82g (0.502mol) of N-hydroxyphthalimide, the mixed solvent of 1.6L acetone and 1.6L ethyl acetate were dropped into the reaction flask equipped with stirring device and condenser, and the stirring was started. Raise the temperature to 53±2°C, when the raw materials are completely dissolved, add 1.0g of azobisisoheptanonitrile, and then start to pass in dry purified air 0.8M 3 / hr, after stirring and reacting for 6 hours, TLC tracked that the reaction of the raw materials was substantially complete. Evaporate acetone and ethyl acetate under reduced pressure, add 400ml of dichloromethane, stir for 30 minutes, remove N-hydroxyphthalimide by filtration, wash the filter cake with 200ml of dichloromethane (recovered N-hydroxyphthalimide is reprocessed can be reused later), combined the dichloromethane solution, cooled to 0°C-10°C under nitrogen protection, added 120g (1.18mol) of triethylami...

Embodiment 3

[0032] Embodiment 3: the preparation of compound D

[0033] Put 82g (0.502mol) of N-hydroxyphthalimide, 1.0g of dibenzoyl peroxide, and 1.6L of cyclohexanone into the reaction flask equipped with a stirring device and a condenser, and then heat to 54°C-55°C ℃, stir until the raw materials are completely dissolved, and pass through dry and purified air (0.8M 3 / hr) until 30 minutes later, 200 g (0.496 mol) of compound B was added, air was continuously introduced, and the reaction was stirred for 6 hours, followed by TLC until the reaction of the raw materials was substantially complete. Distill cyclohexanone off under reduced pressure, add 400ml of dichloromethane, stir for 30 minutes, filter to remove N-hydroxyphthalimide, wash the filter cake with 200ml of dichloromethane, combine the dichloromethane solution, and cool to 0 ℃-10℃, add 120g (1.18mol) of triethylamine under stirring, keep the temperature at 0℃-10℃, add 60g (0.588mol) of acetic anhydride dropwise, and stir fo...

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Abstract

Disclosed is a preparation method of 5,7-pregnadiene-3,20-dione-diethyl ketal. The preparation method comprises: performing dehydration condensation on progesterone by using glycol to protect two carbonyls, so as to obtain a compound B; performing allylic selective oxidization on the compound B to obtain a compound D; performing condensation on the compound D and p-toluenesulfonhydrazide, so as to obtain a compound E; and performing a Shapiro reaction to remove hydrazone from the compound E, so as to obtain 5,7-pregnadiene-3,20-dione-diethyl ketal (a compound A).

Description

technical field [0001] The invention relates to a synthesis method of steroidal compounds, in particular to a new preparation method of 5,7-pregnadiene-3,20-dione-diethylene diketal. Background technique [0002] 5,7-pregnadiene-3,20-dione-diethylene diketal (A) is a key intermediate in the synthesis of dehydroprogesterone (Dydrogesterone). Its structural formula is as follows: [0003] [0004] In the earlier literature Journal of Organic Chemistry (1952), 17, 1369-74, it was reported that two carbonyl groups were protected by dehydration condensation of ethylene glycol from progesterone, and bromination of the allyl position was carried out with NBS to obtain the brominated intermediate product C And C', intermediate C was refluxed in 2,4,6-collidine to prepare compound A, and the overall yield was only 26%. The yield of this route is too low and the pollution of the environment is too large using collidine. U.S. Patent No. 4464298 made appropriate improvements to th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J21/00
CPCC07J21/00C07J21/006C07J7/002C07J15/005C07J41/005
Inventor 张建设王琛琳陈济谷
Owner TAIZHOU HISOUND PHARMA CO LTD
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