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Method for preparing levonorgestrel intermediate condensation compound

A technology of levonorgestrel and condensate, which is applied in the field of Grignard reaction of levonorgestrel intermediates, can solve the problems of affecting the conversion rate and yield of the condensation reaction, unable to carry out the condensation reaction, unable to condense, etc., and achieves elimination of dehydration. The effect of hydroxyl risk, reducing the amount of recycling and ensuring quality

Active Publication Date: 2014-02-05
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The Grignard reaction of the existing levonorgestrel intermediate, its post-processing method is that the Grignard reaction product is first processed by a saturated ammonium chloride solution, and then concentrated, extracted, washed, dehydrated, filtered and re-concentrated to obtain the Grignard product , the post-treatment method is very easy to dehydroxylate the tertiary hydroxyl group during the post-treatment process, resulting in the inability to carry out the condensation reaction, which seriously affects the conversion rate and yield of the subsequent condensation reaction, and sometimes even completely dehydroxylates, resulting in the inability to condense

Method used

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  • Method for preparing levonorgestrel intermediate condensation compound
  • Method for preparing levonorgestrel intermediate condensation compound
  • Method for preparing levonorgestrel intermediate condensation compound

Examples

Experimental program
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Embodiment 1

[0037] Put 10.5Kg of magnesium chips and 1Kg of iodine into the dry reaction tank, then replace the reaction system with nitrogen, then add 20L of tetrahydrofuran into the reaction tank, stir and raise the temperature to about 30℃ to initiate, and then heat to reflux after it stabilizes. Extract 180L of tetrahydrofuran plus 32.5L of ethylene bromide and mix and pump to a high-level storage tank. Add the ethylene bromide and tetrahydrofuran solution dropwise under reflux conditions until the dripping is completed. Continue refluxing for 5 hours. After the reaction is complete, cool to below about 15°C. Add 6-methoxy-1-tetrahydrofuran solution (25Kg of 6-methoxy-1-tetrahydrofuran and 150L tetrahydrofuran), drip and react at room temperature for more than 5 hours, TLC detection, the reaction is complete At 10℃~30℃, add ammonium chloride saturated aqueous solution dropwise to terminate the reaction, stand still to separate the THF solution, extract the aqueous layer with THF, combin...

Embodiment 2

[0040] Put 10Kg of magnesium chips and 0.2Kg of iodine into the dry reaction tank, then replace the reaction system with argon, then add 10L of tetrahydrofuran to the reaction tank, stir and raise the temperature to about 20℃ to initiate, and then heat it to reflux after it stabilizes. Extract 210L of tetrahydrofuran and 32L of ethylene bromide and mix and pump to the high-level storage tank. Add the ethylene bromide and tetrahydrofuran solution dropwise under reflux conditions until the dripping is complete. Continue refluxing for 5 hours. After the reaction is complete, cool down to below about 15°C and add dropwise 6-Methoxy-1-Tetrahydrofuran solution (prepared with 25Kg of 6-Methoxy-1-Tetrahydrofuran and 160L of tetrahydrofuran), after dripping, react at room temperature for more than 5 hours, TLC detection, the reaction is complete, Add ammonium chloride saturated aqueous solution dropwise at 10℃~30℃ to stop the reaction, stand still to separate the THF solution, extract th...

Embodiment 3

[0043] Put 15Kg of magnesium chips and 0.8Kg of iodine into the dry reaction tank, then replace the reaction system with argon, then add 40L of tetrahydrofuran to the reaction tank, stir and raise the temperature to about 25℃ to initiate, and then heat it to reflux after it stabilizes. Extract 160L of tetrahydrofuran plus 35L of ethylene bromide and mix and pump to a high-level storage tank. Add the ethylene bromide and tetrahydrofuran solution dropwise under reflux conditions until the dripping is complete. Continue refluxing for 5 hours. After the reaction is complete, cool the temperature to below about 15°C and add dropwise 6-Methoxy-1-Tetrahydrofuran solution (prepared with 25Kg of 6-Methoxy-1-Tetrahydrofuran and 180L tetrahydrofuran), after dripping, react at room temperature for more than 5 hours, TLC detection, the reaction is complete, Add ammonium chloride saturated aqueous solution dropwise at 10℃~30℃ to stop the reaction, stand still to separate the THF solution, ext...

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Abstract

The invention relates to the field of Grignard reaction of a levonorgestrel intermediate, and particularly relates to a preparation method for a levonorgestrel intermediate condensation compound. The preparation method mainly comprises step of adding a nitrogen-containing organic alkaline reagent as a stabilizer. The organic alkaline reagent plays a role in preventing tertiary hydroxyl from dehydroxylation, so that Grignard hydrolysate is stable, by-products are reduced, the conversion rate of condensation reaction is greatly improved, the weight yield is improved to be about 130% from 93% of the prior art, and the HPLC (high performance liquid chromatography) content of the product reaches 97%-99.8%.

Description

technical field [0001] The invention relates to the field of Grignard reaction of levonorgestrel intermediates, in particular to the post-treatment of levonorgestrel intermediates after the Grignard reaction is completed, and the tertiary hydroxyl groups are easily hydrolyzed under certain conditions, and the invention is a method for preventing dehydroxylation of tertiary hydroxyl groups. Methods. Background technique [0002] Levonorgestrel intermediate condensate, chemical name (E)-2-ethyl-2-(2-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)ethyl)cyclopentane-1,3-dione . [0003] Structural formula: [0004] . [0005] [0006] Levonorgestrel (LNG) is a fully synthetic potent progestin, which is the optically active form of racemic norgestrel, and its activity is 1 times stronger than norethindrone and about 100 times that of norethindrone. The Grignard reaction of the existing levonorgestrel intermediate, its post-processing method is that the Grignard reaction produ...

Claims

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Application Information

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IPC IPC(8): C07C45/68C07C49/753
CPCC07C41/30C07C41/46C07C45/68C07C2601/08C07C2602/10C07C49/753C07C43/23
Inventor 许东新
Owner ZHEJIANG XIANJU PHARMA
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