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Method for preparing levonorgestrel intermediate condensation compound

A technology of levonorgestrel and condensates, which is applied in the field of Grignard reaction of levonorgestrel intermediates, can solve the problems affecting the conversion rate and yield of condensation reaction, the condensation reaction cannot be carried out, and the condensation cannot be carried out, so as to achieve stable reaction Controllable, improved operability, reduced by-product effects

Active Publication Date: 2014-12-10
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

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Embodiment 1

[0036] Put 10.5Kg of magnesium chips and 1Kg of iodine into a dry reaction tank, then replace the reaction system with nitrogen, then extract 20L of tetrahydrofuran and add it to the reaction tank, stir and heat up to about 30°C to initiate, and then heat up to reflux after stabilization, and then Extract 180L of tetrahydrofuran and 32.5L of brominated ethylene and mix them into a high-level storage tank. Add the bromoethylene tetrahydrofuran solution dropwise under reflux until the drop is complete, and continue the reflux reaction for 5 hours. After the reaction is complete, cool down to below about 15°C, drop Add 6-methoxy-1-tetralone tetrahydrofuran solution (prepared by 25Kg 6-methoxy-1-tetralone and 150L tetrahydrofuran), drop it, react at room temperature for more than 5 hours, TLC detection, the reaction is complete , 10 ° C ~ 30 ° C saturated aqueous solution of ammonium chloride was added dropwise to terminate the reaction, the THF solution was separated, the water la...

Embodiment 2

[0039] Put 10Kg of magnesium chips and 0.2Kg of iodine into a dry reaction tank, then replace the reaction system with argon, then extract 10L of tetrahydrofuran and add it to the reaction tank, stir and raise the temperature to about 20°C to initiate, and then heat up to reflux after stabilization. Extract 210L of tetrahydrofuran and 32L of bromide and mix them into a high-level storage tank. Add the bromide tetrahydrofuran solution dropwise under reflux until the drop is complete, and continue the reflux reaction for 5 hours. After the reaction is complete, cool down to below about 15°C and drop 6-methoxy-1-tetralone tetrahydrofuran solution (prepared by 25Kg of 6-methoxy-1-tetralone and 160L tetrahydrofuran), after dropping, react at room temperature for more than 5 hours, TLC detection, the reaction is complete, Add a saturated ammonium chloride aqueous solution dropwise at 10°C to 30°C to terminate the reaction, let stand to separate the THF solution, extract the water lay...

Embodiment 3

[0042] Put 15Kg of magnesium chips and 0.8Kg of iodine into a dry reaction tank, then replace the reaction system with argon, then extract 40L of tetrahydrofuran and add it to the reaction tank, stir and raise the temperature to about 25°C to initiate, and then raise the temperature to reflux after stabilization, and then Extract 160L of tetrahydrofuran and 35L of bromide and mix them into a high-level storage tank. Add the bromide tetrahydrofuran solution dropwise under reflux until the drop is complete, and continue the reflux reaction for 5 hours. After the reaction is complete, cool down to below about 15°C and drop 6-methoxy-1-tetralone tetrahydrofuran solution (prepared by 25Kg of 6-methoxy-1-tetralone and 180L tetrahydrofuran), after dropping, react at room temperature for more than 5 hours, TLC detection, the reaction is complete, Add a saturated ammonium chloride aqueous solution dropwise at 10°C to 30°C to terminate the reaction, let stand to separate the THF solution...

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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] 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 product is firs...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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