A kind of preparation method of tamoxifen citrate e isomer

A technology of tamoxifen and citric acid, applied in the field of drug synthesis, can solve the problems of increased cost, long reaction route, and low content of E-form

Active Publication Date: 2016-05-18
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] 2. Adopting the method of first coupling and then alkylation (see reaction formula 2, US1617890), this synthetic route can only obtain about 12% E isomer, the cost increases, the yield is low, and high purity cannot be obtained product
[0012] The main problem of the above-mentioned method for preparing tamoxifen citrate E-isomer is that the content of E-isomer is lower in the product generated, and the reaction route is longer

Method used

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  • A kind of preparation method of tamoxifen citrate e isomer
  • A kind of preparation method of tamoxifen citrate e isomer
  • A kind of preparation method of tamoxifen citrate e isomer

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Embodiment 1

[0056] The method for preparing the high-purity tamoxifen citrate E isomer of this embodiment is as follows:

[0057] (1) Preparation of the mixture of Z-tamoxifen and E-tamoxifen: add 20g of raw materials (formula I) into a three-necked flask, add 180ml of isopropanol, stir to dissolve, then add 50ml of hydrochloric acid, and heat to reflux for 5h , HPLC monitoring shows that the E isomer is greater than 35% (see HPLC chart figure 1 ), cool to room temperature to crystallize for 2h, filter, the filter cake can be recycled and reused, add 120ml of water to the filtrate, if there is a solid, filter, take the filtrate, adjust the pH to strong alkaline with sodium hydroxide, solids will precipitate, use acetic acid The ethyl ester is extracted until the organic layer has no obvious color, washed with pure water to weakly alkaline, dried with anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 10g of oil, which is a mixture of Z-tamoxifen and E-tamoxifen , E isom...

Embodiment 2

[0062] The preparation method of the high-purity tamoxifen citrate E isomer of this embodiment has the following steps:

[0063] (1) Preparation of the mixture of Z-tamoxifen and E-tamoxifen: add 20g of raw material (formula I) into a three-necked flask, add 20ml of methanol, stir to dissolve, then add 20ml of sulfuric acid, heat to reflux for 6h, HPLC The monitored E isomer is greater than 35% (see HPLC chart Image 6 ), cool to room temperature to crystallize for 5 hours, filter, the filter cake can be recycled and reused, add 10ml of water to the filtrate, if there is solid, filter, take the filtrate, adjust the pH to strong alkalinity with sodium carbonate or sodium bicarbonate, and solids will precipitate , Extracted with dichloromethane until the organic layer has no obvious color, washed with pure water to weakly alkaline, dried with anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 9g of oily substance, namely Z-tamoxifen and E-tamoxifen A mixture o...

Embodiment 3

[0067] The method for preparing the high-purity tamoxifen citrate E isomer of this embodiment is as follows:

[0068] (1) Preparation of the mixture of Z-tamoxifen and E-tamoxifen: add 20g of raw material (formula I) into a three-necked flask, add 200ml of toluene, stir, then add 200ml of hydrochloric acid, heat to reflux for 6h, HPLC monitoring The E isomer is more than 35% (see HPLC chart Picture 11 ), cool to room temperature to crystallize for 5 hours, filter, the filter cake can be recycled and reused, add 160ml water to the filtrate, if there is solid, filter, separate, take the water layer, adjust the pH to strong alkaline with sodium carbonate or sodium bicarbonate, A solid precipitated out, extracted with dichloromethane until the organic layer had no obvious color, washed with pure water until weakly alkaline, dried with anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 6g of oil, which is) Z-tamoxifen and E -Tamoxifen mixture (E isomer content i...

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Abstract

The invention provides a preparation method of a tamoxifen citrate E isomer, which comprises the following steps: 1) with an intermediate for preparing tamoxifen citrate and having a structural formula as shown in the formula I as a raw material, performing a dehydration reaction in an acid condition in a mixed solution of water and organic solvent at certain proportion to obtain a mixture of an intermediate 1 with a structural formula as shown in the formula II and an intermediate 2 with a structural formula as shown in the formula III; 2) in an organic solvent of certain amount, enabling the intermediate 1 and the intermediate 2 to react with citric acid or hydrate thereof, and cooling for crystallization to obtain a mixture of Z-tamoxifen citrate with a structural formula as shown in the formula IV and E-tamoxifen citrate with a structural formula as shown in the formula V; and 3) in the water and organic solvent at certain proportion, performing twice recrystallization of the mixture of Z-tamoxifen citrate and E-tamoxifen citrate. The method provided by the invention can be used for preparing a high-purity tamoxifen citrate E isomer, provides an impurity reference substance for the National Institutes for Food and Drug Control, and solves the problem in E-isomer detection in a practical production process.

Description

Technical field [0001] The invention relates to a preparation method of tamoxifen citrate E isomer, which belongs to the technical field of medicine synthesis. Background technique [0002] The chemical name of tamoxifen citrate is (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine citrate Citrate (Compound IV), which is a non-steroidal anti-estrogen drug, has two isomers, Z-type and E-type, but only Z-type has a therapeutic effect, and E-type exists as an isomer impurity. Tamoxifen citrate was developed by the Imperial Chemical Industry Company (ICI). It was first used in clinical practice in 1971 and was approved by the US FDA in 1978 for the treatment of pre- and post-menopausal breast cancer. [0003] There are several methods for preparing tamoxifen citrate E isomers that have been reported as follows: [0004] 1. Using McMurry coupling method (see Reaction Formula 1, J.Chem.Soc., Perkin.Trans(I),1986,475), the reaction has a certain stereoselectivity (Z / E=3:1), ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/14C07C213/08C07C213/10
Inventor 马立金王庆辉牛明玉朱圣红乔健陆良喆
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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