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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 inability to obtain high-purity products, increased cost, and low content of E isomers

Active Publication Date: 2014-08-20
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Preparation method of tamoxifen citrate E isomer
  • Preparation method of tamoxifen citrate E isomer
  • Preparation method of tamoxifen citrate E isomer

Examples

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Effect test

Embodiment 1

[0056] The preparation method of the high-purity tamoxifen citrate E isomer of the present embodiment, the steps are as follows:

[0057] (1) Preparation of Z-tamoxifen and E-tamoxifen mixture: add 20g of raw material (formula I) to the three-neck flask, add 180ml of isopropanol, stir to dissolve, then add 50ml of hydrochloric acid, heat to reflux for 5h , HPLC monitors that the E isomer is greater than 35% (see HPLC spectrum figure 1), cooled to room temperature and crystallized for 2 hours, filtered, the filter cake can be recycled and reused, and 120ml of water was added to the filtrate, if there were solids, filtered, the filtrate was taken, and the pH was adjusted to strong alkalinity with sodium hydroxide. Extract with ethyl ester until the organic layer has no obvious color, wash with pure water to weak alkalinity, dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain 10 g of oil, which is a mixture of Z-tamoxifen and E-tamoxifen , E isomer con...

Embodiment 2

[0062] The preparation method of the high-purity tamoxifen citrate E isomer of the present embodiment, the steps are as follows:

[0063] (1) Preparation of Z-tamoxifen and E-tamoxifen mixture: add 20g of raw material (formula I) to the three-neck flask, add 20ml of methanol, stir to dissolve, then add 20ml of sulfuric acid, heat to reflux for 6h, HPLC Monitoring E isomer greater than 35% (HPLC spectrum see Figure 6 ), cooled to room temperature and crystallized for 5h, filtered, 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 are precipitated , extracted with dichloromethane until the organic layer has no obvious color, washed with pure water to weak alkalinity, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 9g of oily matter, namely Z-tamoxifen and E-tamoxifen A mixture o...

Embodiment 3

[0067] The preparation method of the high-purity tamoxifen citrate E isomer of the present embodiment, the steps are as follows:

[0068] (1) Preparation of Z-tamoxifen and E-tamoxifen mixture: add 20g of raw material (formula I) to the three-necked flask, add 200ml of toluene, stir, then add 200ml of hydrochloric acid, heat to reflux for 6h, and monitor by HPLC Obtained E isomer greater than 35% (HPLC spectrum sees Figure 11 ), cooled to room temperature and crystallized for 5 hours, filtered, the filter cake can be recycled and reused, and 160ml of water was added to the filtrate, if there were solids, filtered, separated, the water layer was taken, and the pH was adjusted to strong alkalinity with sodium carbonate or sodium bicarbonate, Solids were precipitated, extracted with dichloromethane until the organic layer had no obvious color, washed with pure water until weakly alkaline, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 6 g of ...

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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, belonging to the technical field of drug 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 belongs to nonsteroidal anti-estrogen drugs, has two isomers of type Z and type E, but only type Z has a therapeutic effect, and type E exists as an isomer impurity. Tamoxifen citrate was developed by Imperial Chemical Industries (ICI). It was first used clinically in 1971, and was approved by the US FDA in 1978 for the treatment of breast cancer at various stages before and after menopause. [0003] The preparation method of reported tamoxifen citrate E isomer has following several kinds at present: [0004] 1. Using the McMurry coupling method (see Reaction Formula 1, J.Chem.Soc., Perkin.Trans(I), 1986, 475), the reaction has certain stereoselectivity...

Claims

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Application Information

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Patent Type & Authority Applications(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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