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Industrial preparation process of tamoxifen citrate

A tamoxifen and preparation technology, which is applied in the field of drug synthesis, can solve the problems of restricting the industrial production of tamoxifen citrate, difficulty in product purification, and high cost, and achieve easy recovery and application, easy control of process conditions, The effect of low unit consumption of raw materials

Pending Publication Date: 2022-03-04
BEIJING JINGFENG PHARM (SHANDONG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, when the above-mentioned preparation method is used for industrialized production, there are problems such as product purification difficulty, low yield, and high cost, which restrict the industrialized production of tamoxifen citrate

Method used

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  • Industrial preparation process of tamoxifen citrate
  • Industrial preparation process of tamoxifen citrate
  • Industrial preparation process of tamoxifen citrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] (1) Etherification:

[0061] Add 250.0kg of toluene to the etherification kettle, start stirring, add 23.00kg of sodium hydroxide and 25.00kg of p-bromophenol, raise the temperature to 112°C, reflux with water until no water drops appear continuously, and lower the inner temperature of the etherification kettle to 60°C Next, add 25.00kg of dimethylaminoethyl chloride hydrochloride, raise the temperature to 112°C, reflux reaction until no water droplets appear continuously in the water separator and the reflux toluene is clear, and the reaction is completed; wait until the inner temperature of the etherification tank drops to 35°C Next, put the feed liquid into a centrifuge to filter, rinse the filter residue with toluene, pump the filtrate and eluent into the toluene still, add purified water to stir, let it stand, and separate the water layer, then depressurize at -0.060MPa and 80°C Distillation, the distilled toluene is recovered and used mechanically, and finally the...

Embodiment 2

[0069] (1) Etherification:

[0070] Add 250.0kg of toluene to the etherification kettle, start stirring, add 21.00kg of sodium hydroxide and 25.00kg of p-bromophenol, raise the temperature to 110°C, reflux with water until no water drops appear continuously, and lower the inner temperature of the etherification kettle to 60°C Next, add 23.00kg of dimethylaminoethyl chloride hydrochloride, raise the temperature to 110°C, reflux reaction until no water drops appear continuously in the water separator and the reflux toluene is clear, and the reaction is completed; wait until the inner temperature of the etherification tank drops to 30°C Next, put the feed liquid into a centrifuge for filtration, rinse the filter residue with toluene, pump the filtrate and eluent into the toluene still, stir for 20 minutes, and separate the water layer after standing still, then carry out at -0.070MPa, 70°C temperature Distilled under reduced pressure, the distilled toluene was recovered and used ...

Embodiment 3

[0078] (1) Etherification:

[0079]Add 250.0kg of toluene to the etherification kettle, start stirring, add 25.00kg of sodium hydroxide and 25.00kg of p-bromophenol, raise the temperature to 112°C, reflux with water until no water drops appear continuously, and lower the inner temperature of the etherification kettle to 60°C Next, add 27.00kg of dimethylaminoethyl chloride hydrochloride, raise the temperature to 112°C, reflux reaction until no water drops appear continuously in the water separator and the reflux toluene is clear, the reaction is completed; wait until the inner temperature of the etherification tank drops to 30°C Next, put the feed liquid into a centrifuge for filtration, rinse the filter residue with toluene, pump the filtrate and eluent into the toluene distillation kettle, stir for 20 minutes, separate the water layer after standing, and then carry out at -0.090MPa, 70°C temperature Distilled under reduced pressure, the distilled toluene was recovered and us...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to an industrial preparation process of tamoxifen citrate. The preparation process comprises the following steps: (1) etherification: taking p-bromophenol and dimethylaminochloroethane hydrochloride as raw materials, taking methylbenzene as a solvent, and carrying out etherification reaction under the action of sodium hydroxide to obtain etherate; (2) Grignard reaction: by taking tetrahydrofuran as a solvent, reacting the etherate with an initiator to obtain a Grignard reagent, and then carrying out Grignard reaction on the Grignard reagent and alpha-ethyl desoxybenzoin to obtain a Grignard substance; (3) dehydration and alkalization: carrying out a dehydration reaction on the Grignard substance and hydrochloric acid, and then carrying out an alkalization reaction with a sodium hydroxide solution to obtain tamoxifen free alkali; and (4) salt forming reaction: taking the tamoxifen free alkali and citric acid as raw materials, taking acetone as a solvent, and carrying out salt forming reaction to obtain the tamoxifen citrate. The process conditions are easy to control, the product purity reaches 99.5%, the total yield of the product is high, and the production cost is low.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to an industrial preparation process of tamoxifen citrate. Background technique [0002] Tamoxifen citrate is a common antineoplastic drug, which is a white or off-white crystalline powder and is odorless. Molecular formula is C 26 h 29 NO·C 6 h 8 o 7 , the chemical structural formula is as follows: [0003] [0004] There are two isomers of Z-type and E-type tamoxifen citrate, and only the Z-type has a therapeutic effect. In industrial drug production, the Z-type tamoxifen citrate is mainly synthesized, that is, the synthetic (Z) -N,N-Dimethyl-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]ethylamine citrate. [0005] At present, there are many mature synthetic routes for the synthesis of tamoxifen citrate, such as the preparation method of high-purity tamoxifen citrate disclosed in the patent CN103450036A, using 4-hydroxybenzophenone as raw material, The crude product 2-[4...

Claims

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Application Information

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IPC IPC(8): C07C213/08C07C217/14
CPCC07C213/08C07C213/04C07C217/14
Inventor 张隽李传龙张帅吴祥英周立霞
Owner BEIJING JINGFENG PHARM (SHANDONG) CO LTD
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