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New preparation method of citric acid toremifene intermediate

A technology of toremifene citrate and an intermediate, which is applied in the field of medicine and chemical industry, can solve the problems of water pollution, complicated operation, reduced yield and the like, and achieves the effects of ensuring health, increasing reaction temperature and reducing solid waste.

Inactive Publication Date: 2016-12-07
NINGBO TEAM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high water solubility of ether solvents, a large amount of solvents and some products are brought into the water phase, resulting in a decrease in yield, water pollution, and cumbersome operations.

Method used

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  • New preparation method of citric acid toremifene intermediate
  • New preparation method of citric acid toremifene intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] In a 10L three-necked flask equipped with mechanical stirring, add 400 g of 4-hydroxybenzophenone, 696 g of potassium carbonate, 5.4 kg of toluene, and 140 g of 95% industrial ethanol, and stir at 53-58° C. for 1 hour. After cooling to below 40°C, 436 g of N,N-dimethylaminochloroethane hydrochloride was added, and the temperature was raised to 80-85°C to react for 4 hours. TLC monitors that the conversion of the raw material 4-hydroxybenzophenone is basically complete, cools to below 40° C., adds 2.4 kg of drinking water, stirs, separates layers, and discards the lower aqueous phase. The toluene layer was washed three times with 4.6 liters of 4% sodium hydroxide solution, and then washed twice with 2 liters of drinking water. The solvent was distilled off under reduced pressure at 55-60°C to obtain 521 g of a light yellow oil, which was cooled to obtain a light yellow solid, and the yield of Intermediate 1 was 95.8%.

Embodiment 2

[0020] Throw 1.2kg of tetrahydrofuran and 54g of tetrahydrofuran into a 5L three-necked bottle, control the temperature at 20-28°C, slowly add the tetrahydrofuran solution of cinnamaldehyde (containing 318g of cinnamaldehyde, 960g of tetrahydrofuran) dropwise. Stir for 45 minutes. A solution of intermediate 1 in tetrahydrofuran (containing 465 g of intermediate 1, 1.2 kg of tetrahydrofuran) was added at this temperature. After the addition is complete, stir at 38-43°C for 1 hour. Transfer the reaction solution to a 20-liter glass reactor, add 7 L of tetrahydrofuran, slowly add 132 g of 20% sodium hydroxide solution dropwise, stir for 10 minutes, add 960 g of anhydrous sodium sulfate, and then add dropwise of 132 g of drinking water. Stir for half an hour and filter with suction. The filter cake was washed with 1 L of tetrahydrofuran. Tetrahydrofuran was distilled off under reduced pressure, 2.64kg of toluene was added, heated to 90-100°C to dissolve, slowly cooled to room t...

Embodiment 3

[0022] Put 1080kg of toluene, 28kg of 95% industrial ethanol, 140kg of potassium carbonate, and 80kg of 4-hydroxybenzophenone into a 2000L glass-lined reactor, and stir for 1 hour at 53-58°C. The temperature was lowered to below 40°C, and 87.5 kg of N,N-dimethylaminochloroethane hydrochloride was added under the protection of nitrogen. After the injection was completed, the temperature was slowly raised to 80-85°C and stirred for 4 hours. Cool down to below 40°C, add 500kg of drinking water, stir for 15 minutes, and let stand to separate layers. The upper organic phase was washed three times with 900kg of 4% aqueous sodium hydroxide solution, and the organic phase was washed twice with 800kg of drinking water. The solvent was concentrated under reduced pressure until no distillate was evaporated under the conditions of vacuum degree not lower than 0.085MPa and internal temperature not higher than 80°C to obtain 105.5kg of oily substance, which was light yellow solid after cool...

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Abstract

The invention discloses new methods for producing and preparing a citric acid toremifene key intermediate 4-[2-(N,N-dimethylamino)ethoxy]benzophenone(hereinafter referred to as an intermediate 1) and 1,2-diphenyl-1-[4-[2- ( N,N-dimethylamino)ethoxy]phenyl group]-1,4-butanediol (hereinafter referred to as an intermediate 2). The intermediate 1 is prepared by using a non-water-soluble resolvent as a main solvent, a water-soluble reagent as an auxiliary solvent, and an inorganic base as an acid acceptor, and is formed by an alkylation reaction of 4-hydroxybenzophenone and N,N-dimethylaminoethyl chloride hydrochloride. The reaction speed is high, the post-treatment is simple, convenient and safe, and few three wastes are generated; and the yield and the purity of the intermediate 1 are high, the new method is especially suitable for industrialized production. The intermediate 2 is prepared from cinnamic aldehyde (or cinnamyl alcohol), lithium aluminum hydride and the intermediate 1 in an ether solvent, the post-treatment of the intermediate 2 is performed in a manner of performing destroying with alkali liquor, and drying with a drying agent, and the intermediate 2 is separated in a direct filtering manner. The new method has the characteristics of being quick, environmental-friendly, high in yield and the like.

Description

technical field [0001] The invention relates to a new preparation method and process of a toremifene citrate intermediate, belonging to the field of medicine and chemical industry. Background technique [0002] Toremifene (Toremifene) is an estrogen receptor antagonist antineoplastic drug developed by Finnish Famos Company in 1983 for the treatment of postmenopausal women with estrogen receptor positive or unknown metastatic breast cancer. Lion & Company is listed in the European Union under the trade name of Fareston. Toremifene is administered orally in the form of citrate. Toremifene is similar in structure and mechanism of action to tamoxifen, and belongs to triarylbutene anti-estrogen drugs. Studies in recent years have found that toremifene citrate is an effective drug for inhibiting Ebola virus. [0003] 4-[2-(N,N-Dimethylamino)ethoxy]benzophenone (intermediate 1) and 1,2-diphenyl-1-[4-[2-(N,N-diphenyl Methylamino)ethoxy]phenyl]-1,4-butanediol (intermediate 2) are...

Claims

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Application Information

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IPC IPC(8): C07C217/22C07C213/06C07C217/20C07C213/08
CPCC07C213/00C07C213/06C07C213/08C07C217/22C07C217/20
Inventor 徐骥王毅斌王陈杨赵爱霞汪伟
Owner NINGBO TEAM PHARMA
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