The preparation method of flutamide

A technology of flutamide and isobutyrylaminotrifluorotoluene, applied in the field of medicine, can solve the problems of difficult reaction stirring, long cooling and placing, long production cycle, etc., and achieves the advantages of good product quality, easy temperature control, and shortened production cycle. Effect

Active Publication Date: 2016-01-20
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthetic preparation method document of flutamide has been reported, (synthetic research of anticancer drug flutamide, Pan Weichun etc., chemical journal of Zhejiang University of Technology, 1997,25 (3), 248-251; Non-steroidal antiandrogen drug The synthesis of Flutamide, Xia Peng etc., Chinese Journal of Pharmaceutical Industry, 1989, 20 (8), 341-343); However, in the preparation process of flutamide in the literature, the reaction solution is dropped into ice cubes to prepare the crude product, and then filtered, Benzene recrystallization is used to obtain the fine flutamide; when the reaction solution is crystallized, it is directly dropped into ice cubes, and a large amount of ice cubes are consumed, which makes the reaction difficult to stir. After the dripping, the remaining ice cubes in the reaction kettle have to be taken out , very inconvenient, the production cycle of this step is long (in order to control the process temperature, the dropping time is long, and the cooling time is long), the labor intensity is very large, and the literature adopts the larger toxicity of benzene recrystallization, which has a negative impact on production management and product quality. In view of this, we invented a new method for the preparation of flutamide, the new process is convenient for production and operation, the cycle is shortened, the product yield and quality are stable; and because of the high reaction yield and simple post-treatment, the cost is also greatly reduced

Method used

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  • The preparation method of flutamide

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Experimental program
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Effect test

Embodiment 1

[0023] Add 31 g of fuming nitric acid and 248 ml of concentrated sulfuric acid into the reaction pot, start stirring, and cool with ice-salt water. When the temperature dropped to -5°C, 100 g of m-isobutyramide trifluorotoluene was slowly added. After the addition, keep the reaction at 2-5°C for 2 hours. Then, the reaction solution is added dropwise to an ice-salt water system composed of sodium chloride, crushed ice and water for crystallization, and the dropping temperature is controlled at -5 to 5°C. The dropwise addition time is about 1.5 hours, the solid matter is precipitated, filtered, and then soaked with drinking water, the filter cake, 500ml toluene, and 1g activated carbon are added to the decolorization pot, start stirring, and heat the temperature to 80-85°C. Heat to reflux for 0.5 hour, filter while hot, cool the filtrate below 0°C to crystallize, and centrifuge to obtain the wet crude product of flutamide, dry the wet crude product below 80°C to obtain 59.5 g o...

Embodiment 2

[0025] Add 29 g of fuming nitric acid and 250 ml of concentrated sulfuric acid into the reaction pot, start stirring, and cool with ice-salt water. When the temperature dropped to -5°C, 100 g of m-isobutyramide trifluorotoluene was slowly added. After the addition, keep the reaction at 1-5°C for 2 hours. Then, the reaction solution is added dropwise to an ice-salt water system composed of calcium chloride, crushed ice and water for crystallization, and the dropping temperature is controlled at -5 to 0°C. The dropwise addition time is about 1 hour, the solid matter is precipitated, filtered, and then soaked with drinking water, the filter cake and 500ml toluene are added to the crystallization pot, the stirring is started, and the temperature is heated to 75-80°C. After heating and dissolving, the filtrate was crystallized by cooling below 0°C, and centrifuged to obtain a wet crude product of flutamide, which was dried below 80°C to obtain 60.5 g of a crude product of flutamid...

Embodiment 3

[0027] Add 29 g of fuming nitric acid and 250 ml of concentrated sulfuric acid into the reaction pot, start stirring, and cool with ice-salt water. When the temperature dropped to -5°C, 100 g of m-isobutyramide trifluorotoluene was slowly added. After the addition, keep the reaction at 6-8°C for 1 hour. Then, the reaction solution is added dropwise to an ice-salt water system composed of sodium chloride, crushed ice, and water for crystallization, and the dropping temperature is controlled at -5 to 0°C. The dropwise addition time is about 5 hours, the solid matter is precipitated, filtered, and then soaked with drinking water. Add the filter cake, 500ml toluene, and 1g activated carbon into the decolorization pot, start stirring, and heat the temperature to 80-85°C. Heat to reflux for 0.5 hour, filter while hot, the filtrate crystallizes at 0°C, and centrifuge to obtain the wet crude product of flutamide, dry the wet crude product below 80°C to obtain 56.8 g of the crude prod...

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Abstract

The invention relates to a new preparation method of flutamide. The method comprises the following steps: 1, adding a raw material m-isobutyramidotrifluorotoluene to a mixed acid of sulfuric acid and nitric acid, and carrying out a thermal insulation reaction at 1-8DEG C to obtain a reaction solution; 2, crystallizing through adding the reaction solution to a brine ice system; 3, filtering, washing the resulting solid, and recrystallizing through toluene to obtain crude flutamide; and 4, refining to obtain pure flutamide.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of flutamide, a drug for treating prostate cancer. Background technique [0002] Flutamide, also known as flunitramide, is an antineoplastic drug originally developed by Schering-Plough Company in the United States. It was first launched in the market in 1984. This product is a non-steroidal androgen antagonist, which can be used for the treatment of prostate cancer and prostatic hypertrophy. For adjuvant therapy, this product competes with androgen for the androgen receptor at the tumor site, blocks the uptake of androgen by cells, and inhibits the combination of androgen with the target organ. After combining with the androgen receptor, it forms a receptor complex, enters the nucleus, and binds to nuclear proteins, thereby inhibiting the growth of tumor cells. The synthetic preparation method document of flutamide has been reported, (synthetic research of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/15C07C231/12
Inventor 黄春森杨国军朱占元
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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