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Preparation method of letrozole

A technology of letrozole and its intermediates, applied in the field of preparation of aromatase inhibitors, can solve the problems of cumbersome process operation, high operation risk, long cycle, etc., achieve high yield and purity, simplify the process, and avoid yield low effect

Active Publication Date: 2013-08-14
哈药集团股份有限公司 +1
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Problems solved by technology

This method leads to cumbersome process operation, and the cycle is too long, which not only increases the production cost, but also may affect the yield and quality of the product; the use of n-heptane solvent in the letrozole intermediate (III) is reported in the document US2009 / 0270633 , n-heptane is an extremely flammable solvent with high cost, and the operation risk in industrial production is very high

Method used

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  • Preparation method of letrozole

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Effect test

Embodiment 1

[0024] (1) Preparation of letrozole intermediate III, 4-[1H-(1,2,4-triazolyl)methyl]benzonitrile

[0025] Add 31.4g of compound I, 1,2,4-triazole sodium salt and 400ml of dimethyl sulfoxide solvent in a 1L reaction flask, add 40g of compound II, 4-bromomethylbenzonitrile at room temperature, and react 2 hours. After the reaction, extract the organic phase with 3N hydrochloric acid for 3 times, combine the water phase, add sodium carbonate solution to the water phase for crystallization, then grow the crystal at 0°C for 1.5 to 2 hours, and obtain 30 g of solid letrozole intermediate III by suction filtration. The molar yield is 80%, and the HPLC purity is 99.2%.

[0026] (2) Preparation of Letrozole

[0027] Add 3.84g of potassium tert-butoxide and 28ml of dimethyl sulfoxide solvent to a 250ml four-necked bottle, and lower the temperature to -30°C with liquid nitrogen; use 2g of intermediate III, 1.4g of p-fluorobenzonitrile and 24ml of dimethyl Prepare the intermediate-p-fl...

Embodiment 2

[0030] (1) Preparation of letrozole intermediate III, 4-[1H-(1,2,4-triazolyl)methyl]benzonitrile

[0031] In a 1L reaction flask, add 62.8g compound I, 1,2,4-triazole sodium salt and 1200ml of N-methylpyrrolidone solvent, add 80g compound II, 4-bromomethylbenzonitrile at room temperature, and react 1 hour. After the reaction, use 3N hydrochloric acid to extract the organic phase for 3 times, combine the water phase, add sodium bicarbonate solution to the water phase for crystallization, then grow the crystal at 0°C for 1.5-2 hours, and filter with suction to obtain 61g of solid letrozole intermediate III , molar yield 81.3%, HPLC purity 99.5%.

[0032] (2) Preparation of Letrozole

[0033] Add 3g of potassium tert-butoxide and 40ml of N-methylpyrrolidone solvent into a 250ml four-necked bottle, and lower the temperature to -32°C with liquid nitrogen; use 2g of intermediate III, 1.4g of p-fluorobenzonitrile and 35ml of N-methyl Prepare the intermediate-p-fluorobenzonitrile s...

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Abstract

The invention discloses a preparation method of letrozole. In the method, a process reaction post-processing operation process does not contain a reduced pressure distillation process, so that the reaction time is greatly shortened, the industrial cost is reduced, and the product yield is improved. According to the invention, the use of low-polarity highly-flammable reagents such as n-heptane and the like in the prior art is avoided, the operation risk is reduced, and the production safety is improved; reagents adopted in the invention are all common reagents, therefore, the method is more environment-friendly and economic; and the method is suitable for industrialized mass production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of an aromatase inhibitor. Background technique [0002] Letrozole is a new generation of aromatase inhibitors. It is a synthetic benzyltriazole derivative. Letrozole reduces the level of estrogen by inhibiting aromatase, thereby eliminating the stimulating effect of estrogen on tumor growth. [0003] Studies have shown that letrozole can effectively inhibit the transformation of androgen into estrogen, and estrogen in postmenopausal women mainly comes from the aromatization of androgen precursors in peripheral tissues, so it is especially suitable for postmenopausal breast cancer patients. The in vivo activity of letrozole is 150-250 times stronger than that of the first-generation aromatase inhibitor aminoglutethimide. Due to its high selectivity, it does not affect the function of glucocorticoids, mineralocorticoids and thyroid glands, and large doses have n...

Claims

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Application Information

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IPC IPC(8): C07D249/08
Inventor 孙志嘉王喜军王硕冰母长眀王志强
Owner 哈药集团股份有限公司
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