CN100560573C - A kind of preparation method of high purity letrozole - Google Patents

A kind of preparation method of high purity letrozole Download PDF

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Publication number
CN100560573C
CN100560573C CN 200410080092 CN200410080092A CN100560573C CN 100560573 C CN100560573 C CN 100560573C CN 200410080092 CN200410080092 CN 200410080092 CN 200410080092 A CN200410080092 A CN 200410080092A CN 100560573 C CN100560573 C CN 100560573C
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formula
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compound
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drip
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CN1754876A (en
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刘昆
杨利民
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Beijing D-Venturepharm Technology Development Co., Ltd.
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BEIJING D-VENTURE PHARM T CORP
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Abstract

The present invention relates to a kind of preparation method of high purity letrozole.

Description

A kind of preparation method of high purity letrozole
Invention field
The present invention relates to the preparation method of high purity letrozole.
Background of invention
Letrozole (Letrozole) is an aromatase enzyme inhibitor of new generation, and it descends serum estrogen level by restraining aromatizing enzyme, thereby eliminates the hormesis of female hormone to tumor growth.Its structural formula is as shown below:
Letrozole
Studies show that, Lu Te compares with first-generation aromatizing enzyme inhibitor ammonia, letrozole activity in vivo and in vitro is better than ammonia Lu Te far away, and have very high selectivity, no potential toxicity, better tolerance, pharmacological action strong, the virtuous black body class of the gland material of going up is generated advantage such as do not make significant difference, therefore its antitumor action is stronger, be the choice drug for the treatment of advanced breast cancer at present, can substitute An Lute and megestrol fully.China women with breast cancer patient is numerous, and therefore developing this product at home will obtain good social benefit and economic benefit.
According to the existing literature report, letrozole is mainly according to the method preparation of describing among the patent EP0236940:
Be prepared in this way, the first step product is the mixture of formula I target product and formula II " 1,3, the 4-position isomer ".As this mixture not being made with extra care, effectively to remove the by product of formula II, and continue the preparation letrozole, " 1,3, the 4-position isomer " is extremely difficult in the product that obtains removes, and then influences the purity of product letrozole.
In patent EP0236940, reported with column chromatography and repeatedly the way of recrystallization remove isomer, and adopt this method complicated operation loaded down with trivial details, refining yield is low, and then causes that production efficiency is low, production cost is high.
In the report of patent EP0236940 and other disclosed preparation letrozole methods, do not mention and use economy, effective means to prepare highly purified letrozole, not about effectively making with extra care the report of the method for intermediate yet.
For these reasons, be necessary to develop a kind of simple effectively, easy handling, prepare the method for high purity letrozole economically.
Goal of the invention
The purpose of this invention is to provide a kind of simple effectively, the preparation method of easy handling, economic high purity letrozole.
Summary of the invention
The present invention relates to the preparation method of high purity letrozole.
As previously mentioned, the letrozole preparation method of open report is mainly seen in reported method among the patent EP0236940.But, being difficult to the highly purified product of preparation according to this method, its major reason is the intermediate by-products of production II in preparation process, and then " 1; 3, the 4-position isomer " by product that causes letrozole mixes and is difficult to separate in product, thereby increased the difficulty of preparation high-purity product.In seeing disclosed report, there is not effective solution to the problems described above about the letrozole preparation method.
The present invention then provides a kind of method of effectively avoiding isomer to influence letrozole purity on the basis of a large amount of experiments.We find that in experiment the polarity and the solvability of intermediate formula I compound and its isomer formula II compound are very similar, and method simple, commonly used is difficult to its effective separation.Experiment discoverable type I compound and its isomer formula II compound its reactive behavior with sour salify the time have bigger difference.Therefore, the present invention utilizes the difference of intermediate formula I compound and its isomer formula II compound reactive behavior in salification process, adopt efficient manner to separate, make with extra care out pure substantially formula I intermediate, and then more easily prepare highly purified letrozole product.
General operation process of the present invention is: at first according to the method for describing among the patent EP0236940, and the mixture of preparation formula I and formula II compound.The formula I that obtains and the mixture of formula II compound are dissolved in the suitable solvent, and this solvent comprises that all can dissolve the solvent of said mixture, as water, alcohols, alkane ketone etc., or its mixed solvent, wherein preferred alcohols, more preferably ethanol.In aforementioned gained solution, control adds the amount and the speed of acid, the order that becomes to salt out with control type I and formula II compound, and then reach isolating purpose.Described acid comprises mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, organic acids such as toxilic acid, tartrate, Phenylsulfonic acid, preferred mineral acid, more preferably hydrochloric acid.The formula I compound that separation obtains is proceeded preparation, can easily obtain highly purified letrozole product.
Adopt method of the present invention, can effectively remove in the letrozole product 1,3,4-position isomer impurity has been avoided column chromatography and the repeatedly operation of recrystallization, can realize efficiently, large-scale production letrozole economically.
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Embodiment
The preparation of embodiment 1 high purity letrozole
In 2 liters the reaction flask, add 1 liter of chloroform, stir 60 grams of adding down to cyano group benzyl bromine, 90 grams 1,2,4-triazole, heating reflux reaction 20 hours.Cooling, the sodium hydrogen carbonate solution washing with 5%, organic phase drying.Filter, the filtrate decompression solvent evaporated, the mixture about 82 that promptly gets intermediate formula I compound and its isomer formula II compound restrains.
The above-mentioned 82 gram mixtures (ratio of formula I compound and formula II compound is about 2: 1) that obtain are dissolved in 500 milliliters of ethanol, stir and slowly drip about 30 milliliters of concentrated hydrochloric acid down, remove by filter precipitation.Filtrate continuation adds concentrated hydrochloric acid, generates to no longer including precipitation.Filter the hydrochloride of 74 gram formula I compounds.Get 47 gram free formula I compounds, yield 85% after separating salt.
Add 400 milliliters of N in the reaction flask, dinethylformamide and 65 gram potassium tert.-butoxides are cooled to-10 ℃, stir 0.5 hour.Drip 45.6 gram formula I compound and 300 milliliters of N, about the mixing solutions of dinethylformamide, temperature control-10 ℃.Drip and finish, continue reaction 1 hour.Drip 38.3 grams to fluorobenzonitrile and 300 milliliters of anhydrous N, the mixture of dinethylformamide.Drip and finish, in 0 ℃ of reaction 1.5 hours, reaction finished, and reaction solution is poured in 2 liters of frozen water, stirs 0.5 hour.Filter the letrozole crude product, with 500 milliliters of ethyl alcohol recrystallizations, 37.4 the gram white solids, yield 53%, HPLC purity: 99.63%.

Claims (1)

1, a kind of preparation method of letrozole is characterized by:
In 2 liters reaction flask, add 1 liter of chloroform, stir 60 grams of adding down to cyano group benzyl bromine, 90 grams 1,2,4-triazole, heating reflux reaction 20 hours; Cooling, the sodium hydrogen carbonate solution washing with 5%, organic phase drying; Filter, the filtrate decompression solvent evaporated, the mixture 82 that gets intermediate formula I compound and its isomer formula II compound restrains, and the ratio of formula I compound and formula II compound is 2: 1;
With the above-mentioned mixture that obtains, be dissolved in 500 milliliters of ethanol, stir and slowly drip 30 milliliters of concentrated hydrochloric acids down, remove by filter precipitation; Filtrate continuation adds concentrated hydrochloric acid, generates to no longer including precipitation; Filter the hydrochloride of 74 gram formula I compounds; Get 47 gram free formula I compounds after separating salt;
Add 400 milliliters of N in the reaction flask, dinethylformamide and 65 gram potassium tert.-butoxides are cooled to-10 ℃, stir 0.5 hour; Drip 45.6 gram formula I compound and 300 milliliters of N, about the mixing solutions of dinethylformamide, temperature control-10 ℃; Drip and finish, continue reaction 1 hour; Drip 38.3 grams to fluorobenzonitrile and 300 milliliters of anhydrous N, the mixture of dinethylformamide; Drip and finish, in 0 ℃ of reaction 1.5 hours, reaction finished, and reaction solution is poured in 2 liters of frozen water, stirs 0.5 hour; Filter the letrozole crude product, with 500 milliliters of ethyl alcohol recrystallizations, 37.4 the gram white solids, its HPLC purity is 99.63%.
CN 200410080092 2004-09-28 2004-09-28 A kind of preparation method of high purity letrozole Active CN100560573C (en)

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CN 200410080092 CN100560573C (en) 2004-09-28 2004-09-28 A kind of preparation method of high purity letrozole

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CN100560573C true CN100560573C (en) 2009-11-18

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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7538230B2 (en) 2005-11-14 2009-05-26 Chemagis Ltd. Letrozole production process
US7465749B2 (en) * 2005-11-14 2008-12-16 Chemagis, Ltd. Letrozole purification process
WO2011000396A1 (en) * 2009-07-02 2011-01-06 Synthon B.V. Purification of letrozole intermediate
WO2012025762A2 (en) * 2010-08-27 2012-03-01 Generics [Uk] Limited Pure intermediate
CN103435563A (en) * 2013-08-22 2013-12-11 江苏苏南药业实业有限公司 Method for preparing letrozole
CN103601691A (en) * 2013-10-17 2014-02-26 连云港杰瑞药业有限公司 Preparation method of high purity 4-[1-(1,2,4-triazole)methyl]-cyanophenyl
CN103664810B (en) * 2013-12-11 2016-09-14 深圳劲创生物技术有限公司 A kind of technique synthesizing letrozole
CN109721557A (en) * 2017-10-27 2019-05-07 中国医学科学院药物研究所 Letrozole crystalline substance II type solid matter and preparation method and its pharmaceutical composition and purposes
CN109721558A (en) * 2017-10-27 2019-05-07 中国医学科学院药物研究所 Letrozole crystalline substance type III solid matter and preparation method and its pharmaceutical composition and purposes

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