WO2007144896A1 - Procédé de préparation de létrozole - Google Patents

Procédé de préparation de létrozole Download PDF

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Publication number
WO2007144896A1
WO2007144896A1 PCT/IN2006/000493 IN2006000493W WO2007144896A1 WO 2007144896 A1 WO2007144896 A1 WO 2007144896A1 IN 2006000493 W IN2006000493 W IN 2006000493W WO 2007144896 A1 WO2007144896 A1 WO 2007144896A1
Authority
WO
WIPO (PCT)
Prior art keywords
letrozole
formula
vii
benzonitrile
improved process
Prior art date
Application number
PCT/IN2006/000493
Other languages
English (en)
Inventor
Amala Kishan Kompella
Srinivas Rachakonda
Bhujanga Rao Adibhatla Kali Satya
Nannapaneni Venkaiah Chowdary
Original Assignee
Natco Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Natco Pharma Limited filed Critical Natco Pharma Limited
Publication of WO2007144896A1 publication Critical patent/WO2007144896A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to a novel method of synthesizing 'Letrozole' which is a popular antineoplastic aromatase inhibitor and widely used in the treatment of postmenopausal breast cancer.
  • 'Letrozole' is chemically represented as, 4-[l-(4-Cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl)] benzonitrile.
  • the desired product of the formula III (a) is separated from the impurities using column chromatography technique
  • the column chromatography technique of the purification of the compound of the formula I ⁇ I(a) suffers from the following set backs.
  • Special equipment [ columns] is to be designed in the plant, ii.
  • Column chromatography technique is not adaptable for multi kilograms level manufacture iii. It is very time consuming, as it requires slow elution for efficient separation. iv. It involves huge volumes of solvents, which can harm the environment.
  • Solvents recovery is an important task, as inefficient solvent recovery effects the product costing considerably.
  • Large quantity of chromatography grade adsorbant is required which effects the economy of the process.
  • Specially trained personnel are required to perform column chromatography technique on a manufacturing scale in the plant.
  • a second method is also disclosed in the above patents, which consists of treating N- (t)-Bu- 4-bromobenzamide (IV) with ethyl formate and butyl lithium.
  • the resulting intermediate is converted to the chloro derivative (V) with thionyl chloride condensation of which with
  • the main objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding the drawbacks of the hitherto known processes.
  • Another objective of the present invention is to provide a novel process for the intermediate of the formula VI useful for the preparation of the compound of the formula I
  • Another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding the usage of butyl lithium
  • Yet another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding the usage of column chromatography.
  • Still another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) avoiding low temperatures of the order of -60°C
  • Yet another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) by reducing the number of purification steps
  • Still another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (VII) in which the over all yield is improved
  • Yet another objective of the present invention is to provide an improved process for the preparation of letrozole of formula (I) in which high purity is achieved for the final product.
  • Yet another objective of the present invention is to brominate the compound of the formula VI to yield 4-( ⁇ -Bromo-4-cyanobenzyl)benzonitrile (VII) arid isolate it in pure state
  • Still another objective of the present invention is to condense 4-( ⁇ -Bromo-4- cyanobenzyl)benzonitrile (VII) with 1,2,4-triazole to get Letrozole of the formula(I)
  • the amount of 4-Fluorobenzonitrile used in step (1) may be in the range of l-1.5moles, preferably 1.1 moles.
  • the amount of potassium- (t)-butoxide may be in the range of 2-2.5 moles preferably 2.1 moles.
  • the amount of N-Bromosuccinimide used in step (2) may be in the range of l-1.5moles, preferably 1.2 moles.
  • the amount of 1,2,4-triazole used in step (3) may be in the range of 3-5 moles, preferably 4 moles.
  • the details of the inventions are given in the Examples given below which are provided for illustration only and therefore these examples should not be construed to limit the scope of the invention.
  • the present invention describes a method of preparing Letrozole employing convenient reaction conditions avoiding hazardous and pyrophoric reagents like butyl lithium
  • the method disclosed in the current invention employs convenient operating temperatures and avoids the use of temperatures like -60 0 C, which is difficult to maintain on a manufacturing scale.
  • the method disclosed according to the present invention avoids the formation of large amounts of unwanted side products and the final product can be easily purified to pharmaceutical grade.
  • the method of preparation of the intermediate 4,4'-Dicyanodiphenyl methane (VI) is novel and can be prepared from easily available raw materials in good yields. This intermediate is converted to Letrozole (I) in two steps and this conversion also is novel and is easy to adapt on manufacturing scale.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de létrozole de formule (I), ledit procédé étant nouveau et pratique. Le létrozole est un médicament inhibiteur d'aromatase utilisé dans le traitement du cancer du sein post-ménopause.
PCT/IN2006/000493 2006-06-13 2006-12-14 Procédé de préparation de létrozole WO2007144896A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1027CH2006 2006-06-13
IN1027/CHE/2006 2006-06-13

Publications (1)

Publication Number Publication Date
WO2007144896A1 true WO2007144896A1 (fr) 2007-12-21

Family

ID=38016925

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000493 WO2007144896A1 (fr) 2006-06-13 2006-12-14 Procédé de préparation de létrozole

Country Status (1)

Country Link
WO (1) WO2007144896A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009078036A2 (fr) * 2007-12-11 2009-06-25 Shilpa Medicare Ltd. Procédé et produit intermédiaire du létrozole
US7705159B2 (en) 2005-07-06 2010-04-27 Sicor, Inc. Process for the preparation of letrozole
WO2010146391A1 (fr) 2009-06-15 2010-12-23 Generics [Uk] Limited Synthèse régiosélective de létrozole
CN102070541A (zh) * 2010-10-25 2011-05-25 深圳海王药业有限公司 来曲唑i型结晶及其制备方法
CN102070542A (zh) * 2011-01-24 2011-05-25 蚌埠丰原医药科技发展有限公司 一种合成来曲唑的方法
WO2012025762A2 (fr) 2010-08-27 2012-03-01 Generics [Uk] Limited Intermédiaire pur
CN103435563A (zh) * 2013-08-22 2013-12-11 江苏苏南药业实业有限公司 一种来曲唑的制备方法
JP2015038087A (ja) * 2009-03-24 2015-02-26 ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ 新規なオリゴ官能性の光開始剤
CN105801501A (zh) * 2016-05-10 2016-07-27 浙江工业大学 一种来曲唑的制备方法
CN107109222A (zh) * 2014-12-19 2017-08-29 默克专利股份有限公司 双介晶化合物和介晶介质
CN113620893A (zh) * 2020-05-09 2021-11-09 杭州中美华东制药有限公司 一种来曲唑的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4188226A (en) * 1977-07-18 1980-02-12 Asahi Kasei Kogyo Kabushiki Kaisha Dry image forming material containing diarylhalomethane
US5473078A (en) * 1986-03-07 1995-12-05 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
GB2432157A (en) * 2005-11-14 2007-05-16 Chemagis Ltd Purification of letrozole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4188226A (en) * 1977-07-18 1980-02-12 Asahi Kasei Kogyo Kabushiki Kaisha Dry image forming material containing diarylhalomethane
US5473078A (en) * 1986-03-07 1995-12-05 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
GB2432157A (en) * 2005-11-14 2007-05-16 Chemagis Ltd Purification of letrozole

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
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COLLOQUES INTERNATIONAUX DU CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE , VOLUME DATE 1977, 278(RADICAUX LIBRES ORG.), 531-5 CODEN: COINAV; ISSN: 0366-7634, 1978 *
DATABASE BEILSTEIN [online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 1 January 2005 (2005-01-01), XP002434348, Database accession no. 9799002 (REACTION ID) *
DATABASE BEILSTEIN [online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 1988, XP002434350, Database accession no. 2051121 (REACTION ID) *
DATABASE BEILSTEIN [online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; 1990, XP002434349, Database accession no. 2044982 (REACTION ID) *
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WANG, JUN ET AL: "Synthesis, characterization and single crystal structure of 4,4'-(1H-1,2,4 triazol- 1-methylene)bisbenzonitrile", XP002434346, retrieved from STN Database accession no. 2004:466657 *
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WIERSUM, U. E.: "Preparative flash vacuum thermolysis. Thermal dimerization of tolunitriles, benzylcyanides and benzotrichlorides", XP002434347, retrieved from STN Database accession no. 1980:128542 *
YOUJI HUAXUE , 24(5), 550-553 CODEN: YCHHDX; ISSN: 0253-2786, 2004 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7705159B2 (en) 2005-07-06 2010-04-27 Sicor, Inc. Process for the preparation of letrozole
WO2009078036A3 (fr) * 2007-12-11 2009-10-22 Shilpa Medicare Ltd. Procédé et produit intermédiaire du létrozole
WO2009078036A2 (fr) * 2007-12-11 2009-06-25 Shilpa Medicare Ltd. Procédé et produit intermédiaire du létrozole
JP2015038087A (ja) * 2009-03-24 2015-02-26 ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ 新規なオリゴ官能性の光開始剤
WO2010146391A1 (fr) 2009-06-15 2010-12-23 Generics [Uk] Limited Synthèse régiosélective de létrozole
WO2012025762A2 (fr) 2010-08-27 2012-03-01 Generics [Uk] Limited Intermédiaire pur
WO2012025762A3 (fr) * 2010-08-27 2012-05-03 Generics [Uk] Limited Intermédiaire pur
US9150524B2 (en) 2010-08-27 2015-10-06 Generics [Uk] Limited Pure intermediate
CN103298795A (zh) * 2010-08-27 2013-09-11 基因里克斯(英国)有限公司 用于制备来曲唑的纯中间体
CN102070541A (zh) * 2010-10-25 2011-05-25 深圳海王药业有限公司 来曲唑i型结晶及其制备方法
WO2012055163A1 (fr) * 2010-10-25 2012-05-03 深圳海王药业有限公司 Cristal de létrozole de type i et son procédé de préparation
CN102070541B (zh) * 2010-10-25 2013-07-10 深圳海王药业有限公司 来曲唑i型结晶及其制备方法
CN102070542A (zh) * 2011-01-24 2011-05-25 蚌埠丰原医药科技发展有限公司 一种合成来曲唑的方法
CN102070542B (zh) * 2011-01-24 2013-04-10 蚌埠丰原医药科技发展有限公司 一种合成来曲唑的方法
CN103435563A (zh) * 2013-08-22 2013-12-11 江苏苏南药业实业有限公司 一种来曲唑的制备方法
CN107109222A (zh) * 2014-12-19 2017-08-29 默克专利股份有限公司 双介晶化合物和介晶介质
JP2018501249A (ja) * 2014-12-19 2018-01-18 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ ビメソゲン化合物およびメソゲン性媒体
CN105801501A (zh) * 2016-05-10 2016-07-27 浙江工业大学 一种来曲唑的制备方法
CN113620893A (zh) * 2020-05-09 2021-11-09 杭州中美华东制药有限公司 一种来曲唑的制备方法
CN113620893B (zh) * 2020-05-09 2023-10-03 杭州中美华东制药有限公司 一种来曲唑的制备方法

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