WO2007039912A1 - Procede monotope permettant de preparer un 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile - Google Patents

Procede monotope permettant de preparer un 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile Download PDF

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Publication number
WO2007039912A1
WO2007039912A1 PCT/IN2005/000331 IN2005000331W WO2007039912A1 WO 2007039912 A1 WO2007039912 A1 WO 2007039912A1 IN 2005000331 W IN2005000331 W IN 2005000331W WO 2007039912 A1 WO2007039912 A1 WO 2007039912A1
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formula
compound
methyl
organic solvent
benzonitrile
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PCT/IN2005/000331
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English (en)
Inventor
Venkatasubramanian Radhakrishnan Tarur
Nandu Baban Bhise
Dhananjay Govind Sathe
Chhayendra Janardan Chaudhari
Mehul Ashokkumar Joshi
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Usv Limited
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Priority to PCT/IN2005/000331 priority Critical patent/WO2007039912A1/fr
Publication of WO2007039912A1 publication Critical patent/WO2007039912A1/fr

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    • 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 one pot process for the preparation of highly pure 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I):
  • the present invention also relates to highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) prepared by the above process.
  • Letrozole 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile, commonly known as Letrozole, is an antineoplastic agent. Letrozole is an aromatase inhibitor which prevents formation of estrogen. Although estrogen is a hormone naturally produced by the body, it can stimulate and maintain the growth of certain types of cancer. Letrozole slows or stops the growth of cancer cells by decreasing the amount of estrogen produced and is used to treat advanced breast cancer in postmenopausal women with disease progression after antiestrogen therapy.
  • the compound of the formula (IV) is treated with 4-fluorobenzonitrile of the formula (V) in the presence of potassium tertiary butoxide as a catalyst in N,N-dimethylformamide below 5° C to obtain 4-[l-(4-cyanophenyl)-l-(l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (I).
  • the reaction scheme is as illustrated below:
  • the process uses a mixture of solvents comprising chloroform and acetonitrile to carry out the condensation of ⁇ -Bromotolunitrile with 1,2,4-triazole. Recovery of the solvent mixture is difficult from the reaction mixture and thus cannot be recycled at industrial scale.
  • the time required for the preparation of 4-[l-(l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (IV) is reported to be more than 15 hour.
  • the patent does not mention the purity and yield of 4-[l-(l,2,4- triazol-l-yl)methyl]benzonitrile of the formula (IV).
  • the yield of the compound of the formula (IV) was found to be 20 to 25 %. It was also found to contain undesired isomer of the formula (VI):
  • WO 2004/076409 describes a regiospecific preparation of 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I), substantially free of isomeric impurities of the formulae (VI) and (VII).
  • This process uses protected triazole, to reduce isomeric impurity of the formula (VI) thereby requiring an additional step of deprotection of the compound of the formula (VIII) to obtain 4-[l- (l,2,4-triazol-l-yl)methyl]benzonitrile of the formula (IV). Moreover deprotection with hydrochloric acid and sodium nitrite leads to formation of toxic nitrous acid. If the starting material, oc-halotolunitrile of the formula (II) contains an impurity like 4-toluonitrile the reaction with 4-fluorobenzonitrile may lead to the formation of 4-[l,l-bis(4- cyanophenyl)methyl]benzonitrile (IX) which is undesirable.
  • An object of the present invention is to provide a one pot process for the preparation of 4-[l- cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield and in high purity.
  • Another object of the invention is to provide a cost effective, simple, economical and industrially feasible process for the preparation of highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield.
  • Another object of the present invention is to provide process for the preparation of highly pure 4- [l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield which reduces the process time.
  • Another object of the invention is to provide highly pure 4-[l-cyanophenyl)-l-(l,2,4-triazol-l-yl) methyl] benzonitrile of the formula (I) in high yield prepared by the above process.
  • the alkali metal salts of 1,2,4-triazole of the formula (DI b) used in step (a) are sodium or potassium salts.
  • the organic solvent used in step (a) is selected from dipolar aprotic solvent such as dimethylsulphoxide, dimethylacetamide, 1,2-dimethoxy/diethoxyethane or dimethylformamide; halo substituted or unsubstituted alkyl and aryl hydrocarbons such as hexane, toluene, xylene, methylene chloride, chloroform or dichloroethane; ketones such as acetone, methylisobutyl ketone or methylethylketone; nitriles such as acetonitrile; esters such as ethyl acetate; ethers such as diphenylether or diisopropylether; or alcohols such as ethanol, methanol, isopropanol or t-butanol or
  • the organic solvent used in step (a) is N,N-dimethylformamide or N,N-dimethylacetamide.
  • the condensation of the compound of the formula (II) with 1,2,4- triazole of the formula (in b) is carried out at temperature 40 to 70° C.
  • the base used in step (b) is selected from organic or inorganic base. More preferably the base used in step (b) is n-butyl lithium, sodium tertiary butoxide, potassium tertiary butoxide, potassium or sodium isopropoxide, potassium or sodium ethoxide, potassium or sodium methoxide, sodium hydride, lithium hydride or diisopropyl ethyl amine.
  • the compound of the formula (I) is isolated from the reaction mixture by extracting the reaction mixture with organic solvent selected from ethyl acetate, dichloromethane or chloroform.
  • the organic solvent used in recrystallization of the compound of the formula (I) in step (d) or (d 1 ) is selected from toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, iso-propyl acetate, petroleum ethers, hexane or water or mixtures thereof.
  • the recrystallization of the compound of the formula (I) in step (d) or (d 1 ) is carried out in solvent selected from ethanol or mixture of ethanol-hexane or ethanol-diethyl ether.
  • the stationary phase of the column chromatography used to purify the compound of the formula (I) is selected from silica gel or alumina.
  • the stationary phase of the column chromatography used to purify the compound of the formula (I) is the silica gel having particle size between 60-120 mesh.
  • the mobile phase of the column chromatography used to purify the compound of the formula (I) is selected from aliphatic or aromatic hydrocarbons; alcohols; ketones or aliphatic solvents such as esters, nitriles; halogeneted solvent or mixtures thereof.
  • the mobile phase of the column chromatography used to purify the compound of the formula (I) is mixture of ethylacetate-hexane or mixture of dichloroniethane-acetonitrile.
  • the process of the invention provides Letrozole of the formula (I) in high yield (about 40 to 60 %) and in high purity (> 99.6 %) in a one pot reaction without isolating the intermediate, 4-[l-( 1,2,4- triazol-l-yl)methyl]benzonitrile. It uses a single solvent, which is easily recovered and recycled into the subsequent batch.
  • the impurities level is reduced to 0.4% constituted mainly by 4-[l,l- bis(4-cyanophenyl)methyl]benzonitrile of the formula (IX) and 4-[l-(4-cyanophenyl)-l-(l,2,4- triazol-4-yl)methyl]benzonitrile of the formula (VII).
  • Example 1 oc-Bromotolunitrile (10 g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 ml) for 2hour at 40°C. The reaction mixture was cooled at -5°C and potassium tertiary butoxide (14.3 g, 0.127 moles) was added in small portions for 30 min. The reaction mixture was stirred at 0 to 5°C for 2 hour. To this reaction mixture, 4- fluorobenzonitrile (6.5 g, 0.053 moles) was added in 30 min at -5 to 0 0 C and stirred at 0 to 5°C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
  • 1,2,4-triazole 6.3 g, 0.068 moles
  • Example 2 oc-Bromotolunitrile (10 g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 ml) for 2 hour at 4O 0 C. The reaction mixture was cooled at - 5°C and potassium tertiary butoxide (14.31 g, 0.127 moles) was added in small portions for 30 min. The reaction mixture was stirred at 0 to 5°C for 2 hour. To this reaction mixture, 4-fluorobenzonitrile (6.49 g, 0.053 moles) was added in 30 min at -5 to 0 0 C and stirred at 0 to 5 0 C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
  • 1,2,4-triazole 6.3 g, 0.068 moles
  • the crude Letrozole was purified by column chromatography using 20-50% ethylacetate in hexane as an eluent.
  • the solid obtained was recystallized from ethanol-hexane (250 ml and 25 ml) mixture.
  • the structure was confirmed by IH NMR, IR and mass spectral analysis.
  • Example 3 oc-Bromotolunitrile (1O g, 0.051 moles) was heated with a sodium salt of 1,2,4-triazole (6.3 g, 0.068 moles) in N,N-dimethylformamide (50 mL) for 2 hour at 40°C. The reaction mixture was cooled at -5°C and potassium tertiary butoxide (14.31 g, 0.127 moles) was added in small portion for 30 min. The reaction mixture was stirred at 0 to 5 0 C for 2 hour. To this reaction mixture, A- fluorobenzonitrile (6.49 g, 0.053 moles) was added in 30 min at -5 to O 0 C and stirred at 0 to 5°C for 2 hour. The reaction mixture was poured into cooled 2N hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with water and concentrated under vacuum to yellow solid.
  • 1,2,4-triazole 6.3 g, 0.068 moles
  • the crude was purified by column chromatography using 3 to 10 % acetonitrile in dichloromethane as an eluent.
  • the solid obtained was recystallized from alcohol.
  • the structure was confirmed by IH NMR, IR and mass spectral analysis.

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

Abstract

L'invention concerne un procédé monotope permettant de préparer un 4-[l-cyanophenyl)-l- (1,2,4-triazol-l-yl) methyl] benzonitrile (létrozole) très pur sans isoler l'intermédiaire 4-[l- (l,2,4-triazol-l-yl)methyl]benzonitrile. On condense oc-bromotolunitrile avec un sel de métal alcalin de 1,2,4-triazole dans un solvant organique. On charge un 4-fluorobenzonitrile dans le condensat en présence d'une base afin de fournir un létrozole brut qui est purifié par recristallisation seule ou combiné avec une chromatographie sur colonne.
PCT/IN2005/000331 2005-10-05 2005-10-05 Procede monotope permettant de preparer un 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile WO2007039912A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000331 WO2007039912A1 (fr) 2005-10-05 2005-10-05 Procede monotope permettant de preparer un 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

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PCT/IN2005/000331 WO2007039912A1 (fr) 2005-10-05 2005-10-05 Procede monotope permettant de preparer un 4-[1-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

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Cited By (5)

* 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
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
US8198460B2 (en) 2007-11-28 2012-06-12 Fresenius Kabi Oncology Ltd. Process for preparation of letrozole and its intermediates
CN103664810A (zh) * 2013-12-11 2014-03-26 深圳劲创生物技术有限公司 一种合成来曲唑的工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4978672A (en) * 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
WO2004076409A2 (fr) * 2003-02-06 2004-09-10 Sun Pharmaceutical Industries Limited Procede regiospecifique pour la preparation de 4-[1- (4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4978672A (en) * 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
WO2004076409A2 (fr) * 2003-02-06 2004-09-10 Sun Pharmaceutical Industries Limited Procede regiospecifique pour la preparation de 4-[1- (4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CARROL TEMPLE: "1,2,4-Triazoles", 1981, JOHN WILEY, XP002384403 *

Cited By (9)

* 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
US8198460B2 (en) 2007-11-28 2012-06-12 Fresenius Kabi Oncology Ltd. Process for preparation of letrozole and its intermediates
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
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
US9150524B2 (en) 2010-08-27 2015-10-06 Generics [Uk] Limited Pure intermediate
CN103664810A (zh) * 2013-12-11 2014-03-26 深圳劲创生物技术有限公司 一种合成来曲唑的工艺
CN103664810B (zh) * 2013-12-11 2016-09-14 深圳劲创生物技术有限公司 一种合成来曲唑的工艺

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